The Spectrum of Psychotic Disorders: Neurobiology, Etiology & Pathogenesis

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The Spectrum of Psychotic Disorders

The spectrum of psychotic disorders encompasses as many as 25 different etiologies, ranging from the primary psychoses through those secondary to medical conditions, drugs and medications, and sensory impairments. This book provides a one-stop, comprehensive review of these disorders, and gives quick comparisons for diagnostic decision-making to help with difficult differential diagnoses. Every chapter is uniformly structured to show comparisons between each disorder of presentation, course, and underlying neuropathology. Evidence for each etiology is also rated, indicating the confidence level the reader can place in the current findings. The international team of authors also examines data supporting a unitary neurobiological model of psychosis and the hypothesis that psychosis is a neurobiological syndrome similar to aphasia or apraxia. This book represents a paradigm shift in understanding, classifying, and diagnosing these disorders, providing directions for future research and treatment. It will be of great interest to psychiatrists and neuroscientists alike. Daryl Fujii is a Clinical Neuropsychologist based at the Hawaii State Hospital. Iqbal Ahmed is Professor of Psychiatry at the John A. Burns School of Medicine at the

University of Hawaii.

The Spectrum of Psychotic Disorders Neurobiology, Etiology, and Pathogenesis

Edited by

Daryl Fujii and Iqbal Ahmed

CAMBRIDGE UNIVERSITY PRESS

Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521850568 © Cambridge University Press 2007 This publication is in copyright. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published in print format 2007 eBook (EBL) ISBN-13 978-0-511-29480-8 ISBN-10 0-511-29480-8 eBook (EBL) ISBN-13 ISBN-10

hardback 978-0-521-85056-8 hardback 0-521-85056-8

Cambridge University Press has no responsibility for the persistence or accuracy of urls for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this publication to provide accurate and up-todate information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this publication. Readers are strongly advised to pay careful attention to information provided by the manufacture of any drugs or equipment that they plan to use.

Contents

List of Contributors Preface Acknowledgements

Part I 1

ix xiii xv

Introduction Introduction: Is Psychosis a Neurobiological Syndrome?

3

Daryl E. Fujii and Iqbal Ahmed

Part II 2

Primary Psychotic Disorders Schizophrenia

15

Gerald Goldstein, Daniel N. Allen, and Gretchen L. Haas

3

Schizophrenia among Children and Adolescents

39

Jason Schiffman

4

Late-Life Schizophrenia

59

Katerine Osatuke, John W. Kasckow, and Somaia Mohamed

5

Schizoaffective Disorder

78

Daniel J. Abrams and David B. Arciniegas

6

Schizophreniform Disorder and Brief Psychotic Disorder: The Acute and Transient Psychoses

96

Andreas Marneros and Frank Pillmann

7

Delusional Disorder Theo Manschreck

v

116

vi

Contents

Part III

Mood Disorders

8

Psychosis in Bipolar Disorder

137

Deborah Yurgelun-Todd

9

Psychosis in Major Depression

156

Eric G. Smith, Philip R. Burke, Jessica E. Grogan, Susan E. Fratoni, Chelsea S. Wogsland, and Anthony J. Rothschild

Part IV

Neurodevelopmental and Genetic Disorders

10

Psychosis with Intellectual Disabilities

197

Colin P. Hemmings and Nick Bouras

11

Velo-Cardio-Facial Syndrome

218

Wendy R. Kates and Wanda Fremont

12

Psychosis in Autism

233

Angelina Kakooza-Mwesige, Laura Stoppelbein, and Dirk M. Dhossche

Part V 13

Central Nervous System Disorders Psychotic Disorder Due to Traumatic Brain Injury

249

Daryl E. Fujii, Nikki Panasci Armstrong, and Iqbal Ahmed

14

Schizophrenia-Like Psychosis and Epilepsy

262

Perminder Sachdev

15

Psychosis following Cerebrovascular Accident

285

James A. Bourgeois

16

Psychosis in Patients with Brain Tumors

302

Tamara Dolenc and Teresa Rummans

17

Psychosis Secondary to Infections

316

Sarah Reading and John T. Little

18

Psychosis Secondary to Inflammatory and Demyelinating Disease

337

Katherine H. Taber and Robin A. Hurley

Part VI 19

Substance Abuse and Medications Cannabis-Induced Psychosis Luis Alfonso Nu´n˜ez Domı´nguez

369

vii

Contents

20

Cocaine

382

Daryl E. Fujii and Erin Y. Sakai

21

Methamphetamine

392

Liz Jacobs and William Haning III

22

Medication-Induced Psychosis

406

Junji Takeshita, Diane Thompson, and Stephen E. Nicolson

Part VII

Neurodegenerative Disorders

23

Psychosis Secondary to Alzheimer’s Disease

455

Robert A. Sweet and James E. Emanuel

24

Dementia with Lewy Bodies

472

Sasha Ericksen and Debby Tsuang

25

Parkinson’s Disease

490

David L. Sultzer and George Webster Ross

Part VIII Sensory Impairments 26

Psychosis Associated with Sensory Impairment

513

Suzanne Holroyd

Part IX

Conclusion

27

Conclusion

535

Daryl E. Fujii and Iqbal Ahmed

Index

557

List of Contributors

Daniel J. Abrams University of Colorado School of Medicine Iqbal Ahmed University of Hawaii Daniel N. Allen University of Nevada, Las Vegas David B. Arciniegas University of Colorado School of Medicine

Susan E. Fratoni University of Massachusetts Medical School Wanda Fremont State University of New York, Syracuse

Nikki Panasci Armstrong University of Hawaii

Daryl Fujii Hawaii State Hospital

Nick Bouras Kings College London, United Kingdom

Gerald Goldstein VA Pittsburgh Healthcare System Pittsburgh, PA

James A. Bourgeois University of California, Davis Medical Center Philip R. Burke University of Massachusetts Medical School Dirk M. Dhossche University of Mississippi Medical Center Tamara Dolenc Mayo Clinic James E. Emanuel University of Pittsburgh Medical Center

ix

Sasha Ericksen University of Washington School of Medicine

Jessica E. Grogan University of Houston Gretchen L. Haas University of Pittsburgh William Haning III University of Hawaii Colin P. Hemmings South London and Maudsley NHS Trust, United Kingdom

x

List of Contributors

Suzanne Holroyd University of Virginia Robin A. Hurley VISN 6 MIRECC, Hefner VAMC, WFUSM, BCM Salisbury, North Carolina Elizabeth Jacobs University of Hawaii Angelina Kakooza-Mwesige Makerere University Medical School John Kasckow University of Cincinnati Wendy R. Kates State University of New York, Syracuse John T. Little Johns Hopkins University School of Medicine Theo Manschreck Harvard University Andreas Marneros Martin-Luther-Universita¨t Halle-Wittenberg, Germany Somaia Mohamed Cincinnati VA Medical Center Stephen E. Nicolson Massachusettes General Hospital Luis Alfonso Nu´n˜ez Domı´nguez Centro Me´dico, Navarra, Spain Katerine Osatuke VHA National Center for Organization Development

Frank Pillmann Martin-Luther-Universita¨t Halle-Wittenberg, Germany Sarah Reading Johns Hopkins University School of Medicine Anthony J. Rothschild University of Massachusetts Medical School and UMass Memorial Healthcare, Inc. Teresa Rummans Mayo Clinic Perminder Sachdev University of New South Wales, Australia Erin Y. Sakai Beth Israel Deaconess Medical Center Jason Schiffman University of Hawaii Eric G. Smith University of Massachusetts Medical School and UMass Memorial Healthcare, Inc. Laura Stoppelbein University of Mississippi Medical Center David L. Sultzer University of California at Los Angeles and VA Greater Los Angeles Healthcare System Robert A. Sweet University of Pittsburgh Medical Center Katherine H. Taber VISN 6 MIRECC, Hefner VAMC, WFUSM, BCM Salisbury, North Carolina

xi

List of Contributors

Junji Takeshita University of Hawaii

George Webster Ross VA Pacific Islands Healthcare System

Diane Thompson Queen’s Medical Center

Chelsea S. Wogsland University of Massachusetts Medical School

Debby Tsuang University of Washington School of Medicine

Deborah Yurgelun-Todd Harvard Medical School and McLean Hospital

NaN

Preface

Psychotic disorders of different etiologies have interested both clinicians and researchers, but for different reasons. People with psychosis have been some of the most challenging for clinicians to treat due to the severity and chronicity of symptoms. One potential problematic aspect of treatment is differential diagnosis as psychosis can result from numerous etiologies and many patients have more than one risk factor. A review of the presentation, course and progression, and optimal treatment strategies would certainly be useful for clinicians in making these determinations. For researchers and theoreticians, secondary or ‘‘organic’’ psychotic disorders can provide clues to underlying neurobiological mechanisms of schizophrenia or psychosis in general. Unfortunately, thus far, this potential avenue of research has not been adequately explored. One problem is that the literature on the ‘‘so called’’ secondary psychotic disorders is not readily available for study or review. There are many different etiologies, thus amassing this disparate literature would take a concerted effort. In addition, much of the information on ‘‘organic psychosis,’’ particularly for the obscure etiologies, is provided in case studies or case series, many in difficult-to-find journals. We believe these problems in access to information have prevented researchers from mining this rich resource. The purpose of this book is to address the needs of both clinician and researcher by providing comprehensive reviews of psychotic disorders of different etiologies in one handy resource. For clinicians faced with difficult and fascinating differential diagnoses, this compendium allows quick comparisons useful for diagnostic decision-making. For researchers and theoreticians interested in the neurobiology of schizophrenia and psychosis, we compare and contrast the current data in searching for clues on the neurobiological essence of psychosis. Specifically, we examine the hypothesis that psychosis is a neurobiological syndrome similar to aphasia or apraxia.

xiii

xiv

Preface

There are two unique organizational features of our book. First, each chapter is uniformly structured to aid in comparison of the presentation, course, and underlying neuropathology between each disorder. Second, authors have rated the level of evidence for each etiology indicating the confidence level the reader can place in the current findings. We hope you find this book useful in your practice and research.

NaN

Acknowledgements

There are many people we would like to acknowledge in the making of this book. First, we would like to thank all the contributing authors for their efforts, expertise, and taking time out of their busy schedules to collaborate with us. Second, we would like to thank the researchers who have trodden the path of organic psychosis and inspired us to continue the exploration. These people include: Kenneth Davison and Christopher Bagley, pioneers in compiling information on secondary psychotic disorders; Alwyn Lishman for piquing everyone’s interest in organic psychiatry; and Jeffrey Cummings for his seminal ideas in the neuropsychiatry of psychosis. With this book, we hope to carry the torch in this area of study. Third, we would like to thank the individuals who have facilitated our research over the years: librarian Lisa Anne Matsumoto who special ordered many of our journal articles; and administrative assistant Sharon Lai for her multiple contributions. We would also like to thank Erin Sakai and Cale Palmer for their assistance in compiling and rating the data in the chapters. Last, but not least, we would like to thank our families, without whose love, support, and patience our work could not have been accomplished. Daryl would like to thank his beautiful wife Sam, two eggies Dylan and Cody, loving parents Earl and Judy Fujii, big brother Jay and his family, Naomi and Jarin, grandparents Kenneth Ito and the late Mildred Ito and Shizuko Fujii. Ike would like to thank numerous colleagues, and students who have helped shape his ideas over the years, his co-author Daryl for his years of collaboration and for the active exchange of ideas which led to the writing of the book, and for being the force behind getting these ideas out into the public domain. Finally, he would like to thank his lovely wife Lisa, for her love and enduring support, and his two daughters Yasmin and Jihan for their love and the joy they have provided.

xv

Part I

Introduction

1

Introduction: is psychosis a neurobiological syndrome? Daryl E. Fujii1 and Iqbal Ahmed2 1 2

Hawaii State Hospital University of Hawaii

Psychosis is a state in which the individual experiences a severe disconnection from reality. The most common symptoms associated with psychotic disorders are delusions and hallucinations. Delusions are false beliefs about experiences, oneself, or the environment that cannot be altered in the face of contradictory evidence. An example would be delusions of persecution in which the individual believes that others are tormenting, ridiculing, or intending to harm him or her. Hallucinations involve false perceptions in any sensory modality without insight into their pathological nature. The most common hallucination is auditory, which is generally experienced as ‘‘hearing voices.’’ Other symptoms associated with psychotic disorders include negative symptoms such as restricted emotional expression (flat affect), sparse language output (alogia), poor initiation and persistence of goal-directed behaviors (avolition), disorganized thoughts, speech, or behaviors, or a severe decrease in reactivity to one’s surroundings (catatonia) (American Psychiatric Association, 2000). Psychosis has many etiologies. The Diagnostic and Statistical Manual-IV Text Revision (DSM-IV TR) (American Psychiatric Association, 2000) distinguishes between primary psychotic disorders and those due to other etiologies. Primary psychotic disorders include schizophrenia, delusional disorders, schizoaffective disorder, schizophreniform disorder, and brief psychotic disorder. By contrast, psychosis can be due to a general medical condition such as Dementia of the Alzheimer’s Type (DAT) or traumatic brain injury (TBI), a psychoactive substance such as amphetamines or cannabis, or secondary to a mood disorder such as major depression. The following are brief descriptions of the DSM-IV TR diagnostic criteria for each disorder:

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The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Daryl E. Fujii and Iqbal Ahmed

Diagnostic criteria for schizophrenia A. Two or more of the following symptoms are present: (1) delusions, (2) hallucinations, (3) disorganized speech, (4) grossly disorganized or catatonic behavior, and (5) negative symptoms. B. Dysfunction in social, academic, or occupational achievement. C. Continuous signs of the illness persist for at least six months. D. Exclusion of schizoaffective or mood disorder as an etiology. E. Exclusion of substance use or a general medical condition as an etiology. F. If a premorbid pervasive developmental disorder exists, hallucinations and delusions are present for at least a month to warrant and additional diagnosis of schizophrenia.

Diagnostic criteria for psychotic disorder due to a general medical condition A. Prominent hallucinations or delusions are present. B. There is evidence that the psychotic symptoms are a direct consequence of a general medical condition. C. Psychotic symptoms are not better accounted for by another mental disorder. D. Psychotic symptoms do not occur exclusively during the course of a delirium.

Diagnostic criteria for substance-induced psychotic disorder A. Prominent hallucinations or delusions are present. B. There is evidence that the psychotic symptoms develop within a month of substance intoxication or withdrawal, or the substance is etiologically related to the psychosis. C. Psychotic symptoms are not better accounted for by another mental disorder. D. Psychotic symptoms do not occur exclusively during the course of a delirium. There exists a curious dichotomy in DSM-IV TR criteria between the primary psychotic disorders and Psychotic Disorders Due to a General Medical Condition (PDDGMC) and Substance-Induced Psychotic Disorders (SIPD). In both PDDGMC and SIPD, diagnosis is based on the presence of psychotic symptoms (criterion A) within the context of either a medical condition or substance use (criterion B), while ruling out schizophrenia or delirium as the

5

Introduction: is psychosis a neurobiological syndrome?

cause of the psychosis (criteria C and D). Thus in these two diagnostic categories, the etiology of psychotic symptoms is ‘‘known,’’ while other mental disorders must be ruled out as the cause. By contrast, for primary psychotic disorders, diagnosis is based upon the presence of psychotic symptoms (criteria A and F), the severity and duration of illness (criteria B and C), and ruling out other etiologies (criteria D and E). Thus unlike PDDGMC or SIPD in which the clinician must establish an etiology to make a diagnosis, for the primary psychotic disorders, the etiological concern of the clinician is to rule out other etiologies as causative. If this can be accomplished, then it is assumed that psychosis is due to schizophrenia. The DSM-IV TR nomenclature for psychosis illustrates a major criticism of the classification scheme in general. Unlike general medical disease models, psychiatric diagnoses are often based upon symptom clusters rather than tied to etiology (Pichot, 1994). Indeed, on a practical level, the symptom-based nosology of the DSM-IV TR frequently results in diagnostic dilemmas for clinicians as the presentation of primary and other psychotic disorders are often very similar. For example, the modal patient with psychosis due to cocaine or methamphetamine use, seizure disorder, or TBI generally resembles a patient with schizophrenia, paranoid type (Fujii & Ahmed, 2002a; Post & Kopanda, 1976; Sachdev, 1998; Sato, Numachi & Hamamura, 1992). In addition, studies have found that there is no symptom specific to schizophrenia. Even the once hypothesized schizophrenic marker, Schneiderian First Rank Signs (Schneider, 1959), can be found in bipolar disorder and psychotic disorders of other etiologies (Gonzalez-Pinto et al., 2003; Marneros, 1988; Sato et al., 1992). The following hypothetical case illustrates how similar presentations and different criteria (etiology versus severity/duration of symptoms) can cause problems with differential diagnoses. Let’s say Fred, a 25-year-old male without a previous history of psychosis, comes to the ER for paranoid delusions and auditory hallucinations. He has used methamphetamine daily over a five-year period and is currently intoxicated with methamphetamine. In this case, his diagnosis would most likely be methamphetamine-induced psychosis as the onset of psychosis can clearly be tied to his drug use. By contrast, let’s say that Fred continues to experience paranoid delusions six months after abstinence. According to the methamphetamine literature, it is not uncommon for long-term users to remain symptomatic six months after discontinuing their use (Sato et al., 1992). However, according to DSM-IV TR differential diagnosis recommendations, in this case schizophrenia would have to be considered as the diagnosis due to duration of illness, even if there is no family history of schizophrenia and there is a known potential etiology.

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Daryl E. Fujii and Iqbal Ahmed

Conversely, let’s say that Fred’s cousin has been diagnosed with schizophrenia. Fred’s family predisposition may suggest that he suffers from a primary psychotic disorder. On the other hand, studies have reported that a family history of schizophrenia is a risk factor for substance-induced psychosis such as hallucinogens and cannabis (Tsuang, Simpson, & Kronfold, 1982). Given the fact that monozygotic twins have only a 50% concordance rate for schizophrenia (Gottesman, 1991), environmental events such as the use of methamphetamine may be required to trigger schizophrenia in a genetically vulnerable individual. Thus, in this case, is methamphetamine an environmental factor that triggers the onset of schizophrenia or is it the etiology of the psychosis? How can you rule out which etiology is causative? To further cloud matters, what if Fred were 45 years old instead of 25? Would this affect which etiology is more salient? What if Fred sustained a previous head injury with a seven-day loss of consciousness three months prior to the onset of his delusions and hallucinations? Would the head injury be the etiology of psychosis, the trigger of a schizophrenia episode, a coincidental occurrence, or perhaps a contributing factor to a psychosis? What if he didn’t lose consciousness? In such a case, it would be extremely difficult to rule out schizophrenia, TBI, or methamphetamine as being the primary etiology of the psychosis, rule outs being an essential criterion for each DSM-IV TR category of psychotic disorder. Unfortunately, these issues are not uncommon as about 50% of people who are diagnosed with schizophrenia also have a substance abuse problem (Regier et al., 1990), whereas up to 40% have sustained head injuries (for a review see Fujii, 2005). In such cases, studies have shown that patients who meet criteria for GMC and SIPD are often diagnosed with schizophrenia (Fujii & Ahmed, 2002a; Shaner et al., 1998). Again going back to the DSM-IV TR, diagnostic issues arise because the presentation of schizophrenia is not unique, as no symptom is pathognomonic of the illness. Similarly there is not a definitive biological marker to designate the presence of schizophrenia. Instead, diagnosis is primarily based upon the presence and severity of psychotic symptoms in which no other etiology can be identified. Furthermore, although researchers agree that genetic factors are more important than environmental factors in the transmission of schizophrenia, more than 60% of people with schizophrenia have no family history (Gottesman, 1991). A diagnosis of schizophrenia essentially does not tell us anything about the etiology of the psychosis. Indeed, many speculate that schizophrenia is a heterogeneous illness with more than one etiology (Schroder et al., 1995; Seaton, Goldstein, & Allen, 2001). Due to the inherent problems in DSM-IV TR nomenclature for psychotic disorders, we offer a different conceptual approach. We argue that the separate

7

Introduction: is psychosis a neurobiological syndrome?

categories (primary and other) of psychotic disorders may be a distinction without a difference, as many GMC and SIPD appear to affect the same neurochemical systems and have similar neuropathology to schizophrenia (Fujii & Ahmed, 2004). Schizophrenia has consistently been associated with abnormalities in mesial temporal, frontal areas, and frontal-temporal connectivity (McCarley et al., 1999; Berman & Meyer-Lindenberg, 2004), as well as the dopaminergic system projecting from the ventral tegmental area to the striatum (for a review see Thompson, Pogue-Geile, & Grace, 2005). Among the most common medical etiologies associated with secondary psychosis include disorders affecting temporal structures such as DAT, TBI, and temporal lobe epilepsy (Wragg & Jeste, 1989; Sachdev, 1998; Fujii & Ahmed, 2002a). Similarly, substances that directly affect the transmission of dopamine such as cocaine, methamphetamine, and anti-Parkinsonian medications have been found to induce psychoses in users (Cummings, 1991; Post and Kopanda, 1976; Sato et al., 1992). Furthermore, in many GMC and SIPD a family history of schizophrenia is a risk factor (Sachdev, Smith, & Cathcart 2001; Tsuang et al., 1982). With other neurological syndromes, lesions to specific areas of the brain are associated with concomitant behavioral, emotional, and cognitive sequelae regardless of etiology (Mesulam, 2000). For example, subcortical lesions generally present with cognitive slowing, deficits in attention and concentration, executive functioning, visuospatial skills, and memory, with more problems in retrieval versus memory encoding and storage problems. There is an absence of aphasia, apraxia, and agnosia, and apathy, depression, or personality changes (Lezak, Howieson, & Loring, 2005). Severity of injury is also important for presentation and may be more important than actual etiology in determining presentation. This principle was demonstrated in a study comparing the effects of anoxia versus TBI that found cognition is more closely associated with severity of injury than with etiology (Hopkins, Tate, & Bigler, 2005). In addition, there is emerging evidence indicating that neuropathology resulting in associated sequelae occur in other ‘‘psychiatric’’ disorders such as depression. For example, Hickie et al. (2005) reported that reduced hippocampal volumes in depression are associated with deficits in visual and verbal memory. Given that schizophrenia is a brain disease, why shouldn’t the same principles apply to psychosis? We propose an alternate conceptualization of psychosis. We argue that psychosis is a neurobiological syndrome similar to aphasia and apraxia. Affected structures include frontal systems that would include the frontal-striatal-thalamiccerebellar axis as well as the frontal-striatal-hippocampal axis, and the dopaminergic projections to these areas. Altering this circuit to a significant degree by any

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Daryl E. Fujii and Iqbal Ahmed

means including drugs, disease, trauma, or normal developmental brain changes can result in psychotic symptoms. Our conceptual framework for developing a psychotic disorder is as follows (Fujii & Ahmed, 2002b): 1. Psychosis is associated with abnormal functioning of frontal systems, temporal lobes, and the dopaminergic projections to these areas. 2. All individuals are at risk for developing a psychosis. Contributing factors include: a. genetic predisposition. b. environmental factors. i. damage sustained through trauma, disease, substance abuse. ii. effects of experience on neuronal structures and neurochemical release. c. neuronal and biochemical changes during normal human development. 3. Psychosis will develop when a threshold of damage or changes to frontal systems, temporal structures, and dopaminergic projections is attained. In this framework, anyone would be vulnerable to developing a psychosis once a threshold of damage or changes to the affected structures is reached. For example, if there is a strong genetic predisposition, the onset of psychosis may be inevitable after neuronal pruning during adolescence/early adulthood, or may be expedited with onset in adolescence by an early mild head injury or marijuana abuse. Conversely, for a person with no genetic vulnerability, psychosis may occur in middle age only after multiple head injuries and long-term methamphetamine dependence, or in late life after the onset of DAT. In both cases, life experiences that increase stress or stress response that would in turn increase the amount of dopamine in the brain would also contribute to the initial onset of psychosis or exacerbation of illness. This framework is consistent with the diathesis
stress model of schizophrenia which hypothesizes that the disorder results from an interaction between a biological predisposition and an environmental trigger (Zubin & Spring, 1977). Our model, however, differs in several key aspects: (1) it applies a similar conceptualization to psychotic disorders in general, (2) it specifies and expands potential environmental factors beyond the pre- and perinatal periods, and (3) it also incorporates the effects of normal life-cycle neurological changes in conceptualization beyond young adulthood. Our model is also consistent with newer models of vulnerability for schizophrenia focusing on endophenotypes. For example, Weiser, van Os, & Davidson (2005) argues that impaired cognition is present in both patients with schizophrenia and their first degree relatives more frequently than in the normal population. These broad vulnerabilities, or endophenotypes, are believed to be genetically transmitted. In our conceptual framework,

9

Introduction: is psychosis a neurobiological syndrome?

we argue that vulnerabilities such as impaired cognition can also result from environmental factors. For a more in-depth discussion of the model see Fujii & Ahmed (2002b).

Examining the hypothesis One purpose of the book is to examine the Fujii & Ahmed (2004) hypothesis that psychosis is a neurobiological syndrome. A neurobiological syndrome exists if the following criteria are met: 1. A constellation of symptoms is reliably associated with neuropathology in a circumscribed structural location or neural circuit. 2. Similar neurobiological disturbances (location or neural circuit) secondary to different etiologies would result in similar cognitive or behavioral symptoms. 3. Smaller amounts of similar neurobiologic disturbances are associated with milder symptoms. 4. Additional symptoms such as cognitive, mood, psychiatric, or other associated neurological symptoms are related to other networks simultaneously being affected by underlying neurochemical or neuropathologic processes. 5. Aside from treating the underlying disease process, treatment for the associated symptoms of a neurobiological disorder of different etiologies is similar. This hypothesis will be examined by comparing and contrasting the characteristics of psychotic disorders of different etiologies. If psychosis is a neurobiological syndrome, then psychotic disorders of different etiologies should affect common brain structures and neurochemical systems, and should also overlap in symptoms and presentation. Each chapter will review the literature on a psychotic disorder of a specific etiology. Data in the following areas will be reviewed: (1) epidemiology, (2) age of onset, (3) presentation (positive and negative symptoms, neuropsychological deficits, emotional disorders), (4) course and progression including latency from initial insult to presentation of psychotic symptoms and prodrome, (5) suspected neuropathology, (6) suspected neurochemical pathology, (7) genetic factors, (8) other risk factors, and (9) treatment. In addition, the data for each area will be rated on the quality of evidence according to the Centre for Evidence-Based Medicine Levels of Evidence Grades of Recommendation System criteria (see Appendix at the end of chapter for criteria). This rating is included to inform the reader of the current status of evidence for a specific etiology of psychosis. The data will be evaluated qualitatively for similarities and differences of the aforementioned nine areas between the different etiologies of psychosis. By comparing this information we hope to gain insight into which brain areas are associated with psychosis and patterns in development, presentation,

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Daryl E. Fujii and Iqbal Ahmed

and treatment. These qualitative impressions will be described section by section in the concluding chapter. REFERENCES American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders, 4th edn, text revision. Washington, DC: American Psychiatric Association Press. Berman, K. F. & Meyer-Lindenberg, A. (2004). Functional brain imaging studies in schizophrenia. In Neurobiology of Mental Illness, ed. D. S. Charney & E. J. Nestler. New York: Oxford University Press, pp. 311
23. Cummings, J. L. (1991). Behavioral complications of drug treatment of Parkinson’s disease. Journal of the American Geriatric Society, 39, 708
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94. Fujii, D. E. & Ahmed, I. (2002a). Characteristics of psychosis due to traumatic brain injury: An analysis of case studies in the literature. Journal of Neuropsychiatry and Clinical Neurosciences, 14, 130
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67. Shaner, A., Roberts, L. J., Eckman, T. A., et al. (1998). Sources of diagnostic uncertainty for chronically psychotic cocaine abusers. Psychiatric Services, 49, 684
90. Thompson, J. L., Pogue-Geile, M. F., & Grace, A. A. (2005). Developmental pathology, dopamine, and stress: A model of the age of onset of schizophrenia symptoms. Schizophrenia Bulletin, 30, 875
900. Tsuang, M. T., Simpson, J. C., & Kronfold, Z. (1982). Subtypes of drug abuse with psychosis. Archives of General Psychiatry, 39, 141
7. Weiser, M., van Os, J., & Davidson, M. (2005). Time for a shift in focus in schizophrenia from narrow phenotypes to broad endophenotypes. British Journal of Psychiatry, 187, 203
5. Wragg, R. E. & Jeste, D. V. (1989). Overview of depression and psychosis in Alzheimer’s disease. American Journal of Psychiatry, 146, 577
87. Zubin, J. & Spring, B. (1977). Vulnerability: A new view of schizophrenia. Journal of Abnormal Psychology, 86, 103
26.

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Appendix Descriptors of Oxford Centre for Evidenced-based Medicine Levels of Evidence Criteria (May 2001) www.cebm.net/levels_of_evidence.asp

Level 1a 1b 1c 2a 2b 2c 3a 3b 4 5

Differential dx/symptom prevalence SR with consistency of prospective cohort studies Prospective cohort studies with 1
5 years follow up All or none case studies SR with consistency in 2b rated studies or better Retrospective cohort studies, or those with follow up 51 year Ecological studies SR with consistency of 3b rated studies or better Nonconsecutive cohort studies or studies with very small samples Case-series or superseded reference standards Expert opinion without explicit critique

Treatment SR with consistency of RCTs Individual RCT with a narrow confidence interval All or none single case studies with AB design SR with consistency in 2b rated studies or better Individual cohort study with poor RCT and follow up Outcomes research and ecological studies SR with consistency of case controlled studies Individual case controlled study Case-series and poorly controlled cohort and case-controlled study Expert opinion without explicit critique

SR ¼ systematic review; RCT ¼ randomized control clinical trial Grades of Recommendation

A B C D

Findings based upon consistent level 1 studies Findings based upon consistent level 2 or 3 studies or extrapolated* from level 1 studies Findings based upon level 4 studies or extrapolated* from level 2 and 3 studies Findings based upon level 5 evidence or inconsistent/inconclusive studies at any level

*Extrapolation ¼ findings taken from studies in which the findings are not the primary focus of the study

Part II

Primary Psychotic Disorders

2

Schizophrenia Gerald Goldstein1, Daniel N. Allen2, and Gretchen L. Haas3 1

VA Pittsburgh Healthcare System University of Nevada, Las Vegas 3 University of Pittsburgh 2

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B A B B B B C C C

Introduction Schizophrenia is a chronic psychotic disorder that has apparently existed throughout recorded history. First called ‘‘dementia praecox’’ by Emil Kraepelin, it was renamed by Eugen Bleuler early in the twentieth century to schizophrenia, or more exactly ‘‘the schizophrenias.’’ While the dramatic manifestations of the disorder made it recognizable from antiquity, there was some disagreement as to its identification and it was not until the reforms of DSM-III (the third Diagnostic and Statistical Manual of the American Psychiatric Association) that a consensus was formed regarding criteria for diagnosing the disorder, and its reliable diagnosis was largely achieved. Psychosis has several aspects including the classic symptoms of delusions and hallucinations, impairment of reality testing, and a severity level that substantially interferes in coping with the demands of life. Schizophrenia has all of these aspects and 15

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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so the current (DSM-IV) diagnostic criteria include the symptoms of delusions and hallucinations in addition to disorganization of speech and behavior and the negative symptoms of affective blunting and impairment of purposive behavior, presence of social/occupational dysfunction, and duration of at least six months. There are variations in the pattern of symptoms reflected in the clinical subtypes of paranoid, disorganized, catatonic, undifferentiated, and residual schizophrenia. In this chapter we provide an overview of schizophrenia as the classic disorder defined in DSM-IV which will be contrasted in this book with other psychotic disorders.

Epidemiology Although the lifetime morbid risk of schizophrenia is generally considered to be approximately one percent, prevalence estimates (the number of cases at risk within a defined population over a defined period of time) vary by several-fold. Such variation stems from several factors including variation in definition, variation in the geographic location of the base population, and differences in the case-finding method and diagnostic procedures. Point prevalence, the estimated number of active (i.e., symptomatic) cases on a given date, ranges from 1.4 to 4.6 per 1000 (Jablensky, 2000) and is likely to underestimate true prevalence. Such error can be attributed, in part, to the episodic course of the disorder, with the common inter-episode remission of positive symptoms contributing to underdetection of psychoses. The lack of insight into illness that is a common characteristic of psychosis also likely contributes to under-reporting of symptoms in community-based surveys. Estimates of incidence (the number of first-episode cases in a defined population per year) tend to be more reliable than estimates of prevalence
particularly when based on a common, clearly operationalized definition of onset (e.g., first contact with clinician, first hospitalization, etc.). However, given that schizophrenia is being treated on an outpatient basis more often than ever before, incidence estimates based on hospital admission are likely to underestimate the true values and to reflect an increasing lag time between onset of symptoms and admission to hospital. Variations in the definition or diagnostic criteria for schizophrenia also contribute to variance in incidence estimates. Studies using restrictive criteria are likely to yield lower incidence rates than those using broader definitions (Haas & Castle, 1998). When first contact rates are reported using the more restrictive criteria (e.g., DSM-III-R or ICD10) within a single region (e.g., the United Kingdom), estimates range from 0.08 to 0.14; using the same criteria for a similar region, but controlling for migration and mortality within

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a given district, the estimated prevalence is likely to be higher, as in the study of Jeffreys et al. (1997) in which it is 0.21. Increased mortality has also been reported. Individuals with schizophrenia experience an approximate 20 percent reduction in life compared to the general population (Brown, Inskip, & Barraclough, 2000), with greater mortality in males than females. Increased mortality is caused by a number of factors, including environmental influences such as homelessness, increased death from natural causes, suicide, and accidental death. The lifetime risk for suicide in patients with schizophrenia is estimated to be 5
10% (depending upon how risk is assessed) and is significantly higher than observed in the general population. Increases in mortality also result from comorbid conditions such as cardiovascular disease, diabetes, hypertriglyceridemia, human immunodeficiency virus, and hepatitis (Goff et al., 2005). However, the most common comorbid condition is substance abuse, with up to 65% of patients with schizophrenia having lifetime diagnoses of substance use disorders (Mueser et al., 1990b). While incidence of schizophrenia is consistent across many countries, some subgroups appear particularly susceptible to the disorder, with one of the most striking examples coming from some migrant samples who exhibit markedly increased incidence. An early report by Hemsi (1967) noted that African- and Caribbean-born migrants to the United Kingdom exhibited a high incidence of schizophrenia, a finding which has since been repeatedly demonstrated even in late onset cases (Mitter et al., 2005). Similar findings have also been reported in other countries as well (Cantor-Grace, Zolkowska, & McNeil, 2005), although the cause remains unclear. Environmental factors and in particular psychosocial stress resulting from impoverishment, discrimination, and acculturation have been suggested as major contributing factors (Cantor-Grace et al., 2005; Sharpley et al., 2001), although the direct effects of these factors have not been clearly demonstrated.

Age of onset The onset of the active phase of schizophrenia most commonly occurs in the 20s, although onset can occur in childhood, early adolescence, or in later adulthood. Earlier age of onset is generally associated with poorer outcome (Haas & Garrett, 1998). However, little difference in symptomatology has been noted between early and late onset cases. Older onset may be associated with increased incidence of paranoid delusions and auditory hallucinations (Jeste et al., 1997). Earlier onset cases show greater negative symptoms and disorganization (Kirkpatrick et al., 2000). Differences in age of onset have also been consistently reported between

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males and females with schizophrenia, with females typically experiencing onset three to five years later than males (Haas & Castle, 1998). Males also have poorer premorbid adjustment and more severe deterioration prior to disease onset (Haas & Garrett, 1998). Mitter et al. (2005) found that for schizophrenia-like syndromes that were very late in onset in British-born patients, age of onset for women was approximately 80 years of age, while males had an average age of onset of 75. It has been suggested that at least for some of these late onset cases, schizophrenia symptoms may actually be a prodrome to the development of a degenerative dementia, such as Alzheimer’s disease, although this is probably true for only a subgroup of these patients as most exhibit a pattern of neurocognitive decline consistent with a non-progressive illness (Jeste et al., 1997). Operational definitions of age at onset of illness have been based on the emergence of positive symptoms in large part because of their greater salience and, hence, greater reliability, in dating. Nonetheless, it is recognized that subtle forms of behavioral dysfunction commonly emerge well before that time. Presentation Schizophrenia typically presents with an acute onset of florid symptoms during late adolescence or early adulthood. The initial episode, generally referred to as the ‘‘first break’’ or ‘‘first episode’’, can be most broadly characterized as a loss of contact with reality. Initial symptoms are typically dramatic and include delusions, hallucinations, incoherent speech, and/or disorganized behavior. Social functioning or capacity for independent self-care is substantially reduced and, in most cases, the individual needs to be hospitalized, at least briefly. However, with widespread use of antipsychotic medications and improved case management, it is more typical for patients to be hospitalized for brief periods of time, followed by referral to outpatient treatment while remaining on medication. Over the years, the presentation and conceptualization of schizophrenia have changed. First, with the advent of antipsychotic medications, the severity and duration of the positive symptoms have been reduced in treated cases. Second, the prevalence of certain of the symptoms such as catatonia and so-called ‘‘first-rank’’ symptoms (Schneider, 1957) has decreased. What Kurt Schneider proposed as a set of pathognomonic symptoms that included prominent hallucinations and delusions of mind control (i.e., thought withdrawal, thought insertion, and thought broadcasting) do not occur with sufficient frequency to be given prominence in current diagnostic criteria. Based on recent epidemiologic studies, the most recent version of the DSM (DSM-IV) includes only prominent hallucinations as one of the core criteria for the diagnosis.

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With the introduction of antipsychotic medication, the course of the disorder has changed in certain respects. When the active or acute symptoms have been stabilized on medication, hallucinations are less prominent, delusions tend to be less profound, and speech can become relatively normal. A reduction in the severity of positive symptoms is often accompanied by enhanced ability to maintain self-care; as a result, patients who are compliant with their medication regime can be maintained without inpatient treatment for long periods of time, if not indefinitely. For reasons that are not clear, the nature and prevalence of the so-called ‘‘subtypes’’ of schizophrenia have changed since the advent of the use of antipsychotic medication in the early phase of illness, with the catatonic and disorganized subtypes less common and an increase in the residual subtype. The negative symptoms, which are now recognized as prominent features of some forms of the disorder in the most recent version of the DSM are not readily amenable to pharmacological treatment and do not change dramatically. They include affective blunting, social withdrawal, lack of volition, poverty of speech, and a variety of cognitive deficits. An extensive literature has emerged devoted to characterizing the cognitive deficits and, recently, seeking their correlates in brain structure and function. Cognitive deficits may be reduced with medication, or increase with stress. Many authorities view these deficits as core features of the disorder or endophenotypic markers of the underlying genetics of schizophrenia and, within the last decade, the condition has been more commonly viewed as a cognitive disorder with prominent behavioral features and neurocognitive substrates. Over several decades, various theories have emerged stressing deficits in such cognitive processes as abstract and logical reasoning, memory, social cognition, and attention. Although not formally part of the diagnostic process, cognitive testing is now a well-established procedure for characterization of schizophrenia, and numerous tests have been developed or utilized for that purpose. Many clinicians use intelligence tests and various neuropsychological tests to evaluate cognitive functioning and to provide recommendations for treatment and rehabilitative interventions. This clinical practice has been supported by a wealth of laboratory studies using experimental methods for investigation of various aspects of cognition in schizophrenia. With regard to clinical presentation, two problems have created substantial controversy in this area. The first of these focuses on what has become known as the ‘‘general deficit syndrome.’’ In the search for a general underlying deficit, numerous efforts have been made to identify some specific cognitive deficit that could account for thought disorder
the changes in the formal organization of speech and thinking that are a common feature of schizophrenia. Formal ‘‘thought disorder’’ is manifest as incoherent or loosely organized speech,

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illogical reasoning, oddities of speech such as neologisms, or idiosyncratic associations based on the concrete characteristics of words. When present, such abnormalities of speech and thought tend to persist throughout the course of illness. Beginning in the 1940s, prominent leaders in the field of psychopathology proposed that the underlying deficit in schizophrenia was an impairment of ‘‘abstract attitude’’, as demonstrated by remarkably concrete reasoning on interview, and impaired performance on tests of abstract reasoning. Other explanations stressed the presence of essential or ‘‘core’’ features such as illogical thinking (e.g., syllogistic reasoning), a loss of ego boundaries, and an impairment of body image that led to an inability to separate the self from the outside world, or an inability to distinguish between internal and external events. Several research groups studied attention with reaction time experiments, showing that individuals with schizophrenia could not maintain or flexibly shift across complex concepts or cognitive ‘‘sets.’’ Based on the mounting empirical literature within the then active field of experimental psychology, leaders in the field asserted that individuals with schizophrenia consistently did more poorly than normal control subjects on any cognitive task offered (Chapman & Chapman, 1978). As a consequence of this controversial, but persuasive argument, the presumptive underlying abnormality of cognition became known as the ‘‘general deficit syndrome.’’ In light of the yet controversial but widely accepted notion of a generalized deficit in schizophrenia, investigators who conduct research on cognition in schizophrenia are now required to demonstrate dissociation between performance on different cognitive tasks, ideally equated for difficulty level, to demonstrate that the findings reflect a specific deficit and/or a previously unidentified aspect of thought in schizophrenia that is not a part of a general deficit syndrome. Nonetheless, at present, there appears to be no consensus concerning a single cognitive deficit that characterizes all of schizophrenia. Rather, the heterogeneity across the cognitive test performance profiles of individuals with this disorder indicates that not all individuals with schizophrenia present the same level or pattern of cognitive problems. There is, indeed, substantial variation in performance across individuals, ranging from normal function in some areas of cognition to severely impaired performance that may be undistinguishable from the behavior of elderly individuals with dementing illnesses such as Alzheimer’s disease. One may encounter individuals with fluent and intelligible speech, apparently good reasoning abilities, and no evidence of failures in memory or maintenance of attention, but one may also see individuals with very little intelligible speech, and inability to maintain attention or solve relatively simple reasoning problems. While it is unusual to find superior or normal performance across all tests, near normal performance in general, with superior performance

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sometimes achieved on individual tests is sometimes found. On the other end of the spectrum, some patients with schizophrenia may demonstrate significant impairment on all tests given. Thus, we now speak of ‘‘cognitive heterogeneity’’ in schizophrenia, and while cognitive dysfunction is typically observed among the majority of individuals with the disorder, in contemporary practice, evidence of cognitive performance problems is not used to characterize the disorder, and is not used to make the diagnosis. Efforts have been made to attribute this variability in cognitive functioning to factors other than schizophrenia, often involving demographic and individual difference factors such as age, education, premorbid capabilities, alcohol or drug abuse, or the presence of another illness that impairs brain function. In brief, cognitive heterogeneity in schizophrenia is not readily explained by extraneous factors. Hence, there continues to be an ongoing, unresolved debate as to whether the cognitive heterogeneity reflects variability in general severity of the dysfunction or meaningful subtypes of schizophrenia.

Course and progression Early behavioral abnormalities such as failure to achieve normal developmental milestones, functional decline during adolescence or early adulthood, or transient psychotic symptoms often precede the constellation of symptoms that meet diagnostic criteria for schizophrenia. Thus, the course of schizophrenia includes a premorbid phase (occurring before the active ‘‘malignant’’ phase of illness), and this is often followed by a prodromal phase (marked by onset of subtle symptoms and/or behavioral changes that precede the active phase) in advance of the active symptoms or acute phase of illness. Decades of research on the premorbid period show a robust association between premorbid social, occupational/educational achievement and the longer-term clinical course of schizophrenia, including treatment response, rate of relapse, and level of social and occupational functioning (Fenton & McGlashan, 1987; Gittelman-Klein & Klein, 1969). Whether premorbid functioning influences the individual’s adaptation to the disorder or whether there is some direct relationship between premorbid adjustment and a specific etiologic or pathophysiologic subtype is not known and remains a focus of scientific investigation. Because of the proposed neurodevelopmental origin of schizophrenia (Weinberger, 1987), adjustment prior to the onset of the disorder in the premorbid state has received renewed attention in recent years. Premorbid abnormalities have been identified in academic and social functioning (Allen et al., 2001), motor and intellectual abilities (Aylward, Walker, & Bettes, 1984;

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Bilder et al., 1992; Caspi et al., 2003), and affective responsivity (Walker, Lewine, & Neumann, 1996). These premorbid deficits exhibit significant associations with specific clinical and neurobiologic aspects of the disorder, such as neuroanatomical abnormalities (Walker et al., 1996), neurocognitive functioning (DeQuardo et al., 1994; Levitt et al., 1996; Silverstein et al., 2003), age of symptom onset (Gittelman-Klein & Klein, 1969; Haas & Sweeney, 1992), positive and negative symptoms (Kelley et al., 1992), social skills (Mueser et al., 1990a), intellectual functioning and educational attainment (Allen et al., 2001; Aylward et al., 1984; Bilder et al., 1992), haloperidol treatment response (van Kammen et al., 1996), and disability and long-term outcome (Fleischhaker et al., 2005). Longitudinal studies of children at elevated genetic risk for schizophrenia indicate a statistical relationship between increasing symptoms and poorer adjustment prior to onset of schizophrenia (Dworkin et al., 1991), along with a stability in positive and negative symptom profile from late childhood to adulthood in some who later go on to develop schizophrenia (Cannon & Mednick, 1993). Because premorbid adjustment is not a unitary construct, efforts have been made to determine those abnormalities that are unique to schizophrenia, and those that may be indicators of more general risk for later development of mental illness. Two areas of premorbid functioning that have been examined extensively include premorbid intellectual functioning and premorbid psychosocial functioning. In the absence of longitudinal data, indices of premorbid intellectual functioning have been derived using a number of techniques, such as current patterns of performance on ‘‘hold’’ versus ‘‘non hold’’ subtests from intelligence tests (Bilder et al., 1998), achievement test performance (Kremen et al., 1996), or regression analyses of demographic variables (Vanderploeg, Schinka, & Axelrod, 1996). Premorbid psychosocial functioning is typically determined using scales based on information derived from interviews and ratings that incorporate patient self-reports, family member reports, and available academic, medical, and other pertinent records. One such instrument, the Cannon-Spoor Premorbid Adjustment Scale (PAS) (Cannon-Spoor, Potkin, & Wyatt, 1982), has been widely used to retrospectively collect information concerning academic and social domains of childhood, adolescent, and adulthood functioning. Support for the partial independence of these two domains has been generated through a series of factor analytic studies, most recently using confirmatory factor analysis (Allen et al., 2001). Their validities have been further demonstrated via investigations of their partially independent patterns of association with biological, outcome, symptom, and IQ variables, as well as comparisons between clinical and non-clinical populations (Allen et al., 2001; Cannon et al., 1997; van Kammen et al., 1996).

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Deterioration in premorbid academic functioning may be unique to schizophrenia, while premorbid social deterioration may be a more general feature of severe affective and psychotic illnesses. For example, using the PAS, Cannon et al. (1997) found poor premorbid social adjustment in schizophrenia and bipolar disorder, whereas only the schizophrenia group exhibited impaired academic adjustment. A number of studies have also reported deterioration in academic performance or academic achievement test scores that become increasingly severe during late adolescence for individuals who later go on to develop schizophrenia (Allen et al., 2005; van Oel et al., 2002). In a direct comparison of the course of academic and social premorbid adjustment across age periods, Allen et al. (2005) found that while deterioration is present across both academic and social functioning prior to the onset of schizophrenia, premorbid academic functioning is particularly susceptible to deterioration, most notably in later adolescence as the onset of the active phase of clinical symptoms becomes imminent. This accelerated decline in premorbid academic functioning appears to occur well before the onset of the clinical manifestations of schizophrenia. The cumulative findings also suggest that academic dysfunction or deterioration in childhood or early adolescence is a unique premorbid marker for schizophrenia. Although speculative, such developmental deficits may reflect neurodevelopmental abnormalities that may have a particularly profound effect on basic cognitive functions necessary for adequate performance in academic environments. Prospective studies of offspring at genetic risk for schizophrenia may contribute to better understanding and recognition of the earliest stages of schizophrenia, as well as investigation of genotypic variation and/or variation in the neurobiologic substrates of the psychopathology. The long-term course of schizophrenia is quite variable, with an episodic course for some and chronic, unremitting courses for others. Review of the evidence from international follow-up studies indicates that the five patterns of course and outcome now incorporated into DSM-IV have good empirical support (Jablensky, 2000). Whereas some individuals with an episodic course experience full symptom remission between episodes, others have incomplete remission and yet others experience continuous, unremitting symptoms. Based on the cumulative evidence from prospective longitudinal studies conducted in various regions of the world, it is commonly recognized that the course is without abnormally progressive loss of cognitive function. Although once conceived as an early onset form of dementia (dementia praecox), it is now generally accepted that schizophrenia is not a progressive deteriorative disease of the central nervous system. Neuropsychological cross-sectional studies of age differences in schizophrenia have largely found an absence of more rapid decline in individuals with schizophrenia than in normal controls (Goldstein & Zubin, 1990). The typical course of

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schizophrenia is now thought to be relatively stable with periods of relapse. Positive symptoms may return after substantial remission associated with medication. The reasons for these relapses are partially understood and have mainly to do with failures of medication compliance. Substance abuse and onset of severely stressful life events may be factors, but sometimes relapse occurs without medication nonadherence, substance abuse, or stress
apparently because of some not well understood neurobiological cycle. Neurobiological changes that precede clinical relapse have been identified.

Suspected neuropathology and neurochemical abnormalities While neuropathology and neurochemistry have traditionally been viewed as separate disciplines, this distinction has diminished recently, in part, because of significant advances in molecular biology. In the past, neuropathology has largely involved examination of tissue at autopsy or in conjunction with brain biopsy. Neurochemistry once largely involved the study of biochemical assays, via analysis of blood, cerebral spinal fluid, and urine. It is becoming increasingly possible to do neuropathology studies in living people through advanced imaging techniques that can identify specific tissue abnormalities. It is probably fair to say that traditional neuropathological/neuroanatomic approaches have not been productive in schizophrenia. Autopsy studies have shown areas of tissue abnormality throughout the brain without any clear identification of an area or structure particularly relevant to understanding the etiology of schizophrenia. Neuropathologic examination of tissue has not identified any characteristic pathology in the sense that schizophrenia is not a neoplastic, infectious, vascular, traumatic, or other form of pathological disorder. The closest we come is that it may be related to developmental anomalies, but that possibility is better evaluated with different approaches. Regarding neurochemistry, we have gone through an era of the dopamine hypothesis that turned out to be productive. Briefly, the dopamine hypothesis proposes that an abnormality in the mesolimbic dopaminergic system is a key agent in the pathogenesis of schizophrenia. Evidence for this view came largely from the beneficial effects of drugs that block dopamine receptors. While this hypothesis and other related ones were quite heuristic at their time, new developments in neuroscience have allowed for examination of the underlying molecular biology. Starting with the structural or visible neuropathological findings, there is abundant evidence of brain abnormalities in schizophrenia. Both postmortem and in vivo neuroimaging studies have demonstrated structural changes.

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MRI studies report finding enlarged lateral and third ventricles, decreased (mainly grey matter) brain volume, reductions in volume of the temporal cortex
particularly the hippocampus and the superior temporal gyrus
and reduced size of the prefrontal cortex. By far the most commonly reported neuropathological finding in schizophrenia is enlarged ventricles. However, functional and structural neuroimaging studies have also identified more specific abnormalities in frontal-striatal and temporo-limbic regions, including cortical grey matter volume reductions (Ananth et al., 2002; Gur et al., 2000a; Gur et al., 2000b; Harvey et al., 1993; Sullivan et al., 1998). Frontal lobe regions that have been shown to be functionally or structurally abnormal include the dorsolateral prefrontal cortex (Gur et al., 2000a; Ragland et al., 1998; Weinberger et al., 1992), medial prefrontal cortex and anterior cingulate (Ananth et al., 2002; Haznedar et al., 1997), frontal eye fields (Sweeney et al., 1998), and orbital frontal cortex (Gur et al., 2000a; Malaspina et al., 1998). Abnormalities have also been reported for the superior temporal gyrus (Menon et al., 1995; Shenton et al., 1992; Sullivan et al., 1998), and medial temporal lobe structures (Arnold et al., 1995; Bogerts et al., 1990; Suddath et al., 1989; Suddath et al., 1990). In chronic schizophrenia subjects with a more severe course, and especially males, there appears to be a progressive loss of frontal and posterior, superior temporal grey matter. The question is what produced these changes? One approach has come from magnetic resonance spectroscopy (MRS), an MRIrelated procedure that assesses brain metabolism at a molecular biology level. An initial answer proposed by Pettegrew et al. (1991) was that these morphometric changes reflected a reduction in neuropil secondary to exaggerated synaptic pruning with resultant loss of synapses. Reduction in neuropil would be expected to increase neuronal density, and in fact stimulated by this suggestion increases have been reported in pyramidal cell density in schizophrenia (Selemon, 2004). These findings support the occurrence of neuropil and synaptic loss in schizophrenia. Reductions have also been seen in dendritic spines from cortical pyramidal cells in the frontal cortex (Garey et al., 1998; Glantz & Lewis, 2001) and elsewhere in the cerebral cortex. Thus, the reduction in cortical volume could result from loss of neuropil and synapses and reflect an exaggeration of the normal synaptic pruning which occurs during adolescence. Numerous lines of evidence support a neurodevelopmental role in schizophrenia. Recently, there has been some suggestion that in addition to developmental abnormalities there may be neurodegenerative processes occurring, at least in some schizophrenia patients (Lieberman, 1999; Mathalon et al., 2001), and that this progression may contribute to the cognitive decline observed in some patients (Flashman and Green, 2004; Lieberman, 1999).

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In two longitudinal MRS-cognitive studies, chronic schizophrenia subjects were found to have reduced NAA/PCrþCr in the left hemisphere compared to recent-onset schizophrenia subjects and controls (Molina et al., 2005). The other revealed decreased NAA in the anterior cingulate gyrus in schizophrenia subjects as a function of age and duration of illness (Ende et al., 2000). NAA (N-Acetyl-Aspartate) is a metabolite that is widely recognized as being an indicator of neuronal integrity and is reduced with neuronal loss. The possibility has been raised that antipsychotic medication may produce at least some of these structural alterations, but current evidence suggests that is not the case. To summarize, schizophrenia is now thought to be a neurodevelopmental disorder characterized by initiation of an abnormal pruning process that destroys a substantially more than normal number of neurons. The process appears to involve an abnormality in membrane phospholipid metabolism that produces decreased synthesis of membranes primarily affecting synapses. This process manifests itself as abnormal synaptic pruning of the type that takes place normally in adolescence, at least in non-human primates. 31P MRS (phosphorous spectrum) studies with schizophrenia participants have consistently found alterations of membrane phospholipid metabolism, while 1H MRS (hydrogen spectrum) studies have demonstrated loss of neuronal cells evidenced by reduced NAA. The process appears to involve a cycle of membrane breakdown reflected in the increase of a metabolite called phosphodiester (PDE) followed by attempts at repair reflected in elevation of phosphomonoester (PME). Dopamine becomes involved in this process because of an agent called dopamine-cAMP-regulated phosphoprotein (DARPP) that is involved in phosphorylation of membrane channels and receptors, apparently involved in cell repair. There is the possibility that some individuals with schizophrenia, in addition to these developmental abnormalities, sustain a neurodegenerative process in later life. This group may constitute what has been described as ‘‘Kraepelinian’’ or ‘‘Very Poor Outcome’’ Schizophrenia.

Genetic factors The currently most favored view concerning the basis for these neurobiological phenomena is that they are genetic in origin. There has been an enormous amount of genetic research in schizophrenia ranging from earlier population or family descriptive studies of twins to state-of-the-art laboratory investigations. Probably the best conceptualization of the current status of the field has been made by Weinberger who has written that there are currently several

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promising candidate genes. They are catechol O-methyltransferase (COMT), dysbindin-1, neuregulin 1 (NRG1), metabotropic glutamate receptor 3 (GRM-3), glutamate decarboxylase 1, and disrupted in schizophrenia 1 (DISC1). COMT has probably been the most extensively studied. It affects prefrontal function by altering the regulation of dopamine activity in the brainstem. GRM-3 plays a similar role by affecting glutamate synapses. DISC1 affects hippocampal function, and dysbindin-1 appears to have a general influence on cognitive capacity. These genes are characterized as ‘‘susceptibility genes’’ that may influence development of the schizophrenic phenotype. A detailed description of these and other genes and their possible relations to schizophrenia are presented in an extensive review by Harrison & Weinberger (2005). While the most extensive work has been done with COMT, there is a particularly interesting susceptibility gene from the standpoint of the MRS derived abnormal synaptic pruning theory. It is called neuregulin 1 (NRG1) and is of interest because of its role as a growth factor involved in neuronal migration, axon guidance, synaptogenesis, glial differentiation, and myelination. Harrison and Weinberger conclude that the various candidate or susceptibility genes converge on schizophrenia risk through influencing ‘‘synaptic plasticity and the development and stability of cortical microcircuitry’’ (Harrison & Weinberger, 2005, p. 1). The neuropathological or neuroanatomic and neurochemical conceptualization of schizophrenia as illustrated by studies of visible structural abnormalities such as enlarged lateral ventricles and by the ‘‘dopamine hypothesis’’ are in large part outdated and have been replaced by advanced methodologies in microbiology, neuroimaging, and genetics. This work has not yet led to any definitive conclusions about the specific biology of schizophrenia, although there is abundant evidence of abnormalities in synaptic transmission and microcircuitry in the brain
abnormalities that are apparently influenced by multiple genetic factors, involving numerous genes and gene interactions.

Treatment Pharmacological, somatic, behavioral, and rehabilitative treatments have been developed for schizophrenia over the years, although medication is currently considered an essential component of any treatment program. While it is a chronic disorder, it is probably not productive to characterize it as incurable. It is clearly treatable, and does not resemble incurable illnesses such as certain forms of cancer or dementia in which no form of treatment has any effect on outcome. Remission clearly occurs in schizophrenia, and sometimes

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may exist to the extent that individuals with the disorder have been described as indistinguishable from normal community dwellers. Historically, the use of somatic treatments preceded the advent of the pharmacological treatments, but sometimes they may be used concurrently. They include hydrotherapy, electroconvulsive (shock) therapy (ECT), insulin shock therapy, and psychosurgery. These methods are rarely used in contemporary treatment. The development of new drugs to treat schizophrenia have been a boon to interventions for the disorder, with the most recent strides made in the development of what have been variously referred to as ‘‘atypical,’’ ‘‘second generation,’’ or ‘‘novel’’ antipsychotics (Arnt & Skarsfeldt, 1998). Unlike their predecessors, which were primarily dopamine antagonists, these novel antipsychotics have affinity for serotonergic 5-HT2 receptors and a1 adrenoceptors, in addition to dopamine D2 receptor affinity. Clozapine was the first in this new generation of medications, followed by risperidone, olanzapine, sertindole, and more recently quetiapine. Novel APDs have been shown to produce less extra-pyramidal side effects (EPS) and decrease negative symptoms, including neurocognitive deficits, when compared to traditional antipsychotics, potentially because of their combined serotonergic and dopaminergic affinities. Serotonergic neurons inhibit functioning of the dopaminergic system in midbrain structures, where the dopaminergic system originates (Kelland, Freeman, & Chiodo, 1990), as well as in the striatum and forebrain, including the prefrontal cortex (Ashby et al., 1990). Antagonism of the serotonergic system decreases inhibition of the dopaminergic system which, in turn, may account for the reduction in EPS (striatum) and reduction in negative symptoms (prefrontal cortex) noted following treatment with novel antipsychotic agents (Kapur & Remington, 1996). A major challenge to pharmacological treatment has been the patient who does not respond to these medications. This condition has been described as treatmentresistant schizophrenia, and some years ago attempts were initiated to find new drugs to deal with this difficulty. The most widely studied of these drugs is clozapine, which was shown to be effective with patients who did not respond to the conventional antipsychotic medications. Clozapine has since been established as having third-line status to be used only when there is no response to two other antipsychotic medications. The reason for this policy is that use of clozapine has been associated in some cases with the development of agranulocytosis. Recent research has shown that some of the other atypical medications are superior to haloperidol when used with treatment-resistant patients. Current treatment of schizophrenia in general now includes use of one of the atypical medications, with use of haloperidol or other ‘‘first generation’’ antipsychotics being substantially less common.

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Recent emphasis has been placed on evidence-based treatments whose effectiveness is supported by research. In the case of schizophrenia, Drake et al. (2000) have listed several such areas including (1) use of medications; (2) illness self-management; (3) case management in the community; (4) family psychoeducation; (5) supported employment; (6) substance abuse treatment. There is a developing field of intensive case management in which the patient is followed and appropriate interventions are made from hospitalization through life in the community. One of the first published controlled clinical trials of a psychosocial intervention tested the efficacy of individual analytically oriented psychotherapy for schizophrenia; patients were assigned to one of five treatment regimens: individual psychotherapy alone, antipsychotic medication alone, the combination of the two, ECT, and ‘‘milieu’’ treatment. The contrast between psychotherapy with pharmacotherapy and the psychotherapy with a no-medication placebo showed no independent or incremental benefit of analytically oriented psychotherapy as compared to somatic therapies at either the termination of inpatient treatment or at 3
5 years following treatment termination (May, Tuma, & Dixon, 1981). Empirical findings on contemporary psychosocial interventions for schizophrenia indicate that they have variable efficacy depending on several key factors. Interventions that have empirical support can be conceptualized and organized in terms of four key dimensions: (1) the phase of illness (i.e., early acute versus the later, more stable phase of illness); (2) the specific focus or goals of treatment (e.g., enhancement of compliance with treatment, increasing socialization, versus reduction of positive symptoms); (3) the format of delivery (e.g., individual-, group-, or family-based); and (4) the theoretical model and the related intervention techniques (e.g., behavioral versus cognitive-behavioral). A brief review of the current literature on efficacy of psychosocial treatments for schizophrenia follows. Early phase of illness

Particularly relevant to the treatment of the early phase of schizophrenia is psychoeducation. In general, psychoeducational interventions aim to inform the patient (and significant others) regarding the nature of the disorder, the intended impact of medications and their possible side effects, early warning signs of relapse or recurrence, and other issues particularly pertinent to the transition from acute and intensive care to community-based care. Psychoeducational intervention alone is unlikely to have an impact on treatment adherence, although mixed modality (family and individual) approaches and

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Gerald Goldstein et al.

individual approaches that incorporate behavioral interventions, skills-building, and/or supportive services yield the most consistent and promising evidence for a positive impact on medication adherence (Zygmunt et al., 2002). Also showing evidence for an impact on treatment adherence are family-based psychoeducational approaches of two general types: those that include a behavioral component and specifically focus on family support for treatment adherence (Falloon and Pederson, 1985; Razali and Najib, 2000), and supportive family-based psychoeducation as a component of mixed modality interventions that include either a behavioral component (Azrin & Teichner, 1998) or focus on anticipated stressors, coping skills and problem-solving techniques, as well as the rationale for selected treatments and for long-term adherence to a program of maintenance medication (Goldstein et al., 1978; Hogarty et al., 1979; Glick et al., 1990). Work with the patient and family around identification of early warning signs during the acute phase is a core component of those family interventions that are designed to prepare for transition to community-based care (Glick et al., 1990; Herz and Lamberti, 1995). Empirically supported, family-based psychoeducational interventions launched during the acute episode phase of treatment address such issues of daily living as drug use, stigma, treatment noncompliance, and family criticism or emotional over-involvement (Goldstein et al., 1978; Leff et al., 1982). Family intervention shows a relatively consistent effect of significantly reducing rates of relapse and rehospitalization (Pharoah, Mari, & Streiner, 2003; Pitschel-Walz et al., 2001). Transition to stabilization phase

For the period of symptom resolution, current clinical practice guidelines call for a combination of pharmacologic intervention and supportive psychotherapy or a program of continued case management (Lehman, 1999). A key feature of this early phase of transitional care is the effort to instill hope in order to minimize and/or counteract depression and suicidality. For this phase of treatment, cognitive interventions that aim to combat depressogenic cognitions and enhance everyday coping skills and problem-solving behaviors appear to have utility in forestalling or preventing relapse. Such interventions aim to reduce the emotional impact of the emergence of secondary symptoms (e.g., anxiety, depression, suicidality) that are common to the post-psychotic phase of recovery. During the outpatient stabilization phase, the introduction of focused cognitive techniques within a supportive intervention can be initiated for relief of acute positive symptoms. There is some support for introducing cognitivebehavioral interventions that involve identifying delusional beliefs and learning to question and consider alternative cognitions. Tarrier et al. (2004) showed a greater reduction in anxiety and delusions among patients treated with a brief

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Schizophrenia

cognitive-behavioral therapy than those who received usual care. Drury et al. (1996) reported that an application of traditional cognitive-behavioral therapy is effective in reducing positive symptoms when introduced in combination with family intervention and structured activity interventions during the initial phase of treatment for acute psychosis. One general conclusion from a review of the controlled clinical trials of cognitive-behavioral therapies is that cognitive-behavioral interventions can have a positive impact on positive symptoms for individuals in the early, acute phase of the illness (Drury et al., 1996; Tarrier et al., 2004) as well as during the early stage of relapse (Gumley et al., 2003). It has also been shown to enhance coping with the problems of treatment-refractory positive symptoms. Systematic reviews of the findings from random-assignment clinical trials of cognitive-behavioral therapeutic approaches are handicapped by the heterogeneity of study design, variation in the timing and duration of treatment, phase of illness, and outcome domains measured. Thus, general conclusions from these reviews are equivocal, showing some evidence for positive symptom reduction, particularly during treatment but with questionable durability beyond treatment termination; minimal or no impact on negative symptoms; and no impact on relapse rates (Pilling et al., 2002). Subsequent controlled clinical trials have offered additional support to the evidence base. Applications of cognitive-behavioral approaches for medication non-responsiveness during the maintenance phase of schizophrenia have demonstrated a positive impact on symptom remission. Finally, there is some evidence that a relatively brief (20-session) cognitivebehavioral therapy added to standard multimodal treatment may have an incremental impact on negative symptoms over the long term. In the study by Tarrier et al. (2004), the specific benefits of a cognitive-behavioral therapy were found to be the long-term maintenance of improvement in both positive and negative symptoms at a 12-month follow-up. Cognitive-behavioral interventions that aim to reduce positive symptoms and enhance and maintain compliance with pharmacotherapeutic regimens have some demonstrated efficacy for the stabilization phase of care. Maintenance phase

Continuation of regular contact with a care provider is indicated for the maintenance phase of treatment following recent recovery from an episode and during the inter-episode phase of partial symptom remission. Programmatic psychosocial interventions are generally introduced as part of an overall strategy that aims to promote effective adaptation to the impact of the illness and residual symptoms. Social skills training has been shown to be an effective approach to the problems of illness self-management (Eckman et al., 1992) and

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socialization, although generalization beyond the training setting appears to be limited. In controlled clinical trials of social role therapy and, subsequently, an individually tailored psychotherapy, Hogarty et al. (1997) found that individuals in these social skills interventions showed improvements in social functioning and personal adjustment superior to those of individuals who received a combination of a supportive psychotherapy and family psychoeducation. Components of this multimodal approach include long-term programs of social skill interventions, vocational rehabilitation, and cognitive remediation approaches to enhance social and work role functioning. Cognitive rehabilitation has become an important form of intervention, advancing to comprehensive programs targeted toward direct remediation of the cognitive deficits that characterize schizophrenia. Wykes et al. (2003) have shown success using such techniques as errorless learning to effect improvement in executive function and memory with secondary benefits to self-esteem. Hogarty et al. (2004) have targeted aspects of social cognition, while others have trained a variety of cognitive abilities including facial affect recognition, memory, attention, and the executive abilities associated with the card sorting training. Several programs have integrated cognitive training in vocational applications involving work therapy or supported employment.

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64.

3

Schizophrenia among children and adolescents Jason Schiffman Department of Psychology, University of Hawaii at Manoa

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B
A
B B
B C
B C B

Notes: Age of onset received an A
because this is the defining characteristic of childhood-onset schizophrenia relative to adulthood. It should be noted, however, that the age of onset varies among youth and can range from as early as 5 until 18. Treatment received a B, but the strength of the evidence is among psychopharmacological treatments. To date, psychosocial interventions have not been systematically examined to the degree psychopharmacological treatments have, and would therefore receive a C if rated independently.

Introduction Schizophrenia among young people is a devastating and costly mental illness. Considered a more severe variant of adult schizophrenia, childhood schizophrenia can be a terrifying and debilitating condition for youth and family. Although the disorder is rare, interest in schizophrenia among children and adolescents has 39

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Jason Schiffman

grown as researchers and clinicians recognize the benefits of understanding the disorder. Continued research promises to increase the ability to diagnose and treat early forms of schizophrenia. Additionally, the study of early-onset variants of disorders often enables the examination of a more genetically homogeneous and less environmentally influenced disease condition. As such, understanding earlyonset schizophrenia may possibly provide useful information about the etiology and course of adult-onset schizophrenia (Kumra et al., 2000). Despite growing interest, however, research on schizophrenia among children and adolescents is limited. Several research groups currently pursue studies of individuals with early schizophrenia to discern functional and structural deficits associated with the disorder (e.g., Asarnow & Asarnow, 2003). While ongoing research continues to increase our understanding of biological and environmental factors associated with and contributing to the disorder, the rarity of the condition has resulted in only modest gains in understanding. Factors associated with early-onset schizophrenia such as basic demographics (e.g., prevalence, gender distribution, comorbidity), presentation, course and outcome, neuropathology, genetic factors, and treatment remain areas of relative mystery. Increased knowledge of the general portrait presented by children and adolescents with schizophrenia may increase understanding and have implications for mental health care provision. Epidemiology Prevalence of schizophrenia among youth

Very few studies have tracked rates of schizophrenia among youth in the general population. Gillberg and Steffenburg (1987) estimated very early onset schizophrenia (10 years of age or younger) rates at 1.6 per 100,000 in western Sweden. Remschmidt et al. (1994) suggested that approximately one in 10,000 children develop schizophrenia before 18 years of age. Among slightly older (12 to 19 years) youth receiving psychiatric outpatient services, Evans and Acton (1972) reported that the rate of a more inclusive condition of psychosis was approximately one percent. A study by Thomsen (1996) looked at childhood and adolescent onset schizophrenia throughout Denmark from 1970 to 1993. Findings indicated that 32 children younger than 15 met criteria for schizophrenia between 1970 and 1993, comprising 86% of the psychiatric in-patient population in this age group. As would be expected, the occurrence of schizophrenia increased with age. Between ages 15 and 17, 284 adolescents with schizophrenia were hospitalized from 1970 to 1993. Although informative, this Danish study did not include youth

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served in non-hospital settings. Given a trend towards least restrictive care in the United States, many children and adolescents with schizophrenia in the USA probably receive treatment outside of the hospital. While prevalence estimates in the USA are rare, we recently completed a study of youth with schizophrenia spectrum disorders served by the state mental health system of Hawaii (Schiffman & Daleiden, 2006). Schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder, psychotic disorder NOS) may be of particular interest to researchers and clinicians because they are genetically linked to schizophrenia and are slightly more available for study. Among other findings assessing children and adolescents seeking services through both hospitalization and community clinics served by the state mental health system in Hawaii, we estimated an observed prevalence of 5% among all youth registered for mental health services. As might be expected, the Hawaii analysis, which included home and community services, yielded a slightly lower prevalence rate estimate than that reported in a psychiatric in-patient population (Thomsen, 1996). In general, most studies of the epidemiology of early-onset schizophrenia converge to suggest low rates of the disorder attesting to the rarity of this condition among youth. Additional epidemiological reports are needed to augment the current understanding of schizophrenia in children and adolescents. Overall, Asarnow and Asarnow (2003, p. 461) note that current ‘‘prevalence figures must be viewed as highly tentative until more representative data become available’’. Gender distribution

Previous research suggests a male-to-female ratio ranging from 2:1 to 5:1 (Beitchman, 1985; Evans & Acton, 1972; Green et al., 1992; Hollis, 1995; Thomsen, 1996; Werry, 1992). Findings from the Hawaii study suggest a maleto-female ratio of 1 to 2.38 among youth with schizophrenia spectrum disorders. This range of gender ratios conflicts with general prevalence estimates of adult schizophrenia that suggest approximately equal gender distribution, but is consistent with the notion that males typically have an earlier age of onset than females. Kolvin et al. (1971) suggested that the predominance of males among youth with schizophrenia is a distinguishing characteristic of early-onset schizophrenia. Comorbidity

Youth with schizophrenia typically have multiple diagnoses. A study by Russell, Bott, Sammons (1989) reported that 68% of children with schizophrenia in their sample met criteria for another mental illness. Reports from the literature indicate that externalizing disorders such as conduct or oppositional defiant disorders as

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well as internalizing disorders such as depression are commonly diagnosed along with a schizophrenia spectrum diagnosis (Eggers, 1989; Nicolson et al., 2001; Werry, McClellan, & Chard, 1991). Among youth with psychosis, a study by Biederman et al. (2004) indicated that 131 of 132 identified youth with psychosis had a comorbid disorder. In the Hawaii study, disruptive behaviors and attentional problems were the most frequently diagnosed comorbid conditions for both youth with and without spectrum disorders. The rate of comorbid disruptive behavior and attentional problems among the comparison group of all youth in the system without a schizophrenia spectrum disorder (‘‘non-spectrum youth’’), however, was significantly greater than among youth with spectrum disorders. This pattern of results suggests that youth with disruptive and attentional disorders are more likely to be registered with the Department of Health than youth with any other diagnosis, but this effect was not as pronounced for youth with schizophrenia spectrum disorders. Youth with schizophrenia are also more likely to have mental retardation (Aylward, Walker, & Bettes, 1984). Consistent with that finding, youth in the Hawaii study with spectrum disorders were more likely to have a diagnosis of mental retardation than non-spectrum youth. Aylward et al. (1984) suggested that mental retardation can serve as a premorbid feature of early-onset schizophrenia and may relate to the course of the illness. This link between mental retardation and early-onset schizophrenia, however, may be underrepresented as some research groups exclude youth with severe intellectual disabilities from their studies of childhood schizophrenia (Friedlander & Donnely, 2004). Ethnicity

Given the rarity of the condition, research does not provide a clear description of the ethnic breakdown of youth with schizophrenia. Studying youth in Hawaii offered the advantage of a large multi-ethnic sample. This is particularly beneficial with childhood-onset schizophrenia as demographics in general are poorly understood and under studied. In the Hawaii study, ethnic background did not significantly differ between the spectrum and non-spectrum groups, with the exception of Asian youth (Schiffman & Daleiden, 2006). Our findings indicated that Asian youth accounted for a larger proportion of the spectrum disorder group than the non-spectrum control group of all other registered youth. The proportion of Asian youth in the non-spectrum group (18.2%) was less than the proportion of Asian youth (29.9%) in the general Hawaii population (US Census Bureau, 2000). The proportion of Asian youth in the spectrum group (30.2%) resembled the general population of Asian youth in Hawaii. Studies have reported lower representation among Asian Americans in hospital-based and

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community mental health service populations than expected based on census estimates (Leong, 1994). The source of underutilization is unclear, however, cultural factors may partially account for this finding (Leong, 1994; Sue & Morishima, 1982). The closer approximation to census estimates in the group of youth with schizophrenia spectrum disorders may suggest that, among other possibilities, the severity of spectrum disorders may contribute to the increased likelihood that Asian youth with schizophrenia spectrum disorders receive mental health services.

Age of onset The modal age of onset of typical schizophrenia is in early adulthood, usually before 25 years of age. While specific age cutoffs for early onset vary in the literature, researchers generally consider schizophrenia diagnosed before age 18 as early onset. Diagnoses before age 13 are rare and often labeled as ‘‘very early onset.’’ Given the low base rate of the phenomenon and normal developmental processes (e.g., childhood imagination), diagnosing schizophrenia prior to age seven is extremely uncommon. As might be expected, the rate of schizophrenia among youth increases with age. Among youth in Hawaii, registered youth with a diagnosis of a schizophrenia spectrum disorder in the mental health system were significantly older in relation to all other registered youth (14.6 years versus 12.0 years; Schiffman & Daleiden, 2006).

Presentation First rank symptoms

Current DSM-IV-TR diagnostic criteria for childhood-onset schizophrenia are the same as those used for adult schizophrenia. As with adults, the hallmark symptoms include delusions and hallucinations. When sufficiently severe, only one of these symptoms is required for a diagnosis. Other symptoms include disorganized speech, disorganized or catatonic behavior, and negative symptoms. In addition to the characteristic symptoms, DSM-IV-TR (American Psychiatric Association, 2000) also requires social or occupational dysfunction (generally school performance for young people), symptoms for at least six months, and symptoms not better accounted for by mood disorders, schizoaffective disorder, substance use, a general medical condition, or a pervasive developmental disorder (for pervasive developmental disorders, schizophrenia is given if delusions or hallucinations are present for at least a month).

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Specific patterns of symptom presentation among youth with schizophrenia are not well studied. Russell et al. (1989) reported hallucinations in 80% of their sample of 35 children with schizophrenia, with auditory hallucinations the most common form, followed by visual. Delusions were reported in approximately 63% of cases from this sample. In a descriptive account of 33 youth with schizophrenia, Werry et al. (1994) indicated that 61% of their sample reported hallucinations (57% auditory), and 55% of their sample reported delusions. The authors also noted that delusions tended to be less well-formed relative to adults. Communication may be impaired in youth with schizophrenia, with Caplan (1994) noting three patterns of deficits among 31 children with schizophrenia, including impaired discourse skills, loose associations, and illogical thinking. In a relatively large study of 132 youth with psychosis, Biederman et al. (2004) reported that 44% of the sample suffered from delusions, and 85% hallucinations. Auditory hallucinations were most common (79%), followed by visual (54%), tactile (23%), and olfactory (13%). Within delusions, delusions of persecution and reference were most common (27% and 23% respectively). Approximately 20% of youth expressed other symptoms such as incoherence, loosening of associations, flat affect, and inappropriate affect. Diagnostic methods

Developmental considerations may influence diagnostic decisions when evaluating children for schizophrenia, as the presentation quality of symptoms may differ from those seen in adulthood. For instance, some researchers suggest that negative symptoms are less common among children with schizophrenia, and delusions and hallucinations may be less well developed and involve more childlike themes (monsters or toys versus religious or sexual themes) (Volkmar, 2001). Evidence suggests that when accounting for developmental considerations, schizophrenia in children can be reliably diagnosed (Werry, 1992). Diagnostic interviews, such as the Schedule for Affective Disorders and Schizophrenia for School-Age Children, are useful in increasing the reliability and validity of the diagnosis (Kaufman et al., 1997). This interview provides the assessor developmentally tailored questions assessing for symptoms associated with schizophrenia and other disorders as expressed in childhood. Neuropsychological deficits

In addition to symptom presentation, youth with schizophrenia demonstrate a host of neuropsychological deficits. Most of these deficits are similar to those seen in adult schizophrenia. Kumra et al. (2000) reported that children with schizophrenia (average age 14.4 years) consistently demonstrated one to two

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standard deviation impairment across a range of neuropsychological tests (general IQ, achievement, attention, executive functioning, memory, motor skills, etc.). Likewise, in a review, Asarnow and Asarnow (2003) reported a similar array of neurocognitive deficits among children with schizophrenia (attention, visualmotor coordination and fine motor speed, executive functioning, and various forms of memory). Several studies have looked at particular patterns of neurocognitive deficits among young people with schizophrenia. A study of 17 adolescents with schizophrenia supported the global cognitive dysfunction findings, and specifically noted larger differences between cases and controls on working memory and attention (Kenny et al., 1997). Oie and Rund (1999) also reported similar global impairment among 19 adolescents with schizophrenia compared to control groups with and without other psychiatric conditions (Attention-Deficit Hyperactivity Disorder). The authors indicated particular deficits in the areas of abstraction, visual memory, and motor functioning. Among never medicated, first episode adolescents with psychosis (most of whom either subsequently developed schizophrenia or were deemed to have the disorder after further review of history), Brickman et al. (2004) reported global neuropsychological deficits, with the greatest deficits observed in executive functioning, attention, and memory. The authors also reported relatively intact language functioning, a finding also reported by Kenny et al. (1997). The findings from Brickman et al. (2004) are of particular interest as subjects were free of the potentially confounding impacts of neuroleptic treatment and long duration of illness. Collectively, these findings strongly support global neurocognitive impairment among youth with schizophrenia, with specific areas of relative deficits seeming to fall in the domains of memory (of varying type), attention, executive functioning, and perhaps motor functioning. Psychosis not otherwise specified

Interestingly, studies of neurocognitive functioning reveal that youth with schizophrenia resemble a potentially related group of youth not meeting full criteria for the disorder. As with adults, youth with psychotic symptoms not reaching diagnostic threshold for full schizophrenia are often diagnosed with psychotic disorder NOS. Neurocognitive reports comparing youth with childhood-onset schizophrenia to a group of youth with psychotic disorder NOS suggest few meaningful differences in neurocognitive profiles (McClellan et al., 2004). Given similarities in neurocognitive performance and symptoms presentations, some researchers speculate that psychotic disorder NOS may be a less severe condition genetically related to childhood-onset schizophrenia (Kumra et al., 2000).

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Course and progression The premorbid course of childhood-onset schizophrenia appears associated with an array of functional deficits. Kolvin et al. (1971), as well as others (AlaghbandRad et al., 1995; Hollis, 1995; Nicolson et al., 2000; Russell et al., 1989), report high rates of developmental delays including speech and language and social peculiarities. A more recent study by Nicolson and colleagues (2000) reported that over half of the 49 children with schizophrenia in their sample had premorbid impairment in motor, social, and speech and language functioning. While there was no comparison group in this study, the rate of impairment seems strikingly high and suggests a developmentally deviant premorbid course. The course of childhood schizophrenia once diagnosed is under studied and varies by individual. As seen in adult schizophrenia, it is believed that the progression roughly follows a period of deterioration, followed by stabilization, and hopefully improvement (Merry & Werry, 2001, p. 280). Based on a review of several studies of varying methodology tracking outcome among youth with a schizophrenia diagnosis, reviews by Asarnow, Tompson, and McGrath (2004) and McClellan et al. (2001) indicate that about one-half of youth with schizophrenia remain severely impaired over time, with the other half showing a variable course with some improvement in psychotic symptoms. A longitudinal descriptive report of psychosocial outcome among adolescents with schizophrenia by Lay et al. (2000) indicated that, among those available for follow-up at ten or more years, 83% had at least one re-hospitalization, 57% showed at least moderately vocational impairment, and 75% were supported by either their parents or public means. Generally, most evidence suggests that the majority of youth with schizophrenia show a slower onset and chronic pattern as opposed to an acute psychotic break (Asarnow et al., 2004). While difficult to compare directly, Nicolson et al. (2000) suggest that the premorbid course for individuals with childhood-onset schizophrenia may be worse than the premorbid course for adult-onset schizophrenia. Additionally, it seems that the earlier the onset, the worse the prognosis (Merry & Werry, 2001, p. 294). Among youth with psychotic disorders, those with worse premorbid characteristics and earlier onset tend to have worse outcomes. McClellan and colleagues note that poor premorbid adjustment, negative symptoms, and low IQ predicted poor outcome among youth with psychotic disorders (McClellen et al., 1999; Werry & McClellan, 1992). Similarly, Nicolson et al. (2001) reported that high levels of psychopathology, cognitive deficits, and motor impairments predicted poor outcome among a sample of 26 youth with psychotic disorder NOS. Collectively, these findings suggest that schizophrenia spectrum disorders

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in childhood appear associated with poor long-term outcome, with the worst outcomes associated with earlier onset, poor premorbid functioning, and impairment at intake (Asarnow et al., 2004; Gillberg, Hellgren, & Gillberg, 1993; Werry et al., 1991).

Suspected neuropathology A series of studies from the Child Psychiatry Branch of the National Institute of Mental Health (NIMH) suggest reduction in cerebral volume and pervasive pattern of brain deterioration in childhood-onset schizophrenia. Similar to adult schizophrenia, individuals with childhood-onset schizophrenia tend to have ventricular enlargement and progressive loss of gray matter (4% reduction in cerebral volume) (Rapoport et al., 1997; Rapoport et al., 1999). Confirming initial findings, Sowell et al. (2000) identified a similar reduction in gray matter and enlarged ventricles in an independent sample. Although limited in number, a handful of imaging studies suggest various other brain abnormalities seen in childhood-onset schizophrenia. Findings include abnormalities in the corpus callosum (Jacobsen et al., 1997; Keller et al., 2003; Sowell et al., 2000), and subcortical structures such as the vermis (Jacobsen et al., 1997) and basal ganglia (Blanton et al., 1999). Several follow-up studies from the NIMH group identify brain deterioration over time among youth with schizophrenia. For instance, Giedd et al. (1999) reported progressive brain deterioration among youth with schizophrenia, noting decreases in cerebrum and hippocampus volume, and increases in the lateral ventricles. The rates of deterioration appeared to level off as youth entered adolescence. Thompson (2002), discussing data from this project, noted a relation between rate of temporal cortical loss and positive symptoms, as well as a relation between gray matter loss in the frontal cortices and negative symptoms. In a more detailed and recent analysis, including additional subjects from the NIH project, Sporn et al. (2003) identified progressive loss in the frontal and temporal cortices across multiple assessments, suggesting neural deterioration spreading from parietal regions towards the cortex. Similar to the earlier study, the authors also noted that gray matter loss appeared to level off with age. Gray matter loss was related to premorbid impairment but, in contrast to an earlier report by Thompson (2002), it was also related to greater clinical improvement as measured by the Brief Psychiatric Rating Scale and the Scale for the Assessment of Negative Symptoms scores. The authors speculate that perhaps ‘‘compensatory ‘pruning’ of malfunctioning neural circuits’’ might in part begin to explain the relation

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between clinical improvement and brain volume loss (Sporn et al., 2003, p. 2188). Future imaging work among youth with schizophrenia is needed to replicate these early studies, as well as provide additional findings with respect to brain structure, function, and change over time. Related to imaging studies of neuropathology is the study of neurological functioning. Using a subsample from the above-described NIH study, Karp et al. (2001) noted high rates of neurologic abnormalities, including elevated rates of primitive reflexes and other abnormalities relative to controls, that persisted with age among youth with childhood-onset schizophrenia. These deficits suggest hemispheric inhibition of the brainstem, and strongly support general deficiencies in normal maturation. According to the authors, results from the study highlight the role of genetically mediated early central nervous system insults in the etiology of childhood-onset schizophrenia. Suspected neurochemical abnormalities Little is known about specific neurochemical abnormalities underlying schizophrenia in childhood. Perceiving childhood-onset schizophrenia as a related and continuous disorder with adult schizophrenia allows speculation that neurochemical abnormalities present in adult schizophrenia are similar to those found in childhood schizophrenia (e.g., dopamine, glutamate, serotonin). Much of the evidence for the influence of dopamine in adult schizophrenia comes from the fact that patients respond favorably to anti-dopaminergic medications and that dopamine agonists can cause psychotic symptoms among non-psychiatric individuals. This same pattern is true in children. While enough evidence exists to suggest that dopamine plays a role in childhood schizophrenia, specifics of that role are not understood. The few studies conducted in this domain with children report similar patterns of results as those typically found in adult schizophrenia (Asarnow & Karatekin, 2001). Genetic factors Early onset of schizophrenia seems associated with high genetic loading for the disorder. Research has borne out this relation, noting an increased risk of schizophrenia among the relatives of children with schizophrenia (Asarnow et al., 2001; Sham, MacLean, & Kendler, 1994). Asarnow et al. (2001) reported that the relatives of children with schizophrenia in their study were 17 times more likely to have a schizophrenia spectrum disorder in relation to controls. This risk is obviously far greater than the risk in the general population, as well as greater than that found in similar studies of relatives of adults with schizophrenia

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(three to six times more likely among relatives of adults with schizophrenia). Findings from this report suggest an increased genetic component to schizophrenia in childhood over and above that found in adult schizophrenia. In a similar report, Nicolson et al. (2003) advanced this line of study by including relatives of patients with adult-onset schizophrenia as a control group. Findings confirmed speculations made by Asarnow et al. (2001) that youth with schizophrenia are more likely to have relatives with a schizophrenia spectrum disorder in relation to adults with typical-age-of-onset schizophrenia. Collectively, these findings support the strong role of genetic contributions to early-onset schizophrenia. Other risk factors Obstetrical complication

In two independent samples, Matsumoto et al. (1999; 2001) reported an increase in obstetrical complications (OCs) associated with early-onset schizophrenia (16 years old and younger) in relation to control subjects. In both studies, individuals with obstetrical complications were over three times more likely to develop childhood-onset schizophrenia relative to psychiatric controls. This finding is consistent with other reports suggesting a link between OCs and earlier age of onset in adult schizophrenia (Rosso & Cannon, 2003), and a wealth of literature suggesting increased OCs among individuals with schizophrenia in general. As seen with other correlates, Matsumoto and colleagues suggest that the similarity in the relation between childhood and adult schizophrenia and OCs indicate continuity between the two disorders. Contrary to the findings from Matsumoto et al. (1999, 2001), Nicolson and Rapoport (1999) did not find an elevation in OCs among individuals with childhood-onset schizophrenia. The comparison group employed by Nicolson and Rapoport, however, was composed of the siblings of the patients who may share genetic risk for OCs, rather than genetically independent controls. Interestingly, however, the percentage of individuals with childhood-onset schizophrenia who had OCs were similar in both studies (34.3% in the Matsumoto et al. (2001) sample, 27.7% in the Nicolson and Rapoport (1999) sample). Treatment Level and cost of care

Schizophrenia in adulthood is associated with high levels of care and high cost for services (Cuffel et al., 1996; King, Singh, & Shepherd, 2000). In our analysis

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of youth with schizophrenia spectrum disorders in Hawaii, we found aboveaverage use of more restrictive levels of care. More restrictive levels of care may reflect that youth with schizophrenia spectrum disorders struggle with more severe problems. Problems faced by these youth may require great environmental resources and possibly put these individuals in danger. It is important to note, however, that results from the service analyses in the Hawaii study suggest that approximately four out of five youth with services procured for schizophrenia spectrum problems were treated in home or community settings. Approximately one half received intensive home and community services and almost all received less intensive outpatient services. In addition to requiring more services, we found that youth with spectrum disorders are financially expensive relative to other youth in the system. The average annual cost per youth with a schizophrenia spectrum disorder in Hawaii was $16,420, a rate nearly twice as high as the average annual cost per youth of others in the system. Schizophrenia is an expensive illness to manage, especially among young people. The above-average use of more restrictive services would seem to highlight an opportunity for the development of evidence-based strategies that support management of schizophrenia spectrum disorders in home and community settings. Presently, intervention with neuroleptic medication is the only empirically supported treatment for early-onset schizophrenia. Although the benefits of psychopharmacology are well documented, the intervention is global and does not specifically target individual areas of concern. Mental health therapists are likely to benefit from structured psychosocial strategies effective in helping youth with schizophrenia spectrum disorders. The efficacy of structured psychosocial interventions for early-onset schizophrenia has not yet been systematically assessed. Evidence from a range of areas, however, suggests that a psychosocial intervention targeting specific symptoms might benefit youth with early-onset schizophrenia (discussed below), especially when used as an adjunct to psychopharmacological intervention. Psychopharmacological treatment

Atypical neuroleptics seem to be the most effective means of treating childhood schizophrenia. Most research has focused on clozapine, with more recent studies beginning to investigate other atypical neuroleptics (Zalsman et al., 2003). As in adults, clozapine seems to offer the advantages of effectively treating both positive and negative symptoms, with less extrapyramidal side effects relative to typical neuroleptics. Less side effects, particularly attenuated extrapyramidal symptoms, generally lead to increased tolerability and medication compliance. Potentially fatal risk, however, is associated with clozapine (e.g., agranulocytosis), and

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therefore clozapine is not recommended as the first option in treating early-onset schizophrenia. Rather, non-clozapine atypical neuroleptics, not associated with fatal risk, are generally recommended. Two open-label studies of other atypical neuroleptics (one of risperidone and the other of olanzapine) have been conducted with youth with schizophrenia, with promising results. While these medications are not associated with life-threatening side effects, most do have some significant side effects, including, among others, some extrapyramidal symptoms, and significant and sometimes distressing weight gain and sedation. Given the rarity of the disorder, medication trials pose formidable methodological barriers that have slowed research in this area. In a recent review of the existing literature, Cheng-Shannon et al. (2004) concluded that atypical antipsychotic medications are in fact useful in treating psychosis among youth. The American Academy of Child and Adolescent Psychiatry practice parameters for the treatment of childhood schizophrenia also express this sentiment. Despite these positive conclusions, Remschmidt et al. (2001) estimated that approximately 15% of childhood-onset patients do not respond to typical or atypical neuroleptics. Additionally, while it appears that pharmacological therapy is useful for youth struggling with psychotic symptoms, little is known about the long-term effects of these medications. Frequent and regular contact with the treating psychiatrist is recommended. Psychosocial treatments

Practice parameters for the treatment of childhood schizophrenia established by the American Academy of Child and Adolescent Psychiatry call for a two-pronged symptom-specific and general-functioning approach to treatment. Specific symptom targeting includes addressing positive and negative symptoms directly, while general functioning refers to more broad social, academic, and family needs. The practice parameters call for a ‘‘comprehensive multimodal approach’’ to treatment (McClellan et al., 2001, p. 145), taking into consideration comorbid conditions and developmental considerations. This position is consistent with one study that systematically investigated a comprehensive community treatment approach for a small group of adolescents with schizophrenia reporting positive effects of working with parents, problem solving skills, and re-integration efforts (Rund et al., 1994). University of Hawaii child and adolescent thought disorders program

The Child and Adolescent Thought Disorders Program at the University of Hawaii at Manoa was established in 2003 to provide comprehensive assessment and psychosocial interventions to youth with schizophrenia spectrum disorders in Hawaii. The program is also designed to increase the understanding of thought

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disorders in youth through systematic collection of information from this population. Funding for this program is provided by the Hawaii Department of Health Child and Adolescent Mental Health Division. The clinic was designed with the American Academy of Child and Adolescent Psychiatry practice parameters in mind and serves as an example of the assessment and psychosocial treatments available for youth with schizophrenia. Assessment

Youth with suspected thought disorders eligible for services in our program participate in a thorough mental health examination. The initial assessment battery provides a thorough diagnostic and neuropsychological evaluation to verify diagnosis and identify relative strengths and weaknesses in functioning. The clinic employs a semi-structured interview designed to assess an array of psychopathology in youth, including psychotic processes (Kaufman et al., 1997). To provide more accurate and complete information, we interview the child, parent, and relevant adults in the child’s life (e.g., teacher, treating therapist, psychiatrist, etc.). Self-report questionnaires from various informants supplement interview information. Assessments particularly focus on identifying behaviors of impairment through interview as well as direct observation to help determine specific treatment goals for subsequent intervention. In addition to the diagnostic and functional components, we also offer a screening of neurocognitive functioning. Domains of functioning assessed include areas identified in the literature as potential deficits for youth with schizophrenia. We employ tests of executive functioning, attention, various forms of memory, and an abridged test of intelligence. The neurocognitive examination allows for an assessment of relative strengths and weaknesses in cognitive functioning and provides information useful for recommendations and treatment planning. Treatment

As mentioned above, there are currently no identified evidence-based psychosocial interventions for schizophrenia among youth. We attempt to systematically study our on-going treatment cases to provide useful approaches to treating other youth with similar conditions. The heterogeneity of the disorder, however, makes generalization from one case to the next difficult. To address the issue of variability of individual presentation, we employ a modular approach to therapy containing specific sections for specific problem behaviors. This approach provides our clinicians with a range of strategies to address target behaviors. Our modules are derived from a range of areas, including: cognitive and behavioral treatment for adult schizophrenia; empirically supported therapies for childhood anxiety, depression, and disruptive behavior disorders; social skills training;

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behavioral treatment for autism; community involvement; and motivational interviewing. Even if symptoms directly associated with symptoms of schizophrenia (e.g., hallucinations and delusions) are resistant to treatment, a modular approach is often effective in treating comorbid and related conditions (e.g., specific phobia of water caused by the delusional fear that evil creatures will drown the client). Family services

Additionally, our clinic also offers family therapy and multifamily therapy (McFarlane et al., 1995). Collateral work with parents and close relatives is essential for the complete care of youth with schizophrenia spectrum disorders. Additionally, multifamily therapy has been demonstrated effective in the treatment of adult schizophrenia. These groups focus on problem-solving strategies and community building between families struggling with similar issues. Family work has an underlying goal of reducing critical or over-protective comments from family members, referred to as ‘‘expressed emotion’’. High levels of expressed emotion are associated with relapse among adults with schizophrenia living with their families (Leff & Vaughn, 1985). The role of families in the lives of youth with schizophrenia spectrum disorders is possibly even more powerful and relevant than among adults with schizophrenia, as young people may be even more dependent on family for support. Related to work with the family is the importance of interdisciplinary coordination of services. Youth with schizophrenia often have many health care providers as team members. In addition to the parent(s), psychiatrists, psychologists, teachers, nurses, social workers, individual skills trainers, occupational therapists, and others are often involved in cases. Working collaboratively with all treatment team members is crucial to the functioning and outcome of the child. For all of our cases, we provide ongoing structured single-case evaluation protocols involving multiple informants for therapists to track the effectiveness of specific interventions. Ongoing monitoring and assessment of progress throughout the course of treatment enhances the ability to determine the most effective techniques for specific symptoms in a particular client and enables the monitoring of overall progress.

Conclusions The field of early-onset schizophrenia holds far more questions than answers. While interest and understanding of the disorder continue to grow, many

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unanswered questions remain. By definition, schizophrenia in childhood is similar to adult-onset schizophrenia in terms of defining symptomatology. Certain correlates and expression of the disorder in youth, however, vary relative to typical-onset schizophrenia. Although rates increase with age, the prevalence of early-onset schizophrenia is rare. This fact, perhaps more than any other, contributes to the limitations in understanding the disorder. Despite the rarity of the condition, schizophrenia in young people can be reliably diagnosed and researched. Research has revealed a preponderance of males relative to females and high rates of comorbidity. Additionally, the course of childhood-onset schizophrenia typically appears worse relative to the adult-onset variant of the disorder, with estimates of nearly half of youth diagnosed having poor outcomes. In line with poor prognosis, in vivo neuroimaging studies tend to show progressive deterioration in the brains of youth with schizophrenia. While research has yet to uncover all causal factors, genetics seem to play a large role in the etiology of the disorder. Consistent with our lack of understanding of the disorder, the field has only begun to identify effective treatments for schizophrenia among youth. Psychopharmacological treatment is an essential component to managing the disorder, but is rarely a cure. Comprehensive wrap-around psychosocial services for the youth and family are also important in helping individuals with this condition. Further research investigating all factors associated with childhoodonset schizophrenia, including the etiology, demographic profile, neurological correlates, and course and progression, may provide hope for future treatment of, and recovery from, this devastating condition. REFERENCES Alaghband-Rad, J., McKenna, K., Gordon, C. T., et al. (1995). Childhood-onset schizophrenia: The severity of premorbid course. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 1273
83. American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders, (4th edn., text version). Washington, DC: American Psychiatric Association. Asarnow, J. R. & Asarnow, R. F. (2003). Childhood-onset schizophrenia. In Child Psychopathology, 2nd edn., ed. E. Mash and R. Barkley. New York: Guilford Press, pp. 486
519. Asarnow, R. F. & Karatekin, C. (2001). Neurobehavioral perspective. In Schizophrenia in Children and Adolescents, ed. H. Remschmidt. Cambridge: Cambridge University Press, pp. 135
67. Asarnow, R. F., Nuechterlein, K., Fogelson, D., et al. (2001). Schizophrenia and schizophreniaspectrum personality disorders in the first-degree relatives of children with schizophrenia: The UCLA family study. US Archives of General Psychiatry, 58(6), 581
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94. Aylward, E., Walker, E., & Bettes, B. (1984). Intelligence in schizophrenia: Meta-analysis of the research. Schizophrenia Bulletin, 10, 430
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22. Kaufman, J., Birmaher, B., Brent, D., et al. (1997). Schedule for affective disorders and schizophrenia for school-age children. Present and lifetime version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child and Adolescent Psychiatry, 36(7), 980
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27.

4

Late-life schizophrenia Katerine Osatuke1, John W. Kasckow2, and Somaia Mohamed3 1

VHA National Center for Organization Development Department of Psychiatry, University of Cincinnati 3 Division of Psychiatry, Cincinnati VA Medical Center 2

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B B B B B B C D B

Epidemiology Schizophrenia in the elderly is a special case requiring special management (Altamura & Elliott, 2003). Unlike the extensive research on schizophrenia in young adults, however, little is known about late-life schizophrenia. In a comprehensive review of schizophrenia research by Heaton and Drexler (1987), only 13 of 100 studies included patients of 50 and older. In 1996, only 6% of schizophrenia studies currently published in leading psychiatric journals focused on the elderly (Jeste, cited in Sajatovic et al., 2002). This knowledge gap represents a serious challenge to the field (Palmer, Heaton, & Jeste, 1999), given the current demographic increase in numbers of the elderly, expected to continue over the coming years. General prevalence of schizophrenia is 0.2
2.0%, the common estimate being 0.5
1.0% (DSM-IV). Due to its usually chronic nature, incidence rates are lower 59

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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(estimated 1 per 10,000 yearly). Prevalence is the same for both genders, but the onset is earlier in men. In the growing numbers of geriatric schizophrenia patients, more will be women, reflecting a general demographic trend (Schultz et al., 1997). Geriatric schizophrenia cases include those with early onset (EOS: prior to the age of 40), late onset (LOS: after 40), and very-late onset schizophrenia-like psychosis (first diagnosis at age 60þ) (Altamura & Elliott, 2003). Prevalence, diagnostic subtype, and gender distribution vary greatly for groups with different age of onset: e.g., the paranoid type is the most prevalent in LOS, while the disorganized and catatonic types seem very rare (Jeste & McClure, 1997). LOS is 2
10 times more frequent in women (Jeste & McClure, 1997); most studies report 2:1 to 4:1 female/male ratio (Lehmann, 2003), in sharp contrast to the greater prevalence of men in EOS. Many EOS patients survive into old age (Jeste & McClure, 1997), representing an estimated 85% of all individuals with schizophrenia in the older age groups (Harris & Jeste, 1988).

Age of onset While DSM-III disallowed diagnosing schizophrenia after the age of 45, DSM-III-R permitted it, specifying ‘‘late onset’’ schizophrenia after the age of 45. DSM-IV did not include the age of onset nor an upper age limit. An estimated 13% of all hospitalized schizophrenia patients are first diagnosed in their 40s; 7% in their 50s; and 3% after 60 (Lacro, Harris, & Jeste, 1993). The ECA study reported a one-year community prevalence rate of schizophrenia of 0.6% in the age range of 45
64, and 0.1
0.5% at 65 and older (Regier et al., 1988). Thus, approximately 23.5% of patients have the symptom onset after 40 years of age (Harris & Jeste, 1988). The LOS/EOS distinction is no longer made in the DSM-IV or ICD-10, due to a lack of qualitative differences in symptoms; nevertheless, it is reflected in much past and current research on later-life schizophrenia. LOS cutoff age has been inconsistent across studies (55
65 years in Europe, 45 years in the USA) (Levy & Almeida, 1994). To address the controversy about whether LOS was a legitimate subtype of schizophrenia (Crespo-Facorro et al., 1999; Howard et al., 2000; Jeste et al., 1998b), an international expert panel reviewed all the available MEDLINE articles on LOS in 2000 and concluded that the diagnosis had face and clinical validity, for patients with onset of illness between the ages of 40 and 60 (Howard et al., 2000). The panel recommended the term very late-onset schizophrenia-like psychosis (VLOSLP), for cases with onset after 60. European investigators have also used the terms paraphrenia and late paraphrenia to refer to LOS and VLOSLP, respectively (Palmer, McClure, & Jeste, 2001). Positive symptoms in EOS, LOS, and VLOSLP are similar, but LOS and

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VLOSLP are more likely to occur in women, manifesting predominantly as persecutory delusions, while EOS manifests as formal thought disorder or affective blunting (Howard et al., 2000). Schultz (2001) advocated adding a distinct subtype of ‘‘true LOS’’ patients, whose pathologic process is the same as in EOS but different from degenerative psychosis. Schizophrenia of middle-age onset (MAOS) may have distinctive characteristics as well. Palmer et al. (2001) described MAOS as a primarily neurodevelopmental but also a distinct neurobiological subtype, largely similar to EOS but less prevalent, and different from EOS in several important ways (predominantly paranoid presentation; less negative symptoms and disordered thinking; more stable cognitive functioning; at least partial improvement in a substantial minority of patients).

Presentation Diagnostic criteria for schizophrenia include positive and negative symptoms (hallucinations, delusions, thought disorder, disorganized or unresponsive behavior; affective flattening, avolition, alogia). Cognitive impairment is prevalent, representing a core characteristic of schizophrenia in all age groups and in particular in the elderly with schizophrenia (Arnold & Trojanowski, 1996). Extending across multiple domains, cognitive impairment is not readily accounted for by a single ability deficit or anatomical region, and is not caused by chronic illness, treatment, or institutionalization (Mohamed et al., 1999). Cognitive dysfunction stabilizes in chronic patients, after the initial deterioration (Jeste & McClure, 1997). Cognitive impairments in this group predict impairments in adaptive function, and constitute better predictors of overall outcome than positive or negative symptoms (Harvey et al., 1997b). Cognitive or neuropsychological performance of older patients with better outcomes consistently does not deteriorate with age; they outperform patients with poor outcomes, even in the absence of symptomatic differences (Harvey, 2001). In the elderly with schizophrenia, instrumental and social skills deficits were more strongly correlated with cognitive impairments than with lack of behavioral control (Harvey et al., 1997b). All schizophrenia groups present with more cognitive deficits than controls, on all tasks except memory retention. However, learning, abstraction, and cognitive flexibility are less impaired in LOS than in EOS (Heaton et al., 1994); impaired pre-morbid educational, occupational, or psychosocial functioning is also less likely in LOS (Lehmann, 2003). LOS is prototypical of chronic psychotic disorders; delusions, often bizarre and persecutory, are its most prominent

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symptom (Jeste & McClure, 1997). Auditory hallucinations, including Schneiderian first-rank symptoms (two voices conversing, thought broadcasting), constitute the second most prominent LOS symptom (Jeste & McClure, 1997). Negative symptoms, loose associations, and inappropriate affect are less severe in LOS than in EOS (Jeste & McClure, 1997). LOS patients are less likely to have formal thought disorder and affective blunting, but they may have more colorful hallucinations (Pearlson et al., 1989). Schizophrenia prodromes include social isolation; impaired role functioning; peculiar behavior; poor hygiene; blunted or inappropriate affect; digressive, vague, overelaborate, or circumstantial speech; odd beliefs or magical thinking, influencing behavior inconsistently with cultural norms; unusual perceptions; and marked lack of initiative. These should represent a clear decrease from prior functioning level
a criterion often difficult to evaluate in the elderly (Jeste & McClure, 1997). Psychotic symptoms in the elderly are more likely to reflect a secondary than a primary psychotic disorder, due to identifiable medical or neurological conditions (Jeste & McClure, 1997) necessitating thorough differential diagnostics. The elderly chronic schizophrenia inpatients (i.e. 65þ) may have more negative and less positive symptoms than the younger patients, but they appear similar on affective symptoms or thought disorder (Soni & Mallik, 1993). Cognitive impairment may be greater in patients with more severe negative symptoms (Davidson et al., 1995). Age-related decreases in positive symptoms, with concurrent increases in negative symptoms, may possibly lead to underdiagnosing and under-treating schizophrenia in the elderly (Sajatovic, Madhusoodanan, & Buckley, 2000). High ratings on the activation factor of the PANSS (hostility, poor impulse control, excitement, uncooperativeness, poor rapport, and tension) are inversely correlated with discharge rates into community in elderly schizophrenic inpatients, independently of other symptoms (White et al., 2004). Poverty of speech is more common and severe in geriatric schizophrenia (Harvey et al., 1997a). Disconnected speech was, however, less common and less severe in older schizophrenics (not due to the lower amount of speech that they produce)
an inconsistency possibly pointing to dissimilar cognitive and biological underpinnings of these two dimensions of communication disorder. Diagnosing geriatric schizophrenia may require additional symptom constructs. In factor analyses of the Scales for the Assessment of Positive and Negative Symptoms (SAPS and SANS) for 45
84-year-old schizophrenia outpatients (McAdams et al., 1997), the SAPS bizarre behavior subscale loaded the highest on the depressive symptom factor (not on positive symptoms). The SANS avolition
apathy subscale loaded both on the negative symptom

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and the depressive symptom factors. Bizarre behavior and apathy may thus represent a separate construct related to depression in older schizophrenic populations. Schizophrenic presentation includes three dimensions (Cohen, 1990): psychopathology (symptoms); organic factors; and social functioning. Psychopathology diminishes with age, except in some subgroups (Cohen, 1990), while cognition declines, and ventricle-to-brain ratio (VBR) increases. The size of social network declines but quality of relationships and coping may increase (Cohen, 1990; Cohen et al., 2000). Since these domains are not correlated, clinical measures and outcomes should be established for them separately (Scherrell et al., 1999); furthermore, they must be separately investigated for geriatric populations. Course and progression Long-term outcome studies (Angst, 1988; Ciompi, 1980; McGlashan, 1988; Moller et al., 1988) do not support the previous view of progressive deterioration in schizophrenia. Cognitive and functional decline characterizing an EOS subgroup is not an obligatory outcome even in EOS (Schultz, 2001). Most deficits develop in the first 4
5 years, and stabilize or improve thereafter (Brier et al., 1992). In LOS, initially prominent positive symptoms diminish significantly with age (Lindamer et al., 1999). New symptoms rarely appear (Cohen, 1995). Some investigators believe that negative symptoms dominate the geriatric clinical presentation, while others report negative symptom remission (Cohler & Ferrono, 1987; McGlashan & Fenton, 1992; Schultz et al., 1997). Schizophrenia tends to have a chronic course (Lacro et al., 1993), possibly stabilizing with age (Cohen, 1995; Palmer et al., 1999). One third of chronic patients undergo remission or are left with only mild symptoms (McGlashan, 1988). Some patients thus show complete remission, others exhibit stable dysfunction, and yet others deteriorate, reaching dementia (Carpenter & Kirkpatrick, 1988; Ciompi, 1980; Winokur, Pfohl, & Tsuang, 1987). Long-term follow-up studies over the last 20 years found notable psychiatric improvement in half to two-thirds of elderly patients, but long-term outcomes were still heterogeneous (Lehmann, 2003). One study (Jeste et al., 2003) found age-related symptomatic decrease, even after controlling for duration of illness
yet, the patients were more impaired than controls. These authors disputed that schizophrenia progressively worsens or improves in elderly outpatients, arguing a stable course. Schizophrenia is associated with shorter life span, largely due to preventable extrinsic factors (e.g., unhealthy lifestyle, poor health care, medication side effects) which underscores a need for integrated models of care, particularly for geriatric schizophrenia (Bartels, 2004). Suicide attempts and death by suicide

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are pronounced in schizophrenia; greater hopelessness and longer duration of illness are important risk factors (Tarrier et al., 2004). Among the 1066 elderly schizophrenics in the Barak, Knobler, and Aisenberg (2004) study, 4.6% have attempted suicide. Except an almost significant gender difference (more males in the suicidal group), no specific geriatric risk factors were identified. Heterogeneity in late-life schizophrenia course is of interest because it may imply different subtypes, with dissimilar biological substrates and/or etiology. This possibility was examined in neuropathological studies reviewed in the following section.

Suspected neuropathology Brain-imaging techniques and post-mortem exams (Weiss & Heckers, 2001; Lawrie et al., 1999) consistently demonstrate structural brain abnormalities in schizophrenia. The temporal and frontal lobes are two implicated regions: reduced hippocampal size and related memory deficits appear well documented. Sachdev et al. (2000) found similar patterns of the same magnitude in the elderly schizophrenics, suggesting a lack of progressive deterioration (since illness duration did not make any difference). Neuropathological studies seek to clarify the neurodegenerative versus neurodevelopmental etiology of schizophrenia (Crespo-Facorro et al., 1999), and particularly the controversy of whether functional psychosis without identifiable organicity can begin over the age of 45 (Krull et al., 1991; Lesser et al., 1993; Miller et al., 1991). If no, then LOS would have a different etiology from EOS. Structural brain imaging shows a lack of gross abnormalities in LOS (CoreyBloom et al., 1995; Symonds et al., 1997), documenting some similarities and some differences in structural abnormalities in LOS and EOS (Crespo-Facorro et al., 1999). Krull et al. (1991) reviewed studies of specific cerebral abnormalities possibly causing schizophrenia-like geriatric psychoses, and studies of etiological non-specific abnormalities. As an example of specific pathology, diffuse ventricular dilatation was discovered in 50% and minimal cortical atrophy in 30% of late-onset patients, age 45þ (Haug, 1962). To illustrate non-specific abnormalities, mean VBR is larger in LOS patients (age 60þ) than in normals (Rabins et al., 1987), whereas ventricular enlargement in LOS appears nonsignificantly greater than in normals (Krull et al., 1991; Rabins et al., 1987). Studies also consistently find age-related increases in abnormal white matter hyperintensities (Krull et al., 1991). Postmortem studies established decreases in volume of the hippocampus or parahippocampal gyrus, decreases in the number and size of

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hippocampal neurons, and abnormal neuron orientation (Trojanowski & Arnold, 1995). Apparently, primary schizophrenia can begin after age 45, while depression and organicity may more commonly cause late-onset psychoses in the elderly (Almeida et al., 1995; Harris & Jeste, 1988). Subgroups of patients with schizophrenia without diagnosable organicity confirm a possibility of functional LOS. Symonds and Jeste (1997), using the MRI, showed a similar frequency, type, and severity of tumors and strokes in LOS and EOS, thus demonstrating that LOS can occur in the absence of gross structural brain abnormalities. Howard et al. (2000) concluded that structural changes in MRI among the schizophrenic elderly were independent of age of onset. The few existing studies exploring abnormal brain connectivity in schizophrenia (Arnold, 2001) established specific abnormalities in synapses and synapserelated proteins and mRNAs. Processes explicating illness-related changes in synaptic density included impaired synapse formation, abnormal synaptic pruning (increased or decreased), increased sprouting of new synapses in response to neural injury, or synapse loss due to degenerative process. Arnold (2001) interpreted these findings as evidence of decreased cerebral reserves in schizophrenics, which create more vulnerability to the usual effects of neurodegenerative lesions accumulated with age. Similar to Arnold’s model of interaction between neurodevelopmental and neurodegenerative factors, Crespo-Facorro et al. (1999) described the schizophrenic brain as neurodevelopmentally vulnerable to the illness, but not necessarily symptomatic until a stressor precipitates the disease. Understanding the course has important implications about the neurobiology of schizophrenia: while deterioration may imply neurodegeneration or progressive neural injury, a stable dysfunction could point to neurodevelopmental etiology. However (Arnold, 2001), these constructs may coexist rather than being mutually exclusive. A lack of neuropathological evidence for degeneration or neural injury has been now established almost without controversy, even for the most severely ill, elderly, and deteriorated patients (Arnold, 2001). These results are compelling because neuropathological abnormalities would be most likely to be revealed in older, more severely affected patients, with a longer duration of illness. Examining late-life schizophrenia thus helps better understand the disorder itself (Cohen et al., 2000).

Suspected neurochemical abnormalities Neurochemical findings in the elderly with schizophrenia have been documented as follows. Studies of synaptic integrity have suggested abnormalities in molecular

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signaling pathways (Arnold, 2001). Talbot et al. (2004) found that presynaptic dysbindin-1 reductions are frequent in schizophrenia, and related to glutamatergic alterations in intrinsic hippocampal formation connections. Arnold et al. (1991) used monoclonal antibodies to study the distribution of a key group of developmentally regulated neuronal cytoskeletal proteins in the hippocampal region of postmortem schizophrenic brain samples of geriatric subjects. They found defects in the expression of MAP2 and MAP5, two microtubule-associated proteins anatomically selective for the subiculum and entorhinal cortex. Arnold et al. concluded that MAP2 and MAP5 could underlie some of the previously described cytoarchitectural abnormalities, impairing signal transduction in the affected dendrites of the schizophrenic brain and ultimately affecting higher cognitive functions. Akbarian et al. (1995) also documented a reduced expression of glutamate decarboxylase (GAD) mRNA containing neurons in the dorsolateral prefrontal cortex (DLPFC) in older patients with schizophrenia. They hypothesized that reduced expression of GAD could seriously affect GABAergic synaptic transmission by neurons (Akbarian et al., 1995). Nishioka & Arnold (2004) found oxidative DNA damage and coordinated cell-cycle activation in elderly patients with pooroutcome schizophrenia. Although several of these preliminary neurochemical findings are promising, more research is clearly needed. Establishing the neurochemical etiology of schizophrenia, and specifically of geriatric schizophrenia, remains an important priority.

Genetic factors An estimated 85% of the variance of risk in schizophrenia is accounted for genetically (Cannon et al., 1998; McGuffin et al., 1994; see also Tsuang, Stone, & Faraone, 2000, for discussion of genetic liabilities for psychosis). Prevalence of schizophrenia approximates 7% in siblings and 3% in parents of all probands with LOS; the family history of schizophrenia is similar for LOS and EOS patients (Jeste & McClure, 1997). Gestational and perinatal complications, minor physical abnormalities (e.g., reduced head circumference reflecting decreased brain growth), and delayed childhood development are common history in schizophrenia patients (Arnold, 2001). Premorbid paranoid or schizoid personality traits are frequent in LOS (Jeste & McClure, 1997). Finally, sensory deficits play a role, particularly in LOS, due to a lack of correction of sensory impairment in elderly patients (Prager & Jeste, 1993).

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Other risk factors Studies of life events and familial stresses have suggested that both environmental and interpersonal factors are important in schizophrenia. Several models (Dohrenwend & Dohrenwend, 1980) incorporate these factors. For example, Patterson et al. (1997) examined the relationship between life events, symptoms of psychosis, and their impact on the life quality in geriatric schizophrenia. Increased psychotic symptoms were related to disturbances of psychosocial environment (decreased support, increased life events, increased avoidant coping). Psychosocial factors were weaker predictors of social maladjustment than psychotic symptoms. Depressive symptoms had a central role in predicting social environment. Social maladjustment greatly mediated the relationship between psychotic symptoms and health-related life quality. Some studies claimed no gender differences in clinical presentation and course of schizophrenia (Lehmann, 2003; Soni & Mallik, 1993), while others (Hafner et al., 1993) reported a more favorable course for women, in particular older women. Possibly, gender differences are more pronounced initially, attenuating with age due to female estrogen decline (Hafner et al., 1998). The estrogen also tentatively explains the greater female ratio in LOS: anti-dopaminergic properties of estradiol protect women from puberty to menopause, but not thereafter (Riecher-Rossler et al., 1994). The female bimodal distribution of onset of schizophrenia, with a large peak in young adulthood and a smaller peak around the menopause (Hafner & an der Heiden, 1997), supports the estrogen hypothesis. Increased psychosocial stressors and longevity additionally explain a greater female ratio in LOS (Jeste & McClure, 1997). The respective contributions of genetic, developmental, and environmental factors have implications for treatment, in particular in the context of aging, as discussed in the next section. Treatment Treating geriatric schizophrenia involves numerous challenges (Chan, Parisier, & Neufeld, 1999; Tariot, 1999; Wynn Owen and Castle, 1999). Frequent comorbidity with chronic medical conditions necessitates multiple medications (Kasckow et al., 2003). Polypharmacy, increasingly common with age, heightens the importance of appropriate medication choice. Older patients are more sensitive to side effects, which affects compliance and tolerability of drugs. Their physiologic status ranges from ‘‘physically fit’’ to ‘‘frail’’, widely influencing their response to medications. As the upcoming increases in the elderly patient

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population forecast growing numbers of older schizophrenia patients, awareness of their unique treatment needs becomes extremely important. Pharmacotherapy is the most common approach to treatment of schizophrenia, general or geriatric. Neuroleptic antipsychotic medications, available since the 1950s, have a long-documented effectiveness with younger patients (Kane & Marder, 1993). Many geriatric schizophrenia patients therefore have a long history of taking neuroleptics. Using neuroleptics with the elderly has modest support, in reduced dosages (Jeste et al., 1993; Mulsant & Gershon, 1993). Side effects of neuroleptics are particularly problematic for the elderly. First, sedation may create extreme confusion or agitation (Salzman & Nevis-Olesen, 1992). Second, orthostatic hypotension may result in sharp blood-pressure decrease when standing up, heightening the risks of fall and traumatic injury. These side effects, caused especially by low potency neuroleptics (chlorpromazine, thioridazine, chlorprothixen), make them non-preferred agents for geriatric schizophrenia. Extrapyramidal side effects (EPS), created by high potency neuroleptics, are especially problematic, since they result from drug action on dopamine receptors, and dopamine availability decreases with age (Salzman & Nevis-Olesen, 1992). EPS include parkinsonism (rigidity, tremor, bradykinesia); akathisia (extreme motor restlessness); and tardive dyskinesia (TD; involuntary, repetitive movements, usually facial but occasionally involving the whole body). Parkinsonism and akathisia develop within the first days of treatment or dosage increase. They may pose treatment problems if mistakenly attributed to psychosis, and addressed through further increases in the medication that had created these effects in the first place (Gregory & McKenna, 1994). TD, 5
6 times more prevalent in geriatric than in younger patients (Jeste et al., 1998a), develops after a long period of neuroleptic treatment. It is a highly noticeable, socially stigmatizing side effect, often irreversible even after full medication withdrawal. Atypical antipsychotics available since the 1990s are the first line of treatment for geriatric patients. Five newer antipsychotic drugs are available for use in the United States. Three of these (risperidone, olanzapine, and quetiapine) are used most readily with late-life schizophrenia. The atypical antipsychotic medications are strong antagonists of serotonin receptors, also possessing central dopamine antagonism. These drugs alleviate the positive and negative symptoms, with lower than conventional rates of EPS and TD (Jeste & McClure, 1997). A slower medication response in the elderly requires much lower starting dosages and increase rates of atypical antipsychotics than used for younger patients (Jeste & McClure, 1997). Risperidone, of the benzisoxazole class of compounds, is the drug of choice for addressing geriatric psychoses and behavioral disturbances in dementia (Comaty & Advokat, 2001). Its efficacy and tolerability are superior to haloperidol

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(Marder & Meibach, 1994). Common side effects in the elderly are dose-related, and include postural hypotension, sedation, and EPS; caution has been raised about a possibly higher incidence of cerebrovascular adverse effects with risperidone use. Risperidone nevertheless currently appears the safest antipsychotic (Finkel, 2004), associated with continued symptom improvement, decreases in pre-existing EPS, and low increases in TD in geriatric patients (Davidson et al., 2000). Olanzapine, structurally related to clozapine, acts on multiple neurotransmitters (dopamine, norepinephrine, serotonin, acetylcholine, histamine). Olanzapine has a low rate of EPS (Beasley, Tollefson, & Tran, 1997; Tollefson et al., 1997). Side effects include sedation, orthostasis, and weight gain. Olanzapine has been found safe for geriatric populations, but patient-specific factors remain important given insufficient research on controlled exposure of elderly patients to olanzapine (Kennedy et al., 2001). Elderly patients switched from conventional antipsychotics to olanzapine (vs. risperidone) appear more likely to complete the switching process, and improve on a brief psychological measure of quality of life (Ritchie et al., 2003). In a randomized, double-blind study of the cognitive effects of newer antipsychotics in the elderly (Harvey et al., 2003), low doses of risperidone and olanzapine improved patients’ cognitive functioning in areas previously shown to be related to functional outcomes, while no such improvement has been documented for conventional antipsychotics, generally (Blyler & Gold, 2002; Harvey et al., 2000) or specifically for the elderly (Harvey et al., 2002). Quetiapine is a dibenzothiazepine derivative active at histaminic and adrenergic receptors (Saller and Salama, 1993), with relatively low activity at dopamine and serotonin receptors (Allen, Cooney, & Lawlor, 1994). Quetiapine has minimal effects on EPS. Clozapine is not recommended for the elderly, both because of its side effects that increase with age (Alvir & Lieberman, 1994), and because too little information on ziprasidone and aripiprazole is available for geriatric populations. Medication compliance is complicated by the single most important factor of taking multiple prescriptions several times per day (Lamy, Salzman, & NevisOlesen, 1992). Geriatric non-compliance manifests in overuse, abuse, forgetting, schedule and dosage alterations
versus deliberate underuse due to side effects and cost considerations, typical of younger adults (Lacro & Jeste, 1997). This requires clear instructions and compliance monitoring in the elderly. Psycho-educational and psychosocial approaches have been reported successful with schizophrenia; however, no known studies have focused on older adults. The fragmentary nature of medical, psychiatric, and psychosocial services for the elderly with schizophrenia is a recognized concern (Cohen et al., 2000; Lehmann, 2003; Scherrell et al., 1999). Their medical vulnerabilities, same as for general

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geriatric populations, are frequently not addressed by their health care, due to inadequate coverage, transportation problems, and lack of awareness of medical needs (Roca et al., 1987). Also, the elderly with schizophrenia under-report medical symptoms, pain, or discomfort (Andreasen, 1987), often manifesting their illness through behavioral and cognitive changes (Scherrell, et al. 1999). Older men and women with schizophrenia may have areas of different treatment needs, caused by gender-related vulnerabilities and typical ages of onset. While women may need more focus on coping with relatively recent onset of psychiatric illness (stress, illness acceptance, or basic illness management), men may require attention to comorbid substance abuse, more prevalent in older men (54%) than in older women (10%) with schizophrenia and schizoaffective disorder (Sajatovic et al., 2002). Based on the estrogen hypothesis (protective effects of estradiol on premenopausal women), several studies examined estrogen replacement therapy as a supplement to antipsychotic medications, in elderly postmenopausal women with schizophrenia (Lindamer et al., 1999).

Conclusions The last decade has witnessed a surge of interest in geriatric schizophrenia, although the topic remains acutely under-researched, with many diagnostic, prognostic, etiological, and treatment questions still unanswered. The upcoming increases in the numbers of the elderly heighten the importance of understanding geriatric schizophrenia. Elderly and younger patients differ in nontrivial ways, possibly requiring additional symptom constructs and different explanatory models. Prevalence, gender distribution, presentation, and course of illness (e.g., deterioration versus stable dysfunction) also vary considerably for geriatric populations with different age of onset. The heterogeneity may reflect different underlying subtypes, with dissimilar biological substrates and etiology. Neuropathological studies examining this possibility have found no evidence of neurodegeneration, but increasingly suggested pathology in brain development and connectivity in geriatric schizophrenia. The constructs of neurodegeneration versus neurodevelopmental etiology may coexist, however, rather than being mutually exclusive. As much as 85% of the risk variance for schizophrenia is attributed to genetic factors. Both environmental and interpersonal factors contribute to precipitating and maintaining schizophrenia in the elderly; e.g., social maladjustment mediates the relationship between psychotic symptoms and health-related life quality. Depressive symptoms are the main predictor of social environment for older schizophrenic patients.

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Genetic, developmental, and environmental factors have important implications for treatment. Atypical antipsychotics are currently the first treatment line for schizophrenia. Risperidone, olanzapine, and quetiapine are the newer drugs most readily used with geriatric patients. Medical comorbidity and polypharmacy are common in the elderly, and age-related changes in drug metabolism and receptor sensitivity underscore the importance of optimal medication choices. The many medical, psychiatric, and psychosocial problems faced by older schizophrenic patients require a holistic treatment approach, accounting for patient factors and special needs and challenges in their age group. REFERENCES Akbarian, S., Kim, J. J., Potkin, S. G., et al. (1995). Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Archives of General Psychiatry, 52, 258
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9.

5

Schizoaffective disorder Daniel J. Abrams1 and David B. Arciniegas2 1 2

University of Colorado School of Medicine University of Colorado School of Medicine, Denver, CO

Summary of findings Grade of evidence Epidemiology Age of onset Clinical presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B Bþ B
C C C C C A


Introduction Schizoaffective disorder is characterized by persistent psychotic symptoms and episodic mood disturbances of the depressive, manic, and/or mixed type. However, there remains a lack of consensus regarding the most parsimonious diagnostic framework within which to consider this condition. Some experts assert that schizoaffective disorder reflects the co-occurrence of schizophrenia and a mood disorder, others argue that it is a variant of schizophrenia in which mood symptoms are prominent, and others view it as a mood disorder in which episoderelated psychotic symptoms persist to varying degrees between mood episodes (Dell’Osso et al., 1993; Marneros, Deister, & Rohde, 1990a, 1991). Others avoid categorical approaches to the description of schizoaffective disorder, and instead regard psychosis and emotional dysregulation as dimensional variables that are expressed to greater or lesser degrees among persons with neuropsychiatric symptoms (Liddle, 2001). In this view, schizophrenia in its ‘‘pure’’ form represents 78

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a condition at the severely disordered end of the psychosis continuum and at the normal end of the emotional regulation continuum, bipolar disorder represents the converse of schizophrenia in these regards, and schizoaffective disorder represents a condition in which patients experience symptoms towards the disordered ends of both continua. Such differences in theoretical orientation pervade the clinical and research literature regarding schizoaffective disorder, making difficult the development of a clear clinical and neurobiological framework within which to consider this condition. Historical background

The controversy regarding the optimal formulation of schizoaffective disorder is a longstanding one. Jacob Kasanin is credited with the first description of this condition in 1933 (in reprint as Kasanin, 1994). His formulation of this condition emphasized the combination of symptoms of schizophrenia and also mood (or, in the nosology of his era, ‘‘affective’’) disturbances. Over the following six decades, more than 24 (ostensibly) different definitions of schizoaffective disorder were developed (Winokur, Black, & Nasrallah, 1990), each ascribing greater or lesser weight to either the schizophrenia-like or mood-disorder-like features of this condition. In the first of several efforts to distinguish schizoaffective disorder as a unique clinical condition, the Research Diagnostic Criteria (RDC) (Spitzer, Endicott, & Robins, 1978) described schizoaffective disorder as a condition in which psychotic and mood symptoms sometimes occurred concurrently but in which psychotic symptoms also persisted for at least 1 week in the (relative) absence of mood symptoms. Two diagnostic sub-groups were described on the basis of the quality of the most prominent types of mood symptoms: cyclical, or bipolar, and depressive. The occurrence of at least some degree of depressive symptoms or psychotic ‘‘excitement’’ experienced by persons with schizophrenia presented a substantial diagnostic challenge for clinicians: at what point are mood symptoms among persons with schizophrenia of sufficient prominence to merit a schizoaffective disorder diagnosis? Conversely, how ‘‘absent’’ do those symptoms need to be in order to describe the patient as schizophrenic rather than schizoaffective? Further, to what degree must mood symptoms remit in order to regard inter-episodic persistence of psychotic symptoms as evidence of schizoaffective disorder rather than an incompletely resolved psychotic mood disorder? As Berner and Simhandl (1983) note, leaving poorly defined the severity of mood symptoms required for the diagnosis of schizoaffective disorder results in a more liberal assignment of this diagnosis than does the application of more restrictive diagnostic criteria.

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The DSM-III-R (1987) attempted to refine the diagnosis of schizoaffective disorder by requiring the persistence of psychotic symptoms for at least two weeks beyond the resolution of mood symptoms. Clarifying this further, Marneros et al. (1989) suggest that the diagnosis of schizoaffective disorder be made only when the mood symptoms, when present, are of an overt melancholic or manic quality, and that clinicians should not infer the need to assign a schizoaffective disorder diagnosis to a patient with schizophrenia simply because of the development of relatively minor depressive symptoms or euphoria alone. Beyond these refinements, however, little additional change has been made to this formulation of schizoaffective disorder in subsequent editions of the DSM or in American psychiatric research endeavors. Epidemiology Incidence and prevalence

The DSM-IV-TR cites, without reference, prevalence for schizoaffective disorder less than schizophrenia. Consistent with that estimate, published reports suggest a prevalence of 0.2
1.1% among adults (Marneros, 2003; Scully et al., 2004). However, the frequency of schizoaffective disorder among psychiatrically hospitalized adults is considerably higher (9%) (Zarate et al., 1997). Most studies suggest that schizoaffective disorder occurs less often than either schizophrenia or bipolar disorder. For example, Marneros, Deister, and Rohde (1990b) and Scully et al. (2004) observed schizoaffective disorder to be less common in the population by half when compared to schizophrenia and by two-thirds when compared to type I bipolar disorder. By contrast, Benabarre et al. (2001), in a study of 138 outpatients, report nearly identical rates of schizoaffective disorder and schizophrenia, each of which was slightly half as common as type I bipolar disorder. This wide range of prevalence estimates appears to reflect differences in ascertainment methods, including those arising from population-based vs. hospital-based subject recruitment, the periods over which such assessments are made (i.e., cross-sectional vs. longitudinal), and whether such assessments are made prospectively using clinical interview or retrospectively by chart review (Marneros et al., 1989; Marneros et al., 1991). Among children with psychotic disorders, schizoaffective disorder appears to be a relatively rare occurrence (Werry, McClellan, & Chard, 1991). However, estimating the frequency of schizoaffective disorder among children and adolescents is complicated by a relatively lower symptom/diagnosis stability over time than among adults (Hollis, 2000; McClellan & McCurry, 1999), the relatively high co-morbidity of intellectual disabilities (Friedlander &

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Donnelly, 2004), and as-yet uncertain effects of both substances of abuse and/or medications on clinical presentation among persons in this age range (Malla, Norman, & Scholten, 2000). Although firm estimates of the incidence and prevalence of schizoaffective disorder remain elusive, the literature suggests that it probably occurs no more often than either schizophrenia or bipolar disorder, is most likely less common than both of these conditions, and in all likelihood occurs less often than the frequency with which it is diagnosed in common clinical practice would suggest. The epidemiologic data is insufficiently developed for the purpose of drawing conclusions regarding the conceptualization of schizoaffective disorder as a unique clinical condition, a condition in which schizophrenia and bipolar disorder are comorbid, or instead as a variant of one or the other of these two other major mental illnesses.

Age of onset Schizoaffective disorder exhibits a relatively broad age of onset among adults (del Rio Vega & Ayuso-Gutierrez, 1990; Stieglitz & Helmchen, 1990). For example, Marneros et al. (1990b) prospectively studied by interview and record review approximately 300 subjects divided nearly equally into three groups (schizophrenia, mood disorders, and schizoaffective disorder). Approximately one third of people with schizoaffective disorder developed this condition prior to age 25, one third did so after age 35, and one third became ill in the intervening decade of life. Accordingly, the median age of onset among people with schizoaffective disorder was 29.5 years, while the median ages of onset for schizophrenia and bipolar disorder were 25 and 35 years, respectively. The observation of both later onset in comparison to schizophrenia and earlier onset in comparison to bipolar disorder is a relatively common one in studies that separate adults with schizoaffective disorder from these other diagnostic groups (Angst & Preisig, 1995; Dell’Osso et al., 1993). Although pediatric onset of schizoaffective disorder is uncommon, the age at which this illness first occurs does not appear to differ from that of pediatric-onset schizophrenia or bipolar disorder. When these illnesses develop among children and adolescents, the mean age of onset is approximately 14 years (Werry et al., 1991). The available evidence suggests that schizoaffective disorder differs from schizophrenia and bipolar disorder with respect to age of onset in its adultonset forms, but the interpretation of that evidence is complicated. If schizoaffective disorder represents simply a co-occurrence of schizophrenia and bipolar

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disorder, its age of onset should be nearly identical to schizophrenia (i.e., relatively young). Similarly, if schizoaffective disorder is a psychotic mood disorder with incomplete inter-episodic resolution of psychotic symptoms, then its age of onset should be most similar to that of the primary mood disorders (i.e., relatively older). It appears that each of these scenarios reflects age of onset in about one third of persons with schizoaffective disorder, but fails to describe adequately the age of onset in the remaining third. That the age of onset of schizoaffective disorder both overlaps in many cases with those of schizophrenia and mood disorders and also distinguishes schizoaffective disorder from these other disorders in others cases suggests the possibility that schizoaffective disorder may sometimes represent a schizophrenic illness in which prominent mood disturbances develop, a unique illness in some cases, and a psychotic mood disorder with incomplete inter-episodic resolution of psychotic symptoms in others. Gender

Marneros et al. (1990b) report that two thirds of people with schizoaffective disorder are female, a finding that is consistent with other reports examining this issue (Angst, Felder, & Lohmeyer, 1980; Lenz et al., 1991). There is, however, insufficient data from which to draw firm conclusions regarding gender differences and the role of gender in the development of schizoaffective disorder. Clinical presentation The clinical presentation of schizoaffective disorder varies considerably between and within individuals, and may include nearly ‘‘pure’’ psychotic presentations, similarly ‘‘pure’’ mood symptom presentations, and presentations in which there is an admixture of psychotic and mood symptoms. This variability is reflected in the complexity of the DSM-IV-TR criteria for this diagnosis. First, a disturbance of thought that includes two (or more) of the ‘‘positive’’ symptoms of schizophrenia (i.e., delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior) for a significant portion of time during a one-month period (or less if successfully treated) is required. Mood episodes meeting diagnostic criteria for major depressive episodes (in which depressed mood is a required feature), manic episodes, and/or mixed episodes also must be present for a substantial portion of the total duration of the active and residual periods of the illness. Finally, the diagnosis of schizoaffective disorder requires the presence of delusions or hallucinations for at least two weeks in the absence of prominent mood symptoms (i.e., symptoms meeting DSM diagnostic criteria). As these criteria suggest, patients may present with some or all of these symptoms

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at various times during the course of their illness. The clinical features of schizoaffective disorder will, when viewed only in cross-section, overlap considerably with schizophrenia and other psychotic disorders, major and minor mood disorders, and other neuropsychiatric syndromes (Fabisch et al., 2001; Taylor & Amir, 1994; Whaley, 2002). Accordingly, the diagnosis of schizoaffective disorder entails not only a careful evaluation of the clinical features at the time of any single presentation but also over the entire period of the illness. Course and progression Accordingly, a discussion of the clinical presentation of schizoaffective disorder cannot be divorced from one of the natural history of this condition. Since the clinical features of schizoaffective disorder vary considerably over time in any given patient, establishing a diagnosis of schizoaffective disorder entails accurate characterization of presenting features across multiple points in time. While it may be difficult to conduct this sort of extended evaluation in an era of medical care that imposes limits on clinician time for this purpose, failing to do so will in many cases result in inaccurate diagnosis (Benabarre et al., 2001; Fogelson et al., 1991; Schwartz et al., 2000; Taylor & Amir, 1994; Werry et al., 1991; Whaley, 2002). Assuming that the diagnosis has been made with certainty, the literature regarding natural history and functional outcomes in this population is at times contradictory. Some studies describe the symptomatic and long-term functioning of people with schizoaffective disorder as more like (or worse than) that associated with schizophrenia (Benabarre et al., 2001; Harrow et al., 2000). Others suggest that the long-term symptomatic and functional prognosis associated with schizoaffective disorder is better than that of schizophrenia (Marneros et al., 1989; Tohen et al., 2000) but worse than that of the mood disorders (Benabarre et al., 2001; del Rio Vega & Ayuso-Gutierrez, 1990; del Rio Vega & Ayuso-Gutierrez, 1992). The variability of these observations prompts concerns regarding the accuracy of diagnostic group assignments at the time of entry into the studies of the natural history of schizoaffective disorder. Moreover, other factors such as substance abuse, rapid cycling, family history, and pre- and post-morbid occupational functioning (Nolen et al., 2004), among others, may interact with diagnosis in the determination of the long-term outcome (i.e., natural history) of persons with schizoaffective disorder and are not routinely incorporated into studies of this issue. These cautionary notes notwithstanding, the present review suggests that schizoaffective disorder is associated with more frequent episodes of illness (including both psychotic and mood recurrences), less persistence of delusions,

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and better social adjustment than schizophrenia, and is on balance more similar with respect to natural history to mood disorders than to schizophrenia. Suspected neuropathology The heterogeneity of epidemiological findings regarding schizoaffective disorder is paralleled by a similar degree of heterogeneity in neurobiological findings, regardless of the specific neurobiological aspect under investigation of such studies. Not surprisingly, persons with schizoaffective disorder demonstrate neurobiological abnormalities that distinguish them consistently from healthy comparison subjects. However, these studies only occasionally offer evidence that distinguishes schizoaffective disorder from schizophrenia and/or mood disorders, and particularly bipolar disorder. Whether this reflects a true lack of neurobiological distinction between schizoaffective disorder and these other conditions remains a matter of uncertainty, as very few of these studies attempt to make such distinctions. However, readers should be aware of these issues in study design prior to formulating their own conclusions regarding the neurobiology of schizoaffective disorder in its own right and neurobiological differences, if any, between schizoaffective disorder, schizophrenia, and/or bipolar disorder. Neuropsychological findings

Schizoaffective disorder is associated with impairment in frontally mediated cognition including working memory, alternating attention, information recall, category generation and shifting, abstraction, and motor planning (Brenner et al., 2003; Bryson, Bell, & Lysaker, 1997; Bryson et al., 2002; Gooding and Tallent, 2002; Manschreck et al., 1997; Mitrushina, Abara, & Blumenfeld, 1996). Only rarely was schizoaffective disorder associated with better performance on such tests than schizophrenia (Goldstein, Shemansky, & Allen, 2005; Stip et al., 2005), and data with which to compare the neuropsychological performance of people with schizoaffective disorder to those with bipolar disorder is lacking. Neuroimaging

The neuroimaging literature regarding schizoaffective disorder has, for the most part, employed volumetric magnetic resonance imaging structural techniques, with a few others extending observations to include diffusion tensor imaging and magnetic resonance spectroscopy (Ardekani et al., 2003; Buchanan et al., 2004; Cannon et al., 2002; Keshavan et al., 2003; Prasad, Rohm, & Keshavan, 2004; Stone et al., 2005; Szeszko et al., 2005; Van Erp et al., 2002). Collectively, these studies suggest that schizoaffective disorder is associated with reductions in cerebral

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volumes, particularly in temporal (including medial temporal) and frontal regions, including both gray and white matter. The most consistent area of abnormality across these studies is the medial temporal lobe (i.e., hippocampus and parahippocampal gyri). The pairing of bipolar disorder and schizoaffective disorder in some of these studies and schizophrenia and schizoaffective disorder in others leaves uncertain the distinction between these disorders on the basis of neuroimaging. Electrophysiology

Schizoaffective disorder is associated with abnormal event-related potentials (P50, N100, N400, CNV, and others), auditory M100 localization, somatosensory M20 localization, middle ear muscle activity, and eye movements (Benson et al., 1996; Borenstein et al., 1988; Brenner et al., 2003; Bruder et al., 1998; Kathmann et al., 2003; Kayser et al., 1999; Kayser et al., 2001; Kumar & Debruille, 2004; Lieberman et al., 1993a, b; Olincy & Martin, 2005; Reite et al., 1999; Teale et al., 2000). As with the other categories of neurobiological investigation described in this chapter, subjects with schizoaffective disorder were only rarely studied independently and instead were most often included among groups of subjects with other psychoses (i.e., schizophrenia or bipolar disorder with psychotic features). Two studies (Boutros et al., 1997; Inui et al., 1998) suggest findings of greater similarity between subjects with schizoaffective disorder and bipolar disorder with psychotic features than schizophrenia. Conversely, Olincy & Martin (2005) observed P50 nonsuppression among persons with bipolar disorder with psychotic features and those with schizoaffective disorder, but not among those with bipolar disorder without psychotic features. When viewed in the context of prior studies demonstrating P50 nonsuppression among persons with schizophrenia, this observation would suggest that this electrophysiologic abnormality is associated with psychosis across conventional diagnostic boundaries. Collectively, these observations argue against conceptualizing schizoaffective disorder as a unique entity, at least as viewed from the perspective of electrophysiology, and instead suggest that the presence of psychosis is associated with electrophysiologic abnormalities regardless of whether that psychosis is persistent or episodic. Suspected neurochemical abnormalities Neuroendocrinology

The neuroendocrinology of schizoaffective disorder is the least developed area of neurobiological inquiry, consisting of only three studies to date, all of which

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focused on growth hormone abnormalities in this condition. Among these, Mokrani et al. (2000) observed a difference between subjects with schizoaffective disorder and schizophrenia with respect to growth hormone response to stimulation with clonidine, with the former group more closely resembling subjects with major depressive disorder and the latter demonstrating a response most like that of healthy comparison subjects. However, the studies of Kumar et al. (1993) and Lieberman et al. (1993b) demonstrated similar patterns of growth hormone response to pharmacologic challenge among persons with schizoaffective disorder and schizophrenia. Whether neuroendocrinological abnormalities are functionally significant and/or a means by which to distinguish schizoaffective disorder from other major mental illnesses requires further investigation. Neurochemistry

Meltzer, Arora, & Metz (1984) reviewed studies of the neurochemistry of schizoaffective disorder performed prior to 1984 and concluded that this condition bore similarities to both schizophrenia and bipolar disorder. Specifically, studies of CSF NE levels, PGE1 adenyl cyclase levels, and platelet 5HT content of schizophrenia and schizoaffective disorder suggested similarities between these conditions, whereas platelet 5HT shows similarities between bipolar disorder and schizoaffective disorder but not schizophrenia. Since that time, schizoaffective disorder has been associated with a variety of functionally significant neurochemical abnormalities (Faustman et al., 1999; Laruelle et al., 1993; Sharma et al., 1998). However, none of these studies offer data with which to separate schizoaffective disorder from schizophrenia or bipolar disorder. This remains an understudied aspect of all of these conditions and additional investigation is needed prior to reaching any conclusion regarding the nature of neurochemical abnormalities specific to schizoaffective disorder. Genetic factors Studies of the genetics of schizoaffective disorder have only in rare circumstances been performed in a manner that permits identification of features unique to this condition; instead, subjects with this condition have been included in studies of schizophrenia or bipolar disorder in such a way that the genetic features of this condition, if any, are opaque to explanation with the available data (Dick et al., 2003; Giouzeli et al., 2004; Kirov et al., 2004; Liu et al., 2005; Segurado et al., 2003; Skol et al., 2003; Staddon et al., 2005; Ujike et al., 2001; Wijsman et al., 2003). Among these studies, only Hodgkinson et al. (2004) demonstrate a finding unique

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to schizoaffective disorder, namely a decreased frequency of the common haplotype of intron 1/exon 2 and increase in exon 9 of DISC1. Additional studies of the genetics of schizoaffective disorder are needed in which this condition is considered separate from (or in comparison to) schizophrenia and bipolar disorder. Treatment Given the substantial overlap in clinical and neurobiological features between schizoaffective disorder and both schizophrenia and bipolar disorder, it is not surprising that the treatment of this condition overlaps considerably with these other conditions. Unfortunately, studies describing the treatment of schizoaffective disorder alone are few (Tohen et al., 2001; Vieta et al., 2001). The available data suggests that atypical antipsychotic medications are useful for the treatment of both psychotic and mood symptoms in this population, regardless of whether mood symptoms are manic or depressed (Baethge et al., 2004; Davis & Chen, 2004). Lithium and carbamazepine are also useful agents for treatment of the mood symptoms of people with schizoaffective disorder, although the concept of polypharmacy in the treatment of people with this condition may require reconsideration. For example, Keck, McElroy, and Strakowski (1996) suggest that among agitated schizoaffective patients, antipsychotic medications were more effective than lithium, and among depressed schizoaffective patients combined treatment with antipsychotic medications and antidepressants was no more effective than treatment with antipsychotic medications alone. Although other studies suggest that agents specific to the mood symptoms (i.e., lithium, carbamazepine, antidepressants) and psychotic symptoms (typical or atypical antipsychotics) are required for optimal treatment, it is possible that atypical antipsychotic medications with mood-stabilizing properties such as risperidone, olanzapine, and quetiapine may be sufficient to permit monotherapy with these agents in at least some people with schizoaffective disorder (Baethge et al., 2004; Levinson, Umapathy, & Musthaq, 1999). Additionally, emerging evidence suggests that some atypical antipsychotic agents (i.e., olanzapine, risperidone, and ziprasidone) may also afford improvements in cognition among persons with schizoaffective disorder (Bilder et al., 2002; Harvey, Siu, & Romano, 2004). Additional studies are needed to determine whether such improvements are functionally significant and also whether there are diagnosis-specific differences in the degree of cognitive improvement, if any, afforded by these agents.

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Conclusions The concept of schizoaffective disorder is anchored firmly in its historical conceptualization as a disorder in which both psychotic and mood symptoms manifest in a manner that bears some resemblance to schizophrenia and to bipolar disorder but that is nonetheless distinct from both of these conditions. This assumption has been questioned repeatedly in modern psychiatric discourse, and the available data leaves unanswered the matter of whether schizoaffective disorder is a unique clinical condition. In a psychiatric nosology that requires categorical distinction between conditions, schizoaffective disorder fits reasonably well
more often than not
into either the psychotic or mood disorder categories when attempting to distinguish patients in these categories from healthy comparators and those with non-psychotic mood disorders. When psychosis is the focus of an investigation, schizoaffective disorder is generally found to be similar to schizophrenia with respect to epidemiology, neurobiology, and treatment. By contrast, when studies focus on mood symptoms, schizoaffective disorder is often found to be similar to bipolar disorder with psychotic features. When a categorical approach to diagnosis is used to classify schizoaffective disorder apart from schizophrenia and bipolar mood disorders, only rarely do published findings support such a distinction. We suggest that it is this categorical approach to the diagnosis and study of schizoaffective disorder that limits the quality of the evidence regarding this condition (See Summary of Findings table). While the studies described in this chapter are, in general, of high quality with respect to the scientific question they attempt to address, the general tendency in them to include subjects with schizoaffective disorder among those with either psychosis (i.e., schizophrenia) or mood (i.e., bipolar) disorders limits severely our ability to draw conclusions regarding the nature of this condition both intrinsically and also with respect to the features, if any, that distinguish it reliably from these other conditions. A more productive approach to the study of schizoaffective disorder may be afforded by reconfiguring these studies so as to address a specific dimension of psychiatric illness
i.e., psychosis or mood disturbance
rather than to identify features that support categorical distinctions between the conditions in which such problems develop. Psychosis and emotional dysregulation are in all likelihood dimensional variables of neuropsychiatric function that are expressed clinically to greater or lesser degrees among persons with schizophrenia, bipolar disorder, and schizoaffective disorder (Liddle, 2001). The observation of schizoaffective disorder as a condition with epidemiologic, neurobiological, and treatment-response features that are very much like schizophrenia in some studies and rather more like bipolar disorder in others may reflect biases toward subject

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selection along the dimension of psychosis in the former and emotional dysregulation in the latter. Similarly, investigations of neurobiological features that are dimension-specific tend to demonstrate abnormalities specific to the dimension of neuropsychiatric function under study that cross conventional diagnostic boundaries. The clearest example of this approach to dimensional investigation among persons with psychiatric illnesses is provided by Olincy and Martin (2005), as described in the Electrophysiology section of this chapter. In reviewing the data presented in the preceding sections of this chapter, similar patterns of association between findings and the dimensions of illness and treatment response of subjects included in those studies emerge. It therefore seems reasonable to suggest a research agenda that seeks to characterize these conditions first in terms of their psychotic and emotional dimensions and second, if at all, with respect to categorical distinctions between them. So framing the study of schizophrenia, schizoaffective disorder, and bipolar disorder may facilitate a better understanding of the epidemiology, neurobiology, and treatment needs of patients based on their symptoms irrespective of their categorical (and perhaps largely arbitrary) clinical diagnosis. REFERENCES Angst, J., Felder, W., & Lohmeyer, B. (1980). Course of schizoaffective psychoses: Results of a followup study. Schizophrenia Bulletin, 6(4), 579
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84.

6

Schizophreniform disorder and brief psychotic disorder: the acute and transient psychoses Andreas Marneros and Frank Pillmann Department of Psychiatry and Psychotherapy, Martin Luther University Halle-Wittenberg, Germany

Summary of findings Grade of evidence Epidemiology: Incidence of brief and acute psychoses 1
2/100,000. Amount to 5
10% of inpatients with psychotic disorders. About twice as frequent in females as in males. Higher incidence in developing than in industrialized countries. Age at onset: From early adulthood to old age, median in the fourth decade, tentatively somewhat later than schizophrenia. Presentation: Acute onset of psychotic symptoms, often with characteristic ‘‘polymorphic symptoms’’, i.e. rapidly changing delusions and hallucinations and rapidly changing mood. Resolution of the acute episode is by definition complete, but the optimal duration criterion is still a matter of debate, suggestions ranging from 1
6 months. Course and progression: Relapse is frequent. So are other than brief and acute episodes during follow up, in particular affective and schizoaffective episodes, rarely schizophrenia. Outcome is usually favorable and evidence of long-term deterioration is absent. Suspected neuropathology: No consistent pathophysiological theory available. The clinical course implies the absence of progressive cerebral atrophy, but empirical data are scarce. Suspected neurochemical abnormalities: Despite isolated claims of thyroid or amino acid abnormalities, no consistent pattern has yet been found. Genetic factors: An increased prevalence of affective and psychotic disorders (not necessarily schizophrenia) in relatives indicates the importance of genetic factors. However, neither a phenotype ‘‘breeding true,’’ nor a specific ‘‘disease gene’’ have been identified. 96

B

C B

B

D

D C

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Grade of evidence Other risk factors: Mild or moderate life-events precede brief and acute psychoses more often than schizophrenic episodes. However, stressful life events are not characteristic for the majority of brief and acute psychoses, and the temporal and causal relation of these life events is not as close as suggested by the concept of psychogenic or reactive psychoses. Treatment: During the acute episode, treatment with antipsychotics is indicated in most cases, often supplemented with benzodiazepines, and should usually be continued for two years. Long-term therapy with antipsychotics is necessary in a substantial number of patients. The role of mood stabilizers and antidepressants in long-term therapy of brief and acute psychoses remains to be determined.

C

C

Introduction The criteria for brief psychotic disorder and schizophreniform disorder in the Diagnostic and Statistical Manual DSM-IV attempt to operationally define acute psychotic disorders of brief duration that can be differentiated from schizophrenia in their long-term course. As the optimal definition for these disorders is still under discussion, and to better delineate the subject of this chapter, the relevant diagnostic concepts and their nosological backgrounds need to be briefly reviewed (for a more comprehensive description see Marneros and Pillmann, 2004). The existence of acute psychoses of short duration, often presenting with intensive or even dramatic symptomatology, eventually resulting in full remission, has always been well known to clinicians. When Emil Kraepelin divided the so-called endogenous or functional psychoses into a group of dementia praecox (schizophrenia) and manic-depressive insanity (affective disorders), he conceded that there is a ‘‘not small group of disorders’’ which cannot be allocated
neither to schizophrenia, nor to affective disorders. Doubts about Emil Kraepelin’s dichotomic system, as well as Eugen Bleuler’s conception of schizophrenia, led to concepts such as ‘‘cycloid disorders’’ in Germany, ‘‘bouffe´e de´lirante’’ in France, ‘‘atypical psychoses’’ in Japan, ‘‘reactive or psychogenic psychoses’’ in Scandinavia, etc. (Marneros & Pillmann, 2004; Pillmann & Marneros, 2003; Table 6.1). The Norwegian psychiatrist, Langfeldt (1939), in an attempt to explain his observation that some cases of ‘‘schizophrenia’’ responded favorable to treatment while others failed to show a favorable response, differentiated between

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Andreas Marneros and Frank Pillmann Table 6.1. Some synonyms and partial synonyms of brief and acute psychoses

• • • • • • • • •

Bouffe´e de´lirante (Magnan, Ey) Cycloid psychoses (Kleist, Leonhard, Perris) Psychogenic (reactive) psychosis (Wimmer, Stro¨mgren) Atypical psychosis (Mitsuda) Brief reactive psychosis (DMS-III-R) Non-affective acute remitting psychoses (Susser) Brief psychotic disorder (DSM-IV) Schizophreniform psychosis (good prognostic features) (DSM-IV) Acute and transient psychotic disorders (ICD-10)

a nuclear group of schizophrenia with poor prognosis and a group of ‘‘schizophreniform psychoses’’ with a much better spontaneous prognosis. His criteria for schizophreniform disorder included an acute onset often in relation to a precipitating factor, the presence of confusion during the acute episode, and the absence of schizoid personality traits. The existence of brief good-prognosis psychotic disorders worldwide has been confirmed by several global epidemiological studies initiated by the WHO, showing that such psychoses are much more common in developing countries than in industrialized states (Marneros & Pillmann, 2004). The modern diagnostic systems, such as the Diagnostic and Statistical Manual (APA, 1994) and the International Classification of Diseases (WHO, 1992), tried to harmonize the various regional and national concepts concerning the abovementioned findings. DSM-IV provides the category of brief psychotic disorder (BPD). A diagnosis of BPD requires the presence of delusions, hallucinations, disorganized speech or grossly disorganized or catatonic behavior with a duration of at least one day, but less than one month and an eventual full return to premorbid functioning. In contrast to its predecessor in DSM-III-R, brief reactive psychosis, a severe antecedent stressor is not mandatory (Table 6.2). In DSM-IV, some psychotic disorders of brief duration may also be coded as schizophreniform disorder if they fulfill DSM-IV criteria for schizophrenia for one month (or less, if successfully treated), but remit within six months (Table 6.3). Thus, the main difference between DSM-IV schizophreniform disorder and DSM-IV schizophrenia concerns the six-month duration criterion. ‘‘Good prognostic features’’ are only included as specifiers, but are not obligatory for diagnosis. Some authors presented evidence that many patients with schizophreniform disorder meet the full criteria for schizophrenia at a later time (Strakowski, 1994). Others found evidence of a more favorable outcome in a subgroup of

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Schizophreniform and brief psychotic disorders Table 6.2. Diagnostic criteria for brief psychotic disorder according to DSM-IV

A. Presence of one (or more) of the following symptoms: • delusions • hallucinations • disorganized speech (e.g., frequent derailment or incoherence) • grossly disorganized or catatonic behavior Note: Do not include a symptom if it is a culturally-sanctioned response pattern. B. Duration of an episode of the disturbance is at least 1 day, but less than 1 month, with an eventual full return to premorbid level of functioning. C. The disturbance is not better accounted for by a Mood Disorder with Psychotic Features, Schizoaffective Disorder, or Schizophrenia and is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition. Specify if: With Marked Stressor(s) (brief reactive psychosis): if symptoms occur shortly after, and apparently in response to events that, singly or together, would be markedly stressful to almost anyone in similar circumstances in the person’s culture. Without Marked Stressor(s): if psychotic symptoms do not occur shortly after, or are not apparently in response to events that, singly or together, would be markedly stressful to almost anyone in similar circumstances in the person’s culture. With Postpartum Onset: if onset within 4 weeks postpartum. Source: APA, 1994

Table 6.3. Defining criteria of schizophreniform disorder according to DSM-IV

A. Criteria A, D, and E of schizophrenia are met.1 B. An episode of the disorder (including prodromal, active, and residual phases) lasts at least one month, but less than 6 months. (When the diagnosis must be made without waiting for recovery, it should be qualified as ‘‘Provisional.’’) Specify if: Without Good Prognostic Features With Good Prognostic Features: as evidenced by two (or more) of the following: 1. Acute onset of prominent psychotic symptoms 2. Confusion or perplexity at the height of the psychotic episode 3. Good premorbid social and occupational functioning 4. Absence of blunted or flat affect Source: APA, 1994 1 These criteria include the presence of the characteristic symptoms of schizophrenia, the exclusion of schizoaffective and mood disorders, and the exclusion of the effects of a substance or a general medical condition causing the disorder.

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Andreas Marneros and Frank Pillmann Table 6.4. Research criteria for acute and transient psychotic disorders according to ICD-10 (F23)

G1.

G2.

G3. G4.

G5.

There is acute onset of delusions, hallucinations, incomprehensible or incoherent speech, or any combination of these. The time interval between the first appearance of any psychotic symptoms and the presentation of the fully developed disorder should not exceed 2 weeks. If transient states of perplexity, misidentification, or impairment of attention and concentration are present, they do not fulfill the criteria for organically caused clouding of consciousness as specified for F05.-, criterion A. The disorder does not meet the symptomatic criteria for manic episode (F30.-), depressive episode (F32.-), or recurrent depressive disorder (F33.-). There is insufficient evidence of recent psychoactive substance use to fulfill the criteria for intoxication (F1x.0), harmful use (F1x.1), dependence (F1x.2), or withdrawal states (F1x.3) and (F1x.4). The continued moderate and largely unchanged use of alcohol or drugs in amounts or with the frequency to which the individual is accustomed does not necessarily rule out the use of F23; this must be decided by clinical judgement and requirements of the research project in question. Most commonly used exclusion clause. There must be no organic mental disorder (F00-F09) or serious metabolic disturbances affecting the central nervous system (this does not include childbirth). (The duration of the disorder must not exceed 3 months in subtypes F23.0, F23.3 and F23.8; it may not exceed 1 month in the subtypes F23.1 and F23.2, which include schizophrenic symptoms.)

Source: WHO, 1993

schizophreniform disorder (Zhang-Wong et al., 1995). In particular, the subtype with good prognostic features seems to be characterized by a benign long-term course (Benazzi, 1998; Iancu et al., 2002). Therefore, schizophreniform disorder, as presently defined by the DSM, is a heterogeneous category, which includes a small group of brief and acute psychoses with a benign long-term course (Naz, Bromet, & Mojtabai, 2003). In the tenth revision of the WHO International Classification of Diseases, ICD-10, the category of acute and transient psychotic disorders (ATPD) was created and operationally defined (WHO, 1992). The diagnostic criteria for the ICD-10 category F23 ‘‘acute and transient psychotic disorders’’ can be found in Table 6.4. The group is delineated into five subgroups: • acute polymorphic psychotic disorder with and without symptoms of schizophrenia, • acute schizophrenia-like psychotic disorder,

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• other acute predominantly delusional psychotic disorders, • other ATPD, • unspecified ATPD. But the main and essential group is the group of ‘‘acute polymorphic psychotic disorder’’. The BPD of DSM-IV is more narrowly defined than ATPD in ICD-10 so that every ‘‘brief psychosis’’ could be diagnosed as ‘‘acute and transient psychotic disorder’’, but not vice versa (Pillmann et al., 2002a). In this chapter, we focus on BPD and on those subforms of schizophreniform disorder that are characterized by acute onset and limited duration. To a large extent, this group of patients concurs with the ICD-10 definition of ATPD. As a comprehensive term, ‘‘brief and acute psychoses’’ will be used to denote this patient group. The empirical knowledge on brief and acute psychoses is still very limited. This is true for ICD-10 ATPD and even more for DSM-IV BPD. Studies on schizophreniform psychoses are hampered by an extremely heterogeneous composition of samples. The most comprehensive study on the topic so far is the Halle Study on Brief and Acute Psychoses (HASBAP) comparing a cohort of patients with ICD-10 ATPD with matched controls with schizophrenia and bipolar schizoaffective disorder, as well as with mentally healthy controls (Marneros & Pillmann, 2004). Results from this study will therefore be cited below. Additional knowledge mainly stems from Denmark (Jørgensen et al., 1997), Great Britain (Singh et al., 2004), India (Das, Malhotra, & Basu, 1999; Sajith et al., 2002), and the USA (Susser et al., 1998). Epidemiology Prevalence and incidence

There is little sound epidemiological evidence regarding the frequency of brief and acute psychoses. The interpretation of findings is further complicated by differences in definitions and probably by regional differences in incidence. Schizophreniform disorder has been estimated to have a lifetime prevalence of 0.2%, while BPD is reported as uncommon. Interesting data were reported by Susser and Wanderling (1994) in their re-analysis of data from the WHO Determinants of Outcome of Severe Mental Disorders. They determined the annual incidence per 10,000 people of non-affective acute remitting psychosis (NARP), representing a diagnostic entity roughly equivalent to the group of brief and acute psychoses covered in this chapter. They found the incidence to be 0.486 for males and 0.878 for females in developing countries

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and 0.040 for males and 0.104 for females in industrialized countries. The Nottingham study conducted by Singh et al. (2002) calculated incidence data for ATPD. Initially, an incidence of 3.9 per 100,000 was reported for ATPD, but after revision of the diagnoses at follow-up, this number dropped to 1.36 per 100,000. Compared with epidemiological incidence data, the frequency of brief and acute psychoses as a proportion of inpatients with broad definition psychotic disorders in a particular institution is much more commonly reported. These numbers, however, vary considerably dependent on the definitions used. BPD have been reported to represent 2% of non-organic psychoses, while the frequency of nonaffective acute psychoses in the definition of Susser and Wanderling (1994) has been reported at 3
6%. Acute and transient psychotic disorders have been found in the HASBAP to represent 8.5% of all inpatients treated for a non-organic psychotic disorder (ICD-10 F20), a number consistent with most other studies on ATPD (Marneros & Pillmann, 2004). In conclusion, the limited data available allow a cautious estimate of 1
2 per 100,000 for the yearly incidence of brief and acute psychoses. In clinical inpatient samples, brief and acute psychoses typically represent 5
10% of patients treated for a non-organic psychotic disorder. Developing countries

A considerable body of literature now points to a higher incidence of brief and acute psychoses in developing than in industrialized countries (Marneros & Pillmann, 2004; Susser & Wanderling, 1994; Thara, 2004). In the study mentioned above, Susser and Wanderling (1994) found a tenfold higher incidence of brief and acute psychoses in developing countries than in industrialized countries. Although the number still awaits replication, the phenomenon is consistent with the results of other WHO projects and with the impression of numerous researchers that brief and acute psychoses are particularly frequent in developing countries (Marneros & Pillmann, 2004; Thara, 2004). In fact, a considerable number of studies on brief and acute psychoses have been conducted in these countries, e.g. in India (Das et al., 1999; Sajith et al., 2002; Susser et al., 1998). Both organic and psychosocial factors have been deemed responsible for the difference in incidence, but the ultimate reason remains to be elucidated. Gender difference

A female preponderance can be observed in nearly all samples of brief and acute psychoses. In the HASBAP, the vast majority (78.6%) of patients diagnosed as having an ATPD was female. In other samples of ATPD or non-affective acute remitting psychoses, the proportion of female patients ranges from 60% to 86%

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(Marneros & Pillmann, 2004). This is in contrast to schizophrenia, which has been reported to be at least equally frequent in males as in females, with narrowly defined schizophrenia being probably somewhat more frequent in males. Samples with DSM-IV schizophreniform disorder typically do not show female preponderance, confirming the suggestion that DSM-IV schizophreniform disorder is a heterogeneous category comprising both cases of brief and acute psychoses and of schizophrenia. Age at onset Initially, onset of brief and acute psychoses was most frequently reported in young adults in their late 20s or early 30s. Recent investigations, including the HASBAP, have shown that the disorder may well present for the first time in later life. The patients in the Danish study conducted by Jørgensen et al. (1996) had a mean age at onset of 33 years (range 18
65 years). In the HASBAP, the mean age at onset for ATPD patients was 35.7 years, and more than half of the patients with ATPD became ill after the age of 33 years (Marneros & Pillmann, 2004). Studies from India reported a somewhat earlier mean age at onset of 25
27 years, but these differences may well represent differences in the age distribution of the general populations (Das et al., 1999; Sajith et al., 2002). Everything considered, the onset of brief and acute psychoses seems to occur somewhat later than that of schizophrenia, and definitely later than that of bipolar disorder. A somewhat later onset of brief and acute psychoses than schizophrenia would be compatible with the finding that early onset is a predictor of an unfavorable prognosis in mixed psychotic samples. Presentation In historical concepts of brief and acute psychoses, the sudden onset of rapidly changing psychotic symptoms was regarded as typical (Pillmann & Marneros, 2003). This turbulent symptomatological picture has been described as ‘‘polymorphic’’ or ‘‘cycloid.’’ In contrast to the historical descriptions, neither the criteria for BPD nor those for schizophreniform psychosis or ATPD require the presence of any particular symptom; just of psychotic symptoms in general. The investigation of unselected operationally diagnosed samples of ATPD and BPD, however, has corroborated polymorphic features as a frequent characteristic of brief and acute psychoses. In the HASBAP, rapidly changing delusions were present in 47.6% of the patients, while a rapidly changing mood was found in an even higher percentage, namely 69% (Table 6.5) (Marneros et al., 2005).

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Andreas Marneros and Frank Pillmann Table 6.5. Symptomatology of the index episode in ATPD

n (%) Productive psychotic symptoms (hallucinations and delusions) Hallucinations Delusions Delusions of being influenced First-rank symptoms Rapidly changing delusions Affective disturbance Disturbance of drive and psychomotor disturbances Depressed mood Maniform symptoms Anxiety Rapidly changing mood Thought disorder Bipolar character of symptoms

42 (100) 32 (76.2) 41 (97.6) 21 (50.0) 30 (71.4) 20 (47.6) 42 (100) 36 (85.7) 31 (73.8) 32 (76.2) 32 (76.2) 29 (69.0) 36 (85.7) 12 (28.6)

Source: From Marneros & Pillmann, 2004

This polymorphous symptomatology has also proven to be the main characteristic distinguishing ATPD from schizophrenia and bipolar schizoaffective disorder (Marneros & Pillmann, 2004). An example of rapidly changing delusional topics and other productive psychotic phenomena follows: A 37-year-old physical therapist developed, literally overnight, a multitude of delusional and hallucinatory experiences in rapid succession: within a few hours she believed herself to be pregnant, believed that a certain book contained special references to her, felt persecuted by construction workers, and experienced optical, auditory and coenaesthetic hallucinations accompanied by disturbances of speech, affect and motor behaviour. (From Marneros & Pillmann, 2004)

A bipolarity of mood is found in some patients (28.6% of the HASBAP subjects). In the most typical instances, it manifested itself in the form of a coexistence of ecstatic feelings and feelings of anxiety, often accompanied by accordingly tainted productive symptoms: A 24-year-old cook experienced the onset of her psychotic episode immediately after a dental treatment. She described an ecstatic feeling of happiness combined with the anxiety that something dreadful would happen. The bipolar nature of the affect was mirrored by the contents of her delusions and hallucinations: she was at one time convinced that she was a princess of high birth, and shortly afterwards she was troubled by voices accusing her of having abused her son.

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One of the most frequent symptoms in brief and acute psychoses is anxiety. In the HASBAP, anxiety was significantly more frequent than in schizophrenia or in bipolar schizoaffective disorders. This corroborates the importance of anxiety suggested by historical concepts as the bouffe´e de´lirante (pananxiety) or the cycloid psychoses, especially the ‘‘anxiety-elation psychosis’’ of the Wernicke
Kleist
Leonhard school of thought. Schizophrenic first-rank symptoms are present at a high level in brief and acute psychoses. They do not reliably differentiate this disorder from schizophrenia. In accordance with this finding, there is little difference between the two subgroups of ICD-10 acute polymorphic psychosis with and without schizophrenic symptoms (Marneros & Pillmann, 2004).

Course and progression An acute onset with a rapid transition from a non-psychotic state to florid psychosis is characteristic of brief and acute psychosis. In some cases, ‘‘prepsychotic alterations’’ or ‘‘initial symptoms’’ of a non-psychotic character occur some time before the onset of psychotic symptoms. Initial symptoms of this kind include most frequently sleep disturbances, but also depressed mood and reduced drive. One third of patients show anxiety as an initial symptom. Despite the possibility of initially unspecific symptoms, the transition to a florid psychotic state takes place in a markedly acute manner, most often within two weeks at the longest (as incorporated in the ICD-10 diagnostic criteria for ATPD). Often this transition occurs within 48 hours. The acute onset seems to be an important element in the distinction of these disorders from schizophrenia. At present, acute onset is not formally requested by the DSM definitions of BPD and schizophreniform disorder, but empirical evidence supports the inclusion of an acute onset in future revisions of the classification. The duration of the psychotic episode is an important element of any operational definition of brief and acute psychoses. But there is no consensus on the optimal duration criterion. BPD must resolve within one month, ATPD within three months (or one month if schizophrenic symptoms are present), and schizophreniform disorder within six months. Mojtabai, Varma, & Susser (2000) have suggested generally extending the possible duration of brief and acute psychoses to six months. In the HASBAP, many patients showed very short psychotic periods (mean 17.5 days), but there was no clear evidence that the time criteria of the ATPD definition are more than arbitrary. It may well be that future diagnostic revisions will modify presently accepted duration criteria. Taken together, evidence suggests that reliable criteria for a full remission of the acute

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episode may be more important for the delineation of brief and acute psychoses than strict duration criteria. The typical course of brief and acute psychoses has been described as remitting and relapsing. Follow-up studies of ATPD have shown relapse rates of 33
80% within the first 1
3 years (Jørgensen et al., 1997; Marneros et al., 2003; Singh et al., 2004). Some studies conducted by the Susser group showed considerably lower relapse rates (e.g., 18% within 12 years, Susser et al., 1998), but these studies for inclusion demanded a relapse-free time after the initial episode for up to two years. Data from the HASBAP show that the risk of relapse during the first two years in ATPD is as high as in schizophrenia and may eventually approach 80% even in treated samples. Diagnostic stability is an issue addressed by most brief and acute psychoses follow-up studies. According to the results of the HASBAP, the proportion of patients showing only ATPD episodes in the long run is less than 50%. In those patients who relapse, the occurrence of other than brief and acute psychotic episodes is common. In particular, affective and schizoaffective episodes may occur (Marneros & Pillmann, 2004). However, the number of patients who eventually fulfill criteria of schizophrenia has been low in all studies on ATPD, NARP, or BPD. For example, in the HASBAP sample, after seven years 12.8% of the sample fulfilled the criteria for schizophrenia (Pillmann & Marneros, 2005). In DSM-IV schizophreniform disorder, a later diagnosis of schizophrenia is more frequent (Strakowski, 1994). In contrast, in patients showing the typical polymorphic symptom picture (e.g., the polymorphic subtypes of ATPD), a monosyndromal, diagnostically stable long-term course seems to be more frequent (Marneros & Pillmann, 2004). Historical concepts of brief and acute psychoses have generally stressed the lack of deterioration during long-term course, even though relapses may be frequent (Marneros & Pillmann, 2004; Pillmann & Marneros, 1998; 2003). Although a favorable prognosis (beyond remission of the acute episode) is not a diagnostic criterion of ATPD as defined by ICD-10, the diagnosis of ATPD carries the expectation of a favorable long-term course (WHO, 1992). A number of studies, including the HASBAP, have confirmed a favorable outcome of brief and acute psychoses in terms of global functioning, symptoms, and disability (Jørgensen et al., 1997; Marneros et al., 2003; Pillmann et al., 2002b; Sajith et al., 2002; Singh et al., 2004). In addition, the latest results of the HASBAP indicate that the presence or absence of continuing deterioration after the index episode may be a valid difference between brief and acute psychoses and schizophrenia. The findings in the control group confirm a modest degree of deterioration in the long-term course of schizophrenia, as evidenced by an increase in symptoms and social

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disability and a decrease in global functioning from the first to last follow-up. The same effect was not present in the index group of patients with ATPD, reinforcing the notion of long-term stability in this group (Pillmann & Marneros, 2005).

Suspected neuropathology For a long time, historical concepts of brief and acute psychoses as distinct from schizophrenia have been associated with speculations about different etiological factors acting in both groups of disorders. While in schizophrenia the assumption of a yet to be specified progressive brain disease initially dominated etiological theories, brief and acute psychoses were tentatively linked to the instability of brain stem circuits, humoral factors, epilepsy, psychogenesis and other factors (Pillmann & Marneros, 2003). When cerebral atrophy was described as a feature of schizophrenic psychoses and corroborated by several studies, it was hypothesized that brief and acute psychoses should fail to show this evidence of atrophy. For atypical psychoses and cycloid psychoses, a lower rate of cerebral atrophy, as determined by CCT, was found in comparison to schizophrenia (Hayashi et al., 1992; Ho¨ffler et al., 1997), but there are conflicting findings (Falkai et al., 1995). There is very little evidence from studies using modern definitions of brief and acute psychoses. In the HASBAP, there was an attempt to determine whether abnormalities of the brain scans differentiate between ATPD and the clinical control groups. As part of the standard diagnostic work-up, a computed tomography of the head was performed in most patients. However, a comparison of ATPD and control groups on standardized atrophy indices did not reveal any differences between the groups (Marneros & Pillmann, 2004). Scha¨r et al. (1995) assessed 26 patients with acute psychoses by means of Tc 99m HMPAO SPECT. They concluded that the prevalence of hypofrontality did not differentiate ATPD from schizophrenia, but the small number of patients investigated (only three ATPD patients) grossly limits their findings. Molina et al. (2005) investigated the occurrence of hypofrontality in 13 male patients with first-episode psychosis by means of FDG PET. Diagnoses were confirmed by a two-year follow-up. Six patients with DSM-IV schizophrenia demonstrated a significant hypofrontality in the dorsolateral prefrontal cortex in comparison with non-schizophrenic psychoses (six patients with schizophreniform disorder and one with BPD) and with mentally healthy controls. In conclusion, our pathophysiological understanding of brief and acute psychoses, as well as the data available at present, do not allow for definite conclusions with respect to neuropathological abnormalities in these disorders.

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Suspected neurochemical abnormalities Our state of knowledge regarding neurochemical abnormalities is similarly low. However, an ‘‘organic impression’’ of the symptomatology is not uncommon in ATPD, and may include features such as confusion or disorientation (Murai, Toichi, & Sengoku, 1996). Occasionally, therefore, metabolic or endocrinological mechanisms have been suggested to play a role in the pathogenesis of brief and acute psychoses (Pillmann & Marneros, 2003). Earlier speculations about the role of thyroid dysfunction were not corroborated by the results of the HASBAP, where no abnormalities of thyroid metabolism or vitamin B12 could be detected (Marneros & Pillmann, 2004). Pepplinkhuizen et al. (2003) studied the role of the amino acid serine in patients with acute transient polymorphic psychosis. Patients were loaded with serine and with the amino acids glycine and alanine as controls and subsequently evaluated for the development of psychopathological symptoms. In a subgroup of patients, this biochemical challenge resulted in the reappearance of ‘‘psychedelic’’ psychotic symptoms. Furthermore, significantly lower plasma concentrations of serine were found. For the authors, these results indicated that disturbances in amino acid metabolism may be involved in the emergence of brief and acute psychoses (Pepplinkhuizen et al., 2003). However, they need to be replicated by other groups. In conclusion, with the exception of the suspected cases of disturbed amino acid metabolism, which are awaiting independent replication, no specific neurochemical abnormalities have been found in brief and acute psychoses. Genetic factors There are very few family studies exclusively concerning modern definitions of brief and acute psychoses. Those family studies that used DSM or ICD criteria mostly focused on the ‘‘major’’ categories, namely schizophrenia and affective disorder. A notable exception is the Roscommon Family Study (Kendler et al., 1993). In this study, patients and relatives of patients were investigated according to DSM-III-R criteria. The categories ‘‘schizophreniform,’’ ‘‘delusional,’’ and ‘‘atypical psychotic disorders’’ were combined into the category ‘‘other nonaffective psychoses’’ (ONAP). This category could be partially equivalent to ATPD. Patients diagnosed as having ONAP more frequently (with significance) had schizophrenic relatives, and also (without significance) more relatives with schizoaffective disorders and ONAP. Thus, the Roscommon Family Study supports the idea of a spectrum concept, but not of a separate nosological entity of a ‘‘non-affective non-schizophrenic psychosis’’ (Kendler et al., 1993).

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The most comprehensive family study on patients with ICD-10 ATPD was conducted in Chandigarh, India by Das et al. (1999). The authors recruited 40 probands with ATPD and 40 schizophrenic control probands and personally interviewed 75% of all living first-degree relatives. They found a 3.35 times higher morbid risk for ATPD in relatives of ATPD probands than in relatives of probands with schizophrenia. A 4.5 times higher morbid risk for schizophrenia was found in relatives of probands with schizophrenia than in relatives of probands with ATPD. The overall morbid risk was 8.99 in relatives of probands with schizophrenia, and 4.60 in relatives of probands with ATPD (recalculated from Table 6.3 of Das et al., 1999). Benazzi (1998), conducting a family study on DSM-III-R schizophreniform disorder (good prognosis subtype), found no cases of schizophrenia in the first-degree relatives of his probands, but an elevated risk for affective disorders. In the HASBAP, a detailed family history of each subject was obtained using all available information, including the subjects’ own reports and information from the case records. The relatives themselves were not interviewed. In this study, the rate of psychotic and major affective disorders in first-degree relatives of ATPD patients was increased to a similar degree as in the relatives of patients with schizophrenia and bipolar schizoaffective disorder. There was some indication that in relatives of patients with ATPD, rates of both affective and psychotic disorders were elevated. In contrast, secondary cases in schizophrenia were mostly psychotic, and in bipolar schizoaffective disorder, secondary cases were mostly affective (Marneros & Pillmann, 2004). In conclusion, expectations that genetic epidemiology help define the nosological boundaries of brief and acute psychoses by finding entities ‘‘breeding true’’ have not been fulfilled. As far as the limited evidence goes, patients with brief and acute psychoses have fewer relatives with schizophrenia and more relatives with affective disorders than would be expected if brief and acute psychoses were just less severe forms of schizophrenia. The promising findings of recent years regarding the molecular genetics of schizophrenia (Shirts & Nimgaonkar, 2004) do not yet extend to brief and acute psychoses. Most samples underlying association studies and studies of susceptibility genes include patients with broadly defined schizophrenia. It remains for future research to compare the frequency of certain ‘‘disease genes’’ in schizophrenia and brief and acute psychoses. Other risk factors Further somatic, as well as psychosocial, risk factors have been asserted by some authors for brief and acute psychoses. Investigations carried out in India

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identified antecedent fever as a risk factor for the occurrence of brief and acute psychosis (Collins et al., 1999). In case reports, brief and acute psychoses have been reported in somatic conditions ranging from arachnoid cyst (Bahk et al., 2002) to mediastinal carcinoma metastasis (Scho¨nfeldt-Lecuona et al., 2004). However, this is not a general finding. In the HASBAP, no increased frequency of somatic disorders associated with ATPD could be found (Marneros & Pillmann, 2004). Some authors assumed that the so-called ‘‘atypical psychosis’’ of Japanese psychiatry has some relationship to epilepsy (Hatotani, 1996; Tucker et al., 1986). Inui et al. (1998) reported further evidence of this association, but no such association was found in the HASBAP (Ro¨ttig et al., 2005). There are no investigations with unselected samples of BPD, ATPD, or schizophreniform psychoses that confirm an increased prevalence of EEG abnormalities in these conditions. Another strong tradition views brief and acute psychoses mainly as ‘‘psychogenic’’ or ‘‘reactive’’ disorders (Pillmann & Marneros, 2003). Although the concept of reactive psychosis focuses on psychosocial triggers, in many cases a particular vulnerability of the personality is assumed, most often described as emotionally labile, easily impressed, and prone to disproportionate affective reactions (Stro¨mgren, 1986; Ungvari & Mullen, 2000). To date, empirical studies, however, have not been able to confirm specific personality features to be more prevalent in brief and acute psychoses than in other psychotic disorders. In fact, in the HASBAP, patients with ATPD had fewer abnormalities premorbidly than controls with schizophrenia (Pillmann et al., 2003b). Stressful life events occur more frequently within 6
12 months before an episode of brief and acute psychosis than before an episode of schizophrenia (Marneros & Pillmann, 2004). In contrast, a severe stressor as defined by the ICD-10 seems to be present in no more than 10% of ATPD episodes. This conforms to the obvious rarity of DSM-III-R brief reactive psychoses, for which such a severe and closely timed stressor was mandatory. In conclusion, mild or moderate life events precede ATPD more often than schizophrenic episodes. However, stressful life events are not characteristic of the majority of brief and acute psychoses, and the temporal and causal relation of these life events is not as close as suggested by the concept of psychogenic or reactive psychoses. Treatment The dramatic onset of brief and acute psychoses often calls for emergency treatment. Hospital admission is the rule, and pharmacotherapy is usually indicated. A small minority of patients with very short durations of psychotic symptoms go into remission before specific pharmacotherapy is started. With regard

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to historical concepts of brief and acute psychoses, treatment of the acute episode with electroconvulsive therapy has been advocated by several authors (Little, Ungvari, & McFarlane, 2000; Perris, 1974). However, the mainstay of therapy in brief and acute psychoses is antipsychotic medications. In the HASBAP, 95.2% of the sample were treated with an antipsychotic in the index episode. Some patients with ATPD also need antidepressant therapy or a mood stabilizer, but the vast majority of patients can be treated with only one antipsychotic. Tranquilizers are frequently needed, in particular to treat the prevalent anxiety. Protective measures are also often necessary, as suicide seems to be connected to the acute episode in ATPD (Pillmann et al., 2003a). Of great concern is the question as to how long pharmacotherapy of the acute episode should be continued given the
by definition
transient nature of the psychotic symptoms. Data from controlled studies are missing, therefore we have to refer to observational data. In Jørgensen et al. (1996), 82% of the 51 patients with ATPD were taking antipsychotic medication at the one-year follow-up, although most of them were no longer psychotic. Similarly, in the HASBAP, 71.1% of the patients with ATPD were taking psychotropic medication at follow-up, mainly antipsychotics (Marneros & Pillmann, 2004). Given the high relapse rates during the first two years after an episode of ATPD, a continuation of pharmacotherapy for at least two years appears advisable in the majority of cases. There is little empirical guidance for the long-term therapy of brief and acute psychoses. Evidence-based treatment recommendations and guidelines as in schizophrenia do not exist. While occasionally it is argued that the generally benign course of brief and acute psychoses obviates the necessity of long-term medication (Susser et al., 1998), the relapsing course speaks in favor of prophylactic medication. For the long-term prophylaxis of cycloid psychoses, lithium therapy has been described as effective (Mattsson & Perris, 1973; Perris & Smigan, 1985), but the effectiveness of mood stabilizers in brief and acute psychoses of modern operational definition has not been studied. Naturalistic follow-up data, as obtained with the HASBAP, show that presently most patients are treated with antipsychotics as long-term maintenance medication. In a small group of patients with brief and acute psychoses, it appears to be possible to stop medication during long-term course. In the HASBAP, after seven years approximately 30% of the ATPD patients were doing well without pharmacotherapy (Pillmann & Marneros, 2005). This number has to be taken with caution due to the purely observational character of the study. Evidence from this, as well as from other studies, however, indicates that the proportion of patients in which medication can be discontinued after two years is somewhat larger in brief and acute psychoses than in schizophrenia. Most of the remaining

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patients are currently treated with antipsychotics, with a number of them receiving antidepressants or mood stabilizers. Future research will have to show whether these treatments, in particular mood stabilizers, can substitute for treatment with antipsychotics in brief and acute psychoses. Conclusions Regardless of the diagnostic label used, the core group of acute and transient psychotic disorders can be characterized as a group of disorders which mainly concern females, with possible onset in all ages of adult life, but usually between the thirtieth and fiftieth year of life. Their onset is acute or even abrupt within 48 hours, but the onset is only rarely dependent on acute severe stress in spite of former assumptions. The psychotic period is very short, in some cases even only one day. Their response to antipsychotic drugs is very good and their outcome is usually favorable in spite of the fact that they are usually recurrent. They differ from schizophrenia regarding the gender distribution, age at onset and premorbid level of functioning and social interactions. The level of postepisodic functioning and out is more favorable in ATPD than in schizophrenia. Despite strong similarities, they have essential differences from schizoaffective disorders regarding gender, age at onset, mode of onset, and duration of symptomatology. Although syndromatic instability in long-term course prevents us to assume nosological independence of acute and transient psychotic disorders, their unique features make them a highly interesting group of disorders both from the clinical and the theoretical point of view. They are clinically important for the patients and their relatives
because of their favorable outcome. And they are theoretically important, because a better understanding of acute and transient psychoses may shed light on the relations between the major psychotic disorders and their actiology. REFERENCES APA (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association. Bahk, W. M., Pae, C. U., Chae, J. H., et al. (2002). A case of brief psychosis associated with an arachnoid cyst. Psychiatry and Clinical Neurosciences, 56(2), 203
5. Benazzi, F. (1998). Family history of DSM-III-R schizophreniform disorder with good prognostic features. Canadian Journal of Psychiatry, 43(5), 525
6. Collins, P. Y., Varma, V. K., Wig, N. N., et al. (1999). Fever and acute brief psychosis in urban and rural settings in north India. British Journal of Psychiatry, 174, 520
4.

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32. Falkai, P., Bogerts, B., Klieser, E., et al. (1995). Cranial computed tomography in schizophrenics, patients with cycloid psychoses and controls. In Leonhard’s Impact on Modern Psychiatry, ed. H. Beckmann, and K.-J. Neuma¨rker. Berlin, Wiesbaden: Ullstein Mosby, pp. 213
21. Hatotani, N. (1996). The concept of ‘atypical psychoses’: Special reference to its development in Japan. Psychiatry and Clinical Neurosciences, 50(1), 1
10. Hayashi, T., Watanabe, T., Kitoh, H., et al. (1992). Multivariate analyses of CT findings in typical schizophrenia and atypical psychosis. Japanese Journal of Psychiatric Neurology, 46, 699
709. Ho¨ffler, J., Bra¨unig, P., Kru¨ger, S., et al. (1997). Morphology according to cranial computed tomography of first-episode cycloid psychosis and its long-term-course: Differences compared to schizophrenia. Acta Psychiatrica Scandinavica, 96(3), 184
7. Iancu, I., Dannon, P. N., Ziv, R., et al. (2002). A follow-up study of patients with DSM-IV schizophreniform disorder. Canadian Journal of Psychiatry, 47(1), 56
60. Inui, K., Motomura, E., Okushima, R., et al. (1998). Electroencephalographic findings in patients with DSM-IV mood disorder, schizophrenia, and other psychotic disorders. Biological Psychiatry, 43(1), 69
75. Jørgensen, P., Bennedsen, B., Christensen, J., et al. (1996). Acute and transient psychotic disorder: Comorbidity with personality disorder. Acta Psychiatrica Scandinavica, 94, 460
64. Jørgensen, P., Bennedsen, B., Christensen, J., et al. (1997). Acute and transient psychotic disorder: A 1-year follow-up study. Acta Psychiatrica Scandinavica, 96(2), 150
54. Kendler, K. S., McGuire, M., Gruenberg, A. M., et al. (1993). The Roscommon Family Study. I. Methods, diagnosis of probands and risk of schizophrenia in relatives. Archives of General Psychiatry, 50, 527
40. Langfeldt, G. (1939). The Schizophreniform States. Kopenhagen: Munksgaard. Little, J. D., Ungvari, G. S., & McFarlane, J. (2000). Successful ECT in a case of Leonhard’s cycloid psychosis. Journal of ECT, 16(1), 62
7. Marneros, A. & Pillmann, F. (2004). Acute and Transient Psychoses. Cambridge: Cambridge University Press. Marneros, A., Pillmann, F., Haring, A., et al. (2003). What is schizophrenic in ATPD? Schizophrenia Bulletin, 29(2), 311
23. Marneros, A., Pillmann, F., Haring, A., et al. (2005). Is the psychopathology of acute and transient psychotic disorder different from schizophrenic and schizoaffective disorders? European Psychiatry (in press). Mattsson, B. & Perris, C. (1973). Cycloid psychoses: Aspects of therapy and possible prevention of relapses. Nordisk Psykiatrisk Tidsskrift, 27, 386
91. Mojtabai, R., Varma, V. K., & Susser, E. (2000). Duration of remitting psychoses with acute onset. Implications for ICD-10. British Journal of Psychiatry, 176, 576
80. Molina, V., Sanz, J., Reig, S., et al. (2005). Hypofrontality in men with first-episode psychosis. British Journal of Psychiatry, 186, 203
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60. Naz, B., Bromet, E. J., & Mojtabai, R. (2003). Distinguishing between first-admission schizophreniform disorder and schizophrenia. Schizophrenia Research, 62(1
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8. Pepplinkhuizen, L., van der Heijden, F., Tuinier, S., et al. (2003). The acute transient polymorphic psychosis: A biochemical subtype of the cycloid psychosis. Acta Neuropsychiatrica, 15(1), 38
43. Perris, C. (1974). A study of cycloid psychoses. Acta Psychiatrica Scandinavica, 253(Suppl.), 1
77. Perris, C. & Smigan, L. (1985). The use of lithium in the long-term morbidity suppressive treatment of cycloid and schizoaffective psychoses. In Psychiatry: The State of the Art. Vol. 3. Pharmacopsychiatry, ed., P. Pichot. New York: Plenum, pp. 375
80. Pillmann, F. & Marneros, A. (1998). Acute and transient psychotic disorders: Development of concepts. European Psychiatry, 14(suppl. 4), 321s. Pillmann, F. & Marneros, A. (2003). Brief and acute psychoses: The development of concepts. History of Psychiatry, 14(2), 161
77. Pillmann, F. & Marneros, A. (2005). Longitudinal follow-up in acute and transient psychotic disorders and schizophrenia. British Journal of Psychiatry, 187, 286
7. Pillmann, F., Haring, A., Balzuweit, S., et al. (2002a). The concordance of ICD-10 acute and transient psychosis and DSM-IV brief psychotic disorder. Psychological Medicine, 32, 525
33. Pillmann, F., Haring, A., Balzuweit, S., et al. (2002b). A comparison of DSM-IV brief psychotic disorder with ‘‘positive’’ schizophrenia and healthy controls. Comprehensive Psychiatry, 43(5), 385
92. Pillmann, F., Balzuweit, S., Haring, A., et al. (2003a). Suicidal behavior in acute and transient psychotic disorders. Psychiatry Research, 117, 199
209. Pillmann, F., Blo¨ink, R., Balzuweit, S., et al. (2003b). Personality and social interactions in patients with acute brief psychoses. Journal of Nervous and Mental Disease, 191(8), 503
8. Ro¨ttig, S., Pillmann, F., Blo¨ink, R., et al. (2005). Is there evidence in the EEG for a relationship between ICD-10 ‘‘acute and transient psychotic disorder’’ and epilepsy? Psychopathology, 38, 281
4. Sajith, S. G., Chandrasekaran, R., Sadanandan Unni, K. E., et al. (2002). Acute polymorphic psychotic disorder: Diagnostic stability over 3 years. Acta Psychiatrica Scandinavica, 105(2), 104
9. Scha¨r, V., Zeit, T., Heinemann, F., et al. (1995). Zur Hypofrontalita¨t im 99m-Tc-HMPOASPECT bei ‘‘akuten’’ Psychosen. Nervenheilkunde, 14, 379
84. Scho¨nfeldt-Lecuona, C., Freudenmann, R. W., Tumani, H., et al. (2004). Acute psychosis with a mediastinal carcinoma metastasis. Medical Science Monitor, 11(1), CS6
8. Shirts, B. H. & Nimgaonkar, V. (2004). The genes for schizophrenia: finally a breakthrough? Current Psychiatry Report, 6(4), 303
12. Singh, S. P., Croudace, T., Amin, S., et al. (2002). Incidence, course and outcome of ICD-10 acute and transient psychotic disorders. Acta Psychiatrica Scandinavica, 105(Suppl. 411), 20.

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9. Strakowski, S. M. (1994). Diagnostic validity of schizophreniform disorder. American Journal of Psychiatry, 151, 815
24. Stro¨mgren, E. (1986). Reactive (psychogenic) psychoses and their relations to schizoaffective psychoses. In Schizoaffective Psychoses, ed. A. Marneros and M. T. Tsuang. New York: Springer, pp. 260
71. Susser, E. & Wanderling, J. (1994). Epidemiology of nonaffective acute remitting psychosis vs schizophrenia: Sex and sociocultural setting. Archives of General Psychiatry, 51, 294
301. Susser, E., Varma, V. K., Mattoo, S. K., et al. (1998). Long-term course of acute brief psychosis in a developing country setting. British Journal of Psychiatry, 173, 226
30. Thara, R. (2004). Twenty-year course of schizophrenia: The Madras Longitudinal Study. Canadian Journal of Psychiatry, 49(8), 564
9. Tucker, G. J., Price, T. R., Johnson, V. B., et al. (1986). Phenomenology of temporal lobe dysfunction: A link to atypical psychosis
a series of cases. Journal of Nervous and Mental Disease, 174, 348
56. Ungvari, G. S. & Mullen, P. E. (2000). Reactive psychoses revisited. Australian and New Zealand Journal of Psychiatry, 34(3), 458
67. WHO (1992). The ICD-10 Classification of Mental and Behavioral Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: WHO. WHO (1993). The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, Geneva: WHO. Zhang-Wong, J., Beiser, M., Bean, G., et al. (1995). Five-year course of schizophreniform disorder. Psychiatry Research, 59, 109
17.

7

Delusional disorder Theo Manschreck Harvard University

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B B
B B
C C Cþ Cþ C


Introduction Based on nineteenth-century descriptions of paranoia (particularly those of Karl Kahlbaum (1863) and Emil Kraepelin)(1919), delusional disorder is a recent addition to the classification of mental disorders. Indeed, the DSM IV and ICD-10 definitions (Tables 7.1 & 7.2) have revived the concept of paranoia, refined the criteria for this disorder, delineated better boundaries with other psychotic disorders, especially schizophrenia, and emphasized careful differential diagnosis including exclusion of diseases with known causes and idiopathic disorders (such as bipolar or schizophrenic disorders) (Manschreck, 2000). Despite this promising framework, progress in building knowledge of the features, natural history, neuropathology, and biology of delusional disorder has developed slowly (Table 7.3). The reasons are instructive. The untreated and unrecognized prevalence of this disorder is substantial. Individuals with this condition are frequently free of symptoms besides the delusion. In some cases their 116

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Delusional disorder Table 7.1. DSM IV diagnostic criteria for 297.1 delusional disorder

A. Non-bizarre delusion(s) of at least 1-month’s duration. B. Criterion A for schizophrenia not met. Tactile and olfactory hallucinations may be present, if they are related to the delusional theme. Auditory and visual hallucinations, if present, are not prominent. C. Behavior is not obviously odd nor bizarre, functioning not markedly impaired apart from impact of delusion(s) or its ramifications. D. If mood episodes have occurred concurrently with the delusions, their total duration has been brief relative to the duration of the delusional periods. E. Has never met criteria for schizophrenia, and it cannot be established that a general medical condition or the direct physiological effects of a substance initiated and maintained the disturbance. Types: Erotomanic, Grandiose, Jealous, Persecutory, Somatic, Mixed, Unspecified. Source: (American Psychiatric Association, 1994)

Table 7.2. ICD-10 delusional disorder

A delusion or a set of related delusions other than those listed as typically schizophrenic, (i.e., other than completely impossible or culturally inappropriate) must be present. The delusion(s) must be present for at least 3 months. The criteria for schizophrenia are not fulfilled. No persistent hallucinations in any modality (except transitory or occasional auditory hallucinations but not in the third person or giving a running commentary). Depressive symptoms or episodes may be present, provided the delusion(s) persist at times when there is no disturbance of mood. No organic mental disorder. Specified types: Persecutory, Litiginous, Self-referential, Grandiose, Hypochondriacal (somatic), Jealous, Erotomanic. Source: (World Health Organization, 1993)

Table 7.3. Main features of delusional disorder

Chief feature is a plausible delusion. Not a common disorder, nor rare. Minimal additional symptoms. Several subtypes based on predominant theme (erotic, persecutory, etc.). Difficult to treat and possibly treatment resistant. Distinct from schizophrenia and mood disorder. Etiology is unknown.

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Theo Manschreck Table 7.4. Epidemiological features of delusional disorder

Incidence Prevalence Inpatient psychiatric admissions Lifetime morbidity risk Age at onset Sex ratio

0.7
3.0/100,000 24
30/100,000 1
2% 0.05
0.1% 35
45 (range 18
80) Female 4 male

Source: (Kendler, 1982; Munro, 1999; Manschreck, 2000)

apparent normality may help them avoid drawing attention to their behavior and delusional preoccupations. They deny they are ill, and even the suggestion that they suffer from psychiatric disorder may provoke anger. Further, delusional disorder is a syndrome with an unknown etiology and associated with a number of delusion types. The latter include erotomanic, grandiose, jealous, persecutory, somatic, mixed, and unspecified. This fact has ramifications for diagnosis (there is no diagnostic test), and for its validation as a distinct entity (is it part of a spectrum of related psychotic conditions or one of many heterogeneous disorders with overlapping phenomenologies?) (Serretti et al., 1999). Moreover, the low prevalence of delusional disorder has limited the feasibility of carrying out large-scale studies. Further complicating its infrequent occurrence, delusional disorder patients often present to other medical specialists, judges, attorneys, the police, even pest exterminators, but seldom to psychiatrists. Also, clinical determination that a delusion is not bizarre (implausible and not understandable nor consistent with ordinary life experiences) may be difficult, especially across different cultures. Finally, the temporal stability of the diagnosis has been challenged in some reports (Fennig, Craig, & Bromet, 1996). Nevertheless, gains in understanding delusional disorder have occurred. The purpose of this chapter is to outline in greater detail evidence about this unusual and important psychotic disorder. Epidemiology Prevalence

Delusional disorder is not a common condition. Many have considered it rare. Unfortunately, reliable epidemiologic information is meager. Kendler (1982) assembled various data from 1912 through the 1970s to create estimates of incidence and prevalence (Table 7.4). The relevance of these numbers in relation to the disorder we currently call delusional disorder is questionable. As criteria are refined and applied in population studies, different numbers will probably develop

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(Copeland et al., 1998). Nevertheless, these are useful to guide our thinking. In summary, compared to schizophrenia and mood disorders, prevalence of delusional disorder is much less common. The persecutory type is the most common. Gender differences and other factors

Individuals with delusional disorder are somewhat more likely to be female and to be more socially and educationally disadvantaged compared to individuals with mood disorders where a substantial preponderance of patients are female. In contrast, there is a more equal distribution of gender in the incidence of schizophrenia. Women tend to be older than men when they are diagnosed. It is widely believed that jealous type delusional disorder occurs more often in men than women.

Age of onset The range is fairly wide (18
80 years) but most patients are middle aged at illness onset. Age of onset is later on average than in schizophrenia (by approximately two decades) yet, like schizophrenia, men tend to develop delusional disorder at earlier ages than women. Female cases may predominate in new cases among individuals of advanced age but do not approach the sex ratios characteristic of mood disorder. In one study (Yamada, Nakajima, & Noguchi, 1998), age of onset differed according to delusion type, the oldest age of onset being associated with the persecutory type and the youngest with the somatic type.

Presentation The cardinal feature of delusional disorder is a persistent, non-bizarre delusion not explained by other disorders according to DSM-IV. Onset can be acute or sudden following a precipitating event, or the condition may emerge gradually and become chronic. Insidious onset appears to be the more common pattern. The behavioral and emotional responses associated with delusional disorder are generally consistent with the content of the delusion (Table 7.5). The volitional, thinking, and emotional disturbances of schizophrenia are not present (including most hallucinations which are restricted in delusional disorder). Patients with delusional disorder show little impairment or disorganization in their general behavior or in the clarity and form of their thinking. Mood symptoms, even disorder, are associated with this condition, with onset usually after that of delusional disorder.

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Observed features Anger, irritability, quick annoyance Critical, accusatory behavior Defensiveness Grandiosity, narcissistic or excessive self-importance Hostility, sarcasm Humorlessness Hypersensitivity Litigiousness Obstinacy Seclusiveness Self-righteousness Suspiciousness Violence, aggressiveness Subjective features Overvalued, near delusional ideas Frank delusions (persecutory, jealousy, somatic, erotomanic, grandiose)

The delusions are indeed unusual yet they refer to experiences that can occur in real life, such as being cheated on, physically ill, in love, jealous, or persecuted. Winokur (1977) has suggested that these are possible rather than totally incredible and bizarre delusions, as are commonly found in schizophrenia. Delusions are categorized according to their content. The most common are characterized by persecution, disease (somatic), and jealousy. Delusions are persistent and unarguable. Individuals interpret facts to fit the delusion rather than modifying the delusion to fit the facts. Systemization is present: a single theme or series of connected themes is present which links to the predominant delusion. Normal life and functioning may gradually give way to the intensity of these delusional concerns. Herein lies the source of the dysfunction and impairment in social, occupational, and personal adjustment that accompany this illness. Some have suggested that there is a continuum of psychotic disorder into which delusional disorder falls, somewhere between paranoid personality and the paranoid subtype of schizophrenia, the continuum characterized in terms of behavioral disorganization and impairment of functioning. However, little evidence supports the concept that these disorders share more than overlapping psychopathology. Nevertheless, there have been proposals that a number of delusional conditions such as the Capgras and related syndromes, cycloid and

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reactive psychoses in the European literature, may be related to delusional disorder (Munro, 1999). Associated clinical features

A striking aspect in the clinical presentation of patients with delusional disorder is the absence of specific psychological or mental complaints or striking observable psychiatric features. In fact, there is active denial of the presence of symptoms. To the surprise of most clinicians is the discovery that appearance, thinking, orientation, mood and affect, attentional processes, memory capacity, perceptual processes, and often personality are intact. Thinking is coherent, yet may be abnormal (occasionally bordering on illogical) when delusional beliefs are expressed. In fact, evidence of delusional concerns and absence of insight may be the only observed characteristic features. There may be sarcasm, hostility, and even lack of cooperation because the patient’s agenda is not being addressed and the examiner appears to be on the trail of symptoms the individual denies having. Mental status examination can disclose level of impulsiveness and potential for violent or suicidal behavior. The deluded individual’s degree of self-righteousness and the intensity of the delusional experience, as well as its emotional impact, may be clues to the potential for violent behavior. Plans for harming other people, including homicide and suicidal thinking, are equally important possible features. As comorbidity with depression is high, impulses for self-harm that arise because of frustration, demoralization, and depressed mood or despair are common. Delusions of jealousy, persecution, and erotomania are especially important as they may be associated with possible aggression and violence. Stalking, history of abuse, and arrest records are occasionally encountered. Positive symptoms

First-rank symptoms of schizophrenia as described by Schneider (1959) are not characteristic of delusional disorder. Indeed, the occurrence of first-rank symptoms points to the differential diagnostic possibilities of schizophrenia or another medical condition with features of psychotic psychopathology. Indeed, positive symptoms other than the delusion are not typical. Negative symptoms

Similarly, negative symptoms, a critical dimension of the psychopathology of schizophrenia, are not typically found in delusional disorders. Comorbid mood disorder, such as depression, may result in episodes of reduced motivation and/or ambition and interest, and psychomotor slowing, but not the trait-like durability of negative symptoms typical of schizophrenia. Such ‘‘secondary’’ negative symptoms are also associated with antipsychotic treatment.

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Hallucinations

The presence of hallucinations in delusional disorder cases has been controversial, with some arguing that schizophrenia is a more likely diagnosis and others that delusional disorder is still diagnosable as long as hallucinations are not marked or persistent. There is no final resolution of this issue; DSM-IV (and ICD-10) considers infrequent, poorly organized, simple hallucinations that are not a prominent feature in the mental state to be consistent with delusional disorder. Such hallucinations may be auditory or visual; other types of hallucinations have also been reported. These include tactile or olfactory hallucinations which not only may be present but prominent if they are related to the delusional theme. They tend to be more common in acute cases. Emotional and behavioral symptoms

Patients with delusional disorder show emotional and behavioral response consistent with their experience of delusional concerns (Table 7.5). They may exhibit ideas of reference such that events, comments, looks from others, etc. have special significance for their delusional beliefs. Similarly, dysphoric or irritable mood may be present and understandable as a reaction to their beliefs. Overt anger and potential for violence may characterize individuals with jealousy or persecutory delusional beliefs. On the other hand, somatic delusional individuals may show largely normal moods. Litigious behavior, on the part of persecutory deluded individuals, can be pronounced: bringing suit, letter writing, hiring attorneys, and filing complaints can be common. There are comorbid conditions that can be somewhat difficult to distinguish and may add to the psychopathology. Among these, depression and other mood disorders frequently co-occur in the setting of delusional disorder (Maina et al., 2001; Manschreck, 2000; Munro, 1999). Individuals with comorbid disorders (72%) had an earlier age of onset and presentation of delusional disorder, with the comorbid disorder occurring usually subsequent to the delusional disorder illness. The most common subtype of delusional disorder with comorbid condition (usually mood disorder) is persecutory (54% in Maina et al., 2001). Neuropsychological findings

Psychological assessment may be helpful in revealing evidence of impaired intellectual functioning and may suggest brain abnormality. Differences in the verbal and performance spheres as well as scatter in the overall profile may provide clues indicating a different diagnosis. The limited data that we have on delusional disorder, especially among more chronic cases, suggests that the average patient shows normal or marginally low intelligence which is fairly characteristic of the condition. A comparison of 14 stable outpatients with late-onset delusional

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disorder matched to stable patients with late-onset schizophrenia indicated the presence of neuropsychological impairment in both groups of patients and is probably lower in delusional disorder than in schizophrenia (Evans et al., 1996). Yet the pattern of deficits was similar in both disorders and differences in deficits were not significant. This study, although small in sample size, is instructive. Careful diagnostic and neuropsychological assessments, covering verbal ability, psychomotor skills, abstraction/cognitive flexibility, attention, learning and incidental memory, motor skills, memory, and sensory abilities were administered. The extent to which age influences such results, although the author attempted to control for this, is unclear. Herlitz and Forsell (1996) reported a mild episodic (i.e., in recall tasks) deficit in the absence of other cognitive deficits in 33 elderly subjects with suspected delusional disorder compared to 66 matched controls. Other aspects of neuropsychological function, especially other components of memory, were intact. Course and progression Latency

The characteristics of delusional disorder before its initial presentation and diagnosis are largely unknown. Retrospective accounts of individual cases suggest that certain features are present. For example, there may be no evidence of psychosis in the period prior to presentation (Lewine, 1980). The average duration between onset of symptoms and hospitalization was estimated as 11.9 months in a small cohort of delusional disorder persons. Individual cases may be influenced by a variety of premorbid risk factors. These include isolation, certain personality traits, family history, sensory isolation, and recent immigration. For example, Munro (1999) asserts that many cases appear to arise in a markedly abnormal personality, characterized often by isolation and asocial features. Munro and Chmara (1982) found that 28 percent of a sample of 50 cases had personality disorders, most often schizoid personality disorder. Opjordsmoen and Retterstol (1991) in a study of 72 delusional disorder individuals found evidence of premorbid paranoid personality traits in 43%, avoidant traits in 18%, and schizoid traits in 3%. And Thewissen et al. (2005) have found a relationship between hearing impairment and the onset of psychotic features in a progressive study of a nonclinical population. Initial presentation

The typical case presents after considerable delay and by the most circuitous of routes. There are some cases in which initial presentation is acute, meaning that the development of the delusional thinking has occurred over a relatively short

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period of time. Such patients experience intense preoccupation with the content of the delusional thinking. There is also a tendency early on to experience rather marked mood changes, including irritability and depressive mood, but certainly frustration, disappointment, and demoralization are often present. Many individuals are not seen clinically; as in persecutory and jealousy cases, they voice their concerns to attorneys, the police, and others. Somatic cases bring their concerns to physicians. Psychiatrists and other mental health clinicians are seen last, usually the result of referral or court order. Presentation of psychotic symptoms

Given the limited array of psychopathologic features in delusional disorder, it is not unreasonable to consider that onset begins with the psychotic symptoms, specifically the delusion and its related behaviors. As occupational functioning and intellectual abilities appear to be relatively well maintained, the presence of a delusion and the behaviors associated with the delusion, namely suspiciousness, generally the source of impairment for the patient, are crucial in understanding the nature of this disorder. Prodrome

The prodrome of the illness is therefore not well charted. A number of features may be present. The delusion does not usually occur as a sudden insight, but rather as a culmination of brooding, preoccupations, and possibly odd behaviors on the part of the patient focused on the content of what becomes the delusion. As many cases have a gradual onset, it is likely that the thinking and the concerns associated with that thinking develop over extended periods, perhaps reaching delusional intensity only in the latter stages prior to the development of the illness. Opjordsmoen and Retterstol (1991) found a relationship between duration of symptoms prior to treatment (and diagnosis) and outcome. The longer the duration the poorer the outcome. Much of the evidence on course has come from Nils Retterstol’s personal follow-up and investigation of a large series of cases (Retterstol, 1970; 1991). It has been noted that the onset may begin in adolescence but that most cases occur during middle to late adulthood. There are variable courses including lifelong disorder in many cases. As most studies indicate that delusional disorder is not associated with severe impairment or abrupt changes in personality but rather a gradual or progressive involvement with delusional concerns, this characteristic is also noteworthy. Most patients live a normal life span despite a suicide rate that is considered to be modestly higher than normal. Spontaneous recovery is considered to be low but difficult to ascertain.

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Chronic forms of the illness, that is, patients who present with features of the illness that have been present for more than six months, tend to have an onset early in the fifth decade. Onset is generally acute in two-thirds of cases, and more gradual in the remainder. In Retterstol’s studies, in 53% of the cases the delusion had disappeared at follow-up, was improved in 10%, and was unchanged in 31%. For acute forms of the illness the age of onset is in the fourth decade and recovery occurs in over half the patients. Chronicity develops in nearly 10%, and a relapsing course is seen in 37%. In short, an acute and earlier onset of illness predicts a more favorable outcome. The presence of precipitating factors is often associated with a positive outcome, as is being female and married. Patients with persecutory delusions had the most favorable course and were was a somewhat less favorable course for delusions involving grandeur and jealousy. Patients with delusions of jealousy had fewer hospitalizations and were less likely to show severe psychotic deteriorations. Work status at follow-up has indicated that the majority of patients are employed. Although these observations are limited to a few cases, they provide some basis for being optimistic about this disorder. Perhaps half of the cases may remit, but relapse and chronicity are at least as common. Suspected neuropathology There is no evidence of localized brain pathology to correlate with the psychopathology of patients who suffer from delusional disorder. Because these patients seldom die early and show no consistent abnormalities in neurological examination, the prospect of finding a specific lesion to account for the features of this condition remains distant. Indeed, delusions similar to those of delusional disorders arise in many different disorders, some metabolic in nature and others associated with structural pathology such as degenerative dementias, epilepsy, cerebrovascular disease, extrapyramidal disorder, and traumatic brain injury. Hence, the term ‘‘organic delusional disorder’’ sees frequent use. In fact, there are at least 150 medical conditions in which delusional features have been identified (Manschreck, 2000), a fact that underlines the importance of differential diagnosis, especially because many of these are far more prevalent than delusional disorder. The occurrence of delusions in a variety of disorders with well described neuropathology has led to the proposal that the type of delusional experience that is characteristic of delusional disorders could be associated with subcortical pathology. That is, the elaborate, systematic delusions, tending to be chronic and involving intensely held beliefs and associated with limited if any intellectual impairments, but rather marked affective components, are similar to delusional experiences in patients who suffer from neurologic lesions involving the limbic

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system or subcortical nuclei (McAllister, 1992). This feature, coupled with the observation of the responsiveness of some patients to antipsychotic drug treatment, provides a basis on which to hypothesize the presence of a subcortical pathology, possibly involving temporal and limbic areas (Cummings, 1992). However, the available evidence suggests that, if there is a localizable lesion, it is subtle (Manschreck, 1995; 2000). Imaging studies have yielded subtle findings about delusional disorder. In one study, 16 patients with delusional disorder showed lateral ventricular enlargement greater than in subjects with schizophrenia (n ¼ 31) and almost twice that of age-matched controls (n ¼ 35) (Howard et al., 1994). These same 16 delusional disorder subjects also showed right
left asymmetry significantly greater in the temporal lobes. Delusional disorder patients showed greater dysfunction in saccadic eye movements than normal controls (Gambini et al., 1993). Wada and colleagues (1998) reported reduced regional blood flow in temporal and parietal areas using SPECT probes. Suspected neurochemical abnormalities In efforts to identify the neuropathology of delusional disorder, no specific lesions have been identified, but the search for neurochemical mechanisms underlying the symptomatology has been an area of interest. For example, Morimoto et al. (2002) found that patients with delusional disorder, compared to schizophrenic patients and healthy controls, had higher pretreatment plasma homovanillic levels. They also detected differences in dopamine receptor genetic polymorphisms. When the delusional disorder patients received the antipsychotic haloperidol, they achieved a clinical response with smaller doses compared to acutely psychotic schizophrenic controls. This prompted the researchers to suggest that delusional disorder, because of its focused psychopathology, may in fact be a pure dopamine psychosis. What is interesting about this proposal is that it had been suggested in earlier writings by Munro (1982), who had found that low doses of pimozide, a highly specific dopamine blocking agent, were effective particularly in the somatic form of delusional disorder in his series. These findings create a foundation for hypothesis testing, but much needs to be learned about the neurochemistry of delusional disorder. Genetic factors One of the risk factors for the development of delusional disorder is familial history, suggesting that genetic transmission may have a fundamental role in the production of these disorders. Genetic and family studies indicate possible specific family transmission of delusional disorder. For example, a study of genetic

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Delusional disorder Table 7.6. Prevalence of psychiatric disorders in relatives

Schizophrenia Unipolar depression Bipolar disorder Inferiority feelings Antisocial personality

Delusional disorder n ¼ 58

Schizophrenia n ¼ 585

2 3 0 12 12

7 4 1 4 6

Source: Kendler & Hays (1981) Table 7.7. Other risk factors possibly relevant to etiology

Age Subtle brain abnormality (e.g., head trauma) Social isolation Personality (sensitivity; narcissistic traits) Sensory impairment Immigration Lower socioeconomic status

variation and DNA sequence coding for dopamine D4 receptor protein strongly suggested the involvement of the relevant gene in conferring susceptibility to delusional disorder (Catalano et al., 1993). Comparison subjects either had schizophrenia or were normal controls. Delusional disorder does not appear to be genetically related to schizophrenia (Farmer, McGuffin, & Gottesman, 1984; Howard et al., 1997; Kendler & Hays, 1981; Watt et al., 1980). Findings from family or genetic studies also support the theory that delusional disorder is a distinct entity (Kendler, 1980). There is limited evidence that paranoid and avoidant personality disorder may be common among first-degree relatives of individuals with delusional disorders. If delusional disorder is simply an unusual form of schizophrenia or mood disorder, then the incidence of these latter conditions in the family studies of delusional disorder patient probands should be higher than that of the general population. However, this has not been a consistent finding. For example, a study by Winokur (1985) concluded that patients with delusional disorder are more likely to have family members who show suspiciousness, jealousy, secretiveness, even paranoid illness, than families of controls. Kendler and Hays (1981) found a threefold greater clustering of inferiority feelings among relatives of delusional disorder probands and no evidence of increased schizophrenic prevalence among their relatives (Table 7.6). There is also evidence of increased risk of alcoholism among relatives

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of patients with delusional disorders as compared to probands of schizophrenia, as well as probands with psychotic disorder, NOS, and probands with schizophreniform disorder (Kendler and Walsh, 1995). While it would be premature to suggest that a genetic transmission pattern of substantial influence has been found for this disorder, it is clear that some familial influence is operative. We await the results of additional studies. Other risk factors A number of risk factors in addition to genetic or familial risk have been described as associated with delusional disorder (Table 7.7). Munro (1999) reports in his series that individuals with delusional disorder frequently have a history of ‘‘cerebral insult’’, for example, traumatic brain injury, stroke, and diabetic neuropathy, and a history of psychoactive substance abuse. He argues that subtle brain abnormality may be a predisposing factor for delusional disorder. Others have suggested that aging contributes to risk, also perhaps related to a matrix of changes captured by the term ‘‘subtle brain impairment.’’ Immigration status appears to be an associated finding in many studies of delusional disorder. Kendler (1982) asserted that this association was greater than that for mood disorders or schizophrenia (McGrath, 2005). For example, the rate for delusional disorder in one Norwegian study among immigrants was forty fold that of the indigenous population (Eitinger, 1960), while the rate for schizophrenia was one and a half that of the indigenous population. Sensory deficits, common among older adults, may also be a predisposing factor to psychosis, although there is controversy concerning the specificity of the relationship (Manschreck, 2000; Thewissen et al., 2005). Factors that appear to be unrelated or not particularly relevant to delusional disorder include alcohol use and place of residence (rural or urban) (Kendler, 1982). In sum, the risk factors of lower socioeconomic and educational status, sensory isolation, immigration status, and cerebral insult may be important because of the comparatively low rates of mental disorder found in families of delusional disorder patients. These observations are consistent with Kraepelin’s proposal that environmental factors may be more critical than genetic in the pathogenesis of delusional disorder (paranoia). Treatment Sometimes delusional disorders are actually treated despite the tendency to avoid psychiatric intervention. Patients with the disorder have generally been regarded as difficult to treat, if not treatment resistant, and interventions have often focused

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on managing the morbidity of the disorder by reducing the impact of the delusion on the patient’s and the family’s life (Manschreck, 2000; 2005). Recent evidence has suggested that the outlook can be much less pessimistic. However, treatment is a delicate enterprise with many obstacles. Its goals are first to establish the diagnosis, to decide on appropriate interventions, and to manage complications. Fundamental to success in reaching these goals is an effective and therapeutic relationship, not easy to establish but critical to maintain. The psychiatric clinician in fact may be brought into the net of the delusional thinking. Psychosocial treatments

Limited evidence exists to substantiate the proposition that any particular approach to talking therapy is preferable. Insight oriented therapy is generally contraindicated, but most clinicians view supportive psychotherapeutic approaches possibly augmented by cognitive behavioral interventions as a sensible strategy. The key to treatment is recognition that this is a psychiatric condition that requires openness and reliability from the therapist at a level greater than is usually necessary in other conditions. Considerable skill is essential to deal with the profound and intense feelings that accompany these disorders. Patients appear to have fragile self-esteem and unusual sensitivity. This of course affects their general management and the course of any form of treatment. The strategy is to forge an alliance, avoiding direct questioning of the veracity of the delusion and responding to the sense of distress rather than to the content or characteristics of the delusion itself. As fear and anxiety may stimulate hostility in those with this disorder, it is useful to adopt a flexible approach that enhances empathy but maintains emotional distance with the patient. These individuals are suffering. They feel demoralized, miserable, isolated, abandoned, and unbelieved. Consequently, they may face rejection at home, from police or medical specialists, or on the job. The goals of such therapy are to allay anxiety and to encourage discussion of troubling experiences and consequences of the delusion, hoping thereby to develop an empathic collaboration with the patient. In some cases this strategy may suggest means of coping more successfully with the delusional thinking. Occasionally, intervention may also assist the individual to understand how features such as sensory impairment, social and physical isolation, and even stress contribute to making their condition worse. Cognitive approaches have attempted to reduce delusional thinking in this and other psychotic disorders through modification of the belief itself, a very different strategy focusing on the associated reasoning or the reality testing of the deluded individuals, unlike non-cognitive approaches that center attention on reduction of verbal behavior, that is, talking about the delusion. This strategy seeks a more lasting and meaningful intervention through multiple techniques that keep the

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relationship with the patient collaborative. These techniques include, amongst others, distancing, homework, and examination of emotions associated with the various delusions. The effectiveness of cognitive behavioral therapy has not been studied enough to warrant a strong recommendation, and it is important to understand the value of long-term follow-up as well as short-term impact of these treatments before making a final judgment. Nevertheless, the techniques are promising and suggest the value not only of further research but of thoughtful application of these treatments. Somatic treatment

As delusional disorder is in fact a psychotic disorder, understandably many have thought that it might respond to antipsychotic medication. However, control studies are few and the disorder is uncommon. Hence, evidence to support antipsychotic intervention is limited. Riding and Munro (1975) reported on the treatment of several cases of what was termed monosymptomatic hypochondriacal psychosis with the antipsychotic agent pimozide. This work was replicated in additional publications and indicated that a form of delusional disorder (i.e., the somatic subtype) is a treatable condition with this medication. They further found that in unimproved cases, noncompliance with medication was an important factor affecting outcome. Later, Munro and Mok (1995) reviewed experience with antipsychotic treatment of delusional disorder from the 1960s to 1994, critically analyzing approximately 1,000 articles dating from 1961. They only selected cases where clinical presentations conformed to DSM-IV criteria, and identified 257 cases, of which 209 were sufficiently detailed to report meaningfully about treatment. Only the broadest conclusions could be drawn from their review. Nevertheless, they concluded that delusional disorder was an illness with a reasonably good prognosis when adequately treated. They also observed that treatment response was positive regardless of the specific delusional content (subtype) of the disorder. Interestingly they also noted that pimozide had the strongest evidence of good results in these clinical reports. This writer has reviewed the literature published since 1994 (Manschreck & Khan, 2006). A similar selection process extracted some 221 usable cases. However, of these, only 131 had sufficient treatment information for analysis. A major innovation since Munro and Mok’s review (Munro & Mok, 1995) was the introduction of second generation (atypical) antipsychotic medications that some had predicted might successfully treat delusional disorder. New trends in medication therapy had also emerged during this interval. Among these were polypharmacy regimens including both multiple antipsychotics as well as antipsychotics and other psychotropic agents. The main results were that in the

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best documented cases a positive response was noted in nearly 50%. This observation contrasts with widespread pessimism about treatment in delusional disorder. As the literature seldom provides a forum for negative results and clinicians are reluctant to report such results, the reliance on case study rather than controlled trials and the lack of double blind randomized control studies raise concern about the evidence for this positive response. Despite the introduction of second generation agents over a decade ago, the number of reports is limited and experience thus far, though it parallels those of the older agents, limits major conclusions. Conclusions Delusional disorder remains an enigmatic and largely uncharted subject. Current knowledge, although rudimentary, frames a disorder with devastating psychopathology. Establishing a greater grasp of this condition will depend fundamentally on large-scale studies or more modest scale, systematic research on its many dimensions. A related obstacle is the limited understanding we have of delusions per se.

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4.

Part III

Mood Disorders

8

Psychosis in bipolar disorder Deborah Yurgelun-Todd Harvard Medical School and McLean Hospital

Summary of findings Grade of evidence Epidemiology: Psychotic symptoms occur in about half of bipolar patients, with inconsistencies in sex differences for psychotic symptoms. Age of onset: Psychotic symptoms are more common in early-onset bipolar disorder. Presentation: Delusions (grandiose, influence, or persecution) are the most common psychotic symptoms, with mood incongruent features in about 50% of patients; age of onset may predict the type of psychotic symptoms experienced. Course and progression: Psychotic symptoms predict further psychotic episodes, and are associated with poorer functional outcome. Suspected neuropathology: Shared volumetric reductions in first episode psychotic bipolar and schizophrenia, but reductions in psychotic bipolar are less widespread; psychosis is associated with white matter changes common to bipolar and schizophrenia; a number of neurophysiological changes in psychotic bipolar are more similar to schizophrenia than non-psychotic bipolar. Suspected neurochemical abnormalities: Reduced temporal lobe NAA in psychotic bipolar; post-mortem neurochemical abnormalities show commonalities with schizophrenia; dopaminergic changes in psychotic bipolar. Genetic factors: Shared susceptibility genes for psychotic bipolar with schizophrenia and within families with psychotic bipolar probands; familial aggregation of psychotic features in bipolar families. Other risk factors: Post-partum psychosis; Multiple sclerosis. Treatment: Mood-stabilizers, including lithium and anti-convulsants for acute and maintenance therapy, with adjunctive antipsychotics for 137

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Grade of evidence acute mania and antidepressants for depressive symptoms; integration of psychotherapy has additional benefits; mood-stabilizers and antipsychotics have similar efficacy on psychotic symptoms, with some evidence of an additive effect.

Introduction Bipolar disorder is a prevalent and often debilitating developmental neuropsychiatric illness, which is among the leading causes of disability worldwide. A recent investigation reported bipolar disorders affect approximately 2.3 million individuals in the United States or 1.2 percent of the population in a given year (Narrow et al., 2002). Characterized by severe alterations in mood (i.e. mania, depression) which are generally episodic and recurrent, bipolar disorder is currently considered to have several possible subtypes: bipolar I disorder (with mania, major depression, or mixed dysphoric-excited states), bipolar II disorder (major depression with hypomania), cyclothymic disorder, and bipolar disorder not otherwise specified, as well as the course-specifier rapid cycling (at least four recurrent episodes within one year of assessment) (APA, 1994). Psychotic symptoms are a common feature of bipolar disorder (Benazzi, 1999), most frequently manifesting as grandiose delusions, delusions of persecution, and delusions of influence, with formal thought disorder, hallucinations, and Schneider’s first-rank symptoms also observed but relatively less common. Bipolar patients with prominent psychotic features may even characterize a distinct subgroup (Swann et al., 2001). Moreover, researchers have recently challenged the Kraepelinean view of the dichotomous classification of bipolar disorder and schizophrenia (Kendler, Karkowski, & Walsh, 1998; Ketter et al., 2004). Epidemiology A recent eight-year study of first-episode psychosis observed an annual incidence of bipolar disorder with or without psychosis of 5.2 per 100,000 population aged over 15 years, with no difference in the incidence between males and females (Baldwin et al., 2005). In a 35-year epidemiological study, psychotic symptoms were experienced by 74% of 246 first-episode mania patients diagnosed with bipolar I disorder (Kennedy et al., 2005). An Australian prevalence study of

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112 bipolar I and II patients reported that 86% had experienced delusions, with only 21% ever experiencing hallucinations. More males had a life-time history of delusions than females (88% versus 83%) (Morgan, Mitchell, & Jablensky, 2005). In this study, manic or mixed episodes were present in 18.8% of the patients within the four weeks preceding interview, with 47.6% of these patients exhibiting grandiose delusions at this time. The authors did not report the number of patients presenting with hallucinations, but of those interviewed men were more likely to experience hallucinations and delusions than women (39% versus 21%) (Morgan et al., 2005). This study included only patients in contact with treatment services, therefore it was likely to select far more severe bipolar patients and possibly overestimate the prevalence of psychotic symptoms. In contrast, Yildiz and colleagues observed that only 42% of bipolar patients were positive for a history of psychotic symptoms, with 95% of these psychotic symptoms diagnosed in bipolar I patients. In this retrospective study, life-time history of psychotic symptoms was higher in women than men (48% versus 35%) (Yildiz & Sachs, 2003), in contrast to the aforementioned study. A recent review reported psychotic symptoms in 16
88% of pediatric and adolescent bipolar studies (Pavuluri, Herbener, & Sweeney, 2004), with higher prevalence rate (61
88%) reported in studies that used the Structured Clinical Interview for DSM III-R (SCID) rather than the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS) for diagnosis (Carlson, Bromet, & Sievers, 2000; McClellan et al., 1999; McElroy et al., 1997), indicating that methodological issues need to be considered. Overall, these studies and others (Coryell et al., 2001; Potash et al., 2001; Schulze et al., 2002; Schurhoff et al., 2000) indicate that at least half of patients with bipolar I disorder experience psychotic features at some time and less with bipolar II disorder (Benazzi, 1999; Yildiz & Sachs, 2003), however, further research is required to determined whether differences exist in the occurrence of psychotic symptoms in men and women.

Age of onset The median age of onset of bipolar disorder appears to be in the late teens to early twenties, although both early-onset (pediatric and adolescent) as well as late-onset bipolar disorder are being recognized with increasing frequency (Leboyer et al., 2005). Most studies agree that psychotic symptoms are more common in patients with early-onset than late-onset bipolar disorder; however, methodological differences prevent direct comparison between studies. In a 35-year study of first-episode mania, Kennedy and colleagues reported a significant age of onset effect with 77% of patients experiencing psychotic symptoms with onset earlier

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than 40 years old compared with 61% of patients 40 years old or over (Kennedy et al., 2005). A study of 210 consecutive admissions to psychiatric hospitals reported that 47% of adolescent bipolar patients (under 18 years old) had a history of psychotic symptoms compared with 26% of late-onset patients (over 40 years old) (Schurhoff et al., 2000). Similarly, Schulze and colleagues reported a greater number of patients with a history of delusions and hallucinations with early onset (20 years old or less) compared to late onset (30 years old or more) (Schulze et al., 2002). However, Yildez and colleagues reported that the mean age of onset was significantly younger for patients with a history of psychotic symptoms versus those without in males only in a retrospective study of 328 bipolar patients (Yildiz & Sachs, 2003), in concordance with a study reporting that males were over-represented in the early-onset group (under 21 years old) compared with the late-onset group (over 30 years old) in patients with psychotic features (Carlson et al., 2000). Earlier studies have generally supported the increased prevalence of psychotic symptoms in early-onset bipolar disorder (Ballenger, Reus, & Post, 1982; McGlashan, 1988; Rosen et al., 1983b), although no difference between groups was observed in a small study (Coryell & Norten, 1980), and lower prevalence of psychotic symptoms was reported in adolescents in one prospective study (McElroy et al., 1997). This latter study was methodologically different to previous studies as it compared current psychotic symptoms in hospitalized groups, and the demarcation of age groups (adolescent 12
18 years versus adult 19
45 years) precluded detecting any differences between early- and late-onset bipolar disorder.

Presentation Psychotic symptoms usually manifest during the manic phase as delusions and hallucinations, and these can be mood-congruent or mood-incongruent, with negative symptoms observed in some patients. The presence of these symptoms is associated with poorer functioning and increased hospitalization at the time of illness (Swann et al., 2004). For first-episode early-onset mania in patients seeking treatment, the most common psychotic features in bipolar disorder were grandiose delusions (62%), delusions of persecution (60%), and delusions of influence (38%) (Kennedy et al., 2005), with hallucinations less common (21%) (Morgan et al., 2005). Additionally, 50% of patients had experienced moodincongruent psychotic features and 41% positive formal thought disorder, but for a majority of these patients these psychotic episodes lasted less than one week. The type of psychotic symptoms experienced are associated with the age of onset, with mood-incongruent psychotic features, delusions of persecution and

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influence, and auditory hallucinations more evident in the early-onset group, while visual, somatic, and olfactory hallucinations, although relatively rare in bipolar disorder, are more common in the late-onset group (Kennedy et al., 2005). Similarly, Carlson and colleagues observed more grandiose and paranoid delusions in adolescents compared with late-onset patients, although rates of mood-incongruent delusions and hallucinations in this study were independent of age of onset (Carlson et al., 2000). Neuropsychological and emotional symptoms are dependent on the phase of illness, with depressive and manic episodes involving a complex mix and interplay of mood, motivational, cognitive, somatic, and behavioral symptoms, and residual cognitive impairments are often evident in the euthymic state (Coffman et al., 1990; Joseph, 1999). Bipolar depressed individuals show a decrease in focused attention and goal-directed or motivated behavior across multiple areas of functioning. In contrast, a manic episode is characterized by elevated, expansive, or irritable mood, and is usually accompanied by altered cognitive processing, heightened energy levels, higher sex drive, increased activity levels, pressured thought and speech, and distractibility (Altshuler, 1993; Sapin et al., 1987). Unlike depressed individuals, manic patients show an increased interest in pleasurable activities and a resultant increase in reward-directed behavior.

Course and progression Bipolar disorder is usually recurrent and multiple episodes or prolonged periods of impaired functioning are the rule rather than the exception. Initial symptoms may be manic or depressive with similar frequency at first presentation; there is often a delay between the onset of symptoms and treatment seeking. A survey of 500 patients reported that only 23% of patients consulted a medical professional within six months of initial symptom onset (Lish et al., 1994) and many do not for 5
10 years (APA, 1994). Bipolar has high rates of recurrence, with approximately 90% of individuals who have a single manic episode going on to have a future episode (Gitlin et al., 1995). Recurrent psychosis is predicted by the presence of psychotic symptoms during hospitalization (Goldberg & Harrow, 2004), particularly during the depressive phase (Coryell et al., 2001), and psychotic symptoms in major depression are associated with increased risk for later diagnosis of bipolar I disorder (Akiskal et al., 1995). The average cycle length between the first and second episodes varies between 2
4 years in different studies, with episodes occurring with increasing frequency subsequently (Goodwin & Jamison, 1990). Rapid cycling of at least four affective states per year occurs in 10
15% of patients. Manic episodes begin more abruptly than the relatively slower onset of

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bipolar depression, with symptoms lasting from a few days to several months (Lish et al., 1994). Psychosocial functioning can be affected severely in bipolar disorder, with up to 60% of patients unable to return to a premorbid level of functioning both socially and vocationally (MacQueen, Young, & Joffe, 2001). Comparing outcome for psychotic and nonpsychotic bipolar patients, poorer outcome has been reported in psychotic patients, including higher relapse rates (Tohen, Waternaux, & Tsuang, 1990), greater number of weeks ill (Coryell et al., 2001), and poorer social functioning (Cannon et al., 1997; Rosen et al., 1983a); however, not all studies have observed differences between these groups at outcome (Goldberg & Harrow, 2004; MacQueen et al., 1997). Poorer outcome may be associated with specific psychotic symptoms, for example, mood-incongruent psychosis at first manic episode were associated with shorter remission times (Tohen, Tsuang, & Goodwin, 1992), and poorer overall functioning (Strakowski et al., 2000), and Schneiderian first-rank symptoms predicted poor residential status (Tohen et al., 1992). Seriously impaired bipolar patients are more likely to be male, single, less educated, and more likely to experience hallucinations (31% versus 17%), but not delusions (Morgan et al., 2005).

Suspected neuropathology Bipolar studies have reported that brain abnormalities are mainly regional, particularly in the prefrontal cortical areas, amygdala, and striatum, with whole brain white and gray matter and ventricular volumes relatively less affected (reviewed by Haldane & Frangou, 2004; Strakowski, Delbello, & Adler, 2005). Most research examining brain abnormalities associated with psychosis has compared first-episode psychoses in bipolar patients and schizophrenics. Compared with healthy controls, both first-episode psychotic bipolar and schizophrenic patients have demonstrated a reduction in the volume of the left hippocampus (Velakoulis et al., 1999), anterior cingulate (Hirayasu et al., 1999), left temporal pole gray matter, and a reduction in hemispheric asymmetry (Kasai et al., 2003), with similar decreases in white matter reported in both groups (Farrow et al., 2005). Additionally, a greater proportion of psychotic bipolar and schizophrenic patients exhibit abnormal cavum septi pellucidi than controls, suggesting shared neurodevelopmental abnormalities and associated psychopathological outcome (Kasai et al., 2004). Some studies have identified volumetric changes specific to first-episode schizophrenia that were not apparent in psychotic bipolar disorder. These changes include a reduction in the volume of the superior temporal lobe gyrus (Hirayasu et al., 1998; 2000), insular cortex (Kasai et al.,

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2003), fusiform gyrus (Lee et al., 2002), the left prefrontal gray matter (Hirayasu et al., 2001; Wiegand et al., 2004). Findings specific to first-episode affective psychosis include asymmetry of the posterior amygdala-hippocampal complex (Hirayasu et al., 1998), and changes in the structure of the corpus callosum (Frumin et al., 2002). A recent longitudinal study of first-episode psychosis observed that psychotic bipolar patients exhibited reduced inferior temporal gyri volumes at initial presentation with decline in the anterior cingulate over two years, while schizophrenic patients demonstrated more widespread reductions in fronto-temporal gray matter at initial presentation, with additional losses in the lateral fronto-temporal regions and left anterior cingulate over time (Farrow et al., 2005). In studies that have looked beyond first-episode psychosis, disruptions of white matter connectivity appear to be important in the pathogenesis of psychosis. A computational morphometry study of bipolar patients with a history of psychosis and schizophrenics observed that these patients shared longitudinal and inter-hemispheric white matter abnormalities indicative of disconnectivity between frontal and temporoparietal cortex. However, patients with schizophrenia also exhibited more widespread cortical volume reductions of the fronto-temporal neocortex, medial temporal lobe, insula, thalamus, and cerebellum (McDonald et al., 2005). Interestingly, relatives of psychotic bipolar probands exhibit reduced volumes of the right anterior cingulate and ventral striatum, with familial risk of both schizophrenia and psychotic bipolar disorder associated with reduced white matter in the left frontal and temporoparietal regions (McDonald et al., 2004). These reported white matter changes associated with psychosis are consistent with downregulation of genes related to myelination and oligodendrocyte function observed in both bipolar and schizophrenia brains (Tkachev et al., 2003) and the higher prevalence of white matter hyperintensities in bipolar patients (Ahn et al., 2004). Only a few brain studies have compared bipolar patients with and without psychotic features. Strasser and colleagues demonstrated that psychotic bipolar disorder and schizophrenia were associated with enlarged lateral ventricles compared with nonpsychotic bipolar disorder and controls (Strasser et al., 2005), suggesting that psychotic bipolar disorder is a more homogeneous subgroup, with more similarities to schizophrenia than nonpsychotic bipolar disorder. However, in this study left hippocampal volume was reduced in schizophrenics, but there were no significant differences in hippocampal volume between psychotic and nonpsychotic bipolar patients and controls. Additionally, bipolar patients with a history of psychotic symptoms demonstrated a reversal of the cerebral asymmetry anterior-posterior equivalent current dipole locations compared with both controls and nonpsychotic bipolar patients (Reite et al., 1999). These findings are

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indicative of anatomical displacement of the precentral gyrus, and are similar to that seen in schizophreniform disorders. In a study of psychotic and nonpsychotic depressive patients including some diagnosed with bipolar disorder, shortened REM latency was related to psychotic symptoms independent of illness severity (Stefos et al., 1998).

Suspected neurochemical abnormalities A recent review has comprehensively reported neurochemical alterations in bipolar disorder in studies using proton (1H) and phosphorous (31P) magnetic resonance spectroscopy (MRS) in bipolar disorder (Stork & Renshaw, 2005). This review hypothesized that bipolar disorder was associated with mitochondrial dysfunction, indicated by reports of reduced N-acetylaspartate (NAA), a marker of neuronal dysfunction, as well as increased amino acids (glutamine and glutamate), lactate, and reduced intracellular pH, suggestive of a shift toward glycolysis. Additionally, altered phospholipid metabolism has been observed in bipolar patients, marked by an increase in choline and myo-Inositol, and altered phosphomonoester levels in these studies. There is a relative paucity of data examining the link between psychotic bipolar disorder and neurochemical changes: reduced NAA was observed in the temporal lobe of first-episode psychosis patients with either schizophreniform or bipolar disorder in one study (Renshaw et al., 1995), and NAA/creatine was reduced in the bilateral hippocampus in first-episode bipolar patients with psychosis compared with controls in another (Blasi et al., 2004). These results suggest that the neuronal integrity of the temporal lobes is impaired in bipolar patients with psychotic symptoms, and that these abnormalities are not related to the chronicity of symptoms. Reduced NAA in the hippocampus has also been observed in bipolar patients with and without psychotic symptoms (Bertolino et al., 2003; Deicken et al., 2003), therefore further investigation is required to determine if this finding is specific to psychotic symptoms. In postmortem bipolar disorder and schizophrenia brains, an overlap in the reduced expression of a number of neurochemical markers was suggestive of shared abnormalities in the GABA and developmental/synaptic neurochemical systems in these disorders (Torrey et al., 2005). There is also evidence to support the disruption of serotoninergic (Drevets et al., 1999; Vawter, Freed, & Kleinman, 2000) and dopaminergic (Strakowski et al., 2005) neurotransmitter systems in bipolar disorder. One study has reported that D2 receptor binding is increased in patients with psychotic symptoms only, with a relationship between psychotic symptoms and D2 receptor density (Pearlson et al., 1995), providing support that the dopaminergic system is important for the expression of psychoses.

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Genetic factors Findings from family, twin, adoption, and other genetic studies consistently report a strong genetic component to bipolar disorder that has been comprehensively reviewed (Craddock & Jones, 1999; 2001; Craddock, Dave, & Greening, 2001; Craddock, O’Donovan, & Owen, 2005; Smoller & Finn, 2003). Risk for the disorder increases as the amount of shared genetic material increases, with concordance rates between monozygotic twins approximately 40
70%, and for first-degree relatives 5
10%, compared to a lifetime risk of about 1% in the general population. Heritability is generally more specific for bipolar disorder (McGuffin et al., 2003), but the risks for schizophrenia and psychotic symptoms are also increased in first-degree relatives of bipolar patients (Gershon et al., 1988; Ketter et al., 2004; Maier et al., 1993; Rende et al., 2005). Additionally, bipolar disorder and schizophrenia are both associated with increased familial risk for schizoaffective disorder and there is overlap of the susceptibility genes 10p12
13, 13q32, 18p11.2, and 22q11
13 between these disorders (Berrettini, 2000), suggesting shared genetic risk that may be partially responsible for the expression of psychotic symptoms. Susceptibility genes for psychotic bipolar disorder have also been identified in bipolar families on chromosomal regions 13q31 and 22q12 (Potash et al., 2003b). A genetic role for the expression of psychotic symptoms in schizophrenia and affective disorders has been demonstrated in a number of familial studies. Increased risk for bipolar disorder with psychotic features was observed in relatives of schizophrenia probands, but the increased risk for schizophrenia in relatives of psychotic affective disorder probands did not reach significance (Kendler et al., 1993). Potash and colleagues have identified the familial aggregation of psychotic symptoms (delusions and hallucinations) in two independent samples of bipolar I patients (Potash et al., 2001; 2003a), and another study identified increased susceptibility to delusions amongst families of schizophrenic and bipolar probands (Schurhoff et al., 2003). Additionally, affected siblings with bipolar disorder show a correlation between dimension scores for psychosis (O’Mahony et al., 2002). In contrast, an earlier study reported family linkage of psychotic symptoms in schizophrenia and schizoaffective disorder, but not in unipolar and bipolar disorder; however, the number of subjects was significantly lower in the affective disorder groups (Winokur, Scharfetter, & Angst, 1985). Other risk factors The investigation of non-genetic antecedents to bipolar disorder is at an early and largely inconclusive stage (Goodwin & Jamison, 1990; Tsuchiya,

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Byrne, & Mortensen, 2003). Tsuchiya and colleagues reviewed the literature to identify seven putative socio-environmental risk factors showing evidence of an association with bipolar disorder, including recent stressful life events, socioeconomic status, birth seasonality, obstetric complications, post-partum psychosis, traumatic brain injury, and multiple sclerosis (Tsuchiya et al., 2003). Of these, evidence to indicate a relationship with psychotic symptoms has been reported for post-partum psychosis and multiple sclerosis only. There is convincing evidence to support a link between post-partum psychosis and bipolar disorder based on similar symptomatology, diagnosis and outcome, and family history (Chaudron & Pies, 2003). Women who are diagnosed with post-partum psychosis have a 60
75% risk of recurrence or further affective episodes and approximately 30% are diagnosed with bipolar disorder (Robling et al., 2000; Schopf & Rust, 1994; Videbech & Gouliaev, 1995). There is a higher risk for post-partum psychosis in women with bipolar disorder, with about 30% of women with bipolar disorder meeting the criteria for post-partum psychosis (Chaudron & Pies, 2003; Jones & Craddock, 2001), compared to one in 1000 women experiencing post-partum psychosis in the general population (Videbech & Gouliaev, 1995). In multiple sclerosis, a clinical study reported that 13% of patients with multiple sclerosis have a diagnosis of bipolar disorder (Joffe et al., 1987) and a history of mania or manic psychosis was more common in the ten patients with multiple sclerosis than the 2710 other consecutive admissions to a psychiatric unit (Pine et al., 1995). Additionally, the emergence of psychotic symptoms was associated with first neurological symptoms of multiple sclerosis or relapse in three case reports (Heila, Turpeinen, & Erkinjuntti, 1995; Salmaggi et al., 1995; Young et al., 1997), suggesting that psychotic symptoms were associated with the lesion site. However, a possible shared susceptibility gene locus has also been identified (Bozikas et al., 2003), indicating that there may be a more complex shared etiology. Treatment Bipolar disorder is a complicated and debilitating illness that is best managed by combining treatments of psychopharmacology and psychotherapy. Because there is a large neurobiological and neurochemical component, medication is the first line of defense to stabilize symptoms during treatment; however, there is usually a latency from illness onset to diagnosis and appropriate treatment (APA, 1994). Bipolar disorder carries a threefold increase in medical mortality and increased fatality risk secondary to commonly comorbid substance abuse. Despite these facts, as few as 20% of individuals with bipolar illness are evaluated medically and

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correctly diagnosed, and many are considered to have a unipolar major depressive disorder or schizophrenia. A very important medication in the treatment of bipolar disorder is the mood stabilizer, including lithium and the newer anticonvulsants: divalproex, carbamazepine, and lamotrigine. Other common treatments include typical antipsychotics (haloperidol, perphenazine, and chlorpromazine) and atypical antipsychotics (olazapine, risperidone, ziprasidone, and clozapine). Lithium and anticonvulsants reduce the manic/depressive episode, decrease the occurrence of episodes as well as prevent the worsening of episodes; therefore they are used for the acute and maintenance treatment of bipolar disorder. Lithium is not effective in all patients, particularly in rapid cycling and mixed symptoms, which show better response to anticonvulsants (Mensink & Slooff, 2004). Adjunctive antipsychotics, which are antimanic, sedative, and faster acting, are generally given for treatment of acute mania, particularly when symptoms are more severe, and some antipsychotics have been used as a monotherapy or adjunctive therapy for prophylactic care (Mensink & Slooff, 2004). Depressive symptoms are often treated with antidepressants (SSRIs); however, antidepressants should be used in conjunction with mood stabilizers, particularly lamotrigine, to prevent inducing hypomania and/or mania (Moller & Nasrallah, 2003). Integrating psychopharmacology with psychotherapy has been found to result in fewer and less severe episodes and fewer hospitalizations while also increasing social functioning (Lam et al., 2003). The addition of psychotherapy is generally recommended only for bipolar patients that are not experiencing a manic or psychotic episode. Earlier studies investigating a differential response to lithium by patients with psychotic and nonpsychotic symptoms did not observe consistent differences (Goodwin & Jamison, 1990). More recently, Kafantaris and colleagues reported that adolescent bipolar patients with psychotic symptoms respond less well to lithium monotherapy than adolescent nonpsychotic bipolar patients (Kafantaris et al., 1998), but this difference in response was not observed in adults with and without psychotic symptoms (Coryell et al., 2001). Response rate is better when a mood stabilizer is combined with antipsychotic medication, particularly in cases where psychotic symptoms are present (Delbello et al., 2002). In general, mood stabilizers and antipsychotics have similar efficacy, particularly in the treatment of psychotic symptoms (McElroy et al., 1996; Swann et al., 2001; 2002; Tohen et al., 2002). In treatment-resistant bipolar disorder, adjunctive clozapine was equally effective at treating psychotic and nonpsychotic bipolar disorder (Suppes et al., 1999). Consistent with this, Swann and colleagues have hypothesized that psychotic symptoms represent a more severe form of mania, suggesting that

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treatment of manic symptoms automatically ameliorates psychotic symptoms (Swann et al., 2004).

Conclusions In summary, psychotic symptoms are a common feature of bipolar disorder, and occur in approximately half of patients diagnosed with the illness. Most studies agree that psychotic symptoms are more common in patients with early-onset rather than late-onset bipolar disorder. The types of psychotic symptoms experienced have been associated with age of onset, with auditory hallucinations more prevalent in early-onset groups, while late-onset groups are more prone to experience visual, somatic and olfactory hallucinations. Psychotic symptoms predict further psychotic episodes, and are associated with poorer functional outcome, particularly within the social domain. Brain imaging studies have shown that psychosis is associated with white matter changes common in patients with schizophrenia or bipolar disorder, and several neurophysiological changes associated with psychotic bipolar disorder are more common in schizophrenia than nonpsychotic bipolar disorder. Recent evidence suggests there is an overlap of susceptibility genes for bipolar disorder and schizophrenia, and the risk of developing schizophrenia and psychotic symptoms is increased in first-degree relatives of bipolar patients. Patients with bipolar disorder or schizophrenia both demonstrate increased familial risk for schizoaffective disorder. Therefore, it is not surprising that researchers have recently challenged the Kraepelinean view of the dichotomous classification of bipolar disorder and schizophrenia. Additional research is necessary to clarify the role of psychosis in the diagnosis and treatment of bipolar disorder.

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Psychosis in major depression Eric G. Smith, Philip R. Burke, Jessica E. Grogan, Susan E. Fratoni, Chelsea S. Wogsland, and Anthony J. Rothschild Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B
C B
B C B
C D B


Introduction Major depression with psychotic features (MDpsy) is an under-recognized and understudied disorder despite being a common clinical problem. This difficulty in clinically recognizing the illness, often coupled with fear or a lack of insight on the part of patients, has slowed research advances. This chapter will review the state of knowledge of the epidemiology, age of onset, clinical presentation, course and progression, suspected neuropathology, suspected neurochemical abnormalities, genetic and other risk factors, and treatment of this serious illness.

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Epidemiology The prevalence of unipolar major depression with psychotic features (MDpsy)1 is often underappreciated, both in the general population and in clinical settings. The most recent large-scale epidemiological survey (Ohayon & Schatzberg, 2002) used a novel computer-based diagnostic program on a sizeable European sample (19,000 persons) and found 18.5% of all individuals meeting criteria for major depression met criteria for MDpsy (delusions, hallucinations, or both). While the computerized diagnostic approach had only moderate reliability when compared to psychiatrist interviews (kappa statistics of 0.44
0.78), this estimate is remarkably similar to results obtained in a previous lay interview study, the Epidemiologic Catchment Area study (ECA). The ECA study of a general population sample of 18,000 found that almost 15% of individuals who met criteria for lifetime major depression had a history of psychotic features (Johnson et al., 1991). Because the ECA study did not inquire about delusions of guilt, disease, poverty, or nihilism (common ‘‘mood congruent’’ delusions; see ‘‘Presentation’’ section below), and because of the difficulty obtaining a history of psychotic symptoms in a telephone interview by anonymous lay interviewers, this estimate may represent an underestimate of the community prevalence of MDpsy. (However, the failure of the ECA study to differentiate between psychotic depression and schizoaffective disorder may somewhat counterbalance this bias.) Nevertheless, the close agreement between the ECA estimate and the European study (Ohayon & Schatzberg, 2002) strengthens confidence that MDpsy constitutes between 15
20% of depression that is observed in the community. Both studies suggest that MDpsy is somewhat over-represented in clinical samples relative to its prevalence in the general population. The 2002 study found that individuals with psychotic depression were twice as likely to have a history of past psychiatric consultation, while the ECA study found that those with a history of MDpsy accounted for 20% of the individuals with major depression who received any psychiatric treatment, and 21% of individuals previously hospitalized for depression. In clinical samples, the prevalence of psychotic depression varies from approximately 18
45% of the patients seen with major depression, based on setting and demographics. One survey using DSM-III criteria found that 25% of patients consecutively admitted as inpatients for major 1

Throughout this chapter a distinction has been made when possible: MDpsy refers to the diagnosis of unipolar major depression with psychotic features, ‘‘psychotic depression’’ refers to mixed samples of patients with bipolar and unipolar depression, and ‘‘psychotic affective illness’’ refers to mixed samples that contain patients with unipolar major depression, bipolar depression, or bipolar mania with psychotic features. ‘‘Nonpsychotic depression’’ refers to the portion of any of those samples that did not exhibit psychosis (and so usually, but not always, refers to unipolar major depression without psychotic features).

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depression exhibited psychotic features (Coryell et al., 1984). In a more recent survey, approximately 18% of Danish inpatients with depression admitted for their first inpatient hospitalization were coded as having severe depression with psychotic features by ICD-10 criteria (representing 44% of the patients specified as having severe depression) (Kessing, 2003). A large sample of over 650 inpatients and outpatients given the Diagnostic Interview Schedule for depression found 28% of the sample had MDpsy (Thakur et al., 1999). The prevalence of psychotic depression in clinical samples increases with age (Brodaty et al., 1997), with one study finding psychotic features in 45% of elderly inpatients with depression (Meyers & Greenberg, 1986). In two separate elderly samples that comprised a mix of inpatients and outpatients presenting at a mood disorders clinic, approximately 33% of elderly patients with depression were found to have psychotic features (Brodaty et al., 1991; 1997). In the general population, the overall prevalence of psychotic depression among the elderly (age 60 or older) in Finland has been estimated to be one in 100 (Kivela & Pahkala, 1989). However, the 2002 European study (Ohayon & Schatzberg, 2002) found little difference in prevalence for MDpsy across age groups, with only 0.3% of individuals over 65 reporting depression with psychotic features, compared to 0.4
0.5% of younger individuals. In contrast, a study of 65 inpatients found a bimodal age distribution for MDpsy with the fewest patients having an age between 40 and 50 (Coryell et al., 1986a). Depression is more common in women than men, and this gender distribution is generally replicated for psychotic depression (Brodaty, et al., 1997; Kivela & Pahkala 1989). Both the ECA study and the 2002 European study found women might have a small additional increased risk for psychotic depression. The ECA study found 83% of the MDpsy sample were women compared to 73% of the major depression without psychotic features sample (Johnson, Horwath et al., 1991), while the 2002 study found that 67% of the MDpsy sample were women compared to 59% of the nonpsychotic depression sample (Ohayon & Schatzberg, 2002). Age of onset The ECA study found no statistically significant difference in average age of onset for the MDpsy and nonpsychotic depression samples (Johnson et al., 1991). Risk of onset of major depression overall has been observed to be fairly low until the early teens, and after that, risk of onset is roughly equivalent, regardless of age (i.e. prevalence increases roughly linearly by age) (Kessler et al., 2003). Some maintain that early-onset MDpsy should be considered initial episodes of bipolar disorder until proven otherwise, but this appears to be an

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oversimplification: several studies have demonstrated early-onset MDpsy patients who subsequently go on to develop bipolar disorder while others simply experience unipolar depression (Akiskal et al., 1983; Strober & Carlson, 1982). One study of adolescents hospitalized with unipolar major depression reported that 20% of patients later converted to a bipolar diagnosis over 3
4 years of follow-up. Most of these patients (75%) had a symptom cluster of moodcongruent psychotic features, psychomotor retardation, and rapid symptom onset, compared to only 6% of the ‘‘non-converters’’ (Strober & Carlson, 1982). Another study of 206 unipolar depressed outpatients found a similar 20% conversion rate to bipolar disorder during follow-up for as long as 25 years, with 42% of those converting having psychotic features compared to only 15% of ‘‘non-converters’’ (Akiskal et al., 1983). However, given the preponderance of patients who do not change diagnosis (‘‘non-converters’’), any given depressed patient with psychotic features in either study was more likely to remain with a diagnosis of unipolar depression than convert to a diagnosis of bipolar disorder (Akiskal et al., 1983; Strober & Carlson, 1982). Another recent study with briefer follow-up found only a 13% likelihood of patients with MDpsy suffering a mania or hypomania after 1
2 years (DelBello et al., 2003). These results strongly suggest that no definitive conclusions can be made regarding eventual diagnosis of a young adult with MDpsy. A related issue concerns the diagnostic stability of early-onset MDpsy versus schizophrenia. No studies exist examining MDpsy specifically, but one study of 81 adolescents followed for 10.5 years that classified both initial and subsequent episodes by DSM-IV criteria found that relatively few subjects (16%) with early-onset (diagnosed before 19 years) affective psychosis (40% major depression, 60% bipolar disorder) were later diagnosed with schizophrenia, and that only 5% of the cases originally diagnosed with schizophrenic disorders were later diagnosed with affective psychoses (Jarbin et al., 2003). One important predictor of patients whose diagnoses were changed from affective to schizophrenic disorders was a family history of non-affective psychoses in first- or second-degree relatives (Jarbin & von Knorring, 2003). In contrast, an extremely small study of early-onset patients with psychosis in which initial diagnosis was not necessarily made by DSM criteria in structured interviews found misdiagnosis common, with 55% of patients initially diagnosed with affective psychosis later being diagnosed under DSM-III-R as having schizophrenia, and 17% of patients diagnosed with schizophrenia later being diagnosed as having affective psychosis (McClellan et al., 1993). In sum, a sizeable proportion of patients with early-onset affective psychosis appear either initially or eventually to be bipolar, and a small proportion will later be diagnosed among the schizophrenic illnesses, but bona fide unipolar major depression can present at an early age.

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Late-onset depression with psychotic features may commonly represent MDpsy or a prodromal stage of Alzheimer’s disease or other dementing illness, just as late-onset depression without psychotic features can also be a marker for increased dementia risk (Alexopoulos et al., 1993). One study found that approximately 30% of late-onset MDpsy patients had greater treatment refractoriness and a ‘‘dementia-like presentation’’ (Aronson et al., 1988). In a sample with known Alzheimer’s Disease, depression raised the risk of delusions almost seven fold (Bassiony et al., 2002). Another study found 30
40% of patients with Alzheimer’s disease had depressive and psychotic symptoms, but complete mood or psychotic syndromes were less common (Wragg & Jeste, 1989). In addition, other neurological causes such as intracranial mass lesions can give rise to psychosis in the elderly and the young alike. Some authors (Galasko et al., 1988) recommend that patients with late-onset psychosis, focal neurological signs associated with psychosis, or unusual histories of depression undergo neuroimaging to exclude intracranial lesions. Presentation While the presence of either delusions or hallucinations in the context of a mood episode is required to establish the diagnosis of MDpsy, delusions are more common than hallucinations. One study found only 20% of 137 patients with MDpsy exhibited hallucinations (Parker et al., 1991). A much smaller study found that 50% of patients with MDpsy had hallucinations, but in every case these patients also expressed delusions, and usually the hallucinations and delusions had the same content (Lykouras et al., 1986). For these reasons, psychotic depression is alternatively referred to as ‘‘delusional depression.’’ Children are an exception: one study observed that 48% of children with depression had experienced hallucinations, while fewer than 10% experienced delusions (Chambers et al., 1982). A review of six studies of adults found the most common types of delusions observed in MDpsy were delusions of guilt, punishment, or persecution (44
69%), which were roughly twice as common as delusions of hypochondriasis (11
36%) (Kuhs, 1991). Delusions of poverty or nihilism (typically defined as delusional conviction of the nonexistence of one’s own person, living relatives, or even the whole world) were relatively rare (11.4% or less), except for one study that found a very high prevalence of nihilistic delusions (Frangos et al., 1983). An accompanying survey of 160 consecutively admitted inpatients found a particularly high prevalence of delusions of guilt (82.5%), while delusions of poverty (52%) were more common than delusions of hypochondriasis (39%) or punishment/persecution (30%), and nihilistic ideation was found to be relatively rare (13%) (Kuhs, 1991). Another study

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reported that hypochondriacal and nihilistic ideation were seen more frequently in patients with an age of onset of unipolar psychotic depression greater than 60 years old (Gournellis et al., 2001). The detection of delusions and hallucinations is often difficult in patients with MDpsy because MDpsy patients are often more able to keep their unusual thoughts and feelings to themselves than patients with schizophrenia or mania, and may be embarrassed or recognize that their thinking processes are not quite right (Rothschild and Schatzberg, 1994). As a result, a number of research groups have explored whether other characteristics might help distinguish patients with MDpsy from nonpsychotic depression (Parker et al., 1995). Identified characteristics have included psychomotor disturbance (either retardation or agitation) (Brodaty et al., 1997; Charney & Nelson, 1981), cognitive impairment (Basso & Bornstein, 1999; Belanoff et al., 2001; Jeste et al., 1996; Nelson et al., 1998; Rothschild et al., 1989; Schatzberg et al., 2000; Simpson et al., 1999), paranoid symptoms (Frances et al., 1981; Lykouras et al., 1986), hypochondriasis (Coryell et al., 1984), hopelessness (Frances et al., 1981), anxiety (Charney & Nelson, 1981; Glassman & Roose, 1981; Kuhs, 1991), sleep difficulties (early (Frances et al., 1981; Lykouras et al., 1986), middle (Lykouras et al., 1986), or terminal insomnia (Parker et al., 1995)), appetite or weight loss (Parker et al., 1995), and constipation (Parker et al., 1991; 1995). Patients with MDpsy have also been reported to lack the diurnal variation in mood that endogeneously depressed patients with nonpsychotic depression exhibit (Parker et al., 1991). The most consistent findings appear to be psychomotor disturbance (either agitation or retardation) and guilt (Schatzberg & Rothschild, 1996). An analysis of 21-item HAM-D rating scales for a large sample of patients with psychotic depression found the largest statistically significant differences in severity of guilt and psychomotor retardation, as well as paranoia, poor insight, loss of interest in work and activities, and depressed mood (Lattuada et al., 1999). Negative symptoms have become of increasing interest in schizophrenia research; a single study of 164 inpatients and outpatients (35 with MDpsy) found that negative symptoms were uncommon among subjects with MDpsy (20% of these subjects showed poor rapport, 16% blunted affect, and 16% communication difficulties such as delayed responses to questions), and almost always limited to the acute episode (Husted et al., 1995). A much smaller study of early-onset psychotic patients observed no difference in prevalence of negative symptoms between the unipolar psychotic depression and schizophrenia samples (Hill et al., 2004). A small literature exists on the distinctions between MDpsy and dissociative conditions such as borderline personality disorder. Patients with borderline personality disorder rarely endorse obvious delusions or hallucinations, but

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frequently endorse derealization or depersonalization (Nishizono-Maher, 1993). Another study found a very high prevalence of comorbid PTSD in a clinical sample with MDpsy (almost 60%, 4-fold the prevalence in the nonpsychotic depression sample) (Zimmerman and Mattia, 1999). An extensive debate exists about whether MDpsy should be viewed as a distinct subtype of depression, or merely a particularly severe variant (Cubells et al., 2002; Schatzberg & Rothschild, 1996). The basic arguments supporting its existence as a subtype are: 1) the fact that the illness appears to moderately ‘‘breed true’’ in families, with heritabilities similar to what is observed in schizophrenia; 2) the observation that MDpsy is the most consistent subtype of depression in longitudinal studies (for instance, generally only patients with MDpsy will be prone to psychosis in future episodes of depression); 3) the somewhat distinctive neurochemistry observed in MDpsy, especially the high rate of glucocorticoid dysregulation; 4) the evidence for a distinct treatment response; and 5) the observation that in some studies these differences are observed between MDpsy and nonpsychotic depression samples even when no differences in depression severity exist. Countering these arguments are the observations that in other studies MDpsy has been shown with rating scales to have more severe depressive symptomatology than nonpsychotic depression (Lattuada et al., 1999; Lykouras et al., 1986), the neurochemical differences are not absolute (e.g. severe nonpsychotic depression can often have glucocorticoid regulation abnormalities), and psychosis may only appear in MDpsy patients during their more severe episodes (Coryell et al., 1996). In DSM-III and DSM-III-R a distinction was made between ‘‘mood-congruent’’ psychotic symptoms (delusions of sin, guilt, punishment, inadequacy, illness, nihilism, and related auditory hallucinations such as self-deprecatory voices) and ‘‘mood-incongruent’’ (delusions of persecution, reference, jealousy, control; thought insertion or withdrawal; and auditory hallucinations such as command, persecutory, or commentatory). In a small study of 40 inpatients, no compelling evidence was found justifying the mood-congruent versus mood-incongruent distinction (58% of inpatients show signs of both) (Burch et al., 1994). Other studies offer mixed results on the importance of this distinction. Coryell found in a retrospective chart review that mood congruence versus incongruence appeared to have little prognostic significance; however, when follow-up interviews with patients or relatives were conducted, patients with mood-incongruent symptoms were more likely to have poorer occupational, marital, and mental status functioning (Coryell & Tsuang, 1985). Likewise, another prospective and retrospective study by the same group found trends towards worsened recovery and insight in patients with mood-incongruent symptoms, but these findings did not usually achieve statistical significance (Coryell et al., 1986;

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Tsuang & Coryell, 1993). Another study found mood incongruence predicted worse overall functioning (as indexed by the Global Assessment of Functioning Scale) at 24 months (Fennig et al., 1996a); a review by the same authors concluded that the concept of mood-congruent versus mood-incongruent symptoms in affective psychoses is of limited conceptual value, and primarily helps to predict eventual change to a nonaffective diagnosis (Fennig et al., 1996b). A more recent study found mood-incongruent symptoms to have negative prognostic symptoms for a mixed sample composed of schizophrenic, schizoaffective, and depressed patients (Harrow et al., 2000). Because psychotic symptoms in MDpsy only last as long as the depressive episode, patients with MDpsy have the potential to provide unique information about the consistency of episodic delusions over time, but very limited data exists. One study with limited follow-up information concluded that 80
90% of the patients with recurrent psychotic depression (n ¼ 12) had a similar delusion in their next episode (Lykouras et al., 1985). A second study concluded that delusions tended to be ‘‘of similar form and content from episode to episode’’ without giving specific statistics (Charney & Nelson, 1981). A third study found that only 17% of patients with recurrent psychotic depression exhibited delusions entirely different from those presented at the index episode (Kuhs, 1991). However, only 50% showed thematically identical delusions, with the remainder varying in presentation from episode to episode. The author speculates that these fluctuations are probably due to variations in depressive severity across episodes (Kuhs, 1991). Another study which classified delusions into three broad categories (persecution; bodily disease or damage; or guilt, worthlessness, punishment, and death) found either changes in delusions or multiple delusions to be the norm rather than the exception, with 70% of patients already having a history of delusions from more than one category by their index hospitalization (Miller & Chabrier, 1987). A recent meta-analysis of neuropsychological findings in patients with psychotic depression concluded that psychomotor speed and executive function domains were the most impaired, followed by verbal memory (z scores of
0.6 or worse). Smaller deficits were noted in visual memory, attention, and visual spatial tasks (Fleming et al., 2004). Several authors have noted that the pattern of neuropsychological deficits resembles that observed in schizophrenia, with either similar (Jeste et al., 1996) or lesser (Hill et al., 2004) levels of impairment observed in the psychotically depressed patients. Course and progression MDpsy tends to be a more recurrent illness than nonpsychotic depression, with increased risk for both nonpsychotic and psychotic episodes. In the most

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extensively studied cohort to date, Coryell and coworkers found that individuals with MDpsy relapsed approximately three times faster regardless of whether time to recurrence of any episode was considered or just nonpsychotic episodes (Coryell et al., 1996). A limitation of this cohort is that approximately 28% of the sample have a history of mania, although simultaneously controlling for psychotic features and bipolarity indicated that only psychotic features significantly explained the increased recurrence risk (Black et al., 1988; Coryell et al., 1996). A study examining rehospitalization after first admission found that patients with MDpsy were readmitted 45% sooner than patients with nonpsychotic depression (Kessing, 2003). A number of other studies have also observed that patients with MDpsy exhibit more frequent recurrences (Aronson et al., 1988a, b; Helms & Smith, 1983; Lykouras et al., 1986; Murphy, 1983; Nelson & Bowers, 1978; Robinson & Spiker, 1985; Spiker et al., 1985), although a couple of studies failed to observe increased recurrence risk (Coryell et al., 1987; Lykouras et al., 1994). Once a patient has had an episode of MDpsy, the risk of having psychotic features during future episodes of depression is substantial. Recurrence of psychotic features has been most extensively examined in an eight-year follow-up study of 424 patients with major depression (Coryell et al., 1994). The psychotic subtype was more consistent across episodes than the endogenous or psychomotorically disturbed subtypes, and risk of a new episode with psychotic features was 15-fold higher for patients with MDpsy during their first episode after the index episode compared to patients with nonpsychotic depression during their index episode. Even after four intervening episodes without psychotic features, the risk of developing psychotic features during the next episode of depression was four-fold higher than among patients with only a history of nonpsychotic depression. However, following any specific episode with psychotic features, patients with MDpsy had only a 28
60% chance that their next episode would include psychotic features (Coryell et al., 1994). This is a lower rate than observed in some other studies: one cohort found a striking 83% relapse rate into depression over 34 months, with almost all the relapses including psychotic features (Aronson et al., 1988), while another study found that recurrence of psychosis (judged either retrospectively or prospectively) had occurred or did eventually occur in 92% of patients (Helms & Smith, 1983). However, when compared to patients with schizophrenia, patients with MDpsy were less likely to have delusional symptoms on three separate follow-ups (Harrow et al., 1995). It is not fully known what proportion of the population has recurrent psychotic depression versus single episodes. A study of 42 patients with MDpsy found that 35% of early-onset patients had only a single episode over 34 months of follow-up

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compared to none of the 15 patients with late-onset MDpsy (Aronson et al., 1988b). Another study found patients with late-life MDpsy were more likely to relapse, especially if maintained only on antidepressant monotherapy (Flint & Rifat, 1998b). In addition to the recurrence risk, psychotic depression is associated with greater overall impairment and severity of depressive symptoms, resistance to conventional pharmacotherapies (Schatzberg & Rothschild, 1996), and possibly an increased risk of suicide. Estimates of the degree to which MDpsy increases risk for suicide, suicide attempts, or suicidal ideation vary widely (Table 9.1). Estimates of suicide risk range from a five-fold increase in risk for inpatient suicides (Roose et al., 1983) to no increase in risk in long-term cohort studies of outpatients (Black et al., 1988; Coryell & Tsuang, 1982). Risk of suicide attempts also varies considerably from study to study, from increases of 2.6-fold (Hori et al., 1993) to no increase in risk (Lykouras et al., 2002). Similarly, some studies (Isometsa et al., 1994) but not others (Lykouras et al., 2002) have found MDpsy patients to have an increased risk of using violent methods. Patients with MDpsy have increased use of services, greater disability, and poorer clinical course compared with patients with nonpsychotic depression at both short-term (Coryell et al., 1986b; Rothschild et al., 1993) and longer-term follow-up (Coryell et al., 1996). Several studies have demonstrated residual social and occupational impairment in MDpsy patients despite improvement in psychotic and depressive symptoms at one-year (Rothschild et al., 1993), five-year (Coryell et al., 1990), and ten-year follow-up (Coryell et al., 1996), but a 40-year follow-up study found no consistent trends distinguishing MDpsy from nonpsychotic depression on marital, occupational, residential, or symptomatic outcome ratings (Coryell & Tsuang, 1982). One other study found that patients with MDpsy had greater psychosocial impairment in the five years prior to study entry, but after the first six months of treatment were as likely to recover as patients with nonpsychotic depression over the next 18 months (Coryell et al., 1987). This study also observed that early response to treatment was more predictive of later course for MDpsy patients than nonpsychotic depression patients (Coryell et al., 1987). The social and occupational impairment may be due to subtle cognitive deficits associated with the higher cortisol levels frequently observed in MDpsy patients (Rothschild et al., 1993; Schatzberg & Rothschild, 1988) or other reasons. One recent study found patients with MDpsy had a two-fold greater risk of overall mortality than patients with nonpsychotic depression, and this mortality resulted from medical causes (rather than suicide) in 88% of the deaths (Vythilingam et al., 2003). While MDpsy is more disabling and refractory than nonpsychotic depression, first-episode patients with MDpsy are more likely to recover symptomatically

Patients

Inpatient sample followed prospectively for 34þ years

Inpatient sample followed prospectively for 2
13 years

Inpatient sample followed prospectively for 0
3 years

Coryell & Tsuang (1982)

Black et al. (1988)

Wolfersdorf et al. (1987)

COMPLETED SUICIDE

Study

perceived quality)

OR¼2.1 (not statistically significant)

Completed suicide

MDpsy: 46 pts/52 yo/ 30%M

Nonpsychotic depression:

No difference in suicide rate (MDpsy 3.3%, Nonpsychotic depression 3.4%)

(Both groups had a 7% suicide risk after 34
39 years of F/U)

No difference

Finding (risk in MDpsy versus MDnon-psy)

Completed suicide

Completed suicide

Suicidality measure

Not given

MDnonpsy: 102 pts/ 44yo/42%M

MDpsy: 122 pts/ 44/47%M

Demographics (size of sample/mean age(+SD)/% male)

Very few suicides (4 in MDpsy sample vs 2 in nonpsychotic depression sample) MDpsy sample 1.85 fold as

Longest follow-up available

Comments

Table 9.1. Summary of studies of suicide risk in psychotic major depression (studies in each section are ordered in descending order of approximate

Roose et al. (1983)

Inpatients

Control group: 28 pts/ 58/21%M

Suicide group: 14 pts/56/ 50% M

46 pts/53 yo/ 30%M (Matched)

Pts with MDpsy Completed suicide are 5 as likely to while in commit suicide as hospital, eloped, or pts with MDnon-psy on pass

Suicide would be expected to be 2 more likely in MDpsy group just based on prevalence of men, who have higher completed suicide risk.

Curiously, patients with nonpsychotic depressions were 1.5-fold as likely to be judged suicidal at admission, perhaps because suicidality is an important criteria for hospitalization among the nondelusional population.

likely to endorse past suicide attempts.

Patients

Psychological autopsy

Mixed sample from all MDD suicides over 1 yr.

Study

Robins (1959)

Isometsa et al. (1994)

approximate perceived quality)

MDpsy group MDpsy group also more likely more likely to use violent means (88% vs 59%, to be receiving psych tx (54 to p¼0.03) 39%), and to be hospitalized at time of suicide (21 to 11% but only 4% vs 2% on premises). Completed suicide

MDpsy: 24 pts/50 +13/ 67% M Nonpsychotic depression: 46 pts/50 + 18yo; 61% M

15.9% of the suicide victims with affective disorder had psychosis.

No discrimination between unipolar and bipolar disorder

Fact that these are inpatient suicides may limit generalizability

Comments

Completed suicide

Suicidality measure

Finding (risk in MDpsy versus MDnon-psy)

134 suicides in St. Louis in 1950s

Demographics (size of sample/mean age(+SD)/% male)

Table 9.1. (Cont.) Summary of studies of suicide risk in psychotic major depression (studies in each section are ordered in descending order of

Johnson et al. (1991)

Community, retrospective (ECA study)

SUICIDE ATTEMPTS

Nonpsychotic depression: 662 pts/41 + 16/27%M

MDpsy: 114 pts/42+ 16yo/17%M,

History of suicide attempts

Pts with MDpsy reported a 42-fold risk for past suicide attempts, even after control for sociodemographics, site, other

Little difference between groups was noted in the frequency of suicidal ideation/attempts during worst episodes

None of MDpsy group receiving combination treatment at time of suicide. Since this sample represents all suicides in 1 year, if 15
18% is used as the prevalence of MDpsy among all patients in the community with major depression, the 34% rate of MDpsy in completed suicides represents approximately a 2-fold increased risk.

Patients

Inpatient

Elderly Inpatient

Study

Lee et al. (2003)

Lykouras et al. (2002)

approximate perceived quality)

Nonpsychotic depression:

MDpsy: 40 pts/70 + 6/30%M

105 Total pts

Demographics (size of sample/mean age(+SD)/% male)

Pts with MDpsy had higher risk of suicide attempt

No significant difference (OR ) in risk for current or current þ past suicide attempts

Suicide attempt

psychiatric disorders, or when patients rediagnosed over the next year as having bipolar D/O or schizophrenia were excluded. Suicide attempts

Suicidality measure

Finding (risk in MDpsy versus MDnon-psy)

No difference in risk for violent attempts

Pts with MDPSY also had higher HAM-D scores and lower MMSE scores

Very few differences noted between number or types of symptoms observed during worst episode.

Comments

Table 9.1. (Cont.) Summary of studies of suicide risk in psychotic major depression (studies in each section are ordered in descending order of

Inpatient retrospective

MDnonpsy: 55 pts/47+ 13/47% M

MDpsy: 38 pts/51+ 15yo/44%M

Thakur et al. (1999) Mixed inpatient
MDpsy: 189 pts/ outpatient sample 67% < 60yo/ 33%M

Hori et al. (1993)

64 Pts/70+ 5/23%M

Suicidal attempt, intent, or ideation

Suicide attempt or suicide ideation

Univariate OR of 1.71 but ‘‘suicide potential’’ not significant in

(47% vs 18%) and a 1.25-fold increase of suicidal ideation

MDPSY had 2.6fold risk of suicide attempt

Delusional group had significantly less psychomotor retardation (71% vs 93%). Also had a more intermittent or chronic course versus remitting (only 13% experienced remission while 71% of nonpsychotic depression patients did). Also more likely to use violent methods (56% vs 47%).

Patients

Miller and Chabrier Inpatients, (1987) retrospective

Study

approximate perceived quality)

Extensively matched sample of 45 delusional patients

Nonpsychotic depression: 485 pts/51%< 60yo/37%M

Demographics (size of sample/mean age(+SD)/% male)

Suicide attempts in last 6 mos and over lifetime

Suicidality measure

Pts with somatic symptoms had lower rate of lifetime medically serious attempts than pts with guilt, worthlessness, deserved punishment, and persecution (29% vs 64%)

multiple logistic regression (OR 1.27, CI 0.75
2.15 by clinician rating scale; OR 0.98, CI 0.55
1.75 by self-rated rating scale)

Finding (risk in MDpsy versus MDnon-psy)

Pts with somatic delusions also had statistically significant lower risk of serious suicide attempt in last 6 months, and mean number of lifetime suicide attempts. MDpsy Pts had a nonsignificant 1.5-fold risk of suicide attempts compared to

Comments

Table 9.1. (Cont.) Summary of studies of suicide risk in psychotic major depression (studies in each section are ordered in descending order of

Sax et al. (1997)

Inpatients at first hospitalization

SUICIDAL IDEATION

Typical-onset: 38 pts/ 23yo+2 yo/ 39.5% F Late-onset: 23 pts/49+ 12/56.5%F

Early-onset 27 pts/16 yo/ 48% F

HAM-D Suicide scale

Early-onset group suicidality score4typical onset or late onset group

Study of affective psychosis
MDpsy comprised only 19% of early-onset group, 6% of typical-onset group, and 30% of late-onset group

extensively matched nonpsychotic depressed sample

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and functionally (81% recovered) at six months than patients with other psychotic disorders (36
70%) (Tohen et al., 2000). Suspected neuropathology Neuropathological findings reported as associated with MDpsy include enlarged brain ventricle size, cerebral vascular changes, and P300 and EEG abnormalities. Multiple groups have reported enlarged cerebral ventricles in MDpsy (Jones et al., 1994; Luchins & Meltzer, 1983; Rothschild et al., 1989; Schlegel & Kretzschmar, 1987; Targum et al., 1983). The first study to observe enlarged ventricles in melancholic patients with psychotic depression failed to find statistically significant differences overall, but one quarter of that MDpsy sample had ventricles (ventricle-to-brain ratio, or VBR) that were at least two standard deviations larger than the control group (versus none of the nonpsychotic depression sample) (Targum et al., 1983). Luchins and Meltzer (1983) found mean VBR to be 44% larger in patients with bipolar or unipolar psychotic depression compared to a slightly younger sample with nonpsychotic depression. Fifty-six percent (5/9) of patients with psychotic depression had VBRs greater than one standard deviation larger than the control group versus only 11% (1/9) of the nonpsychotically depressed patients. The authors contrast their findings to reports at the time that VBR was smaller in patients with schizophrenia. A larger study found increased VBRs in patients with psychotic affective illness as well as older patients and male patients and did not find an association between VBR and Dexamethasone Suppression Test (DST) results or unipolar patients versus bipolar patients (Schlegel & Kretzschmar, 1987). Another study found that differences in VBR were more pronounced between patients with psychotic depression than nonpsychotic depression in a group including bipolar patients (Rothschild et al., 1989). One hundred percent of the MDpsy patients had cella media VBR ¸ 0.61 compared to 58% of nonpsychotic depressed patients (p ¼ 0.03). Similar proportions were observed for DST-nonsuppressors versus suppressors, although these results only reached borderline statistical significance (p ¼ 0.067). Sulcal size, a possible indicator of ‘‘atrophy’’, was also judged to be larger in the left and right inferior parietal areas (Brodmann’s areas 39 and 40) of patients with psychotic depression (Rothschild et al., 1989). A study of 54 patients with affective psychosis similarly found larger third ventricle size among patients with psychotic affective illness, but observed that no clear threshold existed between ‘‘normal’’ and ‘‘enlarged’’ ventricles (Jones et al., 1994). A study of older patients found no abnormalities in temporal lobe atrophy, periventricular white matter lesions, DST, or cognitive testing results between the MDpsy and nonpsychotic depression samples, but did find a greater number

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of vascular risk factors and a nonsignificant trend to greater number of deep white matter lesions in the MDpsy sample (O’Brien et al., 1997). Another study of MDpsy patients over 55 years of age found that the absolute volume of prefrontal cortex was smaller in the group with MDpsy than with nonpsychotic depression, and that this decreased volume correlated with Wisconsin Card Sorting performance (Kim et al., 1999). A study of psychiatric symptoms in patients with vascular or Alzheimer’s dementia found delusions or hallucinations common, but these symptoms appear to be more correlated with dementia than depression (Ballard et al., 2000). For instance, among patients with mild dementia (MMSE 4 20), less than 10% of patients with psychotic symptoms had depression (Ballard et al., 2000). Another study found that among individuals with dementia, psychotic symptoms were more likely among individuals with a psychiatric history (Berrios & Brook, 1985). Decreased amplitude and increased latency in P300 event-related potentials have been reported in schizophrenia, but comparatively little data exists for MDpsy. Melancholic patients with MDpsy were found to have decreased P300 amplitude compared to melancholic patients with nonpsychotic depression (Santosh et al., 1994). A study of 22 unipolar depressed patients (82% with major depression, 18% with dysthymia) found that scores on the psychotism subscale of a 90-item symptom checklist correlated with an overall reduction in P300 amplitude, especially over the left temporocentral electrode chain. However, the sample was selected for depression, not psychosis, and none of these subjects had particularly high psychotism scores (Kaustio et al., 2002). In contrast, Salisbury et al. (1998) observed no differences in left temporal amplitude between patients with affective psychosis and healthy controls, but only 14% of those with psychosis had unipolar major depression. EEG studies of MDpsy are also rare. One study found abnormal EEG findings in 17% of a medicated sample of patients with mood-incongruent MDpsy and 10% of patients with mood-congruent MDpsy compared to 3.2% of healthy controls (Inui et al., 1998). Furthermore, 33% of patients with mood-incongruent MDpsy were found to have ‘‘epileptiform’’ EEG variants, compared to 0% of MDpsy patients with mood-congruent psychosis. The authors argue for a possible similar biological substrate for ‘‘atypical psychoses’’ (mood-incongruent MDpsy, schizoaffective disorder, or schizophreniform disorder, all of which had similar proportions of epileptiform variants) (Inui et al., 1998). However, studies of outcome have observed that mood-incongruent MDpsy has outcomes much more similar to mood-congruent MDpsy than schizoaffective disorder or schizophrenia (Coryell and Tsuang 1982). An EEG sleep study found that patients with MDpsy exhibited increased wakefulness, decreased REM sleep, and decreased REM activity compared to patients with nonpsychotic depression after controlling

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for age, severity, and agitation. REM latency appeared to be a marker for duration of illness as well; patients with recent-onset MDpsy had marked initial insomnia and long REM latency, whereas patients with illnesses of longer duration had extremely short REM latencies (Thase et al., 1986). Suspected neurochemical abnormalities Patients with MDpsy frequently exhibit high rates of nonsuppression on the DST with markedly elevated post-dexamethasone cortisol levels and high levels of 24-hour urinary free cortisol. This finding is one of the most reliable alterations of the hypothalamic-pituitary axis in psychiatric patients (American Psychiatric Association, 1987; Rothschild, 2003). While a meta-analysis found the postdexamethasone cortisol nonsuppression rate to be substantially higher in patients with psychotic depression (64%) than nonpsychotic patients (41%) (Nelson & Davis, 1997), this yields a sensitivity of only 64% and specificity of 59%. Studies have observed that using a cutoff value higher than the traditional ¸5 mg/dL of cortisol post-dexamethasone produces greater specificity for MDpsy at the cost of sensitivity. One study found 50% of the MDpsy patients had cortisol values ¸15 mg/dL, compared to only 7% of nonpsychotic depression patients (a sensitivity of 50% and specificity of 93%), and 43% of patients with MDpsy had cortisol values of ¸17 mg/dL, while none of the nonpsychotic depression patients did (sensitivity of 43%, specificity of 100%) (Schatzberg et al., 1983). The DST may also discriminate well between patients with MDpsy and other psychoses such as schizophrenia (American Psychiatric Association, 1987). In one study, 57% of patients with MDpsy had postdexamethasone cortisol values greater then 14 mg/dL, whereas none of the psychotic schizophrenic patients had values that high, and the mean postdexamethasone cortisol level for MDpsy patients (13.0+8.1 mg/dL) was significantly higher than that for the psychotic schizophrenic patients (2.4+2.8 mg/dL; p < 0.05) (Rothschild et al., 1982). The mechanism by which cortisol is associated with psychosis is not exactly clear, but both endogenous (e.g. Cushing disease) and exogenous steroids have been associated with psychosis. Our group has hypothesized that elevated cortisol induces a hyperdopaminergic state (Schatzberg & Rothschild, 1988; Schatzberg et al., 1985); however, one study failed to find evidence of hyperdopaminergic activity in MDpsy (Duval et al., 2000). These authors instead reported a blunted growth hormone response to clonidine that they concluded implies the occurrence of a hyposensitivity of noradrenergic alpha-2 receptors in affective psychosis, rather than dopamine system dysregulation (Mokrani et al., 2000). However, several older studies observed elevated dopamine levels in plasma

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(Rothschild et al., 1987) or homovallinic acid, a dopamine metabolite, in either CSF or plasma of patients with MDpsy (Schatzberg et al., 1995), and MDpsy shows a strong clinical response to combined treatment of antidepressants and dopamine blockers (either typical or atypical antipsychotics) (see ‘‘Treatment’’ section below). A rather consistent neurochemical finding in MDpsy is the reduction of dopamine b-hydroxylase (DBH) activity among patients with MDpsy but not bipolar psychotic depression (Schatzberg & Rothschild, 1996). Five (Cubells et al., 2002; Meltzer et al., 1976; Meyers et al., 1999; Mod et al., 1986; Sapru et al., 1989) of six (Lykouras et al., 1988) studies showed that plasma DBH was significantly reduced in MDpsy versus nonpsychotic depression or normal controls, with a seventh small study showing reductions in DBH that did not reach statistical significance (Eisemann et al., 1983). Because serum DBH did not increase for most patients immediately following successful treatment, one group has suggested DBH may be a trait-dependent rather than state-dependent finding in MDpsy (Meltzer et al., 1976). Low CSF DBH activity has also been associated with psychosis induced by disulfarim (Major et al., 1979) and cocaine (Cubells et al., 2000). However, one study (Hamner & Gold, 1998), but not another (Meltzer et al., 1976), has observed elevated, rather than reduced, DBH activity in psychotic patients with bipolar disorder compared with normal controls and higher DBH levels in patients with schizophrenia than in patients with MDpsy (Meltzer et al., 1976). These authors suggest low DBH may be a trait-specific, rather than state-specific, vulnerability factor. The possibility that 5HT2 receptors may be involved in psychotic depression is weakly hinted at from clinical responses observed with amoxapine (which has both serotonin agonist and dopamine antagonist effects) (Anton & Sexauer, 1983), but this has not been supported by genetic studies (see ‘‘Genetic Factors’’ section below). A few studies have also found lower CSF 5-HIAA (Mendels et al., 1972) or urinary MPHG (Sweeney et al., 1978) in patients with MDpsy compared with nonpsychotic depression. One study examined the relationship between exogenous 5HT (a serotonin precursor) and serum cortisol and found patients with MDpsy to have less of a 5HT-induced increase in cortisol, but it is unclear whether this may be due to higher cortisol at baseline (Meltzer et al., 1984). It has been hypothesized that abnormal cortisol levels in patients with MDpsy might contribute to the profile of neuropsychological deficits observed (Rothschild et al., 1993) (see ‘‘Presentation’’ section above). One study (Belanoff et al., 2001) found that those MDpsy patients who had higher mean afternoon cortisol levels on day of testing compared with the nonpsychotic depression or nondepressed patients had more errors of commission (falsely believing they had been previously presented with words they had not seen)

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and omission (forgetting words that were presented) on a verbal (Wallach Memory) recognition test. This pattern is similar to that observed in healthy comparison subjects given corticosteroids (Belanoff et al., 2001). Genetic factors Family history studies have supported the tendency for MDpsy to ‘‘breed true’’
heritability estimates for MDpsy fall between that of nonpsychotic depression and bipolar disorder. A review of family history studies found that heritability estimates for MDpsy (if a multifactorial model is assumed) ranged from 62
78%, compared to 46
50% for families of patients with nonpsychotic depression (Lykouras et al., 1988). However, one family study found a nonsignificant increased risk of affective illness overall in families of patients with nonpsychotic depression (17% of relatives) compared to MDpsy (12% for probands with mood-congruent depressive psychosis, 6% for mood-incongruent). Families of probands with MDpsy had a higher risk of schizophrenia (2
4% depending on mood congruence, versus 0% for probands with nonpsychotic depression). One study found a significantly higher rate of bipolar I disorder in the families of patients with MDpsy (Prusoff et al., 1984), while another study from the same group found that the children of patients with MDpsy had a three-fold increased risk of cyclothymia (Weissman et al., 1988). Two studies by a second group found that first-degree relatives of patients with MDpsy had increased risk for any affective disorder and a trend towards increased risk for bipolar disorders (bipolar I, II, and cyclothymia) (Goldstein et al., 1998). A finding by this group that first-degree relatives had an increased risk of MDpsy was not replicated in the second study, and another group found no increase in risk of psychosis in relatives of patients with MDpsy compared with nonpsychotic depression (Winokur et al., 1985). A study in Ireland found that the presence of psychotic affective illness (especially mood-incongruent affective illness) in the parents of a child with schizophrenia predicted a four-fold increased risk of schizophrenia in that child’s siblings (Kendler et al., 1996), with the authors speculating that parents with affective psychosis are less severely impaired and thus have a greater chance of passing on psychosis risk to their offspring. One study found that probands with MDpsy and abnormal DST results had both an increased risk of delusions and an increased familial prevalence of depression, but not alcoholism (Bond et al., 1986). The preponderance of studies examining the involvement of specific genes in MDpsy has yielded negative results. One group has reported that none of the serotonin system candidate genes they examined (polymorphisms in the 5HT transporter protein, 5-HT1A, 5-HT2A, and 5-HT2C receptors) appeared to be involved in MDpsy (Serretti et al., 1999a; 1999c; 2000). However, long variants

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of the dopamine D4 gene (allele 7, which is associated with reduced cAMP formation) were found to be statistically significantly associated with the delusional subscale of the HAM-D in a combined sample with bipolar and unipolar depression, as well as for unipolar and bipolar depressed patients analyzed separately (Serretti et al., 1998). This same group found DRD4 variants (specifically, the exon 37 allele variant versus the 2 allele) to be associated with delusional symptoms among a mixed group of 461 patients with major psychoses (Serretti et al., 1999d), but also subsequently reported that in a larger group, DRD4 variants did not appear to play a major role in risk for psychosis (Serretti et al., 1999b). As discussed in the ‘‘Suspected neurochemical abnormalities’’ Section reduced dopamine b-hydroxylase (DBH) activity is a consistent finding in MDpsy, but genetics studies of the DBH gene have yielded mixed results. One study of patients with diagnosed MDpsy found that the most common DBH genotype associated with reduced activity (C-1021T) was not associated with MDpsy, nor were other major dopamine b-hydroxylase variants (Cubells et al., 2002). The study had insufficient power to determine if differences in a minor candidate allele, C1603T, which was more prevalent in MDpsy (14%) than nonpsychotic depression (5%), were statistically significant. The authors speculate that the elevated glucocorticoid levels also consistently seen in MDpsy may reduce DBH gene expression in a non-genetic fashion (such as through binding to a glucocorticoid response element in front of the DBH gene). This remains speculative, however, since acutely administered glucocorticoids increase, rather than decrease, DBH expression in cultured cell models (Cubells et al., 2002). Another study of patients with major depression found a G to A polymorphism at DBH gene nucleotide 444 (which lowers activity of the gene) was not associated with psychotism scores on the Hopkins Symptom Checklist, but was associated with increased interpersonal sensitivity and paranoia subscale scores (Wood et al., 2002). Other risk factors Although premorbid risk factors have been extensively delineated for other psychotic disorders, little evidence exists for MDpsy. Uterine atony and late winter births were associated with increased risk for early onset of affective psychosis in one study (Hultman et al., 1999), though the number of patients with MDpsy was not indicated. In contrast, exposure to influenza five months before birth was shown to be related to decreased rates of affective psychosis (and corresponding increased rates of schizophrenia) in females, but not males (Takei et al., 1993). Premorbid hysterical symptoms and eating disturbances

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during adolescence were associated with later affective psychotic disorder, but of the 28 cases reviewed, only eight had MDpsy (Cannon et al., 2001). Assessments of functioning including the Zigler-Phillips Social Competence Scale and the Social Adjustment Scale (SADS) showed significantly lower levels of premorbid functioning in 22 patients with MDpsy compared to 70 patients with nonpsychotic depression (Sands & Harrow, 1995). Urbanization has been linked to increased rates of both depression and psychosis, although there is no data directly addressing the effect of urbanization on the incidence of MDpsy (Sundquist et al., 2004). Treatment The treatment of MDpsy poses unique challenges. Given the potential for an increased risk of suicidality with MDpsy, the first priority for treatment is to take appropriate steps to assess and ensure safety, including hospitalization if necessary. Once safety issues have been addressed, the American Psychiatric Association practice guidelines recommend treatment with either electroconvulsive therapy (ECT) or an antidepressant plus an antipsychotic (APA, 2000). Several clinical algorithms for the treatment of MDpsy have also been published (Bell & Rothschild, 2004; DeBattista et al., 2002; Iwanami et al., 1999; Wheeler Vega et al., 2000) which incorporate new treatments that have been better studied since the publication of the APA guidelines. A key initial decision in the treatment of MDpsy is whether to pursue pharmacotherapy or move immediately to ECT. ECT has a strong literature documenting its efficacy in MDpsy (Avery & Lubrano, 1979; Avery & Winokur, 1977; Parker et al., 1992; Petrides et al., 2001). A meta-analysis of 44 published studies of treatments of MDpsy compared ECT with medication treatment, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, and typical antipsychotics, alone or in combinations. It found a mean effect size for ECT of 2.3 compared to 1.6 for the combination of TCA and typical antipsychotic therapy (Parker et al., 1992). There is also evidence suggesting ECT may be at least slightly more efficacious in MDpsy than nonpsychotic depression. One of the largest studies of ECT showed a 95% response rate (completers only) for patients with MDpsy versus 83% for major depression without psychosis (Petrides et al., 2001). In addition, response rates in elderly patients with MDpsy in one study were more than three-fold greater for ECT than for pharmacotherapy (Flint & Rifat, 1998a), although this comparison is limited by the study’s brief (six-week) duration. The question of whether response rates to medication treatment differ by age has not been addressed either in meta-analyses (Parker et al., 1992) or recent reviews (Wheeler Vega et al., 2000), but it is a focus of the

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NIMH Study of the Pharmacotherapy of Psychotic Depression (STOP-PD) study, currently ongoing and scheduled for completion in 2007. Current guidelines recommend consideration of immediate ECT if the patient is pregnant, has suicidal intent, is medically unstable (such as patients who are refusing oral intake), or is unable to take oral medications, and some consider it the treatment of choice for elderly patients with MDpsy. One potential disadvantage to ECT is a high rate of early relapse. In one study of 84 patients with major depression, 60% of those assigned nortriptyline and 39% assigned nortriptyline plus lithium maintenance treatment relapsed in the first 24 weeks after ECT completion, with relapse being especially likely in the first month after ECT completion (Sackeim et al., 2001). Other disadvantages of ECT include its limited availability (Bell & Rothschild, 2004) and that some patients find the treatment or associated cognitive effects distressing (Parker et al., 1992). Patients with major depression and comorbid PTSD or major depression plus psychotic symptoms secondary to drug use may be less likely to respond to ECT (DeBattista et al., 2002), so potential ECT candidates should be screened for these conditions. Many experts feel ECT is underutilized as a treatment for MDpsy, possibly due to a negative image perpetuated by film and the media (Fink, 2003). Most studies indicate combination pharmacotherapy with an antidepressant and antipsychotic is more efficacious than either as monotherapy. The largest randomized, placebo-controlled trials of pharmacotherapy for MDpsy showed a statistically significant advantage to combination treatment in one 124-subject trial (with a 64% response rate for olanzapine plus fluoxetine versus a 35% response rate for olanzapine alone and 28% placebo response rate), but only nonsignificant differences between olanzapine plus fluoxetine, olanzapine alone, and placebo in a second 125-subject trial (response rates of 48%, 36%, and 32%, respectively) (Rothschild et al., 2004). In comparison, a smaller (n ¼ 16
18 patients per group) double-blind study of high-dose perphenazine (average dose 49 mg/day) in combination with amitriptyline showed the combination had superior efficacy over either agent as monotherapy (Spiker et al., 1985). This study, which did not include a placebo control, showed response rates (17-item HAM-D rating scale of six or less in combination with an elimination of delusions) of 78% for the combination vs. 41% and 19% for amitriptyline and high-dose perphenazine monotherapy, respectively. However, these results were for completers only: 12% of the sample dropped out and when these are added to the sample in a post hoc estimate of an intent-to-treat approach, the response rates become 64%, 37%, and 18% respectively. These authors also reported that when nonresponders to monotherapy were converted to combination therapy, 71
85% responded, and the response was rapid (usually within one week) (Spiker et al., 1985). A follow-up report noted that levels of amitriptyline and nortriptyline were

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significantly higher in the group receiving combination treatment than those receiving amitriptyline alone (Spiker et al., 1986). Meta-analyses of medication treatment for MDpsy all predate the serotonin reuptake inhibitor (SRI) era (Chan et al., 1987; Parker et al., 1992). One metaanalysis suggested that combination therapy ‘‘is not so distinctly superior’’ to tricyclic (TCA) monotherapy (effect size for 28 studies of TCA alone, 1.16 versus 1.56 for 12 studies of TCA plus typical antipsychotics), and both this meta-analysis and an earlier one (Kroessler, 1985) find typical antipsychotic monotherapy to be as efficacious or slightly more efficacious than TCA monotherapy, in contrast to the Spiker et al. (1985) study. One group (Zanardi et al., 1996) has reported response rates as high as 75% for MDpsy treated with the selective SRI sertraline as monotherapy, although the comparison group of a different SRI, paroxetine, had a high dropout rate and lower efficacy (46%). This study should be interpreted with caution due to its lack of a placebo control and a standardized instrument to diagnose MDpsy in all subjects (Rothschild & Phillips, 1999). Naturalistic studies indicate a low rate of antipsychotic prescribing for patients with MDpsy in the community (Mulsant et al., 1997). This may represent the failure of treaters to diagnose psychotic features in depressed patients. With no head-to-head trials, it is difficult to compare the efficacy of tricyclic antidepressants versus SRIs, or typical antipsychotics versus atypicals. Because of a desire to lower the side-effect burdens, most treatment algorithms recommend initiating combination treatment with an SSRI or venlafaxine plus an atypical antipsychotic. If the patient has responded well to a particular class of antidepressant or antipsychotic in the past, that is often a good starting point for further treatment. When there is no treatment history, beginning treatment with an SRI may have the added advantage of treating post-traumatic stress disorder, an illness shown to be four times more common in MDpsy than nonpsychotic depression (Zimmerman & Mattia, 1999). The antidepressant amoxapine, which is chemically related to the antipsychotic loxapine, was shown to have similar efficacy to amitriptyline plus perphenazine for MDpsy in a single double-blind, randomized study, although there was a tendency towards lower global response rates with amoxapine (Anton & Burch, 1990). However, amoxapine is one of the least prescribed antidepressants and has risks of seizures at higher doses (Wheeler Vega et al., 2000). The trial of an SRI and atypical antipsychotic must include both adequate dosages and duration, typically 8 to 12 weeks, before a determination of effectiveness can be made. For non-responding patients, treatment strategies include the use of a different SRI (or SNRIs, such as venlafaxine or duloxetine) in combination with an atypical antipsychotic, use of TCAs or typical antipsychotics, or commencement of ECT.

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If a patient shows a partial response to an antidepressant/antipsychotic combination, augmentation with lithium may be of benefit. In a retrospective study, lithium augmentation of antidepressant plus antipsychotic combinations was shown to be effective for bipolar depression with psychotic features (89% response rate), but much less effective for MDpsy (25% response rate) (Nelson & Mazure, 1986). Lithium augmentation of an antidepressant/antipsychotic combination doubled response rates in one very small and brief (six-week) study (Flint & Rifat, 1998a). Effective serum levels for lithium augmentation are generally in the 0.5 to 0.8 mEq/L range (Bell & Rothschild, 2004). As usual with lithium treatment, renal function, thyroid function, and electrolytes should be monitored on a regular basis. The effectiveness of lithium augmentation is being evaluated in the NIMH STOP-PD trial. Minimizing exposure to antipsychotics is desirable because of concerns that risks of tardive dyskinesia may be higher in affective psychosis (Rush et al., 1982). Other potential adverse effects include neuroleptic malignant syndrome and metabolic syndromes, such as obesity, diabetes, and dyslipidemia. One study examining duration of antipsychotic treatment found that 73% of 30 patients responding to fluoxetine plus perphenazine, who had perphenazine tapered to discontinuation after four months, did not show any return of their psychotic symptoms in the next 11 months. The remaining 23% of patients were able to be successfully tapered off perphenazine after eight months of combined treatment (Rothschild & Duval, 2003). Although most patients can be tapered off of antipsychotics in this time frame, antidepressant treatment is usually more longterm. One study found that the presence of psychotic features was one of the predictors of a group of patients requiring lengthy antidepressant treatment (36 months on average) to prevent relapse (Aronson & Shukla, 1989). Antidepressants may need to be continued indefinitely, especially if the patient has had more than one major depressive episode in his or her lifetime. As patients with MDpsy often have elevated glucocorticoid levels, the glucocorticoid antagonist, mifepristone, has been investigated as a treatment for MDpsy. The only double-blind, randomized placebo-controlled study of 208 patients with MDpsy failed to find a significant difference between a one-week course of mifepristone or placebo added onto treatment as usual regarding their primary endpoint, improvement in psychosis at day 7 that was sustained to day 28 (DeBattista, 2003). Another randomized, double-blind trial in bipolar patients was largely negative, finding significant decreases in HAM-D and MADRS scores, but only at day 14, not day 7 or day 21 of the trial (Young et al., 2004), and only if a correction for multiple comparisons was not done (Rubin & Carroll, 2004). A small, randomized, open-label inpatient trial (Belanoff et al., 2002) had previously found that 68% of patients receiving mifepristone had a 30% reduction

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in psychosis scores (BPRS positive symptoms scale) and 40% had a 50% reduction in the Hamilton Depression score (21-item) after a week of treatment. The efficacy of mifepristone is currently a topic of intense debate, with some maintaining that the treatment lacks robust findings or a consistent rationale, since in some trials participants have not had demonstrated abnormalities in glucocorticoid levels (Rubin & Carroll, 2004). In addition to medication, the treatment of MDpsy should include a comprehensive psychosocial assessment and treatment plan. Although no studies to date have looked specifically at psychotic depression, the benefit of individual psychotherapy in the treatment of major depression without psychosis is well documented (APA, 2000). In addition, substance abuse can complicate the treatment of depression and should be treated if present. As with all psychiatric disorders, patient and family education is important, as are adequate social supports for patients with MDpsy.

Conclusions Major depression with psychotic features, a disorder with considerable morbidity and mortality, is often not recognized or accurately diagnosed. As a result, patients frequently receive less than optimal treatment and have poorer outcomes. Biological studies have identified distinct characteristics of major depression with psychotic features, including marked dysregulation of the hypothalamicpituitary-adrenal axis and decreased dopamine-beta-hydroxylase activity, although studies of genetic or other risk factors are still inconclusive. The treatments with the best evidence basis continue to be antidepressants plus antipsychotic medications in combination, or electroconvulsive therapy. Further research on this important and common psychotic disorder continues to be acutely needed.

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14.

Part IV

Neurodevelopmental and Genetic Disorders

10

Psychosis with intellectual disabilities Colin P. Hemmings1 and Nick Bouras2 1 2

South London and Maudsley NHS Trust, MHiLD, Guy’s Hospital, London, UK King’s College London, Institute of Psychiatry, Estia Centre, London, UK

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B C C C C D C C C

Introduction People with intellectual disabilities (ID) have higher rates of mental disorders compared to people of more typical intelligence (Smiley, 2005). They can experience the full range of psychotic disorders seen in the wider population (Reid, 1972). However, the evidence base regarding the epidemiology, etiology, assessment, and management of psychotic disorders in people with ID remains limited. Probably the best known and most studied of the psychotic disorders in people with ID as well as in the wider population are the schizophrenias and schizophrenia-associated spectrum disorders. This chapter will focus on these specific psychotic disorders in people with ID. It has long been thought that the relationship between psychoses and intellectual impairment may provide important clues to the etiology of psychoses (Offord & Cross, 1971). Kraepelin (1919) described pfropfschizophrenie as being psychosis literally ‘engrafted’ onto ‘idiocy’ and accounting for 197

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up to 7% of cases of ‘‘dementia praecox.’’ He believed that pfropfschizophrenie was an early-onset and severe form of psychosis in pre-existing ID. Kraepelin also believed that schizophreniform psychosis beginning in the first decade could itself cause ‘‘mental defect’’ (Heaton-Ward, 1977). However for a long time after Kraepelin, most researchers believed that the joint occurrence of both conditions in the same individual was merely a chance combination (Heaton-Ward, 1977). There was accordingly a lack of research interest in the study of co-morbid ID and schizophrenia (Turner, 1989). Recently interest has been renewed, as part of the wider increased research into mental disorders in people with ID. Opinion has also been growing once again that the study of schizophrenia and the schizophrenia-associated spectrum disorders in people with ID may lead to important clues in the understanding of these disorders in the wider population.

Epidemiology For several reasons there have been longstanding difficulties with establishing true incidence and prevalence rates of psychosis in people with ID. Psychosis in people with ID is generally more difficult to detect and diagnose than in the general population. The research in this field has also been hampered by inconsistencies in diagnostic criteria and rating instruments used (Sturmey, 1999). A major reason for the inconsistency of approaches has been the continued doubts about the usefulness of standard diagnostic classification systems in diagnosing psychosis in those with more severe ID. Specific problems of diagnosis

There are many possible pitfalls in the diagnosis of psychosis in people with ID. Sometimes a specific diagnosis of schizophrenia in people with ID is impossible. ‘‘First rank’’ (Schneider, 1959) positive symptoms of schizophrenia are conceptually complex and thus often difficult to reliably assess in people with ID (Hucker et al., 1979). There may be difficulties distinguishing true delusional beliefs and hallucinations from self-talk, fantasies, and talking to imaginary friends, which can be developmentally appropriate for a person with ID (Heaton-Ward, 1977; Hurley, 1996). People with ID often ‘‘remember’’ conversations and think out loud about them. They often do not readily recognise that this is socially inappropriate. Under stress all of these developmentally appropriate features may become more prominent and exaggerated (Hellendoorn & Hoekman, 1992). Formal thought disorder may also be difficult to elicit in people with ID, for it can often be difficult anyway to follow the thread of their speech. People with ID are

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also often hypersensitive to how they are perceived by others, often grounded in real-life experiences of being mocked and rejected (Hurley, 1996). This may be mistaken for delusional persecutory thinking. It has also been suggested that people with ID are more likely to be able to be persuaded of the falseness of the delusional beliefs. Hence it may be more important to observe their readiness to restate their beliefs when not so subject to suggestibility (Hurley, 1996). Apparent ‘‘negative’’ symptoms can also be misattributed to a psychotic disorder when they may be due to many other factors such as institutionalisation, over-sedation, lack of environmental stimulation, and severe cognitive impairment (James & Mukhergee, 1996). Moss, Prosser, and Goldberg (1996) showed negative symptoms to have low specificity for schizophrenia in adults with ID. They found that auditory hallucinations seemed easiest to elicit in people with ID and psychosis, followed by thought disorder, and then by delusions relating to replacement of will. It may be difficult to discriminate psychotic symptoms from baseline features of ID, a diagnostic problem which Sovner and Hurley (1986) termed ‘‘baseline exaggeration.’’ However, the difficulty of differentiating psychotic symptoms and features related to a person’s ID may also lead to the problem of ‘‘diagnostic overshadowing’’ (Reiss, Levitan, & Zyszko, 1982) and psychosis therefore being under-diagnosed in this patient group. Another problem with diagnosing schizophrenia in people with ID is the difficulty of differentiating it from autism. The term ‘‘autism’’ itself was actually coined by Bleuler (1911) to describe social withdrawal in schizophrenia. He included autism as one of the four core characteristics of schizophrenia. Kolvin (1971), though clearly later, showed that the pervasive developmental disorder of childhood autism was distinct from schizophrenia and other psychoses. The risk of schizophrenia in people with autism is also probably no more frequent than that of schizophrenia in the general population, suggesting that autistic spectrum disorders and schizophrenia are not inter-related (Volkmaar & Cohen, 1991). However, it may still be impossible to decide whether a person has autism or the negative symptoms of chronic schizophrenia unless a good developmental history is available (James & Mukhergee, 1996). Unusual preoccupations held rigidly by people with autism may be particularly difficult to differentiate from delusions. Flattened and incongruent affect, poor non-verbal communication, and poverty of speech are commonly seen in autism as well as schizophrenia and so also lead to diagnostic difficulties. Problems with inconsistent criteria

The study of mental disorders in people with ID has been hampered by the use of inconsistent criteria. The major difference in the various approaches used has been whether researchers have used standardised criteria or criteria modified for

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people with ID. For example, Hucker et al. (1979) modified the Research Diagnostic Criteria of Feighner et al. (1972) in their study of schizophrenia in people with ID and thus included features such as ‘‘behaves as if hallucinated’’ as evidence of the disorder. Nor have definitions of the term ‘‘Intellectual Disabilities’’ itself been consistent. However, recent improvement in consistency of criteria used in studies of mental disorders in people with ID has allowed greater comparison between them. The specific problems of diagnosis of schizophrenia in people with ID have improved in recent years with the development of standardised assessment instruments for this patient group. For example, the schizophrenia sections of the PAS-ADD instruments are now available to increase the reliability of the identification of schizophrenia in the ID population (Moss et al., 1996). Limitations of standard classification systems

One of the major reasons why inconsistent criteria have been applied in ID research is that the validity of the standard diagnostic classification systems for use in this patient group is questionable to some degree. In people with mild ID and good verbal skills it seems that the standard classification systems can be used with reliability and validity (Dosen & Day, 2001). By analogy, ICD and DSM criteria for schizophrenia have been shown to be reliable when used with children with typical IQ as young as seven years old (Green et al., 1992). The linguistic competence of a normal seven-year old is similar to an adult with moderate ID (Melville, 2003). The developmental perspective can be illuminative, as complex delusions and hallucinations are unusual in young children but become more frequent in older children and children with a higher IQ (Watkins et al., 1988). Most of the research literature on psychosis in ID has focused on people with mild ID (IQ 50
70). Reid (1972) influentially argued that it is impossible to diagnose schizophrenia in people with limited verbal communication. In practice, this means below an IQ level of around 45. A person with more severe ID has limited verbal expression and ability to employ abstract reasoning, which are essential for the manifestation of the complex, subjective experiences of the language-based symptoms of schizophrenia. Sovner (1986) has described this phenomenon as ‘‘intellectual distortion.’’ Sovner and Hurley (1986) also argued that ‘‘cognitive disintegration,’’ or psychotic-type reactions to stress, occurred in people with ID because of their limited coping abilities. Higher incidence of schizophrenia and related schizophrenia spectrum disorders have been found in those with mild ID compared with more severe ID (Bouras & Drummond, 1992; Cowley et al., 2004). However it remains unclear whether this reflects reality or whether it merely reflects the problems in detection of psychosis in people with more severe ID. The generally accepted criterion for psychosis is the absence of

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insight and loss of sense of reality (Heaton-Ward, 1977). Hence it could be argued that those with severe ID could be all considered psychotic. However, most researchers probably share the view of Heaton-Ward (1977) that a person’s degree of insight and touch with reality cannot be reliably assessed if they do not have a reasonable level of intelligible communication. Prevalence and incidence

Turner (1989) has reviewed the epidemiological studies of prevalence rates of schizophrenia in ID. The studies have converged around point prevalence rates of about 3% and this figure has become widely accepted (Deb, Thomas, & Bright, 2001; Fraser & Nolan, 1994; Turner, 1989). This prevalence rate is around three times higher than in the general population although this is still thought to be an underestimate of the true figure (Turner, 1989). There are no studies published specifically of incidence rates of schizophrenia in people with ID. Reasons for increased prevalence rates

There are three major possibilities for the increased prevalence of schizophrenia in people with ID. First, a lowered IQ could be a premorbid sign of schizophrenia (Gunnell et al., 2002). Second, cerebral abnormalities caused by genetic factors or in utero may cause both ID and SSP. This has been described as the ‘‘common etiology’’ hypothesis (David et al., 1997). Third, low IQ could lead to incorrect social assumptions and thus increased risk of symptoms such as delusions and hallucinations. David et al. (1997) showed that low intellectual ability in itself is a risk factor for schizophrenia and other psychoses, although their study, like the vast majority in schizophrenia research, excluded those with premorbid ID. Other epidemiological factors

Doody et al. (2000) reported that women with ID generally developed schizophrenia later than men with ID, who were also less likely to have a family history of the disorder. They suggested that gender differences in schizophrenia might be more pronounced amongst the co-morbid population, where early cognitive impairment can herald the onset of a more severe form of onset. Cowley et al. (2004) found higher prevalence of schizophrenia and related schizophrenia spectrum disorders with older age, whereas Cooper (1997) found no differences in the prevalence of schizophrenia between younger and older adults with ID. Ethnicity has also been associated with schizophrenia and schizophrenia spectrum disorders in the ID population, with a higher incidence in those of South Asian origin (Chaplin et al., 1996). Cowley et al. (2004) also found lower prevalence rates of schizophrenia and schizophrenia spectrum disorders in white participants compared to non-whites.

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Age of onset Meadows et al. (1991) suggested that schizophrenia might have a significantly earlier age of presentation in people with ID. Fraser and Nolan (1994) believed that the age of onset of psychosis does seem to be earlier in ID but thought that the reasons for this remained unclear. One possibility is that the existence of schizophrenia in the context of ID is more likely to produce a more severe illness with earlier appearance of psychotic symptoms (Meadows et al., 1991). However, there is also the possibility that the presence of schizophrenia increases the likelihood of an individual being diagnosed as having ID, and vice versa (Sanderson et al., 2001). There can sometimes also be a delay in presentation of schizophrenia in people with ID due to the difficulties of detection, including the finding that the onset of psychosis may sometimes be less noticeable in people with ID because florid symptomatology is less common (James & Mukhergee, 1996). However, Doody et al. (1998b) found no significant differences in the ages of first symptoms of schizophrenia, consultation, admission, or diagnosis between subjects with both mild ID and schizophrenia, and matched controls with schizophrenia alone. This was despite the fact that co-morbid subjects had more psychopathology and duration of admissions than the controls. Presentation Turner (1989) described the symptoms of schizophrenia in people with ID as ‘‘often shallow or banal.’’ Because of their reduced opportunity to engage in normal life experiences and social opportunities, the delusions of people with ID, when they occur, may be unremarkable. For example, there is little attempt to interpret strange subjective phenomena and secondary elaboration either of abnormal perceptions or odd beliefs producing complex delusional systems rarely occurs (Reid, 1989). Complex hallucinations such as voices giving as running commentary in the third person or discussing the person between himself or herself are also uncommon. Sovner (1986) described this phenomenon as an example of ‘‘psychosocial masking’’ of symptoms in people with ID. James and Mukhergee (1996) found that the presenting complaints of schizophrenia in people with ID were very often a decline in functioning, deterioration of skills, and social withdrawal, rather than hallucinations and delusions. Reid (1993) suggested that hebephrenic, paranoid, and catatonic subtypes of schizophrenia could all be seen in people with ID. Many clinicians believe though that it is less often possible to sub-classify schizophrenia in people with ID than in those with more typical IQ.

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Positive and negative symptoms

Although researchers in the field of psychosis in ID have used the categorisation of psychotic symptoms into ‘‘positive’’ and ‘‘negative’’ (Andreasen, 1982), the validity of these in the ID population remains unclear (Melville, 2003). There have been conflicting findings; for example, Bannerjee et al. (2001) and Cherry et al. (2000) emphasised positive symptoms in the presentation of schizophrenia in people with ID whilst Doody et al. (1998b) found ‘‘negative’’ symptoms to be more common. Disagreement remains whether or not the presentation of schizophrenia is significantly different in people with and without ID. Most of the literature suggests that there are no substantial differences in the symptoms of schizophrenia between people with ID and people of normal intelligence (Hucker et al., 1979; Meadows et al., 1991; Moss et al., 1996; Reid, 1972). Meadows et al. (1991) suggested that there was no difference whatsoever in the presentations of symptoms of schizophrenia between those with and without ID. Their subjects formed a small, highly selected group of those in hospital. It is possible that those with florid symptomatology would have been more likely to been included within their study. But even with this sample, there was still a trend for less overt psychopathology in thirteen of the sixteen symptoms. Bassett et al. (2003) also found no significant differences in the schizophrenia phenotype between patients with and without ID. However, other studies have found differences in presentation, especially a tendency for less florid positive symptoms of schizophrenia in those with ID. For example, Linnaker and Helle (1994) found that those diagnosed with schizophrenia with the Psychopathology Instrument for Mentally Retarded Adults (PIMRA) had fewer delusions, flatter affect, and more incoherent speech than people with schizophrenia of normal intelligence, especially persecutory delusions and formal thought disorder. Doody et al. (1998b) and Bouras et al. (2004) also found differences between presentations of schizophrenia in the ID and non-ID populations. Emotional and behavioral symptoms

Some researchers have argued that there are possible behavioral manifestations or ‘‘behavioral equivalents’’ of mental disorders such as psychosis in people with ID (Dosen, 2005). However, the association between problem behaviors and schizophrenia is unclear. Certainly some behavioral problems respond to antipsychotic medication suggesting that they may be caused or exacerbated by underlying psychosis that is difficult if not impossible to diagnose clearly using standard diagnostic criteria. It has been argued that people with ID and psychosis may present with other atypical features. For example, hysterical type symptoms

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such as over-breathing, pseudo-fits, gait disturbance, and Ganser states may be more frequent in people with ID and psychosis (Dosen & Day, 2001; Hucker et al., 1979; Reid, 1972). Some schizophreniform psychoses also present acutely with apparent changes in consciousness (Reid, 1993). Turner (1989) reported that disturbed and aggressive behavior, bizarre rituals, and ‘‘hysterical’’ behaviors are relatively more common in ID and may complicate the presentation of psychosis in ID. People with ID and schizophrenia may also present with social withdrawal, fearfulness and sleep disturbance (Eaton & Menolascino, 1982; Myers, 1999). The ‘‘DC-LD’’ guide (Royal College of Psychiatrists, 2001) suggests that early signs of a psychotic illness could be new problem behaviors (especially when odd or bizarre or uncharacteristic for the person), or an increase in frequency or severity of preexisting behaviors. A presumptive diagnosis of schizophrenia in ID may sometimes thus be made on the basis of observations. For example, behavior that might suggest auditory hallucinations could be the person with ID shouting back apparently at people not present when this has not been their previous behavior. Similarly, suspiciousness, blunted or incongruent affect, and social withdrawal not previously part of the person’s personality and behavior could also be suggestive of a schizophreniformtype psychosis. Non-verbal evidence for possible psychosis by necessity becomes of greater diagnostic significance in the more severely intellectually disabled. Earl (1934) suggested that abnormal movement disorders, mannerisms, and stereotypies seen in more severe ID were a ‘‘form of schizophrenia played out upon the psychomotor level rather than the symbolic.’’ It has been claimed that it is possible using observations and non-verbal communication to diagnose schizophrenia in people with more severe ID (Eaton & Menolascino, 1982). The authors believed that three of their patients with severe ID showed evidence of schizophrenia by the presence of bizarre behavior, persistent withdrawal, echolalia, and blunted affect. Cherry et al. (2000) also described characteristics of schizophrenia in a study sample of people with severe or profound ID. Heaton-Ward (1977) argued that for some people with more severe ID, their emotional lability, noisy outbursts, disorganised, purposeless activity, including aggression, destructiveness, and selfmutilation could be considered ‘‘psychotic’’. However, as previously noted he recognised that it would be impossible to determine whether such individuals were demonstrating lack of insight and loss of sense of reality, which is characteristic of true psychosis. This appears to be the mainstream view of researchers in the field. Turner (1989) noted the persistent comment on catatonia in the literature. Hucker et al. (1979), Eaton and Menolascino (1982), and Heaton-Ward (1977) all remarked upon the high proportion of their study samples of subjects with ID and schizophrenia who showed catatonic features. The relationships between

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catatonia, movement disorders, and schizophrenia in ID are complex and as yet under-researched and need further clarification. Neuropsychological findings

Kay (1989) pointed out the overlap in performance on tests of intellect, adaptive behavior, and cognition between people with ID without schizophrenia and people with chronic schizophrenia. An episodic psychotic illness may be associated with a reduction in transient functioning to the mild or even moderate level of ID (Russell & Tanguay, 1981). A chronic psychosis may, however, lead to a prolonged or even permanent reduction in intellectual and social functioning. Sometimes those with chronic schizophrenia are thus mistakenly diagnosed as also having ID, because of deterioration in intellectual functioning. Heaton-Ward (1977) found a 20 percent fall in IQ in some of his patients with ID and schizophrenia over time. There is little specifically published in the literature of neuropsychological findings in people with ID and schizophrenia. Doody et al. (1998b) found that their co-morbid subjects were more likely to have impairment of episodic memory, which may affect their compliance with treatment. They also had greater impairment of theory of mind on second order tests than subjects with schizophrenia and normal pre-morbid IQ (Doody et al., 1998a). Rowe, Rudkin, and Crawford (2000) found that there was an increased rate of mixed handedness among people with co-morbid ID and schizophrenia compared to controls. Mixed handedness is taken as an index of diminished cerebral dominance or laterality and thus these findings also supported the idea of a neurodevelopmental hypothesis of schizophrenia. Weinberger (1987) has suggested that people with ID and schizophrenia form a subgroup of schizophrenia with a neurodevelopmental etiology. Doody et al. (1998b) found evidence consistent with the neurodevelopmental hypothesis in their study of co-morbid ID and schizophrenia. For example, they found that their co-morbid subjects had more ‘‘soft’’ neurological signs than controls. They suggested that there is a form of schizophrenia that manifests in childhood with cognitive impairment prior to the onset of psychotic symptoms.

Course and progression It has long been established that in patients with schizophrenia there is a relationship between pre-psychotic IQ and disease prognosis (Offord & Cross, 1971). There has been very little published, however, into the long-term prognosis in people with ID and schizophrenia. There have not been either any published studies of the latency period or prodrome before presentation of psychotic

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symptoms in this patient group. Most clinicians believe that the course of schizophrenia in people with ID will tend to be more severe than in people with normal IQ. However, again the literature is scant and findings so far are contradictory. For example, Reid (1972) found in his study that the psychoses ran a more benign course in people with ID, especially in those with more severe ID. Bouras et al. (2004) showed that in a group of people with schizophrenia spectrum disorders and ID, matched for duration of illness, there was higher observable psychopathology, more negative symptoms, and greater functional disabilities compared to a group with schizophrenia spectrum disorders attending a general mental health outpatient clinic. The authors suggested that the increased prevalence of observable psychopathology might lead to increased risk of stigma and social isolation for those with schizophrenia who also had ID. The higher rate of negative symptoms seen also might contribute to social withdrawal and isolation and raised the question of whether those with ID as well as schizophrenia might have progressed more rapidly to the chronic deficit state of schizophrenia. The findings of this study suggested that people with ID are more debilitated by schizophrenia than those without ID and may thus need additional input. Doody et al. (1998b) found that patients with dual diagnosis of schizophrenia and ID had fewer psychiatric admissions but for longer periods of time, and that at point of discharge they needed more support than patients with schizophrenia alone. With some outcome parameters, such as total time in hospital and offending behavior, there was no evidence that the co-morbid group were more impaired than the schizophrenia control group. However they also found that those with both conditions received more community supports than control subjects with schizophrenia alone. Doody et al. (2000) showed that in people with co-morbid ID and schizophrenia, males with an early age of onset and no known family history of either ID or schizophrenia were more likely to require care and treatment in a high security hospital.

Suspected neuropathology In the classification systems of DSM-IV (American Psychiatric Association, 1994) and ICD-10 (World Health Organisation, 1992) it is stipulated that schizophrenia should not be diagnosed in the presence of ‘‘overt’’ brain disease, which is more common in people with ID (Hagberg & Kyllerman, 1983). This complicates the study of neuropathology in individuals with both schizophrenia and ID. A recent case-controlled study of volumetric cerebral magnetic resonance reported that, in terms of brain structure, people with ID and schizophrenia resemble those with schizophrenia more closely than those with ID (Sanderson et al., 1999).

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These findings were confirmed by further studies (Moorhead et al., 2004; Sanderson et al., 2001). Sanderson et al. (1999) suggested that the higher frequency of schizophrenia in ID was due to the greater tendency of people with schizophrenia to develop cognitive deficits and that within the ID population there may be people whose deficits result from undiagnosed schizophrenia. These authors support the view that co-morbid schizophrenia and ID may represent an early onset and severe form of schizophrenia, rather than ID complicated by psychosis (Moorhead et al., 2004) Rare congenital syndromes associated with ID can also provide some clues for the study of psychosis in ID. For example, the Andermann syndrome is a variable familial syndrome combining ID, congenital corpus callosum agenesis, peripheral neuropathy, dysmorphic features, and psychosis (Andermann et al., 1972). It thus provides an opportunity to examine the relationship between psychotic symptoms and neuropathology. Filteau et al. (1991) found no significant relationship between corpus callosum agenesis and psychosis. However, there was a relationship between atrophy of the structures in the posterior fossa, including the cerebellum, and psychosis in this syndrome, suggesting that such defects could be associated with psychosis.

Suspected neurochemical abnormalities There have been no reports in the literature of neurochemical abnormalities specific to people with ID and schizophrenia.

Genetic factors Kallman (1938) found no increase in ID in the relatives of people with schizophrenia and vice versa. This study suggested that the co-morbid state was a chance occurrence of two unrelated conditions and contributed to a period of subsequent decreased research interest into co-morbid ID and schizophrenia (Turner, 1989). However Kallman’s study did not consider the co-morbid probands and, when Doody et al. (1998b) considered these, both the prevalence of ID and schizophrenia were increased in the relatives of the co-morbid probands. This suggested that the occurrence of both conditions only by chance was unlikely and supported the idea that a highly familial form of schizophrenia might occur in the ID population. Doody et al. (1998b) also showed that there was a high rate of chromosomal variants in karyotype testing in the co-morbid group. Cytogenetic anomalies, which are often associated with intellectual impairment, may be associated with

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an earlier age of onset of schizophrenia (Bassett et al., 1998). High rates of schizophrenia have been reported in adults with velo-cardio-facial syndrome (VCFS), which is associated with a deletion on chromosome 22 and often, but not invariably, associated with ID. (Scambler, 2000). In a large study of 50 adults with VCFS Murphy, Jones, and Owen (1999) found that fifteen (30%) had psychotic disorder, with twelve (24%) fulfilling DSM-IV criteria for schizophrenia. In addition, 2% of patients with schizophrenia exhibit this 22q11-deletion including 6% of the early-onset cases (Usiskin et al., 1999). Higher rates of 22qds may be present in subsets of schizophrenia with ID (Bassett, Chow, & Weksberg, 2000). Increased rates of dysmorphic features, cognitive impairment, and structural brain abnormalities have led to the proposal of 22q11 as a model for a neurodevelopmental subtype of schizophrenia. However, VCFS is not an entirely suitable model for ID and psychosis as it is not invariably associated with ID. Many studies of VCFS and psychosis have also excluded people with ID. Other genetic syndromes and abnormalities have been associated with ID and psychosis. For example, atypical psychotic symptoms also seem associated with Prader-Willi syndrome, particularly the maternal disomy form of the syndrome (Boer et al., 2002; Verhoeven, Curfs, & Tuinier, 1998). Associations have also been reported between schizophrenia and sex chromosome anomalies (De Lisi et al., 1994), which are in turn associated with an increased likelihood of ID as well as XXYY (Lee, 1996). Schizophrenia and ID in association have also been reported with a wide variety of autosomal chromosomal abnormalities, for example on chromosome 9 (Park et al., 1991) and chromosome 5 (Bennett et al., 1997). Other risk factors Epilepsy

Deb et al. (2001) and Doody et al. (1998b) found that those with schizophrenia and ID were more likely to have epilepsy compared to those with schizophrenia of typical intelligence. Epilepsy can lead to problems with diagnosis, for example differentiating temporal lobe epilepsy from schizophrenia, as well as treatment, as antipsychotics typically lower the seizure threshold. In contrast, Cowley et al. (2004) found that in their study people with epilepsy and ID had a lower incidence of schizophrenia. In this study, level of ID may have been a confounding factor, as epilepsy increases in prevalence in more severe ID (Bowley & Kerr, 2000). The phenomenon of ‘‘forced normalisation’’ has been described in relation to the schizophreniform psychoses of epilepsy (Trimble, 1996) whereby a reduction in seizure activity following the introduction of anticonvulsant agents is associated with an exacerbation of psychosis. It is possible that this mechanism may be of

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etiological importance in a proportion of the co-morbid population (Doody et al., 1998b). Obstetric complications

O’Dwyer (1997) found that, in people who develop ID and psychosis, the number of obstetric complications increases, compared to those matched for age, sex, severity of ID, and epilepsy. These complications included abnormally long labour, dysmaturity, pre-eclamptic toxemia, and maternal episiotomies, all of which may give rise to anoxic cerebral trauma, which the authors concluded was the major etiological factor predisposing people with ID to develop psychoses. Hucker et al. (1979) studied 24 people with ID and schizophrenia, and 40 control subjects. They found higher proportions of people with impaired hearing, gestation below 36 weeks, and low birth weight in the group with schizophrenia. Sensory impairments

Sensory impairments are more common among people with ID (Carvill, 2001). It is not known whether there is a general association between sensory impairments and predisposition to psychosis in people with ID, although many clinicians believe this to be the case. There is a specific association with psychosis in some cases of Usher’s syndrome, which is associated with schizophrenia in about 15% of cases (Hallgren, 1959).

Treatment The principles of treatment of schizophrenia in people with ID are essentially similar to those when the patient is of normal intelligence. The few existing studies have suggested that treatment with antipsychotics in ID is broadly similar in efficacy with no significant risk in side effects (Craft & Schiff, 1980; Reid, 1972). Shedlack et al. (2005) found that in those with schizophrenia spectrum disorders there was substantial improvement in social withdrawal following treatment with both typical and atypical antipsychotic medication. Some studies have reported good effects and fewer side effects with atypical antipsychotics (Advokat, Mayville, & Matson, 2000; Williams et al., 2000). Clozapine also appears to be safe, efficacious, and well tolerated in people with ID and co-morbid mental illness, including schizophrenia (Antonacci & de Groot, 2000). Many clinicians have reported that the optimal dosage levels of antipsychotic medications appear to be lower in ID patients than in patients with normal IQ (Menolascino et al., 1985). The exacerbation of cognitive impairment and the lowering of seizure thresholds can be particular problems in the prescribing of

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antipsychotics for people with ID. There is a consensus that antipsychotic prescribing often needs to be instigated and increased more cautiously than in patients without ID. Overall, there are still too few studies that have been published of people with ID-prescribed antipsychotics for treatment of psychosis rather than for behavioral problems. Duggan and Brylewski (1999) have thus argued that there is insufficient evidence to judge the efficacy of antipsychotics in people with ID. The use of antipsychotics to treat schizophrenia in this patient group therefore is still largely based on extrapolation from the evidence base of general adult psychiatry. There remains an urgent need for randomised controlled trials of the efficacy of antipsychotic medication in people with ID and schizophrenia. Clarke (2001) argued that people with brain pathology are more likely to develop tardive dyskinesia than the general population. In a study of people with ID in a long stay institution (Sachdev, 1992), 34% of those receiving antipsychotic medication had tardive dyskinesia. Accordingly, it has been suggested that clozapine may be a particularly useful antipsychotic for people with ID given a possible propensity towards tardive dyskinesia (Cohen et al., 1991; Rao, Cowie, & Matthew, 1987). However, the evidence for increased risk of tardive dyskinesia due to antipsychotic medication in people with ID and schizophrenia is not conclusive. For example, Gualtieri et al. (1986) found no evidence that ID increased the risk. One possible reason for this discrepancy in findings is that differentiating between movement disorders and medication side-effects is more difficult in patients with ID. Rogers et al. (1991) showed that people with more severe ID also have high rates of motor disorders not attributable to antipsychotic medication. The presence of muscle tone abnormalities and stereotypies including tics, mannerism, and self-stimulatory behaviors can all mask the presence of antipsychotic-induced movement disorders (Shedlack et al., 2005). As well as tardive dyskinesia, neuroleptic malignant syndrome may also be possibly increased in people with ID on antipsychotic medication (Boyd, 1992). Electro-convulsive therapy (ECT) has been used in the treatment of mental disorders in people with ID, but there has been little published regarding its use as treatment of schizophrenia in ID (Chanpattana, 1999). There is also little evidence regarding the use of psychosocial (including family) interventions for people with intellectual disabilities. Behavioral techniques have been used to improve the social skills of individuals with psychosis and ID (Hatton, 2002). The application of either individual or family CBT approaches has not been systematically evaluated adequately as yet in people with ID who have psychosis. A case series of cognitive-behavior therapy for five patients with psychosis and mild ID has been reported (Haddock et al., 2004). This included two cases in which family interventions were also integrated into the individual CBT.

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There are no treatments for schizophrenia therefore which are specific to people with ID. The underlying intellectual impairment does influence the outcome of level of independence and functioning (Reid, 1993). In general, there is evidence to suggest that people with ID and schizophrenia may have even more complex needs than patients with schizophrenia of typical intelligence and thus may be harder to treat. There is some evidence that outcomes may be better when people with both ID and psychosis are treated by specialist rather than generic services (Raitasuo, Taiminen, & Salokangas, 1999).

Conclusions The relationships between ID and schizophrenia remain unclear. We are not likely to see any clear-cut relationships between them when ID is itself on a spectrum with the general population. The relationship between IQ itself and schizophrenia is complex, as lower IQ may cause vulnerability to the development of schizophrenia or be an early manifestation of the disorder (Offord & Cross, 1971). Although in some individuals with ID the development of schizophrenia may be by chance, it seems that for others there may be direct and indirect links. Many believe that co-morbid ID and schizophrenia may often represent a severe form of schizophrenia with poorer outcomes (Doody et al., 1998b) and both arising from the same genetic etiology. The majority of studies of schizophrenia have excluded people with premorbid intellectual disabilities. It is important that further research occurs with those who are co-morbid with schizophrenia and intellectual disabilities. Studying schizophrenia in this particular subpopulation might not only improve diagnosis and treatment but also help to identify those with ID who go on to develop schizophrenia. It may also provide one important way forward in the understanding of schizophrenias in general.

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427.

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Velo-cardio-facial syndrome Wendy R. Kates1,2 and Wanda Fremont1 1 2

Department of Psychiatry and Behavioral Sciences Program in Neuroscience, State University of New York at Upstate Medical University, Syracuse, New York

Summary of findings Grade of evidence Epidemiology: Incidence of psychosis in VCFS is between 10% and 30%; no association between age, gender, IQ, or congenital anomalies and incidence of psychosis. Age of onset: Findings inconsistent. Mean age of onset ranges from 21 years (SD, 5 years) to 26 years (SD, 9 years). Presentation: Findings inconsistent. Some evidence that individuals with VCFS and psychosis have fewer negative symptoms than non-VCFS individuals with psychosis. Course and progression: Unknown. Suspected neuropathology: Enlarged ventricles, and volumetric reductions in posterior regions of the brain, particularly the parietal lobe and cerebellum. Alterations also noted in striatum and thalamus. Although findings are consistent with non-VCFS individuals with psychosis, direct comparisons between VCFS and non-VCFS individuals with psychosis are needed. Suspected neurochemical abnormalities: Unknown. Dopaminergic abnormalities are suspected. Genetic factors: Unknown; however, several genes in the 22q11.2 deleted region are expressed in brain tissue and implicated in psychosis, such as COMT and PRODH. Other risk factors: Unknown; hypothesized risk factors outlined in text. Treatment: Unknown.

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Introduction Velocardiofacial syndrome (VCFS) is a relatively common disorder that affects one in 4000 individuals (Ryan et al., 1997). Caused by a microdeletion on 218

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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chromosome 22q11.2, VCFS, also known as 22q11.2 Deletion Syndrome, is associated with a highly variable phenotype that can include palatal anomalies, conotruncal heart defects, hypocalcemia, velopharyngeal insufficiency, neurocognitive deficits, and behavioral disorders. Up to 30% of adolescents and adults with VCFS eventually develop a psychosis (Bassett et al., 1998; Murphy, Jones, & Owen, 1999), leading several investigators to characterize VCFS as a genetic-based subtype of schizophrenia (Bassett and Chow, 1999). Since the publication in 1992 of the initial report of an association between VCFS and psychosis (Shprintzen et al., 1992), the incidence, clinical phenotype, and molecular basis of psychosis in individuals who harbor this microdeletion has been the subject of increasingly intensive study. Epidemiology Although the behavioral phenotype of children with VCFS is well described (see below), relatively few studies have used structured psychiatric interviews from which specific psychiatric diagnoses can be derived. The few extant studies indicate that up to 45% of children with VCFS are diagnosed with attention deficit disorder, 28% with generalized anxiety disorder, 61% with phobias, between 11% and 33% with obsessive compulsive disorder, and between 18% and 30% with mood disorders (including ultrarapid cycling bipolar disorder with hallucinations) (Arnold et al., 2001; Feinstein et al., 2002; Goldberg et al., 1993; Gothelf et al., 2004; Papolos et al., 1996). There is some evidence, however, to suggest that the psychiatric prevalence rates of several of these disorders in children with VCFS do not differ significantly from cognitively matched samples (Feinstein et al., 2002). As children with VCFS have been followed into adolescence and adulthood, more evidence has emerged that indicates that these children are at increased risk of developing major psychiatric disorders. Higher rates of psychopathology have been reported in published studies; however, the rates differ with respect to the specific diagnosis reported. Several studies have reported an increased incidence of psychosis (10
30%) (Papolos et al., 1996; Pulver et al., 1994; Schwab and Widanhaner, 1999; Shprintzen et al., 1992). Murphy et al. (1999) reported a rate of 30% of psychotic disorders in adults with VCFS. The most common psychotic disorder was schizophrenia (24%) but high rates of schizotypy, a trait marker for schizophrenia were also noted. Additional studies of individuals with VCFS have reported an association between VCFS and schizophrenia (Bassett et al., 1998; Gothelf et al., 1997; Karayiorgou et al., 1995; Usiskin et al., 1999). Bassett and Chow (1999) report that the risk of schizophrenia for an individual with VCFS approaches 25 times the risk in the general population. No differences in age, sex,

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or IQ of individuals with VCFS with or without psychosis have been reported (Murphy et al., 1999). Moreover, no association has been found between occurrence of schizophrenia in VCFS and occurrence of congenital anomalies such as cardiac defects or cleft palate (Bassett et al., 2003; Murphy et al., 1999). Research studies have also been conducted to determine if there is an increased prevalence of chromosome 22q11 deletions in adult schizophrenic patients. Although the true prevalence of VCFS in schizophrenia is difficult to ascertain, the results of the literature indicate that the minimum prevalence rate is between 0.3
2% (Arinami et al., 2001; Bassett et al., 1998; Gothelf et al., 1997; Karayiorgou et al., 1995) as compared to a rate of 1% in the general population. A higher rate of chromosome 22q11 deletion (6%) has been reported in patients with early-onset schizophrenia (before the age of 13 years) (Usiskin et al., 1999). Karayiorgou and Gogos (2004) have suggested that ethnic differences may underlie the 22q11 schizophrenia susceptibility risk. They note that among adult patients, the lowest rate (0.3%) has been reported in a case sample from Japan (Arinami et al., 2001) and the highest rate of a sixfold to sevenfold increase was reported in two independent Caucasian samples (Karayiorgou et al., 1995; Wiehahn et al., 2004). A high prevalence of bipolar spectrum disorders, including bipolar I, bipolar II, and cyclothymia have been noted in adolescents and adults with VCFS. (Papolos et al., 1996). Increased rates of attention deficit disorder (36%), anxiety disorders including simple and social phobia (29%), and obsessive-compulsive disorder (14%) have also been reported in adults (Pulver et al., 1994). Age of onset and presentation The presentation and severity of behavioral, psychological, and cognitive difficulties in children and adults with VCFS varies considerably (Ryan et al., 1997). Although behavioral difficulties have been noted in most children with VCFS, problems may first present during early childhood (3
5), latency age (6
11), or adolescence (12
18). Learning difficulties have been reported in 82
100% of children (Swillen et al., 1999b). Studies using behavioral rating scales noted elevated scores on social problems, attentional problems, withdrawn, and thought problems scales (Heineman-De Boer et al., 1999; Swillen et al., 1999a). Children with VCFS have been described as overactive, impulsive, perseverative, emotionally labile, shy/withdrawn, or disinhibited (Gerdes et al., 1999; GoldingKushner, Weller, & Shprintzen, 1985; Swillen et al., 1999a). It is our experience that children with VCFS also have difficulties with time perception; however, empirical data is needed to substantiate this observation. Social problems are also common, most often involving peer difficulties (Swillen et al., 1997; 1999a).

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A cross-sectional study of children with VCFS (Swillen et al., 1999a) reported a trend that increased with age of more internalizing problem behaviors (withdrawn, somatic complaints, and anxious/depressed) than externalizing behavior (delinquent and aggressive). However, social problems, withdrawal, attention problems, and thought problems were consistently reported across the different age groups. As noted above, some of the behaviors observed in children with VCFS are not uncommon in children with developmental delays. Like patients with VCFS, children with developmental delays and learning disabilities have been reported to exhibit a higher rate of specific psychiatric disorders as well as overreactivity, attentional problems, impulsivity, low frustration tolerance, and perseveration (Beitchman et al., 1986; Beitchman and Young, 1997; Einfeld and Tonge, 1996; Feinstein and Reiss, 1996). Studies are needed, therefore, to differentiate behaviors that are primary psychiatric conditions from behaviors that are due to other risk factors associated with developmental and cognitive delays. Results of studies comparing the clinical phenotype of adults with VCFS and schizophrenia to that of schizophrenic adults without VCFS are not consistent (Bassett et al., 2003; Murphy et al., 1999). Murphy et al. (1999) found that the mean onset age of 26 years (SD, 9 years) for individuals with VCFS was older than individuals without VCFS (mean age: 19 years, SD: 4 years), and that patients with VCFS displayed fewer negative symptoms. In contrast, Bassett et al. (2003) found no differences in age of onset, occurrence of positive and negative symptoms, or severity of anxiety and depression. The discrepancy in these findings may be due to differences in ascertainment: whereas the sample of individuals with VCFS for the former study were recruited from genetics clinics, the sample for the latter study was drawn from individuals initially diagnosed with schizophrenia and later found to carry the 22q11.2 deletion. However, Bassett and coworkers also reported that individuals with VCFS and schizophrenia displayed higher levels of poor impulse control, uncooperativeness, and hostility than non-VCFS individuals with schizophrenia (Bassett et al., 2003), which is consistent with the emotional lability reported in a subset of children with VCFS.

Course and progression It is possible that some of the behaviors observed in childhood are prodromal features of more severe psychiatric illnesses. Research studies suggest that lateronset conditions may be causally connected with VCFS, including schizophrenia (Carlson et al., 1997; Pulver et al., 1994; Shprintzen et al., 1992), bipolar disorder (Papolos et al., 1996), and major depressive disorder (Murphy et al., 1999).

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Descriptions of psychosocial dysfunction that characterize children and adolescents at high risk for developing schizophrenia are consistent with descriptions of children with VCFS and include prominent anxiety and social withdrawal (Hans et al., 1999). Taken as a whole, the literature suggests that VCFS may be a genetic cause of schizophrenia. Further research is needed to determine the validity of an association between chromosome 22q11 deletions and schizophrenia and other psychiatric conditions. Moreover, longitudinal studies of children with VCFS are needed to identify prodromal symptoms and areas of dysfunction that precede the development of psychiatric disorders. Suspected neuropathology The increasingly widespread availability of non-invasive, high resolution MRI has led to an upsurge during the past decade of information about the developing and adult brain in VCFS. Several initial qualitative MRI studies (Chow et al., 1999; Mitnick, Bello, & Shprintzen, 1994) reported the presence of white matter hyperintensities, periventricular cysts, and reduced cerebellar vermi in the brains of individuals with VCFS. More recently, quantitative imaging studies have identified volumetric alterations in brain regions of children and adults with this disorder. Most of these studies are limited by small sample sizes, and vary in the composition of control groups, thus diluting the generalizability of anatomic imaging results. However, several consistent findings have emerged. Relative to typically developing children, patients with VCFS exhibit reductions of approximately 11% in total brain volume (Eliez et al., 2000; Kates et al., 2001). Volumetric studies have indicated that patients with VCFS exhibit alterations in both cortical and subcortical regions of interest. Subcortical regions that appear to be altered in patients with VCFS include the thalamus (Bish et al., 2004), posterior fossa (Eliez et al., 2002b), cerebellum (Eliez et al., 2000), and caudate nucleus (Eliez et al., 2002a; Kates et al., 2004). Volumetric studies of the morphology of the cerebral cortex in children with VCFS have consistently revealed reductions in parietal gray matter volumes (Eliez et al., 2000) and parietal and temporal white matter volumes (Kates et al., 2001). In contrast to posterior regions of the brain, generalized frontal lobe gray and white matter volumes do not appear to be reduced disproportionately to whole brain volume in children with VCFS relative to controls (Eliez et al., 2000; Kates et al., 2001; 2004). However, a recent diffusion tensor imaging study has demonstrated white matter alterations in axonal connections between the frontal and temporal lobes (Barnea-Goraly et al., 2003). In addition, the corpus callosum, comprised of white matter axonal processes that transmit information between cerebral

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hemispheres, appears to be increased in area (Antshel et al., 2005; Shashi et al., 2004; Simon et al., 2005) and displaced posteriorly in children with VCFS. Despite the absence of overall alterations in frontal cortex relative to whole brain volume, frontal
posterior, and inter-hemispheric connections may be disrupted. Due to the increased incidence of schizophrenia in adults with VCFS, the venues from which samples have been ascertained, and the relative unavailability of non-schizophrenic adults with VCFS, imaging studies of adults with VCFS vary in sample composition, limiting our ability to tease out which neuroanatomic alterations are due to VCFS, and which are specific to individuals comorbid for schizophrenia. Extant studies suggest that relative to healthy controls, individuals with VCFS with or without psychosis exhibit increases in ventricular cerebrospinal fluid (Chow et al., 2002; Van Amelsvoort et al., 2004a) and reductions in frontal white matter (Chow et al., 2002), frontal, parietal, and temporal gray matter (Chow et al., 2002; Van Amelsvoort et al., 2001; 2004a), and cerebellar tissue (Van Amelsvoort et al., 2004a). These findings are in agreement with results of imaging studies of children with VCFS without psychosis (Eliez et al., 2000; Kates et al., 2001), and to some extent to non-VCFS adults with psychosis. However, relative to individuals with VCFS without psychosis, individuals with VCFS and psychosis exhibit a generalized reduction in total tissue volume and total white matter volume coupled with selective increases in frontal gray matter volume (Van Amelsvoort et al., 2004a). This may suggest that whereas a generalized disturbance in brain development may increase vulnerability to psychosis in VCFS, alterations in the frontal lobe specifically may be a necessary precursor to the onset of schizophrenia (Van Amelsvoort et al., 2004a). One major caveat is that we do not have a comprehensive understanding of the trajectory of brain development in VCFS. Insofar as the psychiatric phenotype is developmental, we would expect the neuroanatomic underpinnings of that phenotype to be developmental as well. There is preliminary evidence that temporal lobe gray volume decreases with age during adolescence (Eliez et al., 2001). This is consistent with the findings of absolute reductions of temporal gray matter volumes in adults with VCFS (Chow et al., 2002; Van Amelsvoort et al., 2001) but not children with VCFS (although, as noted above, the sample composition of adult and child studies were different). Comprehensive longitudinal studies of children with VCFS, as well as direct comparisons between VCFS adults with psychosis and non-VCFS adults with psychosis, are essential to our understanding of the effect of brain development on neuropsychological function and risk for psychiatric disorder in individuals with this developmental disorder.

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Suspected neurochemical abnormalities The neurochemical abnormalities that increase vulnerability to psychosis in VCFS are not known. Due to the presence of the catechol-O-methyltransferase (COMT) gene at the q11.2 locus of chromosome 22, however, it is strongly suspected that dopaminergic pathways are altered in VCFS. The COMT gene encodes for an enzyme that regulates the degradation of synaptic dopamine levels and which mouse models suggest is expressed throughout brain development (Maynard et al., 2003). Since all individuals with VCFS are missing a single copy of the COMT gene, and therefore will be heterozygous for either the Met or Val allele at this locus, the availability of synaptic dopamine (or other catecholamine neurotransmitters) will most likely be altered (Lachman et al., 1996). We discuss the potential effect of this alteration in more detail below. Genetic factors Although the genetic mechanism that increases vulnerability to psychosis in VCFS is not known, several of the thirty genes that reside within the deleted region are expressed in brain tissue, and have been implicated in schizophrenia in the nonVCFS population (Bilder et al., 2002; Egan et al., 2001; Glatt, Faraone, & Tsuang, 2003; Jacquet et al., 2002; Karayiorgou & Gogos, 2004; Liu et al., 2002a; Matsumoto et al., 2003; Noal et al., 2004; Saito et al., 2003; Sanders et al., 2004; Shifman et al., 2002; Tunbridge et al., 2003; Wonodi et al., 2003). The genes at the 22q locus that are expressed in brain tissue vary according to effects on neurogenesis, migration, and synaptic stabilization (Maynard et al., 2003). Accordingly, the presence of only one copy of each of these genes most likely disrupts both development and function of neuronal circuits (Maynard et al., 2003). To the extent that schizophrenia is associated with alterations in both neural development and function, it seems likely that the alterations of multiple genes within this region converge and interact to produce susceptibility to schizophrenia (Maynard et al., 2003). As noted above, the catechol-O-methyltransferase (COMT) gene has been the subject of extensive investigation. Several functional polymorphisms of this gene, and their combined haplotypes (Bray et al., 2003; Shifman et al., 2002) have been investigated in relation to schizophrenia (Bilder et al., 2002; Egan et al., 2001; Glatt et al., 2003; Liu et al., 2002a; 2002b; 2004; Matsumoto et al., 2003; Shifman et al., 2002; Wonodi et al., 2003). The Val108/158Met polymorphism has been linked to risk for psychiatric disorder, performance on neuropsychological tasks of working memory and executive function, and prefrontal physiology (Akil et al., 2003; Egan et al., 2001; Matsumoto et al., 2003). However, the results of the studies

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investigating this polymorphism have been conflicting, as have the few investigations of the effect of this polymorphism on psychiatric and neurocognitive function in VCFS. Whereas one study found an association between the presence of the Met allele and psychiatric disorder in VCFS (Lachman et al., 1996), a second study found an association between presence of the Val allele and diminished performance on tasks of executive function (Bearden et al., 2004). This ambiguity could be due to the possibility that both alleles contribute to susceptibility to psychosis, depending on interaction with other allelic variants both within and beyond the deleted region (Karayiorgou & Gogos, 2004). It has been hypothesized that one mechanism by which the COMT gene confers susceptibility to schizophrenia is through its interaction with PRODH, a gene in the deleted region that encodes for proline dehydrogenase (Karayiorgou & Gogos, 2004). PRODH is expressed primarily in the adolescent mouse brain, during the stabilization of synaptic connections (Maynard et al., 2003), which appear to be compromised in schizophrenia (Freedman et al., 2001; Mirnics et al., 2001). The role of PRODH in schizophrenia susceptibility is supported by studies of linkage disequilibrium (Liu et al., 2002b; 2004) and genomic rearrangement (Jacquet et al., 2002). Support for the association between PRODH, which appears to modulate glutamatergic activity (Hoogendoorn et al., 2004; Karayiorgou & Gogos, 2004), and schizophrenia is strengthened by evidence that PRODH deficiency in mice is predictive of deficits in prepulse inhibition (Gogos et al., 1999), a deficit that has been described in individuals with schizophrenia (Light and Braff, 1999) and, recently, in non-schizophrenic children with VCFS (Sobin et al., 2005). To date, no investigations of allelic variation in the PRODH gene in VCFS have been reported. Several other genes within the 22q11.2 locus, including ZDHHC8 (Karayiorgou & Gogos, 2004; Liu et al., 2002a) and ARVCF (Sanders et al., 2004), are expressed in either developing or mature brain tissue and have also been implicated in schizophrenia independently of VCFS. Accordingly, it is likely that the heterozygous deletion of multiple genes at this locus is contributing, in complex and interacting patterns, to schizophrenia susceptibility in VCFS. The challenge of identifying the relative contribution of each of these genes to schizophrenia susceptibility has generated enormous interest among both VCFS and schizophrenia investigators, and we can expect significant progress during the next decade. Other risk factors Psychophysiological markers for psychosis have been explored to some extent in VCFS, but the data are sparse. As noted above, deficits in prepulse inhibition,

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which have been widely described in individuals with schizophrenia, have been identified in children with VCFS (Sobin et al., 2005). In addition, smooth pursuit eye tracking deficits, which consititute a fairly robust marker for schizophrenia, are found in a subset of children with VCFS (Kates, unpublished manuscript). Finally, the neurocognitive phenotype of children and adults with VCFS also overlaps with individuals with schizophrenia. Individuals with VCFS display deficits in executive function (Van Amelsvoort et al., 2004b; Woodin et al., 2000) and attention (Sobin et al., 2004; Van Amelsvoort et al., 2004b). The specificity and predictive validity of these markers, however, have not been established. Only longitudinal studies, currently in progress at several research sites, will elucidate the extent to which these are truly risk factors for psychosis in VCFS. Treatment No controlled treatment studies of psychosis in VCFS have been reported. However, the effects of pharmacologic interventions targeted at the COMT enzyme on neuropsychiatric symptoms in VCFS have recently been reported. In one report (Graf et al., 2001), open-label trials of metyrosine, which decreases catecholamine production, were conducted with five individuals with the 22q11.2 deletion and severe neuropsychiatric disorder. All of the individuals in this study were found to have the low-activity, Met allele, presumably resulting in higher levels of synaptic dopamine. Therapeutic levels of metyrosine were associated with moderate improvements in symptomatology in four of the five individuals. This study, coupled with a single-case report of similar findings (O’Hanlon et al., 2003), suggests that controlled studies of pharmacological agents that reduce catecholamine production are warranted with individuals who are comorbid for VCFS and psychosis. Conclusions Although investigations of the association between VCFS and psychosis have yielded much information, it is critical that we implement longitudinal studies that identify the risk factors for severe psychiatric disorder in individuals with this genetic disorder. Although the neuroanatomic, neurophysiological, and neuropsychological phenotype of individuals with VCFS overlap with those with schizophrenia, we do not know which aspects of that phenotype might serve as specific markers or risk factors for the onset of psychosis. Moreover, we do not have a good understanding of whether the behavioral phenotype during childhood increases the risk for the development of severe psychiatric disorder

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in adulthood. Longitudinal studies using structured psychiatric interviews will clarify the extent to which the psychiatric disorders in childhood constitute a prodrome for psychosis in adulthood. Moreover, comprehensive studies of genotype
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12

Psychosis in autism Angelina Kakooza-Mwesige1, Laura Stoppelbein2, and Dirk M. Dhossche2 1 2

Department of Pediatrics & Child Health, Makerere University Medical School, Kampala, Uganda Department of Psychiatry & Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi

Summary of findings Grade of Evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

C C C D D D D D D

Introduction Psychosis has carried different meanings since its introduction more than 150 years ago (Beer, 1996). Others have described the social and intellectual contexts that have shaped the concept of psychosis at different times and places (Berrios, 1987; Beer, 1995). Modern classification systems incorporate psychosis in various disorders as a serious disturbance in ‘‘reality testing’’ expressed as hallucinations, delusions, thought disturbance, disorganized behavior, or catatonia. Recent advances in neuroscience hold the promise of elucidating the brain mechanisms of psychosis and finding improved antipsychotic treatments. Fujii & Ahmed (2004) have recently proposed conceptualizing psychosis as a neurobiological syndrome with its own pathophysiology and treatment algorithm regardless of etiological factors and underlying diagnoses. This view has heuristic value 233

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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for refining current classification systems, focusing research, and tailoring treatments on an individual basis. In this chapter, we report on the characteristics of psychosis superimposed on autism. First, some definitions of autism are presented. In DSM-IV classification, autism covers the group of the Pervasive Developmental Disorders (PDDs) (American Psychiatric Association, 1994), i.e., Autistic Disorder, Asperger Disorder, Childhood Disintegrative Disorder, Rett’s Disorder, and Pervasive Developmental Disorder Not Otherwise Specified (PDD NOS). The PDDs are behavioral syndromes with a broad range of severity and characterized by lifelong impaired communication, impaired social interactions, and repetitive interests and behavior (Wing & Attwood, 1987; Rapin, 1997). DSM-IV diagnostic criteria of AD, AsD, and CDD, are shown in Table 12.1. PDD NOS is a residual category that is used to classify cases that do not satisfy full criteria of AD, AsD, or CDD. Rett’s Disorder is also listed among the PDDs. However, a causal genetic defect on the X chromosome has been identified

Table 12.1. DSM-IV criteria of selected Pervasive Developmental Disorders (PDDs).

Unique features Age of onset Development

Regression Abnormal communication* Shared features

Autistic Disorder (AD)

Asperger Disorder (AsD)

Onset before age 3 Clinically significant delay in language, cognitive development, self-help skills, adaptive behavior, or curiosity about the environment

No clinically significant delay in language, cognitive development, self-help skills, adaptive behavior, or curiosity about the environment No regression -

Regression in 30% þ

Childhood Disintegrative Disorder (CDD)

Onset before age 10 At least two years of apparently normal development

Massive regression þ

Qualitative impairment in social interaction (e.g. impairment in nonverbal behaviors, failure to develop peer relationships, impaired expression of pleasure in other people’s happiness, lack of social or emotional reciprocity) Restricted, repetitive, and stereotyped patterns of behavior, interests, and activities, including motor stereotypies and mannerisms

*qualitative impairments in communication (e.g. delay or lack of spoken language, inability to initiate or sustain a conversation, stereotyped and repetitive use of language, lack of varied make-believe play)

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(Amir et al., 1999). In this report, the PDDs, with the exclusion of Rett’s Disorder, are collectively referred to as autism. The prevalence of autism is 0.1
0.2% (Fombonne, 2003) for narrow diagnosis of autistic disorder and 0.6% for less restrictive diagnoses. Males predominate with approximately a four times higher rate than in females. Prevalence rates have been said to increase, but changes in diagnostic methodology and ascertainment strategy complicate comparisons across time (Fombonne, 2003). The diagnosis of autism is made clinically on the basis of behavioral symptoms that are not apparent until the ages of two to three, at least in classic autism (AD). Although medications can relieve symptoms in some autistic people, there is presently no known cure. The possibility that various metabolic and genetic factors may play a role in the occurrence of autism is a subject of intense research. About one third of autistic people develop some type of epilepsy (Gillberg, 1991b). Increased rates of seizure disorders (Deykin & MacMahon, 1979; Gillberg, 1991b) and worsening of autistic symptoms or overall behavioral deterioration (Gillberg & Schaumann, 1981; Gillberg, 1991a) have been reported around puberty. Cognitive deficits are present in more than half of autistic people (Rutter, 1983).

Epidemiology Reviewing psychosis in autism may appear a daunting task at first sight, or an easy one, depending on one’s perspective, because of the following issues. Leo Kanner separated autism from early-onset psychosis or childhood schizophrenia in 1943 by stating that the condition he described ‘‘differed markedly and uniquely from anything reported so far (Kanner, 1943).’’ Subsequent studies on childhood psychoses have highlighted differences in cardinal symptoms (e.g. absence of hallucinations in autistic children), course of illness, intellectual functioning, sex distribution, social class, brain abnormalities, age of onset, and family history of schizophrenia (Rutter, 1972). Studies support that autism and schizophrenia cannot often be diagnosed in the same patient (Volkmar & Cohen, 1991). Overall, the evidence seems overwhelming that psychosis does not occur often in people with autism justifying the separate classification of autism since DSM-III. However, there continues to be a provision in DSM-IV (American Psychiatric Association, 1994) that schizophrenia can be diagnosed in individuals with autism who develop characteristic features of schizophrenia with prominent delusions or hallucinations for one month. In the next paragraphs, those few studies that have assessed psychotic symptoms in autism will be reviewed. Modern criteria of psychosis and schizophrenia have been applied in a few reports of people with autism, especially of the high-functioning type, who

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develop chronic psychotic disorders similar to schizophrenia (Petty et al., 1984; Clarke et al., 1989; Kurita, 1999). Petty et al. (1984) described the development, by school age or early adolescence, of psychotic symptoms including hallucinations, delusions, and thought disorder satisfying formal criteria of schizophrenia in three children who had been diagnosed with autism during the first years of life. All three cases developed communicative speech and had borderline or normal IQ. The authors note that most autistic children do not develop communicative speech and have IQs in the mentally retarded range, precluding the assessment of hallucinatory experiences, paranoia, and thought disorder, and thus a formal diagnosis of schizophrenia or other psychotic disorder. Clarke et al. (1989) reported two adult cases with Asperger Disorder, one case with atypical autism (PDD NOS) and one case with classic autism, all developing superimposed affective and non-affective psychotic conditions. A fifth case was previously diagnosed with schizophrenia based on enduring obsessional behavior and withdrawal but was rather thought to have Asperger Disorder given the absence of hallucinations or delusions. The authors warn that PDDs may be complicated by psychotic illnesses presenting in adulthood. Conversely, PDDs may be mistaken for psychosis. Volkmar & Cohen (1991) conducted a chart review on 163 adolescents and adults with well documented histories of autism. About half of the patients were largely or entirely mute. DSM-III-R criteria for a lifetime diagnosis of schizophrenia were applied. Only one patient satisfied unequivocal criteria for schizophrenia, according to their assessments. Around 15 years of age, this male patient started complaining of auditory and occasional visual hallucinations. His speech became difficult to follow and he exhibited catatonia on at least one occasion. The patient had a strong family history of schizophrenia. Other patients had fluctuating bizarre interests and preoccupations that were considered part of autism. No other patients presented with hallucinatory experiences. The authors admit that hallucinations and delusions could not be assessed in the non-verbal patients. It was concluded that within the limitations of a chart review and inadequacy of DSM-III-R criteria of schizophrenia in nonverbal autistic populations, schizophrenia was not more common in autism than in the general population. There is also evidence that catatonia may be common in adolescents and young adults with autism (Dhossche et al., 2006b). Only two systematic studies of catatonia in autism have been reported (Wing & Shah, 2000; Billstedt, Gilberg & Gilberg, 2005). They suggest that catatonia-like features are present in about one of seven (12
17%) adolescents and young adults with autism and constitute an important source of impairment in this population. In a recent study, 17% of a large referred sample of adolescents and young adults with autism satisfied

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modern criteria for catatonia (Wing & Shah, 2000). Thirty persons with autism aged 15 or older met criteria for catatonia. Classic autistic disorder was diagnosed in 11 (37%), atypical autism in 5 (17%), and Asperger disorder in 14 (47%). None of those under the age of 15 had the full catatonic syndrome, although isolated catatonic symptoms were often observed. In the majority of cases, catatonic symptoms started between the ages of 10 and 19. Five individuals had brief episodes of slowness and freezing during childhood, before age 10. Schizophrenia was not diagnosed in any of these patients. In a report based on a population study (Billstedt et al., 2005), 13 (11%) of 120 autistic individuals between the ages of 17 and 40 (mean age 25.5 years) had clinically diagnosed catatonia with severe motor initiation problems. Another 4 had several catatonic symptoms but not the full syndrome. Autistic disorder was diagnosed in 8 of the 13 people with catatonia; atypical autism was diagnosed in the remaining 5. The proportion of those with autistic disorder in whom catatonia was diagnosed was 11% (8/73); 14% of those with atypical autism (5/35) had catatonia. An increasing number of case reports and case series of catatonia in autism that satisfy DSM criteria for catatonia have been published over the last 15 years (Realmuto & August, 1991; Dhossche, 1998; Ghaziuddin, Quinlan & Ghaziuddin, 2005; Dhossche et al., 2006b).There is considerable overlap of psychomotor symptoms between the two disorders, e.g. muteness, echolalia, stereotypical movements, and other psychomotor peculiarities (Stoppelbein, Greening & Kakooza, 2006). The progression of autistic symptoms into full-blown catatonia has been described in adolescent cases (Dhossche, 1998). Age of onset Hallucinations, delusions, and catatonia have only been described in post-pubertal patients with autism (Petty et al., 1984; Clarke et al., 1989; Realmuto & August, 1991; Dhossche, 1998; Kurita, 1999; Ghaziuddin et al., 2005). In the catatonia study of Wing & Shah (2000), all of those with catatonia were aged 15 or older. None of those under age 15 had the full syndrome although isolated catatonic symptoms were often observed. In the majority of cases, catatonic symptoms started between 10 and 19 years of age. Five individuals had brief episodes of slowness and freezing during childhood, before age 10. Presentation Autistic people can develop typical symptoms of psychosis, including hallucinations, delusions, thought disorder, and catatonia. Reliance on self-report is

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problematic given the cognitive and verbal deficits in this population. A comprehensive clinical psychiatric evaluation should be conducted to diagnose any type of psychosis in people with developmental disorder. There are no widely accepted standardized diagnostic interviews for psychotic disorders in autism or mental retardation, to our knowledge. It is unknown if current catatonia rating scales are applicable in people with autism. Modified criteria for catatonia in autism allowing for baseline levels of stereotypies, echolalia, and other catatonic symptoms have recently been published (Dhossche, Shah & Wing, 2006a), but these need further testing. High rates of atypical symptoms of psychosis or negative symptoms in autistic people have been reported, but their significance is often unclear. It is unknown if such individuals are prone to develop psychosis or if those symptoms are more related to autism or the frequently associated cognitive deficits. Next, we will review three studies that have directly compared individuals with autism and schizophrenia. Future studies are warranted to show the significance of these findings. Rumsey, Andreasen, & Rapoport (1986) examined 14 adults with DSM-III diagnoses of autism (mostly high-functioning) and used comparison groups diagnosed with schizophrenia and mania. Autistic individuals had a high incidence and severity of poverty of speech, poverty of speech content, perseveration, and affective flattening. They showed significantly less derailment, illogicality, and ‘‘positive thought disorder’’ than schizophrenic or manic patients did. Deficit symptoms, such as negative thought disorder and affective flattening, were similar between autistic and schizophrenic patients. In another study (Dykens, Volkmar & Glick, 1991), thought disorder was assessed in 11 high-functioning autistic young adults utilizing objective ratings and projective tests. Autistic adults showed more poverty of speech than schizophrenic individuals did. No illogicality was manifest in any of the autistic subjects. On the Rorschach’s Schizophrenia Index, no differences were found between autistic and schizophrenic groups suggesting a high incidence of poor reality testing, compromised perceptual accuracy, perceptual distortions, and cognitive slippage in both groups, at least during tests of freeassociation to stimuli. The authors interpret their findings as evidence of shared features of thought disorder between autism and schizophrenia, but confirm that the presence of similar features does not imply continuity of the disorders. Finally, symptoms of 14 males with DSM-III-R autism and 14 males with DSMIII-R paranoid schizophrenia were compared in a recent study (Konstantareas & Hewitt, 2001). Instruments for diagnosis and assessment included a structured clinical interview, a schedule for positive symptoms, and a schedule for

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negative symptoms. None of the men with paranoid schizophrenia met criteria for autism. Seven of those with autism met criteria for schizophrenia, disorganized type, with mainly negative symptoms (affect flattening, alogia, attentional difficulties). Although many subjects with autism made statements that could be interpreted as delusional (‘‘people pick on me’’) or grandiose (‘‘I am the smartest guy around’’), these were not seen as psychotic since they could be explained reasonably by living environment and/or cognitive/emotional immaturity. Course and progression Longitudinal studies of psychosis or catatonia in autism providing information on clinical risk factors and prodromal signs are not available in the literature. In the case reports that were discussed earlier, the psychotic disorder seemed stable and chronic. Larger studies are needed to confirm this. In the study of Wing & Shah (2000), obsessive-compulsive and aggressive behavior preceded catatonia in some. Visual hallucinations or paranoid ideas were occasionally reported, but no diagnosis of schizophrenia could be made. Referred patients with catatonia were significantly more likely than patients without catatonia to have had impaired language and passivity in social interaction before the onset of catatonia. Suspected neuropathology The biological basis of autism and psychosis remains unknown. There are no published accounts of neuropathological findings of psychosis in autism. Developmental processes have been recognized as key to understanding autism (Belmonte et al., 2004). Involvement of different brain areas is widespread and includes the cerebellum, brain stem, frontal lobes, parietal lobes, hippocampus, and amygdale (Palmen et al., 2004). There have been a few attempts to describe a coherent anatomical or pathophysiological theory of autism. There is some variability between those hypotheses depending on whether the authors considered social, cognitive, or affective abnormalities as the primary deficit in autism. For example, Maurer and Damasio (1982) using anatomical and etiological inferences based on a wide range of autistic symptoms concluded that dysfunction of phylogenetically older parts of the frontal and temporal lobes best accounted for the clinical manifestations of autism. Gualtieri (1991) on the other hand noted similarities between autism and the Klu¨ver-Bucy syndrome, a syndrome described in rhesus monkeys after bilateral temporal lobectomies. This suggested to him that deep temporal and frontal lobes may be involved.

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Of some interest is the role of the cerebellum in autism and psychosis. One of the most consistent findings in autism is the selective vulnerability of the cerebellar Purkinje cell (Ritvo et al., 1986; Kemper & Bauman, 1993). Nine brains from patients with well documented autism (six children and three young adult males) have been studied systematically (Bauman, Filipek & Kemper, 1997). All brains showed a marked reduction of Purkinje cells and a variable decrease in granular cells throughout the cerebellar hemispheres. There was no significant gliosis and no retrograde of inferior olivary neurons, suggesting that the abnormalities were acquired early in development at or before the 30th week of gestation. The cerebellum remains an understudied yet important area in both disorders. Evidence for cerebellar involvement in psychosis is limited to imaging studies given the limited number of neuro-anatomical studies. Reductions in cerebellar volume have been reported in chronic schizophrenia (Okugawa, Sedvall & Agartz, 2003), catatonic schizophrenia (Joseph, Anderson & O’ Leary, 1985; Wilcox, 1991), and autism (Courchesne et al., 1988).

Suspected neurochemical abnormalities Neurochemical studies have not been done in people with comorbid autism and psychosis (or catatonia). It is possible that some abnormalities in metabolism of serotonin, dopamine, GABA, and other transmitter molecules are shared between autism and psychosis (and catatonia). However, further speculations are futile at this stage.

Genetic factors Although a medical or neurological disorder is found in a small proportion of cases with autism, most cases are idiopathic. In those cases, a strong genetic component is likely but the pattern of inheritance is complex. Twin studies show a 60
91% concordance rate in monozygotic twins, depending on whether a narrow or broad phenotype is considered. There are no observations of concordance in dizygotic twins under narrow phenotypic definition and a low concordance (10%) under broader phenotypic definition (Bailey et al., 1995). Sibling recurrence rate has been estimated to be 4.5%. This pattern of sharply increasing risk for first-degree relatives and monozygotic twins relative to the population prevalence does not fit a simple dominant or recessive model, but indicates the involvement of multiple genes interacting with one another to lead to disease susceptibility. No definite susceptibility genes for autism have been discovered, despite the encouraging possibility of candidate regions on chromosomes. Molecular genetic

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studies have narrowed down certain candidate regions, with two regions being identified in several (but not all) studies. These are 15q11-13, near the GABAAb3 receptor subunit gene (GABRB3) and a second one on 17q11.2, near the serotonin transporter gene (SLC6A4) (Veenstra-Vanderweele, Christian & Cook, 2004). There are also a few studies that suggest that there are shared genetic risk factors between autism and certain types of psychosis. First, DeLong (1994) found increased rates of affective disorder, particularly bipolar disorder, in family members of autistic probands. In a sample of 40 autistic children and adolescents, without neurological disease, from 37 families, he reported a family history for bipolar disorder in 29 (78%) families. In another family study (Piven et al., 1991), the rate of major depressive disorders was higher in parents of autistic probands than in parents of non-autistic probands. Second, parental schizophrenia-like psychosis and affective disorder were significant risk factors for autism in offspring in a nationwide Danish case-control study of 698 children diagnosed with autism between 1972
1999 (Larsson et al., 2005). Relative risks were 3.44, 95% CI 1.48
7.95 and 2.91, 95% CI 1.65
5.14, for parental schizophrenia-like disorder and affective disorder respectively. Other significant variables were breech presentation (RR ¼ 1.63), low Apgar score at 5 minutes (RR ¼ 1.89), and gestational age at birth less than 35 weeks (RR ¼ 2.45). Weight for gestational age, parity, number of antenatal visits, parental age, or socioeconomic status were not significant risk factors. These findings support that perinatal factors and parental psychopathology are associated with risk of autism. It remains an open question whether perinatal adversity was due to environmental factors, factors associated with autism in the fetus, or a combination of these and possibly other (unmeasured) variables. Finally, it has also been noted that about 40% of children with onset of schizophrenia before age 10 had symptoms of autism during infancy and early childhood (Watkins, Asarnow & Tanguay, 1988). In a sample of children with childhood-onset schizophrenia (COS) (before their 13th birthday), 19 of 75 (25%) of children with COS had a lifetime diagnosis of PDD (Sporn et al., 2004). Two siblings of children with COS were diagnosed with classic autism (AD). This suggests a familial link between certain types of autism and childhood-onset schizophrenia. Future family psychiatric studies assessing psychotic disorders, including catatonic subtypes, as risk factors for autism are warranted. Previous studies have typically not separated out catatonic subtypes of schizophrenia, affective disorder, or other psychotic disorders. The only genome scan reporting on catatonic schizophrenia gave a linkage signal in the region 15q11.2-q21.1

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(Sto¨ber et al., 2000). This region has also been linked with autism (Cook et al., 1998; Menold et al., 2001; Nurmi et al., 2003) and bipolar disorder (Papadimitriou et al., 1998; Otani et al., 2005). Finding shared genes for autism, catatonia, and bipolar disorder would support the hypothesis of common biological pathways between these disorders. GABA receptor subunit genes located on 15q11-13 warrant special attention as candidate shared genes (Dhossche, 2004).

Other risk factors It is conceivable that other risk factors such as adverse life events or medical/ neurological illnesses may precipitate psychosis in some individuals with autism as in individuals without autism or any other developmental disorder. However, there are no systematic studies in this area. The clinician evaluating a possible psychotic episode should inquire about sudden psychosocial changes or adverse events, and rule out medical/neurological illnesses associated with psychosis. Treatment There are no controlled trials of psychosis or catatonia in autism in the literature. However, it is reasonable to treat the autistic patient with current antipsychotic treatment once a diagnosis of psychosis is made. This reflects the practice of using the primary treatments for hyperactivity, aggression, anxiety, and obsessive features in people with autism and other developmental disorders. Atypical antipsychotics, especially risperidone (Hardan et al., 1996; Shea et al., 2004), also seem useful in decreasing the overall level of behavioral and emotional disturbance in autism. There are a handful of case reports of autistic patients diagnosed with a catatonia with a positive response to benzodiazepines (Dhossche & Bouman, 1997; Dhossche, 1998) and ECT (Zaw et al., 1999; Ghaziuddin et al., 2005; Fink, Taylor & Ghaziuddin, 2006). These treatments have shown efficacy in catatonic patients without autism (Fink & Taylor, 2003). Firm conclusions about the efficacy of these treatments in autistic patients with catatonia must await future controlled trials (Dhossche et al., 2006a). Acknowledgements Research support from the Thrasher Research Fund, Salt Lake City, Utah, is gratefully acknowledged.

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5.

Part V

Central Nervous System Disorders

13

Psychotic disorder due to traumatic brain injury Daryl E. Fujii1, Nikki Panasci Armstrong2, and Iqbal Ahmed3 1 2 3

Department of Neuropsychology, Hawaii State Hospital Department of Psychology, University of Hawaii at Manoa Department of Psychiatry, John A. Burns School of Medicine, University of Hawaii at Manoa

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B B B B B C C B C

Introduction Psychotic disorder due to traumatic brain injury (PDDTBI) is a relatively rare disorder that is in the nascent stage of being understood. Despite the paucity of empirical investigations on PDDTBI in the literature, this disorder has the potential to provide clues for understanding schizophrenia and psychosis in general. The purpose of this chapter is to outline existing knowledge on PDDTBI and to examine a possible link between traumatic brain injury (TBI) and psychosis. The literature on PDDTBI is summarized, with the goal of elucidating different aspects of the syndrome, including epidemiological issues, clinical presentation, course and latency of onset, suspected neuropathology, genetic and environmental risk factors, and treatment. The chapter concludes with a proposed model describing the relationship between TBI and psychosis, as well as potential 249

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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mechanisms accounting for latency between sustaining TBI and the onset of psychosis. Epidemiology Recent data estimate that the annual incidence rate of TBI ranges from 100 to 444 per year (Jager et al., 2000; National Institute of Health, 1999), while psychiatric disorders, in general, have been reported to develop in approximately half the people sustaining moderate to severe traumatic brain injury (Fann et al., 2004; Koponen et al., 2002). The most common psychiatric sequelae of TBI are depression (44.3%), post-traumatic stress disorder (14.1%), substance abuse (13%), panic disorder (9.2%), generalized anxiety disorder (9.1%), and obsessive compulsive disorder (6.4%) (Van Reckum, Cohen, & Wong, 2000). Incidence rates of psychotic disorder due to traumatic brain injury (PDDTBI) have ranged from 0.7
8.9% among individuals who sustain TBI (Davison & Bagley, 1969; Fann et al., 2004; Koponen et al., 2002), making it a relatively uncommon, but fascinating psychiatric condition related to TBI. Severity of injury, as measured by duration of loss of consciousness (LOC) and post-traumatic amnesia, varied from mild to severe (Achte, Hillbom, & Aalberg, 1969; Achte et al., 1991; Fujii & Ahmed, 2001; 2002a; Fujii, Ahmed, & Hishinuma, 2004; Sachdev, Smith, & Cathcart, 2001). Although some studies reported the majority of patients who develop PDDTBI sustained a moderate to severe head injury (Achte et al., 1969; Davison & Bagley, 1969; Fujii & Ahmed, 1996; Sabhesan, Arumughan, & Natarajan, 1990), PDDTBI has occurred in patients with mild TBI, including those without loss of consciousness (Fujii & Ahmed, 2002a). Thus, studies examining which severity is most highly associated with PDDTBI remain inconsistent, with one study reporting no relationship (Violin & De Mol, 1987). Despite the seemingly rare occurrence of PDDTBI, it has been suggested that diagnostic issues related to conceptualization of the disorder may contribute to an underestimation of PDDTBI prevalence (Ahmed & Fujii, 1998; Fujii & Ahmed, 2002a). Specifically, Ahmed and Fujii (1998) argue that establishing psychosis as a direct physiological consequence of TBI and determining that the psychosis is not due to another medical condition are both aspects of PDDTBI criteria that can lead to diagnostic difficulties for clinicians. Evidence for the failure to consider TBI as contributory to psychiatric illness supports this assertion. For instance, many patients with psychotic disorders, such as schizophrenia, have sustained TBI (Davison & Bagley, 1969), with one study reporting that 67% of patients sustained TBI within one year of admission to an acute psychiatric hospital, yet TBI documentation was absent in

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the patients’ charts (Burg et al., 1996). Additional studies report that patients who meet DSM-IV (American Psychiatric Association, 1994) criteria for Psychotic Disorder Due to a General Medical Condition, including TBI, typically receive diagnoses of schizophrenia spectrum disorders (Feinstein & Ron, 1990; Fujii & Ahmed, 1996; 2002a). Age of onset A high level of variability exists in the age of onset for PDDTBI. The mean onset reported in most studies is between the mid-20s and mid-30s, with standard deviations as large as 10.2 to 15.4 years (Achte et al., 1969; 1991; Fujii & Ahmed, 2001; 2002a; Sachdev et al., 2001). Although one study that examined war veterans with head injury reported a high percentage of schizophrenic psychosis (56.5%) occurring prior to age 20, such early-onset cases appear to be relatively uncommon and may be associated with a more severe presentation of psychosis (Davison & Bagley, 1969). Presentation Among PDDTBI patients, persecutory delusions are reportedly present in up to 22
80% of all patients (Achte et al., 1969; 1991; Davison & Bagley, 1969; Fujii & Ahmed, 2001; 2002a; Sachdev et al., 2001; Violin & De Mol, 1987) and are ranked first in the majority of studies (Fujii & Ahmed, 2002b), making this delusional subtype the most common psychotic symptom of PDDTBI. Auditory hallucinations are highly prevalent, as well, occurring in 60
93% of all PDDTBI patients (Achte et al., 1969; 1991; Fujii & Ahmed, 2001; 2002b; Sachdev et al., 2001). Although much less common, visual hallucinations (8
32%), negative symptoms (15
22.2%), grandiose delusions (15
20%), somatic delusions (15%), and formal thought disorder (4.4%) have also been reported (Fujii & Ahmed, 2002a; Sachdev et al., 2001). Additionally, intriguing results of one study indicated that experiential factors of substance abuse and sexual disorders were associated with delusions of jealousy and infidelity (Achte et al., 1991). The percentages of seizure disorders among non-psychotic TBI patients is much lower than those observed in PDDTBI patients, suggesting that seizure disorder, particularly temporal lobe epilepsy, is another common sequela of PDDTBI (Lishman, 1997). One study of World War II Finnish soldiers reported that post-traumatic epilepsy occurred more frequently in patients with psychosis than in those without (57.7% vs. 31.8%) (Achte et al., 1969). More recent studies indicate the percentage of seizure-related psychosis in PDDTBI patients ranges

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from 9
34% (Fujii & Ahmed, 2002a; Sachdev et al., 2001); although rates of co-occurrence have reached as high as 67
70% when PDDTBI patients with positive temporal lobe EEG findings, but without a documented history of seizure disorder, have been included in estimation procedures (Achte et al., 1969; Fujii & Ahmed, 1996; 2001; 2002a). Neuropsychological impairments have also been documented in the literature. Specifically, memory and executive functioning deficiencies have been the most consistent finding among PDDTBI patients (Fujii & Ahmed, 2002a; Fujii et al., 2004; Sachdev et al., 2001). Functional deficits in visuospatial and vocabulary domains have been less frequently reported in PDDTBI studies (Fujii & Ahmed, 2002; Fujii et al., 2004).

Course and progression The high variability in latency between TBI and onset of psychotic symptoms is an issue that has continued to challenge researchers when determining the etiological significance of TBI to the development of psychosis. Although the mean latency is four to five years (Achte et al., 1991), the range of documented latencies has spanned as wide as two days to 48 years (Achte et al., 1969); hence, the emergence of psychosis can often be unexpected and bewildering, and can raise doubts about the contributory factor of TBI to the emergence of psychosis. Despite this broad range of latencies, evidence suggests that the modal onset of psychosis lies within the initial two years post-TBI (Fujii & Ahmed, 2002a). For example, one exploration of case studies in the literature reported a highly skewed distribution of latencies that extended up to 34 years, with 38% of patients demonstrating psychotic symptoms within one year of TBI, approximately half of the patients exhibiting symptoms before the second year, and 72% within four years (Fujii & Ahmed, 2002a). Similarly, other researchers reported that roughly 73% of TBI patients experienced psychotic symptoms within five years post-injury (Davison & Bagley, 1969). Further, a study of HMO patients sustaining TBI suggested an increased prevalence of psychotic symptoms from the first to second years post-injury for those with moderate to severe brain injuries (Fann et al., 2004). Although most studies indicate the majority of PDDTBI patients demonstrate symptoms within two years of sustaining injury, one longitudinal study following TBI patients for 30 years suggested a bimodal distribution of onset may exist. Specifically, half of the patients developed psychosis within one year of sustaining a TBI, while the other half developed psychotic symptoms no earlier than 10 years post-injury (Koponen et al., 2002).

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There is some evidence suggesting that differences in onset of psychosis following TBI may be related to type of head injury (e.g., mild vs. moderate/severe; open vs. closed). For example, Fujii and Ahmed (2002a) found that patients experiencing a brief delay between TBI and onset of psychosis (i.e., one year and less) had more mild brain injury as opposed to moderate/severe TBI. Additionally, a previous meta-analysis of the literature reported that most closed head injury patients (52%) demonstrated psychotic symptoms within one year post-injury, and 85% of closed head injury patients exhibited symptoms within five years of TBI (Davison & Bagley, 1969). Similarly, another study with predominantly closed head injury patients reported a mean onset of 5.9 years (Fujii & Ahmed, 1996). By contrast, two studies consisting of World War II veterans with 98.9% sustaining splinter or gunshot wounds report longer latencies. More specifically, one of the studies reported that 60% of patients had latencies of more than five years, while the other indicated a majority of delusional psychoses occurred between 15 and 19 years post-TBI (Achte et al., 1969; 1991). Some evidence indicates that duration of latencies may be associated with different characteristics of TBI or psychosis and therefore may have clinical significance. In particular, people with shorter latencies (i.e., within one year of initial insult) are more likely to have sustained diffuse brain injuries (Davison & Bagley, 1969) and experience visual hallucinations (Fujii & Ahmed, 2002). Additionally, a longitudinal study of Finnish soldiers sustaining missile wounds found that paranoid schizophrenia was common (23%) in cases with short latencies, while delusional disorder was quite rare (4%) in the early-onset cases (Achte et al., 1969; 1991). Conversely, longer latencies have been related to localized temporal lobe damage (Davison & Bagley, 1969), the presence of epilepsy (Davison & Bagley, 1969), and the development of delusional disorder (Achte et al., 1969; 1991). To date, only one study has described prodromal symptoms of PDDTBI (Sachdev et al., 2001). In this study, about half of the patients demonstrated bizarre behaviors, while roughly a third displayed antisocial behaviors, affective instability, and academic or vocational deterioration, and approximately a fifth of the patients exhibited social withdrawal after TBI but before the onset of PDDTBI (Sachdev et al., 2001). The course of illness for PDDTBI patients appears to be highly variable, with both relatively brief and chronic courses reported in the literature. Fujii & Ahmed (2002a) described the course of illness for 25 cases in the existing literature, of which 64% were reported to be improved, 28% reported no improvement, and 8% experienced a progressive worsening of symptoms. Other investigators have associated chronicity with premorbid schizoid personality (Davison & Bagley, 1969). Moreover, individuals who acquire schizophrenic-like psychosis following

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TBI are more likely to demonstrate a chronic course of illness (63%) than those who develop delusional disorder (40%) (Achte et al., 1969; 1991). Suspected neuropathology Despite differences in populations and data collection methods, which have included EEG, lesion location, and imaging techniques, studies have consistently implicated the temporal regions of the brain in the neuropathology of PDDTBI. Although with less consistency, structural damage to the frontal lobes has been reported as well. Specifically, four of five studies with localization data reported predominantly temporal lobe damage on CT or MRI scans, with rates of positive findings ranging from 20.4
39% (Achte et al., 1969; Davison & Bagley, 1969; Sachdev et al., 2001; Violin & De Mol, 1987). The fifth study reported a preponderance of temporal lobe abnormalities (70%) on EEG (Fujii & Ahmed, 2002a). Frontal lobes abnormalities were observed in two of the five studies, with rates ranging from 23.8
42% (Achte et al., 1969; Fujii & Ahmed, 2002a). Findings for hemispheric laterality of lesions remain inconsistent (Fujii & Ahmed, 2002a).

Suspected neurochemical abnormalities There have been no studies directly evaluating neurochemical abnormalities in PDDTBI. Abnormalities in the dopaminergic system have been indirectly implicated as a descriptive study of case studies in the literature reported that neuroleptics were the most efficacious treatment for PDDTBI (Fujii & Ahmed, 2002a).

Genetic factors Research on possible genetic determinants of PDDTBI has been quite limited; however, some biological risk factors have been reported. Male gender is the most commonly cited risk factor for developing PDDTBI (Fujii & Ahmed, 2001). Although there was a definite selection bias in earlier war veteran studies (Achte et al., 1969; 1991), males have been overwhelmingly represented in studies procuring samples from general clinical populations as well, with numbers ranging from 78
100% (Fujii & Ahmed, 2001; 2002a; 2000b; Fujii et al., 2004; Sachdev et al., 2001). Some evidence suggests that a family history of psychotic illness may be a risk factor for PDDTBI. In particular, a family history of schizophrenia was reported

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in 2.9
18% of patients with PDDTBI, which appears to be intermediate between higher incidence rates among patients with schizophrenia and lower rates documented in normal controls (Davison & Bagley, 1969). Mental retardation has also been reported as a potential risk factor for PDDTBI development (Achte et al., 1969). Other risk factors Environmental risk factors for PDDTBI have been noted in the literature. In one study (Fujii & Ahmed, 2001), investigators found that an early TBI, neurological, neurodevelopmental, or learning disorder was a significant risk factor for persons developing PDDTBI after a second TBI, most often occurring in late adolescence or early adulthood. Other risk factors include substance abuse (Nasrallah, 1992) and previous psychological disturbances (Violin & De Mol, 1987). These environmental factors, taken together with genetic risk factors, would suggest that persons developing psychosis post-TBI may have had a previously abnormal or vulnerable brain (Fujii & Ahmed, 2001). Treatment The treatment responsiveness of patients with PDDTBI appears to be highly variable (Fujii, 2002). The most widely used and most efficacious treatments, to date, have been neuroleptics, followed by anticonvulsants and lithium (Fujii & Ahmed, 2002a). Proposed considerations for selection of anti-psychotic medication include the increased sensitivity of the brain-injured patient to the sedating, anti-cholinergic, and seizure threshold-lowering side effects (Ahmed & Fujii, 1998). For example, chlorpromazine has been reported to produce a delusional state, along with cognitive decline (Sandel, Olive, & Rader, 1993). We recommend several pharmacological strategies to treat PDDTBI. Atypical anti-psychotics, such as risperidone, olanzapine, or quetiapine, are recommended for acute or chronic psychotic symptoms associated with TBI, starting at low doses to reduce the risk of side effects. Psychotic agitation may also be acutely managed with parental haloperidol. Benzodiazepines, such as lorazepam or diazepam, should be considered for acute management if seizure activity is thought to be a risk. For acutely psychotic patients who are suspected of having seizure activity, anti-convulsants, such as valproic acid with or without benzodiazepines, are recommended. Anti-convulsants are also recommended for treating symptoms like mood lability, irritability, impulsivity, or affective aggression, and for patients with chronic psychosis who demonstrate EEG abnormalities, such as temporal dysrhythmias.

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Conclusions In summary, PDDTBI is a disorder that has not received much attention from researchers until recently. The sparse and generally descriptive nature of the literature demands large-scale, prospective, longitudinal studies to better illuminate our understanding of the relationship between TBI and psychosis. Thus far, results from studies using diverse populations and methodologies suggest that PDDTBI can result from brain injuries of varying severity, including mild TBI. The clinical presentation of most PDDTBI patients includes persecutory delusions and auditory hallucinations, although negative symptoms, visual hallucinations, thought disorder, and other forms of delusions have been reported in some patients. Studies have consistently implicated lesions to the temporal and frontal lobes in PDDTBI, with deficits to memory and executive functions being the most common neuropsychological impairments. The course and progression of PDDTBI appears to be highly variable. The latency between sustaining TBI and the onset of psychosis has ranged from a few days to 48 years, with the modal onset falling within two years post-injury. Although the distribution seems to be positively skewed, a bi-modal distribution may exist. Some evidence suggests that the duration of latencies may be of clinical importance. Specifically, longer latencies have been associated with temporal lobe pathology, presence of epilepsy, and delusional disorders, while shorter latencies have been associated with diffuse damage, schizophrenia-like psychosis, and visual hallucinations. In terms of treatment, neuroleptics appear to be the most efficacious medications, followed by anti-convulsants and lithium. We conclude with a classification scheme for PDDTBI (Fujii & Ahmed, 2002b) that was adapted from Lishman’s (1997) description of the possible relationships between TBI and psychotic disorder. This conceptual framework is based on the assumption that psychosis is a neurocognitive behavioral syndrome that results from sufficient damage to frontal and temporal structures and the dysregulation of the dopamine system (Fujii & Ahmed, 2002b). Tenets of this framework are presented in Table 13.1. The model of PDDTBI is followed by a discussion on potential explanations for long latencies between TBI and the onset of psychosis. TBI can be the primary cause of psychosis

In this category, psychosis development is directly caused by the TBI. In these cases, there is no family history of schizophrenia and low or no genetic risk for psychosis. TBI sustained in early life appears to be a risk factor for this type of patient (Fujii & Ahmed, 2001).

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1. TBI can be the primary cause of psychosis. 2. TBI can contribute to the development of psychosis through: a. inducing secondary epilepsy which results in a psychosis b. increasing biological vulnerability so that future damage or changes to frontal or temporal structures or the dopamine system will trigger a psychosis c. inducing physiological and psychological changes that render the individual more vulnerable to stress d. triggering a psychotic episode in those who are biologically predisposed. 3. TBI may be unrelated to the development of a psychosis.

TBI can contribute to the development of a psychosis

In the second category, TBI can contribute to the development of psychosis in four ways. One way this can occur is the development of a seizure disorder that in turn generates the development of a psychosis. As mentioned previously, the relationship between seizure disorder and psychotic disorder is well established and seizure disorder is a common sequela of TBI. In addition, while there may not be frank seizure activity seen clinically or on EEG, mechanisms that can lead to seizures, such as kindling, may still be ongoing and eventually can result in the development of psychosis (Kraus, 2000). The second manner that TBI may contribute to the development of a psychosis is to increase biological vulnerability or risk. Vulnerability can be increased by damage to frontal and temporal structures, and subsequent dysregulation of the dopamine system. These structures have been implicated in schizophrenia and other disorders associated with secondary psychosis. Damage to these structures from TBI will render the person vulnerable to develop a psychosis with additional damage or changes to these areas. Psychosis results when a threshold of damage to temporal/frontal structures is reached. In addition to direct structural damage, the sequelae of TBI, such as cognitive deficits, behavioral dyscontrol, and emotional distress (Gualteri & Cox, 1991), can contribute to risk by increasing the individual’s psychological vulnerability to stress. A reduction in coping skills would render one vulnerable to stress that is associated with increases in dopamine release (Roth et al., 1988). Reduced coping abilities may also foster behaviors that would increase the risk for psychosis, such as substance abuse and damage from further TBI. Traumatic brain injury can also contribute to the development of a psychosis by triggering a psychotic episode in patients who have biological risk. In such cases, an individual would already have significant vulnerability to develop

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a psychosis due to frontal and temporal lobe abnormalities. The TBI would raise the person above the threshold for psychosis. For these patients, the development of psychosis may have been inevitable with additional damage or changes, and even mild TBI could trigger a psychosis. Conversely, it is also possible that they may never develop a psychosis if good health is maintained. These four proposed subcategories for how TBI contributes to the development of a psychosis are not mutually exclusive. Hence, these subcategories should be conceptualized as illustrations of different ways that TBI can contribute to meeting the threshold for psychosis. TBI may be unrelated to the development of a psychosis

In the final category, the episode of TBI and the onset of psychosis are unrelated. Simply, the TBI does not cause or contribute to psychosis development. However, the TBI may exacerbate cognitive deficits or the severity and treatability of the psychotic condition. In such cases, there is probably a high genetic loading for schizophrenia, the TBI is very mild without loss of consciousness, or the TBI is sustained after the onset of psychotic symptoms. Explanations for latencies in onset of PDDTBI

As previously discussed, psychosis results when a threshold of damage to temporal and frontal regions is reached. These structural changes cause a dysregulation of neurochemical systems, such as dopamine, glutamate, and GABA, which in turn impairs a person’s ability to perceive and respond to internal and external stimuli (Benson & Stuss, 1990; Cummings, 1992; Selemon & Goldman-Rakic, 1999). In cases of PDDTBI, we agree with Gualteri and Cox (1991) that TBI instigates a pathophysiological process that results in neurochemical dysregulation and ultimately psychosis. It is plausible that TBI can trigger multiple processes that can contribute to the development of psychosis. Given the reported latencies between TBI and the onset of psychosis, it is likely that these processes generally take between one to five years. Several possible contributory mechanisms to developing a psychosis include kindling or sensitization, and to a lesser extent, apoptosis or excitotoxic damage. For instance, kindling in the mesial temporal areas, similar to epilepsy, may contribute to latencies. There is some indirect support that a kindling-type mechanism can cause a delayed onset of psychosis (Sachdev, 1998). In epileptic patients who later develop schizophrenia-like psychosis, there are similar long latencies between onset of seizures and psychosis, reported to be roughly 10
14 years (Slater, Beard, & Glithero et al., 1963). These delays are similar to

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Davison & Bagley’s findings (Davison & Bagley, 1969) of a long delay in onset associated with temporal localization and epilepsy. Kindling and sensitization have been implicated in the progression of symptom severity in schizophrenia as well (Duncan, Sheitman, & Lieberman, 1999). In such cases, a developmental insult has been implicated in reduction of NMDA receptor functioning, and this in turn facilitates sensitization in dopamine systems, resulting in formal illness onset. Slow, progressive changes in the neural networks of the mesial temporal areas triggered by TBI may be another mechanism involved in latencies. Potential changes include Wallerian degeneration, apoptosis, or damage from free radicals or glutamate neurotoxicity, which are abnormally perpetuated beyond the acute and post-acute phases of injury. Latency between TBI and onset of psychosis is believed to vary based upon an interaction between the amount, type, and location of damage, the pathophysiological processes involved, and characteristics of the premorbid brain (Fujii, 1996). Type of damage may be associated with different mechanisms of psychotic development, while amount of damage would contribute to threshold levels. Location of damage would dictate where subsequent pathophysiological processes would occur. For persons with earlier onset PDDTBI, the threshold of damage has been reached, so the pathophysiological processes can occur, or the patient may be biologically predisposed so the pathophysiological processes occur rapidly. This proposal is consistent with reports suggesting that early-onset PDDTBI is associated with a genetic predisposition to schizophrenia (Achte et al., 1991) or more diffuse damage (Davison & Bagley, 1969). Visual hallucinations, which have been associated with earlier onset psychosis, may reflect a more severe or generalized TBI. Several possible explanations for why some PDDTBI patients demonstrate long latencies exist. For some, the threshold of damage has not been attained for the proposed pathophysiological processes to occur. Thus, additional damage or neuronal changes (e.g., normal developmental pruning) may be necessary before a threshold of damage is met to trigger a psychosis. In other patients, a slower process or combination of processes may be involved, such as kindling or sensitization, with or without seizure disorder development, or other processes like degenerative changes described above are required. Development of a seizure disorder may take between one and five years (Annegars et al., 1980), which then triggers the pathophysiological process resulting in psychosis. Therefore, in cases in which latency is longer than five years, it is likely that TBI is a contributor rather than the primary cause of psychosis.

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102.

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Schizophrenia-like psychosis and epilepsy Perminder Sachdev Neuropsychiatric Institute, The Prince of Wales Hospital and School of Psychiatry, University of New South Wales, Sydney, Australia

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

B C B C B C D C D

The association between epilepsy and schizophrenia has attracted the attention of psychiatrists since the nineteenth century (Trimble, 1991). This clinically observed association was seen as a basis for exploration of the pathogenesis of mental illness, with epilepsy-related psychosis as a possible model of schizophrenia. It was this relationship that prompted the exploration of convulsive therapy in the treatment of psychiatric disorders. The pro-convulsant nature of neuroleptic drugs and the occurrence of psychosis with anticonvulsants have further fuelled the interest. We have come a considerable distance since the first efforts of understanding this association, but many aspects of this relationship still remain controversial (Mace, 1993; Mendez et al., 1993; Stevens, 1995; Taylor, 2003; Trimble, 1991; Trimble, Ring, & Schmitz, 1996). This chapter will review the current evidence for the relationship, and attempt to synthesize the understanding that emerges from its examination.

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1. Ictal psychosis: a. Partial complex or psychomotor status b. Simple partial status c. Petit mal status 2. Postictal psychosis: a. Single episode b. Recurrent 3. Brief interictal psychosis a. Alternating psychosis b. Non-periodic 4. Bimodal psychosis 5. Chronic interictal psychosis 6. Anticonvulsant drug-induced psychosis 7. Neuroleptic-induced epilepsy in a schizophrenic patient

Classification A consensus on the classification of schizophrenia-like psychosis associated with epilepsy (SLPE) is lacking, and neither DSM-IV nor ICD-10 has addressed this issue specifically. Application of DSM-IV criteria results in an ambiguous situation in which one can make the diagnosis of a primary psychotic syndrome or secondary syndrome (due to a general medical condition) depending on whether the nature of the evidence prompts one to deduce that the psychotic disturbance is etiologically related to the epilepsy ‘‘through a physiological mechanism’’ (DSM-IV, p. 307). Most often, separate diagnoses of epilepsy and the particular psychotic syndrome are appropriate. In such circumstances, note should be made of the relationship of the psychosis with the onset of epilepsy, seizure frequency, recent seizure episodes, current anticonvulsant medication, EEG abnormalities, and the underlying neurological lesion, if known. Since clinical seizures are the outstanding feature of epilepsy, psychotic syndromes have traditionally been classified according to their temporal relationship to these events, as ictal, postictal (or peri-ictal), and interictal, with the last type being either brief or chronic. For this review, I will retain this classification without implying that these categories are distinct in their pathophysiology or clinical manifestations (Table 14.1).

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Ictal psychosis A non-convulsive status epilepticus can result in symptoms resembling psychosis. The psychosis is necessarily brief, usually minutes to hours. When prolonged into days, it is likely to be ictal behavior that extends postictally. Epidemiology

The true prevalence of ictal psychosis has not been documented, as these patients are generally characterized as suffering nonconvulsive status epilepticus (NCSE). In population-based studies, the annual incidence of status epilepticus (SE) has been estimated as approximately 50 per 100,000 individuals (Shorvon, 1994) of which 4% to 20% (Krumholz, 1999) are NCSE. Of all patients with NCSE, the relative proportion of patients with petit mal SE (PMSE) compared to complex partial SE (CPSE) varies among studies. One found a 3:1 ratio of absence status epilepticus (ASE) compared to CPSE, whereas another population-based study of NCSE found the ratio was reversed (Krumholz, 1999). What proportion of these has psychotic symptoms deserves investigation. Age of onset

Absence seizures usually begin in childhood or early adolescence. Complex partial epilepsy also generally begins in childhood or adolescence, and later onset often suggests secondary epileptogenesis. The duration between onset and the occurrence of NCSE is extremely variable. Presentation

The most common association is with partial complex (or psychomotor) status, and patients may present a wide range of perceptual, behavioral, cognitive, and affective symptoms, often in association with automatisms involving oral activity, picking at clothes, and paucity of speech or mutism (Lee, 1985; Scholtes, Renier, & Meinardi, 1996). These episodes of automatisms may be recurrent, with behavior not being normal in the intervening periods although the patient may respond to simple instructions. Hallucinations may be prominent, and paranoid delusions or overvalued ideas may be present. Consciousness is altered during the episode but may be difficult to test, and patients are amnesic for the episode. Therefore, the appropriate DSM-IV diagnosis would be delirium. Simple partial status may produce affective, autonomic, and psychic symptoms that may include hallucinations and thought disorder in clear consciousness. Insight is usually maintained, and the manifestation is not that of a true psychosis, but the symptoms may be misinterpreted or embellished by the patient, and behavioral disturbance may result (Engel et al., 1991).

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Petit mal status (absence or spike-wave status) results in altered consciousness and such motor symptoms as eyelid fluttering and myoclonic jerks, and it may superficially resemble psychosis with disorganized behavior, but delusions and hallucinations are lacking (Scholtes et al., 1996). Patients almost always have a history of absence seizures or rarely generalized tonic-clonic seizures, and the onset is usually before the age of 20. If it has a later onset, there is frequently an underlying metabolic disturbance (Fenton, 1972). The onset and offset is abrupt, and the episode may last from minutes to several hours or even days. The alteration of consciousness is variable, ranging from slowing of thinking and behavior to marked disorientation to stupor. Neurophysiological disturbance

By definition, ictal psychosis is concurrently associated with epileptic discharges in the brain and, except in some patients with simple partial status (Devinsky et al., 1988), scalp EEG abnormalities are detectable. The majority of discharges in psychomotor status have a focus in the limbic and isocortical components of the temporal lobe, but the focus is extratemporal in about 30% of patients (Williamson & Spencer, 1986), usually in the frontal or cingulate cortex. Since the scalp EEG may be normal in simple partial seizures, the behavioral disturbance may be mistaken to be interictal, and a high index of suspicion is necessary. In such cases, if the patient is on anticonvulsant medication, the dose may have to be reduced, especially if EEG telemetry is planned. Activating techniques such as light sleep or sleep deprivation may be useful, and special recordings (sphenoidal, esophageal, or foramen ovale) may be necessary. Resolution of the disturbance with intravenous diazepam is not diagnostically foolproof as many nonepileptic behaviors may so resolve (Engel et al., 1991, pp. 97
111). Some assistance in diagnosis may come from the examination of serum prolactin levels, which rise after epileptic seizures, peaking at about 20 minutes and returning to baseline around one hour (Trimble, 1978). With partial complex seizures, the rise is less than that after generalized convulsions, but rises above 500 mU/L should be considered as suggestive (Dana-Haeri, Trimble, & Oxley, 1983). A rise may be insignificant or absent after a simple partial seizure. Symptoms may reflect one of two mechanisms (Gloor, 1991): 1. A positive effect of the seizure discharge, i.e. the epileptic discharge activates a behavioral mechanism represented in the area subjected to the discharge. This may result in a myriad of symptoms in the behavioral, cognitive, affective, perceptual, or autonomic domains. 2. A negative effect, i.e. either: a. the individual is unable to engage in a certain behavior owing to the temporary paralysis of the anatomical substrate of that behavior; or

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b. some behaviors are released by the inactivation of structures that normally suppress them. Behavioral disturbance due to a negative effect may occur in other situations, e.g. when the whole cerebral cortex is subjected to a relatively mild form of seizure activity represented by generalized spike and wave discharges. This negative effect may continue postictally, or it may initiate then. Experiential phenomena in ictal psychosis are likely to be due to positive effects, whereas automatisms may be caused by positive or negative effects. Genetics

Genetic factors are known to play a role in many epileptic syndromes. The idiopathic mendelian epilepsies have largely emerged as channelopathies, with mutations identified in a number of genes: nicotinic acetylcholine receptors (CHRNA4, CHRNB2), potassium channels (KCNQ2, KCNQ3), sodium channels (SCN1A, SCN2A, SCN1B), chloride channels (CLCN2), and GABAA receptors (GABRG2, GABRA1) (Steinlein, 2004). These are associated with generalized seizures, often with febrile onset. Nicotinic receptor mutations have been associated with lateral temporal lobe epilepsy. Non-ion channel genes related to idiopathic epilepsy include LGl1 and G-protein coupled receptors (MASS1, VLGR1). In mendelian symptomatic epilepsies, a number of genes have been identified. These include the progressive myoclonic epilepsies: Lafora disease (EPM2A, EPM2B), Unverricht-Lundborg disease (CSTB), neuronal ceroid lipofuscinosis (PPT, CLN2, CLN3, CLN5, CLN6, CLN8), Sialidosis (NEU1), and myoclonic epilepsy with ragged red fibers (MTTK, MTTL1). Neuronal migration disorders with epilepsy and a genetic basis include: Miller-Cieker/ isolated lissencephaly (LIS1), subcortical band heterotopia (DCX), and periventricular nodular heterotopia (FLN1) (Gardiner & Lehesjoki, 2000). The majority of familial epilepsy has a complex non-mendelian pattern of inheritance, and progress in the genetics of these disorders is just beginning to occur. Familial patterns have not been described in SLPE, and the genetics of these syndromes are unknown. Treatment

The treatment of ictal psychosis involves treatment of NCSE and the optimal management of epilepsy thereafter to prevent its recurrence. Postictal psychosis (PIP) The behavioral disturbances that may follow a seizure, or a bout of seizures, have received increased attention in the last two decades (Akanuma et al., 2005;

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Baumgartner et al., 1995; Fisher & Schachter, 2000; Kanemoto et al., 1996a; 1996b; Kanner et al., 1996; Ketter et al., 1994; Krishnamoorthy, 2000; Logsdail & Toone, 1988; Savard et al., 1991; So et al., 1990). Since PIPs are brief and occur in close proximity with seizures, they are ideal for the investigation of some pathogenetic mechanisms of psychosis. They usually follow seizure clusters or a recent exacerbation in seizure frequency (Logsdail & Toone, 1988) that may be related to withdrawal of anticonvulsants, often as a part of the video-EEG monitoring of patients (Kanner et al., 1996; Savard et al., 1991). Epidemiology

Postictal psychoses (PIP) are common in epilepsy-monitoring facilities; 6.4% of the patients in one study developed this syndrome (Kanner et al., 1996), and nearly 10% did so in another study (Kanemoto et al., 1996b). A confounding factor in the evaluation of PIP in video-EEG monitoring facilities is that these patients have often had a withdrawal of their anticonvulsants, and it has been suggested that this itself may result in psychopathology (Ketter et al., 1994) even though psychosis is not usual in the absence of seizures. Presentation

Between the last seizure and the psychosis there is usually a nonpsychotic period, which ranges from a few hours to a few days. In the Kanner et al. (1996) study, it was 12
72 hours and up to one week according to Logsdail and Toone (1988). Some clouding of consciousness is often present in this period, and it may extend to the initial period of psychosis or even the whole episode. The psychotic symptoms are pleomorphic (persecutory, grandiose, referential, somatic, and religious delusions, catatonia, hallucinations, etc.), and affective symptoms (manic or depressive) are often prominent (Kanemoto et al., 1996a; Logsdail & Toone, 1988). First-rank symptoms of Schneider can occur but are rare (Kanner et al., 1996). Postictal psychoses resolve within a few days, with the mean duration in the study by Kanner et al. (1996) being about 70 hours (range ¼ 24
144), and all resolving within one month in the study by Savard et al. (1991). The predisposing factors of PIP are poorly understood. The majority of reported patients suffer from partial complex seizures that are secondarily generalized. Epilepsy has often been present for more than 10 years before the onset of psychosis (Kanemoto et al., 1996b; Kanner et al., 1996; Logsdail & Toone, 1988). EEG abnormalities persist during the psychosis in the majority of cases (Logsdail & Toone, 1988). While Kanner et al. (1996) found no specific predisposing factors that differentiated their psychotic group from a comparable nonpsychotic epilepsy group, Savard et al. (1991) were impressed

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with a high rate of ictal fear, bilateral independent discharges, and gross structural lesions (six out of nine patients), including the presence of alien tissue tumors. Kanemoto et al. (1996a) also noted frequent psychic auras, and Umbricht et al. (1995) noted frequent bitemporal foci in their subjects. In contrast with the other literature, Devinsky et al. (1995) found similar rates of PIP in partial and primary generalized epilepsies, although they did note bilateral independent interictal discharges in those with partial seizures. PIP has also been associated with frontal lobe epilepsy, accounting for three out of eleven cases in one series (Adachi et al., 2000). Five of the 14 patients studied by Logsdail and Toone (1988) had abnormalities on brain computerized tomography (CT). In a magnetic resonance imaging (MRI) study (Kanemoto et al., 1996b), postictal psychosis was most likely to occur in patients with resistant temporal lobe epilepsy stemming from mesial temporal sclerosis, especially on the left side. In summary, the weight of the evidence supports a stronger association with complex partial

Table 14.2. Possible pathogenetic mechanisms of the postictal state with relevance to postictal psychosis

1. Electrophysiological: a. Continuous ictal discharges leading to psychomotor change b. Neuronal ‘‘exhaustion’’ from a seizure cluster 2. Neurotransmitter changes: a. Catecholamine depletion b. Increased postsynaptic dopamine sensitivity c. Increased endogenous opiates d. Increased adenosine e. Increased nitric oxide 3. Postictal inhibitory mechanisms: a. Fast inhibitory postsynaptic potential (GABAA mediated) b. Later hyperpolarizing potential (GABAB mediated) c. After hyperpolarization due to calcium-activated potassium currents d. Na-K hyperpolarizing pumps e. Increased extracellular Kþ f. Hþ induced attenuation of NMDA receptors g. Increased opiates, adenosine and NO 4. Cerebral blood flow alterations due to poor autoregulation 5. Other: a. Low folic acid b. Hyponatremia

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epilepsy, especially of temporal lobe origin, in which there is bilateral pathology, although this relationship is not exclusive. Neurophysiology and neurochemistry

The finding of chronic frequent subictal discharges suggests that ictal activity in the temporal lobe may be directly related to this kind of psychosis. Changes in monoamines, particularly postsynaptic dopamine receptor sensitivity, have been suggested as the mediating mechanism (So et al., 1990). Some support for the dopamine mechanism came from a single photon emission computed tomography (SPECT) study using [(123) I]iodobenzamide that demonstrated low levels of striatal dopamine D2 receptors in patients with peri-ictal psychosis (Ring et al., 1994). Low folic acid levels have been suggested to have a role (Reynolds, 1991), but firm evidence is lacking. More importantly, it would be fruitful to examine PIP in the context of the homeostatic mechanisms that are brought about in the brain to control seizures, which have been divided into electrophysiological mechanisms, cerebral blood flow (CBF) changes, and neurotransmitter and receptor changes (Fisher & Schachter, 2000). Postictal psychosis in this context has been conceptualized as a phenomenon akin to Todd’s paralysis, indicating the postictal inactivation of cortical regions involved in the ictal event, which usually include bilateral medial temporal structures (Engel, 1991, pp. 97
111). An important aspect of seizure termination is active inhibition, in which a number of mechanisms are involved. A hierarchy of inhibition is produced by fast inhibitory postsynaptic potential (IPSP) mediated by GABAA receptors, a later hyperpolarizing potential mediated by GABAB receptors (Fisher & Schachter, 2000) and after hyperpolarization produced by calcium-activated potassium currents. While these inhibitory mechanisms are brief, prolonged inhibition of neuronal activity can be produced by hyperpolarizing pumps, whose object is to restore the steady-state ionic balance after neuronal activity (Table 14.2). Treatment and prognosis

While the resolution of PIP is generally spontaneous, it is aided by neuroleptic medication, usually in small doses. A further seizure may exacerbate the psychosis, and anticonvulsant treatment should be carefully monitored, which includes dealing with non-compliance. The brief psychosis may recur, at a frequency of two to three episodes per year in two studies (Kanner et al., 1996; Lancman et al., 1994), and in some patients
15% in one study (Logsdail & Toone, 1988)
these episodes may become chronic. More longitudinal studies of patients with PIP are needed to examine its course, its likelihood of recurrence, and factors that predispose a transition into chronic interictal psychosis.

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Brief interictal psychosis (BIP) Brief psychotic episodes can also develop when seizures are infrequent or fully controlled. These psychoses last from days to weeks, they are usually self-limiting, and their separation from postictal psychoses may be difficult. Presentation

The phenomenology is characterized by paranoid delusions and auditory hallucinations, but multiple other features, including affective symptoms, may occur (Pakalnis et al., 1987; Ramani and Gumnit, 1982; Tellenbach, 1965; Wolf, 1984). Tellenbach (1965) pointed out the presence of premonitory symptoms such as insomnia, anxiety, feelings of oppression, and withdrawal as heralding the psychosis. The relationship of BIP to seizures and EEG abnormality has received much attention. Inter-ictal implies that these psychoses occur in between seizures rather than in close proximity with them. The favored description is of an alternating psychosis (Tellenbach, 1965), i.e. a brief psychosis alternating with periods of increased seizure activity such that the seizures and psychosis appear antagonistic. Unlike postictal psychosis, this psychosis can be ameliorated by the occurrence of one or more seizures (Wolf, 1991). Neurophysiology and the concept of ‘‘forced normalization’’

The concept of forced normalization (forcierte Normalisierung) (FN) was introduced by Landolt (1953) for the puzzling observation that the EEGs of epilepsy patients often looked less pathological when their behavior had deteriorated. This phenomenon, also called ‘‘paradoxical’’ or ‘‘spurious’’ normalization (Wolf, 1991, pp. 127
42), has been documented by a number of authors (Kristensen & Sindrup, 1987; Pakalnis et al., 1987; Wolf, 1991) with the additional observations that: (1) the EEG may become more, rather than entirely, normal; (2) the manifestation is not always of psychosis, and other disturbances, such as affective symptoms, an anxiety or dissociative state, and behavioral disturbance, may be present; and (3) not all brief interictal psychoses manifest this phenomenon (Ramani & Gumnit, 1982). Forced normalization is not exclusive to inter-ictal psychosis and has been occasionally described with post-ictal psychosis, suggesting a complexity of the relationship of seizure activity with psychosis. Interestingly, Landolt (1953, 1958) described this phenomenon in relation to childhood absence seizures, and some authors have suggested that it is more likely to occur with primary generalized epilepsy (Schmitz, 1998). The neurophysiological basis of forced normalization is not definitely known. One suggestion is that it reflects ongoing subcortical or mesial temporal epileptic activity with enhanced cortical inhibition (Schmitz, 1998; Wolf, 1984). This has

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been referred to as an ‘‘inhibitory surround’’ in response to ongoing seizures. This explanation argues that ongoing epileptic activity is necessary for the maintenance of inhibition as well as the development of psychosis. While the role of inhibition in response to seizure activity, as a homeostatic mechanism against ictal activity, is an appealing hypothesis to explain forced normalization, it is possible that it does not represent ongoing epileptiform activity, but is a prolonged response to preceding epileptiform activity. It is known that occasionally patients may develop prolonged unconsciousness after a seizure or a series of seizures, especially in elderly or ill patients (Willmore, 1976). Todd’s paralysis has been reported to last for up to 36 hours (Rolak et al., 1992). Therefore, it is possible that inhibition after a seizure or a series of seizures may be fairly prolonged. The inhibitory events described above are most likely to occur in close proximity to the seizure focus, thereby reducing the electrical current generated from the focus, and this may be the basis for the normalization. Even a reduction in the frequency of epileptic events will produce a relative normalization. Epidemiology

Alternating psychoses are uncommon, and Schmitz and Wolf (1995) reported three cases of alternating psychosis in 697 epilepsy patients. Ramani and Gumnit (1982) observed forced normalization in only one of nine epilepsy patients who became psychotic while being treated in the hospital for their epilepsy. Treatment

Systematic investigations into treatment are lacking. The disorder is usually selflimiting. Chronic interictal psychosis The investigation of the relationship between epilepsy and chronic SLPE was brought into the modern era by Slater, Beard, and Glithero (1963). For some time, there was high expectation that this would become a model psychosis that would reveal the pathogenesis of schizophrenia. Despite a great deal of further work, many aspects of this relationship remain controversial, and the promised insights have been slow to arrive. Epidemiology

The evidence that there is indeed an affinity between schizophrenia and epilepsy must come from epidemiological data. The epidemiological evidence for this association is summarized in Table 14.3. The rates must be interpreted in light

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Table 14.3. Epidemiological evidence for the association between epilepsy and schizophrenia-like psychosis (SLP)

Measure and Authors

N

%

Prevalence of SLP in epilepsy clinic groups: Gibbs & Gibbs (1952) 11,612

2.8

Currie et al. (1971)

666

1.8

37

8.0

1,611

9.25

697

4.0

1,285

9.1

Standage & Fenton (1975) Mendez et al. (1993)

Schmitz & Wolf (1995) Onuma et al. (1995)

Prevalence of SLP in epileptic patients in community
based studies: Krohn (1961)
2.0 Gudmundsson (1966) Qin et al. (2005)

987

8.1

2.27106

RR2.93 (2.69
2.20)

Prevalence of epilepsy in psychotic patients: Kat (1937) 50,000 Davison & Bagley (1969) Betts (1981, pp. 175
84) 1,950

0.33 1
10 2.1

Annual incidence of psychosis in epileptic patients: Lindsay, Ounsted, & Richards (1979) 87

10

Onuma et al. (1995)

0.3

1,285

Comment

Reliability of psychiatric diagnosis uncertain; majority of subjects young No criteria described; only patients with temporal lobe epilepsy included Temporal lobe epilepsy not different from other epilepsies 1.06% of migraine (comparison) subjects had schizophrenia-like psychosis; comprehensive assessment used DSM-III-R criteria Both generalized and focal epilepsies represented Point prevalence, 4.0% Additional 9% had incapacitating behavioral disorder Entire epileptic population of Iceland studied Danish longitudinal register Risk increased with age and family history of schizophrenia and epilepsy

Estimates from published data Hospitalized patients Temporal lobe epilepsy subjects followed up for 39 years

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of the general prevalences of psychosis, schizophrenia, and epilepsy in the general population. Methodological difficulties in the studies should also be taken into account in the interpretation of the prevalence data. For example, the classic study by Slater et al. (1963) drew its subjects from tertiary centers in two major London hospitals. The overall evidence suggests that SLPE is many times higher in epileptic patients than in the general population. A recent study based on the Danish longitudinal registers is particularly noteworthy for its comprehensive coverage of a population of 2.7 million (Qin et al., 2005). The relative risk of schizophrenia in patients with epilepsy was 2.48 (95% CI 2.20
2.8) and of SLPE 2.93 (2.69
3.20). The risk was the same in men and women, increased with age, and with family history of schizophrenia or epilepsy. Clinical features

Slater et al. (1963) reported that they had found a mean age at onset of about 30 years and that the symptoms were largely paranoid-hallucinatory, commonly associated with catatonia, affective blunting, and volitional symptoms. Phenomenologically, the disorder was indistinguishable from schizophrenia, although the authors reported a better preservation of affect, mood swings, mystical experiences, and visual hallucinations. Investigators in two controlled studies from London (Perez & Trimble, 1980; Toone, Garralda, & Ron, 1982) also noted the largely paranoid-hallucinatory characteristics of the disorder, but they stressed the greater frequency of ‘‘organicity.’’ One report commented on the rarity of negative symptoms, formal thought disorder, and catatonic symptoms (Kraft, Price, & Peltierm, 1984), while another reported that visual hallucinations were more prominent than auditory ones (McKenna, Kane, & Parrish, 1985). In the study by Mendez et al. (1993), the epilepsy-with-schizophrenia group did not differ from the nonepileptic schizophrenic comparison subjects on any psychosis item except increased suicidal behavior. In conclusion, except for minor reported differences, which may be accounted for by selection biases in the comparison group, the chronic psychoses of epilepsy are similar to schizophrenia. Many authors have commented on the relative lack of negative symptoms and a more benign course for epileptic schizophrenia (Perez et al., 1985; Slater et al., 1963) but supportive controlled studies are lacking. Nearly half (45%) of the patients of Slater et al. (1963) had a chronic course. In a 10-year followup study in Japan (Onuma et al., 1991), 64% of the patients had a chronic course. In the absence of an appropriate comparison group, it is difficult to know if this outcome is different from that in schizophrenia with a relatively later age at onset.

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Perminder Sachdev Table 14.4. Putative risk factors for chronic schizophrenia-like psychosis of epilepsy

1. 2. 3. 4.

Age: Early age of onset, but evidence conflicting Sex: A female bias reported by one group but not others Family history: F/H of psychosis or epilepsy Characteristics of epilepsy: a. Many years (usually 10
14) between onset of epilepsy and onset of psychosis b. Severe epilepsy: multiple seizure types, history of status epilepticus, multiple hospital admissions, resistance to drugs c. Partial complex epilepsy, especially of mediobasal temporal lobe origin d. History of secondary generalization e. Left sided focus 5. Neuropathology: a. Presence of neuroembryodysplastic lesions, e.g. gangliogliomas, hamartomas. b. Bilateral pathology 6. Neurological examination: sinistrality

Risk factors of chronic SLP with epilepsy

While a number of studies have examined the risk factors, the literature remains contentious, without a clear consensus emerging on many variables. The putative risk factors are summarized in Table 14.4. Is greater risk of psychosis particular to temporal lobe epilepsy?

Suggestions that psychosis in epilepsy might be exclusively or preferentially associated with temporal lobe epilepsy are supported by a majority of case series (Bruens, 1971; Gibbs, 1951; Perez & Trimble, 1980; Slater et al., 1963; Toone et al., 1982). Mendez et al. (1993) reported a higher rate of partial complex seizures, but not temporal lobe foci, in their group with SLP plus epilepsy. In the large Danish study, the relative risk associated with complex partial epilepsy was slightly but non-significantly higher than other types of epilepsy (Qin et al., 2005) (relative risk after adjustment for complex partial epilepsy 3.38, for other partial epilepsy 3.18, for generalized epilepsy 2.81). Another argument (Stevens, 1991, pp. 79
96) has been that the proportion of temporal lobe epilepsy in epilepsypsychosis patients is no different from that in the adult epileptic population in general, the latter being estimated to be about 60% (Hauser, Amegess, & Rocca, 1996; Shorvon, 1990). This debate, therefore, has not resolved but continues to be in favor of a special, but not exclusive, relationship between SLPE and temporal lobe epilepsy. Additionally, there are neuroimaging and neuropathological data linking the temporal lobe with psychosis.

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There is also a suggestion that the phenomenology of the psychosis associated with TLE is somewhat different from that associated with generalized epilepsy. The latter are reportedly relatively mild, shorter in duration, often associated with confusion in the early stages, and lacking in Schneiderian first-rank symptoms (Small, Milstein, & Stevens, 1962). Laterality of epileptic focus?

Since the suggestion by Flor-Henry (1969) of a preponderance of left-sided pathology in patients with SLPE, many studies have examined this issue. In the EEG studies, the majority opinion favors an excess of left temporal foci in the patients with temporal lobe epilepsy and schizophreniform psychosis (Perez & Trimble, 1980; Sherwin, 1981) although there have been some negative laterality studies (Jensen & Larsen, 1979; Kristensen & Sindrup, 1987; Shukla et al., 1979). There are many problems with the available data. First, the rigour with which laterality was established differs across studies, and the use of surface EEG recordings to establish laterality is open to question. Second, the presence of an epileptic focus on one side does not mean that pathology is restricted to that side. Third, left-sided preponderance of temporal lobe foci may not be restricted to psychotic individuals, as the evidence supports a left-sided bias for temporal lobe epilepsy in general (Currie et al., 1971). Fourth, there is emerging evidence that epilepsy patients with schizophrenia have generalized seizures even when they have a temporal focus (Mendez et al., 1993; Wolf, 1991). Fifth, the instruments and diagnostic criteria used for psychosis are language dependent, thus introducing a left-side bias (Stevens, 1991). The neuroimaging studies that examined laterality were inconclusive (Conlon, Trimble, & Rogers, 1990; Gallhofer et al., 1985; Marshall et al., 1993; Perez et al., 1985; Toone et al., 1982). Neuropathological studies have not supported lateralization of pathology (Bruton, Stevens, & Frith, 1994; Roberts et al., 1990). Therefore, the laterality issue remains undecided, but the importance of a leftsided focus is not striking. It is possible that the structural abnormality in epileptic psychosis is not lateralized and is possibly bilateral, but that the functional abnormality is predominantly left-sided. However, right-sided abnormality seems to be sufficient, and generalization of the epileptic disturbance is commonly present. Genetics

Patients who have SLPE generally have been reported not to have a greater than normal familial aggregation of schizophreniform disorders (Perez et al., 1985; Slater et al., 1963; Toone et al., 1982). In the Danish longitudinal registers study, (Qin et al., 2005) family history of psychosis was associated with a relative risk

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of 3.12 (2.83
3.43) of SLPE. Interestingly, a family history of epilepsy also increased the risk of schizophrenia or SLP, even after adjusting for the effects of personal history of epilepsy and other confounding factors. This familiar aggregation of epilepsy and SLP suggests shared genetic and/or environmental factors. Neuroimaging studies

A few neuroimaging studies must be highlighted in relation to chronic SLPE. An MRI study already referred to (Conlon et al., 1990) did not show any difference in T1 relaxation times between epilepsy-psychosis patients and schizophrenic comparison subjects. There is extensive literature on MRI brain morphometry of schizophrenia and temporal lobe epilepsy, and some of the morphological abnormalities described (large ventricles, small hippocampus) are common to the disorders (Barr et al., 1997). A positron emission tomography (PET) study using 15 O-H2O demonstrated lower oxygen extraction ratios in the frontal, temporal, and basal ganglia regions of psychotic patients with epilepsy than in nonpsychotic epileptic patients (Gallhofer et al., 1985), and a small study using SPECT showed lower left medial temporal blood flow in psychotic than nonpsychotic epileptic patients (Marshall et al., 1993). The left temporal lobe abnormality was supported by another study (Mellers et al., 1998), but a more recent SPECT study of interictal psychosis in patients with TLE failed to find a significant difference from controls, with a trend for increased blood flow in the posterior cingulated region (Guarnieri et al., 2005). The PET study of patients with psychosis by Reith et al. (1994), which included two patients with chronic and two with postictal SLPE, showed higher than normal levels of dopa decarboxylase activity in SLPE and schizophrenia, and it was suggested to be due to suppressed tonic release of dopamine in the striatum because of low corticostriatal glutamatergic input. Neuropathological studies

Neuropathological studies of SLPE have been limited. A large series from London, drawing on subjects with histories of temporal lobectomies, has been reported (Roberts et al., 1990; Taylor, 1975). Taylor (1975) commented that epilepsy patients with SLPE were less likely to have mesial temporal sclerosis and more likely to have alien tissue lesions (small tumors, hamartomas, and focal dysplasias). In the report by Roberts et al. (1990), 40% of patients with SLPE had mesial temporal sclerosis, 20% had alien tissue gangliomas, and 20% had no lesions (49%, 4%, and 15% of the total epileptic group, respectively). Histories of birth injury, head injury, and febrile convulsions were not overrepresented in the group with SLPE, but the frequency of alien tissue tumors and early onset of seizures suggested a developmental lesion in the medial temporal structures that

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Schizophrenia-like psychosis and epilepsy

had been physiologically active from an early age. On the other hand, Stevens (1986, pp. 117
46) reported widespread pathology in six cases of epilepsy and psychosis; the pathology included the hippocampus, hypothalamus, thalamus, pallidum, and cerebellum. In a study by Bruton et al. (1994) epileptic patients with SLPE had larger ventricles, more periventricular gliosis, more focal damage, and more periventricular white matter softenings than nonpsychotic epileptic comparison subjects, but similar rates of mesial sclerosis, suggesting greater nonspecific neuropathology. Possible pathophysiological mechanisms for psychosis in epilepsy

Discussion has centered broadly on two mechanisms: (1) the psychosis is due to the repeated electrical discharges, either directly or through the development of neurophysiological or neurochemical abnormalities; or (2) the epilepsy and psychosis share a common neuropathology that may be localized (emphasis on temporal lobe but also frontal lobe and the cerebellum) or widespread in the brain. Both mechanisms may be operative, the latter being primary and the former modifying the presentation, determining exacerbations and remissions, or being the proximate cause. The possible roles of psychological factors, neurotoxicity of anticonvulsant drugs, deficiencies (e.g. folic acid), and abnormal experiences seem to be of secondary importance. Composite model

An attempt at a synthesis of the pathophysiological hypotheses is presented in Figure 14.1. According to this view, epilepsy patients who develop chronic SLPE have a brain lesion that makes them vulnerable to psychosis. This lesion may be neurodevelopmental, leading to cortical dysgenesis, or be acquired through trauma, hypoxia, infection, etc. The abnormality may be widespread but is particularly likely to involve the limbic structures, leading to abnormalities of connectivity of these structures to their afferent and efferent projection regions. Since the development of medial temporal structures is asymmetric, it may explain some of the laterality data. The abnormality is likely to cause electrical storms in the limbic cortex, with seizures occurring at an early age. The occurrence of frank seizures or microseizures exacerbates the abnormality owing to kindling mechanisms or the regenerative and neuroplastic changes involving axonal sprouting, synaptic reorganization, dendritic changes, glial changes, etc. In due course, these result in disruption of anatomically distributed functional systems and lead to SLPE, accounting for the ‘‘affinity’’ between epilepsy and SLPE. Seizures, either by the presence of continuous subictal activity or by their modulation of catecholamine and pre- and post-synaptic glutamatergic and GABAergic activity, modulate the expression of the psychosis or act as brakes,

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Figure 14.1. Possible pathophysiological mechanisms for the association between epilepsy and schizophrenia-like psychosis

sometimes leading to the impression of antagonism. There may be long-term changes in the balance between excitation and inhibition. The picture is further complicated by drug therapy, with its potential for neurotoxicity, and psychosocial factors related to epilepsy, a chronically disabling and stigmatizing illness. Treatment

Patients chronically affected by SLPE must be treated as for schizophrenia in general. In using antipsychotic drugs, one must be mindful of the potential of these drugs to worsen seizure control. Drugs differ in their potential to worsen seizures (Table 14.5), with atypical neuroleptics in general being worse than the classical drugs. Of atypical antipsychotics, risperidone is the safest and clozapine most epileptogenic, with the effects being dose-related. However, with good monitoring of seizures, all antipsychotics can be used in epileptic patients. Compliance with anticonvulsant drugs should be carefully monitored in psychotic patients. Hospitalization may be necessary to observe more complex cases. Benzodiazepines can be used to control agitation or insomnia, but their abrupt cessation may precipitate seizures. Lithium does worsen seizure control. In a patient with marked abnormality of mood or florid delusion and hallucinations, electroconvulsive therapy can be used if drug treatment is ineffective or slow in producing a response. A patient with SLPE needs intensive rehabilitation, much like one with schizophrenia. The presence of SLPE is not a contraindication to surgical treatment of epilepsy. However, it is important to distinguish the psychiatric disturbance from the seizures, and inform the patient that the psychosis will most

279

Schizophrenia-like psychosis and epilepsy Table 14.5. The relative risk of seizures with antipsychotic drug used

High risk

Intermediate risk

Low risk

Clozapine (HD to MD) Chlorpromazine (HD)

Clozapine (LD) Chlorpromazine (MD to LD) Olanzapine Quetiapine Thioridazine

Haloperidol Trifluoperazine Fluphenazine Flupenthixol Pimozide Molindone Risperidone

Note: HD high dose; MD moderate dose; LD low dose Source: Adapted from: Alldredge (1999)

likely not improve with the surgery. There are cases in which SLPE worsens after surgery, but this is not the usual case. It is also important that the psychotic patient is able to give informed consent for the procedure. Acknowledgements Angie Russell helped with manuscript preparation. The work was supported by a Progam Grant (ID350833) from the National Health and Medical Research Council of Australia. REFERENCES Adachi, N., Onuma, T., Nishiwaki, S., et al. (2000). Inter-ictal and post-ictal psychoses in frontal lobe epilepsy: A retrospective comparison with psychoses in temporal lobe epilepsy. Seizure, 9, 328
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Psychosis following cerebrovascular accident James A. Bourgeois University of California, Davis Medical Center, Sacramento CA, USA

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

C C C C C D None reported C C

Introduction Psychosis is a term for a series of psychiatric symptoms that have in common clinical evidence of impairment in reality testing. Specific symptoms characteristic of psychotic disorders include hallucinations (sensory experience without sensory input, an impairment between internal sensory experience and external stimuli), illusions (distortions of sensory input at the level of perception), and delusions (fixed, false beliefs in the context of intact sensory processing, thus a disorder of attribution). In addition, ‘‘psychosis’’ also applies to deficits in cognitive organization (not just impairment in memory). Examples of cognitive disorganization include the inability to initiate and persevere on mental tasks, impaired language use (e.g., inappropriate rhyming or use of bizarre sentence constructions), and deficient affective modulation or control (e.g., affect that is discordant to the ongoing emotional status, or silly, labile, or odd).

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It is important to distinguish between isolated symptoms of psychosis (which can be classified among the symptom types above) that reflect a ‘‘primary’’ psychotic disorder versus those psychotic symptoms that may be best attributed to another psychiatric illness. Other psychiatric illnesses that may also feature psychotic symptoms include mood disorders (e.g., major depression with psychotic features and bipolar I disorder, manic episode with psychotic features), substance use disorders, delirium, and dementia. While the psychotic symptoms seen in these other psychiatric conditions may substantially overlap with the psychotic symptoms of ‘‘primary’’ psychotic disorder, the context will be different. Mood disorder episodes with psychotic features include profound depression, mania, or a ‘‘mixed state’’ of alternating mania and depression. Substance userelated psychosis is seen in the context of substance intoxication or withdrawal, or, less frequently, persistent psychosis after withdrawal. Psychosis in delirium features other symptoms of delirium, e.g., acute or subacute onset, fluctuating level of consciousness and clinical course, alterations of circadian rhythm, and variable decrements of cognitive performance. Finally, psychosis in dementia is typically associated with cognitive impairment and a gradually declining clinical course. It is customary to classify a ‘‘psychotic disorder’’ when psychosis is the predominant area of mental functioning affected by a psychiatric illness, whether ‘‘primary’’ or ‘‘secondary’’ to a focal CNS lesion. Psychosis referable to a stroke (which is also called ‘‘post-CVA psychosis’’), therefore, will phenomenologically resemble a ‘‘primary’’ psychotic disorder (e.g., schizophrenia or delusional disorder) but will occur in a time frame suggesting proximity and thus a causal or at least inferential relationship to the cerebrovascular accident. As such, an inferential connection must be drawn from a presumed sequence of: pre-morbid negative psychiatric history 4 documented cerebrovascular accident 4 new onset of psychotic symptoms to declare a case as one of ‘‘post-CVA psychotic disorder’’ with reasonable clinical certitude. This chapter will review existing literature on this subject, almost all of which is derived from clinical reviews, case reports or small case series, in an attempt to derive characteristic clinical patterns for this clearly relatively rare phenomenon. Epidemiology The prevalence of psychotic disorder specifically caused by cerebrovascular accident appears to be low (Richardson, 1992). Most of the literature on this phenomenon is based on case reports and case series, data sources not lending themselves readily to epidemiological inference. The prevalence of mania (technically a mood disorder but included here since patients may often present with psychotic symptoms) has been estimated at 1% following CVA

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(Robinson, 1998; cited in Carota et al., 2002). The true prevalence of psychosis following stroke is unknown but is probably less than the 1% risk for mania (Carota et al., 2002). Systemic studies of the incidence and prevalence of psychosis following CVA are lacking (Dupont, Cullum, & Jeste, 1988). As overall incidence and prevalence rates are indeterminate, it is not possible to definitively speculate about gender differences in post-CVA psychosis, due to the small number of cases described in detail in the literature. The cases discussed and referenced later in this chapter reflect an equal sex distribution. In addition to the apparently rare occurrence of psychosis attributable to cerebrovascular accident, there is the critical issue of phenomenology. ‘‘Psychosis’’ as usually understood in the bulk of the psychiatric literature usually refers to ‘‘positive’’ symptoms (e.g., delusions and hallucinations) and ‘‘negative’’ symptoms (e.g., disorganized thought processes, idiosyncratic use of language, and regressed emotional and motor behavior). In the post-CVA psychosis patient, there is a risk of other cortical abnormalities: e.g., amnesia, visual-spatial orientation deficits, and other cognitive deficits that may collude to create a picture of ‘‘psychosis’’ that is qualitatively different from the psychosis seen in schizophrenia and other solely ‘‘psychiatric’’ disorders. As such, the literature on post-stroke psychosis must be read with due caution as to the phenomenological and neuropsychiatric co-morbidities contained in patients’ clinical presentations. As such, the association of stroke with psychosis remains an elusive construct. Battaglia and Spector (1988) completed CT scans of 45 patients presenting with their first psychotic episode. Two had CT evidence suggesting cerebrovascular disease relating to the psychotic illness. One was a 35-year-old female with bizarre behavior, labile affect, hallucinations, and disorganized thought processes. CT revealed ‘‘decreased attenuation near the right frontal horn, cortical and mild central atrophy . . . possibly consistent with a frontal white matter infarct.’’ The other was a 21-year-old male with violent behavior, paranoid ideation, and somatic delusions. He had a seizure disorder since the age of six. CT revealed a ‘‘lucency though the left caudate nucleus, possibly indicating a basal ganglia infarct.’’ Inferring causality of psychosis from cerebrovascular lesions in this particular cohort would imply a risk of 4% for stroke in an unselected group of psychotic patients, but does not address the inverse construct, which is the risk of psychosis in CVA patients. Since there are few cases in the literature, it is not possible to definitively comment on the age of onset for post-CVA psychosis. All of the cases included here occurred in adults, with a broad age range from the 20s to over 80. Of note is that the age of onset of ‘‘pure’’ psychotic illness in schizophrenia-spectrum patients is usually before age 30, while the onset of psychosis in old age is much more likely to be attributable to structural and/or metabolic factors.

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Presentation The presentation of psychosis following stroke defies ‘‘clean’’ demarcation along habitual lines of psychiatric diagnostic classification. Thus, the clinician may expect to encounter the much more common post-CVA depression and vascular dementia (which can both antedate and follow the CVA) in the post-CVA patient manifesting psychotic symptoms. Indeed, the post-CVA psychosis is often a complex phenomenon that effectively ‘‘bridges’’ the border between psychiatry and neurology. Some symptoms, such as the denial of ‘‘ownership’’ of a paretic extremity (somatophrenia) and the sense of ‘‘reduplication’’ of body parts (pseudopolymelia) can be logically classified as ‘‘somatic delusions’’ by psychiatric terminology as well as ‘‘anosognosia’’ in neurologic terminology (Carota et al., 2002). Carota et al. (2002) described four specific ‘‘symptom clusters’’ for postCVA psychosis: 1. affective (which would include mania and psychotic depression); 2. paranoid delusions; 3. confusional state (which may overlap with delirium and vascular dementia); and 4. changes in mood with behavioral disturbances. According to a review by Dupont et al. (1988), the possibility of CVA as a cause of late-life new onset delusions should be actively considered. This is especially important if such a patient appears on clinical examination to be disoriented and exhibiting other cognitive impairments. A review of poststroke psychotic syndromes by Starkstein, Robinson, and Berthier (1992) distinguished between hallucinations (disturbed perceptions with impaired insight) and hallucinosis (similar perceptions but with preserved insight) in post-CVA psychosis. Regarding the usual classification of psychotic symptoms into the familiar categories of positive symptoms, negative symptoms, and cognitive/emotional/ behavioral symptoms, many cases of post-CVA psychosis are ‘‘mixed.’’ In addition, neuropsychological findings reflecting cognitive impairment have been seen in post-CVA psychosis. Unfortunately, formal neuropsychological testing has not always been obtained in case reports of post-CVA psychosis, so a connection between post-CVA psychosis and dementia (either pre-existing or as a consequence of CVA) remains speculative. There are too few cases in the literature to develop a ‘‘characteristic’’ description of post-CVA psychosis based on phenomenology alone, although the several cases of post-CVA ‘‘delusional misidentification’’ syndromes are striking and may represent psychotic symptoms somewhat more specific to the post-CVA psychotic condition. These phenomena include reduplicative paramnesia, Capgras’ syndrome and Fregoli’s syndrome (Carota et al., 2002; Hudson & Grace, 2000). In reduplicative paramnesia (also called ‘‘environmental reduplication’’), the patient cannot

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acknowledge the place and delusionally believes him/herself to be in different place. On mental status testing, this technically is ‘‘disorientation’’ and could be initially attributed to a cognitive disorder, such as dementia or delirium. Within reduplicative paramnesia, three subtypes have been described. ‘‘Place reduplication’’ involves the existence of two identical places, which are named the same, but are physically distant from each other (Carota et al., 2002). ‘‘Chimeric assimilation’’ means that two place identities are ‘‘combined,’’ e.g., the patient believes him or herself to be in the ‘‘home’’ that has somehow been ‘‘transformed’’ into a hospital (Carota et al., 2002). Finally, ‘‘extravagant spatial localization’’ infers that the patient believes him or herself to be in another place, often a familiar one (Carota et al., 2002). Simultaneous presence of spatial neglect and visualspatial defects cannot completely account for these delusions. Post-CVA psychosis with disorientation for place and/or reduplicative paramnesia

Fisher (1982) reported seven cases of disorientation for place following nondominant cerebral hemisphere CVA. Case 1 was a 72-year-old man with occlusion of the right internal carotid artery and a lesion in the inferior right parietooccipital region. He had variable disorientation for place (onset one week later), thinking himself to be in various cities on different dates. He spontaneously improved after 33 days. Case 2 was a 66-year-old man with thrombosis of the right internal carotid artery who was also variably disoriented for place (onset immediately post-stroke), with several erroneous cities stated sequentially as his location. He improved within five weeks. Case 3 was a 44-year-old man who had a stroke following clipping of a ruptured internal carotid-posterior communicating aneurysm. This patient also exhibited disorientation (onset three days later), believing himself to be in various different places. He improved by day 22. Case 4 was a 71-year-old man with onset one week after neurological signs of disorientation. He later suffered a progressive course consistent with Alzheimer’s disease. Case 5 was an 80-year-old man with a thrombosis of the right internal carotid artery. He also believed himself to be in various different cities. Case 6 was a 64-year-old woman with a rupture of a right middle saccular aneurysm. She believed that her kitchen was located in the hospital, near her room. This improved within five weeks. Case 7 was a 62-year-old woman with a right thalamic hemorrhage. She experienced disorientation for place (with misidentification of the city) that persisted for one year. Berthier and Starkstein (1987) described a 63-year-old male with visual, tactile, and auditory hallucinations and delusions (including somatic delusions). He exhibited confabulation and confused the identities of others. EEG revealed right paroxysmal slowing without seizure activity. He would ‘‘misplace’’ the hospital in different cities. He also displayed apathy, elation, and irritability.

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Residual neurologic deficits that may have contributed to his psychiatric state were hemispatial neglect, motor impersistence, constructional apraxia, acalculia, and spatial dysgraphia. CT revealed extensive right fronto-temporo-parietal infarction and mild ventricular dilatation. Formal cognitive testing included Wechsler Adult Intelligence Scale-Revised (WAIS-R) verbal IQ 97, performance IQ 77, and a 91 on the Wechsler Memory Scale. He was unable to complete any categories on the Wisconsin Card Sorting Test (WCST). Six months later he was significantly improved, having cleared the hallucinations, reduplication, and somatic delusions. He was then able to complete three WCST categories. Leiguarda (1983) described a 74-year-old man with an acute hemiparetic stroke with right thalamic hemorrhage with extension into the posterior limb of the internal capsule and to the ventricular system. Moderate cortical atrophy and ventricular dilatation were also noted. Five days after onset, he was disoriented to place, stating he was in another nation. He subsequently reported disorientation to several other cities. This symptom continued until his death two months later. Ruff and Volpe (1981) reported a 23-year-old woman with right fronto-parietal hematoma and arterio-venous malformation (AVM) of the right middle cerebral artery with environmental reduplication. After neurosurgical intervention, she claimed to be in her home, not the hospital. Psychological testing showed impaired spatial perception and visual memory. Within ten days, her psychosis and visual-spatial difficulties resolved. Post-CVA psychosis with capgras’ syndrome

Capgras’ syndrome is the patient’s belief that a familiar individual (which may include the patient) has been replaced by an identical-appearing ‘‘imposter’’ (Carota et al., 2002; Dupont et al., 1988). Collins et al. (1990) reported Capgras’ syndrome associated with CVA of the right internal capsule. A 69-year-old female presented with irritable and suspicious behavior. She had refused to allow firefighters to enter her home to extinguish a house fire, claiming that they were not ‘‘real firemen.’’ She also assaulted a group of neighbors by pouring water on them, claiming that the women were not ‘‘real neighbors.’’ She also claimed that her sister had been replaced by a double. She had paranoid delusions about objects in her apartment being moved and her having been victimized by a laser beam. She was treated first with droperidol and then trifluoperazine, and her symptoms resolved in three weeks. Post-CVA psychosis with fregoli’s syndrome

Fregoli’s syndrome is the attribution of a psychological characteristic from one person to another or the delusional misidentification of familiar persons disguised as others (Carota et al., 2002). De Paw, Szulecka, and Poltock (1987) described

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a case following a CVA. A 66-year-old female presented with a four-month history of new onset psychosis. She had become convinced that her cousin had moved into her neighborhood, and that the cousin and a companion were in disguise and following her in a threatening manner. Formal testing revealed WAIS between 80 and 90 (verbal IQ 85, performance IQ 78) and a 27 on the Mini Mental State Examination (MMSE). CT revealed low attenuation of the right posterior temporal area, suggesting infarct of the posterior temporal branch of the right middle cerebral artery, and a moderate degree of cortical atrophy. She was treated with trifluoperazine 15 mg po qhs for three months, during which time her delusions initially cleared. Two months later, her symptoms recurred. She was then treated with carbamazepine 800 mg qd for six weeks, without improvement. Subsequent treatment with pimozide 10 mg qd resulted in improvement, but only re-start of trifluoperazine completely relieved her delusional symptoms. Hudson and Grace (2000) reported a 71-year-old woman who misidentified her spouse as her (deceased) sister while also claiming that her home was now a ‘‘duplicate’’ of her real home. These symptoms began within days of the onset of neurological symptoms. The patient had an area of likely ischemic damage to the anterior portion of the right fusiform gyrus and middle and anterior temporal gyri, with associated hippocampal and parahippocampal atrophy. These symptoms were unchanged two years later. Neuropsychological assessment revealed average to above average verbal IQ, but a performance IQ 25 points lower than verbal IQ. She also had impaired visual attention, visual memory, and executive functions. The authors postulated that the delusions were due to disruption of connections between the fusiform gyrus and inferior and medial aspects of the right temporal lobe, interrupting continuity between areas responsible for facial and scene recognition. Cases of post-CVA psychosis with various psychotic, mood, and cognitive symptoms

Bogousslavsky et al. (1988) described a 73-year-old female with excessive speech, delirium, inappropriate humor, disinhibited and inappropriate comments, delusions, and confabulations present acutely with a new CVA. She completed no WCST categories. CT revealed a recent right thalamic infarct in the posterior thalamo-subthalamic paramedian artery territory and an old lacunar lesion in the head of the left caudate nucleus. EEG revealed slowing on the anterior regions, predominating on the right. SPECT showed hypoperfusion in the right thalamic region with associated hypoperfusion on the right cortex, mainly in the frontal area. Within two months, her behavior had improved. At six months, she showed further behavioral improvement and was then able to compete three WCST categories.

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Levine and Finklestein (1982) presented a series of eight cases of psychosis following vascular lesions of the posterior portion of the right cerebral hemisphere. Seven had new onset seizures post-CVA, and there was a temporal relationship between seizures and psychosis. The cases ranged in age from 23
85; five were female. Specific lesions included parieto-occipital hemorrhage and temporo-parieto-occipital infarction each in two cases, with temporo-parietal infarction, temporoparietal contusion, temporoparietal hemorrhage, and posterior embolic infarction in one case each. Psychotic symptoms included hallucinations in all cases, delusions in seven, and agitation in five. Onset of psychotic symptoms ranged from one month to 11 years after CVA. Case 1 was a 47-year-old woman with CVA and right posterior intracerebral hematoma and EEG with right temporal slowing, with onset of seizures six days after presentation. Nearly four months after CVA she was readmitted, with psychosis consisting of delusional misidentification, disorientation for place, disorganization, and paranoid delusions. She received with phenytoin up to 1200 mg qd, carbamazepine 800 mg qd, and trifluoperazine 80 mg qd, but continued to be psychotic for three weeks until she died of a pulmonary embolus. Case 2 was a 58-year-old woman with right parieto-temporal hemorrhage. Eight months later, she developed hallucinations and paranoid delusions. EEG revealed right temporal slowing without paroxysmal activity. She was treated with phenytoin, and the hallucinations resolved two days later. Nineteen months later, after stopping anticonvulsant treatment, she developed motor seizures. She improved with IV phenytoin, but developed hallucinations yet again. Repeat EEG now showed slowing over the right hemisphere and frontal sharp waves. Case 3 was a 34-year-old woman who 11 years previously had had an episode of hand weakness followed by personality changes including distancing from friends and irritable, spiteful behavior. At age 45, she developed paranoid delusions, hallucinations, and visual misidentification. A WAIS revealed verbal IQ 71 and performance IQ 51. EEG revealed bursts of generalized sharp waves while awake and fronto-temporal slowing during sleep. CT showed an old infarction in the temporo-parietal region. She was treated with phenothiazines and haloperidol, and her psychotic symptoms improved within two months. The presentation of post-CVA psychosis can also contain symptoms suggestive of mania as seen in classic bipolar disorder. McGilchrist et al. (1993) reported a 43-year-old man with intermittent apathy, inappropriate affect, disinhibited social behavior and disturbed cognitive function. CT revealed an infarct in the right thalamus. His psychiatric symptoms were treated with tricyclic antidepressant and electro-convulsive therapy, with minimal improvement. Six months later, with continued and worsening psychiatric symptoms, a repeated CT revealed bilateral thalamic infarcts. SPECT showed hypoperfusion of the frontal lobes and thalami bilaterally. Full scale IQ was 107, and he performed poorly on the Rey-Osterrieth

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figure, Trial Making Test, and Cognitive Estimates Test. He later experienced mania, including pressured speech, flight of ideas, increased sleep, delusions of self-reference and visual hallucinations. He responded to lithium carbonate and remained stable for six months. Mesulam et al. (1976) reported three cases of acute confusion following right middle cerebral artery infarctions. Case 1 was a 61-year-old man with acute onset of incoherence, agitation, diminished attention, and grossly impaired cognition. He had auditory hallucinations, disorientation, paraphasias, and circumlocutions. Technetium scanning revealed abnormality in the right parieto-occipital region. Case 2 was a 65-year-old man with confusion and incoherent speech. He was disoriented and agitated with significant cognitive impairment. Technetium scanning revealed abnormality in the right parieto-temporal region. Case 3 was a 74-year-old man with confusion, disorientation, and agitation. Paraphasic errors were present. CT revealed an abnormality in the right inferior frontal gyrus. These cases had the common symptoms of inattentiveness, distractibility, inability to ‘‘grasp’’ the current situation, incoherent stream of thought, disorganized behavior, disorientation, anomia, dysgraphia, and lack of insight. Pakalnis, Drake, and Kellum (1987) presented a 52-year-old woman with abrupt onset of agitation, delusions of ‘‘demonic possession,’’ visual hallucinations, and depression. These symptoms followed a cranial ‘‘pressure’’ sensation. She also showed mild disorientation to time. CT revealed a lacunar infarct in the right parieto-occipital region. Her agitation responded to haloperidol 15 mg qd. The authors believed that her lesion’s involvement of the geniculocalcarine tract might have accounted for the prominence of the visual hallucinations. Peroutka et al. (1982) reported a 72-year-old woman with acute onset of psychosis following a right temporo-parieto-occipital infarction. She presented acutely with auditory and visual hallucinations following a sudden, severe headache. Two days later, she heard a loud buzzing noise and believed that a ‘‘bee’’ was in her home. She later hallucinated various ‘‘people’’ and ‘‘a fire.’’ These hallucinations were accompanied by paranoid delusions. She also had tactile hallucinations of having her hair ‘‘pulled.’’ EEGs revealed slowing over the right hemisphere on day 5, which was significantly improved by day 20. WAIS full scale IQ was 98, verbal IQ was 104, and performance IQ was 90. She had abnormal visual-spatial performance on psychological testing. Her hallucinations resolved on haloperidol 15 mg qd. Price and Mesulam (1985) presented five patients aged 45
78 with psychosis following right hemisphere infarctions. All showed agitation, inattention, suspiciousness, paranoia, hallucinations, and lack of insight. Case 1 was a 66-yearold man with delusions, numerical obsessions and a belief that he would win the lottery. EEG was normal, while CT revealed right parietal infarction.

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Treatment with imipramine, haloperidol, and benztropine was ineffective. Three months later, he had episodes of left upper extremity weakness, along with inattentiveness and impaired visual-spatial skills. Repeated CT showed a small lacunar infarct in the right anterior internal capsule in addition to the previous lesion. His behavioral symptoms gradually resolved. Case 2 was a 45-year-old woman with a resolved episode of left hemiparesis ten years earlier. At age 45, she had four psychotic episodes (duration between one day and one week) in a period of eight months. These included visual and auditory hallucinations, delusions of poisoning and being killed, associated with panic and depression. CT revealed an old infarct in the white matter of the right frontal region. EEG showed bitemporal epileptiform activity during drowsiness and sleep. She responded to phenobarbital. Case 3 was a 61-year-old woman with agitation, anorexia, and suicidality, who threatened to kill her husband and attempted to set her home afire. She was inattentive and disoriented, unconcerned, perseverative, and had visual-spatial impairment. CT was unremarkable, and EEG showed mildly slowed background activity. She was treated with haloperidol. Five months later, a repeat EEG showed paroxysms of right posterior temporal sharp theta waves. Her behavior later spontaneously improved. Case 4 was a 78-year-old woman with abrupt onset of confusion, fears of being poisoned, and delusions of being ‘‘Hitler.’’ EEG showed intermittent rhythmic sharp theta waves with phase reversal in the right parietal region. Diphenylhydantoin was ineffectual. Haloperidol decreased her agitation but she continued to have episodic exacerbation of her psychotic behavior. Case 5 was a 76-year-old man with acute onset confusion, irritability, indifference, perseveration, and visual-spatial impairment accompanied by left-sided motor deficits. He was delusional about a ‘‘plot’’ against him, and repeatedly attempted to flee. He was also convinced that he was in a ‘‘prison’’ or a ‘‘hotel.’’ EEG showed background slowing; CT showed no focal lesions. Richardson (1992) described a 64-year-old man who developed hallucinations, delusions, and agitation after a right hemisphere cerebrovascular accident in the temporo-parieto-occipital region. He presented acutely with left-sided weakness and confusion with agitation. He was noted to gesture about his hospital room at ‘‘bugs’’ and ‘‘animals.’’ He was noted to be talking to himself, but stated that his ‘‘grandson’’ was present; he later claimed that a ‘‘baby was in bed’’ with him. He responded to haloperidol, which improved his symptoms within one week. Serra Catafau, Rubio, and Peres Serra (1992) reported a 68-year-old male with left hemiparesis and paresthesias who experienced vivid visual hallucinations of people, animals, and houses limited to the left visual field. He retained insight (recognizing that these were hallucinations) and intact cognition. CT revealed atrophy, while MRI showed ischemia of the right posterior thalamocapsular region. EEG showed low voltage waves with diffuse fast rhythms and theta waves

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on the right temporal region. His visual hallucinations resolved. The authors speculated that lesions of the nucleus reticularis might have been implicated. Feinberg and Rapcsak (1989) reported a similar case. An 83-year-old man experienced vivid visual hallucinations of people and animals. The hallucinations were very frightening to the patient and he needed restraint for subsequent agitation. MRI revealed increased signal intensity of the right dorsomedial thalamus. These visual hallucinations resolved within three days. Course and progression The latency from initial cerebrovascular lesion to the presentation of psychotic symptoms is variable. Post-stroke psychotic symptoms can present simultaneously with the acute neurological findings of CVA or can manifest much later (Berthier & Starkstein, 1987; Bogousslavsky et al., 1988). Duration is usually brief (hours to weeks or months), but can persist indefinitely (Berthier & Starkstein, 1987; Bogousslavsky et al., 1988; Carota et al., 2002; Fisher, 1982). Among their eight cases reported by Levine and Finklestein (1982), post-CVA psychosis developed acutely, within hours to days, and had variable duration, from days to months. Two patients had clear recurrences; two others were suspected to have had recurrences as well. Similarly, the influence of psychopharmacologic treatment on course and prognosis suffers from insufficient cases in the literature to offer clarity. Suspected neuropathology A specific and detailed anatomic basis for post-CVA psychosis has not been identified (Dupont et al., 1988). However, the bulk of cases suggest localization to the right side of the brain, suggesting a mixed model of diffuse cortical injury combined with more focal lesions in many cases (Dupont et al., 1988). There have also been reports of psychosis following brainstem stroke (Dupont et al., 1988). Delusional misidentification symptoms in acute stroke have been associated with ‘‘disconnection’’ of cortical areas representing face (the fusiform gyrus) and place (parahippocampal gyrus) perception from areas of the right temporal lobe, where functions of long-term memory, memory retrieval, and visual recognition are localized (Carota et al., 2002). According to Hudson and Grace (2000), the misidentification syndromes may be related to right temporal lobe lesions. The areas of the temporo-parietal-occipital junction and the thalamus appear most commonly in post-CVA psychosis (Carota et al., 2002; Fisher, 1982; Starkstein et al., 1992). Pre-existing cortical atrophy may increase risk for post-CVA psychosis (Carota et al., 2002; Starkstein et al., 1992). Right-sided thalamic infarct has

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been associated with ‘‘manic delirium’’ and visual hallucinations (Carota et al., 2002; Serra Catafau et al., 1992). It has been postulated that the hallucinations experienced by post-CVA psychotic patients may follow activation of regions near the occipital cortex, triggering the experience of visual stimuli (Carota et al., 2002). Levine and Grek (1984) addressed the anatomic basis of post-CVA delusions. They compared nine cases with right-sided CVA and delusions to 16 similar CVA patients without delusions. Symptomatically, the nine delusional patients had symptoms including ‘‘confabulation, disorientation, false identities, and unreasonable beliefs about the future.’’ The patients with delusions did not have lesions in a specific area of the right hemisphere that distinguished them from the nondelusional patients. However, patients with delusions had larger ventricles and wider sulci (consistent with pre-CVA brain atrophy) than non-delusional comparison subjects. There was a trend for delusions to be more common in older patients. Levine and Grek (1984) hypothesized that, due to the apparent importance of pre-CVA atrophy in their study, the condition of the brain unaffected by the acute CVA (particularly the left cortex) may determine whether a right-sided CVA patient develops post-stroke psychosis. A presumed model offered is that delusions following stroke depend on an interaction between the focal right-sided lesion and diffuse pre-existing brain atrophy. This may be due to combined impairments in memory and thought that results in delusional confusion. Rabins, Starkstein, and Robinson (1991) reported five patients with atypical schizophreniform psychosis following right hemisphere stroke, which were compared to matched controls with similar lesion size and location but no psychosis. The psychotic patients had a larger frontal horn ratio and larger third ventricle ratio than controls. The authors suggested that pre-existing subcortical atrophy and right hemisphere lesion were risk factors for post-CVA psychosis. A cautionary note is struck by Howard et al. (1995), who compared a group of 38 patients with late-onset (after age 60) psychosis and normal volunteers. They found that periventricular and deep white matter and subcortical hyperintensities on MRI were not more common in the group with psychosis than controls. The relationship between seizures and post-CVA psychosis may be of importance. In the eight cases of Levine and Finklestein (1982), seizures preceded the onset of psychosis in five patients and followed the onset of psychosis in two others. Despite this coincidence, the specific relationship of seizure and psychosis in these patients remains unclear. As all of their patients had lesions in the temporo-parieto-occipital region, Levine and Finklestein (1982) surmised that spatial disabilities in right hemisphere stroke patients might contribute to psychosis. An epileptic discharge in the right hemisphere (some with minimal motor

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manifestations) could precede psychosis, which represents an unstable pathophysiological state in the course of recovery from seizure activity in this region. A review by Starkstein et al. (1992), focusing primarily on hallucinatory symptoms post-CVA, also associated seizures and subcortical atrophy with these symptoms. Richardson (1992) described two models for post-stroke psychosis. One presentation is in patients without chronic disease who develop post-CVA psychosis at a time distant from CVA; these patients often have epileptic activity on EEG and clinically respond to anticonvulsants. The other type has chronic illnesses antedating stroke and develop psychosis soon after CVA; presumably, atrophy from the antecedent conditions predispose to the post-CVA psychosis. This group responds with some variability to antipsychotic agents. Staton, Brumback, and Wilson (1982), in an in-depth presentation of a head injury (not stroke) patient with reduplicative paramnesia, considered this symptom to be a ‘‘disconnection syndrome of memory.’’ The neuropsychological battery of their patient localized deficits to the right hemisphere, primarily the posterior association cortex. Because of the prominence of disorientation with reduplicative paramnesia, Staton et al. (1982) considered reduplicative paramnesia to be consistent with a primary ‘‘amnesia,’’ similar to Korsakoff syndrome. Since there is a disorientation component, this symptom cluster (and similar ones, such as Capgras’ syndrome) blurs the distinction between ‘‘purely cognitive’’ symptoms and ‘‘purely psychotic’’ ones. They speculated that the deep white temporo-parieto-occipital junction was a location where ‘‘disconnection’’ of the memory system could plausibly produce disorientation. In a similar, albeit non-CVA case, Wilcox and Waziri (1983) reported a case of a woman with Capgras’ syndrome who had neuropsychological testing and evoked potential evidence of right hemisphere dysfunction, despite an unremarkable CT scan. Her Capgras’ delusion consisted of a belief that her parents had been killed and replaced by doubles. She responded to a trial of haloperidol 20 mg qhs, but did not achieve full remission. While not addressing post-stroke psychosis, per se, Joseph et al. (1999) studied 10 psychiatric inpatients (nine with paranoid schizophrenia and one with bipolar disorder), all of whom experienced reduplicative paramnesia (RP), one of the delusional misidentification syndromes anecdotally reported in post-stroke psychosis. Compared to controls with similar psychiatric illness but without RP, the RP subjects had more cortical (frontal, temporal, and occipital lobes) atrophy, cortical fissure enlargement, and deep brain atrophy. The authors concluded that bilateral anterior cortical, brain stem, and cerebellar vermis atrophy may be implicated in the genesis of RP and other delusional misidentification syndromes. An intriguing model for CVA and psychosis is presented by Iizuka et al. (2003). They studied stroke-like lesions in the MELAS syndrome, which is a constellation

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of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Their study included MRI, EEG, and SPECT within one month of onset. They examined four stroke-like episodes in three patients. Two presented with psychosis. In three of the stroke-like episodes, seizure developed in association with the stroke-like lesion. The MRI findings progressed from the temporal cortex to parietal or occipital cortex. However, of the two patients with psychosis, one had a right-sided lesion on MRI, while the other had a left-sided lesion. Suspected neurochemical abnormalities The literature to date offers little guidance as to neurochemical abnormalities in post-CVA psychosis. Response of at least some cases to trials of antipsychotic medication leads to the suggestion that dopamine blockade by the typical antipsychotic agents described reverses a relative hyper-dopaminergic condition, but this is speculative at best.

Genetic factors There are no reported genetic factors in post-CVA psychosis. Other risk factors The only additional risk factor for post-CVA psychosis is old age (Carota et al., 2002; Levine and Grek, 1984), which is difficult to separate from the general increased risk of CVA in the elderly.

Treatment Prospective treatment-response studies for post-CVA psychosis are unavailable (Dupont et al., 1988). For antipsychotic treatment of post-stroke psychosis, atypical antipsychotic medications are preferred (Chemerinski & Robinson, 2000). As most stroke patients are older and many have pre-existing cortical atrophy and/or vascular dementia, lower starting doses of antipsychotic medications (e.g., risperidone 0.5 mg po bid) are recommended, with cautious dose escalations as necessary to control symptoms. In cases that are refractory to treatment with atypical antipsychotics, especially if there is clinical suspicion of a seizure disorder and/or an abnormal EEG, a trial of anticonvulsants may decrease psychotic symptoms (Chemerinski & Robinson, 2000). Certainly, it would appear to be prudent to consider anticonvulsants earlier

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if the patient has a documented abnormal EEG. In some cases, especially with incomplete response to antipsychotic or anticonvulsant medication, combined therapy with atypical antipsychotics and anticonvulsants may be considered. Duration of treatment should be individualized. As duration of symptoms appears quite variable, with some reports of apparent spontaneous recovery accompanied by other cases with persistent symptoms, a reasonable course of action would be to offer antipsychotic (and/or anticonvulsant) medication for several months with close monitoring, followed by a cautious tapering of medication and close surveillance for recurrence of symptoms. Patients who experience a prompt re-emergence of psychotic symptoms after medication is stopped should be re-treated. In any patient with a documented history of CVA, vigilance for the later emergence (even years later) of psychotic symptoms is warranted. It is reasonable to obtain new neuroimaging and EEG in the case of onset of psychotic symptoms that occur well after the initial stroke. Further episodes of psychotic symptoms should lead to a trial of antipsychotic and/or anticonvulsant therapy. Consideration of cholinesterase inhibitors for concurrent cognitive symptoms, as is increasingly routine for vascular and Alzheimer’s dementia, appears prudent as well. Antidepressants for mood and anxiety symptoms should also be integrated into the treatment model, targeting specific mood symptoms. Psychiatric referral should be considered at a low clinical threshold in the post-CVA psychosis patient. Due diligence in monitoring for suicidality, homicidality, and psychotic disorganization is needed, with hospitalization for the dangerous and unstable patient. Conclusions Psychosis following cerebrovascular accident is an infrequently reported neuropsychiatric illness. While the clinical phenomenology of post-stroke psychosis may resemble that of more common psychotic disorders (e.g., schizophrenia), there may be associated cognitive, mood, or anxiety symptoms in the post-stroke presentation. The cases in the literature suggest that post-stroke psychosis may be preferentially associated with right-sided vascular lesions, via an unknown mechanism. Clinical intervention with conventional psychopharmacologic agents may be associated with symptomatic improvement. REFERENCES Battaglia, J. & Spector, I. C. (1988). Utility of the CAT scan in a first psychotic episode. General Hospital Psychiatry, 10, 398
401.

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31. Bogousslavsky, J., Ferrazzini, M., Regli, F., et al. (1988). Manic delirium and frontal-like syndrome with paramedian infarction of the right thalamus. Journal of Neurology, Neurosurgery, and Psychiatry, 51, 116
19. Carota, A., Staub, F., & Bogousslavsky, J. (2002). Emotions, behaviors, and mood changes in stroke. Current Opinion in Neurology, 15, 57
69. Chemerinski, E. & Robinson, R. G. (2000). The neuropsychiatry of stroke. Psychosomatics, 41, 5
14. Collins, M. N., Hawthorne, M. E., Gribbin, N., & Jacobson, R. (1990). Postgraduate Medical Journal, 66, 1064
7. De Paw, K. W., Szulecka, T. K., & Poltock, T. L. (1987). Fregoli syndrome after cerebral infarction. Journal of Nervous and Mental Disease, 175, 433
8. Dupont, R. M., Cullum, C. M., & Jeste, D. V. (1988). Poststroke depression and psychosis. Psychiatric Clinics of North America, 11, 133
49. Feinberg, W. M. & Rapcsak, S. Z. (1989). ‘‘Peduncular hallucinosis’’ following thalamic infarction. Neurology, 39, 1535
6. Fisher, C. M. (1982). Disorientation for place. Archives of Neurology, 39, 33
6. Howard, R., Cox, T., Almeida, O., et al. (1995). Biological Psychiatry, 38, 86
91. Hudson, A. J. & Grace, G. M. (2000). Misidentification syndromes related to face specific area in the fusiform gyrus. Journal of Neurology, Neurosurgery, and Psychiatry, 69, 645
8. Iizuka, T., Sakai, F., Kan, S., & Suzuki, N. (2003). Slowly progressive spread of the stroke-like lesions in MELAS. Neurology, 61, 1238
44. Joseph, A. B., O’Leary, D. H., Kurland, R., & Ellis, H. D. (1999). Bilateral anterior cortical atrophy and subcortical atrophy on reduplicative paramnesia: A case-control study of computed tomography in 10 patients. Canadian Journal of Psychiatry, 44, 685
9. Leiguarda, R. C. (1983). Environmental reduplication associated with a right thalamic haemorrhage. Journal of Neurology, Neurosurgery, and Psychiatry, 46, 1154. Levine, D. N. & Finklestein, S. (1982). Delayed psychosis after right temporoparietal stroke or trauma: Relation to epilepsy. Neurology, 32, 267
73. Levine, D. N. & Grek, A. (1984). The anatomic basis of delusions after right cerebral infarction. Neurology, 34, 577
82. McGilchrist, I., Goldstein, L. H., Jadresic, D., & Fenwick, P. (1993). Thalamo-frontal psychosis. British Journal of Psychiatry, 164, 113
15. Mesulam, M.-M., Waxman, S. G., Geschwind, N., & Sabin, T. (1976). Acute confusional states with right middle cerebral artery infarctions. Journal of Neurology, Neurosurgery, and Psychiatry, 39, 84
9. Pakalnis, A., Drake, M. E., & Kellum, J. B. (1987). Right parieto-occipital lacunar infarction with agitation, hallucinations, and delusions. Psychosomatics, 28, 95
6. Peroutka, S. J., Sohmer, B. H., Kumer, A. J., et al. (1982). Hallucinations and delusions following a right temporoparietooccipital infarction. Johns Hopkins Medical Journal, 15, 181
5. Price, B. H. & Mesulam, M. (1985). Psychiatric manifestations of right hemisphere infarctions. Journal of Nervous and Mental Disease, 173, 610
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9. Richardson, J. K. (1992). Psychotic behavior after right hemispheric cerebrovascular accident: A case report. Archives of Physical Medicine and Rehabilitation, 73, 381
4. Robinson, R. G. (1998). Poststroke mania: Prevalence and clinical symptoms. In The Clinical Neuropsychiatry of Stroke. Cambridge, UK: Cambridge University Press, pp. 297
302. Ruff, R. L. & Volpe, B. T. (1981). Environmental reduplication associated with right frontal and parietal lobe injury. Journal of Neurology, Neurosurgery, and Psychiatry, 44, 382
6. Serra Catafau, J., Rubio, F., & Peres Serra, J. (1992). Peduncular hallucinosis associated with posterior thalamic infarction. Journal of Neurology, 239, 89
90. Starkstein, S. E., Robinson, R. G., & Berthier, M. L. (1992). Post-stroke hallucinatory delusional syndromes. Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 5, 114
18. Staton, R. D., Brumback, R. A., & Wilson, H. (1982). Reduplicative paramnesia: A disconnection syndrome of memory. Cortex, 18, 23
6. Wilcox, J. & Waziri, R. (1983). The Capgras symptom and nondominant cerebral dysfunction. Journal of Clinical Psychiatry, 44, 70
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Psychosis in patients with brain tumors Tamara Dolenc and Teresa Rummans Mayo Clinic

Summary of findings Grade of evidence Epidemiology Age of onset Presentation Course and progression Suspected neuropathology Suspected neurochemical abnormalities Genetic factors Other risk factors Treatment

C C C C C D D D D

Introduction Primary brain tumors are a diverse group of neoplasms arising from the brain parenchyma (primarily from astrocytes, oligodendrocytes, and less frequently ependymal cells), meninges, pituitary region, pineal region, and skull base. To this date, over 120 types of brain tumors have been identified. The incidence of primary brain tumors varies by gender and geographic location, and has risen over the past decades. The most common histologic tumor types are meningiomas (27%), glioblastomas (21%), other astrocytomas (11%), neuromas (8%), and oligodendrogliomas (4%). Histologic tumor types affecting children are different from those in adults. For gliomas and meningiomas, the incidence increases with age, reaching a peak in late adulthood. Primary CNS lymphoma is rare, representing about 1% of all primary brain tumors; its incidence has dramatically increased in the past decades, in part due to the AIDS epidemic (Batchelor, Dorfman, & Hunter, 2005; DeAngelis, 2001). 302

The Spectrum of Psychotic Disorders: Neurobiology, Etiology, and Pathogenesis, ed. Daryl Fujii and Iqbal Ahmed. Published by Cambridge University Press. ß Cambridge University Press 2007.

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Most brain tumors in adults are supratentorial. Primary brain tumors are most commonly located in the posterior fossa (30%), frontal and temporal area (22%), and less commonly in the parietal area (12%), pituitary (10%), and the occipital lobes (4%). In children, primary brain tumors are primarily infratentorial. Brain metastases typically arise in mid-to-late adulthood, are common, and affect up to 25% of cancer patients. They most commonly originate from primary cancers of lung, breast, gastrointestinal tract, kidney, and skin. Testicular and thyroid cancer, though uncommon, also frequently metastasize to the brain (Batchelor et al., 2005; DeAngelis, 2001). Although the overall prevalence of occult tumors in psychiatric patients is unknown, brain tumors have been found in only a small percentage of institutionalized psychiatric patients, and have been associated with diverse psychopathology, including psychosis. While psychosis can occur with tumor in any part of the brain and with any histologic tumor type, psychotic symptomatology most commonly occurs with tumors located in the frontal and temporal lobes and with bilateral involvement (Lisanby et al., 1998; Price, Goetz, & Lovell, 2002; Roy-Byrne & Upadhyaya, 2002). Tumor treatments, such as surgery, chemotherapeutic agents, interferon, corticosteroids, and antiepileptic levetiracetam can also produce psychosis (Gilbert, 2004; Holland, Fasanello, & Ohnuma, 1974; Kerschner & Wang-Cheng, 1989; Lisanby et al., 1998; Ron et al., 1992). Epidemiology About 40,000 Americans per year are diagnosed with a primary brain tumor (17,000 are malignant) and about 170,000 with brain metastases. Although brain tumors account for only 2% of all cancers, they result in a disproportionate share of cancer morbidity and mortality. In 2002, malignant brain tumors claimed 13,000 deaths (Central Brain Tumor Registry, 2002; DeAngelis, 2001). Brain tumors in psychiatric patients

The epidemiological studies of psychiatric symptomatology in brain tumor patients are limited and often flawed as a result of small sample sizes, inconsistent diagnostic criteria, and methodological and reporting flaws, which makes it difficult to estimate how common psychiatric symptoms in brain tumor patients really are. It has been reported that primary brain neoplasms are more common in psychiatric patients than in psychiatrically healthy controls (Lisanby et al., 1998; Price et al., 2002). The review of 19 autopsy studies spanning over 80 years (from 1884 to 1964) found the prevalence of brain tumors in psychiatrically hospitalized patients at about 2
3%. A general hospital series yielded a lower rate

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of around 2%. Five chart review and hospital census studies in psychiatric hospitals, involving over 250,000 patients, found an even lower brain tumor rate of 0.1% (Lisanby et al., 1998). In contrast with psychiatric patients in general, the prevalence of brain tumors in patients with psychosis is unknown. Psychiatric symptoms in brain tumor patients

Our present understanding of psychiatric phenomenology in brain tumor patients is based on the findings of retrospective case reports and uncontrolled case series, many of which were published decades ago. Due to the inconsistent criteria for diagnosing psychiatric disorders in the studies predating the implementation of the Diagnostic and Statistical Manual of Mental Disorders (DSM) (American Psychiatric Association, 2000), there are significant difficulties with interpreting and comparing results of different studies (Price et al., 2002; Rogers & Mendoza, 2005). Nonetheless, it is generally believed that the prevalence of psychopathology in this population is higher than in the general population. The two largest studies found the prevalence rates of psychiatric symptoms in brain tumor patients at 51% and 78%. There is a divergent opinion in the literature on the prevalence of psychotic symptoms in patients with brain tumors, with prevalence rates varying from 2% to 50% (Filley & Kleinschmidt-DeMasters, 1995; Price et al., 2002; Rogers & Mendoza, 2005).

Age of onset and presentation The development of psychosis in patients with brain tumors can occur at any age and obviously follows the age distribution of the specific tumor types. Intracranial neoplasms generally produce progressive symptoms. Brain tumor-related psychiatric symptoms typically develop over a period of weeks to months. The initial symptoms are often vague and nonspecific. In some cases, the onset of psychopathology may be abrupt (i.e., the acute apoplectic onset is associated with hemorrhage or development of hydrocephalus). Occasionally, psychiatric symptoms may be present for years prior to neurologic signs, and in some cases brain tumor may only be diagnosed post mortem. However, there is no uniform presentation of psychotic symptoms in patients with brain tumors (Filley & Kleinschmidt-DeMasters, 1995; Keschner et al., 1938; Lisanby et al., 1998). Most commonly, psychotic symptoms due to a brain tumor may mimic primary psychotic disorders, like schizophrenia and delusional disorder, major depressive or bipolar disorder. Psychotic symptoms may follow seizures, which are common with brain tumors, especially if located in the temporal lobes (Davies & Clarke, 2004).

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The few retrospective reports that exist on psychotic symptoms in brain tumor patients primarily describe perceptual disturbance and delusional thinking. Hallucinations in brain tumor patients tend to be less complex than in patients with schizophrenia. Visual hallucinations seem to be more common than auditory hallucinations, and are generally short lasting and rarely well formed. Nonetheless, there are reports of brain tumor patients with auditory hallucinations, ranging from simple sounds, like ringing, humming, or buzzing, to more complex perceptual disturbance. In addition, delusions secondary to brain tumors are commonly of paranoid or persecutory type and less complex than those occurring in primary chronic psychotic disorders. Nevertheless, establishing the diagnosis of a brain tumor solely on the psychotic symptom pattern is not possible (Filley & Kleinschmidt-DeMasters, 1995; Keschner et al., 1938).

Course and progression Determining the diagnosis always requires an integration of diverse information from the history of present illness, past medical and psychiatric history, family history, the mental status and neurologic examination, as well as pertinent diagnostic tests. In the presence of soft neurologic signs or new-onset seizures, an underlying neurologic condition such as a brain tumor should be strongly considered. Psychiatric symptoms are often the earliest and sometimes the only symptom of an intracranial tumor, and the diagnostic possibility of a brain tumor should always be considered in patients with new-onset psychosis (Fogel & Stoudemire, 2000). The wide variety of psychiatric symptoms that occur with brain tumors, however, makes diagnosing and localizing lesions on the sole basis of psychiatric phenomenology difficult (Lisanby et al., 1998). When this is possible, the most appropriate DSM-IV TR diagnosis is psychosis due to a general medical condition (i.e., brain tumor) or psychosis secondary to tumor-related treatments (i.e., surgery, chemotherapy, corticosteroids, interferon, levetiracetam). Also, the brain tumor and associated edema, elevated intracranial blood pressure, brain radiation, chemotherapeutic agents, and interferon have all been associated with delirium. Other physical symptoms indicating possibility of underlying brain tumor include: – headaches of new onset or changed in characteristics, as well as nocturnal, positional, or if present immediately after waking up – nausea and vomiting – visual, auditory changes, and vertigo – other focal neurologic signs, like weakness, sensory loss, and ataxia

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– acute or slow changes in one’s cognition, behavior, or personality, especially when coupled with neurologic symptoms (Batchelor et al., 2005; Lisanby et al., 1998; Maity et al., 2004; Price et al., 2002). Additional information that can help differentiate primary from secondary psychotic disorder includes an elevated prolactin level, EEG (especially if showing focal abnormalities), and most importantly a gadolinium-enhanced magnetic resonance imaging (MRI) which has replaced computerized tomography (CT). The sensitivity of MRI to pathologic alterations in the brain tissue, its superior anatomic resolution, and its ability to differentiate varying tissue types within tumors favors its use in patients with a suspected brain tumor. However, CT remains superior for visualizing intratumor calcifications and bone erosions. Patients with medical contraindication to MRI, like implanted cardiac pacemaker or ferromagnetic foreign body, should be imaged with CT. The definitive diagnosis of a brain tumor, though, usually requires histopathological assessment, which is the gold standard for diagnosis (Batchelor et al., 2005). The course of psychosis in brain tumor patients is poorly understood. In untreated tumors, the symptomatology, including psychosis, tends to be progressive. Appropriate tumor treatment may alleviate or remove psychotic symptoms, but also can exacerbate or worsen psychosis. Prognosis is variable: while glioblastoma multiforme, a high-grade glioma, continues to have extremely poor prognosis, meningioma or pituitary adenoma may be completely cured or their growth stopped with appropriate treatment. Suspected neuropathology Parenchymal brain tumors are thought to produce symptoms by three main mechanisms: (1) infiltration along nerve fiber tracts typical of low-grade astrocytomas and oligodendrogliomas, (2) displacement of brain tissue and production of vasogenic edema typical of cerebral metastases, and (3) mass growth and destruction of surrounding neuropil that occurs with rapidly growing aggressive tumors, such as high-grade astrocytomas (Maity et al., 2004). The tumor size and rate of growth, associated cerebral edema, mass effect, increased intracranial pressure, hydrocephalus, secondary cerebral ischemia, and tumor secretions may contribute to development of psychosis. Genetic, developmental, and environmental factors are also believed to impact the symptom occurrence. Pre-existing psychiatric problems may predispose someone to developing psychiatric symptoms, such as psychosis, when brain tumor develops (Lisanby et al., 1998; Price et al., 2002; Weitzner, 1999). Tumor-related psychosis tends to be more common in the elderly but also occurs in younger adults and children (Lisanby et al., 1998). Psychotic symptoms

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have been associated with a variety of tumor types, yet to this date no histologic tumor type has been particularly associated with psychosis. While the findings of reports addressing the impact of tumor laterality on the development of psychotic symptoms are inconsistent, patients with bilateral involvement seem to be at a higher risk for psychosis (Price et al., 2002). Certain tumor locations have been associated with specific psychotic symptoms. For example, frontal lobe tumors have been associated with auditory and olfactory hallucinations (Azuonye, 1997; Takeuchi et al., 1993), ideas of reference, frank olfactory and paranoid delusions, and Capgras syndrome (Avery, 1971; Durani, Ford, & Sajjad, 1991; Keschner et al., 1938; Kim, 1991; Rogers & Mendoza, 2005; Sato et al., 1993; Takeuchi et al., 1993). Temporal lobe tumors have produced non-specific hallucinations and delusions, along with mood changes but typically preserved affect. In some cases, but not all, these features help distinguish psychosis due to temporal lobe tumors from schizophrenia (Binder, 1983; Filley & Kleinschmidt-Demasters, 1995; Kan et al., 1989; Keschner et al., 1938; Malamud, 1967; Okada, Aida, & Abe, 1992; Roberts, Williams, & Stack, 1987). Parietal and occipital tumors are less often associated with psychotic symptoms than tumors in the frontal and temporal lobes, and have been associated with paranoid delusions and delusional misidentification syndromes, like Capgras syndrome, as well as schizophrenia (Roberts et al., 1987). With occipital tumors, visual hallucinations, paranoid ideation, and frank delusions have been described (Binder, 1983; Nagaratnam, Virk, & Brdarevic, 1996; Rogers & Mendoza, 2005). Tumors below tentorium tend to have lower incidence of psychiatric symptoms than supratentorial lesions. Nonetheless, psychiatric symptomatology noted in these patients is as diverse as with supratentorial lesions, and auditory and visual hallucinations, and delusions have been described (Cairns, 1950; Maiuri et al., 2002; Pollak et al., 1996; Sandyk, 1993; Wilson, 1946). Cerebellar and cerebellopontine tumors and aqueductal stenosis have been associated with hallucinations and paranoid delusions (Nadvi & Ramdial, 1998; Parisis et al., 2003; Sadamoto et al., 1993). Peduncular hallucinosis with vivid life-like complex visual hallucinations has been described with tumors compressing the midbrain (Miyazawa et al., 2001; Nadvi & Ramdial, 1998; Parisis et al., 2003; Sadamoto et al., 1993). Psychosis has also been reported in patients with subcortical tumors in the diencephalic and periventricular area (Buchanan & Abram, 1975; Carson et al., 1997; Coppola et al., 2002; Craven, 2001; Izci et al., 2003; Kugaya et al., 1996; Lobosky, Vangilder, & Damasio, 1984; Mahendran, 1998; Upadhyaya & Sud 1988). Corpus callosum tumors have been associated with paranoid thinking and koro, an otherwise typically culture-bound syndrome (Durst & Rosca-Rebaudengo, 1988).

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Psychiatric presentation of pituitary tumors is diverse and reflects not only tumor location and growth into other structures but also the impact of the altered hormonal levels. Pituitary adenomas are commonly associated with hyperprolactinemia and Cushing’s syndrome, which have both been associated with auditory and visual hallucinations, ideas of reference, paranoid and other delusional thinking, and psychosis (Gerson & Miclat, 1985; Saad et al., 1984; Sandyk, Bergsneider, & Iacono, 1987; Tran & Elias, 2003).

Suspected neurochemical abnormalities The specific pathophysiology of psychosis in brain tumor patients has not been thoroughly studied. In contrast with schizophrenia, in which neuroanatomic, cytoarchitectural, neurochemical, and neural circuitry disturbances have been extensively researched, little is known about suspected neurochemical correlates of psychosis in the presence of a brain tumor. No dopaminergic, glutamatergic, or cholinergic neurochemical abnormalities have been reported in tumor-associated psychosis. Our present understanding of the pathophysiology of schizophrenia can therefore inform, yet not fully explain, the appearance and characteristics of psychotic symptoms in brain tumor patients; the pathophysiology of psychotic symptomatology with brain tumors remains to be fully elucidated. Disruption of the neural circuits connecting the nearby and distant brain areas probably plays a major role, and may help conceptualize the astonishingly similar symptomatology with tumors in grossly different locations.

Genetic and other risk factors Genetic factors are thought to contribute to development of rare hereditary tumors occurring in neurofibromatosis type 1 and 2, tuberous sclerosis, von Hippel-Lindau disease, and Sturge-Weber syndrome. The occurrence of psychosis in those populations is unknown. These risk factors, however, account for only a small amount of cases, and in the majority of patients the combined effects of genetic and environmental factors are probably responsible for brain tumor development. The most commonly identified risk factors for brain tumors are brain radiation and immunosuppression. Risk factors for tumor-related psychosis are unknown. While some brain tumors have gender predilection (i.e., meningioma is more common in women, prostate cancer brain metastases occur only in men, and breast cancer metastases primarily in women), no overt gender differences in the incidence of tumor-related psychosis have been established.

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A number of tumor treatments may exacerbate psychotic symptoms. Surgery, chemotherapeutic agents (L-asparaginase, tamoxifen), corticosteroids, interferon, and levetiracetam all can induce psychosis (Kershner & Wang-Cheng, 1989; Rogers & Mendoza, 2005). Dopamine agonists (i.e., bromocriptine and lisuride) produced psychotic symptoms, including hallucinations and delusions, in eight out of 600 treated for a pituitary tumor (Turner et al., 1984). Individual cases of new-onset psychosis with bromocriptine-treated prolactinomas have also been described (Peter, Autz, & Jean-Simon, 1993). Little is known about psychosocial risk factors for psychosis in this patient population. Patient’s premorbid personality and coping style, personal and family psychiatric history, the availability of social support, presence of physical or psychological impairment, and the effects of brain tumor treatments are all believed to impact the emergence, nature, and severity of psychotic and other psychiatric symptoms (Price et al., 2002; Weitzner, 1999). Treatment Treatment of psychosis in patients with brain tumors is complicated. Clearly the elimination of the tumor and its related conditions may greatly improve psychotic symptoms; however, these tumor treatments may also produce psychotic symptoms. Surgical treatment may resolve or alleviate tumor-related psychopathology but also result in worsening of psychosis. The increase in psychotic symptoms is most frequently associated with post-operative delirium, which may result from the intraoperative injury, brain edema, and high-dose corticosteroid treatment. This is often temporary but may require use of antipsychotic medication (Andermann et al., 1999; Keshavan, Kahn, & Brar, 1988; Kumar et al., 1999; Scott, 1970). While the exact incidence of brain radiation-related neurotoxicity is unknown, it is estimated that diffuse radiation injury occurs in up to half of treated patients (Maity et al., 2004). Somnolence, nausea, and irritability are common in the first post-radiation months, and brain necrosis with cognitive impairment may occur. Brain radiation alone has, however, not been associated with psychosis (Maity et al., 2004). Chemotherapeutic agents can be neurotoxic (Gilbert, 2004). L-asparaginase has been associated with hallucinations, delusions, and delirium (Holland et al., 1974) and tamoxifen with reversible encephalopathy and delusions (Ron et al., 1992). Psychosis also occurs with corticosteroid treatment and interferon use (Gilbert, 2004; Kerschner & Wang-Cheng, 1989). Brain tumor patients often have difficulties with executive functioning and cognitive flexibility, which may interfere with successful treatment intervention.

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Since psychosis can have a major detrimental impact on a patient’s ability to make decisions and compliance with medical and surgical treatment, rapid and appropriate treatment is important. Only a few retrospective case reports exist to guide us in the treatment of tumor-related psychosis. In these cases, antipsychotic agents have been found to successfully treat brain-tumor-related psychosis in some but not all patients (Price et al., 2002; Rogers & Mendoza, 2005). In the absence of prospective randomized control trials, the treatment of brain-tumor-related psychotic symptoms is modeled on the established treatments of primary psychotic disorders. Prior to starting an antipsychotic agent, patients should have a thorough medical evaluation. This begins with a history of all the medications including complementary or over-the-counter treatments that the person is taking. Most antipsychotics are metabolized in the liver and have the potential to interact with other medications being metabolized through the cytochrome P-450 system. Examples of this potential interaction include antipsychotic and antiepileptic medications. Carbamazepine induces this system and can lead to lower blood levels of other medications metabolized through the same system. On the other hand, valproic acid can inhibit the system, leading to toxic levels of medications metabolized through the cytochrome P-450 system. Physical exam and laboratory assessment can help determine whether someone may develop some of the potential side effects associated with antipsychotics. For example, antipsychotics can aggravate existing obesity or orthostatic hypotension. Assessing cardiac and liver function is essential, as all antipsychotics have the potential to impact these areas. QTc interval found on an ECG should be established prior to initiating any antipsychotic medication. A prolonged QTc interval of greater than 450 milliseconds predisposes an individual to potential cardiac toxicity with antipsychotics. It is always clinically wise to use as few medications as possible to achieve the desired therapeutic effect. As with patients with other brain pathology, patients with brain tumors are more susceptible to psychotropic side effects, such as extrapyramidal, anticholinergic, epileptogenic effects, and sedation. It is thus recommended to ‘‘start low and go slow,’’ keeping in mind that brain tumor patients may require equivalent doses of psychotropics to those used in patients without brain lesions (Price et al., 2002; Roy-Byrne & Upadhyaya, 2002). For short-term treatment, haloperidol may be the agent of choice although it has a high potential for extrapyramidal side effects; its intravenous administration may be particularly useful for rapid onset of action and has been associated with a lower risk of extrapyramidal effects. If, however, a patient has had tumorassociated seizures, an agent like risperidone, that may even raise seizure threshold, is preferred. For patients who are overweight, the antipsychotic

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agents associated with significant weight gain (i.e., olanzapine) should be avoided. All antipsychotics can cause hyperprolactinemia and therefore should be avoided, if possible, in patients with pituitary prolactinomas (Melkersson & Hulting, 2000; Pal & Sarino, 2000). Psychosis developing in patients taking antiepileptic levetiracetam is best treated by changing the antiepileptic medication. To this date, evidence is limited on the recommended duration of antipsychotic therapy, therefore once the medication has been started, the need for ongoing treatment should be repeatedly reassessed. The decision has to be made on a caseby-case basis, carefully assessing the patient’s psychiatric symptomatology, the status of a brain tumor, its treatment, medical and psychiatric comorbidities, as well as the medication’s effectiveness and tolerability (Price et al., 2002; RoyByrne & Upadhyaya, 2002). Electroconvulsive therapy (ECT), though primarily used to treat depression and less frequently mania, can also be used to treat medication-resistant psychosis. The presence of an intracranial mass alone without elevated intracranial pressure is a relative contraindication for the use of ECT. Case reports have documented the successful use of ECT in these patients. However, rapid demise can occur in those with both brain tumor and increased intracranial pressure. Consequently, caution should be used if ECT is being considered for one with a known brain tumor, and evaluation immediately prior to ECT for presence of increased intracranial pressure should occur (Greenberg et al., 1988; Kohler & Burock, 2001; Maltbie et al., 1980; McKinney, Beale, & Kellner, 1998; Patkar et al., 2000; Starkstein & Migliorelli, 1993). Conclusions Brain tumors, although relatively rare, are often disabling and fatal. Though uncommon in psychiatric patients, they are often misdiagnosed, especially if neurological findings are absent or minimal. Psychotic symptoms may be harbingers of a brain tumor, in many cases occurring months before the emergence of hard neurologic signs. Psychosis is most frequent with temporal and frontal lobe tumors, and tends to be more common with bilateral involvement and in the elderly. Due to their nonspecific nature, tumor-related psychotic symptoms are not pathognomic for a brain tumor and may mimic psychosis in other primary psychiatric illnesses, like schizophrenia, delusional disorder, major depression, mania, or dementia. Therefore, in any patient with a new onset of psychosis, brain tumor should be entertained, especially if psychotic presentation is atypical or coupled with neurologic symptoms. Tumor treatment can resolve symptoms, but may also further brain injury and aggravate psychosis. Surgery, radiation therapy, certain chemotherapeutic agents, corticosteroids, interferon, and levetiracetam

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can all exacerbate or propagate psychosis. When treating psychosis directly, a careful selection of an antipsychotic agent or treatment such as ECT is necessary to account for the anticipated drug
drug interactions and adverse effects. When these guidelines are followed, safe and effective treatments can be used to minimize the impact of psychosis in brain tumor patients.

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17

Psychosis secondary to infections Sarah Reading and John T. Little Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD

Introduction This section focuses on selected infectious diseases that have been directly associated with neuropsychiatric syndromes, specifically those resulting in secondary psychosis. Secondary psychosis is a severe abnormality of thought content or form due to an identifiable medical or neurological condition that can have many manifestations (Cummings, 1985; 1988). Although there is no single area where brain injury will reproducibly induce psychosis, temporo-parietal regions, caudate nuclei, and cholinergic and dopaminergic tracts appear to be important substrates in many cases of psychosis (Gaudreau & Gagnon, 2005; Iyo, Sekine, & Mori, 2004; Seeman et al., 2005; Shaw et al., 2004). Definition and diagnostic criteria Using the nomenclature of the Diagnostic and Statistical Manual of Mental Disorders (DSM IV; American Psychiatric Association, 1994), secondary psychosis may be classified as Delirium Due to a General Medical Condition, Psychotic Disorder Due to a General Medical Condition, or Mood Disorder Due to a General Medical Condition, with Psychotic Features. Psychosis in delirium occurs only during the episode of delirium. Delirium is an acute syndrome secondary to a medical condition with disturbance in consciousness, attention, and cognition, and which may fluctuate over hours (American Psychiatric Association, 1994). The latter two diagnoses refer to psychosis due to a general medical or neurological condition in which either the psychosis or the mood symptoms predominate. In this chapter we shall focus on psychosis secondary to infectious causes. While most infectious causes of psychosis have viral etiologies resulting in encephalitis, other infectious agents such as bacteria, fungi, and parasites may also invade the nervous system and

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cause the syndrome. Due to the legion types of CNS infections which may cause secondary psychoses, we shall only consider selected conditions in detail. These conditions were chosen based on their prevalence, the availability of literature on their psychiatric manifestations, and their importance in neuropsychiatry. Viral infections Viruses are intracellular parasites of living cells. These replicating biologically active particles carry genetic information in either DNA or RNA molecules, but not both. Viruses replicate by using their genetically active nucleic acids to subvert the metabolic activities of the cell that they infect to bring about the synthesis and reassembly of their component parts (Sherris, 1990). Human immunodeficiency virus (HIV) Summary of findings Grade of evidence Epidemiology: 0.5
15% in individuals with HIV-1. Age of onset: No data. Presentation: Persecutory delusions, auditory hallucinations. Course and progression: Highly variable. Suspected neuropathology: Subcortical neurodegeneration. Suspected neurochemical abnormalities: High levels of intracellular free calcium. Genetic factors: No data. Other risk factors: No data. Treatment: Atypical antipsychotic agents.

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Epidemiology

Acquired immune deficiency (AIDS) results from infection with human immunodeficiency viruses, of which two are currently known, HIV-1 and HIV-2. Globally, the vast majority of AIDS cases result from HIV-1 infection, whereas AIDS secondary to HIV-2 appears to be confined primarily to a region in West Africa (Lishman, 1997, pp. 317
21). An estimated 36 million people worldwide are infected with HIV (Piot et al., 2004). Whereas psychotic symptoms may occur in delirium secondary to HIV infection, HIV may also cause a new-onset psychosis in the absence of delirium. Large-scale surveys have found the

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prevalence of new-onset psychosis to be less than 0.5% among individuals infected with HIV-1 while chart review studies have found the prevalence ranging from 3
15%. Thus secondary psychotic symptoms are uncommon but not rare in HIV-infected populations (Alciati et al., 2001; Koutsilieri et al., 2002; Sewell et al., 1994). Age of onset

There is little or no published data on the age of onset associated with HIV psychosis. Presentation

The clinical presentation of new-onset psychosis due to HIV infection is extremely variable. Delusions are the most common psychotic symptom in HIV infection. In some series, delusions with persecutory, grandiose, or somatic components, account for almost 90% of the cases of psychosis in individuals infected with HIV. Persecutory themes can be quite elaborate. Somatic delusions as well as delusions of thought insertion, thought broadcasting, and of passivity and control are also described. When hallucinations occur, auditory hallucinations are slightly more common than visual hallucinations. A majority of studies also report disorders of thought process, including loosening of associations or frankly disorganized thinking. Disturbances of affect commonly coexist with the psychosis, with anxiety being the most prevalent symptom, followed by depressed mood, euphoria, or irritability. Bizarre behavior is also commonplace in these settings (Atkinson et al., 1988; Harris et al., 1991; Sewell et al., 1994). Course and prognosis

The course and prognosis are highly variable in psychosis secondary to HIV and depend on whether specific complicating conditions coexist. For example, concurrent dementia due to HIV disease indicates a poor prognosis. There is some evidence that death occurs earlier in patients with psychosis compared to nonpsychotic patients with similarly advanced HIV disease. In the short term, prognosis with regard to symptom control is quite favorable, with most patients responding to low-dosage regimens of antipsychotic medications (Dolder, Patterson, & Jeste, 2004). Suspected neuropathology

A number of hypotheses have been proposed in an attempt to explain the pathogenesis of new-onset psychosis in HIV infection: (1) brain damage from some other opportunistic infection; (2) an inferior immune response in

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the CNS that allows for more damage from infectious pathogens (Sewell et al., 1994); (3) subcortical neurodegeneration caused by HIV itself or in the presence of other viral infections (Hinkin et al., 2001); (4) psychosis secondary to HIV encephalopathy (Halstead et al., 1988); or (5) the psychosis is due to an underlying dementia (El Mallakh, 1992). Despite the fact that none of these hypotheses fully explain the pathogenesis of new-onset psychosis in HIV disease, continued examination of these hypotheses may provide valuable insight into the prevention and treatment of new-onset psychosis in HIV infection (Dolder et al., 2004). Suspected neurochemical abnormalities

It has been suggested that high levels of intracellular free calcium can lead to inappropriate neurotransmitter release that may contribute to psychosis in HIV (El Mallakh, 1991). Genetic factors

There is little or no published data on genetic factors associated with HIV psychosis. Other risk factors

There is little or no published data on other risk factors associated with HIV psychosis. Treatment

Treatment for new-onset psychosis associated with HIV infection or existing psychosis in concomitant HIV infection requires a combination of pharmacotherapy and psychosocial interventions. Results from published reports (Harris et al., 1991; Sewell et al., 1994) suggest that HIV infected patients with psychosis generally respond well to antipsychotic medications, but that these individuals are especially sensitive to their side-effects (Hinkin et al., 2001; Sewell, 1996; Shedlack et al., 2005). HIV-infected patients are particularly susceptible to extra-pyramidal symptoms (EPS) and tardive dyskinesia (TD) induced by conventional antipsychotic agents (Ayuso, 1994). The likelihood of patients with AIDS developing EPS or TD from typical antipsychotic agents was reported to be more than twice that in non-AIDS patients after controlling for the mean dose and body weight (Hriso et al., 1991). Atypical antipsychotic agents, therefore, are the treatment of choice for HIV-related psychosis.

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Herpes simplex encephalitis (HSE) Summary of findings Grade of evidence Epidemiology: 0.001% in individuals with HSV-1. Age of onset: Peak ages between 60
64 years. Presentation: Auditory, olfactory, and gustatory hallucinations. Course and progression: Both acute and chronic presentations; often rapid onset of acute symptoms, the chronic course can develop over time with slow progression to psychosis. Suspected neuropathology: Gray matter lesions in medial temporal cortex and other limbic areas; hemorrhagic necrosis. Suspected neurochemical abnormalities: No data. Genetic factors: No data. Other risk factors: No data. Treatment: Antiviral agents, antipsychotic agents, carbamazepine.

B C B B

B

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Epidemiology

Herpes simplex encephalitis results from infection from Herpes Simplex Virus, type 1 (HSV-1) and accounts for approximately 10% of all cases of viral encephalitis in the United States (Tyler, 2004). Only about one in 100,000 persons affected with HSV-1, however, will actually develop HSV encephalitis (Corey, 1990). Age of onset

There is a bimodal distribution of HSE with only a third of cases occurring in those less than 20 years old and a half in those aged 50 years or more. In a recent polymerase chain reaction (PCR) study of 516 patients with clinical evidence of encephalitis, 7.4% of cases were due to HSV infection and most HSE cases were in those 40 years of age or older (Koskiniemi et al., 1996). The peak incidence of HSE occurred in subjects aged between 60 and 64 years, for whom HSV accounted for 37.5% of all cases of encephalitis (Tyler, 2004).

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Presentation

Typically there is rapid onset with severe illness in the acute stage. Pyrexia and seizures are frequent in all age groups, meningeal irritation is common, and drowsiness or global confusion is prominent. In some cases the psychological symptoms can predominate (Drachman & Adams, 1962). Hallucinations can resemble those of delirium tremens in being vivid and colorful, and in provoking a marked emotional reaction. Other symptoms can include anosmia, olfactory and gustatory hallucinations, or marked memory impairment out of proportion to the impairment of intellect (Steadman, 1992). Finally, there have been isolated cases of chronic HSV infections leading to temporal lobe seizures, disorders that have been associated with personality change and olfactory hallucinations (Cornford & McCormick, 1997). Course and prognosis

Treatment is often a matter of urgency and the outcome depends on the speed with which treatment is initiated. Before the advent of acyclovir, mortality exceeded 70% and prognosis was poor as only a minority of individuals could return to normal function (Illis & Merry, 1972). With acyclovir the prognosis has improved considerably, but when the temporal lobes have been damaged the consequences can still be grave. Seizures, dysphasia, personality change, and severe amnestic states have been described (Oxbury & MacCallum, 1973). Even with patients who make apparently excellent recoveries, neuropsychological testing may reveal evidence of cognitive deficits (Gordon et al., 1990). Suspected neuropathology

Pathologic changes characteristic of other forms of encephalitis are seen with perivascular infiltration of lymphocytes and histocytes in the cortex and adjacent white matter, proliferation of microglia, and the formation of glial nodules. Microscopically, Cowdry type A inclusion bodies are often detected in affected neuronal cells. The cerebral cortex is mainly affected in adults (Lishman, 1997, p. 356). MRI evaluation reveals the characteristic findings of medial temporal lobe and insular involvement. The lesions usually begin in the medial temporal cortex, with bilateral spread along limbic pathways to the orbital frontal lobe and insular cortex. Parietal, occipital, brain stem, internal capsule, and cingulate gyrus involvement often occurs with further spread, but the basal ganglia and lobar white matter are relatively spared (Wasaya et al., 2005). There have been EEG abnormalities reported with HSV encephalitis and have included frontotemporal delta slowing, periodic lateralized epileptiform discharge, and runs of spike activity. EEG can normalize after treatment but has a poor correlation with overall outcome (Misra & Kalita, 1998).

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Suspected neurochemical abnormalities

There is little or no published data on neurochemical abnormalities associated with HSV psychosis. Genetic factors

There is little or no published data on genetic factors associated with HSV psychosis. Other risk factors

There is little or no published data on other risk factors associated with HSV psychosis. Treatment

The management of the patient with suspected HSV-1 encephalitis parallels the diagnostic tests, immediate antiviral chemotherapy being mandatory. Given the appropriate clinical setting, acyclovir is promptly administered (Johnson, 1996; Vernassiere et al., 2003). Toxicity is usually mild and not treatment-limiting; it may include thrombocytopenia, increased transaminases, creatinine, and BUN. In rare cases of significant treatment-limiting acyclovir side effects or of acyclovir resistance, vidarabine or foscarnet are alternative antiviral agents that can be given (Vernassiere et al., 2003). Supportive measures in the management of a patient with suspected HSV-1 encephalitis are extremely important and psychotic symptoms should be treated with antipsychotic agents. Further, a number of case reports have suggested that the addition of carbamazepine can result in marked reduction in EEG-detected seizure activity and in the frequency of emotional outbursts, extending to as much as one year after treatment (Gaber & Eshiett, 2003; Vallini & Burns, 1987).

Bacterial infections Bacteria are small micro-organisms without mitochondria whose nuclear material consists of a single large, double-stranded DNA molecule without a surrounding nuclear membrane (Sherris, 1990). Bacterial infections that have a predilection for the central nervous system can first present with psychiatric symptoms, particularly hallucinations and delusions. We will focus here on two prototypical spirochetal infections that may specifically present with psychotic symptoms. Spirochetes differ from other bacteria in that they have a flexible cell wall around which several fibrils (small filamentous structures) are wound (Neidhardt, 1990).

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Lyme disease Summary of findings Grade of evidence Epidemiology: 0.008% in general US population. Age of onset: No data. Presentation: Persecutory delusions; auditory olfactory, and visual hallucinations. Course and progression: Widely variable. Suspected neuropathology: Frontal lobe white matter hyperintensities, frontal hypoperfusion. Suspected neurochemical abnormalities: No data. Genetic factors: No data. Other risk factors: No data. Treatment: Antimicrobial therapy, antipsychotic agents.

B N/A C C D N/A N/A N/A B

Epidemiology

Erythema migrans, the early skin lesion now recognized as pathognomonic for Lyme disease, was first reported in 1970 (Scrimenti, 1970) and Lyme arthritis was first identified in 1977 (Steere et al., 1977). In 1982 Burgdorfer identified a new bacterium, the Borrelia spirochete, in the midgut of a tick that had caused an erythema migrans rash (Burgdorfer et al., 1982). This spirochete, similar in several respects to the agents of syphilis, was named Borrelio burgdorferi in honor of its founder. The disorder is now referred to as either Lyme disease or Lyme borreliosis. The infection is now endemic in Europe, Asia, and in more than 15 states in the USA. Since surveillance was begun in the USA in 1982, the number of reported cases has increased dramatically. In 2002, a total of 23,763 cases of Lyme disease were reported to the United States Centers for Disease Control and Prevention (CDC), yielding a national incidence in the United States of 8.2 cases per 100,000 population. Most cases occur in northeastern, mid-Atlantic, and north central states (Centers for Disease Control, 2004b). In Europe, Lyme borrreliosis is widely established in forested areas. The highest reported frequencies of the disease are in middle Europe and Scandinavia, particularly in Germany, Austria, Slovenia, and Sweden (Stanek, 1999). The infection is also found in Russia (Korenberg, 1994), China, and Japan (Masuzawa, 2004). Lyme borreliosis in all locations is transmitted by ticks of the Ixodes ricinus complex (Lane, Piesman, & Burgdorfer, 1991; Spielman, 1994). These ticks have

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larval, nymphal, and adult stages and require a blood meal at each stage. The risk of infection in a given area depends largely on the density of these ticks as well as their feeding habits and animal hosts, which have evolved differently in different locations. The most common carriers of the tick are deer and the white-footed mouse. However, these ticks have been found on at least 30 types of wild animals and 49 species of birds (Anderson, Magnarelli, & McAninch, 1988). Age of onset

There is little or no published data on the age of onset of psychosis associated with Lyme disease. Presentation

Lyme borreliosis is often classified into three stages: early localized, early disseminated, and late. Early infection consists of a localized erythema migrans, followed within days or weeks by disseminated infection that affects the nervous system, heart, or joints, followed within weeks or months, by late persistent infection (Steere, 2001). Approximately a third of patients do not recall any rash and the flu-like symptoms may be mild (Fallon et al., 1992), so they may not realize that they have been infected and later neurological or neuropsychiatric symptoms may be the presenting complaint (Fallon et al., 1993). The psychiatric symptoms associated with Lyme disease can include depression (Barr et al., 1999; Fallon & Nields, 1994; Logigian, Kaplan, & Steere, 1990), obsessive compulsive disorder (Leonard & Swedo, 2001), anxiety, and panic disorder. There is only a sparse world literature on the psychotic manifestations of Lyme disease consisting mostly of case reports of paranoid delusions (Diringer, Halperin, & Dattwyler, 1987; Fallon et al., 1995; Hess et al., 1999; Omasits, Sieser, & Brainin, 1990; Pfister et al., 1993; Roelcke et al., 1992; Stein et al., 1996), auditory hallucinations (Diringer et al., 1987; Fallon et al., 1995; Hess et al., 1999; Omasits et al., 1990; Pfister et al., 1993; Roelcke et al., 1992), olfactory (Reik et al., 1985), and visual hallucinations (Hess et al., 1999) associated with infection. These reports are provocative and suggest that more systematic and standardized studies could lead to a better understanding of the burden of psychosis with this infectious process. Course and prognosis

Acute disseminated disease occurs during the first month, with the most common symptoms being fatigue, myalgia or arthralgia, headache, fever or chill, and stiff neck. In 20% of persons infected with B. Burgdorferi who do not receive antibiotic treatment, no other symptoms beyond erythema migrans develop. The description of Lyme disease as flu-like is misleading because Lyme disease does not include any cough, sore throat, or other symptoms of upper respiratory

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tract infections. If untreated, Lyme disease may disseminate to other organs and produce subacute or chronic disease. Subacute symptoms can develop over months. Signs and symptoms of CNS infection develop in about 15% of untreated patients. Typically these present as fluctuating meningitis accompanied by facial palsy and a peripheral neuropathy (Steere, 1989). The course and prognosis of the psychiatric manifestations vary widely and depend on the early identification of the underlying infectious process. Suspected neuropathology

Specific neuropathology associated with Lyme disease has not been determined. There have been reports of frontal lobe white matter hyperintensities by MRI in subjects with CNS involvement of Lyme disease (Belman et al., 1992) and in one case report of a patient with a psychotic manifestation of Lyme disease a SPECT scan showed hypoperfusion in deep frontal lobe regions (Stein et al., 1996). Suspected neurochemical abnormalities

There is little or no published data on neurochemical abnormalities associated with psychosis secondary to Lyme disease. Genetic factors

There is little or no published data on genetic factors associated with psychosis secondary to Lyme disease. Other risk factors

There is little or no published data on other risk factors associated with psychosis secondary to Lyme disease. Treatment

Lyme disease is usually treated successfully with antimicrobial therapy (Reik et al., 1985). However, some treated individuals have persistent subjective complaints, and a few patients fail to respond to antibiotic therapy, as evidenced by signs of persistent infection (Belman et al., 1992; Steere, 1989). For patients with late disease presenting chiefly as arthritis, neurological and neuropsychiatric symptoms, response to treatment is typically slower and prolonged administration of parenteral penicillin is usually necessary (Belman et al., 1992). Some cases are treatment refractory and progress to post-treatment Lyme disease syndrome, or chronic Lyme disease (Klempner et al., 2001). When psychotic symptoms are present, antipsychotic agents are given concomitantly with appropriate antimicrobial therapy.

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Syphilis Summary of findings Grade of evidence Epidemiology: 0.002
8% worldwide with significant geographic differences. Age of onset: No data. Presentation: Insidious personality change, cognitive impairment, dysphoric or elevated mood, hallucinations, delusions, or delirium. Course and progression: Widely variable; can move from progressive disorientation, convulsions, tremors, incontinence, euphoria, and depression, to delusions, hallucinations with impaired memory and judgment. Mild or early case has a greater chance of spontaneous resolution. Suspected neuropathology: Widely variable; diffuse cortical degeneration and infarcts, frontal and parietal white matter hyperintensities, frontal hypoperfusion. Suspected neurochemical abnormalities: No data. Genetic factors: No data. Other risk factors: No data. Treatment: Low concentrations of Penicillin G, antipsychotic agents.

B N/A B B

C

N/A N/A N/A B

Epidemiology

In 2001 the number of reported cases of syphilis in the United States was 2.2 cases per 100,000 population (Centers for Disease Control, 2004a). In Western Europe, syphilis prevalence has declined substantially since the peak after the Second World War, with incidence rates below 5 per 100,000 in the majority of countries (Costello et al., 1998; Garcia-Lechuz et al., 1999; Paget & Zimmermann, 1997). In contrast with the decline in rates observed in Western Europe, since 1989 there has been an alarming increase in infection rates of syphilis in the newly independent states of the former Soviet Union. The incidence of syphilis has increased from 5
15 per 100,000 observed in 1990 to as high as 120
170 per 100,000 of population in 1996 in the newly independent states of the former Soviet Union (Renton et al., 1998). In the Western Pacific, relatively high prevalence rates of syphilis have been found in Cambodia (4%), Papua New Guinea (3.5%), and the South Pacific Islands (8%) (World Health Organization, 1999). Age of onset

There is little or no published data on the age of onset associated with neurosyphilis.

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Presentation

Syphilis passes through a series of frequently overlapping stages. The spirochete, Treponema pallidum, causes syphilis and is spread through contact with infectious lesions or body fluids. Patients typically develop a skin lesion (chancre) at the site of inoculation approximately 21 days after exposure. Signs and symptoms of secondary syphilis typically begin four to ten weeks after the appearance of the chancre. Rash is the presenting complaint in more than 70% of patients. Secondary syphilis can resolve without treatment, although approximately one quarter of untreated patients develop recurrences during the four years following infection, most frequently in the first year (Clark, 1954). The CDC differentiates early and late latent syphilis as asymptomatic infection during the first year following infection and during the period thereafter, respectively. Approximately a third of patients with untreated secondary syphilis develop late tertiary disease (Clark, 1954; Golden, Marra, & Holmes, 2003). Tertiary syphilis may present as a central nervous system disease, neurosyphilis. Early neurosyphilis occurs within weeks to a few years after primary infection and may be asymptomatic. Symptomatic forms of early neurosyphilis include meningitis, with or without cranial nerve or eye involvement. Late neurosyphilis affects the meninges and brain or spinal cord parenchyma, is extremely rare in the antibiotic era, and usually occurs decades after primary infection. Manifestations of late neurosyphilis include general paresis with psychotic features, and tabes dorsalis, a spinal cord disorder with sensory ataxia and bowel and bladder dysfunction (Golden et al., 2003). General paresis involves the general deterioration of mental and physical capabilities. Symptoms typically begin ten to fifteen years after the initial infection and include subtle cognitive and emotional changes, such as problems with concentration and irritability; if untreated, it can lead to memory loss, confabulation, anomia, apraxia, or pseudobulbar palsy. Neurosyphilis may present with virtually any psychiatric symptom, including insidious personality change, cognitive impairment, dysphoric or elevated mood, hallucinations, delusions, or delirium (Dawson-Butterworth & Heathcote, 1970; Emsley et al., 1988; Rundell & Wise, 1985). Late psychiatric manifestations of neurosyphilis consist predominantly of dementia that is indistinguishable from other forms of dementia, and includes impaired judgment, confusion, and lack of insight (Dawson-Butterworth & Heathcote, 1970). Course and prognosis

Approximately a third of patients with untreated infection develop late sequelae (Clark, 1954; Golden et al., 2003). Untreated paretic neurosyphilis is characterized by progressive decline of the intellect and general deterioration

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of motor function to ultimate paralysis and death. Convulsions are frequent in later stages of the disease. Spontaneous remissions and improvement may occur without specific treatment. In a five-year follow-up of patients with neurosyphilis, 50% of patients showed resolution of disorientation, convulsions, tremors, incontinence, euphoria, and depression, while only 25% of patients showed resolution in delusions, hallucinations, and impaired memory, judgment, speech, and calculations. Mild or early cases predictably have a greater chance in showing resolution of symptoms. Patients with active disease, as evidenced by CSF pleocytosis, were more likely to respond to treatment than were patients with static pathology without CSF pleocytosis (Graman, Trupei, & Reichman, 1987). Men are more likely to have confusion after ten to fifteen years, while women are more often dysarthric and depressed (Dawson-Butterworth & Heathcote, 1970). Suspected neuropathology

In neurosyphilis, or general paresis, there is extensive cortical degeneration of the brain and large numbers of T. pallidum are found in the affected areas. There are high rates of white matter hyperintensities in the frontal and parietal lobes, as well as generalized atrophy. Patients present with focal neurological findings secondary to multiple small infarcts due to an endarteritis that produces hypertrophy of the intimal layer of the vasculature and fibroblastic proliferation (Gabay, Hallinan, & Lovett, 1983; Russouw et al., 1997). Neuroimaging with CAT scanning or SPECT show multiple diffuse cortical infarcts (Ortego et al., 1995). Suspected neurochemical abnormalities

There is little or no published data on neurochemical abnormalities associated with neurosyphilis. Genetic factors

There is little or no published data on genetic factors associated with neurosyphilis. Other risk factors

There is little or no published data on other risk factors associated with neurosyphilis. Treatment

Treponema pallidum is killed by low concentrations of penicillin G. Long exposure to penicillin is required in established disease, probably because of

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the long generation time of the organism and its inaccessibility in some lesions. Alternative regimens of Amoxicillin and Ceftriaxone have been used successfully but their efficacy has not been documented in large-scale studies (Mohr et al., 1976; Tramont, 1976). Spontaneous remissions and improvement may occur without specific treatment. Treatment effectively arrests the course of the disease. Functional return depends upon the stage of the disease at which treatment was begun and upon the acuteness of the disorder. In severely demented patients, a complete cure cannot be expected (Bordon et al., 1995). Psychiatric symptoms due to neurosyphilis should be addressed therapeutically in the same manner as the psychiatric illnesses that they mimic. Other infections Parasitic

Despite the relative infrequency of parasitic infections in the temperate, highly sanitized societies of the industrialized world, parasitic diseases remain among the major causes of death worldwide. Two parasitic infections with specific predilection for the CNS are briefly reviewed. Malaria is responsible worldwide for 273 million clinical cases and 1.12 million deaths annually. More than 40% of the global population (42.1 billion people) is estimated to be at risk for malaria. Malaria occurs in approximately 100 countries, but is mainly confined to the developing tropical areas of Africa, Asia, and Latin America (Toure & Oduola, 2004). Cerebral malaria is the most potentially life threatening neurological complication. Varied psychiatric manifestations have been described as a part of cerebral malaria including psychosis, manifested as paranoid delusions, often accompanied by manic syndromes in the acute stage and depression as a late sequelae. These psychiatric manifestations may be the first presenting feature in patients with acute uncomplicated malaria, especially in association with hyperpyrexia. Of note, neuropsychiatric complications have also been associated as side effects from certain antimalarial drugs (Daroff et al., 1967; Kochar & Shudhakaran, 1998; Prakash & Stein, 1990; Weinke et al., 1991). Worldwide, neurocysticercosis is another common parasitic infection of the human central nervous system, and its epidemiology is changing with increased migration of human tapeworm carriers from endemic regions. Neurocysticercosis is caused by neuronal infection by the larval form of the pork tapeworm Taenia solium (Garcia et al., 2003). Clinical signs vary depending upon the size and stage of the parasites and location of lesions. Various psychiatric symptoms are known to occur in neurocysticercosis; however, depression, rather than psychosis, seems

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to be the most common presentation (Forlenza et al., 1997; Shriqui & Milette, 1992; Tavares, 1993). Neurocysticercosis should be considered in the differential diagnosis of psychiatric disease in the context of endemic T solium, or a history of exposure to human carriers (Schantz et al., 1992). Fungal

Fungi are a distinct class of micro-organisms, a few of which can produce diseases in humans, and even fewer may cause CNS manifestations (Johnson & Naraqi, 1993; Ryan, 1990). An exception to this rule is in immunocompromised patients, where fungal infections may lead to CNS complications that can include major depression, adjustment disorder with depressed mood, and delirium with affective, delusional, or cognitive dysfunction (Detmer & Lu, 1986). Prion

The transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders of humans and animals that share a common feature, i.e., the conversion of the cellular prion protein into disease-specific species. The altered isoforms are believed to be responsible for neuropathologic changes and disease transmissibility (Puoti et al., 1999). Human Creutzfeldt-Jakob disease (CJD) is the most notable neurodegenerative disorder caused by prions. Creutzfeldt-Jakob disease (CJD) is a rare dementia characterized by a rapidly progressive course (Will & Ward, 2004). Psychiatric symptoms, including depression and personality change, occur early in the clinical course in about a third of cases (Brown et al., 1979) and in one series, 10% of patients were first admitted to psychiatric wards (Puoti et al., 1999). Psychiatric symptoms associated with CJD have led to erroneous initial diagnoses of functional psychosis (Keshavan, Lishman, & Hughes, 1987), depressive pseudodementia (Azorin et al., 1993), or hysteria (Stevens & Lament, 1979). Conclusions Hallucinations and delusions may become manifest by central nervous system infiltration of specific infectious agents. The medical literature suggesting infectious causes of psychotic phenomena consists primarily of case reports or anecdotal observations and so there is a need for more systematic study of these conditions. While direct and rapid antimicrobial management of the underlying infection is the mainstay of treatment, appropriate psychiatric treatment can provide substantial relief to the patient and greatly facilitate medical management of the underlying infectious process.

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Psychosis secondary to inflammatory and demyelinating disease Katherine H. Taber and Robin A. Hurley VISN 6 MIRECC, Hefner VAMC, WFGSM, BCM, Salisbury, North Carolina

Multiple sclerosis Grade of evidence Epidemiology: 430/100,000 in northern Europe, southern Australia, middle North America, less elsewhere; Relapsing-remitting form 2
3 female: 1 male. Age of onset: Most 20s
40s. Presentation: Psychosis can be presenting symptom. Course and progression: Psychosis commonly episodic. Suspected neuropathology: Demyelination and axonal destruction, brain atrophy, inflammation; Myelin-directed inflammatory autoimmune process; Psychosis correlated with frontal and/or temporal abnormalities. Suspected neurochemical abnormalities: Inflammatory cytokines, autoantibodies, matrix metalloproteinases, and reactive oxygen species may participate in disease; Glutamate excitotoxicity may cause oliogodendrocyte injury/death. Genetic factors: Multiple genes contribute to susceptibility; Major histocompatibility complex
chromosome 6p21. Other risk factors: Environmental; Viral exposure. Treatment: Multiple agents in limited patients: some successes, haloperidol; increased side effect vulnerability.

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Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating illness that can affect any aspect of the central nervous system. Neuropsychiatric (NP) symptoms may be the presenting complaints or may arise during the course of illness (Asghar-Ali et al., 2004; Feinstein, 2004). Epidemiology

Prevalence of MS varies considerably by geographic region (Noseworthy et al., 2000). Prevalence is highest (greater than 30 per 100,000) in northern Europe, southern Australia, and middle North America. MS is uncommon in India, the Orient, the Arabian peninsula, and continental South America (Compston, 1999). Prevalence in the United States (USA) ranges from 85
190 per 100,000 (Mayr et al., 2003; Noonan, Kathman, & White, 2002). A geographic gradient has been suggested, with lower rates in the southern USA (Herna´n, Olek, & Ascherio, 1999; Noonan et al., 2002). Incidence varies from approximately 4
8 per 100,000 (Mayr et al., 2003). While there is evidence for an increase in incidence during the last 100 years, a recent study suggests that prevalence and incidence have been stable over the past 20 years (Mayr et al., 2003). The relapsing
remitting form of MS is more common in females (about two or three to one) (Compston, 1999; Keegan & Noseworthy, 2002). Primary progressive MS affects men and women equally (Keegan & Noseworthy, 2002). Age of onset

Initial presentation for the relapsing
remitting form is commonly in the second to fourth decades (Herna´n et al., 1999; Noseworthy et al., 2000). Childhood onset does occur. MS may be under-diagnosed in this age group (Ghezzi, 2004; Ruggieri et al., 2004). Presentation

This disorder is traditionally viewed as a solely neurological condition. However, a meta-analysis concluded that 40.4% had neuropsychiatric (NP) symptoms (Davids, Hartwig, & Gastpar, 2004). Reports indicate a 50% lifetime risk of depression with a 7
14 times risk of suicide over the general population (Feinstein, 2004; Schapiro, 2002). In one study, 17 of 23 MS patients had affective disorders (74%) (Lyoo et al., 1996). In their literature review, those authors found a range from 6
54% of depression in MS. Bipolar symptoms can be twice as common in MS as the general population (Feinstein, 2004; Modrego & Ferra´ndez, 2000). A prospective study found 95% of patients with measurable NP symptoms: depression (79%), hallucinations (10%), and delusions (7%) (Diaz-Olavarrieta et al., 1999). All were in remission. None were receiving steroids or psychotropic medication. Reported NP symptoms include slowed cognition,

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executive dysfunction, depression, pathological crying, personality changes, mania, and psychosis. Delusions and/or hallucinations are generally found as part of an affective illness (e.g. mania with psychosis). There are rare care reports in the literature with pure psychosis and no affect component. (Asghar-Ali et al., 2004; Carson & Searle-White, 1996; Clarke, Wadhwa, & Leroi, 1998; Heila¨, Turpeinen, & Erkinjuntti, 1995; Hurley et al., 1999; Mendhekar, Mehta, & Puri, 2004; Modrego & Ferra´ndez, 2000; Zarei et al., 2003). Course and progression

The most common pattern (about 85%) is relapsing
remitting, with full recovery after an episode (Keegan & Noseworthy, 2002). Most will eventually develop secondary-progressive MS in which full recovery no longer occurs. Less common (about 15%) is primary-progressive in which symptoms do not remit (Keegan & Noseworthy, 2002). Prognosis varies widely. By 15 years, 10
15% of patients are wheelchair bound while 20
25% are still ambulatory (Keegan & Noseworthy, 2002). Females generally have a better prognosis than males (Keegan & Noseworthy, 2002). With an early onset (before age 16) progression may be slower (Ghezzi, 2004). Psychosis can occur at all stages of the illness. Case reports indicate that psychosis is commonly episodic (Carson & Searle-White, 1996; Felgenhauer, 1990; Modrego & Ferra´ndez, 2000). Neuropathology

The classic histopathology is characterized by demyelination and inflammation surrounding venules and extending into the myelin sheath (Noseworthy et al., 2000). Infiltrating cells include T lymphocytes (CD4 and CD8 phenotypes), activated macroglia, and plasma cells (Owens, 2003). Infiltration of these cells and inflammatory cytokines produced in situ are directly associated with demyelination and plaque formation. The current interpretation is of a myelin-directed inflammatory autoimmune process. T lymphocyte response to an infectious agent (e.g. Epstein-Barr virus) is a popular hypothesis (Owens, 2003). The structural and immunological characteristics of plaques are relatively uniform within each individual, but vary considerably between individuals, suggesting MS may be a constellation of syndromes with different pathogenic mechanisms (De Groot et al., 2001; Lucchinetti et al., 2000). A recent study has questioned the autoimmune hypothesis, presenting data supporting apoptotic oligodendrocyte death as the initiating event, with inflammatory responses secondary to myelin phagocytosis (Barnett & Prineas, 2004). Common supratentorial lesion locations are periventricular white matter, inner surface of the corpus callosum, and cortical gray/white junction (Bakshi et al., 2004). Most are bright on T2 weighted (T2W) magnetic resonance

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images (MRI) and best visualized with fluid-attenuated inversion-recovery (FLAIR) technique (Figure 18.1). T2W MRI is nonspecific, as inflammation, edema, demyelination, axonal loss, and repair processes will appear similar (De Groot et al., 2001; Meier et al., 2004). These MRI-visible lesions are frequently neurologically silent. Areas of active inflammation can be detected by contrastenhanced MRI. Some lesions are dark on T1W MRI. Lesions that remain dark, rather than resolving, may represent permanent axonal loss (Meier et al., 2004). Correlation between lesion load and clinical disability is better for lesions that are dark on T1W than are bright on T2W MRI (Bakshi et al., 2004). Patients with NP symptoms or psychosis had a heavier lesion burden in the temporal lobes than those without (Feinstein, Du Boulay, & Ron, 1992; Honer et al., 1987). Both euphoria and hallucinations may correlate with moderately severe frontotemporal abnormalities (Diaz-Olavarrieta et al., 1999). Frontal lobe abnormalities (lesions in two, hypometabolism in one) have been reported in patients with manic psychosis (Heila¨ et al., 1995; Modrego & Ferra´ndez, 2000).

Figure 18.1. Magnetic resonance image of a young female patient with multiple sclerosis (MS). (Axial FLAIR MRI of a female who was hospitalized on two occassions previously
once for mania and once for depression. Note the generalized atrophy and the periventricular oval-shaped lesions that are characteristic of MS. She presented with intractable insomnia, anxiety, depressed mood, suicidal ideation, bradykinesia and bradyphrenia. Although she had none of the classical clinical signs of MS, subsequent testing confirmed the diagnosis.)

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Suspected neurochemical abnormalities

Various proposed mechanisms have been suggested to explain relapsing
remitting symptoms in MS including axonal demyelination/remyelination and inhibition of axonal function by inflammatory cytokines (Neumann, 2003; Noseworthy et al., 2000). Autoantibodies, matrix metalloproteinases, and reactive oxygen species may also participate (Neumann, 2003). Glutamate excitotoxicity has been implicated. Activated macrophages and microglia increase synthesis of glutamate in and around MS lesions (Neumann, 2003; Werner, Pitt, & Raine, 2001). Axonal injury correlates with presence of glutamate-producing macrophages and microglia (Werner et al., 2001). A recent study found increased glutamate in cerebrospinal fluid of MS patients. Higher levels are correlated with active disease (e.g. clinical symptoms and contrast-enhancing lesions) (Sarchielli et al., 2003). Oligodendrocytes may be central to white matter glutamate homeostasis, which is impaired in MS lesions and surrounding normal appearing white matter (Pitt et al., 2003; Werner et al., 2001). Proton magnetic resonance spectroscopy (MRS) studies have shown neuronal dysfunction in white matter areas that appear normal on MRI, supporting the hypothesis of more widespread axonal pathology (Filippi et al., 2003; He et al., 2005). A recent whole-brain MRS study of early MS supported the presence of permanent axonal injury, in contrast to reversible inflammation-related dysfunction (Filippi et al., 2003). There are conflicting studies, so this is controversial (Vrenken et al., 2005). Genetic factors

The familial recurrence rate for MS is 15% (Compston, 1999). Concordance rate is 25
30% for monozygotic and 3
5% for dizygotic twins (Compston, 1999; Keegan & Noseworthy, 2002). Ethnicity appears to be a risk factor, with people of European ancestry at higher risk than those of African or Asian ancestry (Compston, 1999). Evidence suggests that more than one gene contributes to susceptibility. The major histocompatibility complex (MHC) is associated with susceptibility to MS (Herrera & Ebers, 2003). The apolipoprotein E epsilon4 allele has been implicated in a more rapidly progressing form (Herrera & Ebers, 2003; Keegan & Noseworthy, 2002). There is increasing evidence of genetic heterogeneity (Sotgui et al., 2004). Other risk factors

There are clear environmental influences. High MS rates in northern Europeans are not found in their children following migration to southern Africa; prevalence of MS in children of immigrants from Africa to the United Kingdom increases

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(Compston, 1999). Viral exposure has been linked to relapse. Early viral exposure increases the risk of MS (Compston, 1999; Keegan & Noseworthy, 2002). Treatment

There are MS treatments for acute exacerbations and those that affect the longterm course (disease-modifying therapy). Interventions should include immunotherapeutic and symptom-based pharmacotherapies and rehabilitation, psychosocial interventions, and patient/family education (Schapiro, 2002). Current research focuses on therapeutics that interrupt the inflammatory cascade (Adorini, 2004; Fox & Ransohoff, 2004). Corticosteroids are the mainstay for acute exacerbations, intravenous methylprednisolone, followed by oral prednisone. Plasmapheresis is used for patients unresponsive to corticosteroids. Side effects are a concern as corticosteroids can induce psychiatric conditions (mania, depression, psychosis, and rarely cognitive decline) (Brown & Chandler, 2001; Sirois, 2003; Wada et al., 2001). Steroid-induced psychosis can include hallucinations, delusions, agitation, disorganized behaviors, or thought processing abnormalities. Generally these symptoms improve with dose tapering and/or administration of neuroleptics (haloperidol, less commonly olanzapine or risperidone). Occasionally, carefully titrated lithium or other mood stabilizers are prescribed (Sirois, 2003). With lithium or carbamazepine, the clinician must watch carefully for renal compromise (corticosteroid-induced) or carbamazepineinduced decreases in prednisolone levels (Sirois, 2003). Lithium-induced delirium is a high risk in neurologically compromised patients. A recent retrospective study found recurrent episodes in seven out of 15 patients with corticosteroid-induced mood disorder, and two out of three patients with corticosteroid-induced psychosis (Wada et al., 2001). All patients with psychosis were responsive to haloperidol (3 mg/day). Disease-modifying therapies for MS include interferon (IFN) ß, glatiramer acetate, or mitoxantrone (Goodin, 2004). General concensus is that these agents, although costly (over $10,000 annually), are partially effective in decreasing relapses and/or delaying progression (Noseworthy et al., 2000). Given the risk of depression with IFN-ß, patients with a history of depression should be prescribed a selective serotonin reuptake inhibitor (SSRI) and monitored closely. The evidence-based treatment for psychosis in MS is very limited (no FDA approved medicines), with only case reports, letters to the editor, expert opinion, and community standard to guide the practitioner (Feinstein & Ron, 1998; Goodin, 2004). A PubMed search found one case review and eight other published letters to the editor or case reports that specifically address the treatment of psychosis due to MS in the last ten years. The case review study included 44 patients with psychosis due to eight different neurological conditions

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(five with MS) (Feinstein & Ron, 1998). All patients were treated successfully with low doses of haloperidol (