Schizoaffective Disorders: International Perspectives on Understanding, Intervention and Rehabilitation

SCHIZOAFFECTIVE DISORDERS: INTERNATIONAL PERSPECTIVES ON UNDERSTANDING, INTERVENTION AND REHABILITATION No part of thi...

Author: Kam-shing Yip

24 downloads 855 Views 3MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form

DOWNLOAD PDF

SCHIZOAFFECTIVE DISORDERS: INTERNATIONAL PERSPECTIVES ON UNDERSTANDING, INTERVENTION AND REHABILITATION

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

SCHIZOAFFECTIVE DISORDERS: INTERNATIONAL PERSPECTIVES ON UNDERSTANDING, INTERVENTION AND REHABILITATION KAM-SHING YIP EDITOR

Nova Science Publishers, Inc. New York

Copyright © 2009 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA AVAILABLE UPON REQUEST ISBN 978-1-60741-215-1 (E-Book)

Published by Nova Science Publishers, Inc.   New York

CONTENTS Preface Chapter 1

Chapter 2

Chapter 3

vii Controversies and Difficulties in Theoretical Underpinning of Schizoaffective Disorders Kam-shing Yip Understanding the Needs, Resilience and Recovery of Persons with Schizoaffective Disorder: Related Theories and Conceptual Underpinnings Kam-shing Yip Schizoaffective Psychosis and Schizophrenia with- or without Affective Syndrome: A Comparative Clinical, Neuropsychological and Molecular-genetic Study V. E. Golimbet, M. V. Alfimova, V. G. Kaleda, L. I. Abramova, G. I. Korovaitseva, O. M. Lavrushina, and T. V. Lezheiko

Chapter 4

Diagnostic Controversies in Schizoaffective Disorder Nathaniel Hurwitz and C. Raymond Lake

Chapter 5

Neuropsychological Deficits in Schizoaffective Disorder Barton W. Palmer and Gauri N. Savla

Chapter 6

Ego Functioning, Cognition, and Illness Characteristics of Persons with Schizoaffective Disorder: Distinctive Features and Response to Vocational Rehabilitation Morris D. Bell, Randall Richardson, and Tamasine Grieg

Chapter 7

Chapter 8

Boredom, Hallucination-proneness and Hypohedonia in Schizophrenia and Schizoaffective Disorder McWelling Todman, Daniel Sheypuk, Kristin Nelson, Jason Evans, Roger Goldberg,and Evangeline Lehr Schizoaffective Disorder in China: Controversies and Reality in China Zhi-zhong Lian and Kam-shing Yip

1

27

69

89 115

135

153

179

vi Chapter 9 Index

Contents Managing the Suicidal Risk in Pregnant Schizoaffective Women Salvatore Gentile

197 229

PREFACE Ever since Krapelin’s (1899) classical volume on dementia praecox, persons with both features of schizophrenia and affective disorders are attended by scholars and practitioners in mental health services. Kasanin (1933) seemed to be first one in using the term `schizoaffective psychosis’ and `schizoaffective disorders’ in describing nine patients who had both psychosis and affective disorder symptoms. These patients had good prognosis and later fully recovered from the mental disorder. This new disorder, being closely resemble to both schizophrenia and affective disorder, needs a clear diagnostic criteria and operationalization in clinical practice. Robins and Gitze (1970) suggests five areas to validate schizoaffective disorder including clinical description, laboratory studies, delimitation from other disorders, follow up studies and family studies. In fact, up to now, there are still controversies in defining and interpreting schizoaffective disorder (Bottlender & Muller, 2003; Welner, et.al., 1977; Evans, et.al., 1999; Marneros & Akiskai, 2007). Despite related controversies and argument, schizoaffective disorder is a crucial mental illness that demands attention and study from both scholars and clinicians. However, most of these discussions are merely debates focused on diagnosis, etiology and genetics of persons with schizoaffective persons. Although there is a long awareness of the uniqueness of schizoaffective disorder, comparing the rich theoretical underpinnings in schizophrenia and mood disorders, the studies of schizoaffective disorder are thin and insufficient. After a long history of conceptual development, these two groups of mental illness are profoundly studied, explained and articulated by biochemical, psychodynamic, cognitive, existential, phenomenological, sociological, cultural and humanistic perspectives. In each perspective, there are numerous accounts, and research in describing persons with schizophrenia or mood disorder. For persons with schizophrenia, apart from the dominant explanations form cognitive deficit models as well as the biochemical model and genetic models, there are plies of explanations from various perspectives such as Laing’s divided self (1960) and Jaspers (1946/1963) meaningfulness of primary and secondary delusion as well as Schneider’s (1959) first rank symptoms. There seems to have enough evidence showing that severe cognitive impairment for persons with schizophrenia is due to self fragmentation, self splitting and confusion of self boundary (Blatt & Wild, 1976). Similarly, in the studies of mood disorders, there are numerous renounced theories interpreting the mood disorder in particular depressive disorder, ranging from Freud’s (1938) introjection of loss to Beck’s (1976) sense of helplessness, worthlessness and meaninglessness. There are numerous arguments such as Frankl’s (1963) loss of life meaning and Kohut’s (1971, 1972 & 1973) loss of idealized objects. There seems to have sufficient evidences that intensive negative mood and negative schema in depression may be due to the loss

viii

Kam-shing Yip

of objects, persons, interpersonal relation, personal prestige and status that the person with depression is firmly attached to. Nevertheless, all these rich and in-depth discussions are left out in conceptualizing schizoaffective disorders. Most discussions and debates in schizoaffective disorder are an entity of schizophrenia disorder, depressive disorder or a new form of disorder. The ignorance of rich theoretical traditions of mood disorders and schizophrenia may lead to a thin and insufficient theoretical underpinning in the diagnosis, treatment, intervention and rehabilitation of persons with schizoaffective disorder. The particular needs and hardships of persons with schizoaffective disorder are far beyond the agenda of scholastic research. Based on client’s in-depth interview and self narration, Yip (2006) affirmed that people with schizoaffective disorder suffered labelling and symptoms from both schizophrenia and affective disorders. In this book, the writers try to recapture such rich arguments and theoretical traditions in mood disorders and schizophrenia in describing the understanding, interacting, diagnosis, treatment and rehabilitation of persons with schizoaffective disorders. Chapter one is an outline and description about the international perspective on the controversies and difficulties in theoretical underpinnings of schizoaffective disorder. In this chapter, Kam-shing Yip outlined the development of the concepts, diagnosis and etiology of schizoaffective disorders. The concept of schizoaffective disorder began with Kraepelin’s discovery mental illness between schizophrenia and manic depressive entity. In 1930s, Kassanin was the first scholar in using the term `schizoaffective disorder’ in clinical studies. In DSM II diagnosis of schizoaffective disorder was affirmed. Previous and recent literatures tend to show that there are four controversies in the diagnosis and interpretation of schizoaffective disorder. Firstly, schizoaffective disorder can be considered as a variant of schizophrenia. Secondly, it can be regarded as a variant of affective disorder. Thirdly, it can be an intermediate entity between schizophrenia and affective disorder. Fourthly, it can be interpreted as a continuum of functional psychosis with schizophrenia at one end and affective psychosis at the other end of the spectrum. With all these theoretical positions, the writer has done a literature archives on related literatures in Science Citation Index. There are altogher 494 articles with the title of `schizoaffective disorder’ appeared in the SCI. However, most of them merely described schizoaffective disorder as an entry of schizophrenia. Majority of the articles focused on issues on biochemical and genetics, diagnosis and etiology. They tended to neglect or undermine clients’ experiences, psychosocial theories and studies on persons with schizoaffective disorder. All these articulations may have important implications on understanding, treatment and rehabilitation of persons with schizoaffective disorder. The empathetic stand towards persons with schizoaffective disorder is further extended and elaborated in Chapter two. Kam-shing Yip tried to outline a multi-dimensional frame in understanding the needs, resilence and recovery of persons with schizoaffective disorder. The chapter began with an initial articulation of subjective experiences, needs, resilience and recovery of persons with schizoaffective disorder. By means of a case illustration of a Chinese male adult, the writer attempted to recapture various theoretical underpinnings of schizoaffective disorder. As related concepts of schizoaffective disorder are comparatively thin and insufficient, the writer revisited various concepts in interpretation of schizophrenia, major depressive disorders and bipolar disorder. Within these groups of the conceptualisation, the experiences and needs of persons with schizoaffective disorder can be reconceptualized in four different ways. The first type of interpretation is to understand the experiences and needs of persons with schizoaffective disorders in terms of related theories of schizophrenia. The

Preface

ix

second type is to interpret the experiences and needs of persons with schizoaffective disorders in terms of related theories of depression. The third type is to interpret such experiences and needs in terms of related theories of bipolar disorder. The fourth type is to interpret such experiences and needs in terms various combinations of all these theories. There may three ways of combining theories of depressive disorders, schizophrenia and bipolar disorders. Firstly, the manifestation of one/two type/s of symptom is to cope with or suppress the manifestation of another one/two type of symptoms. Secondly, the full manifestation of one/two type/s of symptom can lead to the manifestation of another one/two types of symptoms. Thirdly, coexistence of any two/three types of symptoms implies a delicate balance for the individual in facing environmental stresses and personal conditions. Chapter three is written by Vera Golimbet and his colleagues from Russia. They reported the findings of a comparative clinical, neuropsychological and molecular-genetic study on 184 patients with schizoaffective psychosis (SA) and 872 patients with schizophrenia (170 SPA with affective syndrome and 702 SP without affective syndrome). These 3 groups have been compared for clinical symptoms, self-rated personality characteristics and neurocognitive traits. Molecular genetic study has been carried out to determine genotypes for the T102C polymorphism of the serotonin receptor type 2A (5-HTR2A) gene, the 5-HTTLPR polymorphism of the serotonin transporter gene and the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene. The clinical study revealed significant between-group differences: positive symptoms were mostly pronounced in patients with SP, while the SPA and SA groups had similar scores, and negative symptoms tended to gradual decreasing as SP>SPA>SA. Patients both with SPA and SA had higher scores on anxiety and depressive-related items as compared to the SP group. The latter was featured by the highest scores on the items related to cognitive and volition symptoms which, analogous to negative symptoms, decreased gradually in the SPA and SA groups. All the groups significantly differed by personality characteristics. No between-group differences were found for neurocognitive traits. Molecular-genetic study revealed that, comparing to controls, the SA group was featured by the specific genotypes distribution, namely by the higher frequency of the ss 5-HTTLPR and the A2A2 (CC) 5HTR2A genotypes and a genetic variant represented by the combination of the 5-HTTLPR ss and the BDNF Met-allele. The results of the study revealed that SA is more closely related to SPA than to SP by clinical symptoms and molecular-genetic characteristics. Also, in genetic view, SA seems to be a separate entity, being characterized by the lowest ratings of negative symptoms, one of the most stable characteristics of schizophrenia, which is thought to be underpinned by genetic factors, and by a combination of genotypes of the candidate genes for major psychosis that discriminates it distinctly from SP and SPA. Chapter four is written by Nathaniel Hurwitz and Raymond Lake about the diagnostic controversies of persons with schizoaffective disorders. They criticize the current diagnosis of schizoaffective disorders is lack of laboratory test evidence. The ‘schizoaffective’ diagnosis cannot be reliably identified. Furthermore, it offers nothing but the opportunity cost of not treating mood, violating ‘do no harm.’ It is common to have affective and mood changes in psychotic transformation. Schizophrenia researchers disbelieve the Kraepelinian dichotomy. Unlike families with Huntington’s disease that all show the same, single abnormality, families with multiple functionally psychotic members show a variety of genetic abnormalities. Not only do gene-abnormality profiles vary across different families, but there

x

Kam-shing Yip

are often multiple different psychiatric diagnoses within individual families − and even within individual family members. Many groups have found genetic overlap in bipolar and schizophrenia. Others have reported that all three diagnostic categories (schizophrenia, schizoaffective and bipolar) share genetic susceptibility loci. Regarding brainwave measures, a discussion of ERP findings in “schizoaffective” disorder is necessarily a discussion of findings in schizophrenia since most work has been done with patients carrying that diagnosis. Furthermore, “schizoaffective” fell under the schizophrenia section in the original DSM and remains there in the DSM-IV. Thus, many studies lump so-called “schizoaffectives” together with schizophrenics in a combined group that is then compared with a control group. There is a clinical findings showing that dysregulated mood leads to psychosis. Untreated or badly responding psychotic mood disorder ends up looking like classically described schizophrenia. Related literatures showed many functionally psychotic patients, prolonged stabilizing mood could decrease long term impairment. It can attain by mood stabilizers and gradual reduction of neuroleptics over many months while educating the patient and family about mood disorder, psychosis in mood disorder, evidence of recurrence, and an appropriate temporary adjustment in stressful life activities. Removal of the meaningless and malignant ‘schizoaffective’ label would help rekindle the lithium trial. Chapter Five is written by Barton W. Palmer, Gauri, N. Savla in United States. They attempt to describe neuropsychological deficits in persons with schizoaffective disorder. This chapter begins with an overview about the cognitive and neuropsychological deficits in schizophrenia. The writers tend to assert that neuropsychological deficits are quite similar among patients with schizophrenia and schizoaffective disorder. Related studies are consistent in showing that the level, pattern, and frequency of neuropsychological impairment among patients with schizoaffective disorder are indistinguishable from those seen in patients with schizophrenia. There is also evidence those persons with schizoaffective disorder and those with paranoid subtype of schizophrenia may, on average, have slightly better neuropsychological performance than those with undifferentiated or disorganized subtypes of schizophrenia. There is no pattern of neuropsychological deficits is unique to schizophrenia and/or schizoaffective disorder. For memory, there is limited data specifically examining savings (percent retention) for schizoaffective disorder patients separately. Compared with schizophrenia, schizoaffective disorder patients show substantial forgetting than among patients with schizophrenia. Some published reports have documented that patients with schizophrenia and schizoaffective disorder have equivalent impairments on the WCST performance. Interestingly, non-institutionalized individuals with schizophrenia or schizoaffective disorder tend to stay stable in their neuropsychological ability. However, chronically institutionalized patients appear to be at higher risk for progressive cognitive decline than expected for their age. All these have important implications in neuropsychological assessment, pharmacologic interventions and related treatments. Chapter Six is written by Morris D. Bell, Randall Richardson and Tamasine Grieg in the United States. They examined ego functioning, cognition and illness characteristics of persons with schizoaffective disorder in vocational rehabilitation services. In this chapter, the writers reported on 422 (200 with schizophrenia; 70 with schizoaffective disorders) patients enrolled in a series of vocational rehabilitation studies. They examined the differences between schizophrenia and schizoaffective disorder groups on background and illness characteristics, cognitive ability, ego functioning, and work outcome measures. Community functioning was measured using the Quality of Life Scale. A significant difference between

Preface

xi

the schizophrenia and schizoaffective disorder patients appeared on the Common Objects and Activities subscale (por=2 weeks) at first admission for schizophrenia was 83%.” In the first psychotic episode, 71% had clinically significant depressive symptoms. The N=130 subset were compared with N=130 controls and N=130 new onset unipolar depressed patients. Both ill groups showed parallel prodromal depressive symptoms. It was not until emergence of psychosis, years after onset of symptoms, that the schizophrenia versus the depression groups could be distinguished from eachother. In a follow up paper, the authors report data they gathered from 107 first episode cases of schizophrenia, whom they followed for an average of 11.2 years showing [1] depression is the most frequent symptom throughout the course of schizophrenia, and [2] “psychosis risk increases when depressive and anxiety symptoms increase and decreases when these symptoms decrease” [59]. A diagnosis of psychotic depression, but not schizoaffective, would have begged lithium trial which would likely have improved many patients’ outcomes. Occam’s Razor (if one thing explains multiple findings it is probably their cause, rather than the coincidental occurrence of multiple independent events), is a basic diagnostic tenet. Psychotic mood disorder explains psychosis and mood disturbance. By the current DSM (DSM-IV) the rates of “non-affective psychosis” depend on how broadly one defines mood. Broad ways to define mood episodes would be around a couple of weeks of not functioning normally because one is too depressed, or [2] a few days of being noticably exceedingly abnormally hyper or talking way too much while not needing sleep and feeling unlike oneself. But, “patients don’t read textbooks” (presentations don’t correspond to classic descriptions), and the clinician really wants to know if anything like any of that ever happened. The next step is contacting the witnesses of the abnormal state (often family) to ensure that multiple streams of information dovetail. The reason this is so important is that the real question one is asking oneself is, “is there evidence that this patient has a recurrent mood episode component

Diagnostic Controversies in Schizoaffective Disorder

93

to his/her illness dictating prevention of kindling as a primary intervention to prevent secondary psychotic exacerbation?” Even in well defined illness, like clot-rupture and subsequent myocardial infarction, patients don’t present with consistent symptomatic reports. Given the complexity of the protein cascades involved with mood and psychosis regulation, the subjective retrospective endorsement of episodes of psychosis without mood symptoms doesn’t specify anything of known meaning. Thus, while as for psychotic mood disorder, the checklists for schizoaffective disorder also explain multiple findings, there is no clinical or scientific justification for the inclusion of the items that purport to define schizoaffective as a specific illness. The approach of those clinicians who aggressively stabilize their patients’ moods is to work under a presumption of psychotic mood disorder in new onset functional psychosis until proved otherwise. The only clinical pharmacologic question is what medication trials are most appropriate to maximize the probability of optimizing the patient’s function. The goal is to optimize mood stabilization, then gradually taper off antipsychotic medications, as tolerated, several months down the road, due to their malignant side effects (more later) and not adding anything. There will be some patients who will not do well and will require permanent clozapine or other antipsychotic medications to even function at a markedly subpremorbid level, but others can be stabilized and rejoin peers. Concerns have been raised that young mood disordered patients are diagnosed with ‘schizo’ prefaced illness and consequently denied a lithium trial [60, 61]. Mood disorder kindles resulting in adverse outcomes [62, 63].

THE INTERVENTION AND ULTIMATE RISE OF SCHIZOAFFECTIVE In 1933, in an American Journal of Psychiatry article entitled, “The acute schizoaffective psychoses”, Dr Kasanin, who was working under a grant to study schizophrenia, described a set of 9 cases initially diagnosed with dementia praecox or schizophrenia. Though these patients had hallucinations and/or delusions, they differed from the classic Bleulerian description of schizophrenia due to: 1. active premorbid social adjustment and acute onsets, 2. prominent mood symptoms, and 3. return to normal function following brief psychosis (weeks to months) [64]. Based on literature search for articles citing schizoaffective disorder, the diagnosis received little attention through the mid 1960s [65, 66]. Still, it was included in the DSM in 1952. Subsequent to its inclusion, there was a precipitous rise in publications about schizoaffective [66]. There has been robust debate as to the validity of Kraepelinian dichotomy versus a continuum of functional psychotic illness from worst to best prognosis. In other words, are bipolar illness and schizophrenia two separate illnesses, or is there one problem that can manifest different levels of severity? Schizoaffective offers a simple route to say both and neither, somewhere in between, and depression too. But while in concept, schizoaffective is largely thought of as a merging of schizophrenia and affective disorder, with an intermediate prognosis between the two, in practice, the term is often applied to impoverished chronically cocaine or phencyclidine exposed patients. This is partially driven by an insurance-reimbursement for hospitalization requirement to label patients with diagnoses other than psychosis or mood disorder from neurotoxic drug exposure. In fact the population of crack addicted patients labeled schizoaffective by the

94

Nathaniel Hurwitz and C. Raymond Lake

psychiatrists at one major east coast university is so high, that some residents and faculty have at times renamed the category ‘schizocrackfective’. There is ample evidence that chronic cocaine exposure is neurotoxic; where is Occam?. Part of the rationale in claiming that recurrent affective illness is diagnostically legitimate is its response to specific disease modifying drug properties. Lithium reduces the frequency and severity of recurrent mood episodes in psychotic mood disorder. There is no ‘antischizophrenia’ drug. There are only antipsychotics, which reduce psychosis; And psychosis is not disease specific. One pillar of the dopamine theory of schizophrenia (psychosis) is that the typicals’ antipsychotic potencies vary in a dose dependant manner on D2 occupancy. Specific PET demonstrates similar levels of D2 blockade (70-80% D2 occupancy) for both typical and atypical antipsychotics. But the distribution of D2 blockade is different [67-70]. The atypical antipsychotic medications show a relatively lower striatal (roughly 55% D2 occupancy) but higher temporal lobe D2 occupancy by raclopride PET studies, compared to typical antipsychotics. This might account for their different pharmacodynamic properties. Clearly, dopamine may represent a common final pathway in functional psychosis. By analogy, opiate analgesics reduce acute pain across numerous diagnoses, but other question lists, physical examination, and lab test data are required to diagnose the source of pain. Notably, while undoubtedly effective in acute pain, multiple studies have demonstrated detrimental effects of chronic opiate administration on pain control [71-73]. Some patients complain of severe pain but seem to ambulate and interact with no difficulty at all. Video cameras have caught patients receiving disability for severe joint conditions engaging in extremely strenuous activities. Similarly, some seemingly fully functional patients happily tell us that they are hearing voices and see knives flying about. We have no lab tests for pain and no lab tests for auditory hallucinations. Yet, in severely ill patients, these symptoms clearly exist. Neuroimaging studies demonstrate neural underpinnings. For instance, all studies of chronic pain show anterior cingulate activation regardless of primary source (arm, leg, gut, etc.) [65, 74-80]. And fMRI studies of humans diagnosed with schizophrenia indicating with button presses the onsets and offsets of perceived auditory hallucinations show temporal lobe speech area activation [81]. Though still in the experimental stages, transcranial magnetic stimulation timed to decrease activity in Wernike’s area decreases auditory hallucination complaints in patients diagnosed with schizophrenia [82]. The connection between auditory hallucinations and L temporal lobe speech mediating regions is strong. L temporal lobe dysfunction has been identified in patients described as bipolar, schizoaffective, schizophrenic and depressed [55, 83]. Discussion in the literature raises several possible links between “schizoaffective disorder” (SAD), schizophrenia, and mood disorders. We assessed a fairly large sample of articles (N=257) which weighed in on the differential diagnosis of functional psychosis. Based on our interpretation of the author’s conclusions, we assigned each article to one of the following five categories: [1] SAD = schizophrenia, [2] SAD = continuum/heterogeneous, [3] SAD = mood disorder, [4] SAD = separate disease, or [5] inconclusive/ambivalent. We submit that the author’s diagnostic and not their scientific impressions likely mediated their differences of opinion since groups generally agree about findings. But two groups could report a set of genetic testing results that show the greatest number of abnormalities in schizophrenia followed by schizoaffective, then bipolar I, and the first group could say this


95

suggests that schizoaffective is schizophrenia, while the other group could say that those findings are consistent with schizoaffective’s being a distinct disease. It might best serve patients to consider functional psychosis as [1] a severity marker for hereditary affective illness, or [2] an extremely rare debilitating syndrome characterized by early childhood aloofness, gradual peri-adolescent mood decline, subacute withdrawal, then disorganization, and subsequently a persistently much lower level of functioning. Some might agree to this, but insist on calling syndrome 2 schizophrenia. The problem with the term ‘schizophrenia’ is that treatment courses and outcomes, and family and patient expectations are very different for ‘schizophrenia’ versus the indistinguishably presenting psychotic depression. The two diagnoses compete for the same presentation. The opportunity cost of not treating the possible mood component far exceeds problems with not diagnosing nonaffective psychosis.

UNRELIABILITY The relative merits of various semantic options depend, to some degree, on their reliability. The DSM was largely developed as a research tool so separate groups who study the same disease category would be studying similar patients. This says nothing about validity (truth), only whether different diagnosticians will agree. Clinicians cannot agree about who has schizoaffective disorder [84-86]. Volmer-Larsen et al (2006) used a checklist based diagnostic algorithm and two psychiatrist reviewers to reevaluate all cases (N=59) discharged with a diagnosis of schizoaffective in 2002 from two university hospitals in Copenhagen. Reevaluation diagnoses were allocated by algorithm results and crossvalidated by reviewer consensus. None met DSM-IV life-time criteria for schizoaffective disorder [87]. Maj et al (2000) reported that while Cohen’s kappa inter-rater reliability for DSM-IV items defining a manic episode were .71, and for a major depressive episode .82, it was .22 for schizoaffective disorder [88]. Reduction in severity and frequency of affective episodes with appropriate pharmacotherapy can be demonstrated. Thus, in identifying affective psychotic episodes, reliability translates in a very real way to outcomes for patients, regardless of the validity of attached semantics. But the ‘schizoaffective’ diagnosis cannot be reliably identified. Furthermore, it offers nothing but the opportunity cost of not treating mood, violating ‘do no harm.’

PSYCHOSIS AS SEVERITY For now, it makes sense to use psychosis as a severity modifier. By analogy, respiratory failure occurs across a variety of different pneumonias, which are labeled ‘pneumonia’ until an organism is grown from a sample, at which time the disease receives a more specific label like ‘Klebsiella pneumonia’. But the respiratory failure aspect relates to severity, and requires non-specific care across the etiologically different pneumonias. Specific antibiotics attack infection based on antibiotic susceptibility testing. Patients are weaned from ventilator as soon as possible due to the malignant effects of being ventilated. Similarly, psychosis is nonspecific and requires treatment with antipsychotic medications across the variety of causes

96


(cocaine induced, dementia associated, affective, etc.); And the parallel goal is limiting exposure to toxic but necessary, acutely-stabilizing antipsychotic medications. The long term SE profiles for neuroleptics are considerably worse than for mood stabilizers, though lithium is much less safe in noncompliant patients due to its narrow therapeutic window. The underlying cause of psychosis dictates the long term plan. Cocaine dependence requires substance use therapy. Cocaine immunization to prevent it’s crossing the blood brain barrier may someday be available [89-91]. Alzheimer’s medications may temporarily delay further cognitive decline [92, 93]. Mood stabilizing/antidepressant/anti-anxiety medications are titrated to optimally regulate mood and prevent reemergence of psychosis [94]. Since the vast majority of schizophrenia diagnosed patients enrolled in studies have been chronically ill, it is possible that highly kindled mood disorder accounts for their chronic psychosis. There is no way to know. Multiple studies using a variety of outcome measures show a spectrum of disease severity by diagnostic group: affective psychosis is best, schizoaffective intermediate, and schizophrenia worst prognosis. For affective disorders, the DSM-IV uses psychosis as a severity modifier only, but psychosis serves as diagnostic criteria for schizoaffective and schizophrenic illness. Some might argue that the question of diagnostic labels is purely semantic. But it is not since semantics dictate treatment. It is hard to imagine psychotic transformation without mood disturbance. Both depression [95-98] and sleeplessness heralding onsets and exacerbation of psychosis are described in schizophrenia [99, 100]. This alone indicates that schizophrenia researchers disbelieve the Kraepelinian dichotomy. Some might legitimately object to the notion of eliminating the use of ‘schizo’ prefixed terms based on so-called “negative syndrome” schizophrenia: patients with lower intellectual capacity who are aloof and odd as children, then become progressively more constricted in late adolescence, then exhibit stable constricted disorganization as adults. Schizophrenia might seem an appropriate term for these very rare negative syndrome patients. And negative syndrome schizophrenia has shown higher concordance than positive syndrome in monozygotic twins [101, 102]. For such cases, the diagnosis ‘Psychosis NOS’ seems most appropriate. Ongoing review of the history and search for organic factors is indicated. Past depressive episodes may be hard to identify when superimposed on adolescence, a time of rapid brain change and expected mood fluctuation [56]. A difficult process of sequential pharmacologic trials seeking optimal stabilization should be undertaken. The bottom line is that, in reality, broad application of the term schizophrenia to both positive and negative syndrome patients often undermines assiduous pursuit of target mood symptoms. This harms patients.

GENETICS Concordance for psychotic illness (schizophrenia diagnosis) in monozygotic twins is high (50-80%), but not 100% [103-106]. Most diagnosis heritability studies show that mood disorders in first degree relatives of schizophrenics are more common than schizophrenia is in relatives of patients with mood disorders. Studies show a mixture of both in the relatives of so-called “schizoaffective” probands [107, 108]. Genetic studies could help sort this out. The human genome has been sequenced and a search for the genetic causes of functional psychosis is under way. However psychiatric genetics faces unique difficulties. Unlike


97

families with Huntington’s disease that all show the same, single abnormality, families with multiple functionally psychotic members show a variety of genetic abnormalities. Not only do gene-abnormality profiles vary across different families, but there are often multiple different psychiatric diagnoses within individual families − and even within individual family members. Many groups have found genetic overlap in bipolar and schizophrenia [109-118]. Others have reported that all three diagnostic categories (schizophrenia, schizoaffective, bipolar) share genetic susceptibility loci [119, 120]. The presence in one person of more than one susceptibility locus may cause a multiplicative susceptibility effect [121]. Valles (2000) reported that an increased number of bipolar-diagnosed relatives was associated with increased diagnostic rates for schizophrenia in a family [122]. Valles and others suggest that psychosis is “a non-specific indicator of illness severity” and that “it may be useful to consider the combined findings [about heritability] in a framework of a ‘continuum of severity’.” Ketter (2004) conclude there is “a broad genetic vulnerability to psychosis in general” rather than specifically to schizophrenia or bipolar disorder [123]. Torrey et al 2005 examined 100 candidate RNA, protein and other neurochemical markers in 60 brains post mortem (15 controls, 15 schizophrenic, 15 bipolar, 15 non-psychotic depression). Abnormalities in bipolar and schizophrenia overlapped 65% [124]. DISC1 (disrupted in schizophrenia 1) is one example of a genetic abnormality associated with psychosis [125-127]. DISC1 was first identified in a large Scottish family with a chromosomal abnormality that segregated with mental illness. Mental illness was defined broadly and included schizophrenia, schizoaffective disorder, recurrent major depression, adolescent conduct disorder, and emotional disorders [128]. None of the normal karyotype family members carried a psychiatric diagnosis. In mice, DISC1 is involved with two critical brain development periods: [1] E13.5, consistent with neurogenesis and neuronal migration, and [2] postnatal at P35 consistent with onset of puberty [129]. DISC1 abnormalities have been linked to abnormalities in verbal working memory and P300 amplitude reductions. A number of key central nervous system proteins have been linked to DISC1 leading to “the concept of the DISC1 pathway in normal and disturbed brain development and function” [125]. One wonders if DISC1 pathway derangements play a role in the prodromal mood episodes of DISC1 mutant patients who subsequently become psychotic. Since they point to more reliable diagnoses, and thus pave the way for more appropriate treatments, strides in genetic research are encouraging. One obvious question is, if there are valid markers, why are we employing an extraneous diagnostic terminology at all? That is, if genetic cluster A responds to drug AA, who needs irrelevant labels like schizophrenia, schizoaffective, depression, or bipolar? The answer is that not only is the genetic marker level currently in early investigational stages, but since concordance for psychotic illness is less than 100% in monozygotic twins, the genes are not the disease. Someday genetic profiles will likely demonstrate who is vulnerable to severe functional psychotic disease, and which specific (hopefully benign) supplements or other therapies will prevent it. Until then, the semantics matter, and the use of affective labels for almost all functional psychosis would optimally serve patients. Though some patients would get and fail a lithium trial, many patients who now suffer disabling disease kindling would be helped−possibly even saved from ever experiencing psychosis.

98


BRAIN MAPPING Rather than trying to cover fMRI, PET and other imaging modalities, our discussion will focus mainly on evoked response potential (ERP), the oldest and best-established brain mapping technique. ERPs are brainwave measures generated by averaging many brain responses to the same stimulus type. The term "endophenotype", meaning a subtle vulnerability-associated brain processing abnormality, has been applied to brainwave findings that differentiate psychiatrically diagnosed versus control groups. A discussion of ERP findings in “schizoaffective” disorder is necessarily a discussion of findings in schizophrenia since most work has been done with patients carrying that diagnosis. Furthermore, “schizoaffective” fell under the schizophrenia section in the original DSM and remains there in the DSM-IV. Thus many studies lump so-called “schizoaffectives” together with schizophrenics in a combined group which is then compared with a control group [130-136]. The most common ERP paradigm is the auditory oddball, so named because it involves a sequence of 2 tones: an infrequent ‘oddball’ tone (about 20% of stimuli), and a frequent ‘standard’ tone (80%). Subjects press a button upon detecting the oddball (target) but not the standard (non-target) tones. The oddball target P300 (“P” for positive, and “300” for 300 milliseconds or about 1/3 of a second after the target tone) is linked to the referencing of the incoming tone with temporarily stored ‘target’ and ‘non-target’ tone information (working memory). The most reported finding in psychiatric ERP research is oddball-generated target P300 amplitude reduction. Initially reported and highly replicated in schizophrenia research [137143], P300 reductions have also been reported in groups diagnosed with bipolar [137, 144], acute mania [143], depression [145-147], PTSD [148-150], alcoholism [151, 152], antisocial personality [152-154], borderline personality [155, 156], and OCD, as well as in relatives of manic depressive probands [157]. The New York High-Risk Project gathered auditory oddball ERP data at mean age 15 and diagnostic measures at mean age 25 from offspring of the following three groups: schizophrenic disorder N=24, affective disorder N=26, and normal N=70. Reduced P300 amplitude at mean age 15 associated with worse Global Personality Function at mean age 25 for subjects from both the schizophrenic and affective parental groups versus the control parental group. Unlike the P300 which depends on factors involved with consciously manipulating information, the earlier P50 brain response is considered ‘automatic’. Gating refers to the relative reduction in ERP component amplitude, in response to the second versus the first of two proximate stimuli. The standard method to elicit P50 gating is to administer sets of paired clicks (1/2 second apart) with about 8 seconds between serial pairs. Normal 'gating' is considered around a 70% reduction in amplitude of the second click's P50 versus the first. Gating is thought to mirror circuitry normally responsible for ignoring irrelevant sensory input, like background noise. Reduced P50 gating was first described as an endophenotype for schizophrenia and has since been reported in bipolar, and PTSD diagnosed patients [158] [ [159-161]. Due to poor signal to noise ratio (the P50 is often not much larger in amplitude than many people’s ‘background’ alpha rhythm), reliability for P50 gaiting is good only within a few labs. Still, although many labs cannot demonstrate P50 gating, it does exist; Just like the auditory


99

oddball, P50 gating has been demonstrated with intracranial electrodes in surgical epilepsy patients. MEG, the magnetic cousin of EEG might someday solve the poor signal to noise ratio problem from which P50 gating suffers. Lu et al (2007) demonstrated reduced M50 (magnetic P50) noise with MEG versus EEG [162]. A specific allelic variation in a region coding a promotor for the alpha-7 acetylcholine nicotinic receptor on chromosome 15 (CHRNA7) has been associated with P50 gating suppression. As well, that smoking normalizes P50 gating-reduction in schizophrenia diagnosed subjects has been linked to abnormalities in the alpha-7 nicotinic receptor. Martin et al (2007) studied the association of CHRNA7 allelic promotor variants with abnormal P50 gating in patients diagnosed with bipolar-type schizoaffective disorder. Data previously obtained from schizophrenia-diagnosed and control subjects were used for group comparisons. Subjects with diagnosed schizophrenia, regardless of allele status, demonstrated abnormal gating. But in both schizoaffective and control subjects gating was variant dependant. The authors concluded that “in persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia,” though their results show parallels between gating-variance dependance in the schizoaffective and control groups, distinct from the schizophrenia diagnosed group. Mismatch Negativity (MMN) is an ERP measure reflecting automatic environmental change detection [163]. Hall et al (2007) gathered P300, P50, and mismatch negativity (MMN) from 10 monozygotic twins discordant for bipolar illness, six monozygotic twins concordant for bipolar illness, and 78 control twin pairs [144]. Results showed reduced P300 and P50 gating, but no MMN difference in bipolar patients. That this study shows P50 reduction in bipolar diagnosed but not their very close relatives, while another study, cited above, showed P50 reduction in relatives of bipolar probands, speaks to the difficulty with this technique. Unlike the P50, a different ERP measure - N100 - shows its changes clearly to the naked eye. Furthermore, the N100 is barely detectable in 5-6 year olds and steadily and markedly deepens with increasing age through around 18 years old. In schizophrenia diagnosed patients, decreases in N100 are as robust as the changes in P300. Were high-risk children routinely tracked, it is possible that N100 amplitude trajectories would be found to fall off normal growth curves. One could hypothesize that the N100 changes would be coincident with the dysthymic/depressed/withdrawn episodes and/or the anxiety/sleep-disturbance episodes that usually precede obvious frank psychosis. We should note that a teenager acting ‘moody’ for a couple weeks does not constitute an affective episode. However, a significant interruption in normal development might be suspected in a teen who is uncharacteristically ‘moody’ or withdrawn, and has a newly abnormal ERP marker (e.g. age-specific N100 amplitude drops by one standard deviation). When normative data become available, and atrisk children are routinely tracked, the goal of early intervention may become a reality. P50 gating (and P300 reduction) may someday prove to be non-specific markers for susceptibility to develop whatever more specifically runs in the family. As with genetic studies, the most-replicated ERP findings in schizophrenia research were subsequently sought and found in groups carrying other diagnoses including bipolar, depressed and “schizoaffective”. Also, similarly to genetic markers, some ERP measures may differentiate schizophrenia versus bipolar diagnosed groups. That would be an expected result from

100


comparing highly kindled versus stabilized affective psychosis groups. Since longitudinal studies that could differentiate malignant versus expected changes over time have not been performed, it is not yet known whether candidate 'endophenotypes' have predictive value. Several high-risk (to develop schizophrenia) studies have followed families with schizophrenia-diagnosed parents [164-167]. Were normative data available and P300, N100, MMN and P50 measures gathered, relationships between endophenotypes and developing psychosis might have been delineated. Over 20 years ago, Roth et al asserted that "it remains to be determined to what extent [P3 amplitude reduction] reflects a global impairment, regardless of specific clinical state or diagnosis, and to what extent it reflects specific symptomatology or disorder subtype." This is still the case.

RESEARCH STRENGTHS AND PITALLS It has been argued that since the diagnosis of schizophrenia is itself questionable, the research conclusions in schizophrenia are invalid. That is not the case. The more basic research is, the more broadly it can be applied. Substituting the word “psychosis” for the word “schizophrenia”, it becomes clear that the groundwork to optimally treat, and someday prevent, functional psychosis has been laid. Meaningful measures like the oddball target P300, N100, P50 gating, and MMN, have been well enough characterized that it is evident that they should be gathered on a large scale to define population norms. The pitfall is that translating basic findings from benchside to bedside cannot be accomplished without logical diagnostic terminology. It is instructive to note that the nature of chest pain is completely non-diagnostic for myocardial infarction, but troponin is. Patients with auditory hallucination complaints (AH) are an unequivocal group. They are undoubtedly complaining of hearing voices. Then, those with abnormal baseline Wernike’s activation by fMRI could be identified as Wernike’s Activation + AH patients (WAH), and that actually means something as opposed to ‘schizoaffective’ or ‘schizophrenia’. Patients with explosive aggression undoubtedly have that. Holes in walls prove the point. But considering that aggressive children are labeled ‘ADHD’ and increasingly labeled ‘bipolar’, those words in children tell a person nothing about those labeled. Freud initially had a neurobiological bent, but became frustrated. Like Bleauler and Kaepelin, Freud’s crossectional descriptions of behavior were on the money, but etiologic arguments were off base. His thought that major psychotic illness was a consequence of oral stage fixation illustrates the need to stay with neurobiological pathways. Still, around the age of one, maximal synaptic density is achieved, followed by successive waves of synaptogenesis and larger scale synaptic reduction, thus, Freud was correct in noting critical developmental stages for future vulnerability to mental illness. Notably, there is a vast change in brain architecture around the time of malignant psychiatric transformation in functional psychosis, and under influence of the same hormones that effect puberty. The term ‘pruning’ has been applied to the 40-60% reduction in synaptic connections that progresses from back (visual cortex) to front (auditory/verbal cortex) from about the ages of 10 through 25 [168]. Prodromal affective symptoms are described during this time frame, and late-pruning auditory cortical dysfunction and functional psychosis associate [169].


101

Woods et al (2003) recently assessed a large number of local teenagers who responded to adds targeting teens experiencing perceptual disturbance symptoms [170]. Subjects were randomized to olanzapine versus placebo arms. Results did not show strong efficacy, but weight gain was very problematic. Still, the feasibility of studying earlier brain changes and attempting primary prevention was demonstrated. The key weakness might have been that subjects were not preselected for positive family histories of psychosis. Computer modeling has been used to explore the effects of pruning [171]. Reducing connections between two input/output structures improved the efficiency of a neural network tasked with using a limited set of words to form sentences. However, over pruning inserted words and neologisms where the rule set dictated pauses [171, 172]. Progress in schizophrenia research has laid the foundation to pursue a logical roadmap towards optimal neuroprotection. NMDA receptors, calcium channel-associated glutamate receptors subserving biochemical memory formation, play a key role in psychosis associated neurotoxicity. Adults but not children manifest psychotic reactions to NMDA blockers. That is why ketamine is routinely used in pediatric but seldom in adult medicine. Parallel time courses for NMDA-blocker induction of psychosis and endogenous functional psychosis has led to the glutamate hypothesis [173-176]. Excitotocicity, or free radical formation resulting from the leakage of high energy electrons along the electron transport chain associated with glutamatergic dysfunction, is the primary neurotoxic process implicated in functional psychosis. There is, by most counts, hippocampal cell loss, but no gliosis (scarring) in postmortem brains from functional psychosis patients [177-183]. What is suggested is an early migrational abnormality which subserves mood disorder followed by malignant psychotic transformation in a percentage of those affected. Excitotoxicity and associated apoptosis (programmed cell death) are the only known mechanisms yielding agliotic neuronal cell loss. NMDA blockade induced excitotoxicity in animal models is reduced by preapplication of D2 blocking drugs, and those atypicals tested demonstrated an approximately 2:1 increased experimental neuroprotective effect [184-187]. Lithium frustrates excitotoxicity in animal models as well [188-197]. Decreased superoxide dismutase blood levels (free radical scavenging capacity) has been demonstrated in new onset functional psychosis [24]. Cytochrome C in the electron transport chain shares a key role in both generation of free radicals in excitotoxicity and as an obligate docking site for apoptosis mediating proteins [198-207]. Thus, excitotoxicity and apoptosis are directly linked. In fact, it is because cell loss in excitotoxicity is apoptosis mediated that scarring does not occur. Tracking at risk groups through the pruning period is clearly indicated. Our question is, in light of the mood disorder that precedes psychotic break by years, and the demonstration of lithium’s neuroprotective effects against excitotoxin damage, shouldn’t we be asking if treating the prodrome could prevent the subsequent need for antipsychotic medications? Children’s head circumferences, weight, and height are routinely measured and plotted on standardized growth curves. Rapidly changing percentiles in these parameters clue clinicians to developing problems, allowing further investigation and early intervention. There are cheap, valid, and readily available methods to measure attention and auditory cortical development [208-213]. In the audiology literature, small but adequately powered studies have shown a vast change in a standard auditory-evoked-potential (AEP) measure which can be seen very clearly with the naked eye [211-219]. Yet normative data have not

102


been gathered to allow the same ‘growth curve’ type of measurements that are done for pediatrics to be done for psychiatry. Rather, the vast majority of psychiatric research continues to focus on chronically ill adult patients who have been medicated for years and are diagnosed with schizophrenia. Resources must be allocated towards following large samples who have yet to develop disease and away from studying functional abnormalities in already diagnosed patients. That would gather normative data and track changes heralding malignant transformation. In other words, clinically useful lab tests should be developed. The genetic testing of multiply effected families yields critically important information. But, again, the yet undiagnosed children in these families must be tracked with functional measures. In high risk studies, approximately 20 percent of male and 10% of female offspring develop disease. That is a high percentage, and if population norms were delineated, prospectively following a large number of high risk children with a battery of brain measurements should allow the assessment of prodromal stabilization and primary prevention of psychosis. But before progressing from benchside to bedside, the pitfall of employing diagnostic terminology whose seminal concepts predate biological pathway considerations must be overcome. When we study problems like aggression, depression, psychosis, and kindling, we will develop the means to determine initial treatment and monitor treatment response in psychiatry as is the case for the rest of medicine, with meaningful lab tests.

CONCLUSION There is a clinical concept that in susceptible patients, dysregulated mood leads to psychosis. And instability begets worse future instability. One consequence of the existence of ‘schizo’ prefaced diagnoses is diminished efforts to regulate mood. Resultant kindling of psychotic mood disorder and associated neurotoxicity may thereby yield the clinical picture of persistently low functioning. That is, untreated or badly responding psychotic mood disorder ends up looking like classically described schizophrenia. Peri-adolescence appears to be a critical period of vulnerability, though there are features including genotypes that could be identified very early. Definitive tests unequivocally identifying patients’ illnesses will someday eliminate the ‘risk/benefit’ ratio assessment of applying a label. Early stabilization of psychosis is essential, as psychosis is a toxic state. Prevention of recurrence is essential as well. Many already chronically ill patients will likely require permanent stabilizing neurolepticization. It is not known in how many of them mood stabilization would have been neuroprotective. And the linearity of the process is unknown- it may be that preventative strategies through the pruning stage would completely eliminate the need for later treatment. Labels that emphasize basic description, like acute, subacute, chronic, and psychosis, mania, and depression leave open the door for further exploration: ie: 1. “why is he depressed?”, or 2. “why is she psychotic?”. 3. “why is he manic?” [does he need an inpatient drug rehabilitation?]. But the labels schizophrenic and schizoaffective do not lead to the question, “why is he schizophrenic?”, and “why is she schizoaffective?”. In a high paced world, “schizo” prefaced labels translate directly into chronic neurolepticization. The literature suggests that in a large number of functionally psychotic patients, diligently stabilizing mood could decrease long term impairment. One clinical strategy is to


103

aggressively pursue mood stabilization and then gradual reduction of neuroleptics over many months while educating the patient and family about mood disorder, psychosis in mood disorder, evidence of recurrence, and an appropriate temporary adjustment in stressful life activities. Many patients who’ve had functionally psychotic episodes function normally for years on lithium. Removal of the meaningless and malignant ‘schizoaffective’ label would help rekindle the lithium trial.

REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9]

[10] [11] [12]

[13]

[14]

[15] [16] [17] [18]

Ng, K.C., Deep vein thrombosis: a study in clinical diagnosis. Singapore Med J, 1994. 35(3): p. 286-9. Levi, M., W. Hart, and H.R. Buller, [Physical examination--the significance of Homan's sign]. Ned Tijdschr Geneeskd, 1999. 143(37): p. 1861-3. Kraepelin, E., Clinical Psychiatry. 1913, New York: William Wood Company. Kraepelin, E., Die Erscheinungsformen des Irreseins. Zeitschrift fur die gesamte neurologie und Psychiatrie. Vol. 62. 1920. 1-29. Bleuler, E., Dementia Praecox or the Group of Schizophrenias. 1911/1950, New York: International Universities Press. Bleuler, E., Textbook of Psychiatry. 1924, New York: The Macmillan Company. 635. Schneider, K., Clinical Psychopathology. 1959, New York: Grune & Stratton, Inc. DSM-IV. Cooper, J.E., Kendall, R.E., Gurland, B.J., Sharpe, L., Copeland, J.R.M., Psychiatric Diagnosis in New York and London Institute of Psychiatry London. Maudsley monograph Series. Vol. 135. 1972, Oxford: Oxford University Press. pp. 136-138. Kendell, R.E. and J. Gourlay, The clinical distinction between the affective psychoses and schizophrenia. Br J Psychiatry, 1970. 117(538): p. 261-6. Ollerenshaw, D.P., The classification of the functional psychoses. Br J Psychiatry, 1973. 122(570): p. 517-30. Pope, H.G., Jr. and J.F. Lipinski, Jr., Diagnosis in schizophrenia and manic-depressive illness: a reassessment of the specificity of 'schizophrenic' symptoms in the light of current research. Arch Gen Psychiatry, 1978. 35(7): p. 811-28. Stoll, A.L., , Shifts in diagnostic frequencies of schizophrenia and major affective disorders at six North American psychiatric hospitals, 1972-1988. Am J Psychiatry, 1993. 150(11): p. 1668-73. Post, R.M., R. Susan, and B. Weiss, Sensitization, kindling, and carbamazepine: an update on their implications for the course of affective illness. Pharmacopsychiatry, 1992. 25(1): p. 41-3. Goldberg, J.F., J.L. Garno, and M. Harrow, Long-term remission and recovery in bipolar disorder: a review. Curr Psychiatry Rep, 2005. 7(6): p. 456-61. Post, R.M. and S.R. Weiss, Convergences in course of illness and treatments of the epilepsies and recurrent affective disorders. Clin EEG Neurosci, 2004. 35(1): p. 14-24. Post, R.M., Neurobiology of seizures and behavioral abnormalities. Epilepsia, 2004. 45 Suppl 2: p. 5-14. Amann, B. and H. Grunze, Neurochemical underpinnings in bipolar disorder and epilepsy. Epilepsia, 2005. 46 Suppl 4: p. 26-30.

104


[19] Ozyurt, B., , Oxidative stress in prefrontal cortex of rat exposed to MK-801 and protective effects of CAPE. Prog Neuropsychopharmacol Biol Psychiatry, 2007. [20] Emsley, R., J. Rabinowitz, and R. Medori, Remission in early psychosis: Rates, predictors, and clinical and functional outcome correlates. Schizophr Res, 2007. 89(13): p. 129-39. [21] Coyle, J.T. and P. Puttfarcken, Oxidative stress, glutamate, and neurodegenerative disorders. Science, 1993. 262(5134): p. 689-95. [22] Carbone, S., , Duration of untreated psychosis and 12-month outcome in first-episode psychosis: the impact of treatment approach. Acta Psychiatr Scand, 1999. 100(2): p. 96-104. [23] Mahadik, S.P. and S. Mukherjee, Free radical pathology and antioxidant defense in schizophrenia: a review. Schizophr Res, 1996. 19(1): p. 1-17. [24] Mukerjee, S., , Impaired antioxidant defense at the onset of psychosis. Schizophr Res, 1996. 19(1): p. 19-26. [25] Mahadik, S.P., , Elevated plasma lipid peroxides at the onset of nonaffective psychosis. Biol Psychiatry, 1998. 43(9): p. 674-9. [26] Lew, P.C., J. Lewis, and I. Story, Inter-therapist reliability in locating latent myofascial trigger points using palpation. Man Ther, 1997. 2(2): p. 87-90. [27] Gerwin, R. and S. Shannon, Interexaminer reliability and myofascial trigger points. Arch Phys Med Rehabil, 2000. 81(9): p. 1257-8. [28] Gerwin, R.D., , Interrater reliability in myofascial trigger point examination. Pain, 1997. 69(1-2): p. 65-73. [29] Njoo, K.H. and E. Van der Does, The occurrence and inter-rater reliability of myofascial trigger points in the quadratus lumborum and gluteus medius: a prospective study in non-specific low back pain patients and controls in general practice. Pain, 1994. 58(3): p. 317-23. [30] Wolfe, F., , The fibromyalgia and myofascial pain syndromes: a preliminary study of tender points and trigger points in persons with fibromyalgia, myofascial pain syndrome and no disease. J Rheumatol, 1992. 19(6): p. 944-51. [31] Salamone, J.D., M.S. Cousins, and S. Bucher, Anhedonia or anergia? Effects of haloperidol and nucleus accumbens dopamine depletion on instrumental response selection in a T-maze cost/benefit procedure. Behav Brain Res, 1994. 65(2): p. 221-9. [32] Ikemoto, S., Dopamine reward circuitry: Two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev, 2007. [33] Barbano, M.F., , Mesolimbic dopamine drives the diurnal variation in opiate-induced feeding. Pharmacol Biochem Behav, 2005. 81(3): p. 569-74. [34] Kalivas, P.W. and N.D. Volkow, The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry, 2005. 162(8): p. 1403-13. [35] Goto, Y. and A.A. Grace, Dopaminergic modulation of limbic and cortical drive of nucleus accumbens in goal-directed behavior. Nat Neurosci, 2005. 8(6): p. 805-12. [36] Grace, A.A., , Regulation of firing of dopaminergic neurons and control of goaldirected behaviors. Trends Neurosci, 2007. 30(5): p. 220-7. [37] Onn, S.P. and A.A. Grace, Repeated treatment with haloperidol and clozapine exerts differential effects on dye coupling between neurons in subregions of striatum and nucleus accumbens. J Neurosci, 1995. 15(11): p. 7024-36.


105

[38] Tohen, M., , Efficacy of olanzapine in acute bipolar mania: a double-blind, placebocontrolled study. The Olanzipine HGGW Study Group. Arch Gen Psychiatry, 2000. 57(9): p. 841-9. [39] Lehmann, H.E. and G.E. Hanrahan, Chlorpromazine; new inhibiting agent for psychomotor excitement and manic states. AMA Arch Neurol Psychiatry, 1954. 71(2): p. 227-37. [40] Kimmel, S.E., , Clozapine in treatment-refractory mood disorders. J Clin Psychiatry, 1994. 55 Suppl B: p. 91-3. [41] Gispen, W.H., [Nobel prize in physiology of medicine for year 2000 for research of signal transduction in the nervous system]. Ned Tijdschr Geneeskd, 2000. 144(46): p. 2184-7. [42] Burki, H.R., , Clozapine and the dopamine hypothesis of schizophrenia, a critical appraisal. Pharmakopsychiatr Neuropsychopharmakol, 1975. 8(3): p. 115-21. [43] Meltzer, H.Y. and S.M. Stahl, The dopamine hypothesis of schizophrenia: a review. Schizophr Bull, 1976. 2(1): p. 19-76. [44] Suppes, T., , Clozapine in the treatment of dysphoric mania. Biol Psychiatry, 1992. 32(3): p. 270-80. [45] Banov, M.D., , Clozapine therapy in refractory affective disorders: polarity predicts response in long-term follow-up. J Clin Psychiatry, 1994. 55(7): p. 295-300. [46] Frankenburg, F.R. and M.C. Zanarini, Uses of clozapine in nonschizophrenic patients. Harv Rev Psychiatry, 1994. 2(3): p. 142-50. [47] Muller-Oerlinghausen, B., A. Berghofer, and M. Bauer, Bipolar disorder. Lancet, 2002. 359(9302): p. 241-7. [48] Tondo, L., , Lithium treatment and risk of suicidal behavior in bipolar disorder patients. J Clin Psychiatry, 1998. 59(8): p. 405-14. [49] Muller-Oerlinghausen, B., Arguments for the specificity of the antisuicidal effect of lithium. Eur Arch Psychiatry Clin Neurosci, 2001. 251 Suppl 2: p. II72-5. [50] Schou, M., The early European lithium studies. Aust N Z J Psychiatry, 1999. 33 Suppl: p. S39-47. [51] Barraclough, B., Suicide prevention, recurrent affective disorder and lithium. Br J Psychiatry, 1972. 121(563): p. 391-2. [52] Baastrup, P.C. and M. Schou, Lithium as a prophylactic agents. Its effect against recurrent depressions and manic-depressive psychosis. Arch Gen Psychiatry, 1967. 16(2): p. 162-72. [53] Angst, J., , Lithium prophylaxis in recurrent affective disorders. Br J Psychiatry, 1970. 116(535): p. 604-14. [54] Stancer, H.C., F.W. Furlong, and D.D. Godse, A longitudinal investigation of lithium as a prophylactic agent for recurrent depressions. Can Psychiatr Assoc J, 1970. 15(1): p. 29-40. [55] Klein, D.N., S.A. Shankman, and S. Rose, Dysthymic disorder and double depression: Prediction of 10-year course trajectories and outcomes. J Psychiatr Res, 2007. [56] Karlsson, L., , Differences in the clinical characteristics of adolescent depressive disorders. Depress Anxiety, 2006. [57] Dunner, D.L., Dysthymia and double depression. Int Rev Psychiatry, 2005. 17(1): p. 38.

106


[58] Hafner, H., , Schizophrenia and depression: challenging the paradigm of two separate diseases--a controlled study of schizophrenia, depression and healthy controls. Schizophr Res, 2005. 77(1): p. 11-24. [59] Hafner, H., [Is the schizophrenia diagnosis still appropriate?]. Psychiatr Prax, 2007. 34(4): p. 175-80. [60] Wagemaker, H., S. Lippmann, and J.R. Cade, Acutely psychotic patients: a treatment approach. South Med J, 1985. 78(7): p. 833-7. [61] Gomez, G.E., Lithium treatment present and future. J Psychosoc Nurs Ment Health Serv, 2001. 39(8): p. 31-7. [62] Kendler, K.S. and M.T. Tsuang, Identical twins concordant for the progression of affective illness to schizophrenia. Br J Psychiatry, 1982. 141: p. 563-6. [63] Post, R.M., Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry, 1992. 149(8): p. 999-1010. [64] Kasanin, J., The acute schizoaffective psychoses. 1933. Am J Psychiatry, 1994. 151(6 Suppl): p. 144-54. [65] DSM-I. Diagnostic and Statistical Manual of Mental Disorders, first edition. 1952, Washington, DC: American Psychiatric Press, Inc. [66] Lake, C.R. and N. Hurwitz, Schizoaffective disorders are psychotic mood disorders; there are no schizoaffective disorders. Psychiatry Res, 2006. 143(2-3): p. 255-87. [67] Xiberas, X., , Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry, 2001. 179: p. 503-8. [68] Remington, G., , A PET study evaluating dopamine D2 receptor occupancy for longacting injectable risperidone. Am J Psychiatry, 2006. 163(3): p. 396-401. [69] Mizrahi, R., , Adverse subjective experience with antipsychotics and its relationship to striatal and extrastriatal D2 receptors: a PET study in schizophrenia. Am J Psychiatry, 2007. 164(4): p. 630-7. [70] Natesan, S., , Dissociation between in vivo occupancy and functional antagonism of dopamine D2 receptors: comparing aripiprazole to other antipsychotics in animal models. Neuropsychopharmacology, 2006. 31(9): p. 1854-63. [71] King, T., , Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? Neurosignals, 2005. 14(4): p. 194-205. [72] Hama, A., A. Basler, and J. Sagen, Enhancement of morphine antinociception with the peptide N-methyl-D-aspartate receptor antagonist [Ser1]-histogranin in the rat formalin test. Brain Res, 2006. 1095(1): p. 59-64. [73] King, T., , Role of NK-1 neurotransmission in opioid-induced hyperalgesia. Pain, 2005. 116(3): p. 276-88. [74] Geha, P.Y., , Brain activity for spontaneous pain of postherpetic neuralgia and its modulation by lidocaine patch therapy. Pain, 2007. 128(1-2): p. 88-100. [75] Staud, R., , Brain activity related to temporal summation of C-fiber evoked pain. Pain, 2007. 129(1-2): p. 130-42. [76] Zhuo, M., Molecular mechanisms of pain in the anterior cingulate cortex. J Neurosci Res, 2006. 84(5): p. 927-33. [77] Baliki, M.N., , Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J Neurosci, 2006. 26(47): p. 12165-73.


107

[78] de Leeuw, R., , The contribution of neuroimaging techniques to the understanding of supraspinal pain circuits: implications for orofacial pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2005. 100(3): p. 308-14. [79] Buffington, A.L., C.A. Hanlon, and M.J. McKeown, Acute and persistent pain modulation of attention-related anterior cingulate fMRI activations. Pain, 2005. 113(12): p. 172-84. [80] Peyron, R., B. Laurent, and L. Garcia-Larrea, Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin, 2000. 30(5): p. 263-88. [81] Dierks, T., , Activation of Heschl's gyrus during auditory hallucinations. Neuron, 1999. 22(3): p. 615-21. [82] Hoffman, R.E., , Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a fifty patient sample. Biol Psychiatry, 2005. 58(2): p. 97-104. [83] Chen, X., , Regional gray matter changes in bipolar disorder: a voxel-based morphometric study. Aust N Z J Psychiatry, 2007. 41(4): p. 327-36. [84] Roy, M.A., , Clinical and methodological factors related to reliability of the bestestimate diagnostic procedure. Am J Psychiatry, 1997. 154(12): p. 1726-33. [85] Hiller, W., , An empirical comparison of diagnoses and reliabilities in ICD-10 and DSM-III-R. Eur Arch Psychiatry Clin Neurosci, 1993. 242(4): p. 209-17. [86] Steiner, J.L., , A comparison of the structured clinical interview for DSM-III-R and clinical diagnoses. J Nerv Ment Dis, 1995. 183(6): p. 365-9. [87] Vollmer-Larsen, A., , Schizoaffective disorder-- the reliability of its clinical diagnostic use. Acta Psychiatr Scand, 2006. 113(5): p. 402-7. [88] Maj, M., , Reliability and validity of the DSM-IV diagnostic category of schizoaffective disorder: preliminary data. J Affect Disord, 2000. 57(1-3): p. 95-8. [89] Meijler, M.M., , Development of immunopharmacotherapy against drugs of abuse. Curr Drug Discov Technol, 2004. 1(1): p. 77-89. [90] Martell, B.A., , Vaccine pharmacotherapy for the treatment of cocaine dependence. Biol Psychiatry, 2005. 58(2): p. 158-64. [91] Hrafnkelsdottir, K., J. Valgeirsson, and S. Gizurarson, Induction of protective and specific antibodies against cocaine by intranasal immunisation using a glyceride adjuvant. Biol Pharm Bull, 2005. 28(6): p. 1038-42. [92] Farlow, M.R. and J.L. Cummings, Effective pharmacologic management of Alzheimer's disease. Am J Med, 2007. 120(5): p. 388-97. [93] Cosman, K.M., L.L. Boyle, and A.P. Porsteinsson, Memantine in the treatment of mildto-moderate Alzheimer's disease. Expert Opin Pharmacother, 2007. 8(2): p. 203-14. [94] Davis, J.M., Z. Wang, and P.G. Janicak, A quantitative analysis of clinical drug trials for the treatment of affective disorders. Psychopharmacol Bull, 1993. 29(2): p. 175-81. [95] Jarbin, H. and L. Hansson, Adult quality of life and associated factors in adolescent onset schizophrenia and affective psychotic disorders. Soc Psychiatry Psychiatr Epidemiol, 2004. 39(9): p. 725-9. [96] Muller, M.J., Gender-specific associations of depression with positive and negative symptoms in acute schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry, 2007. [97] Kasckow, J., , Suicidality in middle aged and older patients with schizophrenia and depressive symptoms: relationship to functioning and Quality of Life. Int J Geriatr Psychiatry, 2007.

108


[98] Becker, R.E., J.A. Colliver, and S.J. Verhulst, Diagnosis of secondary depression in schizophrenia. J Clin Psychiatry, 1985. 46(11 Pt 2): p. 4-8. [99] Poulin, J., , Sleep architecture and its clinical correlates in first episode and neuroleptic-naive patients with schizophrenia. Schizophr Res, 2003. 62(1-2): p. 14753. [100] Singh, M.M. and J.M. Smith, Sleeplessness in acute and chronic schizophrenia-response to haloperidol and anti-parkinsonism agents. Psychopharmacologia, 1973. 29(1): p. 21-32. [101] Walker, E. and R.J. Lewine, The positive/negative symptom distinction in schizophrenia. Validity and etiological relevance. Schizophr Res, 1988. 1(5): p. 31528. [102] Dworkin, R.H. and M.F. Lenzenweger, Symptoms and the genetics of schizophrenia: implications for diagnosis. Am J Psychiatry, 1984. 141(12): p. 1541-6. [103] Moskalenko, V.D., [Monozygotic and dizygotic twins concordant with regard to schizophrenia]. Zh Nevropatol Psikhiatr Im S S Korsakova, 1977. 77(1): p. 98-95. [104] McGuffin, P., , Twin concordance for operationally defined schizophrenia. Confirmation of familiality and heritability. Arch Gen Psychiatry, 1984. 41(6): p. 5415. [105] Farmer, A.E., P. McGuffin, and Gottesman, II, Twin concordance for DSM-III schizophrenia. Scrutinizing the validity of the definition. Arch Gen Psychiatry, 1987. 44(7): p. 634-41. [106] Onstad, S., , Twin concordance for DSM-III-R schizophrenia. Acta Psychiatr Scand, 1991. 83(5): p. 395-401. [107] Taylor, M.A., Are schizophrenia and affective disorder related? A selective literature review. Am J Psychiatry, 1992. 149(1): p. 22-32. [108] Kendler, K.S., , Examining the validity of DSM-III-R schizoaffective disorder and its putative subtypes in the Roscommon Family Study. Am J Psychiatry, 1995. 152(5): p. 755-64. [109] Maier, W., A. Zobel, and M. Wagner, Schizophrenia and bipolar disorder: differences and overlaps. Curr Opin Psychiatry, 2006. 19(2): p. 165-70. [110] Schurhoff, F., , Familial aggregation of delusional proneness in schizophrenia and bipolar pedigrees. Am J Psychiatry, 2003. 160(7): p. 1313-9. [111] Schulze, T.G., , Genotype-phenotype studies in bipolar disorder showing association between the DAOA/G30 locus and persecutory delusions: a first step toward a molecular genetic classification of psychiatric phenotypes. Am J Psychiatry, 2005. 162(11): p. 2101-8. [112] Berrettini, W.H., Are schizophrenic and bipolar disorders related? A review of family and molecular studies. Biol Psychiatry, 2000. 48(6): p. 531-8. [113] Craddock, N. and M.J. Owen, The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry, 2005. 186: p. 364-6. [114] Craddock, N., M.C. O'Donovan, and M.J. Owen, Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophr Bull, 2006. 32(1): p. 9-16. [115] Berrettini, W., Evidence for shared susceptibility in bipolar disorder and schizophrenia. Am J Med Genet C Semin Med Genet, 2003. 123(1): p. 59-64. [116] Berrettini, W., Bipolar disorder and schizophrenia: convergent molecular data. Neuromolecular Med, 2004. 5(1): p. 109-17.


109

[117] Schumacher, J., , Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder. Mol Psychiatry, 2004. 9(2): p. 203-7. [118] Cannon, T.D., The inheritance of intermediate phenotypes for schizophrenia. Curr Opin Psychiatry, 2005. 18(2): p. 135-40. [119] Cardno, A.G., , Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry, 1999. 56(2): p. 162-8. [120] Cardno, A.G., , A twin study of genetic relationships between psychotic symptoms. Am J Psychiatry, 2002. 159(4): p. 539-45. [121] Jones, H.B. and M. Faham, Evidence and implications for multiplicative interactions among loci predisposing to human common disease. Hum Hered, 2005. 59(3): p. 17684. [122] Valles, V., , Increased morbid risk for schizophrenia in families of in-patients with bipolar illness. Schizophr Res, 2000. 42(2): p. 83-90. [123] Ketter, T.A., , Psychotic bipolar disorders: dimensionally similar to or categorically different from schizophrenia? J Psychiatr Res, 2004. 38(1): p. 47-61. [124] Torrey, E.F., , Neurochemical markers for schizophrenia, bipolar disorder, and major depression in postmortem brains. Biol Psychiatry, 2005. 57(3): p. 252-60. [125] Hennah, W., , Genes and schizophrenia: beyond schizophrenia: the role of DISC1 in major mental illness. Schizophr Bull, 2006. 32(3): p. 409-16. [126] Blackwood, D.H. and W.J. Muir, Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia. Neurotox Res, 2004. 6(1): p. 35-41. [127] Blackwood, D.H., , Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet, 2001. 69(2): p. 428-33. [128] St Clair, D., , Association within a family of a balanced autosomal translocation with major mental illness. Lancet, 1990. 336(8706): p. 13-6. [129] Schurov, I.L., , Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment. Mol Psychiatry, 2004. 9(12): p. 1100-10. [130] Ford, J.M., , Synch before you speak: auditory hallucinations in schizophrenia. Am J Psychiatry, 2007. 164(3): p. 458-66. [131] Butler, P.D., , Subcortical visual dysfunction in schizophrenia drives secondary cortical impairments. Brain, 2007. 130(Pt 2): p. 417-30. [132] Uvarova, L.G. and M.V. Alfimova, [Peculiarities of EEG dynamics in cognitive activity demanding persistent attention in patients with schizophrenia and schizoaffective psychosis and their relatives]. Zh Nevrol Psikhiatr Im S S Korsakova, 2005. 105(8): p. 41-6. [133] Kim, D., , Dysfunction of early-stage visual processing in schizophrenia: harmonic analysis. Schizophr Res, 2005. 76(1): p. 55-65. [134] Weisbrod, M., , Genetic influence on auditory information processing in schizophrenia: P300 in monozygotic twins. Biol Psychiatry, 1999. 46(5): p. 721-5. [135] Bruder, G., , Left temporal lobe dysfunction in schizophrenia: event-related potential and behavioral evidence from phonetic and tonal dichotic listening tasks. Arch Gen Psychiatry, 1999. 56(3): p. 267-76.

110


[136] Eyler, L.T., , Abnormal brain response of chronic schizophrenia patients despite normal performance during a visual vigilance task. Psychiatry Res, 2004. 130(3): p. 245-57. [137] O'Donnell, B.F., , Auditory event-related potential abnormalities in bipolar disorder and schizophrenia. Int J Psychophysiol, 2004. 53(1): p. 45-55. [138] Duncan, C.C., Event-related brain potentials: a window on information processing in schizophrenia. Schizophr Bull, 1988. 14(2): p. 199-203. [139] Roth, W.T., , Auditory event-related potentials in schizophrenia and depression. Psychiatry Res, 1981. 4(2): p. 199-212. [140] Ford, J.M., , N1 and P300 abnormalities in patients with schizophrenia, epilepsy, and epilepsy with schizophrenialike features. Biol Psychiatry, 2001. 49(10): p. 848-60. [141] Turetsky, B.I., T.D. Cannon, and R.E. Gur, P300 subcomponent abnormalities in schizophrenia: III. Deficits In unaffected siblings of schizophrenic probands. Biol Psychiatry, 2000. 47(5): p. 380-90. [142] Ward, P.B., , Auditory selective attention and event-related potentials in schizophrenia. Br J Psychiatry, 1991. 158: p. 534-9. [143] Vilela, C., , [P300 and neuropsychological tests in schizophrenia and bipolar patients]. Rev Neurol, 1999. 28(6): p. 608-12. [144] Hall, M.H., , Genetic overlap between bipolar illness and event-related potentials. Psychol Med, 2007. 37(5): p. 667-78. [145] Mao, W., Y. Wang, and D. Wang, Cognitive impairment in major depressive disorder revealed by event-related potential N270. Clin EEG Neurosci, 2005. 36(1): p. 9-14. [146] Dietrich, D.E., , Target evaluation processing and serum levels of nerve tissue protein S100B in patients with remitted major depression. Neurosci Lett, 2004. 354(1): p. 6973. [147] Gangadhar, B.N., , P300 amplitude in non-bipolar, melancholic depression. J Affect Disord, 1993. 28(1): p. 57-60. [148] Karl, A., L.S. Malta, and A. Maercker, Meta-analytic review of event-related potential studies in post-traumatic stress disorder. Biol Psychol, 2006. 71(2): p. 123-47. [149] Araki, T., , Association between lower P300 amplitude and smaller anterior cingulate cortex volume in patients with posttraumatic stress disorder: a study of victims of Tokyo subway sarin attack. Neuroimage, 2005. 25(1): p. 43-50. [150] Charles, G., , P300 in posttraumatic stress disorder. Neuropsychobiology, 1995. 32(2): p. 72-4. [151] Malone, S.M., W.G. Iacono, and M. McGue, Event-related potentials and comorbidity in alcohol-dependent adult males. Psychophysiology, 2001. 38(3): p. 367-76. [152] Costa, L., , Frontal P300 decrements, alcohol dependence, and antisocial personality disorder. Biol Psychiatry, 2000. 47(12): p. 1064-71. [153] Kiehl, K.A., , Brain potentials implicate temporal lobe abnormalities in criminal psychopaths. J Abnorm Psychol, 2006. 115(3): p. 443-53. [154] Bernat, E.M., , Violent offending predicts P300 amplitude. Int J Psychophysiol, 2007. [155] Ceballos, N.A., , Brain maturation in conduct disorder versus borderline personality disorder. Neuropsychobiology, 2006. 53(2): p. 94-100. [156] Kutcher, S.P., , Auditory P300 in borderline personality disorder and schizophrenia. Arch Gen Psychiatry, 1987. 44(7): p. 645-50.


111

[157] Pierson, A., , Information processing deficits in relatives of manic depressive patients. Psychol Med, 2000. 30(3): p. 545-55. [158] Freedman, R., , The genetics of sensory gating deficits in schizophrenia. Curr Psychiatry Rep, 2003. 5(2): p. 155-61. [159] Hong, C.J., , Association study of the human partially duplicated alpha7 nicotinic acetylcholine receptor genetic variant with bipolar disorder. Neurosci Lett, 2004. 355(1-2): p. 69-72. [160] Schulze, K.K., , P50 Auditory Evoked Potential Suppression in Bipolar Disorder Patients With Psychotic Features and Their Unaffected Relatives. Biol Psychiatry, 2006. [161] Olincy, A. and L. Martin, Diminished suppression of the P50 auditory evoked potential in bipolar disorder subjects with a history of psychosis. Am J Psychiatry, 2005. 162(1): p. 43-9. [162] Lu, B.Y., , Improved test-retest reliability of 50-ms paired-click auditory gating using magnetoencephalography source modeling. Psychophysiology, 2007. 44(1): p. 86-90. [163] Ford, J.M., W.T. Roth, and B.S. Kopell, Attention effects on auditory evoked potentials to infrequent events. Biol Psychol, 1976. 4(1): p. 65-77. [164] Mednick, S.A., A longitudinal study of children with a high risk for schizophrenia. Ment Hyg, 1966. 50(4): p. 522-35. [165] Mednick, S.A. and T.F. McNeil, Current methodology in research on the etiology of schizophrenia: serious difficulties which suggest the use of the high-risk-group method. Psychol Bull, 1968. 70(6): p. 681-93. [166] Mirsky, A.F. and C.C. Duncan, Pathophysiology of mental illness: a view from the fourth ventricle. Int J Psychophysiol, 2005. 58(2-3): p. 162-78. [167] Mirsky, A.F., , Adult outcomes of high-risk children: differential effects of town and kibbutz rearing. Schizophr Bull, 1985. 11(1): p. 150-4. [168] Huttenlocher, P.R. and A.S. Dabholkar, Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol, 1997. 387(2): p. 167-78. [169] Feinberg, I., Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res, 1982. 17(4): p. 319-34. [170] Woods, S.W., , Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenic prodrome. Biol Psychiatry, 2003. 54(4): p. 45364. [171] Hoffman, R.E. and T.H. McGlashan, Synaptic elimination, neurodevelopment, and the mechanism of hallucinated "voices" in schizophrenia. Am J Psychiatry, 1997. 154(12): p. 1683-9. [172] Hoffman, R.E. and S.K. Dobscha, Cortical pruning and the development of schizophrenia: a computer model. Schizophr Bull, 1989. 15(3): p. 477-90. [173] Krystal, J.H., , NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl), 2003. 169(3-4): p. 215-33. [174] Abi-Saab, W.M., , The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry, 1998. 31 Suppl 2: p. 104-9. [175] Olney, J.W. and N.B. Farber, Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry, 1995. 52(12): p. 998-1007.

112


[176] Farber, N.B., , Age-specific neurotoxicity in the rat associated with NMDA receptor blockade: potential relevance to schizophrenia? Biol Psychiatry, 1995. 38(12): p. 78896. [177] Arnold, S.E., , Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry, 1998. 55(3): p. 225-32. [178] Marenco, S. and D.R. Weinberger, The neurodevelopmental hypothesis of schizophrenia: following a trail of evidence from cradle to grave. Dev Psychopathol, 2000. 12(3): p. 501-27. [179] Arnold, S.E., Cellular and molecular neuropathology of the parahippocampal region in schizophrenia. Ann N Y Acad Sci, 2000. 911: p. 275-92. [180] Falkai, P. and B. Bogerts, Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatry Neurol Sci, 1986. 236(3): p. 154-61. [181] Squires, R.F., , Reduced [3H]flunitrazepam binding in cingulate cortex and hippocampus of postmortem schizophrenic brains: is selective loss of glutamatergic neurons associated with major psychoses? Neurochem Res, 1993. 18(2): p. 219-23. [182] Benes, F.M., The relationship between structural brain imaging and histopathologic findings in schizophrenia research. Harv Rev Psychiatry, 1993. 1(2): p. 100-9. [183] Eastwood, S.L., , Decreased expression of mRNAs encoding non-NMDA glutamate receptors GluR1 and GluR2 in medial temporal lobe neurons in schizophrenia. Brain Res Mol Brain Res, 1995. 29(2): p. 211-23. [184] Farber, N.B., , Antipsychotic drugs block phencyclidine receptor-mediated neurotoxicity. Biol Psychiatry, 1993. 34(1-2): p. 119-21. [185] Olney, J.W. and N.B. Farber, Efficacy of clozapine compared with other antipsychotics in preventing NMDA-antagonist neurotoxicity. J Clin Psychiatry, 1994. 55 Suppl B: p. 43-6. [186] Farber, N.B., , Olanzapine and fluperlapine mimic clozapine in preventing MK-801 neurotoxicity. Schizophr Res, 1996. 21(1): p. 33-7. [187] Olney, J.W. and N.B. Farber, NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia. Neuropsychopharmacology, 1995. 13(4): p. 335-45. [188] Chen, R.W. and D.M. Chuang, Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem, 1999. 274(10): p. 6039-42. [189] Chuang, D.M., The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Ann N Y Acad Sci, 2005. 1053: p. 195-204. [190] Shao, L., L.T. Young, and J.F. Wang, Chronic treatment with mood stabilizers lithium and valproate prevents excitotoxicity by inhibiting oxidative stress in rat cerebral cortical cells. Biol Psychiatry, 2005. 58(11): p. 879-84. [191] Nonaka, S., C.J. Hough, and D.M. Chuang, Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-Daspartate receptor-mediated calcium influx. Proc Natl Acad Sci U S A, 1998. 95(5): p. 2642-7. [192] Nonaka, S. and D.M. Chuang, Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats. Neuroreport, 1998. 9(9): p. 2081-4.


113

[193] Hashimoto, R., , Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation. J Neurochem, 2002. 80(4): p. 589-97. [194] Chuang, D.M., , Neuroprotective effects of lithium in cultured cells and animal models of diseases. Bipolar Disord, 2002. 4(2): p. 129-36. [195] Hashimoto, R., , Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology, 2002. 43(7): p. 1173-9. [196] Bown, C.D., J.F. Wang, and L.T. Young, Attenuation of N-methyl-D-aspartatemediated cytoplasmic vacuolization in primary rat hippocampal neurons by mood stabilizers. Neuroscience, 2003. 117(4): p. 949-55. [197] Ma, J. and G.Y. Zhang, Lithium reduced N-methyl-D-aspartate receptor subunit 2A tyrosine phosphorylation and its interactions with Src and Fyn mediated by PSD-95 in rat hippocampus following cerebral ischemia. Neurosci Lett, 2003. 348(3): p. 185-9. [198] Twiddy, D., , Pro-apoptotic proteins released from the mitochondria regulate the protein composition and caspase-processing activity of the native Apaf-1/caspase-9 apoptosome complex. J Biol Chem, 2004. 279(19): p. 19665-82. [199] Gottlieb, R.A., Programmed cell death. Drug News Perspect, 2000. 13(8): p. 471-6. [200] Eguchi, Y., , ATP-dependent steps in apoptotic signal transduction. Cancer Res, 1999. 59(9): p. 2174-81. [201] Slee, E.A., , Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol, 1999. 144(2): p. 281-92. [202] Yoshida, H., , Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell, 1998. 94(6): p. 739-50. [203] Niquet, J., D.W. Seo, and C.G. Wasterlain, Mitochondrial pathways of neuronal necrosis. Biochem Soc Trans, 2006. 34(Pt 6): p. 1347-51. [204] Nakano-Okuda, Y., , Effects of edaravone on N-methyl-D-aspartate (NMDA)-mediated cytochrome c release and apoptosis in neonatal rat cerebrocortical slices. Int J Dev Neurosci, 2006. 24(6): p. 349-56. [205] Francisconi, S., , Mitochondrial dysfunction and increased sensitivity to excitotoxicity in mice deficient in DNA mismatch repair. J Neurochem, 2006. 98(1): p. 223-33. [206] Luetjens, C.M., , Delayed mitochondrial dysfunction in excitotoxin neuron death: cytochrome c release and a secondary increase in superoxide production. J Neurosci, 2000. 20(15): p. 5715-23. [207] Lewen, A., P. Matz, and P.H. Chan, Free radical pathways in CNS injury. J Neurotrauma, 2000. 17(10): p. 871-90. [208] Johnstone, J.R., , Cochlear action potential threshold and single unit thresholds. J Acoust Soc Am, 1979. 65(1): p. 254-7. [209] Wang, Q., , Reaction time of the Continuous Performance Test is an endophenotypic marker for schizophrenia: a study of first-episode neuroleptic-naive schizophrenia, their non-psychotic first-degree relatives and healthy population controls. Schizophr Res, 2007. 89(1-3): p. 293-8. [210] Levy, F. and G. Hobbes, The influences of social class and sex on sustained attention (vigilance) and motor inhibition in children. Aust N Z J Psychiatry, 1979. 13(3): p. 231-4.

114


[211] Ponton, C., , Maturation of human central auditory system activity: separating auditory evoked potentials by dipole source modeling. Clin Neurophysiol, 2002. 113(3): p. 40720. [212] Ponton, C.W., , Maturation of human cortical auditory function: differences between normal-hearing children and children with cochlear implants. Ear Hear, 1996. 17(5): p. 430-7. [213] Ponton, C.W., , Maturation of human central auditory system activity: evidence from multi-channel evoked potentials. Clin Neurophysiol, 2000. 111(2): p. 220-36. [214] Goodin, D.S., , Age-related variations in evoked potentials to auditory stimuli in normal human subjects. Electroencephalogr Clin Neurophysiol, 1978. 44(4): p. 447-58. [215] Wetzel, N., , The development of involuntary and voluntary attention from childhood to adulthood: a combined behavioral and event-related potential study. Clin Neurophysiol, 2006. 117(10): p. 2191-203. [216] Eggermont, J.J. and C.W. Ponton, Auditory-evoked potential studies of cortical maturation in normal hearing and implanted children: correlations with changes in structure and speech perception. Acta Otolaryngol, 2003. 123(2): p. 249-52. [217] Sharma, A., , Developmental changes in P1 and N1 central auditory responses elicited by consonant-vowel syllables. Electroencephalogr Clin Neurophysiol, 1997. 104(6): p. 540-5. [218] Gomes, H., , Spatiotemporal maturation of the central and lateral N1 components to tones. Brain Res Dev Brain Res, 2001. 129(2): p. 147-55. [219] Tonnquist-Uhlen, I., , Maturation of human central auditory system activity: the Tcomplex. Clin Neurophysiol, 2003. 114(4): p. 685-701. [220] Velakoulis, D., , Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, firstepisode psychosis, and ultra-high-risk individuals. Arch Gen Psychiatry, 2006. 63(2): p. 139-49. [221] Hoffman, R.E., , Transcranial magnetic stimulation of left temporoparietal cortex in three patients reporting hallucinated "voices". Biol Psychiatry, 1999. 46(1): p. 130-2.

In: Schizoaffetive Disorders Editor: Kam-shing Yip

ISBN 978-1-60456-948-3 © 2009 Nova Science Publishers, Inc.

Chapter 5

NEUROPSYCHOLOGICAL DEFICITS IN SCHIZOAFFECTIVE DISORDER Barton W. Palmer* and Gauri N. Savla University of California, San Diego, Department of Psychiatry 3350 La Jolla Village Drive, 116A-1, San Diego, CA 92009, USA

INTRODUCTION As reflected in the World Health Organization’s (WHO) International Classification of Diseases (ICD-10) [1] and the American Psychiatric Association’s (APA) Diagnostic and Statistical Manual (DSM-IV-TR) [2] the focus in diagnosis of schizoaffective disorder, as well as its treatment, is on the presence of affective and psychotic symptoms. By contrast, neuropsychological deficits are not generally among the first characteristic which comes to mind when thinking about schizoaffective disorder. Nonetheless, as with schizophrenia, a majority of persons with schizoaffective disorder exhibit mild-to-moderate neuropsychological deficits [3-8]. These neuropsychological deficits may have a deleterious effect on everyday functioning beyond the effects of primary psychopathology, and thus represent potentially important, albeit traditionally ignored, targets of primary intervention [9, 10]. In the following pages we provide an overview of neuropsychological functioning in schizoaffective disorder in terms of conceptual history, contemporary findings regarding neuropsychological deficits in schizoaffective disorder, and the relationship of neuropsychological deficits to level of everyday functioning. We also consider the effects of treatment on neuropsychological deficits in schizoaffective disorder, including recent efforts to develop pharmacologic and psychosocial (cognitive rehabilitative) interventions that directly target the neuropsychological deficits associated with psychotic disorders.

*

Email: [email protected]

116

Barton W. Palmer and Gauri N. Savla

HISTORICAL CONSIDERATION Origin and Controversies of the Construct of Schizoaffective Disorder The distinction between schizophrenia and mood disorders is generally traced to Kraepelin’s division of dementia praecox from what he labeled ‘manic-depressive insanity’ [11, 12]. Descriptions of persons whose symptoms involved a combination of the two syndromes were published virtually simultaneously with Kraepelin’s efforts to distinguish the two conditions (e.g. see Dunton [13]). Kraepelin [14] acknowledged the existence of patients with a mixture of such symptoms, but generally held that a distinction could be drawn based on course and outcome of the condition. In particular he posited that dementia praecox was characterized by a pattern of progressive deterioration versus a more benign course and outcome characterizing affective disorders [15, 16]. (As discussed below, subsequent evidence suggests that the typical long-term course of schizophrenia is more stable than Kraepelin initially believed.) Although its conceptual roots are even older [16-18], the term “schizoaffective” was introduced in 1932 by Kasanin [19] when he described a series of cases of persons evidencing what he labeled “acute schizoaffective psychoses.” Kasanin did not provide a detailed description of cognitive functioning among these patients, but he did note that each had average or superior intelligence, and that intellectual functions were “intact” during the clinical mental status examinations. The patients were also noted to have good premorbid psychosocial functioning, with acute onset. This relative sparing of intellectual functions, as well as the acute (rather than insidious) onset stood in contrast to what Kasanin and Bowman [20] contemporaneously described as “constitutional schizophrenia,” the latter resembling more recent descriptions of “ “type II” or deficit syndrome: schizophrenia [21, 22]. Contemporary diagnostic criteria for schizoaffective disorder emphasize the prominence and pattern of schizophrenic and affective symptoms [1, 2], rather than the acute onset or longterm course, so the degree to which the syndrome described by Kasanin actually overlaps with the contemporary concept of schizoaffective disorder is unclear. The concept of schizoaffective disorder has been controversial from its inception [16, 23]. For instance, in 1936, Hunt and Appel [24] stated, “As to the actual existence of this mixed group of schizo-affective or thymo-phrenic psychoses there can be no doubt” (p. 314), whereas one of the discussants for the same paper (whose comments were included at the end of the published manuscript) asserted “though the symptoms of manic-depression and of schizophrenia may blend, the roots are different” (p. 337). Today, there remains little disagreement that some patients present with a mixture of symptoms of schizophrenia and mood disorders, but there remains considerable debate and uncertainty regarding whether schizoaffective disorder is a distinct condition, a variant of schizophrenia, or a variant of psychotic mood disorders [7, 23, 25]. The appropriate grouping of schizoaffective disorder may also depend on subtype (bipolar or depressed) [26]. There are also suggestions that a categorical nosology is fundamentally flawed, and that a multidimensional model might have better construct validity and clinical/research heuristic value [11, 27, 28].

Neuropsychological Deficits in Schizoaffective Disorder

117

Historical Considerations of Schizophrenia as a Neurocognitive Disorder The historical view of neurocognitive impairment in schizophrenia has itself had a long and circuitous history. Kraepelin [14] described dementia praecox as involving impairment in “volition” and “will,” and Zec [29] has made an cogent argument that Kraepelin’s views very much parallel contemporary descriptions of schizophrenia as a disorder of executive functions. Kraepelin [14] also suggested that dementia praecox was associated with neuropathology in the frontal, as well as the temporal brain regions, writing, “If it should be confirmed that the disease attacks by preference the frontal areas of the brain, the central convolutions and the temporal lobes, this distribution would in a certain measure agree with our present views about the site of the psychic mechanisms which are principally injured by the disease. On various grounds it is easy to believe that the frontal cortex, which is specially well developed in man, stands in closer relation to his higher intellectual abilities…On the other hand, the peculiar speech disorders resembling sensory aphasia and the auditory hallucinations, which play such a large part, probably point to the temporal lobe being involved” (p. 219).

Together with the cortical-subcortical connections, the frontal and temporal regions remain among the areas and systems of primary focus in contemporary neurophathological models of schizophrenia [30-35]. Despite the initial momentum toward a neurocognitive model of schizophrenia provided by Kraepelin’s descriptions of dementia praecox, and consistent psychometric reports documenting the frequency of intellectual/cognitive impairments among persons with schizophrenia [36-41], the first half of the 20th century included considerable debate regarding psychogenic versus biological (“organic”) models of schizophrenia [39, 42-44]. Through the late 1960s, there was a tendency among some researchers and clinicians, at least within the United States, to interpret deficient performance on neuropsychological tests by patients with schizophrenia and other “functional psychosis” as reflecting deficits engaging in the tasks (due to symptoms and motivation) rather than reflecting the genuine neurocognitive dysfunction associated with “organic” dysfunction [38, 45, 46]. The “functional” versus “organic” argument faded in the last third of the 20th century with the rise in biological psychiatry and cognitive neuroscience, as well as accumulating evidence that patients with “functional psychoses” had neurocognitive deficits that were often indistinguishable from those with documented “organic” brain injuries [38, 45].

CONTEMPORARY FINDINGS ON NEUROPSYCHOLOGICAL ASPECTS OF SCHIZOAFFECTIVE DISORDER Neuropsychological Deficits in Schizoaffective Disorder and Schizophrenia The historical and ongoing controversy regarding the concept of schizoaffective disorder has substantially influenced the neuropsychological literature on this condition. In particular, the vast majority of neuropsychological studies in which patients with schizoaffective disorder have been examined as a group distinct from schizophrenia were focused on

118


evaluating the validity of that distinction from a neurocognitive perspective [3-8, 26, 47-56]. The findings from such studies are consistent in showing that the level, pattern, and frequency of neuropsychological impairment among patients with schizoaffective disorder are indistinguishable from those seen in patients with schizophrenia [4, 5, 7, 8, 48, 51-54]. A few studies have found isolated group mean differences between schizoaffective versus schizophrenia patients on specific neurocognitive test scores [3, 50, 55, 56], but such differential impairment findings generally emerged from post-hoc analyses (rather than as confirmation of specific a priori hypotheses) within the context of many non-significant neurocognitive differences between the two groups. No clear pattern of consistent differences on any particular cognitive ability emerged across studies. Moreover, schizophrenia and schizoaffective patients show similar impairment in mean neuropsychological performance relative to healthy controls [3, 7, 47, 51, 57, 58], and with isolated exceptions [56] relative to those with bipolar disorder [51, 58] and/or unipolar depression [5, 51, 54]. In part due to relatively small subgroup sample sizes, most of the studies comparing neuropsychological performance of patients with schizoaffective disorder to those with schizophrenia have emphasized whole groups, rather than subtype analyses (such as depressed versus bipolar subtypes of schizoaffective disorder, and/or standard schizophrenia subtypes). However, there is some evidence those persons with schizoaffective disorder and those with paranoid subtype of schizophrenia may, on average, have slightly better neuropsychological performance than those with undifferentiated or disorganized subtypes of schizophrenia [6, 47]. Indeed, one of the rationale for considering schizoaffective disorder as a subtype of schizophrenia, at least from the perspective of neuropsychological data, is that there exists at least as much heterogeneity within the standard category of schizophrenia as between schizoaffective disorder and schizophrenia. Because of such considerations, many of the neuropsychological studies of schizophrenia include and combine patients with schizoaffective disorder within the schizophrenia group [59].

Severity and Prevalence of Neuropsychological Deficits As true with virtually every dimension of schizophrenia and schizoaffective disorder, even within the traditional clinical subgroups, there is substantial within-group heterogeneity in terms of the range and pattern of neuropsychological functioning [6, 60]; the neuropsychological deficits can range from minimal to severe impairment. On average, however, patients with schizophrenia evidence mild-to-moderate neuropsychological deficits across a range of more specific cognitive abilities [61-63]. Based on a comprehensive metaanalysis of 204 studies published between 1980 and 1997, Heinrichs and Zakzanis [64] concluded that 60-80% of people with schizophrenia have at least mild neuropsychological deficits. That conclusion is consistent with findings from our research group at the University of California, San Diego [60] and others [6, 65, 66] indicating that approximately a quarter of patients with schizophrenia or schizoaffective disorder retain normal range neuropsychological profiles. The degree or proportion of such persons who would have had even higher neuropsychological abilities in the absence of schizophrenia or schizoaffective disorder remains a point of controversy [65-68].


119

Specific Neuropsychological Abilities and their Measurement There is no pathognomonic neuropsychological sign of schizophrenia and/or schizoaffective disorder, i.e., no pattern of neuropsychological deficits is unique to schizophrenia and/or schizoaffective disorder, nor has one been found that is common to all patients or an independently identifiable subtype [69, 70]. However, some of the most frequently impaired abilities include attention, working memory, auditory and visual episodic learning and memory, psychomotor speed, and executive functions [61, 63, 64, 71]. Comprehensive review of the multitude of neuropsychological tests used to operationalize these and other potentially relevant neuropsychological constructs, and the range of neuroantomic and neurophysiologic substrates of each, would go beyond the intended scope of the present chapter (interested readers are referred to Lezak [72] and to Sharma and Harvey [73]). Nonetheless, as the labels for neuropsychological constructs and measures are not used in a fully uniform or consistent way across all research or clinical settings, it may be helpful to consider some examples of the array of different tests used to measure a few of these more specific neuropsychological constructs.

Attention As true of the standard labels for many neuropsychological abilities, “attention” is a broad term that covers a number of more specific behaviors, subsumed by an array of different neurophysiologic processes, and the ways in which the term is used colloquially, in clinical psychology and clinical neuropsychology, and in cognitive neuroscience are not always fully synonymous [74, 75]. One skill generally included under the rubric of attention is “vigilance.” Vigilance involves maintaining “response readiness” for a particular stimulus or event [75]. An example of a vigilance task used widely in schizophrenia research is the identical pairs version of the Continuous Performance Test (CPT-IP) [76], during which the examinee must rapidly respond when he or she detects a pair of identical successive numbers during computer presentation of a series of numbers. Because first-degree relatives of persons with schizophrenia also show impaired CPT-IP performance, the latter task has been suggested as a potential endophenotype measure for use in genetic studies of psychosis [77]. Another common meaning or form of “attention” is the ability to choose or filter relevant from irrelevant stimuli. The idea that schizophrenia may be fundamentally characterized by deficits in selective attention (or “filtering”) has a long history [14, 78, 79]. One example of such a task the Digit Span Distractibility Task [80], in which the examinee is presented with two intermingled strings of digits, one spoken with a male and the other with a female voice. The task is to ignore (filter out) the man’s voice, and attend to and immediately recall the number string spoken by the woman. (This task was used in one of the early randomized clinical trails suggesting second generation antipsychotic medications might have a beneficial, albeit quite modest, effect on neurocognitive deficits [81].) It might also be noted that outside the context of clinical neuropsychological tests, there has also been considerable interest and research on pre-conscious or sensory gating mechanism in schizophrenia and related psychoses [82]. An advantage of the latter forms of measures, in addition to the fact that they target more circumscribed neurocircuits or systems, is that the measures of sensory/pre-conscious are not dependent on the patient’s conscious effort. It is therefore easier to disintangle primary attentional (or pre-attentional) deficits from the potential interference of psychotic symptoms on sustained effort. (Interested readers are

120


referred to Braff and Light [82] for an excellent review of the use of such measures in schizophrenia research.)

Working Memory “Working memory” is a concept closely related to attention as well as to executive functioning; it involves the ability to hold and manipulate information in one’s mind for brief durations of time (generally on the order of seconds) while that information is processed [83, 84]. The essential form of Baddeley’s [83, 84] widely used model of working memory consists of three primary components: (a) two resource limited systems for short term storage and manipulation of auditory versus visual information (the “phonological loop” and “visuospatial sketchpad”), and a “central executive” responsible for allocation of resources between the auditory versus visual systems. The prototypic example of auditory working memory is the Digit Span task from the various incarnations of David Wechsler’s intelligence and memory scales [85]. In this task the examinee is asked to repeat strings of numbers (or increasing length) in forward order, and later in reverse order. (This forward task is sometimes describes as a meaure of “basic attention,” but it is highly correlated with the backward span task so may be more accurately described as a transient working memory task [86].) A common form of spatial working memory task used in schizophrenia research involves presenting a stimulus somewhere on a visual array, and then requiring the examinee to recall the position after a delay (with or without an intervening distracter task) [87]. There is also a spatial analogue to the Digit Span task on the Wechsler Memory Scale – Third Edition (WMS-III) [88], although there has been some debate regarding whether the Spatial Span and Digit Span tasks are fully analogous as measures of spatial and auditory working memory, resepctively [89]. As noted in a recent meta-analysis from Lee and Park [90], working memory deficits in schizophrenia are common; deficits in at least the visual form of working memory have also been reported specifically for patients with schizoaffective disorder [7, 50]. Indeed, some investigators and theorists have suggested that deficits in working memory may underlie many of the other schizophrenia-related deficits including executive dysfunction and some aspects of thought disorder [91]. Auditory and Visual Episodic Declarative Learning and Memory Although cognitive neuroscience has delineated a wider typology of memory systems, (see Squire [92]), much of the research on memory in schizophrenia has been on declarative episodic memory for auditory or visually presented stimuli, such as learning and recall of word lists, memory of story passages, and/or memory of geometric designs [93]. For example, prototypical word list learning tasks involve reading a word list to an examinee, asking him or her to repeat back as many words as he or she can recall, and then repeating that procedure over several trials to evaluate his or her ability to learn the information [9496]. Some versions include implicit semantic categories which may aid learning and recall if the examinee thinks to organize his or her learning or recall strategy in reference to semantic relationships [94, 96]. Research is quite consistent in demonstrating patients with schizophrenia often have impaired performance on tasks of episodic declarative memory [93]. For instance, in their meta-analyses of studies published between 1980 and 1997 that compared neuropsychological


121

performance among schizophrenia patients versus healthy comparison subjects, Heinrichs and Zakzanis [64] found the mean effect size (corrected for sample size differences) for verbal memory was d = 1.41 (the lowest two effect sizes were Block Design, a measure of visualconstructional ability, d = 0.46, and Vocabulary, a measure of crystallized verbal ability, d = 0.53). In Fioravanti ’s [71] meta-analysis of studies published between 1990 and 2003, they also found the highest mean effect sizes in terms of memory tests, but they also noted the considerable heterogeneity in observed effect sizes between various studies It may be important to distinguish between difficulties with acquisition of new information and/or efficiency of its retrieval, from actual loss of the memory trace. To distinguish encoding, forgetting, and retrieval deficits, clinicians as well as researchers frequently compare delayed versus immediate recall scores, and free-recall versus recognition scores [97]. For instance, a substantial decline in free recall performance from the immediate to delayed recall trials may indicate “rapid forgetting”; the latter is considered a hallmark of Alzheimer’s disease [98], but is rare among persons with schizophrenia or schizoaffective disorder [62]. In that sense of the word “memory” as “forgetting”, memory tends to be relatively unaffected in schizophrenia. Of note, the latter suggestion is also consistent with Kraepelin’s [14] observations of patients with dementia praecox, as he wrote “Memory is comparatively little disordered. The patients are able, when they like, to give a correct detailed account of their past life, and often know accurately to a day how long they have been in the institution (pp. 17-18).” [Although there is limited data specifically examining savings (percent retention) for schizoaffective disorder patients separately, it appears that if anything, even fewer schizoaffective disorder patients show substantial forgetting than among patients with schizophrenia [3)].] Alemen ’s [93] meta-analysis of different types of memory test scores suggested that free-recall measures yield the largest mean effect size (overall free recall d=1.21; verbal free recall d = 1.20 to 1.22; visual free recall d = 1.00 to 1.09). The mean recognition memory effect size (patients versus healthy comparison subjects) found in Alemen ’s [93] metaanalysis was d=0.64. Although the latter is within the range traditionally labeled as a “medium” effect size [99], it contrasts with the “large” mean effect size, d=1.21, seen for free recall. Paralleling the findings of Fioravanti et al, however, Alemen noted considerable heterogeneity in the size of effect sizes observed among the individual studies.

Psychomotor Speed The term “psychomotor speed” may be conceptualized as having two primary components: (a) mental processing speed (independent of the motor requirements), and (b) efficiency of psychomotor integration (requiring translation of thoughts or intentions into action) [63]. Two of the most widely used measures of psychomotor speed the Digit Symbol task and the Trail Making Test. As noted in Boake’s [100] and Tulsky ’s [101] fascinating overviews of the origins of cotemporary of intelligence tests, the present form of the widely used Digit Symbol-Coding task [102] has undergone only minor modifications since first introduced in the early 1900s. The test consists of a series of nine numbers printed at the top of a page, each paired with a unique symbol. Below this number-symbol key, is a matrix of numbers with blank boxes below each number. The examinee’s task is to rapidly fill in the boxes below each number with the symbol that is paired with it per the key. Very rapid performance taps into visualmemory, as quick response is facilitated by learning the pairings (rather than requiring

122


repeated checking of the key). However, the test is most frequently interpreted in terms of psychomotor speed. The stimuli for the Trail Making Test also have undergone relatively little modification over the past 60 to 70 years [103]. The most widely used contemporary form consists of two parts [104]. In part A, the examinee is required to rapidly connect a series of circled numbers, without lifting his or her pencil from the page, in ascending order. Part B consists of intermixed circled letters and numbers. The examinee’s task is to rapidly alternate between the letters and numbers in ascending order, i.e., drawing a line from the number 1 to the letter A, to the number 2, to the letter B, and so forth.. As the latter task requires repeated switching between two series, it is sometimes described as a test of “mental flexibility” and is thereby categorized with “executive functions.” Psychomotor speed tasks are purported to be among the most sensitive to virtually any form of neurological injury [72]. Indeed, in a recent report of a meta-analysis of schizophrenia studies employing Digit Symbol, Dickinson [105] concluded “digit symbol coding yields the largest impairment documented in the schizophrenia clinical neuropsychology literature” (p. 539).

Executive functions Pinning down a precise definition of “executive functions” is difficult. Faced with a similar challenge in a prior review of executive dysfunction in schizophrenia (see Palmer and Heaton [106]), we previously suggested the following functional description of executive skills as “those cognitive processes which permit an adaptive balance of initiation, maintenance, and shifting of responses to environmental demands permitting goal directed behavior” (pp. 63-64). We also previously noted that “abilities underlying such activities may include: search of knowledge, abstraction and planning, evaluation/decision-making skills, initiation, self-monitoring, mental-flexibility and inhibition of immediate/reflex responses in pursuit of a longer term goal” (p. 53). There is also an overlap between the construct of executive functions and working memory, in that the “central executive” aspect of working memory is itself a type of executive function [107]. The Wisconsin Card Sorting Test (WCST) [108, 109] has perhaps been the single most widely used measure of a specific neuropsychological ability in schizophrenia research [110]. This task consists of four stimulus card which vary in terms of the shape (form) of objects, the number, and the color of the depicted objects. The examinee’s task is to sort a series of cards in a deck in reference to the four stimulus cards. No information is provided to the examinee regarding the potential dimensions against which to sort, but after each response the examinee is told whether the card placement was correct or incorrect (thus, the examinee must abstract and test out different possible sorting rules). Unbeknownst the examinee, the sorting principle changes several times during the test; thus successful performance also requires him or her to be able to abandon a previously adaptive response in favor of the new implicit rule. The test yields a number of different scores, but the one most frequently examined in reference to schizophrenia is the number of “preservative responses” (reflecting a failure to adaptively switch sorting strategies) [111]. The first published study documenting that patients with schizophrenia show impaired performance on the WCST was reported over half a century ago [37]. A number of published reports have documented that patients with schizophrenia and schizoaffective disorder have equivalent impairment on this task [3, 4, 7, 48, 49].


123

Another widely used “executive function” test with a long history in schizophrenia research is the Stroop task [112, 113]. There are a number of different forms of the Stroop task, but the core common component involves presenting the examinee with a series of words that refer to color names; the words are printed in ink of different colors (usually a color discordant with the content of the word), such as the word “blue” printed in green ink. The examinee’s task is to ignore the meaning of the word, and instead vocalize the name of the color of ink it is printed in. Although there is not full consensus on the precise cause of the “Stroop effect”, this task can be quite difficult because it requires inhibition of what is usually a more automatic (or quickly processed) reading response, in favor of a less automatic or habitual (and slower) color naming task demand [112, 114]. (Note, this task is sometimes categorized, perhaps appropriately as a measure of selective attention [113]. The uncertainty regarding which cognitive function under which to categorize such a widely used measure further illustrates the need to attend to the specific manner in which neuropsychological constructs are operationalized, not simply the verbal summary labels.)

Course of Neuropsychological Deficits in Schizophrenia and Schizoaffective Disorder Premorbid and Peri-onset Cognitive Deficits A wealth of data support the prevailing model of schizophrenia as a neurodevelopmental condition [110, 115-117]. Included in that support is evidence of subtle premorbid impairment in cognitive functions among some of those who subsequently develop schizophrenia or schizoaffective disorder [118-120]. For instance, Reichenberg [53] presented an interesting retrospective analysis of premorbid cognitive and behavioral data collected by the Israeli draft board (when subsequent patients were age 16 or 17 years) on persons who were subsequently developed schizoaffecitve disorder, schizophrenia, or bipolar disorder. The the patients with schizoaffective disorder and schizophrenia showed premorbid deficits relative to non-patient matched comparison persons, whereas the persons who developed bipolar disorder manfests less premorbid cognitive or behaviorl dysfunction. Bilder et al [118] estimated that approximately 60% of the cognitive deficits in schizophrenia or schizoaffective disorder accumulates during early childhood and adolescence, but they also provide evidence that a further decline in neurocognitive functioning typically occurs around the time of initial onset (“first episode”) of the psychopathologic symptoms. Long-term Course of Cognitive Deficits As noted above, Kraepelin’s view was that dementia praecox was characterized by a progressively deteriorating course of mental functioning. This pessimistic view of the longterm prognosis for schizophrenia was influential throughout much of the 20th century [121, 122]. However, a wealth of contemporary neuropsychological data reported in the last two decades has persuasively refuted that view. Among non-institutionalized individuals (who make up the bulk of patients with schizophrenia today [123, 124]), patterns of neuropsychological ability tend to stay remarkably stable even with fluctuations in severity of symptoms; this is true regardless of which specific neurocognitive abilities are examined

124


[125-128]. The one exception to this generally positive and remarkably consistent finding is that elderly patients who have been chronically institutionalized appear to be at higher risk for progressive cognitive decline than expected for their age [129]. This decline does not appear to be attributable to an increased risk of Alzheimer’s disease [129].

RELATIONSHIP IN EVERYDAY FUNCTIONING Neuropsychological abilities are among the strongest predictors of functional independence in schizophrenia, such that persons with worse neuropsychological abilities tend to have lower levels of everyday functioning, e.g., in basic and instrumental activities of daily living, as well as the broader aspects of social/occupational functioning [10, 130, 131]. Neurocognitive deficits also appear to be among the strongest predictors of functional outcome among patients with bipolar disorder [132, 133]. Severity of negative symptoms is also associated with worse functional independence. However, outside the context of acute exacerbations of psychoses, severity of positive symptoms (such as delusions and hallucinations) have little discernable influence on functioning [10, 131]. Findings in regard to the relative importance of specific neurocognitive abilities as predictors of specific or overall everyday functioning are more equivocal [134]. Based on the frequency with which specific neuropsychological abilities have been reported as significant correlates of specific components of everyday functioning, there had been some suggestions that verbal episodic and working memory, certain executive functions, and/or certain aspects of attention/vigilance might be particularly important for certain types of independent functioning and community outcome [10]. Although such differential relationships seem likely from a rational viewpoint, efforts to empirically document differential relationships are hampered by the multifactorial nature of most neuropsychological tests [135, 136], and the long-recognized but persistent problem of a lack of measures of different cognitive abilities with documented psychometric equivalence [137]. In clinical application, as well as future research, further clarity might be garnered through deconstruction of the neurocognitive and functional constructs into more specific terms, e.g., by examining the relative functional impact of different forms of “executive functions” (cf. Jefferson et al [138]). Paralleling the approach taken in clinical neuropsychological assessments, particularly emphasized in the “process approach” [139], it may also be helpful to examine the patterns of specific errors on neuropsychological tests and functional outcomes.

TREATMENT ISSUES Effects of Psychotropic Medications The classic empirical literature on the neuropsychological effects of conventional neuroleptic medications in patients with schizophrenia yielded somewhat equivocal results, but the overall conclusion was generally that any deleterious or beneficial were minimal relative to the existing inter-patient heterogeneity in cognitive functioning [140, 141]. Results


125

from a more recent meta-analysis, however, suggest that there might be some beneficial neurocognitive effects which at least warrant further empirical inquiry [142]. Over the past ten years, there have been a number of studies and meta-analyses (e.g. see Woodward [143]) on the neuropsychological effects of second-generation (a.k.a. ‘atypical’) antipsychotic medications. There appears to be some evidence of modest neurocognitive improvements, but there is no full consensus on such efficacy [144]. Most researchers seem to agree that any improvement that is present is modest relative to the overall cognitive deficits. That is, the effects are at best characterizable as improvements, rather than a “normalization” of the cognitive functions. One recently published large scale head-to-head comparison of four antipsychotic medications (three second generation, and one conventional) showed modest improvements with all compounds, but no differential cognitive benefit from any one of the antipsychotic medications over the others (including the conventional neuroleptic.) [145]. Among the mood stabilizers, lithium appears to have some modest adverse effects on psychomotor/mental processing speed, and episodic verbal memory [146-148]. There are also potential subtle cognitive effects from other mood stabilizers and antidepressant medications, but the overall neuropsychological effect of such medications does not appear to be substantial relative to the overall impairments associated with schizophrenia or bipolar disorder [149].

Neuropsychological Deficits as a Target of Treatment As exemplified by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) projects, there has been recent interest among academic researchers, government agencies, and the pharmaceutical industry in the possibility of developing medications which directly target the cognitive deficits associated with schizophrenia [9, 150, 151]. This line of inquiry remains in its early stages, but the breadth and magnitude of these efforts provides reason for optimism about the long-term possibility of developing effective pharmacologic treatments for the neurocognitive deficits in schizophrenia and schizoaffective disorder. Beyond pharmacologic treatments, there is an also increased interest in the potential added value of non-pharmacologic interventions in reducing neurocognitive deficits in schizophrenia, or at least reducing their functional impact [152, 153]. Restorative interventions, as the name implies, are aimed at “restoring” (or at least improving) cognitive functions toward “normal” levels. Given the neurodevelopmental nature of the cognitive deficits in schizophrenia and schizoaffective disorder, the notion of “restoration” may not be fully applicable [152, 153], so these may be more appropriately conceptualized as “cognitive enhancing” interventions. Compensatory approaches, also called “cognitive prosthetics” aim at training patients to bypass their deficits and word around them. Environmental approaches generally fall under the broad realm of compensatory approaches, but involve overt manipulations in the patients’ home, school or work environment to reduce cognitive demands [152, 153]. While most studies of the current cognitive interventions demonstrate an improvement in cognitive test performance and/or a reduction in the functional impairment, additional research is still needed to document the degree of, and factors fostering real-world

126


generalizability of skills and long-term maintenance of effects in terms of real-world functioning (see review by Twamley [152]).

CONCLUSION Neuropsychological impairment is a functionally and clinically important dimension of schizoaffective disorder. Although the psychotic and affective symptoms associated with this condition are often appropriately the initial focus of acute treatment, stabilization of psychopathology should be viewed as one of the tasks, not the sole task, in clinical management of this condition. Although there is considerable variability between patients in terms of the level and pattern of impairment, most individuals have some areas of relative strength. Thus, while pharmacologic interventions resulting in substantial, functionally relevant, degrees of neurocognitive improvement are still in the relatively early phases of development, neuropsychological assessment can be of considerable aid in treatment planning and management even in the absence of readily available methods to eliminate such deficits [154]. Because of the relevance of cognitive deficits to functional living skills, neuropsychological assessment should be considered as an integral part of overall patient care to aid in long-term treatment planning, and to identify neuropsychological areas of cognitive strengths that may be utilized to compensate for other deficits.

REFERENCES [1]

[2]

[3] [4]

[5]

[6]

[7]

[8]

World Health Organization. International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Version for 2007. Available via internet at: http://www.who.int/classifications/icd/en/ [Accessed July 16, 2007] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders - Text Revision. 4 ed. Washington, DC: American Psychiatric Association 2000. Beatty WW, Jocic Z, Monson N, Staton RD. Memory and frontal lobe dysfunction in schizophrenia and schizoaffective disorder. J Nerv Ment Dis. 1993 Jul;181(7):448-53. Beatty WW, Jocic Z, Monson N, Katzung VM. Problem solving by schizophrenic and schizoaffective patients on the Wisconsin and California Card Sorting Tests. Neuropsychology. 1994 Jan;8(1):49-54. Evans JD, Heaton RK, Paulsen JS, McAdams LA, Heaton SC, Jeste DV. Schizoaffective disorder: a form of schizophrenia or affective disorder? J Clin Psychiatry. 1999 Dec;60(12):874-82. Goldstein G, Jo Shemansky W, Allen DN. Cognitive function in schizoaffective disorder and clinical subtypes of schizophrenia. Archives of Clinical Neuropsychology. 2005 Mar;20(2):153-9. Gooding DC, Tallent KA. Spatial working memory performance in patients with schizoaffective psychosis versus schizophrenia: A tale of two disorders? Schizophr Res. 2002 Jan;53(3):209-18. Miller LS, Swanson-Green T, Moses JA, Faustman WO. Comparison of cognitive performance in RDC-diagnosed schizoaffective and schizophrenic patients with the


[9]

[10] [11] [12] [13] [14] [15]

[16] [17] [18] [19] [20] [21]

[22] [23] [24] [25] [26] [27]

[28]

127

Luria-Nebraska Neuropsychological Battery. J Psychiatr Res. 1996 Jul-Aug;30(4):27782. Buchanan RW, Davis M, Goff D, Green MF, Keefe RS, Leon AC, A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull. 2005 Jan;31(1):5-19. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. 1996 Mar;153(3):321-30. Craddock N, Owen MJ. The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry. 2005 May;186:364-6. Mondimore FM. Kraepelin and manic-depressive insanity: an historical perspective. Int Rev Psychiatry. 2005 Feb;17(1):49-52. Dunton WR. The Cyclic Forms of Dementia Praecox. American Journal of Insanity. 1910;66:465-76. Kraepelin E. Dementia praecox and paraphrenia. New York: Krieger 1971/1919. Berrios GE, Luque R, VillagrÃ¡n JM. Schizophrenia: A conceptual history. International Journal of Psychology & Psychological Therapy. 2003 Dec;3(2):111-40. Tamura H. A conceptual history of schizoaffective psychosis. International Medical Journal. 1998 Sep;5(3):217-27. Maj M. The evolution of some European diagnostic concepts relevant to the category of schizoaffective psychoses. Psychopathology. 1984 Jul-Aug;17(4):158-67. Maj M. Evolution of the American concept of schizoaffective psychosis. Neuropsychobiology. 1984;11(1):7-13. Kasanin J. The acute schizoaffective psychoses. Am J Psychiatry. 1933;90(1):97-126. Bowman KM, Kasanin J. Constitutional schizophrenia. Am J Psychiatry. 1933;90(3):645-58. Buchanan RW, Strauss ME, Kirkpatrick B, Holstein C, Breier A, Carpenter WT, Jr. Neuropsychological impairments in deficit vs nondeficit forms of schizophrenia. Arch Gen Psychiatry. 1994, Oct;51(10):804-11. Crow TJ. The two-syndrome concept: origins and current status. Schizophr Bull. 1985;11(3):471-86. Lake CR, Hurwitz N. Schizoaffective disorders are psychotic mood disorders; there are no schizoaffective disorders. Psychiatry Res. 2006 Aug 30;143(2-3):255-87. Hunt RC, Appel KE. Prognosis in the psychoses lying midway between schizophrenia and manic-depressive psychoses. Am J Psychiatry. 1936;93(313-339). Marneros A. The schizoaffective phenomenon: the state of the art. Acta Psychiatr Scand Suppl. 2003(418):29-33. Maj M. Neuropsychological functioning in schizoaffective disorder, depressed type. Acta Psychiatr Scand. 1986 Nov;74(5):524-8. Allardyce J, Gaebel W, Zielasek J, van Os J. Deconstructing Psychosis Conference February 2006: The Validity of Schizophrenia and Alternative Approaches to the Classification of Psychosis. Schizophr Bull. 2007; 33(3):863-7. Kempf L, Hussain N, Potash JB. Mood disorder with psychotic features, schizoaffective disorder, and schizophrenia with mood features: trouble at the borders. Int Rev Psychiatry. 2005 Feb;17(1):9-19.

128 [29]

[30] [31]

[32]

[33] [34] [35]

[36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46]

[47]

Barton W. Palmer and Gauri N. Savla Zec RF. Neuropsychology of schizophrenia according to Kraepelin: disorders of volition and executive functioning. Eur Arch Psychiatry Clin Neurosci. 1995;245(45):216-23. Halliday GM. A review of the neuropathology of schizophrenia. Clin Exp Pharmacol Physiol. 2001 Jan-Feb;28(1-2):64-5. Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl). 2004 Jun;174(1):151-62. Lichter DG, Cummings JL. Introduction and overview. In: Lichter DG, Cummings JL, eds. Frontal-subcortical circuits in psychiatric and neurological disorders. New York: Guilford Press 2001:1-43. Shad MU, Tamminga CA, Cullum M, Haas GL, Keshavan MS. Insight and frontal cortical function in schizophrenia: a review. Schizophr Res. 2006 Sep;86(1-3):54-70. Weinberger DR, Aloia MS, Goldberg TE, Berman KF. The frontal lobes and schizophrenia. J Neuropsychiatry Clin Neurosci. 1994 Fall;6(4):419-27. Winterer G, Coppola R, Egan MF, Goldberg TE, Weinberger DR. Functional and effective frontotemporal connectivity and genetic risk for schizophrenia. Biol Psychiatry. 2003 Dec 1;54(11):1181-92. Bolles M, Goldstein K. A study of the impairment of "abstract behavior" in schizophrenic patients. Psychiatr Q. 1938;12:42-65. Fey ET. The performance of young schizophrenics and young normals on the Wisconsin Card Sorting Test. J Consult Psychol. 1951 Aug;15(4):311-9. Heaton RK, Baade LE, Johnson KL. Neuropsychological test results associated with psychiatric disorders in adults. Psychol Bull. 1978 Jan;85(1):141-62. May JV. The dementia praecox-schizophrenia problem. Am J Psychiatry. 1931;11(3):401-46. Rabin AI. Test-score patterns in schizophrenia and non-psychotic states. Journal of Psychology: Interdisciplinary and Applied. 1941;12:91-100. Rabin AI. The use of the Wechsler-Bellevue scales with normal and abnormal persons. Psychol Bull. 1945 Jul;42(7):410-22. Babcock H. Dementia praecox: a psychological study. Oxford, England: Science Press 1933. Bleuler EP. The physiogenic and psychogenic in schizophrenia. Am J Psychiatry. 1930;10(2):203-11. Spielmeyer W. The problem of the anatomy of schizophrenia. The Journal of Nervous and Mental Disease. 1930;73(3):241-4. Leonberger FT. The question of organicity: Is it still functional? Professional Psychology: Research and Practice. 1989 Dec;20(6):411-4. Watson CG, Thomas RW, Andersen D, Felling J. Differentiation of organics from schizophrenics at two chronicity levels by use of the Reitan-Halstead organic test battery. J Consult Clin Psychol. 1968 Dec;32(6):679-84. Bornstein RA, Nasrallah HA, Olson SC, Coffman JA, Neuropsychological deficit in schizophrenic subtypes: Paranoid, nonparanoid, and schizoaffective subgroups. Psychiatry Res. 1990 Jan;31(1):15-24.

Neuropsychological Deficits in Schizoaffective Disorder [48]

[49]

[50]

[51]

[52]

[53]

[54] [55]

[56]

[57] [58]

[59]

[60]

[61] [62]

[63]

129

Brenner CA, Lysaker PH, Wilt MA, O'Donnell BF. Visual processing and neuropsychological function in schizophrenia and schizoaffective disorder. Psychiatry Res. 2002 Aug 30;111(2-3):125-36. Fiszdon JM, Richardson R, Greig T, Bell MD. A comparison of basic and social cognition between schizophrenia and schizoaffective disorder. Schizophr Res. 2007 Mar;91(1-3):117-21. Gruber O, Gruber E, Falkai P. Articulatory rehearsal in verbal working memory: a possible neurocognitive endophenotype that differentiates between schizophrenia and schizoaffective disorder. Neurosci Lett. 2006 Sep 11;405(1-2):24-8. Manschreck TC, Maher BA, Beaudette SM, Redmond DA. Context memory in schizoaffective and schizophrenic disorders. Schizophr Res. 1997 Aug 29;26(2-3):15361. Moses JA. Performance of schizophrenic and schizoaffective disorder patients on the Luria-Nebraska Neuropsychological Battery. International Journal of Clinical Neuropsychology. 1984;6(3):195-7. Reichenberg A, Weiser M, Rabinowitz J, Caspi A, Schmeidler J, Mark M, A population-based cohort study of premorbid intellectual, language, and behavioral functioning in patients with schizophrenia, schizoaffective disorder, and nonpsychotic bipolar disorder. Am J Psychiatry. 2002 Dec;159(12):2027-35. Silverstein ML, McDonald C, Meltzer HY. Differential patterns of neuropsychological deficit in psychiatric disorders. J Clin Psychol. 1988 May;44(3):412-5. Stip E, Sepehry AA, Prouteau A, Briand C, Nicole L, Lalonde P, Cognitive discernible factors between schizophrenia and schizoaffective disorder. Brain Cogn. 2005 Dec;59(3):292-5. Walker E. Attentional and neuromotor functions of schizophrenics, schizoaffectives, and patients with other affective disorders. Arch Gen Psychiatry. 1981 December 1, 1981;38(12):1355-8. McClure RK. The visual backward masking deficit in schizoaffective disorder. Prog Neuropsychopharmacol Biol Psychiatry. 1999 Jul;23(5):785-90. Fleck DE, DelBello MP, Zimmerman ME, Getz GE, Shear PK, Strakowski SM. Selective attention in schizoaffective disorder: pilot data. Schizophr Res. 2004 May 1;68(1):109-10. Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr Res. 2004 Dec 15;72(1):41-51. Palmer BW, Heaton RK, Paulsen JS, Kuck J, Braff D, Harris MJ, Is it possible to be schizophrenic yet neuropsychologically normal? Neuropsychology. 1997 Jul;11(3):43746. Bowie CR, Harvey PD. Cognition in schizophrenia: impairments, determinants, and functional importance. Psychiatr Clin North Am. 2005 Sep;28(3):613-33, 26. Heaton R, Paulsen JS, McAdams LA, Kuck J, Zisook S, Braff D, Neuropsychological deficits in schizophrenics. Relationship to age, chronicity, and dementia. Arch Gen Psychiatry. 1994 Jun;51(6):469-76. Savla GN, Moore DJ, Palmer BW. Cognitive functioning in schizophrenia. In: Mueser KT, Jeste DV, eds. Clinical Handbook of Schizophrenia. New York: Guilford Press. in press.

130 [64] [65]

[66] [67] [68]

[69] [70] [71]

[72] [73] [74] [75] [76]

[77] [78] [79] [80]

[81]

[82] [83] [84]

Barton W. Palmer and Gauri N. Savla Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology. 1998 Jul;12(3):426-45. Heinrichs W, Miles A, McDermid Vaz S, Zargarian T, Miki A, Smith D. Verbally gifted schizophrenia patients and healthy controls: Differences in functional status but not cognition? [Abstract]. Schizophr Bull. 2007;33(2):560-1. Miki A, Heinrichs W, Smith D. Evidence for neuropsychological normality in a subgroup of patients with schizophrenia. Schizophr Bull. 2007;33(2):568-9. Allen DN, Goldstein G, Warnick E. A consideration of neuropsychologically normal schizophrenia. J Int Neuropsychol Soc. 2003 Jan;9(1):56-63. Wilk CM, Gold JM, McMahon RP, Humber K, Iannone VN, Buchanan RW. No, it is not possible to be schizophrenic yet neuropsychologically normal. Neuropsychology. 2005 Nov;19(6):778-86. Blanchard JJ, Neale JM. The neuropsychological signature of schizophrenia: generalized or differential deficit? Am J Psychiatry. 1994 Jan;151(1):40-8. Heinrichs RW. The primacy of cognition in schizophrenia. Am Psychol. 2005 Apr;60(3):229-42. Fioravanti M, Carlone O, Vitale B, Cinti ME, Clare L. A meta-analysis of cognitive deficits in adults with a diagnosis of schizophrenia. Neuropsychol Rev. 2005 Jun;15(2):73-95. Lezak MD, Howieson DB, Loring DW, Hannay HJ, Fisher JS. Neuropsychological assessment. 4th ed. Oxford ; New York: Oxford University Press 2004. Sharma, T., Harvey, P. D. (Eds). Cognition in Schizophrenia. Oxford, UK: Oxford University Press 2000. Pashler HE. The psychology of attention. Cambridge, MA: The MIT Press 1998. Raz A, Buhle J. Typologies of attentional networks. Nat Rev Neurosci. 2006 May;7(5):367-79. Cornblatt BA, Lenzenweger MF, Erlenmeyer-Kimling L. The continuous performance test, identical pairs version: II. Contrasting attentional profiles in schizophrenic and depressed patients. Psychiatry Res. 1989 Jul;29(1):65-85. Cornblatt BA, Malhotra AK. Impaired attention as an endophenotype for molecular genetic studies of schizophrenia. Am J Med Genet. 2001 Jan 8;105(1):11-5. Silverman J. The problem of attention in research and theory in schizophrenia. Psychol Rev. 1964 Sep;71(5):352-79. Reed JL. Schizophrenic thought disorder: A review and hypothesis. Compr Psychiatry. 1970 Sep;11(5):403-32. Oltmanns TF, Neale JM. Schizophrenic performance when distractors are present: attentional deficit or differential task difficulty? J Abnorm Psychol. 1975 Jun;84(3):205-9. Green MF, Marshall BD, Jr., Wirshing WC, Ames D, Marder SR, McGurk S, Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry. 1997 Jun;154(6):799-804. Braff DL, Light GA. Preattentional and attentional cognitive deficits as targets for treating schizophrenia. Psychopharmacology (Berl). 2004 Jun;174(1):75-85. Baddeley AD, Hitch G. Working memory. In: Bower GA, ed. The psychology of learning and motivation. New York: Academic Press 1974:47-89. Baddeley AD. Working Memory. New York: Oxford University Press 1986.

Neuropsychological Deficits in Schizoaffective Disorder [85]

131

Tulsky DS, Saklofske, D., Heaton, R.K. Clinical interpretation of the WAIS-III and WMS-III. Amsterdam ; Boston: Academic Press 2003. [86] Twamley EW, Palmer BW, Jeste DV, Taylor MJ, Heaton RK. Transient and executive function working memory in schizophrenia. Schizophr Res. 2006;87:185-90. [87] Park S, Holzman PS. Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry. 1992 Dec;49(12):975-82. [88] Wechsler D. Wechsler Memory Scale - Third Edition (WMS-III). Adminstration and Scoring Manual. San Antonio: The Psychological Corporation 1997. [89] Wilde N, Strauss E. Functional equivalence of WAIS-III/WMS-III digit and spatial span under forward and backward recall conditions. Clin Neuropsychol. 2002 Aug;16(3):322-30. [90] Lee J, Park S. Working memory impairments in schizophrenia: a meta-analysis. J Abnorm Psychol. 2005 Nov;114(4):599-611. [91] Goldman-Rakic PS. Working memory dysfunction in schizophrenia. J Neuropsychiatry Clin Neurosci. 1994 Fall;6(4):348-57. [92] Squire LR. Memory systems of the brain: a brief history and current perspective. Neurobiol Learn Mem. 2004 Nov;82(3):171-7. [93] Aleman A, Hijman R, de Haan EH, Kahn RS. Memory impairment in schizophrenia: a meta-analysis. Am J Psychiatry. 1999 Sep;156(9):1358-66. [94] Benedict R, Schretlen D, Groninger L, Brandt J. Hopkins Verbal Learning Testrevised: Normative data and analysis of inter-form and test-retest reliability. Clin Neuropsychol. 1998;12:43-55. [95] Boake C. Édouard Claparède and the auditory verbal learning test. J Clin Exp Neuropsychol. 2000 Apr;22(2):286-92. [96] Delis DC, Kramer JH, Kaplan E, Ober BA. California Verbal Learning Test-second edition. Manual. San Antonio, TX: The Psychological Corporation 2000. [97] Tulsky DS, Chiaravalloti N, Palmer BW, Chelune G. The Wechsler Memory Scale, Third Edition: A new perspective. In: Tulsky D, Saklofske D, Heaton RK, Chelune G, Ivnik R, Bornstein RA, , eds. Clinical interpretation of the WAIS-III and WMS-III. San Diego, CA Academic Press 2003:93-193. [98] Troster AI, Butters N, Salmon DP, Cullum CM, Jacobs D, Brandt J, The diagnostic utility of savings scores: differentiating Alzheimer's and Huntington's diseases with the logical memory and visual reproduction tests. J Clin Exp Neuropsychol. 1993 Sep;15(5):773-88. [99] Cohen J. Statistical Power Analysis for the Behavioral Sciences. Hillsdale, NJ: Lawrence Erlbaum Associates, Inc. 1988. [100] Boake C. From the Binet-Simon to the Wechsler-Bellevue: tracing the history of intelligence testing. J Clin Exp Neuropsychol. 2002 May;24(3):383-405. [101] Tulsky DS, Saklofske DH, Zhu J. Revising a standard: An evaluation of the origin and develoment of the WAIS-III. In: Tulsky DS, Saklofske DH, Chelune GJ, Heaton RK, Ivnik RJ, eds. Clinical interpretation of the WAIS-III and WMS-III. San Diego, CA: Academic Press, 2003:43-92. [102] Wechsler D. Wechsler Adult Intelligence Scale - Third Edition (WAIS-III). Adminstration and Scoring manual. San Antonio, TX: The Psychological Corporation 1997.

132


[103] Partington JE, Leiter RG. Partington's Pathways Test. Psychological Service Center Journal. 1949l 1:11-20. [104] Reitan RM, Wolfson D. The Halstead-Reitan neuropsychological test battery: Theory and clinical interpretation. 2nd ed. Tucson, Ariz.: Neuropsychology Press 1993. [105] Dickinson D, Ramsey ME, Gold JM. Overlooking the obvious: a meta-analytic comparison of digit symbol coding tasks and other cognitive measures in schizophrenia. Arch Gen Psychiatry. 2007 May;64(5):532-42. [106] Palmer BW, Heaton R. Executive dysfunction in schizophrenia. In: Sharma T, Harvey P, eds. Cognition in Schizophrenia: Impairments, Importance and Treatment Strategies. New York: Oxford University Press 2000:52-72. [107] Baddeley A. The central executive: a concept and some misconceptions. J Int Neuropsychol Soc. 1998 Sep;4(5):523-6. [108] Berg EA. A simple objective technique for measuring flexibility in thinking. J Gen Psychol. 1948(39):15-22. [109] Heaton R, Chelune G, Talley J, Kay G, Curtiss G. Wisconsin Card Sorting Test Manual. Revised and Expanded. Odessa, FL: Psychological Assessment Resources, Inc. 1993. [110] Green M. Schizophrenia from a neurocognitive perspective: Probing the inpenetrable darkness. Boston: Allyn and Bacon 1998. [111] Li CS. Do schizophrenia patients make more perseverative than non-perseverative errors on the Wisconsin Card Sorting Test? A meta-analytic study. Psychiatry Res. 2004 Dec 15;129(2):179-90. [112] MacLeod CM. Half a century of research on the Stroop effect: an integrative review. Psychol Bull. 1991 Mar;109(2):163-203. [113] Henik A, Salo R. Schizophrenia and the stroop effect. Behav Cogn Neurosci Rev. 2004 Mar;3(1):42-59. [114] Dyer FN. The Stroop phenomenon and its use in the study of perceptual, cognitive, and response processes. Memory & Cognition. 1973 Vol. 1(2), Apr:106-20. [115] Rapoport JL, Addington AM, Frangou S, Psych MR. The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry. 2005 May;10(5):434-49. [116] McGrath JJ, Feron FP, Burne TH, Mackay-Sim A, Eyles DW. The neurodevelopmental hypothesis of schizophrenia: a review of recent developments. Ann Med. 2003;35(2):86-93. [117] Lencz T, Cornblatt B, Bilder RM. Neurodevelopmental models of schizophrenia: pathophysiologic synthesis and directions for intervention research. Psychopharmacol Bull. 2001 Winter;35(1):95-125. [118] Bilder RM, Reiter G, Bates J, Lencz T, Szeszko P, Goldman RS, Cognitive development in schizophrenia: follow-back from the first episode. J Clin Exp Neuropsychol. 2006 Feb;28(2):270-82. [119] Cannon TD, Bearden CE, Hollister JM, Rosso IM, Sanchez LE, Hadley T. Childhood cognitive functioning in schizophrenia patients and their unaffected siblings: a prospective cohort study. Schizophr Bull. 2000;26(2):379-93. [120] Davidson M, Reichenberg A, Rabinowitz J, Weiser M, Kaplan Z, Mark M. Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. Am J Psychiatry. 1999 Sep;156(9):1328-35.


133

[121] Jeste DV, Symonds LL, Harris MJ, Paulsen JS, Palmer BW, Heaton RK. Non-dementia non-praecox?: Late-onset schizophrenia. American Journal of Geriatric Psychology. 1997;5:302-17. [122] Palmer BW, McClure FS, Jeste DV. Schizophrenia in late life: findings challenge traditional concepts. Harv Rev Psychiatry. 2001 Mar-Apr;9(2):51-8. [123] Cohen CI, Cohen GD, Blank K, Gaitz C, Katz IR, Leuchter A, Schizophrenia and older adults. An overview: directions for research and policy. Am J Geriatr Psychiatry. 2000 Winter;8(1):19-28. [124] Horan ME, Muller JJ, Winocur S, Barling N. Quality of life in boarding houses and hostels: a residents' perspective. Community Ment Health J. 2001 Aug;37(4):323-34. [125] Kurtz MM. Neurocognitive impairment across the lifespan in schizophrenia: an update. Schizophr Res. 2005 Apr 1;74(1):15-26. [126] Rund BR. A review of longitudinal studies of cognitive functions in schizophrenia patients. Schizophr Bull. 1998;24(3):425-35. [127] Heaton RK, Gladsjo JA, Palmer BW, Kuck J, Marcotte TD, Jeste DV. The stability and course of neuropsychological deficits in schizophrenia. Arch Gen Psychiatry. 2001 Jan;58(1):24-32. [128] Nayak GV, Moore DJ, Roesch SC, Jeste DV, Heaton RK, Palmer BW. Use of hierarchical linear modeling to evaluate longitudinal neuropsychological performance in middle-aged and older schizophrenia patients J Int Neuropsychol Soc. 2005;11:175. [129] Harvey PD. Cognitive impairment in elderly patients with schizophrenia: age related changes. Int J Geriatr Psychiatry. 2001 Dec;16 Suppl 1:S78-85. [130] Green MF, Kern RS, Braff DL, Mintz J. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the "right stuff"? Schizophr Bull. 2000;26(1):119-36. [131] Kurtz MM. Symptoms versus neurocognitive skills as correlates of everyday functioning in severe mental illness. Expert Rev Neurother. 2006 Jan;6(1):47-56. [132] Dickerson FB, Boronow JJ, Stallings CR, Origoni AE, Cole S, Yolken RH. Association between cognitive functioning and employment status of persons with bipolar disorder. Psychiatr Serv. 2004 Jan;55(1):54-8. [133] Martinez-Aran A, Vieta E, Colom F, Torrent C, Sanchez-Moreno J, Reinares M, Cognitive impairment in euthymic bipolar patients: implications for clinical and functional outcome. Bipolar Disord. 2004 Jun;6(3):224-32. [134] Velligan DI, Bow-Thomas CC, Mahurin RK, Miller AL, Halgunseth LC. Do specific neurocognitive deficits predict specific domains of community function in schizophrenia? J Nerv Ment Dis. 2000 Aug;188(8):518-24. [135] Gladsjo JA, McAdams LA, Palmer BW, Moore DJ, Jeste DV, Heaton RK. A six-factor model of cognition in schizophrenia and related psychotic disorders: relationships with clinical symptoms and functional capacity. Schizophr Bull. 2004;30(4):739-54. [136] The Psychological Corporation. WAIS-III/WMS-III Technical Manual. San Antonio, TX: Author 1997. [137] Chapman LJ, Chapman JP. Problems in the measurement of cognitive deficit. Psychol Bull. 1973 Jun;79(6):380-5. [138] Jefferson AL, Paul RH, Ozonoff A, Cohen RA. Evaluating elements of executive functioning as predictors of instrumental activities of daily living (IADLs). Arch Clin Neuropsychol. 2006 May;21(4):311-20.

134


[139] Kaplan E. A process approach to neuropsychological assessment. In: Dennis M, Kaplan E, Posner MI, Stein DG, Thompson RF, eds. Clinical neuropsychology and brain function: Research, measurment, and practice. Washington D.C.: American Psychological Assocation 1988:129-67. [140] Cassens G, Inglis AK, Appelbaum PS, Gutheil TG. Neuroleptics: effects on neuropsychological function in chronic schizophrenic patients. Schizophr Bull. 1990;16(3):477-99. [141] Spohn HE, Strauss ME. Relation of neuroleptic and anticholinergic medication to cognitive functions in schizophrenia. J Abnorm Psychol. 1989 Nov;98(4):367-80. [142] Mishara AL, Goldberg TE. A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book. Biol Psychiatry. 2004 May 15;55(10):1013-22. [143] Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol. 2005 Sep;8(3):457-72. [144] Carpenter WT, Gold JM. Another view of therapy for cognition in schizophrenia. Biol Psychiatry. 2002 Jun 15;51(12):969-71. [145] Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry. 2007 Jun;64(6):633-47. [146] Pachet AK, Wisniewski AM. The effects of lithium on cognition: an updated review. Psychopharmacology (Berl). 2003 Nov;170(3):225-34. [147] Honig A, Arts BM, Ponds RW, Riedel WJ. Lithium induced cognitive side-effects in bipolar disorder: a qualitative analysis and implications for daily practice. Int Clin Psychopharmacol. 1999 May;14(3):167-71. [148] Lund Y, Nissen M, Rafaelsen OJ. Long-term lithium treatment and psychological functions. Acta Psychiatr Scand. 1982 Mar;65(3):233-44. [149] Bearden CE, Hoffman KM, Cannon TD. The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. Bipolar Disord. 2001 Jun;3(3):106-50; discussion 51-3. [150] Fenton WS, Stover EL, Insel TR. Breaking the log-jam in treatment development for cognition in schizophrenia: NIMH perspective. Psychopharmacology (Berl). 2003 Sep;169(3-4):365-6. [151] Gold JM. Cognitive deficits as treatment targets in schizophrenia. Schizophr Res. 2004 Dec 15;72(1):21-8. [152] Twamley EW, Jeste DV, Bellack AS. A review of cognitive training in schizophrenia. Schizophr Bull. 2003;29(2):359-82. [153] Velligan DI, Kern RS, Gold JM. Cognitive rehabilitation for schizophrenia and the putative role of motivation and expectancies. Schizophr Bull. 2006 Jul;32(3):474-85. [154] Palmer BW. The expanding role of neuropsychology in geriatric psychiatry. Am J Geriatr Psychiatry. 2004 Jul-Aug;12(4):338-41.

In: Schizoaffetive Disorders Editor: Kam-shing Yip

ISBN 978-1-60456-948-3 © 2009 Nova Science Publishers, Inc.

Chapter 6

EGO FUNCTIONING, COGNITION, AND ILLNESS CHARACTERISTICS OF PERSONS WITH SCHIZOAFFECTIVE DISORDER: DISTINCTIVE FEATURES AND RESPONSE TO VOCATIONAL REHABILITATION Morris D. Bell*, Randall Richardson, and Tamasine Grieg Department of Psychiatry, Yale University School of Medicine, Psychology Service 116B, VACHS, 950 Campbell Avenue, West Haven, CT 06516, USA

OVERVIEW Patients entering rehabilitation with a diagnosis of schizoaffective disorder are regarded as having deficits similar to those with schizophrenia. Yet, they often have a history of better psychosocial functioning, which suggests that they might respond better to rehabilitation than their counterparts with schizophrenia. In this chapter, we review literature on features of schizoaffective disorder that may be distinctive from schizophrenia. We then examined these features in a large sample of patients who entered a vocational rehabilitation program, comparing them with patients with schizophrenia in the same program. Finally, we looked for differences between the two groups in their rehabilitation course and outcome.

*

E-mail: [email protected]

136

Morris D. Bell, Randall Richardson and Tamasine Grieg

THE SCHIZOAFFECTIVE CONUNDRUM: TWO DISORDERS OR ONE Related Debates Since Kasanin first used the term “schizoaffective” in 1933 to identify a psychotic syndrome marked by mood disturbance, there has been persistent debate as to the validity of the diagnostic category. Like schizophrenia patients, schizoaffective patients experience hallucinations and delusions, thought disorder, negative symptoms, and poor cognitive functioning. On the other hand, they also display many symptoms associated with major depression or bipolar disorder such as depressed mood, disinterest in activities, frequent crying, heightened activity, expansiveness and irritability. This has caused some to question whether schizoaffective disorder shouldn’t be viewed as more similar to an affective illness with psychotic features. However, the persistence of psychotic symptoms in the absence of mood disturbance in schizoaffective disorder is the key factor that distinguishes it from mood disorders with psychotic features (DSM-IV-TR; APA, 2000). If patients have schizophrenia symptoms and also have mood symptoms, one might reasonably expect that they would have a worse course than patients with just schizophrenia symptoms. After all, having two sets of symptoms should be more disabling than one. And indeed, in their self-report, schizoaffective patients tend to rate themselves as the most severely ill. According to clinician ratings on the other hand, they are generally viewed as intermediate between schizophrenia and bipolar disorder in terms of illness severity (Averill , 2004). But even in clinician ratings, perspectives diverge: on cross-sectional assessments of symptoms schizoaffective patients are typically placed closer to the schizophrenia end of the spectrum. When the course of illness is taken into consideration however, the prognosis is more akin to that of bipolar patients, suggesting an intermediate outcome (Benabarre , 2001). Those that argue for a unitary syndrome point to differences in presentation, course and outcome from either schizophrenia or bipolar disorder. At the same time, the disorder combines some features of both diagnostic categories. The complexity of the diagnosis, and absence of clear nosologic boundaries between schizoaffective disorder and related syndromes has led some psychopathologists (e.g., Taylor & Amir, 1994; Yasamy, 1987) to suggest that schizoaffective disorder highlights the failure of categorical diagnosis based on signs and symptoms. This view has encouraged some researchers in the phenomenology of the psychoses to call for a dimensional perspective, in which key features such as cognitive impairment, positive symptoms and mood disturbance are viewed as independent continua; the extent of each in a single individual determining the diagnostic picture (Harrow , 2000). According to this perspective, schizoaffective disorder is diagnosed when pathology is present on each of these three dimensions. Yet others (e.g. Ketter , 2004) support a mixed dimensional/categorical perspective, in which these disorders are viewed along a continuum for the purpose of understanding their shared and discrete characteristics; yet viewed categorically for the purpose of making reliable diagnoses.

Ego Functioning, Cognition, and Illness Characteristics of Persons …

137

Genetics of Schizoaffective Disorder Research into the genetic underpinnings of schizoaffective disorder has thus far failed to clarify the discussion surrounding this syndrome. Family and genetic studies have drawn into question the nosological distinctions between schizophrenia and affective disorders that have been historically assumed (Berretini, 2000a). Findings from the New York High Risk Project have shown that schizoaffective disorder is as likely to occur among the relatives of schizophrenia probands as those of probands with bipolar disorder (Erlenmeyer-Kimling , 1995). Similarly, Bramon and Sham (2001) have reported that there are no risk factors that set schizoaffective disorder apart from either schizophrenia or affective disorders. Although the genetic profiles underlying schizophrenic and manic syndromes appear to have shared, as well as discrete features (Berretini, 2000b), there is no evidence at present to suggest that the genetic liability to schizoaffective disorder is in any way distinguishable from the other two syndromes (Maier , 2005). Indeed, studies attempting to define the specific loci on the human genome that may be associated with these disorders have found that the loci that are implicated in schizoaffective disorder can be found in both schizophrenia and affective disorders (Berretini, 2000a). Perhaps for this reason researchers have been unable to clearly document genetic transmission of schizoaffective disorder as a diagnostic entity (Abrams, 1984).

Neurocognition in Psychosis Cognitive deficits are now recognized to be a central feature of schizophrenia (Bartok , 2005), appearing in the prodromal stage (Niendam, 2003), following remission of acute phases (Bilder , 2000), and in the residual stages (Harvey, 2001). Cognitive impairments also appear in the first order relatives of schizophrenic probands (Niendam, 2003). Children who later develop schizophrenia and their siblings show similar patterns of deficits involving spatial reasoning, verbal knowledge, perceptual-motor speed, and speeded processes of working memory. However, the probands exhibit more severe deficits in perceptual-motor speed and speeded processes of working memory than their unaffected siblings (Niendam, 2003). Similarly, a meta-analysis of studies examining cognitive deficits in schizophrenia patients found that 87% of their cognitive deficits can be explained by a general slowdown of processing speed (Schatz, 1998). Still, there is continuing debate about whether these impairments are generalized or converge in a profile that may be specific to schizophrenia (Dickinson , 2004).

Neuroleptics and Neurocognition Although medications have proved quite helpful in improving clinical symptoms, they have been relatively ineffective in addressing cognitive impairments. This is a crucial target area because these impairments are believed to have a significant impact of psychosocial functioning (Green, 1996). Prevailing opinion holds that conventional neuroleptics have not been helpful in improving cognitive symptoms, although a recent meta-analysis of clinical trials revealed small to moderate cognitive advantage among patients taking these

138

Morris D. Bell, Randall Richardson and Tamasine Grieg

medications (Mishara & Goldberg, 2004). The claims of cognitive improvements from treatment with second generation neuroleptics appear to have been overstated however (Harvey & Keefe, 2001), and a large study performed by investigators independent of industry found no support for such claims (Lieberman , 2005).

Cognition in Schizoaffective Disorder Despite a growing awareness literature on cognitive impairments in psychotic disorders, relatively little has been said about cognitive impairments with regard to schizoaffective disorder in particular. Investigations have yielded mixed results, suggesting alternately that schizoaffective patients were indistinguishable from non-clinical controls (Buhler , 1991); were similarly impaired as schizophrenic patients (Miller , 1996); were no different from nonpsychotic affective disorder patients (Zihl , 1998) and were intermediate between schizophrenia and affective disorder patients in memory and general intellectual ability (Maj, 1986). More recent studies have examined differential performance between schizoaffective and schizophrenia patients in key domains of processing. For example, Stip and colleagues (2005) found differences between these diagnostic groups in visual-motor speed and explicit memory. Other researchers have found that memory disorders are shared between the two groups, rendering them distinct from non-psychotic affective disorders on this dimension (McIntosh , 2005). A recent cluster analysis revealed that cognitive functioning is a heterogeneous dimension in psychosis, such that some patients are severely impaired, whereas others appear neuropsychologically normal. These researchers determined that schizoaffective and paranoid schizophrenia appear at all levels of performance, but are more likely to be in the upper end of the functional continuum, while disorganized and undifferentiated patients are more likely to be at the lower end of the continuum (Goldstein et al, 2005).

EGO FUNCTIONING IN SCHIZOPHRENIA AND SCHIZOAFFECTIVE DISORDER Given the better premorbid function and milder course of schizoaffective disorder than schizophrenia, it is worthwhile to consider whether their capacity for psychological integration will also be better. One approach to defining and measuring psychological fitness relies on the psychoanalytic concept of ego functioning. This term refers to the set of psychological qualities that permit an individual to cope with both internal and external pressures and to navigate the world in an effective way. To accomplish these aims an individual must employ several skills adaptively, including reality testing, interpersonal relatedness, and self-regulation. Several researchers have attempted to operationally define and quantify ego functioning as the psychological basis for mental health and illness. Most notably, Bellak, Hurvich and Gediman (1973) reviewed the historical literature on ego functioning and defined 12 key components. This framework was the foundation upon which Bell (1995) constructed the Bell Object Relations and Reality Testing Inventory (BORRTI).

Ego Functioning, Cognition, and Illness Characteristics of Persons …

139

Object relations and reality testing were selected for scientific study because they represented central features of psychotic disorders and were amenable to a nomothetic approach to psychometrically sound instrument development. The object relations scales include Alienation, Insecure Attachment, Egocentricity and Social Incompetence. Reality testing scales include Reality Distortion, Uncertainty of Perception, and Hallucinations and Delusions. The BORRTI has been found to have excellent discriminant validity between schizophrenia, borderline, other Axis II disorders and healthy community adults (Bell, 1995). Six distinct BORRTI profiles within schizophrenia samples have been identified and found to have predictive and discriminant validity as well (Bell , 1986; Bell , 2001). The BORRTI also has cross-cultural validity, as shown in a study of schizophrenia patients in Brazil (Bell & Bruscato, 2002). In the study described here, we compare ego functioning in patients with schizophrenia and schizoaffective disorder. To our knowledge this is the first attempt to quantify and characterize these two diagnostic groups on this dimension.

VOCATIONAL REHABILITATION, SCHIZOPHRENIA AND SCHIZOAFFECIVE DISORDER Diagnosis has generally been a weak predictor of vocational outcomes in psychiatry. The first statement on the issue was by Anthony and Jansen (1984), who argued that diagnosis and symptoms were unrelated to vocational functioning within psychiatric populations. However, more recent work has found that having a schizophrenia diagnosis as compared to affective illness or other diagnosis is a negative predictor of supported employment success (Cook, 2005). Some have argued that any differences in outcomes between schizophrenia patients and others diminish with better rehabilitation programming (Mueser & McGurk, 2004). Whether patients with schizoaffective disorder have a better rehabilitation course than patients with schizophrenia remains an open question. Although the literature cited earlier concludes that patients with schizoaffective disorder demonstrate better community functioning, it is unknown whether these advantages translate into improved outcomes in vocational rehabilitation.

THE CURRENT STUDY In this chapter we report on 422 patients enrolled in a series of vocational rehabilitation studies. We examined the differences between schizophrenia and schizoaffective disorder groups on background and illness characteristics, cognitive ability, ego functioning, and work outcome measures. We hypothesized that differences would generally favor schizoaffective patients and that such differences might influence the course and outcome of vocational rehabilitation.

140

Morris D. Bell, Randall Richardson and Tamasine Grieg Table 1. Participant Characteristics

n Schizophrenia Subtype Paranoid Disorganized Residual Undifferentiated Gender Male Female* Ethnicity White Black Hispanic Asian Other Ever Married* Age Education Full Scale IQ Age at 1st Hosp. Lifetime Hosp.

Medications Atypical Conventional Both None

Schizophrenia (n=302) %

N

Schizoaffective (n=121) %

203 20 23 56

67 7 8 18

— — — —

— — — —

278 24

92 8

102 19

84 16

189 95 13 4 1 97 Mean 42.19 12.77 92.88 24.59 9.54

63 31 4 1 0.33 32.55 Std Dev 8.37 2.34 14.37 6.69 10.11

85 33 3 0 0 61 Mean 43.28 13.02 95.31 26.45 9.49

71 27 2 0 0 50 Std Dev 9.29 2.27 16.02 7.71 8.95

n 86 92 10 12

Schizophrenia (n=200) % 43 46 5 6

N 39 25 6 2

Schizoaffective (n=72) % 54 35 8 3

*p

Schizoaffective Disorders: International Perspectives on Understanding, Intervention and Rehabilitation

Perspectives On Rehabilitation And Dementia

Malaria (Perspectives on Diseases and Disorders)

Hepatitis (Perspectives on Diseases and Disorders)

Pathology and Intervention in Musculoskeletal Rehabilitation

Perspectives In Rehabilitation Ergonomics

Vestibular Rehabilitation (Contemporary Perspectives in Rehabilitation)

Understanding Sports and Eating Disorders

Humanitarian Intervention and International Relations

International Perspectives On Household Wealth

British and Canadian Perspectives on International Law

Fundamental Perspectives on International Law

Perspectives on Disability and Rehabilitation: Contesting Assumptions, Challenging Practice

International Perspectives on Youth Conflict and Development

International Perspectives on Diversity and Inclusive Education

Understanding Anger Disorders

Understanding Anger Disorders

Development Intervention: Actor and activity perspectives

International Perspectives on Child & Adolescent Mental Health (International Perspectives on Child and Adolescent Mental Health)

Emotions and Understanding: Wittgensteinian Perspectives

Noyes' Knee Disorders: Surgery, Rehabilitation, Clinical Outcomes

Neuropsychological Rehabilitation: A Resource for Group-Based Education and Intervention

Understanding Film: Marxist Perspectives

Understanding Film: Marxist Perspectives

Understanding Josephus: Seven Perspectives

Understanding Film: Marxist Perspectives

Anxiety Disorders in Children and Adolescents: Research, Assessment and Intervention

Neuropsychological Assessment and Intervention for Childhood and Adolescent Disorders

Schizoaffective Disorders: International Perspectives on Understanding, Intervention and Rehabilitation

Perspectives On Rehabilitation And Dementia

Malaria (Perspectives on Diseases and Disorders)

Hepatitis (Perspectives on Diseases and Disorders)

Pathology and Intervention in Musculoskeletal Rehabilitation

Perspectives In Rehabilitation Ergonomics

Vestibular Rehabilitation (Contemporary Perspectives in Rehabilitation)

Understanding Sports and Eating Disorders

Humanitarian Intervention and International Relations

International Perspectives On Household Wealth

British and Canadian Perspectives on International Law

Fundamental Perspectives on International Law

Perspectives on Disability and Rehabilitation: Contesting Assumptions, Challenging Practice

International Perspectives on Youth Conflict and Development

International Perspectives on Diversity and Inclusive Education

Understanding Anger Disorders

Understanding Anger Disorders

Development Intervention: Actor and activity perspectives

International Perspectives on Child & Adolescent Mental Health (International Perspectives on Child and Adolescent Mental Health)

Emotions and Understanding: Wittgensteinian Perspectives

Noyes' Knee Disorders: Surgery, Rehabilitation, Clinical Outcomes

Neuropsychological Rehabilitation: A Resource for Group-Based Education and Intervention

Understanding Film: Marxist Perspectives

Understanding Film: Marxist Perspectives

Understanding Josephus: Seven Perspectives

Understanding Film: Marxist Perspectives

Anxiety Disorders in Children and Adolescents: Research, Assessment and Intervention

Neuropsychological Assessment and Intervention for Childhood and Adolescent Disorders

Recommend Documents