Treating Depression Effectively: Applying Clinical Guidelines, Second Edition

Treating Depression Effectively Applying Clinical Guidelines second Edition Sidney H Kennedy Raymond W Lam David J Nutt...

Author: Sidney H. Kennedy | Raymond W. Lam | David J. Nutt | Michael E. Thase

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Treating Depression Effectively Applying Clinical Guidelines second Edition

Sidney H Kennedy Raymond W Lam David J Nutt Michael E Thase

Treating Depression Effectively

Treating Depression Effectively Applying Clinical Guidelines Second Edition

Sidney H Kennedy MD FRCPC Professor of Psychiatry University of Toronto Psychiatrist-in-Chief University Health Network Toronto, Canada

Raymond W Lam MD FRCPC Professor and Head Division of Clinical Neuroscience University of British Columbia Vancouver, Canada

David J Nutt DM FRCP FRCPsych FMedSci Professor of Psychopharmacology University of Bristol Bristol, UK

Michael E Thase MD Professor Department of Psychiatry University of Pennsylvania School of Medicine Philadelphia, PA, USA

© 2007 Informa UK Ltd First edition published in 2004 by Martin Dunitz, now part of Informa Healthcare. Second edition published in the United Kingdom in 2007 by Informa Healthcare, Telephone House, 69-77 Paul Street, London, EC2A 4LQ. Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37/41 Mortimer Street, London W1T 3JH. Registered in England and Wales number 1072954 Tel: +44 (0)20 7017 5000 Fax: +44 (0)20 7017 6699 Website: www.informahealthcare.com All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information or instructions on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. A CIP record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data Data available on application ISBN-13: 978 0 415 43910 7 ISBN-10: 0 415 43910 8 Distributed in North and South America by Taylor & Francis 6000 Broken Sound Parkway, NW, (Suite 300) Boca Raton, FL 33487, USA Within Continental USA Tel: 1 (800) 272 7737; Fax: 1 (800) 374 3401 Outside Continental USA Tel: (561) 994 0555; Fax: (561) 361 6018 Email: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel: +44 (0)1264 332424 Email: [email protected] Composition by Scribe Design Ltd, Ashford, Kent, UK Printed and bound in Great Britain by MPG Books, Bodmin, Cornwall, UK

Contents

About the authors Preface

vi vii

1 Prevalence, burden and diagnosis

1

2 Principles of management

9

3 Psychotherapies, alone and in combination

29

4 Evolution of antidepressant agents

49

5 Evidence based antidepressant selection across depressive disorders

61

6 Practical issues in using antidepressants

75

7 Sequential pharmacotherapies and treatment-resistant

93

depression 8 Neuromodulation and other physical treatments

105

9 Complementary, light, sleep deprivation and exercise therapies

119

10 Depression in women

129

11 Depression in children and adolescents

145

12 Depression in late life

155

13 Psychiatric and physical comorbidities in depression

167

Index

177

About the authors

Sidney H Kennedy MD FRCPC

David J Nutt DM FRCP FRCPsych

Professor of Psychiatry

FMedSci

University of Toronto

Professor of Psychopharmacology

Psychiatrist-in-Chief

Dean of Clinical Medicine and

University Health Network

Dentistry

200 Elizabeth Street

Head of the Department of Clinical

Eaton North, 8th Floor, Room 222

Medicine

Toronto, ON, M5G 2C4

University of Bristol

Canada

Psychopharmacology Unit School of Medical Sciences

Raymond W Lam MD FRCPC

University Walk

Professor and Head

Bristol BS8 1TD

Division of Clinical Neuroscience

United Kingdom

University of British Columbia 2255 Wesbrook Mall

Michael E Thase MD

Vancouver, BC, V6T 2A1

Professor

Canada

Department of Psychiatry University of Pennsylvania School of Medicine 3535 Market St, Room 689 Philadelphia Veterans Association Medical Center University of Pittsburgh School of Medicine Philadelphia, PA 19102 USA

Preface

This is the second edition of Treating Depression Effectively. The first edition was inspired by the Canadian Network for Mood and Anxiety Treatments (CANMAT, www.canmat.org) ‘Clinical guidelines for the treatment of depressive disorders’1 published by the Canadian Psychiatric Association in 2001. Members of this CANMAT Depression Work Group were Murray Enns, Stanley Kutcher, Sagar Parikh, Arun Ravindran, Robin Reesal, Zindel Segal, Lillian Thorpe, Pierre Vincent and Diane Whitney, with Sidney Kennedy and Raymond Lam as co-chairs. Since publication of the first edition in 2004, there have been significant advances in the triad of pharmcotherapies, psychotherapies and somatic therapies. In this edition we have attempted to present these advances using the same reader-friendly format. We are very grateful to all our colleagues for their contributions and acknowledge the importance of their work as the foundation for this volume, and to our families for their patience and support. We also appreciate the role of Beata Eisfeld who provided editorial assistance for the first edition and Sakina Rizvi for this edition. Sidney H Kennedy Raymond W Lam David J Nutt Michael E Thase

1. CANMAT Depression Work Group. Clinical guidelines for the treatment of depressive disorders. Can J Psychiatry 2001; 46 (Suppl 1): 1S–92S.

Chapter 1

Prevalence, burden and diagnosis Prevalence, course and burden of illness Major depressive disorder (MDD) is among the most prevalent of medical illnesses. Recent epidemiological studies have highlighted the similarity in prevalence rates of depression in different countries (Figure 1.1). For many patients, depression is a chronic and recurrent illness. In follow-up studies, up to 30% of patients with MDD are still depressed after one year, 18% are ill after two years and 12% remain ill after five years. Many patients treated for MDD still have residual and subsyndromal symptoms that result in poor outcomes, including higher risk for relapse and suicide, poor psychosocial function and higher mortality from other medical diseases. Among patients who recover from a depressive episode, over 50% will have a recurrence. Given the high prevalence of depression, it is not surprising that the socioeconomic costs are also high. The World Health Organization (WHO), in an updated 2000 study comparing all medical illnesses, reported that depression remains the fourth leading cause of disability adjusted life years (DALYs) and accounts for 4.4% of total worldwide DALYs. This ranges from 8% of the total burden in the Americas to 1.2% in Africa (Table 1.1). The economic costs associated with premature mortality (e.g. from suicide), and the indirect costs such as reduced productivity and days off work are staggering. People with depression are four times more likely to have days off work than people without depression (Figure 1.2). In the USA, the annual direct costs (hospitals, medications, doctor fees) of treating depression are estimated at US$12.4 billion. In the UK, excess mortality is estimated to cost over £4.7 million per year, while in Canada, the indirect cost of depression (lost productivity) is estimated at C$2.53 billion. Many nations now recognize that the diagnosis and treatment of depression are priorities for the medical system.

2 Treating Depression Effectively

Belgium

5

France

9.1

Germany

3.8

Netherlands

6.9

Spain

6.2

UK

9.9

Canada

6

USA

10.3 0

2

4

6

8

10

12

% of general population with MDD Figure 1.1 Six-month prevalence of MDD across different countries.

Table 1.1 Worldwide Disability Adjusted Life Years attributed to depression (estimates for 2000) WHO regions

% of total DALYs

Ranking in region

Americas Europe Western Pacific South East Asia Eastern Mediterranean Africa

8 6.1 6.0 4.7 3.5 1.2

1 3 2 4 5 13

WHO – World Health Organization epidemiological subregions. DALYs – Disability Adjusted Life Years. Adapted from Ustun et al. 2004.

Diagnosis of depression The diagnostic criteria for an episode of MDD are similar in both the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) (Table 1.2) and the International Classification of Diseases,

Prevalence, burden and diagnosis 3

14 12

Lost work days

10 8 6 4 2 0 France

Germany

Spain

UK

USA

Figure 1.2 Lost work days in the last 6 months in depressed and nondepressed workers: , depressed; , non-depressed.

10th revision (ICD-10). Table 1.3 shows the differentiating features between MDD and normal bereavement. Despite the wide acceptance of these criteria, MDD is not well recognized or diagnosed in primary care settings because the presenting complaints are often physical in nature, such as insomnia, fatigue and pain. Moreover, one of the most prominent and disturbing features for patients suffering from major depressive disorder is disturbed sleep. The association between sleep disturbance and clinical depression has long been recognized. Almost all patients with MDD report some form of sleep difficulty including insomnia, oversleeping and poor quality sleep. The most reliable and predictable sleep abnormalities of depression include a sleep continuity disturbance, diminished slow wave sleep (SWS) (delta), a shortened rapid eye movement (REM) latency and an alteration in the temporal distribution of REM sleep. Patients seen in primary care who present with unexplained physical symptoms should be screened for the presence of MDD (Table 1.4). While screening questionnaires can be used, a quick two-question screening for depression is helpful in these presentations:


Table 1.2 DSM-IV-TR criteria for the diagnosis of major depressive episode A. Five (or more) of the following symptoms have been present during the same twoweek period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure: 1. Depressed mood most of the day or nearly every day, as indicated by either subjective report (e.g. feels sad or empty) or observation made by others (e.g. appears tearful). Note: in children and adolescents, can be irritable mood. 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day or nearly every day (as indicated by either subjective account or observation made by others). 3. Significant weight loss when not dieting or weight gain (e.g. a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: in children, consider failure to make expected weight gains. 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day (observable by others; not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick). 8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others). 9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan or a suicide attempt or a specific plan for committing suicide. B. The symptoms do not meet criteria for a mixed episode. C. The symptoms cause clinically significant distress or impairment in social, occupational or other important areas of functioning.

1. In the last month, have you been bothered by little interest or pleasure in doing things? 2. In the last month, have you been feeling down, depressed or hopeless? An answer of ‘Yes’ to either question should trigger a more detailed assessment.

Diagnostic instruments for clinical use Semistructured clinical interviews can also help to confirm or validate a clinical diagnosis. For primary care physicians, the PRIME-MD interview


Table 1.3 Features that help distinguish between bereavement and a major depressive episode Feature

Bereavement

Major depressive episode

Time course Feelings of worthlessness Suicidal ideas Delusions of guilt, etc. Psychomotor changes Functional impairment

Less than two months Absent Absent Absent Mild agitation Mild

More than two months Present Common Possible Marked slowing Marked to severe

Table 1.4 Patients with the following factors are at high risk for MDD and should be screened for depressive illness (level 2) • • • • • • •

Sleep disturbances Chronic pain Chronic physical illness (diabetes, heart disease, etc.) Unexplained somatic symptoms Frequent visits Postpartum state Psychosocial stressor

(Primary Care Evaluation of Mental Disorders) takes approximately nine minutes to administer and has good predictive power for depression. For specialists, the Structured Clinical Interview for DSM-IV-TR (SCID) is the most widely used instrument, but it requires training, is difficult to use and takes an hour or more to administer. The Mini International Neuropsychiatric Interview (MINI) is a more practical and convenient instrument and is available in a number of languages (free download available at www.medicaloutcomes.com). The MINI takes 15–20 minutes to administer and aids in the diagnosis of 15 major psychiatric conditions in DSM-IV-TR and ICD-10. A major diagnostic issue is differentiating between bipolar and unipolar depression. Hypomanic episodes, in particular, are difficult to identify in routine clinical practice. A scale such as the Mood Disorders Questionnaire may be a helpful tool to screen for bipolarity.


Table 1.5 Specifiers of MDD according to DSM-IV-TR Specifier

Key features

With melancholic features

Non-reactive mood, anhedonia, weight loss, guilt, psychomotor retardation or agitation, morning worsening of mood, early morning awakening

With atypical features

Reactive mood, oversleeping, overeating, leaden paralysis, interpersonal rejection sensitivity

With psychotic features

Hallucinations or delusions

With catatonic features

Catalepsy (waxy flexibility), catatonic excitement, negativism or mutism, mannerisms or stereotypies, echolalia or echopraxia. This subtype is not commonly seen in clinical practice

With chronic pattern

Two years or more with full criteria for major depressive episode

With seasonal pattern

Regular onset and remission of depressive episodes during a particular season (usually fall/winter onset)

With postpartum onset

Onset of depressive episode within four weeks postpartum

Subtypes of MDD DSM-IV-TR includes a number of subtype specifiers for MDD based on crosssectional clinical features or patterns of depressive episodes (Table 1.5). These various subtypes of MDD may have important implications for the selection of treatment and, ultimately, prognosis (see Chapter 5). ‘Anxious depression’ is not listed as a subtype within DSM-IV-TR, but the term is often used to describe depressed patients who experience a preponderance of worry, tension and somatic symptoms related to anxiety. Symptoms of anxiety occur in 60–90% of patients with MDD, and up to 50% of MDD patients may have a comorbid anxiety disorder (see Chapter 13).

Conclusions Major depressive disorder is among the most common and debilitating of medical illnesses. The burden of depression is being increasingly recognized


as a major public health concern in part because of the severe economic consequences of absenteeism and reduced productivity due to depression in the work force. The diagnosis and differential diagnosis of depression require careful attention to emotional, physical and cognitive signs and symptoms, as well as the course and context of episodes. Diagnostic instruments can be useful for busy clinicians to help identify and characterize symptoms of depression. Distinguishing the various subtypes of depression (or episode specifiers in DSM-IV) is also important because of different options for treatment selection.

Bibliography Buysse DJ, Germain A, Nofzinger EA, Kupfer DJ. Sleep and mood disorders. In: Stein DJ, Kupfer DJ, Schatzberg AF, eds. The American Psychiatric Publishing Textbook of Mood Disorders. Arlington, VI: American Psychiatric Publishing, 2006: 717–37. Hirschfeld RM, Williams JB, Spitzer RL et al. Development and validation of a screening instrument for bipolar spectrum disorder: The Mood Disorder Questionnaire. Am J Psychiatry 2000; 157: 1873–5. Lepine JP, Gastpar M, Mendlewicz J, Tylee A. Depression in the community: the first pan-European study DEPRES (Depression Research in European Society). Int Clin Psychopharmacol 1997; 12: 19–29. Ohayon MM, Schatzberg AF. Using chronic pain to predict depressive morbidity in the general population. Arch Gen Psychiatry 2003; 60: 39–47. Parikh SV, Lam RW, CANMAT Depression Work Group. Clinical guidelines for the treatment of depressive disorders: I. Definitions, prevalence and health burden. Can J Psychiatry 2001; 46 (Suppl 1): 13S–20S. Spitzer RL, Williams JB, Kroenke K et al. Utility of a new procedure for diagnosing mental disorders in primary care. The PRIME-MD 1000 study. JAMA 1994; 272: 1749–56. Ustun TB, Ayuso-Mateos JL, Chatterji S et al. Global burden of depressive disorders in the year 2000. Br J Psychiatry 2004; 184: 386–92. Weissman MM, Bland RC, Canino GJ et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA 1996; 276: 293–9. Wilson S, Argyropoulos S. Antidepressants and sleep; a qualitative review of the literature. Drugs 2005; 65: 927–47.

Chapter 2

Principles of management

The management of major depressive disorder (MDD) involves establishing a correct diagnosis and applying evidence based and goal directed principles of treatment. These treatment principles include recognizing and treating any coexisting medical conditions, building a therapeutic alliance with patients and choosing an appropriate treatment, as well as monitoring and maintaining response (Table 2.1).

Set goals of treatment The overall goals of treatment are to achieve remission of symptoms, restore quality of life and prevent relapse or recurrence. The treatment of depression consists of two phases – acute and maintenance – each with specific goals,

Table 2.1 Nine principles of management for a major depressive episode • • • • • • • • •

Set clear goals for treatment Assess and treat comorbid medical conditions Assess suicide risk Establish a therapeutic alliance Consider psychotherapy Choose an appropriate antidepressant Enhance adherence (compliance) to treatment regimen Monitor treatment outcome Maintain response to treatment


Table 2.2 The phases of treatment of depression Phase

Duration

Objectives

Activities

Acute

6–12 weeks or longer

Remission of symptoms Establish therapeutic alliance Return to previous full Provide education function Choose treatment Monitor response

Maintenance

Six months following remission, or longer

Prevention of relapse and recurrence Rehabilitation Monitor for recurrence

Provide education Manage side-effects

objectives and activities (Table 2.2). There is increasing recognition of the importance of achieving full remission of symptoms and a return to baseline psychosocial function.

Treat comorbid medical conditions Many medical conditions and medications are associated with symptoms of depression. It is important to recognize, investigate and treat comorbid conditions. Tables 2.3 and 2.4 show some general medical conditions and medications that are frequently associated with depression. However, depression can also coexist with these conditions, and requires independent treatment (see Chapter 13).

Assess suicide risk Suicide risk should be regularly assessed throughout the course of treatment; when appropriate, family or friends should also be consulted. Paradoxically, suicide risk may increase when patients begin to show response, partly because improvement in energy level may precede improvement in mood. Table 2.5 shows risk factors that are statistically correlated with suicide. One of the strongest clinical predictors is hopelessness, and hence the assessment of suicide risk should include inquiries into the patient’s plans or hopes. Table 2.6 shows the questions from the Mini International Neuropsychiatric Interview (MINI) that help assess suicide risk. The management of suicidal thoughts can include distraction techniques (e.g. taking a walk or calling a friend), keeping a list of reasons for living and access to telephone crisis lines. Involving the patient and significant others

Principles of management 11

Table 2.3 General medical conditions frequently associated with depression Neurological disorders Alzheimer’s disease Cerebrovascular disease Cerebral neoplasms Cerebral trauma Central nervous system (CNS) infections Dementia Epilepsy Extrapyramidal diseases Huntington’s disease Hydrocephalus Migraine Multiple sclerosis Narcolepsy

Endocrine disorders Adrenal Cushing’s Addison’s hyperaldosteronism Menses-related Parathyroid disorders Thyroid disorders Vitamin deficiencies B12/folate vitamin C niacin thiamine Other disorders

Parkinson’s disease

Acquired immune deficiency

Progressive supranuclear palsy

syndrome (AIDS)

Sleep apnea

Cancer

Wilson’s disease

Cardiopulmonary disease Klinefelter’s syndrome Myocardial infarction Porphyrias Postoperative states Renal disease and uremia Systemic neoplasms

Systemic disorders Viral and bacterial infections Inflammatory disorders Rheumatoid arthritis Sjögren’s syndrome Systemic lupus erythematosus Temporal arteritis

in the treatment plan is useful, as is documenting treatment plans. Patients who are at high suicide risk require urgent referral or hospitalization, which may include involuntary admission under local mental health laws.

Establish a therapeutic alliance As with any treatment plan, informed consent should be obtained from the patient and/or the family. This provides an opportunity for education, which includes a brief discussion of the causes of depression, its symptoms, options for treatments, risks and benefits of such treatments, possible side-effects and expectation of remission (Table 2.7). Primary care physicians are in a good position to establish a strong alliance as they already have a therapeutic


Table 2.4 Medications frequently associated with depression Antibacterials and antifungal agents Ampicillin Clotrimazole Cycloserine Dapsone Griseofulvin Metronidazole Nitrofurantoin Sulfonamides Streptomycin Tetracycline Thiocarbanilide Cancer drugs Beiomycin C-asparaginase Mithramycin Trimethoprim Vincristine Zidovudine

Analgesics and anti-inflammatory agents Fenoprofen Ibuprofen Indomethacin Opiates Phenacetin Phenylbutazone Pentazocine Stimulants and appetite suppressants Amphetamine Diethylpropion Phenmetrazine Sedatives and hypnotics Barbiturates Benzodiazepines Chloral hydrate Ethanol Psychotropic medications Antipsychotics

Cardiac and antihypertensive drugs Beta-blockers Clonidine Digitalis Guanethidine Hydralazine Lidocaine Methyldopa Prazosin Reserpine Procainamide

Neurological agents Amatadine Baclofen Bromocriptine Carbamazepine Levodopa Methosuximide Phenytoin Tetrabenazine

relationship with the patient from continuity of care. Through better understanding of the illness and its expected course, patients may have more trust in the proposed treatment plans. Patients may also feel more in control as they are actively involved in the decision-making process.

Consider psychotherapy Psychotherapy is an effective treatment for depression in motivated patients. The evidence for efficacy is greatest for structured, time-limited


Table 2.4 continued Steroids and hormones Corticosteroids Danazol Oral contraceptives Norethisterone Triamcinalone

Miscellaneous drugs Acetazolamide Anticholinesterases Choline Cimetidine Cyproheptadine Disulfiram Isotretinoin Meclizine Metaclopramide Methysergide Pizotifen Salbutamol

Table 2.5 Risk factors associated with suicide Demographic

Clinical

Male Adolescent or geriatric age Unemployed Socially isolated Single/separated/divorced Poor support network

History and severity of prior attempts Family history of depression and suicide Hopelessness Impulsive and agitated state Psychotic features Alcohol and substance abuse Borderline/antisocial personality traits Chronic medical or psychiatric illnesses Recently discharged from hospital

psychotherapies, particularly cognitive behavior therapy (CBT), interpersonal psychotherapy (IPT) and problem-solving therapy (PST, developed specifically for primary care) (Table 2.8). For MDD of mild to moderate severity, these psychotherapies are as efficacious as antidepressants and can be used as monotherapy (see Chapter 3). The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) has been developed for use in chronic depression, with validation in a large clinical trial. Unfortunately, access to therapists who are trained in these evidence based psychological treatments is limited in most countries.


Table 2.6 Suicidality assessment from the MINI* In the past month did you:

YES points

C1. Think that you would be better off dead or wish you were dead? C2. Want to harm yourself? C3. Think about suicide? C4. Have a suicide plan? C5. Attempt suicide?

NO

YES

1

NO NO NO NO

YES YES YES YES

2 6 10 10

In your lifetime: C6. Did you ever make a suicide attempt? NO YES Add the total number of points for the answers (C1–C6) checked YES and specify the level of suicide risk as follows SUICIDE RISK – CURRENT Low Moderate High

4 TOTAL ________

0–5 points 6–9 points 10 or more points

*Adapted with permission from Sheehan et al. 1998.

Table 2.7 Suggested topics to be discussed before initiating treatment • Depression is a medical disorder with serious consequences • The cause of depression is multifactorial, including biological/genetic factors (‘chemical imbalance in the brain’; changes in neurotransmitters that are corrected by medications), psychological experiences and social and economic stressors • Effective treatment is available with medications and/or psychotherapies • Adherence to treatment is important because the treatments take time

Whether or not formal psychotherapy is offered, physicians should also provide supportive interventions that may improve patient outcomes (Tables 2.9 and 2.10).

Choose an appropriate antidepressant Antidepressants are often the treatment of choice for depression in primary care settings. A number are now available with different neurochemical actions and side-effect profiles. Most systematic reviews have not shown any clinically significant differences in standard response rates among antidepressants, but


Table 2.8 Evidence based psychotherapies for treatment of depression (Level 1) Psychotherapy

General principles

Length of therapy

Cognitive behavior therapy (CBT)

Identify automatic, maladaptive thoughts and distorted beliefs that lead to depressive moods Learn strategies to modify these beliefs and practice adaptive thinking patterns Use a systematic approach to reinforce positive coping behaviors

12–16 sessions

Interpersonal psychotherapy (IPT)

Identify significant interpersonal/relationship issues 12–16 sessions that led to, or arose from, depression (unresolved grief; role disputes; role transitions; social isolation) Focus on one or two of these issues, using problem-solving, dispute resolution and social skills training

Problem-solving therapy (PST)

Use a structured approach to identify and actively 6–8 sessions solve problems that contribute to depression

Cognitive behavioral analysis system of psychotherapy (CBASP)

Use a combination of techniques from cognitive 16–20 sessions and interpersonal therapies to motivate patients with chronic depression to change their behaviors

Table 2.9 Simple and supportive interventions to manage depression (Level 3) • • • •

Arrange regular follow-up visits Use the power of the prescription pad to ‘prescribe’ one brief walk per day and one pleasurable activity per day Keep a daily mood chart Recommend ‘bibliotherapy’ for depression, e.g. self-help workbooks: The Feeling Good Handbook by David D Burns (Plume Books, 1999); Mind Over Mood by Dennis Greenberger and Christine A Padesky (Guilford Press, 1995); the Self-Care Depression Patient Guide (available for free download at www.mheccu.ubc.ca)


Table 2.10 Helpful web resources for depression (Level 3) • • • • • •

The Blue Pages (Australia) Canadian Network for Mood and Anxiety Treatment MacArthur Foundation Initiative (Primary Care; USA) Mental Health on the Internet (Canada) National Institute of Mental Health (USA) PsychDirect (Canada)

• STAND (Stress, Anxiety and Depression; UK)

www.bluepages.anu.edu.au www.canmat.org www.primary-care.org www.mentalhealth.com www.nimh.nih.gov www.psychdirect.com

www.depression.org.uk

Table 2.11 Five simple messages to promote medication adherence (Level 2) • • • • •

Antidepressants are not addictive Take your medication every day as prescribed It may take two to four weeks to start noticing improvement Do not stop medication without talking to your doctor, even if you are feeling better Mild side-effects are common but are usually temporary. If you have more sideeffects than you think reasonable, call your doctor

there are some clinical factors that are important to consider when choosing a medication (see Chapters 4, 5 and 6).

Enhance treatment adherence Adherence or compliance is crucial in the successful treatment of depression. Some simple messages to patients from their physicians have been shown to greatly enhance adherence to medication (Table 2.11).

Monitor treatment outcome Patients should initially be followed on a weekly or bi-weekly basis until they achieve remission. Follow-up frequency can then be reduced to monthly or less often, depending on individual circumstances. Most patients begin to respond to treatment within two to four weeks, show a good clinical response within six to eight weeks, and achieve full remission of symptoms by 8–12 weeks. Recovery of full baseline function to pre-depressed levels may take longer. If there is no response at all after four


weeks of treatment, a change in the treatment plan is indicated (e.g. increasing the dose). Response can be tracked using validated symptom rating scales. Traditionally, response is defined as a 50% or greater reduction in score from baseline, while remission is defined as a score within the normal (not depressed) range. Decisions about strategies for non-response or inadequate response (see Chapter 7) are often based on degree of response as measured by severity scores. Termed ‘measurement-based care’, this approach has been found to increase response to treatment. There are many validated rating scales to assess severity of depression. The most widely used interviewer-rated scales include the Hamilton Depression Rating Scale (HDRS/HAM-D, various versions; most commonly used in its version with 17 items, HAM-D17) and the Montgomery Asberg Depression Rating Scale (MADRS). One version of the HDRS includes items for so-called atypical symptoms of depression, such as overeating and oversleeping; other abbreviated versions (e.g. the HAM-D7, see Table 2.12) were developed for ease of administration by family physicians, psychiatrists and other healthcare specialists. Patient-rated scales include the Beck Depression Inventory II (which includes items for atypical symptoms), the Hospital Anxiety and Depression Scale (HADS) and the Patient Health Questionnaire (PHQ), an easy-to-use, self-rated version of the PRIME-MD that is validated in primary care settings. Some of these measures are included in the Appendix to this chapter.

Maintenance response to treatment For patients with a single episode of depression, the risk of relapse is two times higher in the first year following remission of symptoms than in the next year. Hence, once patients are in full remission from MDD, maintenance issues (e.g. how long a patient should continue to take their medication) become important. Remission is an important target for both acute and maintenance phases, as residual symptoms increase the relapse/recurrence rate, the degree of chronicity and suicide rate, and are associated with poor quality of life and greater health services utilization. Psychoeducation in the maintenance phase focuses on recognizing early signs of relapse or recurrence, and on adherence to medications. Practical aspects of maintenance therapy are summarized in Table 2.13.


Table 2.12 Seven-item Hamilton Rating Scale for Depression (HAM-D7) Please enter the appropriate score for each item Item Legend 1. Depressed mood

0. Absent 1. These feelings indicated only on questioning 2. These feelings spontaneously reported verbally 3. Communicates feeling states non-verbally, i.e. through facial expression 4. Patient reports virtually only these feeling states in his or her spontaneous verbal and non-verbal communication

2. Feelings of guilt

0. Absent 1. Self-reproach, feels he or she has let people down 2. Ideas of guilt or rumination over past errors or sinful deeds 3. Present illness is a punishment; delusions of guilt 4. Hears accusatory or denunciatory voices and/or experiences threatening visual hallucinations

3. Work and activities

0. No difficulty 1. Thoughts and feelings of incapacity, fatigue or weakness related to activities, work or hobbies 2. Loss of interest in activities, hobbies or work, either directly reported by subject or indirect in listlessness, indecision and vacillation 3. Decrease in actual time spent in activities or decrease in productivity. In hospital rate 3 if subject does not spend at least three hours a day in activities (hospital job or hobbies) exclusive of ward chores 4. Stopped working because of present illness. In hospital, rate if subject engages in no activities except ward chores, or if subject fails to perform ward chores unassisted

4. Anxiety psychic

0. No difficulty 1. Subjective tension and irritability 2. Worrying about minor matters 3. Apprehensive attitude apparent in face or speech 4. Fears expressed without questioning

Score


Table 2.12 continued Please enter the appropriate score for each item Item Legend 5. Anxiety somatic

0. Absent 1. Mild 2. Moderate 3. Severe 4. Incapacitating

6. Somatic 0. None symptoms (general) 1. Heaviness in limbs, back or head. Backaches, headache, muscle aches. Loss of energy and ‘fatigability’ 2. Any clear-cut symptoms rate 2 7. Suicide

0. Absent 1. Feels life is not worth living 2. Wishes he or she were dead or any thoughts of possible death to self 3. Suicide ideas or gestures 4. Attempts at suicide (any serious attempt rates 4) Total Score

Score

Interpretation

0–3 4–7 8–15 15 or higher

Normal range; remission Mild severity Moderate severity Marked/severe severity

Score


Table 2.13 Recommendations for maintenance treatment of major depressive disorder Recommendations

Evidence

All patients should continue on antidepressants for at least six months after a full remission of symptoms

Level 1

Patients with the following risk factors require longer maintenance treatment – at least two years, and for some, lifetime: • Chronic episodes (> 2 years’ duration) • Severe episodes (suicidality; psychotic depression) • Resistant or hard-to-treat episodes • Frequent episodes (two episodes in past two years) • Recurrent episodes (three or more lifetime episodes) • Older age (>65 years)

Level 2

The antidepressant dosage in the maintenance phase should be the same dosage as in the acute phase

Level 2

If the decision is made to discontinue an antidepressant, the antidepressant should be tapered slowly to avoid discontinuation symptoms

Level 3

Psychoeducation about early signs of relapse should continue (e.g. recurrence of sleep disturbances) and patients should have regular follow-up every two to three months

Level 3

Psychotherapy, e.g. cognitive behavior therapy (CBT), may be helpful to prevent relapses

Level 2

Comorbid medical conditions and psychiatric disorders should be treated and rehabilitation programs (e.g. vocational counseing) may be helpful

Level 3


Appendix Montgomery Asberg Depression Rating Scale (MADRS) Note: Each item is scored on a 0–6 scale. Although the anchors list only even scores, odd numbers can be used if the rating is between scores. Response 1. Apparent sadness Despondency, gloom and despair that is more than just ordinary transient low spirits

Score

No sadness Looks dispirited but does brighten up without difficulty Appears sad and unhappy most of the time Looks miserable all the time; extremely despondent

0 2

2. Reported sadness Reports of depressed mood regardless of whether it is reflected in appearance or not. This includes low spirits, despondency or the feeling of being beyond help and without hope. Rate according to intensity duration and the extent to which the mood is reported to be influenced by events

Occasional sadness in keeping with the circumstances Sad or low but brightens up without difficulty Pervasive feelings of sadness or gloominess. The mood is still influenced by external circumstances Continuous or unvarying sadness, misery or despondency

0

3. Inner tension Feelings of ill-defined discomfort, edginess, inner turmoil, mental tension mounting to panic, dread or anguish. Rate according to intensity, frequency, duration and the extent of reassurance called for

Placid with only fleeting inner tension Occasional feelings of edginess and ill-defined discomfort Continuous feelings of inner tension or intermittent panic which the patient can only master with some difficulty Unrelenting dread or anguish; overwhelming panic

4. Reduced sleep Reduced duration or depth of sleep compared to the subject’s own normal pattern when well

Sleeps as usual Slight difficulty dropping off to sleep; slightly reduced light or fitful sleep Sleep reduced or broken by at least two hours Less than 2–3 hours of sleep

5. Reduced appetite Loss of appetite compared with when well. There may be a loss of desire for food or the need to force oneself to eat

Normal or increased appetite Slightly reduced appetite No appetite and food is tasteless Needs persuasion to eat at all

4 6

2 4

6

0 2 4

6

0 2 4 6 0 2 4 6

22 Treating Depression Effectively 6. Concentration difficulties Difficulties in collecting one’s thoughts mounting to an incapacitating lack of concentration. This is rated according to the intensity, frequency and degree of incapacity produced

7. Lassitude Difficulty in getting started; slowness in initiating and performing everyday activities

8. Inability to feel Reduced interest in the surroundings or in activities that normally give pleasure. The ability to react with adequate emotion to circumstances is reduced

9. Pessimistic thoughts Feelings of guilt, inferiority, self-reproach, sinfulness, remorse or ruin

No difficulties with concentrating Occasional difficulties in collecting one’s thoughts Difficulties in concentrating and sustaining thought which reduces the ability to read or hold a conversation Unable to read or converse without great difficulty

0 2

Hardly any difficulty in getting started; no sluggishness Difficulties in starting activities Difficulties in starting simple routine activities which are carried out with effort Complete lassitude; unable to do anything without help

0

Normal interest in the surroundings and in other people Reduced ability to enjoy usual interests Loss of interest in the surroundings; loss of feelings for friends and acquaintances Emotionally paralyzed; unable to feel anger, grief or pleasure; complete or even painful failure to feel for close relatives and friends None Fluctuating ideas of failure, self-reproach or self-depreciation Persistent self-accusation or definite but still rational ideas of guilt or sin; increasingly pessimistic about the future Delusions of ruin, remorse or unredeemable sin; self-accusations which are absurd and unshakeable

4

6

2 4

6

0 2 4

6

0 2 4

6


10. Suicidal thoughts Feeling that life is not worth living and/or that a natural death would be welcome; presence of suicidal thoughts and the making of preparations for suicide

Enjoys life or takes it as it comes Weary of life; only fleeting suicidal thoughts Probably better off dead; suicidal thoughts common and suicide is considered as a possible solution but without specific plans or intentions Explicit plans for suicide when there is an opportunity; active preparations for suicide Total score

Score

Interpretation

0–11 12–19 20–29 30 or higher

Normal range; remission Mild severity Moderate severity Marked/severe severity

0 2 4

6


Hospital Anxiety and Depression Scale (HADS) Doctors are aware that emotions play an important part in most illnesses. If your doctor knows about these feelings he or she will be able to help you more. This questionnaire is designed to help your doctor know how you feel. Read each item and place a firm tick in the box opposite the reply that comes closest to how you have been feeling in the past week. Do not take too long over your replies: your immediate reaction to each item will probably be more accurate than a long thought-out response. Tick only one box in each section 1. I feel tense or wound up: ➂ Most of the time ➁ A lot of the time ➀ Time to time 0 Not at all

2. I still enjoy the things I used to enjoy: 0 Definitely as much ➀ Not quite so much ➁ Only a little ➂ Hardly at all

3. I get a sort of frightened feeling as if something awful is about to happen: ➂ Very definitely and quite badly ➁ Yes but not too badly ➀ A little, but it doesn’t worry me 0 Not at all

4. I can laugh and see the funny side of things: 0 As much as I always could ➀ Not quite as much now ➁ Definitely not so much now ➂ Not at all

5. Worrying thoughts go through my mind: ➂ A great deal of the time ➁ A lot of the time ➀ From time to time but not too often 0 Only occasionally

6. I feel cheerful: ➂ Not at all ➁ Not often ➀ Sometimes 0 Most of the time

7. I can sit at ease and feel relaxed: 0 Definitely ➀ Usually ➁ Not often ➂ Not at all

8. I feel as if I am slowed down: ➂ Nearly all the time ➁ Very often ➀ Sometimes 0 Not at all

9. I get a sort of frightened feeling like butterflies in the stomach: 0 Not at all ➀ Occasionally ➁ Quite often ➂ Very often

10. I have lost interest in my appearance: ➂ Definitely ➁ I don’t take so much care as I should ➀ I may not take quite as much care 0 I take just as much care as ever


11. I feel restless as if I have to be on the move: ➂ Very much indeed ➁ Quite a lot ➀ Not very much 0 Not at all

12. I look forward with enjoyment to things: 0 As much as ever I did ➀ Rather less than I used to ➁ Definitely less than I used to ➂ Hardly at all

13. I get sudden feelings of panic: ➂ Very often indeed ➁ Quite often ➀ Not very often 0 Not at all

14. I can enjoy a good book or radio or TV program: 0 Often ➀ Sometimes ➁ Not often ➂ Very seldom

Total for odd-numbered questions Anxiety score:

Total for even-numbered questions Depression score:

Scoring: On either subscale a score of 8 or more is significant; a score of 11 or more is highly significant


Patient Health Questionnaire – PHQ-9 (www.primary-care.org) 1. Over the last 2 weeks, how often have you been bothered by any of the following problems?

Not at all (0)

Several days (1)

More than half the days (2)

Nearly every day (3)

a. Little interest or pleasure in doing things b. Feeling down, depressed or hopeless c. Trouble falling/staying asleep; sleeping too much d. Feeling tired or having little energy e. Poor appetite or overeating f. Feeling bad about yourself, or that you are a failure, or have let yourself or your family down g. Trouble concentrating on things, such as reading the newspaper or watching TV h. Moving or speaking so slowly that other people could have noticed. Or the opposite: being so fidgety or restless that you have been moving around more than usual i. Thoughts that you would be better off dead or of hurting yourself in some way

2. If you checked off any problem on this questionnaire so far, how difficult have these problems made it for you to do your work, take care of things at home or get along with other people? Not difficult

Somewhat

Very

Extremely

at all

difficult

difficult

difficult

Total score __________

Instructions: how to score the PHQ-9 Major depressive disorder is suggested if: 1. Of the nine items, five or more are checked as at least ‘more than half the days’;


2. Either item a. or item b. is positive, that is, at least ‘more than half the days’. Other depressive syndrome is suggested if: 1. Of the nine items, a, b. or c. is checked as at least ‘more than half the days’; 2. Either item a. or item b. is positive, that is, at least ‘more than half the days’. Also, PHQ-9 scores can be used to plan and monitor treatment. To score the instrument, tally each response by the number value under the answer headings, (not at all = 0, several days = 1, more than half the days = 2 and nearly every day = 3). Add the numbers together to total the score on the bottom of the questionnaire. Interpret the score by using the guide below.

Guide for interpreting PHQ-9 scores Score

Action

0–4

The score suggests the patient may not need depression treatment

5–14

Mild major depressive disorder. Physician uses clinical judgment about treatment, based on patient’s duration of symptoms and functional impairment

15–19

Moderate–major depressive disorder. Warrants treatment for depression, using antidepressant, psychotherapy or a combination of treatment

20 or higher

Severe major depressive disorder. Warrants treatment with antidepressant, with or without psychotherapy, follow frequently

Functional health assessment The instrument also includes a functional health assessment. This asks the patient how emotional difficulties or problems impact work, things at home or relationships with other people. Patient responses can be one of four: not difficult at all; somewhat difficult; very difficult; extremely difficult. The last two responses suggest that the patient’s functionality is impaired. After treatment begins, functional status and number score can be measured to assess patient improvement.

Conclusions Treating depression effectively requires a long-term focus, since it is important not only to get patients well, but also to keep them well. Attending to

28 Treating Depression Effectively the principles of management for patients with depression: careful diagnostic assessment; recognition of the various tasks and goals for acute and maintenance phases of treatment; selection of evidence-based treatments; appropriate monitoring and follow-up will provide the best chance for optimal outcome and restoring full psychosocial function.

Bibliography Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. J Pers Assess 1996; 67: 588–97. Cummings JL. Clinical Neuropsychiatry. Orlando, FL: Grune & Stratton, 1985. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6: 278–96. Hirschfeld RM, Williams JB, Spitzer RL et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry 2000; 157: 1873–5. Kroenke K, Spitzer RL, Williams JB. The PHQ–9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16: 606–13. McIntyre R, Kennedy S, Bagby RM, Bakish D. Assessing full remission. J Psychiatry Neurosci 2002; 27: 235–9. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–9. Reesal RT, Lam RW, the CANMAT Depression Work Group. Clinical guidelines for the treatment of depressive disorders. II. Principles of management. Can J Psychiatry 2001; 46 (Suppl 1): 21S–8S. Sheehan DV, Lecrubier Y, Sheehan KH et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD–10. J Clin Psychiatry 1998; 59 (Suppl 20): 22–33. Spitzer RL, Williams JBW, Gibbon M, First MB. Structured Clinical Interview for DSMIV (SCID-IV). Washington, DC: American Psychiatric Press, 1995. Trivedi MH, Rush AJ, Wisniewski SR et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 28–40. Wilkinson MJ, Barczak P. Psychiatric screening in general practice: comparison of the general health questionnaire and the hospital anxiety depression scale. J R Coll Gen Pract 1988; 38: 311–13.

Chapter 3

Psychotherapies, alone and in combination

Introduction Psychotherapy is the oldest form of treatment for depression still in wide use, yet historically it has been the least well established in terms of evidence from controlled clinical trials. Once relegated to the sidelines of research on the differential therapeutics of mood disorders, several forms of depression-focused psychotherapy have now been identified as being efficacious treatments of major depressive disorder (MDD). These contemporary, depression-focused forms of therapy are characterized by a number of elements that have permitted investigation in controlled clinical trials: (1) they are intended to be shorter-term, time-limited interventions (which approximate the length of the acute phase of pharmacotherapy); (2) they are conducted according to procedurally specified protocols; and (3) they are targeted to relieve the core symptoms of the depressive disorder. The empirically verified forms of psychotherapy for depression have evolved from the disparate traditions of radical behaviorism, psychoanalysis and social work. Although each of these depression-focused psychotherapies emphasizes the importance of different aspects of the patient’s phenomenological world, e.g. cognitive, behavioral or interpersonal factors that may be related to the onset or persistence of the depressive state, there are nevertheless a number of common or pan-theoretical elements. All emphasize pragmatic approaches to ‘here and now’ problems and a high level of activity on the part of the therapist. Monitoring of symptom outcomes is an integral part of treatment, and measures such as the Beck Depression Inventory are used routinely to document progress. The depression-focused psychotherapies also make ample use of psychoeducation, including both information

30 Treating Depression Effectively about the nature of depression and how the methods of therapy will be used to address these problems. Many patients perceive these therapies to be directly relevant to their problems and experience an immediate moraleboosting effect, which serves to amplify expectations for success. Of course, the depression-focused psychotherapies also build upon a foundation of basic psychotherapeutic skills. These skills include the abilities to form an effective working alliance with the patient, maintain professional boundaries and promote a safe therapeutic milieu.

Treatment overview and limitations The recommendations included in this chapter are based on the results of studies using specific forms of cognitive, behavioral and interpersonal psychotherapy. While evidence from randomized controlled trials (RCTs) is central to establishing treatment efficacy, it is noted that not all treatments have been evaluated in this manner. Moreover, the number of studies available to evaluate a particular treatment is not a reliable indicator of the intervention’s inherent worth. Thus, the statement: ‘There is no evidence that Treatment X is effective’ should not be viewed as synonymous with the statement that: ‘Treatment X is not effective’. Psychoanalytic psychotherapy, which has seldom been studied in controlled trials, represents a case in point. That said, an evidence-based approach to therapeutics gives higher rankings to interventions that have been evaluated in multiple RCTs and have been shown to have effects that surpass those of credible control groups (i.e. pill placebo or pseudotherapy conditions). Depression-focused psychotherapy can be provided by clinical psychologists, psychiatrists and experienced masters degree prepared clinicians (e.g. social workers, nurses and counselors). In our experience, virtually all capable therapists can learn to conduct at least one type of depression-focused psychotherapy. At least six months of supervised practice, augmented by readings and watching videotapes, is usually needed to achieve the minimum level of competence used to qualify therapists for participation in research studies. Some forms of therapy, such as Beck’s model of cognitive therapy, may require an even longer period of training and supervision. Although all forms of depression-focused psychotherapy have been adapted for use in group and couples formats, most research studies mirror practice patterns by continuing to emphasize individual models of treatment. Sessions typically last 45–60 minutes and are conducted either twice

Psychotherapies, alone and in combination 31

weekly or once a week. The latter is assuredly more common; the former may convey some advantage early in the course of treatment when working with more severely or chronically depressed patients. A standard course of therapy thus consists of 12–20 sessions provided across three to four months. Extended models of continuation (up to nine months) and maintenance (up to three years) phase psychotherapy have been developed for the treatment of patients at high risk for relapse or recurrence. It is noted that relatively few practitioners have received extensive training in one or more of these forms of therapy. Moreover, even fewer practicing clinicians actually employ ‘pure’ models of psychotherapy; most prefer to use an eclectic mix of interventions. If the specific techniques used in the different models of depression-focused psychotherapy actually contribute to treatment efficacy, eclecticism may run the risk of diluting the utility of therapy. In cognitive therapy, for example, several groups have found that routinely using an agenda to begin sessions and carefully attending to homework assignments correlate with better outcomes. As neither of these relatively basic strategies are particular favorites of a traditionally trained therapist, it is plausible that deviations from the ‘pure’ model of therapy may reduce efficacy. Therefore, the guidelines outlined below may not be applicable to the more widely practiced, eclectic forms of psychotherapy.

Indications for psychotherapy alone Several factors may be used to guide case selection for treatment with a depression-focused psychotherapy alone, instead of pharmacotherapy. First and foremost, the depression-focused psychotherapies have not been evaluated for treatment of the most severe depressive states, such as psychotic depression. Some evidence suggests that patients presenting with more severe forms of recurrent depression may be less likely to respond to psychotherapy alone (as compared with the combination of psychotherapy and pharmacotherapy). Similarly, psychotherapy alone should not be used to treat bipolar depression without appropriate concomitant pharmacotherapy. Case selection should therefore focus on ambulatory patients with mild-tomoderately severe non-psychotic, non-bipolar depressive disorders. As is the case for other interventions, better outcomes are usually observed among people with more acute, circumscribed problems. A second important factor is patient preference. Some people have decidedly non-medical treatment preferences and feel more comfortable approaching

32 Treating Depression Effectively their problems from a psychosocial perspective. Yet others have comparably strong negative biases against psychotherapy. When all other factors are equal, patients should be able to receive their treatment of first choice. Availability of therapists is sometimes a rate-limiting step, particularly in rural areas. If a therapist is not trained in one of the newer, empirically validated therapies, factors such as communication with the referring physician, assessing syndromal outcome, and willingness to refer back for pharmacotherapy when the patient is not responding to treatment can serve as proxies for quality control.

General principles of cognitive, behavioral and interpersonal therapies Many practitioners blend cognitive and behavioral therapies, the result being referred to as cognitive behavior therapy (CBT). In the following brief descriptions, however, these models will be described separately for heuristic reasons.

Cognitive therapy Beck’s model of cognitive therapy (CT) is based on the proposition that changes in depressed patients’ maladaptive ways of thinking are the most direct means to achieve durable symptomatic relief. CT is aimed at modifying three levels of cognition. At the most fundamental level are schemas, which are the core beliefs or unspoken principles that organize perception and guide behavior. The knowledge of how to tie a shoe lace is an example of a simple schema used in everyday life. Of greatest relevance to depression are schemas about lovability, self-worth, fairness and the trustworthiness of significant others. At a second, more accessible level are dysfunctional attitudes, which are the more specific rules that translate or operationalize schemas. For example, someone with a schema of low self-worth may approach life with the following operational attitude: ‘I must succeed at everything I do’. A depressogenic attributional style (i.e. the predisposition to view a negative event to have large, irreversible effects) is another example of this level of cognitive dysfunction. At the most superficial level are the thoughts, images, memories and daydreams that constitute the depressed person’s waking mental life. These various types of ‘surface’ cognition can be recorded as a way of objectifying a


depressed individual’s running negative commentary about self, the world and the future (which was referred to by Beck as the ‘cognitive triad’). When such spontaneous cognitions are associated with dysphoric effects, they are referred to as automatic negative thoughts. Turning one of Freud’s dictums on its head, Beck asserted that affect is the ‘royal road to cognition’. Cognitive therapists help patients to recognize the link between depressive feelings and habitual ways of thinking and begin to organize automatic negative thoughts into themes, which in turn can guide case formulations about schematic vulnerability. The cognitive model of psychopathology also emphasizes the importance of information processing biases that tend to increase states of affective distress. These biases include processes such as selective abstraction, overgeneralization, emotional reasoning, all-or-none thinking, personalization and ‘mind-reading’. During depressive states memory retrieval is biased, with relatively decreased access to positive or disconfirmatory memories and greater access to mood-congruent, negatively themed memories. Effective cognitive therapists employ a high degree of structure to help patients focus on learning more active and effective ways of coping. Each session is organized around an agenda that almost always includes three activities: symptom evaluation; review of homework; and selection of new homework activities. These tasks are sandwiched around two or three other segments of in-session work. Therapists use a style of interaction referred to as collaborative empiricism, which emphasizes guided discovery (also known as Socratic questioning). The therapist’s role as a guide or teacher is thus emphasized, although it should not be at the expense of maintaining an empathic rapport. Therapists seek explicit feedback at each transition point in a session to help ensure that patients are in ‘synch’ with the material being discussed, and feel understood by (and connected to) the therapist. In a typical course of CT (Table 3.1), the early phase (e.g. sessions 1–6) emphasizes establishing a therapeutic relationship, enculturating patients to the style of the therapy, educating them about the cognitive model of treatment, identifying target symptoms and setting shorter-term goals and establishing the relationship between depressive feelings and automatic negative thoughts. In practice, it is usually helpful to also use behavioral activation strategies (described below) to help patients begin to engage in more productive activities. The middle phase of therapy (e.g. sessions 7–12) centers around extensive use of a systematized approach to addressing automatic negative thoughts.


Table 3.1 Phases of treatment with CT Early phase (sessions 1–6) • Establishes therapeutic relationship • Identifies target symptoms and short-term goals • Educates about model and clarifies links between depressive feelings and automatic negative thoughts Middle phase (sessions 7–12) • Systematized approach to addressing automatic negative thoughts – Daily Record of Dysfunctional Thoughts Later phase (session 13 to end) • Identification of risk factors for relapse • Implementation of balanced view of self, the world and the future • Preparation for termination

Using a form called the Daily Record of Dysfunctional Thoughts, patients learn to focus on periods of low mood by recording the following sequence: the event; mood state (pre-intervention); automatic negative thoughts; rational alternatives; and mood state (post-intervention). Asking patients to write down their automatic negative thoughts as well as rational alternatives helps the individual to examine the basis for these and to consider different (less biased) interpretations. The later phases of CT (e.g. sessions 13 through termination) address preparing the patient for termination, including the identification of highrisk situations relevant to relapse risk and facilitating self-directed learning via more independent homework tasks. Longer-term goals are set and a life plan is developed to help guide goal attainment. Ideally, a successfully treated patient will have recognized their schematic vulnerability, practiced living with more functional attitudes and have begun to implement a life plan that will support a more balanced way of thinking about oneself, the world around and the future. In some countries it may be difficult to find a capable, well-trained cognitive therapist. Where available, local professional societies may be helpful. Alternatively, the shortage of trained therapists may be offset by the use of computer-assisted models of CT, such as the one developed for CD-ROM by Wright, Wright and Beck. A number of useful self-help manuals are also available, including Mind Over Mood (Greenberger and Padesky, 1995) and The Feeling Good Handbook (Burns, 1999).


Behavior therapy Behavior therapies (BTs) are based on the fact that depression is associated with decreased levels of operant (goal-directed) behavior and a resulting deficit in positive reinforcement. The anhedonia of depression may actually reduce the reinforcing ‘power’ of pleasurable activities, underpinning cognitions such as ‘Why bother – it won’t make a difference’. Most depressed people also manifest behavioral excesses (i.e. crying, complaining and other signs of hyperarousal including anxiety and insomnia). A third set of targets for behavioral interventions results from recognition that some people prone to depression have longstanding difficulties in assertiveness, conflict resolution and problem solving. These social skill deficits increase the likelihood of difficulties in both intimate relationships and vocational pursuits. In the early stages of behavior therapy, patients learn to monitor their moods and activities and to rate the associated degree of mastery and pleasure. Typically, a patient would be asked to keep an hour-by-hour or day-by-day log of their activities and mood states. If this functional analysis reveals deficits in mastery or pleasure, homework assignments are used to increase the level of behavioral activation. Large, potentially overwhelming tasks are tackled by homework assignments that break down a complex chain of behaviors into more manageable units; this technique is referred to as graded task assignment. Specific behavioral strategies, including progressive deep muscle relaxation, diaphragmatic breathing and thought stopping, are utilized when indicated to help patients cope with symptoms of anxiety and insomnia. Social skills training (including behavioral rehearsal and role playing) might be used later in the course of therapy to help increase self-confidence and address the patient’s difficulties in relationships. Similarly, a step-wise approach to problem solving may be used to help patients incorporate a more systematic method into their repertoire to help lessen the impact of future stressors. The book Coping with Depression (Beck and Greenberg, 1974) outlines a 12-session course of behavior therapy developed for individual or group interventions.

Cognitive Behavioral Analysis System of Psychotherapy A hybrid model of treatment, referred to as the Cognitive Behavioral Analysis System of Psychotherapy (CBASP), was developed by McCullough (2000) to address the more pervasive and longstanding problems of patients with chronic forms of depression. CBASP is distinguished from CT by the use of a standardized, relationship-based approach to problem solving. This method builds upon a situational analysis of behavior by incorporating the patient’s desired

36 Treating Depression Effectively outcomes and an appraisal of what prevented obtaining that desired outcome. In short, CBASP takes a very ‘molecular’, situation-by-situation approach to help patients learn to become more effective in their interpersonal relations. CBASP was initially developed and tested as a 12-week (16–20 session) intervention. As clinical experience with more complex and dysfunctional populations has accrued, therapists have often added an additional continuation phase, which permits four to six additional months of less frequent sessions to work on generalization and mastery of the skills learned during the acute phase of therapy.

Interpersonal psychotherapy By contrast, interpersonal psychotherapy (IPT) uses more conventional ‘talk therapy’ strategies to address the problems that patients face in relation to the onset or persistence of the depressive disorder. There is a basic assumption in IPT that depression is a biopsychosocial phenomenon, and that addressing interpersonal difficulties, whether they are contributing factors or consequences of the disorder, will facilitate symptomatic improvement. Paradoxically, IPT is the form of depression-focused psychotherapy that most explicitly embraces a medical or illness model, yet takes the most decidedly traditional approach to foster symptom resolution. The work of IPT revolves around addressing problems in one or more of the following themes: unresolved grief; role transitions; role disputes; and interpersonal deficits (i.e. loneliness and social isolation). This therapy is less structured than CT or CBASP, although therapists may actively assist the patient to clarify, resolve and/or better cope with their interpersonal problems. Strategies include eliciting emotional expression to facilitate grief work, brainstorming to identify novel methods to resolve impasses in communication with significant

Table 3.2 Phases of treatment with IPT Early phase (sessions 1–6) • Establish a working alliance • Provide education about depression and the IPT model • Develop interpersonal industry Middle phase (sessions 7–12) • Work on resolution of problem areas defined in early phase, e.g. facilitate grief work, resolve impasses in communication with significant others, etc. Later phase (sessions 13–16) • Review course of treatment and suggest techniques to deal with anticipated future problems


others, acceptance of problems that cannot be changed and encouragement to try out different types of social activities to reduce social isolation. IPT is typically conducted with 12–16 weekly sessions (Table 3.2), which can be viewed as divisible into three phases. Therapists use the earlier sessions to develop the interpersonal inventory, as well as to establish a working alliance, provide education about depression and acclimatize patients to the workings of psychotherapy. The middle phase of IPT is intended for work on resolution of one or more of the problem areas noted on the interpersonal inventory. Although IPT does not prescribe the use of specific cognitive or behavioral strategies or make regular use of formal homework assignments, there is a degree of technical eclecticism permitted that results in overlap with CT and BT. A final or termination phase (e.g. sessions 13–16) is devoted to reviewing the course of treatment and discussing anticipated future problems. One resource for learning more about IPT is the textbook A Comprehensive Guide to Interpersonal Psychotherapy (Weissman et al., 2000).

Effectiveness of depression-focused psychotherapies As of March 2007, there are more than 100 published studies that have evaluated the efficacy of one or more forms of depression-focused psychotherapy. The most clear-cut evidence comes from studies that have used waiting lists or pseudotherapy control conditions. A number of meta-analyses document that cognitive and behavioral therapies have definite efficacy when compared with these relatively weak standards. Although only a few IPT studies used such a low contact control condition, these studies consistently documented significant antidepressant effects. For psychiatrists, RCTs that compare a depression-focused psychotherapy with antidepressant pharmacotherapy provide a more meaningful index of therapeutic benefit. This design also permits the efficacy of the active comparator – pharmacotherapy – to be established in relation to a pill placebo. Again, meta-analyses document efficacy: all three forms of depression-focused psychotherapy have effects that are comparable (definitely not inferior) to those documented for antidepressants as administered in these trials. Unfortunately, as only a few of these RCTs have employed a pill placebo control group, one could still assert that the studies do not unequivocally confirm the efficacy of psychotherapy (i.e. it is possible that the RCTs systematically sampled from patient groups that are less responsive to pharmacotherapy). Although the weight of evidence from published RCTs favors CT, there is little evidence that one model of depression-focused therapy is more effective

38 Treating Depression Effectively than any other. This is particularly true after the impact of the allegiance of the studies’ principal investigators is taken into account. It is not clear if the allegiance effect reflects a higher level of expertise with the particular model of therapy or, more likely, a greater expectation that the ‘chosen’ therapy will be more effective. The only way to neutralize an allegiance effect is to ensure that each therapy in a comparative study is administered with a comparable level of expertise, enthusiasm and expectation. Only two published trials have directly compared CT and IPT. Results from the first of these studies, the Treatment of Depression Collaborative Research Project (TDCRP), have had the most impact. This trial was relatively large (i.e. 250 patients), had the imprimatur of the US Government’s National Institute of Mental Health and exemplified the state of the art in psychotherapy outcome research at the time the study was conducted (1981–84). Moreover, in addition to using an active control group, treatment with the antidepressant imipramine, the study included a fourth group that received double-blind placebo. Overall, the TDCRP found some advantage for each of the active treatments when compared to the placebo control group, but the differences were modest and inconsistent. Among the less severely depressed subgroup of patients (~60% of the sample), the patients treated with placebo generally did as well as those who received the active treatments. In the more severely symptomatic subgroup, imipramine therapy was definitely superior to placebo, with IPT and CT showing intermediate effects. Comparing the two psychotherapies, non-significant trends favored IPT over CT, and there was some evidence of differential predictors of psychotherapy response. Within the IPT cell, therapy was more effective among patients with endogenous features, less pathologic personality profiles and less social impairment. Among those treated with CT, outcomes were better for married patients, as well as those with atypical depression or relatively low levels of cognitive distortions. A strong therapeutic alliance was predictive of improvement in all four treatment modalities, whereas chronicity of illness predicted poorer across-the-board outcomes. The second trial compared response to IPT and CBT among a predominantly male, human immunodeficiency virus (HIV)-positive patient group with either dysthymia or MDD. In this 16-week trial, IPT (n = 24) and supportive therapy plus imipramine (n = 26) were comparably effective and both interventions were significantly more effective than both CT (n = 27) and supportive therapy alone. Comparing the two psychotherapies, the outcome of the IPT group was strikingly superior to that of the CT group (e.g. a mean difference in final Hamilton Rating Scale for Depression (HAM-D) scores of nearly 0.8 standard deviation units).


Table 3.3 Recommendations for individual, group and marital therapies Therapeutic choice

Recommendations

Evidence

First

Individual CBT or IPT for non-psychotic non-bipolar MDD Group formats of CBT: there is less evidence for efficacy of group as compared to individual forms of psychotherapy and the latter is recommended for treatment of more severe depressive episodes

Level 1

Marital or couples therapy, in patients with significant marital distress

Level 2

Second

Third

Level 2

Although a number of studies have compared CT and BT, most studies were inconclusive because of low statistical power and, frankly, flawed by strong investigator allegiance effects. One large (n = 150) study found CT, BT and their combination to be comparably effective treatments for outpatients with mild-to-moderately severe depressive episodes. In a subsequent report, this group of investigators both confirmed and extended these findings, with the more severely depressed subset of the BT group improving as much as patients randomly assigned to paroxetine and significantly more so than those treated with double-blind pill placebo. Several randomized studies have contrasted group and individual forms of CT or BT. Results of meta-analyses of comparative studies documented that group therapies were effective (compared to waiting list controls), with antidepressant effects that approached the magnitude of individual therapy. Likewise, both BT and CT have been modified for the treatment of depression within couples therapy formats. Among depressed patients with distressed marriages, the couples approach had antidepressant effects comparable to individual CT, with broader, mode-specific effects on dyadic adjustment. This information is summarized in Table 3.3.

Other psychosocial treatments for depression The simplest, least expensive approach to treatment is bibliotherapy (Table 3.4), which relies upon books such as The Feeling Good Handbook (Burns, 1999) to convey the therapeutic intervention. A number of studies have compared bibliotherapy to a waiting list control condition in patients with milder depressive states.


Table 3.4 Recommendations for other psychosocial treatments Therapeutic choice

Recommendations

Evidence

First

None are recommended in lieu of standard treatments Exercise is an effective adjunct to standard treatments

Level 1

Second

Bibliotherapy – this should be considered an adjunct treatment to other first line treatments

Level 2

Third

Yoga – this should be considered an adjunct treatment to other first line treatments

Level 3

A meta-analysis of the first six studies concluded that bibliotherapy has a definite therapeutic effect, which may be especially useful for depressed people who are unable to see a psychotherapist. In the 21st century it is likely that bibliotherapy will be replaced by various forms of internet- and computer-administered therapy. A number of studies have found that internet applications of CT likewise have antidepressant effects that surpass the improvements observed in waiting list control conditions. In one recent randomized controlled study, a hybrid model of therapy utilizing DVD-ROM modules and brief ‘in person’ sessions was at least as effective as a full course of conventional CT. Computerized CT has also proved effective when evaluated in depressed patients in primary care. Yoga and meditation may facilitate self-awareness, acceptance and tolerance of affective experience, which are useful skills for dealing with some aspects of depression, such as anxious hyperarousal and ruminative negative thinking. However, there are no well-controlled RCTs of these approaches. Mindfulness based stress reduction combines mindfulness meditation and yoga, while mindfulness based cognitive therapy (MBCT) provides information about depression as well as cognitive therapy based exercises. Positive results with MBCT for relapse prevention have been reported. By contrast, aerobic exercise has been studied and found to have antidepressant effects of sufficient magnitude to warrant use as a routine adjunct to all standard therapies (see Chapter 9).

Preventive effects of depression-focused psychotherapies The relatively higher shorter-term costs of the depression-focused psychotherapies could be offset if it was shown that treatment had enduring


effects on subsyndromal, residual symptoms or relapse rates. This is particularly important because the well-established preventive effects of pharmacotherapy are essentially lost within six months of stopping antidepressants. Some evidence of durability of antidepressant effects following acute phase CT has been reported. Follow-up studies of a number of the early RCTs contrasting CT and pharmacotherapy have yielded fairly consistent findings that suggest some enduring benefit over one or two years. In these studies, patients who had responded to pharmacotherapy had a higher probability of relapse after withdrawal of medication than patients who had responded to CT (e.g. 50–66% relapse risk following medication discontinuation versus 20% following termination of CT). The major exception to this pattern of results came from the follow-up of the TDCRP, in which patients treated with CT were about as likely to relapse as were patients who had been treated with other modalities (i.e. interpersonal psychotherapy, imipramine and clinical management, or placebo and clinical management). Although these results are not indicative of a more durable benefit, it should be recalled that CT was not a particularly effective treatment in that study and the absence of a significant difference between the groups treated with imipramine and placebo calls into question the power/assay sensitivity of the design. In addition a lack of evidence of enduring antidepressant effects was observed for IPT in either the TDCRP or the initial RCT conducted by the treatment’s developers. Work by Thase, Jarrett and their colleagues suggests that an enduring benefit following a time-limited course of CT is contingent upon achieving a full and stable remission within the first eight weeks of therapy. When response was so classified in two independent studies, fewer than 10% of this remitted group relapsed across one year after treatment termination, as compared to 50–60% of those who responded in a slower or less complete manner.

Continuation phase psychotherapy Based on the association between residual symptoms and/or slower remission and relapse following termination of acute phase CT, Jarrett and colleagues developed a ten-session, eight-month model continuation phase CT. The efficacy of this strategy was suggested in a case control study and confirmed (relative to an assessment-only control condition) in a prospective RCT. Of note, patients who had remitted rapidly during acute phase CT


Table 3.5 Recommendations for psychotherapy as maintenance treatment Recommendations

Evidence

• There is limited evidence to recommend psychotherapy as maintenance treatment

Level 2

• Acute phase treatment with CT may have sustained benefits that provide modest protection against relapse

Level 2

• Longer-term models of CT and IPT may reduce relapse rates, although there is insufficient evidence about the optimal frequency and duration of maintenance sessions

Level 2

obtained no further objective benefit from the additional therapy sessions included in the continuation phase. In other words, their low risk of relapse could not be reduced further. For the patients whose response to CT was slower or less complete, by contrast, continuation phase therapy conveyed a three-fold reduction in relapse risk. Maintenance phase models of psychotherapy have been developed as an analog to prophylactic pharmacotherapy (Table 3.5). Three studies have investigated the impact of monthly sessions of IPT after successful acute phase treatment in combination with antidepressants. In the first study of adults with a history of highly recurrent depressive episodes, monthly sessions of IPT resulted in a modest reduction in recurrence risk after withdrawal of pharmacotherapy. However, maintenance IPT did not significantly extend survival time for patients who continued to take imipramine, and the effect of IPT alone paled in comparison with the preventive effect of the antidepressant. In the other two studies, which focused on recurrent depression in late life, the effects of IPT and antidepressants alone (study 1: nortriptyline; study 2: paroxetine) were modest when compared with maintenance therapy with the combination. In fact, in the second study, maintenance IPT alone did not significantly reduce the relapse of recurrence compared to placebo.

Combining antidepressants and psychotherapy For many years, combined treatment was one of the cornerstones of the practice of psychiatry. However, in an era of limited resources, the additional costs of combined treatment (not only economic costs but also costs associated with side-effects and time for treatment) may not be justified if results are not


Table 3.6 Recommendations for concurrent combined treatment Therapeutic choice

Recommendations

Evidence

Acute phase treatment – concurrent combined treatment is recommended in the following circumstances: First

Severe depression – IPT + pharmacotherapy are more effective than either treatment alone Chronic depression – although the combination of Cognitive Behavioral Analysis System of Psychotherapy (CBASP) and nefazodone was more effective than either treatment alone, nefazodone is no longer available and replication is required with an available antidepressant

Level 1 Level 2

Maintenance phase treatment – concurrent combined treatment is recommended in the following circumstances: First Elderly patients – IPT + nortriptyline reduces recurrence Level 2 rates compared to either treatment alone in patients treated with the combination in the acute phase

clearly superior to monotherapies. Despite the public health importance of this issue, there are very few adequately powered studies evaluating combined treatment. There are three key reasons to consider combining psychotherapy and pharmacotherapy (Table 3.6): (1) increasing acute phase efficacy; (2) broadening the scope of response; and (3) reducing the subsequent risk of relapse/recurrence. Nevertheless, most of the earlier studies of combined treatment failed to detect additive effects on any of these indices. In fairness, however, it is likely that this lack of effect was probably the result of a type 2 error, because none of these studies had adequate statistical power to detect moderately sized additive effects. Alternatively, it is plausible that it is not necessary to combine treatment modalities for the relatively easier-to-treat depressions, i.e. milder, more acute first or second episode cases without significant comorbidity, and that the modest ‘average’ advantage of combined treatment in smaller controlled studies reflected the heterogeneity of the patient groups studied (i.e. an admixture of easier and more difficult-to-treat cases). Evidence in support of both propositions is found in a pooled analysis of 595 depressed outpatients who had received 16 weeks of CT, IPT alone or IPT plus antidepressants. There was a modest difference in remission rates among the less severely depressed patients (psychotherapy alone, 37%; combined treatment, 48%). The magnitude of this difference is comparable to

44 Treating Depression Effectively the ‘not statistically significant’ differences observed in the early controlled trials of combined treatment. By contrast, combined treatment conveyed a marked advantage (over psychotherapy alone) for patients with more severe depressive episodes (remission rates: 49% versus 25%). Further evidence that combined treatment conveys a large advantage for a more difficult-to-treat subset of patients was revealed in a large RCT delimited to patients with chronic forms of depression. In this multicenter trial, the combination of nefazodone and CBASP was significantly more effective than either treatment alone (response rates for CBASP, nefazodone and the combination were 48%, 48% and 73%, respectively). The advantage of adding CBASP to nefazodone was particularly evident among the subset of patients with a history of physical, emotional or sexual trauma. Unfortunately, nefazodone is no longer available and these results require replication with other antidepressant medications. Curiously, although anxiety disorder and personality disorder comorbidities are also widely thought to increase treatment difficulty, there have been no prospective studies to date to systematically evaluate the additive effects of psychotherapy and pharmacotherapy in such complicated patients. With a few exceptions, combined treatment is provided by either a psychiatrist or a primary care physician and a non-medical therapist working together. When two clinicians are involved, ongoing communication to lessen the impact of splitting, provision of coherent education about both modalities and explicit respect for the other member of the treatment team are important ingredients. We are not aware of any studies formally comparing single- and two-provider forms of combined treatment.

Sequential combined treatment Combined treatment can also be provided in sequence (Table 3.7). Results of one case control study suggested that it may be more efficient to provide IPT and pharmacotherapy in sequence rather than routinely start the therapies in combination. Specifically, 79% of the group treated with IPT followed, if indicated, by pharmacotherapy achieved remission, as compared with 66% in a historical comparison group that was treated with both IPT and imipramine from the outset of treatment. Conversely, the benefit of adding CT to antidepressant medications was demonstrated in three studies: two focusing on patients who obtained partial remission on antidepressants and one studying patients with highly recurrent depression who were being


Table 3.7 Recommendations for sequential combined treatment. Sequential application of therapies (i.e. adding psychotherapy following partial response to pharmacotherapy) may be an effective strategy Therapeutic choice

Recommendations

Evidence

First

Adding CT to treat residual depressive symptoms after acute treatment with pharmacotherapy improves remission rates and reduces relapse/recurrence rates Adding pharmacotherapy for women with partial or no response after acute treatment with IPT improves remission rates

Level 2

Level 3

withdrawn from medication. In all three trials CT reduced the risk of relapse, and, in two of the studies, patients who received CT were significantly more likely to discontinue antidepressants without relapsing. In a large sequencing trial that mainly involved switch and augmentation pharmacotherapy (STAR*D – see Chapter 7 page 93 for review) CT was surprisingly unacceptable as an option for two-thirds of eligible candidates. Response and remission rates among those who accepted this option was comparable to the pharmacotherapy groups, although the time to response/remission was approximately 3 weeks in the group that had added to ongoing citalon therapy as compared to those in the medication regimmen group. Two studies have evaluated the preventive effects of a modified form of group CBT emphasizing the use of mindfulness based cognitive therapy strategies (MBCT); both studies compared MBCT with treatment as usual (TAU) for relapse prevention in patients who had both recovered from a recent episode of recurrent depression and elected to stop antidepressant medication. Both studies found that MBCT significantly reduced the risk of recurrence, particularly among patients who had experienced three or more lifetime depressive episodes.

Conclusions There is sufficient evidence to consider three forms of depression-focused psychotherapy (CT, BT and IPT) to be effective treatments for mild-tomoderately severe, non-bipolar depressive disorders. When available and

46 Treating Depression Effectively preferred by the patient, these therapies may be first choice interventions. Concurrent depression-focused psychotherapies also increase the effectiveness of pharmacotherapy for patients with severe, recurrent or chronic depression. Sequential application of treatments is a possible alternative. Although long-term enduring benefits have not been definitively established, some evidence does support preventive effects following termination of CT or with continuation of CT or IPT.

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Psychotherapies, alone and in combination 47 Frank E, Grochocinski VJ, Spanier CA et al. Interpersonal psychotherapy and antidepressant medication: evaluation of a sequential treatment strategy in women with recurrent major depression. J Clin Psychiatry 2000; 61: 51–7. Freud S. Mourning and melancholia. In: Strachey J, ed. The Standard Edition of the Complete Psychological Works of Sigmund Freud, Vol. 20. London: Hogarth Press, 1957: 87–174. Gloaguen V, Cottraux J, Cucherat M, Blackburn IM. A meta-analysis of the effects of cognitive therapy in depressed patients. J Affect Disord 1998; 49: 59–72. Greenberger D, Padesky CA. Mind Over Mood. New York: Guilford Press, 1995. Hollon SD, DeRubeis RJ, Evans MD et al. Cognitive therapy and pharmacotherapy for depression. Singly and in combination. Arch Gen Psychiatry 1992; 49: 774–81. Hollon SD, DeRubeis RJ, Shelton RC et al. Prevention of relapse following cognitive therapy vs medications in moderate to severe depression. Arch Gen Psychiatry 2005; 62: 417–22. Hollon SD, Jarrett RB, Nierenberg AA et al. Psychotherapy and medication in the treatment of adult and geriatric depression: which monotherapy or combined treatment? J Clin Psychiatry 2005; 66: 455–68. Hollon SD, Stewart MO, Strunk D. Enduring effects for cognitive behavior therapy in the treatment of depression and anxiety. Annu Rev Psychol 2006; 57: 285–315. Jarrett RB, Kraft D, Doyle J et al. Preventing recurrent depression using cognitive therapy with and without a continuation phase: a randomized clinical trial. Arch Gen Psychiatry 2001; 58: 381–8. Keller MB, McCullough JP, Klein DN et al. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 2000; 342: 1462–70. Klerman GL, Weissman MM, Rounsaville BJ, Chevron ES. Interpersonal Psychotherapy of Depression. New York: Basic Books, 1984. Kovacs M, Rush AJ, Beck AT, Hollon SD. Depressed outpatients treated with cognitive therapy or pharmacotherapy. A one-year follow-up. Arch Gen Psychiatry 1981; 38: 33–9. Loizzo J. Meditation and psychotherapy. In: Muskin P, ed. Review of Psychiatry, Vol. 19. Washington, DC: American Psychiatric Association Press, 2000: 147–97. Markowitz JC, Svartberg M, Swartz HA. Is IPT time-limited psychodynamic psychotherapy? J Psychother Pract Res 1998; 7: 185–95. McCullough JP. Treatment of Chronic Depression. New York: Guilford Press, 2000. McRoberts C, Burlingame GM, Hoag MJ. Comparative efficacy of individual and group psychotherapy: a meta-analytic perspective. Group Dyn Theor Res Pract 1998; 2: 101–17.

48 Treating Depression Effectively Nemeroff CB, Heim CM, Thase ME et al. Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc Natl Acad Sci USA 2003; 100: 14293–6. Proudfoot J, Ryden C, Everitt B et al. Clinical efficacy of computerised cognitivebehavioural therapy for anxiety and depression in primary care: randomised controlled trial. Br J Psychiatry 2004; 185: 46–54. Ravindran AV, Anisman H, Merali Z et al. Treatment of primary dysthymia with group cognitive therapy and pharmacotherapy: clinical symptoms and functional impairments. Am J Psychiatry 1999; 156: 1608–17. Reynolds CF III, Frank E, Perel JM et al. High relapse rate after discontinuation of adjunctive medication for elderly patients with recurrent major depression. Am J Psychiatry 1996; 153: 1418–22. Reynolds CF 3rd, Dew MA, Pollock BG et al. Maintenance treatment of major depression in old age. N Engl J Med 2006; 354: 1130–8. Segal ZV, Kennedy SH, Cohen NL, the CANMAT Depression Work Group. Clinical guidelines for the treatment of depressive disorders. V. Combining psychotherapy and pharmacotherapy. Can J Psychiatry 2001; 46 (Suppl. 1): 59S–62S. Segal ZV, Whitney DK, Lam RW, the CANMAT Depression Work Group. Clinical guidelines for the treatment of depressive disorders. III. Psychotherapy. Can J Psychiatry 2001; 46 (Suppl. 1): 29S–37S. Simons AD, Murphy GE, Levine JL, Wetzel RD. Cognitive therapy and pharmacotherapy for depression. Sustained improvement over one year. Arch Gen Psychiatry 1986; 43: 43–8. Svartberg M, Stiles TC. Comparative effects of short-term psychodynamic psychotherapy: a meta-analysis. J Consult Clin Psychol 1991; 59: 704–14. Teasdale JD, Segal ZV, Williams JM et al. Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. J Consult Clin Psychol 2000; 68: 615–23. Thase ME. When are psychotherapy and pharmacotherapy combinations the treatment of choice for major depressive disorder? Psychiatr Q 1999; 70: 333–46. Thase ME, Simons AD, Cahalane J et al. Severity of depression and response to cognitive behavior therapy. Am J Psychiatry 1991; 148: 784–9. Thase ME, Greenhouse JB, Frank E et al. Treatment of major depression with psychotherapy or psychotherapy–pharmacotherapy combinations. Arch Gen Psychiatry 1997; 54: 1009–15. Thase ME, Friedman ES, Biggs MM et al. Cognitive therapy versus medication in augmentation and switch strategies as second-step treatments: a STAR*D report. Am J Psychiatry 2007; 164: 739–52. Weissman MM, Markowitz JC, Klerman GL. A Comprehensive Guide to Interpersonal Psychotherapy. New York: Basic Books, 2000. Wright JH, Wright AS, Albano AM et al. Computer-assisted cognitive therapy for depression: maintaining efficacy while reducing therapist time. Am J Psychiatry 2005; 162: 1158–64.

Chapter 4

Evolution of antidepressant agents In the beginning … All currently available antidepressants fit into one of three pharmacological classes (Figure 4.1). In each class the first or prototypical drug was discovered empirically. For the first two classes, this was as a result of astute clinical observation of patients who were receiving the drugs for other disorders: tuberculosis (TB) in the case of the monoamine oxidase inhibitors (MAOIs) and schizophrenia in the case of the tricyclic antidepressants (TCAs). In the third class, the discovery was made on the basis of animal studies with

1950s

Enzyme inhibitors

Uptake blockers

MAOI

TCA

1960s Subtype1970s

5-HT2C selective

Mianserin

selective MAOI Trazodone

1980s

1990s

NE selective

NE+DA

Receptoracting drugs

NRI

RIMA

Bupropion

SNRI

SSRI Nefazodone Mirtazapine

2000s

Agomelatine

Figure 4.1 Evolution of antidepressants. MAOI, monoamine oxidase inhibitor; RIMA, reversible inhibitor of monoamine oxidase A; NE, norepinephrine; 5-HT2C, serotonin; TCA, tricyclic antidepressant; DA, dopamine; SSRI, selective serotonin reuptake inhibitor; NRI, norepinephrine reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor.

50 Treating Depression Effectively agents that showed similar behavioral properties to established drugs, despite different pharmacological mechanisms. This last class of antidepressants has been somewhat refined over the past couple of decades as scientific advances continue to identify the most relevant receptors for antidepressants to act upon. Since these empirical and serendipitous beginnings, each class of antidepressant drug therapy has undergone major growth and refinement. The biggest gains have been in the areas of increased tolerability and safety; in terms of efficacy the gains have been less apparent.

Enzyme inhibitors The irreversible monoamine oxidase inhibitors (MAOIs) This was the first class of antidepressants to be identified. In the late 1940s isoniazid and related compounds were used to treat TB patients, many of whom experienced a sense of elation even though they were experiencing little or no improvement in their physical health. This led to early clinical trials and the use of these drugs in depressed patients, with considerable success. At the same time it became known that the link between all these drugs was the property of inhibiting the enzyme MAO, hence the name MAO inhibitors. This enzyme blockade prevents the degradation of amines, especially serotonin (5-HT2C) and norepinephrine (NE). By the 1960s it was recognized that there were two forms of MAO, type A and type B, both of which were irreversibly blocked by the MAOIs. Because the type A enzyme is responsible for the metabolism of NE and 5-HT2C, this became the main target for antidepressant drug development. Selective but irreversible MAO-A antagonists such as pargyline were tested, but they were disappointing as antidepressants, so were not licensed. Later, the selective and irreversible MAO-B antagonist selegiline was synthesized and shown to be of use in Parkinson’s disease, probably because dopamine is mostly metabolized by the B form of the enzyme. In 2006, a transdermal selegiline patch became available in the United States as a treatment for depression. This delivery system avoids first-pass hepatic metabolism and yields plasma drug levels that are high enough to achieve central inhibition of both MAO-A and MAO-B without inhibiting MAO-A in the intestine and liver. This allows a normal diet without restrictions on tyramine-containing foods at the lower dosages of the treatment.

Evolution of antidepressant agents 51

Reversible MAOIs An earlier step in the evolution of the MAOIs came with the development of the RIMA agents such as moclobemide and befloxatone. The acronym is derived from ‘reversible inhibitor of monoamine oxidase A’. Conventional MAOIs destroy the MAO enzyme by binding to it irreversibly. As a consequence, little enzyme is left to metabolize other amines, such as tyramine, found in many foods and medicines. High concentrations of tyramine are found in fermented meat, yeast preparations and mature dairy products. Tyramine is usually metabolized by MAO in the gut wall and liver, so little enters the body. However, MAOIs stop this local breakdown, allowing tyramine to enter the central nervous system where it is taken up into amine neurons, displacing neurotransmitter monoamines from their storage vesicles. When large amounts of tyramine are ingested, a massive release of amines can occur, with potentially disastrous consequences due to increased blood pressure and hyperthermia – ‘the cheese reaction’. By contrast, RIMAs do not permanently inactivate the MAO enzyme. They simply compete with amines at the active site of the enzyme. This means that, in the presence of rising tyramine levels, the RIMA agent will be displaced, freeing the enzyme to break down potentially harmful tyramine. Moreover, as RIMAs only block the A form of the enzyme and tyramine is a substrate for both A and B enzyme, there is plenty of spare MAO to complete the metabolism. The RIMAs are fairly safe drugs, although a mild cheese reaction can be observed, particularly at higher than recommended doses (in the case of moclobemide, this means a daily dose of 900 mg or more). There are also risks of interactions with sympathomimetic drugs such as cold cures, and the serotonin syndrome has been observed when moclobemide is combined with a selective serotonin reuptake inhibitor (SSRI) antidepressant or with the serotonin precursor, tryptophan.

Amine uptake blocking agents The tricyclic antidepressants (TCAs) Imipramine is a derivative of the first antipsychotic chlorpromazine. In the late 1950s it was tested in schizophrenia: it had little effect on the psychotic symptoms but was observed to elevate mood. Soon, imipramine and its close relative amitriptyline were tested in depressed patients and found to have good efficacy.

52 Treating Depression Effectively In 1964 Iversen and colleagues showed that imipramine prevented the uptake of tritiated NE into brain tissue. This heralded the beginning of the ‘neurotransmitter/transporter’ era in pharmacology, with the subsequent discovery of different families of transporters that regulate neurotransmitter concentrations in the synaptic cleft. These transporters are targets for a variety of psychotropic drugs. It also contributed to the emerging NE theory of depression and antidepressant drug action, as several TCAs such as nortriptyline and protriptyline were NE selective uptake blockers. In recent years, several NE reuptake inhibitors (NRIs) of non-tricyclic structure have been developed. These include maprotiline and reboxetine as well as the NE/dopamine uptake blockers bupropion and nomifensine. Nomifensine was withdrawn worldwide in the mid-1990s due to an unacceptably high incidence of hematological adverse effects, but these other agents will be discussed in later chapters (see Chapters 5 and 6).

The selective serotonin reuptake inhibitors (SSRIs) The next advance occurred when Carlsson and Ross observed that the TCAs also blocked the uptake of 5HT into synaptosomes. This provided support for the 5-HT2C theory of depression, and suggested that selective 5-HT2C uptake blockers might also be antidepressant. The effectiveness of clomipramine, a relatively 5-HT2C-selective TCA, supported this view, but the real breakthrough came with the synthesis and testing of the first SSRI, zimelidine. Even though it had a totally different profile of side-effects compared with the TCAs and was safe in overdose, zimelidine’s useful life was cut short by reports of rare but severe cases of hepatitis and Guillain–Barré syndrome. The company that developed it thought that these adverse effects were a consequence of blocking 5-HT2C reuptake and discontinued their SSRI development program. However, other companies took a different view and were later confirmed as correct with the development of a series of SSRIs that have proved to be exceptionally safe and effective antidepressant and anxiolytic agents. Although efficacy and side-effects across drugs in the SSRI class are generally similar, there are some pharmacological distinctions. Citalopram selectively blocks the 5-HT2C transporter (SERT), paroxetine blocks SERT and to a lesser extent the NE transporter, while sertraline mainly blocks SERT and has a minor blocking effect on the dopamine (DA) transporter. The discovery that escitalopram – the active S enantiomer of citalopram – has unexpectedly greater efficacy than the parent compound citalopram (which is an equal


mixture of both S and R enantiomers) has revitalized research in the area of 5-HT2C uptake blockade. It is now clear that the added efficacy seen with escitalopram is due to the fact that the R enantiomer attenuates the neurochemical actions of the S, so reducing its efficacy. Additionally it has been discovered that escitalopram, as well as blocking the 5-HT2C uptake tranporter, also binds to another (allosteric) site on the complex. This may give it greater ability to prolong the inhibition of 5-HT2C uptake and and has led to the descriptor ‘allosteric serotonin reuptake inhibitor’ (ASRI).

Dual-action antidepressants In recent years, the potential advantages of dual 5-HT2C and NE reuptake blockade compared with either alone have been reported. First, the Danish University Antidepressant Group conducted three studies that compared the TCA clomipramine at high doses with paroxetine, citalopram and moclobemide

in

severely

depressed

hospitalized

patients.

In

each

study

clomipramine showed superior efficacy, which they attributed to the NE uptake blocking properties of a metabolite of clomipramine as well as the 5-HT2C-blocking properties of the parent compound. Second, Nelson et al. (1991) showed that an SSRI (fluoxetine) combined with an NRI (desipramine) produced a more rapid outcome than fluoxetine alone. These findings have supported the development of the dual-action nonTCA uptake blockers venlafaxine, milnacipran and duloxetine. In a series of meta-analyses, venlafaxine has been shown to have superior response and remission rates compared with the SSRIs in depressed patients. It should be noted, however, that remission rates for SSRIs in these comparison studies are generally lower than those reported in other SSRI trials, and more often involve fluoxetine as the SSRI competitor. Hence, the issue remains controversial, and requires adequately powered trials to compare remission rates between SSRI and serotonin and norepinephrine reuptake inhibitor (SNRI) agents. Interestingly, among the SSRI class, paroxetine has been suggested to have dual 5-HT2C and NE effects ‘in vitro’ (a finding that distinguishes it from other SSRIs, though the main metabolite of fluoxetine, norfluoxetine, is also somewhat of an NE uptake blocker). In one study, paroxetine was shown to have comparable efficacy to TCAs in hospitalized patients. There is also evidence that mirtazapine, which promotes 5-HT2C and NE transmission, has superior efficacy to SSRIs in severely depressed patients. Milnacipran is available in France, Japan and some other countries. It displays greater NE- than 5-HT2C-blocking effects – the opposite of venlafaxine.


NE Attention

Mood

5-HT2C

Sleep Obsessions

Drive Appetite

Anxiety Loss of pleasure

Negative cognitions

DA

Figure 4.2 Neurotransmitters and depressive symptoms.

This dual-uptake blocking drug has been shown to be effective in a number of clinical trials in depression. Early data suggest that it may show increased efficacy compared with SSRIs such as fluoxetine. Duloxetine is the newest member of this class. It is a more potent dual reuptake inhibitor than venlafaxine. At a standard dose of 60 mg daily, blockade of both 5-HT2C and NE transporters has been reported. In contrast, venlafaxine requires a dose increase from 75 to 150 mg for comparable NE blockade to occur. There are interesting theoretical reasons why an antidepressant that acts on more than one transmitter system might have superior efficacy. Although increasing the actions of either 5-HT2C or NE is an effective way to treat depression, there is some evidence that these two transmitter systems have rather different effects on the various physical and emotional functions that are disrupted in depression (Figure 4.2). Although there is considerable overlap between transmitters and symptoms, some symptoms are more relevant to either 5-HT2C or NE. The implication of this differentiation of transmitter functions is that certain antidepressants might preferentially treat some depressive symptoms and not others. So, an NE-enhancing antidepressant might be preferred in individuals who are lacking in energy, drive or attention, whereas a more 5-HT2C-targeting drug


would be preferred in patients with prominent obsessional or anxiety symptoms. Dual-action or triple-action agents would be effective across more than one symptom cluster; however, the development of triple-acting agents has been hampered by their substantial adverse effect profile, presumably related to additive adverse effects from the elevations of each neurotransmitter.

Receptor-acting drugs These are the third class of antidepressants, and again they were discovered before a theory of action was developed. The first two drugs in this class (mianserin and trazodone) were both found to have antidepressant activity in animal and other preclinical models of antidepressant action. On this basis they were taken into human trials, where they proved effective. Subsequent animal studies helped to unravel their mode of action, although it should be said that this issue is still debated. The first theory to explain the therapeutic actions of mianserin was that of α2-adrenoceptor antagonism. This fitted with emerging ideas about antidepressant mechanisms for other treatments, such as TCAs and electroconvulsive therapy (ECT). A decrease in α2-adrenoceptor function would remove autoinhibition of NE neurons, so increasing NE concentration in the synaptic cleft. Based on this theory, mirtazapine and other α2-adrenoceptor antagonists (e.g. fluparoxan and idazoxan) were evaluated in clinical trials. Only mirtazapine proved to be both effective and well tolerated, possibly because it is also a 5HT2 and 5HT3 receptor antagonist. Mianserin (available in many European countries but not in the USA or Canada) and trazodone also interact with 5HT receptors. Mianserin antagonizes 5HT1A and 5HT2C receptors, whereas trazodone acts through its own 5HT2-blocking effects and through its metabolite mCPP (metachlorophenylpiperazine), which has 5HT1 and 5HT2C agonist properties. Both are prototypes for antidepressants in this class. Mirtazapine is a refinement of mianserin with 5HT2 and 5HT3 receptor-blocking activity, which likely explains the virtual absence of 5HT-mediated side-effects such as headache, sexual dysfunction, insomnia and nausea. Mirtazapine also has less α1adrenoceptor blocking affinity than mianserin, but is a potent histamine H1 receptor blocker, so both agents promote sleep and can cause daytime sedation, especially early in treatment. Nefazodone is a follow-up compound of trazodone that is a weak 5HT uptake blocker and a potent 5HT2 receptor antagonist. Its side-effect profile is distinct from the SSRIs based on less

56 Treating Depression Effectively sexual dysfunction and sleep disturbance. However, its use has recently been restricted to named patients in some countries due to reported cases of hepatotoxicity and it is withdrawn from the European market. A completely new approach to the treatment of depression involves melatonergic and serotonergic receptors. Agomelatine is a novel agent that is both a melatonergic receptor agonist (MT1 and MT2 receptors) and a 5-HT2C antagonist. Agomelatine has been shown to correct circadian and sleep abnormalities found in depression. In addition, rat microdialysis studies have shown that the 5HT2C receptor antagonist actions lead to elevations in dopamine and norepinephrine in the frontal cortex. It seems likely that these receptor actions contribute to its antidepressant profile, which is characterized by an at least equivalent antidepressant efficacy to that of other currently used antidepressants, an improvement of disturbed sleep in depressive patients and a low incidence of sexual adverse effects.

Delayed onset of antidepressant action One of the goals of antidepressant discovery has been the development of compounds with a faster onset of action. The prevailing view of the typical three to four week therapeutic delay with most antidepressants is that it takes

Raphe Forebrain

SSRIs 5HT1A 5HT1B 5HT1D

5HT neuron

5HT

5HT

5HT2C –ve

–ve

5HT2A 5HT1A

5HT1B/D

Figure 4.3 Serotonergic synapse: effect of uptake blockade.

5HT3


this long to disable compensatory receptor-based mechanisms that initially offset the uptake blockade or amine oxidase inhibition. To some extent the receptor-blocking drugs should be free of this problem, although clinical data have been equivocal. For example, mirtazapine does seem to produce significantly greater improvements in mood and anxiety symptoms as well as sleep, compared with SSRIs during the first two weeks of treatment, although these differences are not sustained after six to eight weeks of treatment. Improvements in anxiety symptoms and depression associated sleep disturbances were also observed under agomelatine treatment. A targeted approach to this issue came from animal studies in which blockade of the presynaptic 5HT1A autoreceptor by antagonists such as pindolol produced a rapid rise in 5HT in the cortex. However, a clinical trial programs to test combined SSRI/pindolol therapy (with both fluoxetine and paroxetine) failed to produce support for the approach. This may have been because pindolol also blocks the post-synaptic 5HT1A receptor, which likely needs to be stimulated to mediate the antidepressant cascade (Figures 4.3 and 4.4), or alternatively because the clinically tolerated doses of pindolol were too low to block enough of the autoreceptors to release the inhibition.

Firing rate of raphe

Therapeutic level 5HT concentration in cortex

SSRI treatment 4

0 Weeks

Figure 4.4 Time lag of SSRIs.


Conclusions Many antidepressants have been discovered through serendipity. However, intense research efforts over the past 50 years have led to a better understanding of their pharmacology and modes of action in the brain, with a focus on the adaptive brain changes that alleviate depression. All three classes of antidepressants have been subject to significant refinements in drug action, resulting in improved adverse effect and safety profiles. Current evidence supports the recruitment of more than one neurotransmitter system to address the range of symptoms associated with major depressive disorder, and the targeted interference with certain post-synaptic receptor systems especially 5HT2 receptor antagonism, to minimize adverse effects and improve disturbed sleep in depressive patients. New approaches to the treatment of depression and an understanding of the pharmacology of antidepressants can improve their use both as single agents and when combined with other antidepressants in cases of treatment resistance, partial response and unwelcome adverse effects.

Bibliography Audinot V, Mailliet F, Lahaye-Brasseur C et al. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn Schmiedebergs Arch Pharmacol 2003; 367: 553–61. Beasley CM Jr, Nilsson ME, Koke SC, Gonzales JS. Efficacy, adverse events, and treatment discontinuations in fluoxetine clinical studies of major depression: a meta-analysis of the 20-mg/day dose. J Clin Psychiatry 2000; 61: 722–8. Carlsson A, Corrodi H, Fuxe K, Hokfelt T. Effect of antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-alpha-ethylmetatyramine. Eur J Pharmacol 1969; 5: 357–66. Clerc G. Antidepressant efficacy and tolerability of milnacipran, a dual serotonin and noradrenaline reuptake inhibitor: a comparison with fluvoxamine. Int Clin Psychopharmacol 2001; 16(3): 145–51. Healy D. The Antidepressant Era. Cambridge, MA: Harvard University Press, 1997. Iversen LL. The Uptake and Storage of Noradrenaline in Sympathetic Nerves. London: Cambridge University Press, 1967. Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol 2006; 16: 93–100.

Evolution of antidepressant agents 59 Millan MJ, Mauricette B, Gobert A, Dekeyne A. Anxiolytic properties of agomelatine, an antidepressant with melatonergic and serotonergic properties: role of 5HT2C receptor blockade. Psychopharmacology 2005; 177: 448–59. Nelson JC, Mazure CM, Bowers MB Jr, Jatlow PI. A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry 1991; 48: 303–7. Nutt D. Mirtazapine: pharmacology in relation to adverse effects. Acta Psychiatr Scand 1997; 96 (Suppl 391): 31–7. Nutt DJ, Glue P. Clinical pharmacology of anxiolytics and antidepressants: a psychopharmacological perspective. In: File S, ed. Psychopharmacology of Anxiolytics and Antidepressants. New York: Pergamon Press, 1991: 1–28. Patkar AA, Pae CU, Masand PS. Transdermal selegiline: the new generation of monoamine oxidase inhibitors. CNS Spectr 2005; 11: 363–75. Ross SB, Renyi AL. Inhibition of the uptake of tritiated 5-hydroxytryptamine in brain tissue. Eur J Pharmacol 1969; 7: 270–7. Smith D, Dempster C, Glanville J et al. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a metaanalysis. Br J Psychiatry 2002; 180: 396–404. Stahl SM, Entsuah R, Rudolph RL. Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients with depression. Biol Psychiatry 2002; 52: 1166–74. Thase ME. Treatment of severe depression. J Clin Psychiatry 2000; 61 (Suppl. 1): 17–25. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 2001; 178: 234–41.

Chapter 5

Evidence based antidepressant selection across depressive disorders Evidence based criteria for choosing an antidepressant Major depressive disorder (MDD) exists in many clinical forms, which may reflect different biological and environmental disturbances. Clinicians recognize distinct subtypes of MDD, which are described in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IVTR), but not in the International Classification of Diseases, 10th revision (ICD-10) (see Chapter 1). The following guidelines are offered for the pharmacological treatment of MDD, and, where evidence is available, its subtypes dysthymic disorder, minor depressive disorder and recurrent brief depression are also considered. The reader is reminded that the lack of evidence for a particular antidepressant treatment should not be equated with evidence for lack of efficacy. The process for developing evidence based therapeutic choices uses standard methods. Criteria from the periodic health examination guidelines were used to establish levels of evidence for specific treatments (see Table 5.1), and recommendations for therapeutic choices incorporate clinical evidence on tolerability and safety as well as effectiveness and efficacy (Table 5.2).

Major depressive disorder Selective serotonin reuptake inhibitors (SSRIs) and various dual-action agents have superior side-effect and safety profiles and generally comparable efficacy


Table 5.1 Criteria for levels of evidence Level of evidence

Criteria

1

Meta-analysis or replicated randomized controlled trial (RCT) that includes a placebo condition At least one RCT with placebo or active comparison condition Uncontrolled trial with ten or more subjects Anecdotal case reports

2 3 4

Table 5.2 Criteria for therapeutic choices Therapeutic choice

Criteria for levels of evidence

First

Level 1 or Level 2 evidence + clinical support

Second

Level 1, Level 2 or Level 3 evidence + clinical support

Third

Level 1, Level 2, Level 3 or Level 4 evidence + clinical support

Not recommended

Level 1 or Level 2 evidence for lack of efficacy, or insufficient information to evaluate efficacy

Table 5.3 Recommendations for treatment of MDD Therapeutic choice

Recommendations

Evidence

First

SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), agomelatine, bupropion and mirtazapine Higher rates of remission have been reported with venlafaxine and particularly in severe depression with escitalopram

Level 1 Level 1

Second

Among TCAs amitriptyline and clomipramine have greater efficacy than SSRIs in hospitalized depressed patients (safety and tolerability issues need to be considered)

Level 2

Third

Other TCAs and MAOIs (lower recommendation because of safety and tolerability issues)

Level 2

Evidence based antidepressant selection across depressive disorders 63

to tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). This has resulted in their adoption as first-choice antidepressants for the treatment of MDD. Recent evidence has been presented to support higher rates of remission for some dual-action agents compared with SSRIs (Table 5.3). Definitions of response and remission are reviewed in Chapter 2.

Treatment options for subtypes of MDD Current diagnostic criteria for MDD (DSM-IV and ICD-10) focus on a unitary concept of depression, although the following subtype specifiers: atypical features; melancholic features; chronic pattern; psychotic features post partum onset (see Chapter 10); and seasonal pattern, as well as severity, have been evaluated in a limited number of studies.

MDD with atypical features – atypical depression This disorder is characterized by preservation of mood reactivity, often with reversed diurnal mood change (better in the morning) accompanied by at least two of the following symptoms: excessive appetite or weight gain, increased sleeping, heaviness of limbs (leaden paralysis) or extreme sensitivity to perceived rejection. The evidence to support one antidepressant or class of antidepressants over another is limited, mainly because there have been very few studies that have focused exclusively on ‘atypical depression’. In one study, fluoxetine and imipramine were equally effective, although fluoxetine was better tolerated. Sertraline and moclobemide were also equally effective for atypical depression, with some quality of life advantages for sertraline. While phenelzine was superior to imipramine and is historically associated with the treatment of atypical depression, it is considered a second line agent due to safety and tolerability issues (Table 5.4).

Table 5.4 Recommendations for treatment of MDD with atypical features Therapeutic choice

Recommendations

Evidence

First

Fluoxetine; sertraline (and probably other SSRIs); moclobemide

Level 2

Second

Phenelzine (choice reduced due to poor tolerability)

Level 2

Third

Imipramine

Level 2


Melancholia

Severity

Treatment resistance

Figure 5.1 Melancholia, severity and treatment resistance.

Melancholia, severity and treatment resistance There is considerable overlap between the terms ‘melancholia’, ‘severity’ and ‘treatment resistance’ in relation to an episode of major depression (Figure 5.1). However, these terms are not synonymous, and the same treatment recommendations do not apply across groups. The implications of ‘melancholia’ and ‘severity’ for treatment outcomes will be discussed in this chapter, while the broader issue of treament resistance will be considered in Chapters 7 and 8.

MDD with melancholic features – melancholia The specifier ‘with melancholic features’ requires complete or almost complete loss of pleasure (anhedonia) and loss of mood reactivity, accompanied by several other symptoms. As well as the distinct symptom profile, there is evidence to suggest that physiological disturbances, particularly in the hypothalamic–pituitary–adrenal axis, distinguish patients with melancholic versus non-melancholic features, and that differences in response rates to various treatments also exist. For example, TCAs and several dual-action agents have been investigated in melancholia and found to be superior to SSRIs. Clomipramine was associated with higher remission rates than sertraline, paroxetine and moclobemide in individual trials, and in a meta-analysis, other TCAs were superior to SSRIs but produced worse side-effects.


Table 5.5 Recommendations for treatment of MDD with melancholic features Therapeutic choice

Recommendations

Evidence

First Second Third

Mirtazapine; paroxetine; venlafaxine Clomipramine; duloxetine; nortriptyline Citalopram; fluoxetine; moclobemide

Level 1 Level 1 Level 2

Venlafaxine produced higher remission rates than fluoxetine, and nortriptyline was also more effective than fluoxetine in elderly melancholic patients. These findings were not supported by a separate meta-analysis, in which paroxetine, moclobemide and venlafaxine were as effective as TCAs. Also, in an analysis of pooled data, duloxetine had equivalent efficacy in patients with melancholic features compared to those without melancholic features (Table 5.5). Preliminary evidence suggests that agomelatine also is effective in patients with melancholic features.

Severity The DSM-IV-TR categorizes major depressive episodes as mild, moderate or severe according to the intensity of symptoms. Other indices of severity include suicide risk, hospitalization status and diagnostic subtype. Although the presence of melancholia is often viewed as a proxy for severity, this need not be the case, as melancholic patients manifest a range of severities. In practical terms, most evaluations of severity are based on a minimum threshold on a rating instrument such as the Hamilton Depression Rating Scale (HDRS) or the Montgomery Asberg Depression Rating Scale (MADRS). Examples include a score of 24 or greater on the 17-item HDRS and 30 or more on the MADRS. Evaluating efficacy in severe populations is a valuable secondary analysis for antidepressants, as not all SSRIs have shown equal effects in this group. For example, escitalopram was superior to other SSRIs and comparable to venlafaxine, especially in ‘severe depression’. Preliminary evidence suggests that this may also be true for agomelatine.

MDD with psychotic features – psychotic major depression The presence of distinct phenomenology, particularly mood-congruent delusions or hallucinations, particularly together with evidence of dopamine– corticosteroid abnormalities in psychotic major depression (PMD), suggest

66 Treating Depression Effectively that specific treatment approaches are required. Unfortunately, there are too few adequately powered trials to provide definitive recommendations. In many instances, psychotic and non-psychotic depressed patients have been compared ‘post hoc’ from trials that were completed under controlled and uncontrolled conditions. Although there are isolated reports that SSRI monotherapy is effective as a treatment for PMD (sertraline and paroxetine), this approach does not have widespread clinical acceptance. The most commonly investigated treatments involve a combination of antidepressant–antipsychotic medications or electroconvulsive therapy (ECT). In one study, the combination of amitriptyline and perphenazine was significantly better than either alone. In a meta-analysis, ECT was superior to TCA alone, but was not significantly better than the combination of TCA and antipsychotic therapy. Bilateral ECT was also more effective than unilateral ECT. However, the recurrent nature of PMD and the high relapse rate associated with ECT support the use of pharmacotherapy for acute treatment and prophylaxis. Although atypical antipsychotics (particularly olanzapine, risperidone and quetiapine) may be effective antidepressant monotherapies, they have also been evaluated in combination with an SSRI and are recommended in the acute treatment of PMD (Table 5.6; see also Chapter 7). While still investigational, preliminary results suggest that mifepristone, a potent antagonist of type II glucocorticoid and progesterone receptors and also known as RU486, has antipsychotic but not antidepressant effects in PMD.

Table 5.6 Recommendations for treatment of psychotic major depression Therapeutic choice

Recommendations

Evidence

First

Electroconvulsive therapy (ECT) Antipsychotic + antidepressant (olanzapine or risperidone with SSRI or SNRI)

Level 1 Level 2

Second

Typical antipsychotic + amitriptyline Mifepristone + antidepressants

Level 2 Level 2

Not recommended

Monotherapy with SSRIs

Level 2 but limited clinical support


Table 5.7 Recommendations for treatment of winter depression Therapeutic choice

Recommendations

Evidence

First

Bright light therapy; fluoxetine; bupropion XL (for prevention) Moclobemide; sertraline Agomelatine; citalopram; escitalopram; tranylcypromine

Level 1

Second Third

Level 2 Level 3

MDD with seasonal pattern – winter depression Winter depression refers to the most prevalent form of MDD with a seasonal pattern. Clinical guidelines for winter depression support light therapy as a first-choice therapy (see Chapter 9). In a double-blind study of light with placebo pills versus fluoxetine with placebo light, there was no difference in response rates between fluoxetine and light treatment groups, although there was an early but unsustained advantage for light therapy. Among other antidepressants that have been evaluated, sertraline and moclobemide were effective, while agomelatine, bupropion, citalopram, escitalopram and tranylcypromine were beneficial in open trials (Table 5.7). Placebo controlled trials have found bupropion XL to have a prophylactic effect if taken through fall and winter, and it is now licensed for this indication in the United States.

MDD with anxiety – anxious depression Although ‘anxious depression’ is not specified as a subtype of MDD within DSM-IV-TR, most patients (60–90%) with a primary diagnosis of depression also experience symptoms of anxiety, and up to 50% of MDD patients meet criteria for at least one comorbid anxiety disorder. Individuals who suffer from anxious depression tend to have higher severity scores on depression rating scales; greater functional and psychosocial impairment; higher suicide risk; and a poorer prognosis following treatment, when compared to depressed individuals with low levels of anxiety. Most SSRIs, venlafaxine and agomelatine have proven efficacy in the treatment of generalized anxiety disorder and other anxiety disorders, which supports their use in anxious depression. A widely held clinical perception that bupropion SR is less effective in depressed patients with high levels of anxiety is not substantiated in various comparisons with SSRIs.


Table 5.8 Recommendations for treatment of ‘anxious depression’ Therapeutic choice

Recommendations

Evidence

First

Citalopram; escitalopram; mirtazapine; moclobemide; paroxetine; sertraline; venlafaxine; agomelatine

Level 1

Second

Amitriptyline; fluvoxamine; imipramine; trazodone

Level 1

Not recommended

Lorazepam or other benzodiazepines

Level 2

In three meta-analyses, moclobemide, mirtazapine and venlafaxine respectively were as effective as active comparators and superior to placebo. Paroxetine and sertraline were as effective as clomipramine, while fluvoxamine and lorazepam were comparable in efficacy. Other studies also support the efficacy of paroxetine and agomelatine in reducing symptoms of anxiety associated with depression. Clonazepam augmentation of fluoxetine was superior to fluoxetine alone in the first three weeks of a double-blind trial, although dependency concerns restrict recommendations for ongoing benzodiazepine prescription (Table 5.8).

MDD with chronic pattern – chronic depression Chronic depression, dysthymic disorder and double depression (a major depressive episode superimposed on dysthymia) are often indistinguishable. For some patients, the duration of symptoms may be as long as 30 years prior to treatment. Despite the limited number of trials, there is evidence that several antidepressants are more effective than placebo in the acute treatment of dysthymia. In a meta-analysis, fluoxetine, sertraline, MAOIs (including moclobemide) and TCAs all had equivalent efficacy, although TCAs were associated with more side-effects and higher dropout rates. There were no significant differences in rates of response between patients with pure dysthymia and those with double depression. For this reason, the term ‘chronic depression’ is preferred. Sertraline is the most investigated SSRI as a treatment for chronic depression, and had advantages over imipramine in a large trial. Also, in patients over the age of 60, who were treated in primary care settings, paroxetine was superior to placebo. Venlafaxine and mirtazapine were effective in open trials (Table 5.9), while combined pharmacotherapy with nefazodone and a


Table 5.9 Recommendations for treatment of chronic depression/dysthymic disorder Therapeutic choice

Recommendations

Evidence

First

Fluoxetine; fluvoxamine; moclobemide; paroxetine; sertraline

Level 2

Second

Desipramine; imipramine

Level 2

Third

Mirtazapine; venlafaxine

Level 3

modified form of cognitive behavior therapy (CBT) – Cognitive Behavioral Analysis System of Psychotherapy (CBASP) – produced superior results compared to either treatment alone (see also Chapter 3). Since, nefazodone has been withdrawn, these results require replication with another antidepressant.

Minor depressive disorder Minor depression (mDD) is characterized by depressed mood or anhedonia, accompanied by 1–3 additional depressive symptoms that are present for at least two weeks. Particularly in older adults, this is the most prevalent form of depression, although the majority of these patients remain in primary care settings and are rarely seen by psychiatrists. While SSRIs such as sertraline have been effective in the treatment of late-life mDD, several trials in primary care settings support a combined pharmacotherapy–psychotherapy approach: paroxetine and problem-solving treatment were both superior to placebo in a primary care trial in patients over 60 years of age, and elsewhere, paroxetine was superior to maprotiline in a middle-life population. There were also some trends to support exercise combined with sertraline over usual care in older mDD adults. Fluvoxamine was associated with a significant decrease in depressive symptomatology and an improvement in psychosocial functioning in an open-label trial (Table 5.10).

Recurrent brief depression In recurrent brief depression (RBD), the number and severity of symptoms are comparable to MDD but the duration is shorter: at least two days but less than two weeks. Despite case reports describing the effectiveness of fluoxetine, mirtazapine, reboxetine and tranylcypromine, neither fluoxetine nor


Table 5.10 Recommendations for treatment of mDD and RBD Therapeutic choice Recommendations*

Evidence

mDD First

Paroxetine (based on individuals aged 60 years and older)

Level 2

Fluvoxamine Maprotiline

Level 3 Level 2

Second

RBD Not recommended No available support for antidepressant treatment

Level 2

*Combining pharmacotherapy with exercise or focused psychotherapy has advantages.

paroxetine was superior to placebo under controlled conditions. The frequency and design of assessments in these trials may account for the negative results (Table 5.10).

Conclusions While most antidepressants have demonstrated efficacy across a spectrum of depressed subpopulations, there is evidence to support specific interventions in certain populations, including PMD and winter depression. Progress in defining subgroups of depressed patients based on unique psychobiology, while promising, has not yet led to unique targeted treatments for distinct subpopulations.

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Evidence based antidepressant selection across depressive disorders 73 Sogaard J, Lane R, Latimer P et al. A 12-week study comparing moclobemide and sertraline in the treatment of outpatients with atypical depression. J Psychopharmacol 1999; 13: 406–14. Stahl SM, Entsuah R, Rudolph RL. Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients with depression. Biol Psychiatry 2002; 52: 1166–74. Stamenkovic M, Blasbichier T, Riederer F et al. Fluoxetine treatment in patients with recurrent brief depression. Int Clin Psychopharmacol 2001; 16: 221–6. Szegedi A, Wetzel H, Angersbach D et al. Response to treatment in minor and major depression: results of a double-blind comparative study with paroxetine and maprotiline. J Affect Disord 1997; 45: 167–78. Thase ME, Fava M, Halbreich U et al. A placebo-controled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia. Arch Gen Psychiatry 1996; 53: 777–84. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 2001; 178: 234–41. Thase ME, Nierenberg AA, Keller MB, Panagides J, the Relapse Prevention Study Group. Efficacy of mirtazapine for the prevention of depressive relapse: a placebo-controlled double-blind trial of recently remitted high-risk patients. J Clin Psychiatry 2001; 62: 782–8. Tignol J, Stoker MJ, Dunbar GC. Paroxetine in the treatment of melancholia and severe depression. Int Clin Psychopharmacol 1992; 7: 91–4. World Health Organization. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Geneva: World Health Organization, 1992. Zanardi R, Franchini L, Gasperini M et al. Double-blind controled trial of sertraline versus paroxetine in the treatment of delusional depression. Am J Psychiatry 1996; 153: 1631–3.

Chapter 6

Practical issues in using antidepressants

Factors influencing antidepressant choice Selective serotonin reuptake inhibitors (SSRIs) and dual-action antidepressants are the predominant first choice treatments for major depressive disorder, although the evidence in favor of superior efficacy compared to classical antidepressants is limited. Their superior safety and tolerability profiles account for their widespread use, yet side-effects are not insubstantial and vary across drug classes and within each drug class. Some of the antidepressants described in Figure 6.1 (bupropion, duloxetine, milnacipran, moclobemide, reboxetine and selegiline) may not be available in certain countries; agomelatine, a melatonergic agonist and serotonergic antagonist agent, is currently under review. This chapter will address dosing, side-effects, drug interactions, overdose toxicity and discontinuation-emergent symptoms. Because comparisons of side-effects across drugs and drug classes are limited by the absence of direct ‘head-to-head’ trials, those side-effects that occurred with a frequency ≥10% and ≥30% compared to placebo are reported. Clinicians should be aware of the benefits and prototypic side-effects associated with each antidepressant class, and develop expertise in using one or two drugs from each class.

First generation antidepressants The monoamine oxidase inhibitors (MAOIs) Although no longer first line agents, the monoamine oxidase inhibitors (MAOIs) continue to serve as a valuable third line alternative when other


First generation

Second generation

Third generation

MAOI RIMA

SSRI

SNRI

Melatonergic

Phenelzine Tranylcypromine Selegiline patch Moclobemide

Citalopram Fluoxetine Fluvoxamine Paroxetine CR Sertraline

Venlafaxine XR Milnacipran Duloxetine

Agomelatine

TCA

ASRI

NDM

Amitriptyline Clomipramine Nortriptyline and others

Escitalopram

Bupropion SR/XL

NRI

NaSSA

Reboxetine

Mirtazapine

Figure 6.1 Antidepressant classification by mechanism of action. MAOI, monoamine oxidase inhibitor; RIMA, reversible inhibitor of MAO-A; TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor; ASRI, allosteric serotonin reuptake inhibitor; NRI, norepinephrine reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; NaSSA, noradrenergic and specific serotonergic antidepressant; NDM, norepinephrine and dopamine modulator; Melatonergic, melatonergic (MT1 and MT2) agonist and 5-HT2C antagonist.

Table 6.1 Dosing of MAOIs Drug Starting*

Dosage adjustment (mg) Usual High†

Irreversible Isocarboxazid Phenelzine Tranylcypromine

10–20 15–30 10–20

30–40 45–75 30–60

60 90–120 70–90

Selegiline transdermal

6/24 hours

6/24 hours

12/24 hours

Reversible Moclobemide

200–300

450–600

900

*Lower starting dose indicated with previous sensitivity to side-effects or with polypharmacy; often applies to elderly patients. †Higher doses often exceed recommended upper limits in formularies; these doses should be used with caution.

Practical issues in using antidepressants 77

Table 6.2 Frequently reported side-effects across MAOIs Antidepressant

Incidence of side-effects ≥ 10%

≥ 30% Moclobemide

None

Insomnia Excitement; hypomania Headache Dry mouth

Blurred vision Hypotension/dizziness GI distress

Isocarboxazid

None

Headache Dry mouth Tremor

Hypotension/dizziness GI distress

Phenelzine

Dry mouth Sexual dysfunction

Drowsiness; sedation Insomnia Excitement; hypomania Blurred vision Constipation

Tremor Hypotension/dizziness Tachycardia; palpitations GI distress

Selegiline transdermal

None

Local skin reactions

Hypotension; insomnia

Tranylcypromine

None

Drowsiness; sedation Insomnia Excitement; hypomania

Hypotension/dizziness Tachycardia; palpitations

GI, gastrointestinal.

Table 6.3 Dosing of TCAs* Drug Starting†

Dosage adjustment (mg) Usual High‡

Tertiary amines Amitriptyline Clomipramine Imipramine

25–50 50–75 50–75

75–200 100–250 100–250

250–300 300–450 300–450

Secondary amines Desipramine Nortriptyline

25–50 25–50

75–150 75–150

200–300 200

*These are five examples of TCAs; other TCAs include doxepin, dosulepin, maprotiline, protriptyline and trimipramine. Maprotiline is a heterocyclic antidepressant. †Lower starting dose indicated with previous sensitivity to side-effects or with polypharmacy; often applies to elderly patients. ‡Higher doses often exceed recommended upper limits in formularies; these doses should be used with caution.

78 Treating Depression Effectively classes of agents are ineffective or intolerable (Table 6.1). Phenelzine is effective in the treatment of ‘atypical depression’, while tranylcypromine is often reserved for previously treatment-resistant depression. Selegeline (L-deprenyl) has recently become available in the United States as a transdermal preparation. By avoiding first-pass hepatic metabolism, dietary precautions are not required within the recommended dose range. It is necessary to carry out an antidepressant ‘washout’ before starting MAOIs. In most cases, 10–14 days is adequate, but fluoxetine requires a fourto five-week washout because of the long half-life of its metabolites. In general it is important to initiate treatment at a low dose with gradual dose increments. A two-week washout period is also necessary following discontinuation of any irreversible MAOI, before starting another antidepressant. The two main limitations of MAOIs are the high side-effect burden (Table 6.2) and concerns about food and drug interactions. Dizziness and orthostatic hypotension are common to all MAOIs, are often dose related and frequently result in drug discontinuation. Insomnia and sexual dysfunction are also frequently encountered adverse events. However, the collection of data on sideeffects for these antidepressants was less rigorous than would occur today, so accurate prevalences are difficult to establish. In clinical practice, side-effects can sometimes be minimized by altering the timing of dosing. For example, in some patients, switching from morning to night-time dosing may reduce insomnia. Foods with high tyramine content, including red wines, tap beer, aged cheeses, smoked meats, yeast extracts and pickled fish should be avoided because of the risk of a hypertensive crisis. Decongestants and over-thecounter cough medicines containing pseudoephedrine or ephedrine may also produce a hypertensive reaction and should also be avoided. Moclobemide, as a reversible and selective inhibitor of the MAO-A enzyme, is available in most countries, and when used within usual dose ranges does not require dietary restrictions. It is an alternative to SSRIs, particularly when tolerability is a significant issue. A washout of two to three days is required following moclobemide discontinuation. Although other reversible and selective MAO-A inhibitors were evaluated in clinical trials, none is available by prescription. Selegiline, an irreversible, but selective inhibitor of MAO-B, has been approved as an adjunctive treatment for Parkinson’s disease for many years. To overcome concerns about tyramine-mediated food and drug interactions, a selegiline transdermal system has been developed, and was approved for the treatment of depression by the US Food and Drug Administration (FDA) in 2006.


The tricyclic antidepressants (TCAs) TCAs continue to be prescribed worldwide (Table 6.3), although in most countries they are considered second line agents due to their limited safety and tolerability. Among the tertiary amines, amitriptyline, clomipramine and imipramine are the main mixed-uptake blocking agents (see Chapter 4) and have been most extensively investigated. In meta-analyses of TCAs compared to SSRIs, amitriptyline was more effective in hospitalized depressed patients compared to SSRIs, although discontinuation rates were also higher. Amitriptyline, usually at a sub-antidepressant dose, continues to be prescribed for the management of chronic pain, but this may decrease in response to recent reports that several dual-action antidepressants (duloxetine, milnacipran and venlafaxine) effectively treat painful physical symptoms, including diabetic neuropathic pain. While clomipramine is often used to treat hospitalized depressed patients in Europe, it is only indicated for the treatment of obsessive compulsive disorder in the United States. Desipramine and nortriptyline are secondary amines that preferentially block norepinephrine (NE) reuptake. They respectively display linear and curvilinear dose–response pharmacokinetics. Monitoring of TCA plasma levels is recommended for therapeutic and safety reasons. A major limitation of TCAs is their actions beyond inhibition of NE or serotonin (5HT) transporters, including effects on cholinergic muscarinic,

Psychomotor activation Sexual dysfunction Psychosis Activating side-effects DA reuptake 5HT2 H1 antagonism inhibition agonism

Sedation/ drowsiness Weight gain Blurred vision Dry mouth Constipation Sinus tachycardia Urinary retention Memory dysfunction

Traditional antidepressants

Ach antagonism α1 antagonism Priapism

5HT 3 agonism 5HT reuptake inhibition NE reuptake inhibition

α 2 antagonism

Postural hypotension Dizziness Reflex tachycardia

Nausea

GI disturbances Activating effects

inaryg – Ur outh ActivatinV m y Dr tion – mor-C n rete ts – Tre s effec trouble

Figure 6.2 Antidepressant side-effects. Ach, acetylcholine; DA, dopamine. Adapted with permission from Richelson, 1993.


Table 6.4 Frequently reported side-effects across TCAs Antidepressant


Amitriptyline

Dry mouth; sedation Weight gain

≥ 10% Disorientation/confusion Asthenia; fatigue Blurred vision Constipation Sweating

Tremor Orthostatic hypotension/dizziness Tachycardia; palpitations ECG changes

Clomipramine Dry mouth Sexual dysfunction

Insomnia Blurred vision Constipation Sweating Tremor Weight gain (over 6 kg)

Orthostatic hypotension/dizziness Tachycardia; palpitations ECG changes GI distress

Imipramine

Dry mouth Orthostatic hypotension/dizziness

Drowsiness; sedation Sweating Insomnia Delayed micturition Excitement; hypomania Tremor

Desipramine

None

Blurred vision Dry mouth Constipation

Nortriptyline

None Asthenia; fatigue Dry mouth

Disorientation/confusion Constipation Tremor

Delayed micturition Tachycardia; palpitations

ECG, electrocardiogram.

α-adrenergic and histamine H1 receptors (Figure 6.2). Antagonism of these receptors may result in various side-effects: anticholinergic and cardiovascular effects are the most prevalent, especially in elderly patients. Side-effects for the most frequently prescribed TCAs are reviewed in Table 6.4.

Second and third generation antidepressants The selective serotonin reuptake inhibitors (SSRIs) Greater tolerability and once-daily dosing have contributed to the widespread adoption of SSRIs as first line antidepressants. For many patients the starting dose is the effective dose in both acute and maintenance phases of treatment. When required, dose increments can be made


Table 6.5 Dosing of SSRIs Drug Starting* Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline

10–20 10 10–20 50–100 10–20 25–50

Dosage adjustment (mg) Usual High† 20–40 10–20 20–40 150–200 20–40 50–100

60 30 60–80 400 60 150–200


without altering the once-daily dosing schedule (Table 6.5). Recent evidence supports differences in mechanisms and outcomes with escitalopram, the only member of the allosteric serotonin reuptake inhibitor (ASRI) subclass. At a dose of 10 mg, escitalopram appears to be a more potent inhibitor of the 5HT transporter and a more efficacious antidepressant than the equivalent dose of citalopram (the racemic mixture of Scitalopram and R-citalopram). This has been linked to the existence of secondary allosteric binding sites on the 5HT transporter, to which the S isomer (escitalopram) binds in a manner more favorable to antidepressant action than the combined R and S isomers contained in citalopram. Gastrointestinal (GI) side-effects, especially nausea, are common, particularly during the first one to two weeks of SSRI treatment (Table 6.6). High rates of sexual dysfunction are reported on direct questioning, but these rates are probably comparable to those encountered with classical TCA and MAOI therapies.

Serotonin and norepinephrine reuptake inhibitor (SNRI) and other antidepressants Venlafaxine, milnacipran and duloxetine all inhibit both 5HT and NE reuptake, albeit in different ratios. Venlafaxine more potently inhibits the 5HT transporter, milnacaprin has more NE inhibiting effects and duloxetine appears to provide a more balanced dual inhibition. Desvenlafaxine succinate (DVS), an active metabolite of venlafaxine, received FDA approval for the treatment of major depressive disorder (MDD) in 2007.


Table 6.6 Frequently reported side-effects across SSRIs* Antidepressant ≥ 30%


Citalopram Escitalopram†

None

Drowsiness; sedation Insomnia Headache Asthenia; fatigue Dry mouth

Sweating Tremor GI distress Sexual dysfunction

Fluoxetine

Sexual dysfunction

Drowsiness; sedation Insomnia Disorientation/confusion Headache Asthenia; fatigue

Dry mouth Tremor Orthostatic hypotension/dizziness GI distress

Fluvoxamine

GI distress Sexual dysfunction

Drowsiness; sedation Insomnia Excitement; hypomania Headache Asthenia; fatigue

Dry mouth Constipation Sweating Tremor

Paroxetine

Sexual dysfunction

Drowsiness; sedation Insomnia Headache Asthenia; fatigue

Sweating Tremor Orthostatic hypotension/dizziness

Sertraline

GI distress Sexual dysfunction

Drowsiness; sedation Insomnia Excitement; hypomania Headache

Dry mouth Tremor Orthostatic hypotension/dizziness

*Adapted from Kennedy et al., 2001. †Escitalopram is the stereoisomer of citalopram – comparable side-effects to citalopram have been reported.

Mirtazapine acts on both systems by blocking inhibitory receptors, so indirectly increasing NE and 5HT release, while bupropion has dual-uptake blocking actions on the dopaminergic and noradrenergic systems. Agomelatine is a novel antidepressant which acts as a melatonergic (MT1 and MT2) agonist and a 5HT2C antagonist (Table 6.7). Because of these diverse mechanisms of action, agents in this class have different side-effect profiles. Bupropion, with dopaminergic effects, tends to be alerting, and if taken at night would be likely to increase insomnia.


Table 6.7 Dosing of SNRI and other antidepressants Drug Starting* Agomelatine Bupropion (bupropion SR) Desvenlafaxine succinate (DVS) Duloxetine Milnacipran Mirtazapine Tianeptine Trazodone Venlafaxine (venlafaxine XR)

25 75 50 60 100 30 37.5 150–200 37.5–75

Dosage adjustment (mg) Usual High† 25–50 150–300 100 60–120 200 30–45 37.5 300–400 112.5–225

50 375–450 200 120 60 37.5 600 300–375


On the other hand, trazodone and mirtazapine, because of their 5HT 2 receptor-blocking properties, usually improve sleep. As a melatonergic agonist and a 5HT 2C antagonist agomelatine is not associated with the various receptor-mediated side-effects described in Figure 6.2 (see also Chapter 4). Preliminary evidence suggests that it is particularly effective in restoring restful sleep without causing daytime sleepiness, and is unlikely to cause sexual dysfunction (Table 6.8).

Other antidepressants with transporter actions Reboxetine is a NE reuptake inhibiting antidepressant that is prescribed in a dose range of 4–12 mg. Noradrenergic side-effects include dry mouth, constipation, insomnia and sweating. Tianeptine, a glutamate modulator, is prescribed at a dose of 37.5 mg and has been associated with rare cases of insomnia, dry mouth, paresthesia and chest pain. Tianeptine has an effective clinical profile and preclinically is a potent regulator of neuroplasticity.

Comparing side-effects across SSRIs and SNRIs and other antidepressants Early side-effects of SSRIs typically involve central nervous system (CNS) and GI system disturbances that are usually self-limiting. Delayed side-effects such as


Table 6.8 Frequently reported side-effects across SNRI and other antidepressants Antidepressant ≥ 30%


Agomelatine Bupropion

None None

DVS

Nausea Insomnia

Duloxetine

GI distress

Drowsiness; sedation Insomnia Dry mouth Dizziness

Constipation Orthostatic hypotension/dizziness Constipation; insomnia

Mirtazapine

Drowsiness; sedation Dry mouth Weight gain (over 6 kg)

Asthenia; fatigue Blurred vision

Constipation

Trazodone

Drowsiness; sedation

Asthenia; fatigue Dry mouth

Orthostatic hypotension/dizziness GI distress

Venlafaxine

GI distress Sexual disturbances

Drowsiness; sedation Insomnia Excitement; hypomania Headache Asthenia; fatigue

Dry mouth Constipation Sweating Orthostatic hypotension/dizziness

Milnacipran

None Insomnia Excitement; hypomania Headache Dry mouth Blurred vision Abdominal pain Asthemia Anorexia Dizziness; vertigo Sweating

Constipation Sweating Tremor GI distress Dry mouth Constipation Sexual dysfunction Nervousness

GI, gastrointestinal.

sexual dysfunction, weight gain and apathy may occur during ongoing treatment, and in many cases do not remit until after treatment is discontinued.

Sleep, alertness and neurocognition CNS side-effects associated with the SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs) lie midway between more alerting agents such as


bupropion, and more sedating agents such as mirtazapine. SSRIs and SNRIs may also cause initial drowsiness and sedation but at a lower rate and level of intensity. Fluvoxamine and fluoxetine have been associated with apathy and indifference, although it is often difficult to distinguish between druginduced apathy and residual symptoms of depression. The anticholinergic actions of TCAs and paroxetine affect cognitive function and have been shown to delay word recall. Ironically, most antidepressants have a pronounced inhibitory effect on rapid eye movement (REM) sleep, which further disrupts circadian rhythm, in a disorder characterized by circadian rhythm disturbance: the majority of antidepressants prolong REM latency, disrupt sleep continuity and decrease total REM sleep. Agomelatine does not appear to have any adverse effects on sleep, alertness or neurocognition and may improve the sleep disruption found in depression.

Metabolism and weight change Antidepressant-related weight gain is one of the main reasons for poor treatment adherence and drug discontinuation, and it is more likely to occur in patients who are overweight or obese prior to treatment. Rapid weight gain with TCAs and mirtazapine has been linked to blockade of histamine H1 receptors, resulting in increased carbohydrate craving and food intake. Weight gain during MAOI therapy is more likely to be caused by fluid retention.

Table 6.9 Conclusions about weight gain during antidepressant treatment Conclusions Acute phase Weight neutral SSRIs; agomelatine; bupropion; duloxetine; moclobemide; venlafaxine Weight gain Mirtazapine results in weight gain of 7% or more in up to 14% of patients TCAs cause weight gain in a significant proportion of patients Maintenance phase Data on weight change with maintenance treatment are inconclusive Low rates of weight gain (< 10%) are reported with bupropion and moclobemide

Evidence


Level 2

86 Treating Depression Effectively Minimal weight loss may occur during the first few weeks of SSRI or SNRI treatment because of nausea, although weight gain during long-term SSRI treatment has been reported, especially with paroxetine. Agomelatine and bupropion SR/XL do not appear to cause weight gain. Short-term trials suggest that venlafaxine, milnacipran and duloxetine are also weight-neutral (Table 6.9).

Sexual dysfunction Agomelatine, bupropion and mirtazapine are associated with low levels of sexual dysfunction, while fluoxetine, paroxetine, sertraline, venlafaxine and other SSRIs are associated with diminished arousal and orgasmic dysfunction in up to 50% of patients. Men are more likely to report sexual dysfunction with SSRIs than are women (Table 6.10).

Potential for drug–drug interactions Most antidepressants are metabolized by one or more of the cytochrome P450 (CYP) hepatic isoenzymes. Pharmacokinetic interactions occur when a co-prescribed medication acts as an inhibitor or inducer of one or more of these isoenzymes (Table 6.11). Among SSRIs, fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19, fluoxetine and fluvoxamine are potent CYP2C9 inhibitors and fluoxetine and paroxetine potently inhibit CYP2D6. Among the other antidepressants, including SNRIs, none is a potent inhibitor of CYP isoenzymes, although duloxetine is a moderate inhibitor of CYP2D6.

Table 6.10 Frequency of sexual dysfunction during antidepressant treatment (Level 2) Incidence of sexual dysfunction 30%

Agomelatine Bupropion Mirtazapine Moclobemide

Citalopram Duloxetine Escitalopram Venlafaxine

Fluoxetine Fluvoxamine Paroxetine Sertraline


Protein binding may also influence the potential for drug interactions. When a highly protein-bound drug is displaced, there is a greater increase in the amount of unbound drug in plasma compared with a drug that has low protein binding. This is particularly a problem with the anticoagulant warfarin, because dangerous alterations in clotting time can occur. Among currently available antidepressants, venlafaxine has the lowest degree of protein binding and would be least affected by competitive displacement.

Table 6.11 Pharmacokinetics of second and third generation antidepressants Medication

Biotransformation pathways

Half-life (hours)

Protein binding (%)

Second generation Bupropion SR Hydroxylation involves CYP2B6

21

84 (parent)

Citalopram and escitalopram

Demethylation in two steps involves CYP2C19, 2D6 and 3A4

37 (citalopram) 30 (escitalopram)

80

Duloxetine

Oxidation (involves CYP2D6 and 1A2), methylation and no active conjugation (sulfate and metabolite glucuronide)

9–19

>95 (parent)

Fluoxetine

Demethylation involves CYP2D6

96–144

95

Fluvoxamine

Demethylation and deamination involve CYP2D6 and 1A2

17–22

80

Mirtazapine

Demethylation and hydroxylation involve (parent) CYP2D6, 1A2 and 3A4

20–40

85 (parent)

Paroxetine

Oxidation and demethylation involve CYP2D6

24

95

Sertraline

Demethylation involves CYP3A4

25–26

98

Venlafaxine

O-demethylation involves IR/XR CYP2D6 and others

5–7 (parent) 11–13 (ODV)

27 (parent) 30 (ODV)

1–2

95

Third generation Agomelatine Metabolism involves CYP1A2 and CYP2C9 ODV, O-desmethylvenlafaxine.


Safety in overdose In countries where TCA prescriptions remain high, death following overdose continues to be an important concern. Among TCAs and MAOIs, desipramine and tranylcypromine have been the most lethal. Venlafaxine has also been linked to higher rates of death by suicide. However, these uncontrolled retrospective reports do not take into account prior psychiatric history, including suicidality, severity of depression and previous treatment resistance.

Discontinuation and discontinuation-emergent symptoms Discontinuation rates in the 15–30% range are typical during acute treatment, and are significantly higher in patients who receive TCAs compared with SSRIs. Discontinuation rates are also likely to be higher in actual practice than in clinical trials. Unfortunately, there are no consistent evidencebased biological markers to predict recurrence of depression, although some demographic and clinical parameters have been identified as risk factors (see Chapter 2). At the end of two years, patient and physician should confer about stopping medication. The decision reflects a balance between the benefits (preventing recurrence) and the risks (side-effects, cost and inconvenience) of staying on medication versus discontinuation. Patients who decide to discontinue an antidepressant should be educated about prodromal symptoms that might signal impending recurrence. These are often specific for a given individual, and may include alterations in sleep and appetite, lowering of mood or other idiosyncratic changes such as increased sensitivity to emotional films or literature. Relapse may be preceded by periods of life stress, and patients should be warned to be more vigilant about their mood when under stress. Although discontinuation-emergent effects were observed with TCAs, the experience of many patients who rapidly discontinued SSRIs or venlafaxine highlighted the importance of tapered discontinuation. Tapering, and in some cases substituting one or two doses of fluoxetine, may prevent or alleviate these symptoms. However, tapering does not guarantee the prevention of at least some discontinuation symptoms. Agents with a short half-life are the most likely to be associated with discontinuation-emergent symptoms such as nausea, insomnia, sweating, headache and delirium. These agents include venlafaxine, paroxetine and fluvoxamine. However, discontinuation of newer agents, such as agomelatine, does not appear to result in these symptoms.


Conclusions Despite advances in treatment options, many patients do not achieve remission, and frequently experience recurrence. This limitation in effectiveness across antidepressant classes, and the side-effect burden associated with current antidepressants, in particular CNS side-effects, weight gain and sexual dysfunction, argue for exploration of alternative therapeutic targets in the treatment of depression. Clinicians are advised to have a working knowledge of standard dosing, side-effect and safety profiles as well as drug interactions and discontinuation effects for antidepressants from established and emerging classes.

Bibliography Ackerman S, Nolan LJ. Bodyweight gain induced by psychotropic drugs: incidence, mechanisms and management. CNS Drugs 1998; 9: 135–51. Arroll B, Macgillivray S, Ogston S et al. Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann Fam Med 2005; 3: 449–56. Bauer M, Bschor T, Kunz D et al. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psychiatry 2000; 157: 1429–35. Bezchlibnyk-Butler KZ, Jeffries JJ. Clinical Handbook of Psychotropic Drugs, 10th edn. Toronto: Hogrefe & Huber, 2006. Bialos D, Giller E, Jatlow P, Docherty J, Harkness L. Recurrence of depression after discontinuation of long-term amitriptyline treatment. Am J Psychiatry 1982; 139: 325–9. Buckley NA, McManus PR. Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ 2002; 325: 1332–3. Clayton AH, Montejo AL. Major depressive disorder, antidepressants, and sexual dysfunction. J Clin Psychiatry 2006; 67 (Suppl 6): 33–7. De Vry J, Schreiber R. Effects of selected serotonin 5-HT(1) and 5-HT(2) receptor agonists on feeding behavior: possible mechanisms of action. Neurosci Biobehav Rev 2000; 24: 341–53. Dewan MJ, Anand VS. Evaluating the tolerability of the newer antidepressants. J Nerv Ment Dis 1999; 187: 96–101. Fulton B, Benfield P. Moclobemide: an update of its pharmacological properties and therapeutic use. Drugs 1996; 52: 450–74.

90 Treating Depression Effectively Furukawa TA, McGuire H, Barbui C. Meta-analysis of effects and side-effects of low dosage tricyclic antidepressants in depression: systematic review. BMJ 2002; 325: 991. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug–drug interactions: an update. Curr Drug Metab 2002; 3: 13–37. Kennedy SH. Agomelatine: an antidepresant with a novel mechanism of action. Future Neurol 2007; 2: 145–51. Kennedy SH, Eisfeld BS, Dickens SE et al. Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline, and venlafaxine. J Clin Psychiatry 2000; 61: 276–81. Kennedy SH, Lam RW, Cohen NL, Ravindran AV, the CANMAT Depression Work Group. Clinical guidelines for the treatment of depressive disorders. IV. Medications and other biological treatments. Can J Psychiatry 2001; 46 (Suppl 1): 38S–58S. Kennedy SH, Holt A, Baker GB. Monoamine oxidase inhibitors. In: Sadock BJ, Sadock VA, eds. Comprehensive Textbook of Psychiatry, 8th edn. Baltimore: Lippincott, Williams and Wilkins, 2004: 2854–63. Kennedy SH, Fulton KA, Bagby RM et al. Sexual function during bupropion or paroxetine treatment of major depressive disorder. Can J Psychiatry 2006; 52: 234–42. Kent JM. SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet 2000; 355: 911–18. Kramer JC, Klein DF, Fink M. Withdrawal symptoms following discontinuation of imipramine therapy. Am J Psychiatry 1961; 118: 549–50. Loo H, Saiz-Ruiz J, Costa E et al. Efficacy and safety of tianeptine in the treatment of depressive disorders in comparison with fluoxetine. Hum Psychopharmacol 2001; 16: S31–8. Mayers AG, Baldwin DS. Antidepressants and their effect on sleep. Hum Psychopharmacol Clin Exp 2005; 20: 533–59. McIntyre RS, Soczynsk JK, Konarski JZ et al. The effect of antidepressants on lipid homeostasis: a cardiac safety concern? Expert Opin Drug Saf 2006; 5: 523–37. Montgomery SA, Kennedy SH, Burrows GD et al. Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study. Int Clin Psychopharmacol 2004; 19: 271–80. Nutt DJ. Tolerability and safety aspects of mirtazapine. Hum Psychopharmacol 2002; 17 (Suppl 1): S37–41. Richelson E. Review of antidepressants in the treatment of mood disorders. In: Dunner DL (ed). Current Psychiatric Therapy, 2nd edn. Seattle: WB Saunders Company, 1992: 282–95.

Practical issues in using antidepressants 91 Rosenbaum JF, Zajecka J. Clinical management of antidepressant discontinuation. J Clin Psychiatry 1997; 58 (Suppl 7): 37–40. Rosenbaum JF, Fava M, Hoog SL et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998; 44: 77–87. Rubino A, Roskell N, Tennis P et al. Risk of suicide during treatment with venlafaxine, citalopram, fluoxetine, dothiepin: retrospective cohort study. BMJ 2007; 334: 242. Sussman N, Ginsberg DL. Weight effects of nefazodone, bupropion, mirtazapine, and venlafaxine: a review of available evidence. Prim Psychiatry 2000; 7: 33–48. Vanderkooy JD, Kennedy SH, Bagby RM. Antidepressant side-effects in depression patients treated in a naturalistic setting: a study of bupropion, moclobemide, paroxetine, sertraline, and venlafaxine. Can J Psychiatry 2002; 47: 174–80. Wilson S, Argyropoulos S. Antidepressants and sleep: a qualitative review of the literature. Drugs 2005; 65: 927–47. Zajecka J, Tracy KA, Mitchell S. Discontinuation symptoms after treatment with serotonin reuptake inhibitors: a literature review. J Clin Psychiatry 1997; 58: 291–7. Zimmerman M, Posternak MA, Attiullah N et al. Why isn’t bupropion the most frequently prescribed antidepressant? J Clin Psychiatry 2005; 66: 603–10.

Chapter 7

Sequential pharmacotherapies and treatment-resistant depression There is no generally accepted evidence-based sequence for antidepressant interventions. However, there is agreement that several strategies should be considered. These include optimization, switching, augmentation and combination strategies (Figure 7.1). Until recently, no single large trial had been carried out to compare many of these options. This chapter will review results from the first such trial published in 2006 on sequential treatments and extend the discussion to other treatment options, including the role of atypical antipsychotics. Neuromodulatory therapies including electroconvulsive therapy (ECT) and other somatic treatments also have an important role to play in treatment-resistant depression (TRD) and are discussed in Chapter 8.

Overview of STAR*D results A large effectiveness trial sponsored by the US National Institute of Mental Health, involving over 40 psychiatric and primary care sites and more than 3000 ‘real world’ patients, was published in 2006. This Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was designed to include generalizable samples and to ensure the delivery of adequate treatments in a sequenced design. Citalopram was selected as the first-level antidepressant, and approximately 30% of depressed patients achieved remission after treatment for up to 14 weeks. Patients who did not achieve remission were encouraged to proceed to each of the next treatment levels until they did achieve symptom remission.


Optimization (up to 12 weeks)

Failure to achieve remission

Switch

Combine

Failure to achieve remission

Combine

Switch

ECT

Novel therapies

Figure 7.1 Sequential approach to treatment-resistant depression.

Level 2 and 3 interventions involved either switching or augmentation/ combination strategies. Although assignment to Level 2 and Level 3 treatments was random, patients were allowed to exercise choices about the acceptability of each option. The switching options at Level 2 were: another selective serotonin reuptake inhibitor (SSRI) (sertraline) or one of two dualaction drugs (bupropion SR or venlafaxine XR). Approximately one in four patients achieved remission at this level, irrespective of the substitution. Level 2 augmentations to citalopram involved either bupropion SR or buspirone, and approximately 30% achieved remission in each of these groups. Cognitive therapy was also an option for switching and for augmentation at Level 2. At Level 3, switching to mirtazapine or nortriptyline were the options, and remission rates of 12% for mirtazapine and 20% for nortriptyline were reported. These were not significantly different, because of the small sample size. The augmentation options at this level were lithium and triiodothyronine (T3). Again, modest remission rates were reported: 16% for lithium and 25% for T3, and these differences were not statistically different.

Sequential pharmacotherapies and treatment-resistant depression 95

Finally, at Level 4, approximately 100 of the original 4000 enrolled patients were randomly assigned to receive open-label treatment with either tranylcypromine or venlafaxine XR plus mirtazapine. Remission rates were not significantly different (7% for the tranylcypromine group and 14% for the venlafaxine XR plus mirtazapine group). This large sequenced trial will likely provide valuable additional information about patient characteristics associated with favorable outcomes for each level of treatment. More importantly, it may also contribute to the literature on predictive factors for poor outcome. The STAR*D study also highlights the high attrition rate in long-term studies, paricularly where multiple consents and randomizations are required. It is extremely unfortunate that adequate samples within the subtrials were not available to detect statistically significant and clinically meaningful differences among the various switching and combination strategies. The adoption of a ‘self selection’ option within the design of STAR*D did add to the ‘real world’ generalizability of the trial, but it also prevented a comparison between these combination and switching therapies.

Treatment-resistant depression Treatment-resistant depression (TRD) is a relative concept. Several definitions have been proposed, ranging from non-specific (inadequate response following adequate antidepressant therapy) to more operationally defined (failure to respond to two adequate trials of different classes of antidepressants). Others have suggested staging levels of resistance, with a recommendation that treatment with first line antidepressants from SSRI and serotonin and norepinephrine reuptake inhibitor (SNRI) classes should precede trials of

Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

Failure of one adequate AD trial

Stage 1 resistance plus failure in a distinctly different pharma class

Stage 2 resistance plus failure of adequate TCA trial

Stage 3 resistance plus failure of adequate MAOI trial

Stage 4 resistance plus failure of course of bilateral ECT

Figure 7.2 Proposed switching sequence for treatment-resistant depression. Treatment resistance can be conceptualized as a continuum, beginning with the first failure to respond to an adequate trial of an antidepressant (AD). Adapted with permission from Thase and Rush, 1997.

96 Treating Depression Effectively tricyclic antidepressant (TCA) and monoamine oxidase inhibitor (MAOI) antidepressants before moving to ECT (see Figure 7.2). While most studies of TRD have used this definition for eligibility, it poses several disadvantages: it does not include augmentation or combination strategies and does not distinguish between full and partial clinical response. The remainder of this chapter will focus on the evidence to support various switching and combination strategies, including the data from STAR*D.

Optimization Practically speaking, optimization usually means increasing to the maximum approved dose or until limited by side-effects. Particularly for TCAs, plasma monitoring is an important aspect of clinical care. Most TCAs have a linear dose–response relationship with the exception of nortriptyline, which has a limited ‘window’ of therapeutic efficacy, above which antidepressant effects are reduced. In contrast, SSRIs do not show a dose–response pattern, which limits the value of obtaining plasma levels. Among the dual-action agents, venlafaxine shows most evidence of a dose–response relationship, with superior response rates at the higher dose ranges; this has been linked to the engagement of norepinephrine (NE) transporter blockade at doses of 125 mg or more. Duloxetine has yet to be evaluated at higher than recommended dose levels, while mirtazapine does not appear to offer increased effectiveness above 60 mg daily. Safety concerns about increased risk of seizure limit the use of bupropion beyond 450 mg daily. Agomelatine has only been evaluated at 25 mg and 50 mg doses in clinical trials, so there is no evidence to support its use at other doses. Patient differences also need to be considered. Genetically determined differences in drug metabolism include cytochrome P450 polymorphisms, and variations in monoamine transporters such as the serotonin transporter. These individual differences influence the experience of thereapeutic and adverse effects and may result in some patients requiring higher than usual doses, while others may require very low doses. Brain imaging studies of receptor or transporter occupancy may offer a clinically useful measure of maximum dosing, although these techniques are not available routinely.

Switching Switching medications is typically the first recommended strategy, but even after STAR*D there is no evidence to guide the clinician in deciding whether


to switch from or augment the index antidepressant. In two studies, these strategies yielded different results. In the first, there were no differences between optimization (higher-dose fluoxetine), augmentation (lithium added to standard-dose fluoxetine) and combination (desipramine added to fluoxetine), although lower than usual doses were prescribed in the combination and augmentation groups. In the second study, optimization (higherdose sertraline) was less effective than the combination of mianserin and sertraline. In the absence of evidence-based results, practical considerations, including the side-effect burden of a particular medication, whether there is a partial response and previous medication history, should all be taken into account to guide the sequence of treatment selection.

Practical aspects of switching Antidepressants can be switched either within a medication class or to a different class. There is no evidence to support switching within the TCA class, but switching among SSRIs may be an option, particularly when the reason for switching is lack of tolerability. However, most clinicians switch from one class of antidepressant to another when there has been no response to the first drug (e.g. from SSRI to dual-action or TCA). The judicious use of MAOIs remains an option for TRD, provided that appropriate dietary and drug precautions are followed. Generally, there is no need for a washout period between stopping one antidepressant and starting another. As the first antidepressant is being tapered, the new agent is added (‘cross-over’), but some patients may experience additive side-effects in the overlap period. For a patient who has not tolerated the first antidepressant, it may be wise to provide a washout period, allowing the side-effects to dissipate before starting a second antidepressant. An important exception involves starting or stopping MAOIs. When starting, it is necessary to implement a two-week washout (four to five weeks for fluoxetine). When stopping an MAOI there is also a need to wait two weeks before starting another antidepressant (including the switch from phenelzine to tranylcypromine). As a reversible MAOI, moclobemide only requires a two- to four-day washout after it is discontinued. Drug–drug interactions related to the cytochrome P450 system must also be considered during a cross-over switch. For example, when switching from fluoxetine (a long half-life SSRI that significantly inhibits CYP2D6) to

98 Treating Depression Effectively desipramine (a TCA that requires this isoenzyme for metabolism), the starting dose of desipramine should be lower than usual. If problems emerge, an electrocardiogram and plasma levels of desipramine should be obtained as there is significant risk for cardiotoxicity.

Augmentation and combination therapies Technically, ‘augmentation’ describes adding a medication that by itself is not an antidepressant to a recognized antidepressant. The addition of a second antidepressant at subtherapeutic doses is also considered to be an augmentation strategy, while ‘combination’ therapy involves the prescription of two antidepressants at therapeutic doses. However, these terms are often used interchangeably, as in STAR*D. There have been relatively few controlled trials to evaluate augmentation strategies for TRD. There is most evidence to support antidepressant augmentation with lithium and olanzapine, athough the comparable outcomes with lithium and T3 augmentation as Level 3 interventions in STAR*D support renewed interest in thyroid augmentations (Table 7.1). Lithiuminduced side-effects are dose related, and in STAR*D were more burdensome than side-effects with T3.

Atypicals as augmentation therapies There is emerging evidence that novel antipsychotic agents are effective augmentation agents for non-psychotic major depressive disorder (MDD) and TRD. Compared to typical or first generation antipsychotic agents (e.g. haloperidol), these agents produce lower rates of extrapyramidal symptoms or tardive dyskinesia. On the other hand, concerns about weight gain and dysregulation of glucose metabolism have been raised. Among these ‘atypicals’ there is most evidence to support olanzapine as an augmentation therapy with SSRIs. Olanzapine (5–15 mg daily) in combination with fluoxetine (20–60 mg daily) was significantly more effective than either agent alone for TRD in several trials. Risperidone was also more effective than placebo when combined with SSRI and non-SSRI antidepressants. This was replicated in a second study, where risperidone augmentation of citalopram under unblinded conditions enhanced response in TRD, but this combination was not superior to placebo augmentation of citalopram in preventing relapse. In 2007 only openlabel trials have been published to support the role of other atypicals (quetiapine, ziprasidone and aripiprazole) as augmentors, often in TRD.


Table 7.1 Recommendations for augmentation strategies in treatment-resistant depression Therapeutic choice

Recommendations

Dose

Evidence

First

Lithium

Level 1

Olanzapine Triiodothyronine (T3)

600–900 mg or to therapeutic serum levels 5–15 mg 25–50 µg

Second

Risperidone Buspirone Psychostimulants*

0.5–2 mg 30–60 mg Usual doses


Third

Lamotrigine Trazodone Tryptophan†

100–200 mg 100–200 mg 2–4 g


Not recommended

Pindolol

7.5–1.5 mg

Level 1

Level 1 Level 2

*Enhances motivation and energy. †Limited availability.

Other augmentation strategies Buspirone, a partial post-synaptic 5HT1A agonist with a metabolite that promotes NE neuron-firing, was beneficial in a number of open-label studies, but a placebo-controlled trial was negative. Subsequently, in STAR*D, the effect of adding buspirone to citalopram was comparable to adding bupropion at the Level 2 stage. Pindolol, a beta-blocking drug that, in low doses, also acts as a specific antagonist of the 5HT1A presynaptic autoreceptor, was also investigated to see whether it accelerated onset of action and increased response rates. However, in a large randomized study, pindolol failed to augment either an SSRI or clomipramine in TRD. Tryptophan is a natural amino acid and a precursor of serotonin. Limited evidence exists to support the use of tryptophan as an augmentation agent (see Chapter 9 for further discussion). Although there is a long tradition of using psychostimulants to augment antidepressants, the evidence from randomized controlled trials (RCTs) for both methylphenidate and modafinil, a non-dopaminergic stimulant, confirms enhanced effects on energy and alertness but not mood, as a

100 Treating Depression Effectively consequence of augmentation therapy. There is also anecdotal evidence to support the use of trazodone in low doses as an augmentation strategy, although trazodone is mainly prescribed as a hypnotic, at doses that are considerably below the antidepressant dose range.

Combination strategies One of the first combination antidepressant strategies to be evaluated involved adding an MAOI to a TCA. However, in the only controlled trial, this combination was not superior to treatment with either agent alone, and given the safety concerns it is rarely used. Since then numerous combinations have been advocated, but surprisingly few have been studied in a controlled design. Two antidepressants with different monoaminergic actions are often prescribed in TRD (Table 7.2). Theoretically this should enhance antidepressant effects. For example, combining desipramine and an SSRI provides both NE and serotonin (5HT) transporter inhibition. Unfortunately, the combination of fluoxetine and desipramine has potentially dangerous kinetic interactions that may result in high plasma desipramine levels and cardiac death. If this combination is used it requires careful monitoring. In other cases the combination may allow one agent to offset the adverse effects of the other in addition to enhancing antidepressant outcomes. This has been the rationale for bupropion combinations with an SSRI or venlafaxine to increase remission rates and improve sexual dysfunction. Similarly, adding mirtazapine to an SSRI or venlafaxine provides potential additional antidepressant action and may also improve sleep, nausea or sexual dysfunction. Mianserin, like mirtazapine, has presynaptic α2-blocking properties that indirectly enhance both noradrenergic and serotonergic transmission. This drug has been effective in combination with TCAs as well as sertraline and fluoxetine. Generally, adding two antidepressants in combination is well tolerated, but drug–drug interactions must be considered. Several combination strategies were evaluated in the STAR*D protocol: at Level 2 adding bupropion to citalopram; and at Level 4 combining venlafaxine XR and mirtazapine. The citalopram–bupropion combination was one of the few to achieve a statistical advantage, while the mitazapine–venlafaxine XR combination was only evaluated under open conditions in a relatively small population of depressed patients who had failed three previous trials within the STAR*D protocol.


Table 7.2 Recommendations for combination strategies in treatment-resistant depression Therapeutic choice

Recommendations

Evidence

First

SSRI + mirtazapine/mianserin

Level 2

Second

SSRI/SNRI + bupropion SR

Level 3

Third

SSRI + TCA (caution for increased serum TCA levels with some SSRIs) SSRI + RIMA*

Level 2 Level 3

*Caution for serotonin syndrome. RIMA, reversible inhibitor of monoamine oxidase A.

Conclusions Advantages of switching from one to another antidepressant, compared to augmentation or combination strategies, include the simplicity of monotherapy and the lack of potential drug–drug interactions. Monotherapy may also, but not necessarily, lead to fewer side-effects and better adherence. On the other hand, augmentation and combination strategies have the potential advantage of building on a partial response, avoiding potential discontinuation symptoms, and the possibility of achieving a rapid response. Adding another agent also buys more time for a latent therapeutic effect from the index medication. The drawbacks to combination antidepressant use include the possibility that a patient might simply have responded to monotherapy with the second agent, yet he or she is exposed to additional side-effects and the extra cost of a second medication. Finally, the differences between sequential build combinations and immediate combination strategies have generally not been evaluated. While the field of sequenced antidepressant strategies, including the role of single versus combination treatments, has received considerably more attention in the new millenium, it is still not possible to provide evidence based guidelines to support or abandon many suggested options. Nevertheless the burgeoning use of atypical antipsychotic agents in the treatment of depression, as well as the provocative but frequently unanswered questions raised by STAR*D has highlighted the need for further large randomized controlled trials in TRD.


Bibliography Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry 1996; 53: 842–8. Barbee JG, Jamhour NJ. Lamotrigine as an augmentation agent in treatment-resistant depression. J Clin Psychiatry 2002; 63: 737–41. Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: metaanalysis of placebo-controlled studies. J Clin Psychopharmacol 1999; 19: 427–34. Baumann P, Nil R, Souche A et al. A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin Psychopharmacol 1996; 16: 307–14. DeBattista C, Solvason HB, Poirier J et al. A prospective trial of bupropion SR augmentation of partial and non-responders to serotonergic antidepressants. J Clin Psychopharmacol 2003; 23: 27–30. Farvolden P, Kennedy SH, Lam RW. Recent developments in the psychobiology and pharmacotherapy of depression: optimising existing treatments and novel approaches for the future. Expert Opin Investig Drugs 2003; 12: 65–86. Fava M. Diagnosis and definition of treatment resistant depression. Biol Psychiatry 2003; 53: 649–59. Fava M, Alpert J, Nierenberg A et al. Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine. J Clin Psychopharmacol 2002; 22: 379–87. Fava M, Rush JA, Wisniewski SR et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry 2006; 163: 1161–72. Kennedy SH, Eisfeld BS, Meyer JH, Bagby RM. Antidepressants in clinical practice: limitations of assessment methods and drug response. Hum Psychopharmacol 2001; 16: 105–14. Kennedy SH, Lam RW, Cohen NL, Ravindran AV. Clinical guidelines for the treatment of depressive disorders. IV. Medications and other biological treatments. Can J Psychiatry 2001; 46 (Suppl 1): 38S–58S. Kennedy SH, McCann SM, Masellis M et al. Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry 2002; 63: 181–6. Kennedy SH, Segal ZV, Cohen NL et al. Lithium carbonate versus cognitive therapy as sequential combination treatment strategies in partial responders to antidepressant medication: an exploratory trial. J Clin Psychiatry 2003; 64: 439–44.

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104 Treating Depression Effectively Trivedi MH, Rush J, Wisniewski SR et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 28-40. Zullino D, Baumann P. Lithium augmentation in depressive patients not responding to selective serotonin reuptake inhibitors. Pharmacopsychiatry 2001; 34: 119–27.

Chapter 8

Neuromodulation and other physical treatments

Approximately 50% of patients fail to achieve an adequate response to a first antidepressant treatment, and over half of those fail to respond to a second pharmacotherapy approach. However, with the increase in evidence supporting neuromodulatory therapies, these treatments provide a viable alternative for the treatment of depression, although many are investigational options. This chapter will evaluate the evidence to support electroconvulsive therapy, repetitive transcranial magnetic stimulation, vagus nerve stimulation and deep brain stimulation.

Electroconvulsive therapy Among currently available physical treatments for depression, electroconvulsive therapy (ECT) is the most established and most effective. It appears to have faster and more marked effects than antidepressant drugs as well as a plausible rationale for activity. ECT has been shown to stimulate amine function in a progressive fashion, starting with dopamine (DA), then norepinephrine (NE) and finally serotonin (5HT). These neurochemical changes and sequential alterations in second messengers and growth factors probably underlie the mechanism of action of ECT to ameliorate the many symptoms of depression (Figure 8.1).

Efficacy and indications A sustained response rate of 80% and a remission rate of 75% were achieved in a prospective acute trial of bilateral ECT (and these rates were higher in the psychotic major depression group compared to the non-psychotic group). However, many of the trials involving ECT have methodological limitations. In particular, many are uncontrolled, and there are very few

106 Treating Depression Effectively Seizure number 1–2

Enhance dopamine receptor function

3–5

Enhance synaptic norepinephrine

6–8

Enhance 5HT function

Figure 8.1 Proposed sequential neurotransmitter mechanisms following ECT.

direct comparisons between ECT and selective serotonin reuptake inhibitor (SSRI) or dual-action antidepressants. There is evidence to suggest that response rates to ECT are higher in elderly patients compared with middle-life patients. This means that it is often used as a first choice in elderly depressed patients, particularly those experiencing psychotic or melancholic symptoms. Polarity of mood disorder does not appear to influence outcome, although chronicity of episode and comorbid personality disorders are predictors of a poor response. It has also been suggested that patients who are resistant to antidepressants have both a lower response rate to ECT and a higher relapse rate within six months, although naturalistic studies do not show a relationship between antidepressant refractoriness and clinical outcome. Careful pre-anesthetic examination is essential, particularly for patients who have additional risk factors, including myocardial ischemia, cardiac arrhythmias, a pacemaker or an abdominal aneurysm. Indications for ECT are presented in Table 8.1. Apart from raised intracranial pressure, there are no absolute contraindications.

Treatment parameters With fewer hospital beds available for psychiatric admissions and shorter lengths of stay in inpatient units, ECT is increasingly provided on an ambulatory or outpatient basis. During the acute-treatment phase, ECT should be administered two or three times weekly for up to six weeks, and a typical

Neuromodulation and other physical treatments 107

Table 8.1 Indications for ECT • • • • • • •

Acute suicidal ideation Psychotic major depression Catatonia Treatment-resistant depression Repeated medication intolerance Rapidly deteriorating physical status (food/fluid refusal) Prior favorable response

course is between six and 20 treatments. A less frequent schedule may minimize some of the immediate cognitive side-effects of ECT, but response is slower. Electrode placement may be unilateral (UL) to the non-dominant hemisphere, or bilateral (BL). Patients who receive UL-ECT (Figure 8.2) usually experience less short-term impairment of memory or language. However, it can be harder to achieve an adequate duration of seizure, making it especially important to optimize the electrical dose relative to the seizure threshold at the first treatment. Individual assessment of seizure threshold is critical because there is at least a 12-fold range in seizure threshold among patients. The effectiveness of ECT depends on both duration and intensity of seizures. Seizures should last at least 25 seconds and should be monitored visually, and if possible by electroencephalogram (EEG). Accurate visual

Figure 8.2

Patient about to receive ECT.


Table 8.2 Strategies to promote seizure activity • Increase the electrical charge • Discontinue any drugs that raise seizure threshold, e.g. benzodiazepines; valproic acid; carbamazepine • Use a seizure threshold-lowering agent such as caffeine or doxapram • Switch from UL to BL placements

monitoring is best done using a blood pressure cuff to exclude muscle relaxant from one arm, so that muscle contractions can be seen. Recommendations to manage inadequate seizure activity are provided in Table 8.2.

Adverse effects ECT is a safe procedure. Mortality and morbidity rates are extremely low in the modern era, approximating to the risk of general anesthesia. Mortality associated with ECT is estimated to be 0.2 per 100 000 treatments, and is most often related to cardiovascular anesthetic complications. The adverse event rate associated with ECT is around 0.4%. Adverse events can include musculoskeletal or dental injuries, superficial skin burns, oral lacerations and persistent myalgia (secondary to the muscle relaxant). Nausea, headaches and muscle aches are common post-treatment events, which can be treated with antiemetics or analgesics. Cognitive side-effects associated with ECT have limited its level of recommendation in the treatment of depression. These effects are well documented, and include an acute confusional state lasting minutes to hours, as well as anterograde and retrograde amnesia. Subjective complaints of immediate and often persistent (at least two months) deficits in some aspects of autobiographical memory (mostly impersonal memories such as public events) occur frequently. In some studies, objective memory testing six months after treatment showed a marked improvement compared to the depression-associated pretreatment memory, although persistent lacunae of memory deficits for events occurring around the time of the ECT are common. In a prospective study, the administration of BL-ECT and sine wave stimulation were associated with more severe and persistent cognitive deficits. In addition, electrical dosages above threshold levels, more frequent administration (three times rather than twice a week) and persistence of depressed mood have been associated with cognitive impairment.


Table 8.3 Indications for maintenance ECT • • • • •

History of previous response to ECT Failure to remit with pharmacotherapy – non-response or intolerance Frequent recurrence of depressive episodes Recurrent delusional (psychotic) major depression Patient preference

Maintenance ECT ECT may also be used as a maintenance treatment, with titration schedules ranging from once weekly to once monthly. In one randomized study with a six-month follow-up after a successful acute course of bilateral ECT, there were no differences between continuation ECT and a combination of nortriptyline and lithium. Continuation or maintenance ECT (Table 8.3) is less likely to cause cognitive side-effects, possibly due to the longer time interval between treatments. There is no credible evidence that ECT causes any form of structural brain damage; in fact electroshock in animals has been shown to promote neurogenesis, and prospective neuroimaging studies using computed tomography (CT) or magnetic resonance imaging (MRI) techniques show no structural changes in the brain after ECT.

ECT in combination with antidepressant medication There is very little evidence to suggest that combining antidepressants with ECT improves the response. When patients are receiving ECT, they have usually failed antidepressant treatment, so it does not make much sense to continue the same medication. Starting a new medication during ECT causes clinical confusion about both efficacy and side-effects. Also, there is no good evidence that starting an antidepressant concurrently with ECT improves outcome, and it has also been reported that in some cases antidepressant drugs, including SSRIs, may prolong seizure duration. The usual practice is therefore to start medication after the last ECT session. There are claims that concurrent lithium therapy is responsible for delirium or prolonged confusion after ECT. For this reason most ECT protocols require discontinuation of lithium before initiating ECT. The use of sedatives including benzodiazepines and anticonvulsants, such as carbamazepine or valproic acid, may inhibit seizures or shorten seizure duration, and therefore their use with ECT is not recommended.


Table 8.4 Summary of evidence regarding ECT Recommendations

Evidence

• ECT is an effective treatment for major depressive disorder (MDD)

Level 1

• Indications for ECT include acute suicidal risk, severe physical deterioration, • depression with psychotic features, treatment resistance to medications and patient preference

Level 2

• Unilateral electrode placement requires suprathreshold current for optimal • results

Level 2

• Side-effects of ECT are greater with BL electrode placement and frequently • include retrograde memory disturbance

Level 2

• Maintenance ECT should be considered when pharmacotherapies have • been ineffective or intolerable

Level 3

Prevention of relapse following ECT Without some form of maintenance treatment, the rate of relapse following ECT is high: between 50% and 95% within six months. Predictors of relapse include medication resistance prior to ECT and greater severity of depression. Maintenance pharmacotherapy for at least one or two years is nearly always indicated to prevent relapse, yet there are very few studies to inform clinicians about treatment selection. The combination of nortriptyline and lithium was significantly more effective in reducing relapse rates following ECT compared to nortriptyline alone. Continuation ECT was also as effective as the combination of nortriptyline and lithium in reducing relapse. Medications that were ineffective when used in an optimal fashion prior to ECT should not be used for post-ECT maintenance. Recommendations for ECT are summarized in Table 8.4.

High frequency repetitive transcranial magnetic stimulation Efficacy and indications The non-invasive nature of this treatment increases its potential application compared to other more invasive neuromodulatory therapies. Repetitive transcranial magnetic stimulation (rTMS) involves repeated subconvulsive magnetic stimulation delivered with a wand positioned over the left dorsolateral prefrontal cortex (Figure 8.3).


Figure 8.3 Patient about to receive rTMS, sitting relaxed and awake before application of high frequency stimulation. (Courtesy of Dr Jeff Daskalakis.)

Positive results in a number of small randomized trials are supported by meta-analyses, comparing high frequency rTMS to sham conditions, antidepressant medications and ECT. Although ECT was superior to rTMS in major depressive disorder (MDD) patients with psychotic symptoms, non-psychotic patients responded equally well to both treatments. The authors of a recent review concluded that while it is premature to recommend rTMS in the treatment of depression, this method deserves further investigation. Prefrontal atrophy, non-response to pharmacotherapy and the presence of psychotic or melancholic symptoms are predictive of non-response. This treatment, and those that follow, are summarized in Table 8.5.

Treatment parameters rTMS involves the stimulation of cortical neurons by magnetic induction, using a brief, high-intensity magnetic field. The electrical current is rapidly turned on and off to produce a time-varying magnetic field lasting 100 to 200 microseconds. Repetitive stimulation with frequencies in the range of 1 to 20 Hz is applied over the course of about 30 minutes during a treatment session. The magnetic pulse crosses the scalp almost painlessly, causing neuronal stimulation and depolarization to a depth of about 2 cm below the surface of the brain. The strength of the magnetic field is insufficient to reach deeper subcortical cingulate or limbic structures. Mild headache and discomfort at the site of stimulation are the main side-effects.


Table 8.5 Recommendations for investigational neuromodulation therapies Recommendations

Evidence

• rTMS: preliminary evidence supports the efficacy of rTMS in non-psychotic • and non-TRD populations

Level 2

• VNS received FDA approval as an adjunctive long-term treatment of TRD

Level 2

• DBS: preliminary results for TRD await replication under RCT conditions

Level 3

• Neurosurgical procedures including subcaudate tractotomy and anterior • cingulotomy have support in TRD from case series only

Level 4

rTMS, repetitive transcranial magnetic stimulation; TRD, treatment-resistant depression; VNS, vagus nerve stimulation; FDA, Food and Drug Administration; DBS, deep brain stimulation; RCT, randomized controlled trial.

Combination with antidepressants Potential clinical uses include the treatment of medication-refractory patients, perhaps in place of ECT. Because of its rapid onset of effect, it may also hasten clinical response in conjunction with antidepressants. As yet, however, there is no consensus about the optimal treatment parameters, including frequency and anatomic location of stimulation. Most of the positive results have yet to be replicated, the follow-up periods are brief (two to four weeks) and there are no long-term or maintenance studies. In summary, rTMS is an attractive alternative to ECT because it is noninvasive, can be conducted in outpatient settings, does not require anesthesia or sedation and has no effects on cognition and virtually no other side-effects.

Vagus nerve stimulation: efficacy and treatment parameters Vagus nerve stimulation (VNS) is approved for the treatment of drug-refractory epilepsy and in the United States received approval in 2005 for treatment-resistant depression (TRD), although there is as yet no acute double-blind evidence for the effectiveness of VNS in TRD.


Figure 8.4 Schematic to illustrate lead and stimulator positions for vagus nerve stimulation. Treatment with VNS requires the surgical insertion of an electrical wire around the left vagus nerve in the neck (Figure 8.4). This is connected to a stimulator located in the chest wall, which delivers continuous but intermittent (30 seconds on, 5 minutes off) pulsed electrical signals to the vagus nerve. The stimulation parameters, including intensity, frequency and duration of stimulation, can be programmed. In an open trial, intermittent stimulation of the vagus nerve resulted in a 40% response rate in patients with TRD. In a subsequent randomized trial with a sham condition (the stimulator was turned off), there were no differences in response or remission rates between the active and sham conditions at the end of eight weeks. However, with prospective open-label follow-up there was continued improvement in VNS-treated patients after one and two years, a similar time course of response to that seen in epilepsy patients treated with VNS. The VNS-treated patients also had better outcomes than a comparison group of patients with TRD who received usual care. These positive results led to the Food and Drug Administration (FDA) approval of VNS for TRD. Besides the surgical and postoperative risks, the most common side-effect is voice alteration or hoarseness.


Figure 8.5 Deep brain stimulation electrodes inserted and connected to subclavicular pacemaker. The stimulator remains on all the time and batteries last 3–5 years.

Deep brain stimulation Deep brain stimulation (DBS) represents a unique targeted intervention for TRD in which electrodes are neurosurgically implanted in bilateral areas of the brain and electrical stimulation is applied (Figure 8.5). Safety and efficacy data were first acquired in Parkinson’s disease, where stimulation of the subthalamic nucleus markedly improved tremor and rigidity. Advances in functional and structural neuroimaging techniques and the emergence of a hypothesis of ‘depression neurocircuitry’ created favorable conditions for an investigational protocol to be conducted in highly treatment-resistant depressed patients. Although there is no clear consensus on the optimal target, evidence from functional imaging studies supports the selection of subgenual cingulate Brodmann area 25 (BA25) as the target for bilateral stimulation. Increased


activity in BA25 has been demonstrated using positron emission tomography in healthy volunteers during sadness and in depressed patients before treatment. This overactivity decreased following effective antidepressant treatment. By continuously providing electrical stimulation to this overactive region, depolarization reduces the hyperactivity, and in a preliminary report was associated with a clinically and statistically significant response in a small clinical sample of patients with TRD. Other investigators have proposed stimulation in the anterior limb of the internal capsule or in the nucleus accumbens. Controlled trials are now required; randomized, doubleblind studies are possible because there is no sensation with stimulation, so the stimulator can be switched on and off without either the evaluator or the patient being aware of its status.

Lesion based neurosurgery Additional neurosurgery techniques use precise computer guided stereotactic techniques to position small lesions in different limbic areas of the brain. The lesion locations currently targeted are anterior cingulotomy or capsulotomy and subcaudate tractotomy. While there are no controlled studies of modern limbic surgery yet reported, several case series with long-term follow-up show benefits with minimal side-effects in highly refractory patients. Also, a multinational study using a non-invasive gamma knife approach is ongoing.

Conclusion These developments in neuromodulation techniques reflect advances in theoretical models for depression, paired with emerging technologies to deliver continuous or intermittent electrical stimulation and years of experience with applying the procedures in other disease conditions. While results beyond ECT are preliminary, each of these neuromodulation treatments has the potential to improve outcome for selected patient groups.

Bibliography Berman RM, Narasimhan M, Sanacora G et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol Psychiatry 2000; 47: 332–7.

116 Treating Depression Effectively Bourgon LN, Kellner CH. Relapse of depression after ECT: a review. J ECT 2000; 16: 19–31. Duman RS, Malberg J, Nakagawa S, D’Sa C. Neuronal plasticity and survival in mood disorders. Biol Psychiatry 2000; 48: 732–9. George M, Belmaker R. Transcranial Magnetic Stimulation in Psychiatry. Washington, DC: American Psychiatric Press, 2000. George MS, Nahas Z, Bohning DE et al. Vagus nerve stimulation therapy: a research update. Neurology 2002; 59: S56–61. Giacobbe P, Kennedy SH. Deep brain stimulation for treatment-resistant depression: a psychiatric perspective. Curr Psychiatry Rep 2006; 8: 437–44. Husain MM, Rush AJ, Rink M et al. Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report. J Clin Psychiatry 2004; 65: 485–91. Janicak PG, Dowd SM, Martis B et al. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized trial. Biol Psychiatry 2002; 51: 659–67. Kellner CH, Knapp RG, Petrides G, Rummans TA. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry 2006; 63: 1337–44. Kennedy SH, Giacobbe P. Treatment resistant depression: a focus on neuromodulation therapies. Ann Clin Psychiatry 2007; in press. Lam RW, Bartley S, Yatham LN et al. Clinical predictors of short-term outcome in electroconvulsive therapy. Can J Psychiatry 1999; 44: 158–63. Lisanby SH, Maddox JH, Prudic J et al. The effects of electroconvulsive therapy on memory of autobiographical and public events. Arch Gen Psychiatry 2000; 57: 581–90. Malhi GS, Sachdev P. Novel physical treatments for the management of neuropsychiatric disorders. J Psychosom Res 2002; 53: 709–19. Mayberg HS, Lozano AM, Voon V et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005; 45: 651–60. Mayur PM, Gangadhar BN, Subbakrishna DK, Janakiramaiah N. Discontinuation of antidepressant drugs during electroconvulsive therapy: a controlled study. J Affect Disord 2000; 58: 37–41. Nahas Z, Teneback C, Chae JH et al. Serial vagus stimulation functional MRI in treatment resistant depression. Neuropsychopharmacology 2007 Jan 3; [Epub ahead of print].

Neuromodulation and other physical treatments 117 Nutt DJ, Glue P. The neurobiology of ECT: animal studies. In: Caffey CE, ed. ECT: From Research to Clinical Practice. Washington, DC: American Psychiatric Association, 2000: 241–65. Potokar J, Wilson SJ, Nutt DJ. Do SSRIs prolong seizure duration during ECT? Int J Psychiatry Clin Pract 1997; 1: 277–80. Rabheru K, Persad E. A review of continuation and maintenance electroconvulsive therapy. Can J Psychiatry 1997; 42: 476–84. Rush AJ, George MS, Sackeim HA et al. Vagus nerve stimulation (VNS) for treatmentresistant depressions: a multicenter study. Biol Psychiatry 2000; 47: 276–86. Sackeim HA, Prudic J, Devanand DP et al. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry 2000; 57: 425–34. Sackeim HA, Haskett RF, Mulsant BH et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA 2001; 285: 1299–307. Sackeim HA, Prudic J, Fuller R et al. The cognitive effects of electroconvulsive therapy in community settings. Neuropsychopharmacology 2007; 32: 244–54. Tew JD Jr, Mulsant BH, Haskett RF et al. Acute efficacy of ECT in the treatment of major depression in the old-old. Am J Psychiatry 1999; 156: 1865–70. UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet 2003; 361: 799–808.

Chapter 9

Complementary, light, sleep deprivation and exercise therapies

Introduction There has been a growing demand for ‘natural therapies’, including herbal preparations, light therapy, sleep deprivation and exercise, in recent years. While some of these treatments have been evaluated under controlled conditions, many, particularly herbal remedies, have only anecdotal and historical evidence to support their effectiveness. There is also limited knowledge about dose regimens and concerns about internal consistency in the manufacturing processes. This chapter will consider each of these approaches. Only studies that describe diagnostic criteria for the inclusion of depressed patients and include accepted outcome measures are considered.

St John’s Wort Extracts of the plant St John’s Wort (Hypericum perforatum) have been reported to elevate mood and have been a popular form of herbal therapy, especially in central Europe, for many years. Since the publication of a metaanalysis in 2001 supporting the efficacy of H. perforatum in depression of mild-to-moderate severity, there have been at least three large trials, two in the USA and one in France, that met standards for good clinical trial design.


Table 9.1 Side-effects and drug interactions of Hypericum perforatum Side-effects

Drug interactions

Gastrointestinal discomfort Photosensitivity Fatigue Hypomania

Serotonin syndrome with SSRI Decreased effect of warfarin and protease inhibitors due to enzyme induction

In both US studies, H. perforatum was no more efficacious than placebo, although in one of these trials the active comparator agent, sertraline, was also no more effective than placebo. In contrast, results of the European placebo-controlled trial in mild-to-moderate depression were positive. Up to nine potentially active ingredients have been identified, with evidence to suggest that hyperforin has mild inhibitory effects on the serotonin transporter and monoamine oxidase as well as weak effects on γ-aminobutyric acid (GABA) receptors. It is likely that different preparations contain different amounts of hyperforin and other ingredients such as hypericin. The dosages of H. perforatum used in trials ranged from 300 to 900 mg daily. Side-effects appear to be milder and less frequent than those reported with standard antidepressants. There are, however, reports of interactions between H. perforatum and several prescription medications, including selective serotonin reuptake inhibitors (SSRIs) (Table 9.1).

Omega-3 fatty acids and inositol Phospholipids are the main structural elements of all internal and external neuronal membranes, and contain both highly unsaturated fatty acids from the omega-3 or omega-6 series as well as inositol. Dietary sources of omega-3 essential fatty acids include cold-water fish such as salmon and halibut, as well as canola and soybean oils. These fatty acids may have therapeutic benefits in atherosclerotic heart disease as well as depression. Three types of omega-3 fatty acids are particularly important to humans: α-linolenic acid, eicosapentaenoate (EPA) and docosahexanoic acid (DHA). Building on previous reports of phospholipid abnormalities in depressed patients, several investigators have added EPA to standard antidepressants in unresponsive patients and reported antidepressant benefits. In contrast,

Complementary, light, sleep deprivation and exercise therapies 121

no significant differences were found between placebo and DHA in a US study. There is also evidence that omega-3 fatty acids may help to protect against relapse when added to traditional mood stabilizers in bipolar patients. Side-effects include gastrointestinal discomfort, flatulence and a malodorous ‘fishy’ breath. Overall, the heterogeneity of populations and trial methodologies including dosing of fish oils does not provide sufficient evidence to recommend these supplements as primary antidepressant therapies, although they may have a potential benefit as augmentation therapies. Inositol is thought to act as a second messenger for 5HT2 receptors. Several small clinical trials suggest that inositol may be helpful in depression and anxiety disorders, although it has not been effective as an adjunctive agent with SSRIs. It requires large oral doses (12 g) and may cause gastrointestinal distress and fish-like odors.

S-adenosyl methione S-adenosyl methione (SAMe) is a naturally occurring amino acid derivative that is found in all cells. It plays a role in methylation, and as a dietary supplement may increase the availability of neurotransmitters including the monoamines: serotonin (5HT), dopamine (DA) and norepinephrine (NE). In a meta-analysis of studies comparing SAMe mainly to low-dose tricyclic antidepressants (TCAs) there was comparable antidepressant effectiveness, and in several cases patients on SAMe developed mania. There are no comparisons with SSRI or dual-action antidepressants. Although SAMe has been of interest to practitioners of complementary medicine for over a decade, it has only recently emerged in the USA as a popular self-administered treatment for depression. Nausea is a relatively common side-effect.

Tryptophan Tryptophan was withdrawn in the USA and several European countries in 1990 following the outbreak of eosinophilia myalgia syndrome, which was traced to the presence of a bacterial contaminant in a single manufacturing batch of the product. It has continued to be available by prescription only in Canada, where it is subject to higher levels of quality control than non-prescription health supplements.

122 Treating Depression Effectively Although there is limited evidence that tryptophan has antidepressant effects on its own, there is more evidence to support its use as an augmentation therapy in depressed patients, including evidence that it improves sleep when combined with fluoxetine. It is generally well tolerated, but may cause serotonergic syndrome when used in high doses with high-dose SSRI therapy. Tryptophan in doses of 2–6 g daily is also used as a hypnotic.

Dehydroepiandrosterone Dehydroepiandrosterone (DHEA) is a precursor of androstenodione, which is converted to estrogens and androgens. Although there are some preliminary reports of its antidepressant properties, potential adverse effects, including increased risk of prostate cancer and liver toxicity, should limit its use in depressed patients. The above complementary preparations are summarized in Table 9.2.

Table 9.2 Conclusions about complementary therapies Preparation St John’s Wort Contradictory findings in major depressive disorder (MDD) Limited support for use in mild depression Drug interactions have been reported Omega-3 fatty acids Potential augmentation strategy Inositol Some evidence of antidepressant effects; use limited by large dosing requirements

Evidence

Level 1

Level 2

Level 3

SAMe Limited antidepressant benefit with low-dose TCAs

Level 2

Tryptophan Limited antidepressant augmentation and hypnotic effects

Level 2

DHEA Potential hazards may outweigh antidepressant benefits

Level 2


Light therapy Efficacy The efficacy of light therapy (LT) for winter depression – major depressive disorder (MDD) with seasonal pattern (see Chapter 5) – has been established with response rates of 60% and higher. LT was comparable in outcome to fluoxetine in one of the few randomized controlled trials (RCTs) to directly compare antidepressants and LT. In contrast, the efficacy of light therapy alone in the treatment of non-seasonal depressive disorders has yet to be established. While a Cochrane systematic review found evidence for beneficial effects of light in non-seasonal depression, this was based on small studies with many methodological limitations, so there is currently insufficient evidence to recommend LT alone for non-seasonal depression. However, its use in combination with antidepressant medications may speed response and be more effective than antidepressant monotherapy for some patients.

Treatment parameters The fluorescent light box is the ‘gold standard’ light device, although a recent meta-analysis supported the role of dawn-simulating alarm clocks but not rechargeable light visors. The recommended treatment regimen requires exposure to light at an intensity of 10 000 lux for 30 minutes daily, in the early morning, as soon as possible after awakening (Table 9.3). The light box should have an ultraviolet (UV) filter to screen out harmful UV rays. Improvement in symptoms may be apparent during the first week, but full response usually takes two to four weeks.

Table 9.3 Summary of evidence regarding light therapy Recommendations

Evidence

• Demonstrated efficacy for winter depression of mild-to-moderate severity

Level 1

• An adequate trial requires two to four weeks of fluorescent light at an intensity of 10 000 lux for 30 minutes each day in the early morning

Level 2

• Patients usually need to continue daily light therapy throughout the winter and can discontinue treatment in the summer

Level 3

• There is insufficient evidence to recommend light therapy for long-term or maintenance use

None


Table 9.4 Adverse effects of light therapy • • • • • • • •

Eyestrain Headache Nausea Sedation Visual disturbances Agitation or feeling ‘wired’ Sweating Hypomania or mania

Side-effects are usually minimal and transient (see Table 9.4). They may be alleviated by a reduced dose of light; there is no evidence of ocular damage with proper use of LT. Nevertheless, ophthalmological assessment and monitoring are recommended if patients have ocular risk factors for potential light toxicity, such as pre-existing retinal disease, or are being treated with photosensitizing medications including phenothiazine antipsychotics, lithium, melatonin or St John’s Wort.

Maintenance and prevention Since most patients experience rapid recurrence of symptoms after discontinuation of LT, it should be continued throughout the period of risk for winter depression and discontinued during the summer months. There are few data on long-term or maintenance use of light therapy for seasonal (winter) or non-seasonal depression. Other conditions where LT may be beneficial are premenstrual dysphoric disorder, bulimia nervosa, depression during pregnancy and delayed sleep phase disorder.

Sleep deprivation Efficacy Total sleep deprivation (TSD) can improve depressive symptoms, sometimes dramatically. On occasion, manic switches have been triggered in bipolar patients. Unfortunately, the antidepressant effect of TSD is usually transient, and most patients relapse after even a brief recovery of sleep, leaving a minority (up to 15%) in sustained remission.


In an effort to prevent this rapid relapse after TSD, modified partial sleep deprivation (i.e. sleep deprivation in the second half of the night) has been evaluated with some success. Unfortunately, even partial sleep deprivation is difficult for patients to continue for more than a week, and when carried out in hospital is quite demanding of nursing staff.

Treatment parameters Given the rather simple procedure, sleep deprivation may be considered as an alternative approach, particularly when a rapid response is required (e.g. in acutely suicidal inpatients). One protocol supported in the literature includes three TSD periods within one week. During each 48-hour period, the patient is awake from 7am on day 1 to 7pm on day 2 (36 hours of sleep deprivation) followed by recovery sleep from 7pm to 7am on day 3 (12 hours of sleep). The sleep deprivation period is then repeated.

Combination and maintenance Strategies to sustain the antidepressant effect include combining sleep deprivation with antidepressant medications, lithium, pindolol, light therapy and, paradoxically, tryptophan depletion. Placebo-controlled studies are obviously difficult to conduct for such a treatment, but several controlled studies of sleep deprivation support these combined treatments. Sleep deprivation has no evidence base to recommend it as a maintenance therapy.

Exercise Intuitively, exercise makes sense as an adjunct to virtually all forms of antidepressant treatment. Unfortunately there are very few studies involving exercise that meet methodological standards. In one controlled trial involving elderly people with depression, exercise alone was as effective as sertraline alone or the combination of both, although sertraline produced a faster onset of response. In a six-month follow-up to this study, the exercise group had a lower relapse rate than did the medication group. A subsequent randomized controlled trial supported aerobic exercise over non-aerobic exercise as an effective treatment for mild to moderate MDD. Including exercise in a treatment program may also help to address concerns about medicationrelated weight gain. The above therapies are summarized in Table 9.5.


Table 9.5 Recommendations for light, sleep and exercise therapies Recommendations

Evidence

Light therapy Efficacy in winter depression

Level 1

Sleep deprivation Effective transient treatment for MDD May augment other treatments Response may be maintained using medications or bright light Exercise May be effective in patients with minor depressive disorder (mDD) Useful to augment first-line treatments

Level 2

Level 1

Conclusions Complementary or nutriceutical therapies have produced uneven results. The evidence to support St John’s Wort as a primary antidepressant is limited. On the other hand, preliminary evidence suggests at least that some omega-3 fish oils may augment standard antidepressant agents. Light therapy has comparable efficacy to SSRIs for winter depression. While sleep deprivation may provide a transient response even in severe major depression, it is difficult to implement and impractical as a sustained intervention. Finally, there is growing evidence to support exercise, particularly aerobic, as a treatment or adjunct to other therapies for depression.

Bibliography Appleton KM, Hayward RC, Gunnell D et al. Effects of n-3 long-chain polyunsaturated fatty acids on depressed mood: systematic review of published trials. Am J Clin Nutr 2006; 84: 1308–16. Dunn AL, Trivedi MH, Kampert JB, Clark CG, Chambliss HO. Exercise treatment for depression: efficacy and dose response. Am J Prev Med 2005; 28: 1–8. Freeman MP, Hibbeln JR, Wisner KL et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry 2006; 67: 1954-–67. Giedke H, Schwarzler F. Therapeutic use of sleep deprivation in depression. Sleep Med Rev 2002; 6: 361–77.

Complementary, light, sleep deprivation and exercise therapies 127 Golden RN, Gaynes BN, Ekstrom RD et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. Am J Psychiatry 2005; 162:656–62. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John’s Wort) in major depressive disorder. JAMA 2002; 287: 1807–14. Jorm AF, Christensen H, Griffiths KM, Rodgers B. Effectiveness of complementary selfhelp treatments for depression. Med J Aust 2002; 176: S84–96. Kripke DF. Light treatment for nonseasonal depression: speed, efficacy, and combined treatment. J Affect Disord 1998; 49: 109–17. Lam RW, Levitt AJ. Canadian Consensus Guidelines for the Treatment of Seasonal Affective Disorder. Vancouver, BC: Clinical & Academic Publishing, 1999. Lam RW, Levitt AJ, Levitan RD et al. The Can-SAD study: a randomized controlled trial of the effectiveness of light therapy and fluoxetine in patients with winter seasonal affective disorder. Am J Psychiatry 2006; 163: 805–12. Lawlor DA, Hopker SW. The effectiveness of exercise as an intervention in the management of depression: systematic review and meta-regression analysis of randomised controlled trials. BMJ 2001; 322: 763–7. Lecrubier Y, Clerc G, Didi R, Kieser M. Efficacy of St. John’s Wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial. Am J Psychiatry 2002; 159: 1361–6. Lee TM, Chan CC. Dose-response relationship of phototherapy for seasonal affective disorder: a meta-analysis. Acta Psychiatr Scand 1999; 99: 315–23. Levitan RD, Shen J-H, Jindal R et al. Preliminary randomized double-blind placebocontrolled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects. J Psychiatry Neurosci 2000; 25: 337–46. Marangell LB, Martinez JM, Zboyan HA et al. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexanoic acid in the treatment of major depression. Am J Psychiatry 2003: 160: 996–8. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002; 159: 477–9. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry 2002; 59: 913–19. Shelton RC, Keller MB, Gelenberg A et al. Effectiveness of St John’s Wort in major depression: a randomized controlled trial. JAMA 2001; 285: 1978–86. Tuunainen A, Kripke DF, Endo T. Light therapy for non-seasonal depression. Cochrane Database Syst Rev 2004; (2): CD004050.

128 Treating Depression Effectively Wirz-Justice A, van den Hoofdakker RH. Sleep deprivation in depression: what do we know, where do we go? Biol Psychiatry 1999; 46: 445–53. Wolkowitz OM, Reus VI, Keebler A et al. Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry 1999; 156: 646–9.

Chapter 10

Depression in women

Introduction This chapter addresses the treatment of depressive disorders during different reproductive events in the life cycle of women (Figure 10.1).

Gender differences in depression Women are almost twice as likely to suffer from major depressive disorder (MDD) as men, beginning in early adolescence and continuing through to menopause. Atypical depression and seasonal (winter) depression occur even more frequently in women than in men. Women are likely to have an earlier age of onset, and experience longer episodes and more recurrences than

Menarche

Perimenopausal depression

PMDD

Depression in pregnancy

Menopause

Pregnancy

PPD PPP

Infertility depression

Postmenopausal depression

Miscarriagerelated depression

Figure 10.1 Depression and the reproductive cycle in women. PMDD, premenstrual dysphoric disorder; PPD, postpartum depression; PPP, postpartum psychosis.

130 Treating Depression Effectively men. Episodes in women tend to be more functionally disabling, and are more expensive to treat when employment costs are included. Rates of comorbid psychiatric disorders also differ between men and women. Comorbid anxiety disorders are three times more prevalent in women; comorbid eating disorders and somatization disorders occur more commonly in women, whereas alcohol/substance abuse and dependence are more prevalent in men. Although borderline, histrionic and dependent personality disorders are diagnosed more frequently in women, the traditional assumption that personality disorders are more prevalent in women than men has been challenged. Rates of attempted suicide are also more prevalent in women, while completed suicide is approximately three times more prevalent in men. The reasons for this gender difference in so many depression-related phenomena are not well understood, but probably relate to a combination of physical, psychological and social factors. Women have faster rates of serotonin (5HT) metabolism than men, and so may be more vulnerable to reductions in the availability of the precursor amino acid

L-tryptophan.

Neurosteroid levels alter markedly during the menstrual cycle and in pregnancy, and these can induce alterations in other neurochemicals. Social roles, especially those limiting self-effectiveness and financial autonomy, may evoke a sense of helplessness. Violence to women is an additional risk factor.

Gender differences in treatment response Psychotherapy Several studies indicate that both men and women have similar outcomes with cognitive behavior therapy (CBT), although one study indicated that women with greater symptom severity were less likely to achieve remission than were men. On the other hand, women have been reported to benefit more than men from group therapy and interpersonal psychotherapy (IPT).

Pharmacotherapy Gender differences in pharmacokinetic and pharmacodynamic effects of psychotropic medications may be related to the effects of female hormones on the absorption and bioavailability of medications, to differing distributions of lean/adipose body tissue, to differences in hepatic blood flow and possibly to the effects of the menstrual cycle. With comparable oral dosing, women are likely to have higher plasma levels of antidepressant medications and experience more frequent side-effects than men. They may also be more

Depression in women 131

concerned about antidepressant-induced weight gain than men, and this should be taken into account when prescribing an antidepressant, especially when weight gain has been one of the features of the depression.

Electroconvulsive therapy (ECT) Seventy percent of patients who receive ECT are women, which reflects the greater prevalence of depression among women. Evidence indicates that women may have lower seizure thresholds than men, and that gender differences in lateralization of brain function may produce differences in cognitive side-effects of ECT (see Chapter 8 for a full discussion of ECT).

Premenstrual dysphoric disorder Prevalence The diagnosis of premenstrual dysphoric disorder (PMDD) according to DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision) requires five or more symptoms, for most of a 12month time span, which start after ovulation and disappear shortly after the onset of menses (Table 10.1). They should be confirmed by at least two months of prospective ratings and cause functional impairment. Although not singled out as a core symptom, irritability is considered by many to be of particular importance. The prevalence of PMDD among women in their reproductive years is between 2% and 10%.

Psychotherapy for PMDD In a randomized controlled trial (RCT), 10 sessions of CBT delivered over six months were as effective as fluoxetine for PMDD, with better maintenance of treatment effects one year later. Other approaches, including lifestyle therapy, stress management and attention to diet, have been recommended but not evaluated.

Pharmacotherapy for PMDD There is strong evidence that selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of PMDD. Citalopram, escitalopram, fluoxetine, paroxetine and sertraline have all been shown to be superior to placebo, and in several cases more effective than noradrenergic antidepressants (desipramine, bupropion and maprotiline). Fluoxetine has been evaluated more frequently than the other SSRIs. The non-selective SRI clomipramine has also been shown to be effective (Table 10.2).


Table 10.1 Symptoms of PMDD Five or more symptoms must be present, with at least one being 1, 2, 3 or 4: 1. Sad, hopeless or self-deprecating feelings 2. Tense, anxious or ‘on edge’ state 3. Marked lability of mood with frequent tearfulness 4. Persistent irritability, anger and increased interpersonal conflicts 5. Decreased interest in usual activities 6. Difficulty concentrating 7. Fatigue, lethargy or lack of energy 8. Changes in appetite often associated with binge eating or craving 9. Hypersomnia or insomnia 10. Subjective feeling or being overwhelmed or being out of control 11. Physical symptoms such as breast tenderness or swelling, headaches, or sensations of ‘bloating’ or weight gain

Table 10.2 Recommendations for the treatment of PMDD Therapeutic choice

Recommendations

Evidence

First

Citalopram; escitalopram; fluoxetine; paroxetine; sertraline Clomipramine

Level 1

Second

Level 2

There is evidence to support intermittent dosing during the luteal phase only for various SSRIs including citalopram, escitalopram, paroxetine and sertraline, and these brief treatments did not result in significant discontinuation symptoms. Gonadotropin-releasing hormone therapies may be used to suppress ovulation, but are associated with substantial side-effects. There is insufficient evidence to recommend alternative therapies, including St John’s Wort and evening oil of primrose.

Depression during pregnancy Prevalence During pregnancy, approximately 20% of women have some depressive symptomatology, and about 10% develop a major depressive episode (MDE). These rates are comparable to those in non-pregnant women. Risk factors


include prior history of depression, younger maternal age, limited social support, living alone, greater number of children, ambivalence about pregnancy, negative life events and low socioeconomic status.

Treating depression during pregnancy Psychotherapy There is evidence to support the efficacy of psychotherapy for depression during pregnancy. IPT was significantly more effective than a parenting education control program in rates of maternal improvement and mother–infant interactions. Although cognitive behavior therapy (CBT) has demonstrated efficacy in postpartum depression, its role in treating depression during pregnancy has not been reported.

Pharmacotherapy Concerns about potential adverse effects of antidepressants on fetal development have restricted the opportunity to carry out randomized trials. Nevertheless, data on efficacy and safety for SSRIs in almost 3000 depressed pregnant women have been published. Over 2000 of these cases involved the use of fluoxetine, where third trimester use has been linked to jitteriness. In a meta-analysis, the relative risk of major malformation with SSRI, norepinephrine reuptake inhibitor (NRI) and dual-action antidepressants (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine,

sertraline,

reboxetine,

venlafaxine,

nefazodone,

trazodone,

mirtazapine and bupropion) was 1.01. The authors concluded that these antidepressants were not associated with an increased risk of malformations above the population level of 1–3%. However, concerns have been expressed about third trimester use of SSRIs – particularly paroxetine – and an increased incidence of cardiac malformations. Two large prospective surveys from the European Network of Teratology Information Services (ENTIS) and the Swedish Medical Birth Registry indicated no causal relationship between in utero exposure to antidepressants and adverse pregnancy outcome. In a subsequent matched comparison of infants born to mothers receiving tricyclic antidepressants (TCAs) and SSRIs compared to an unexposed comparison group, there was a decrease in gestation, birth weight and Apgar score in the infants of SSRI-treated mothers. There were no differences in the infants exposed to TCAs. Neither class was associated with congenital malformations or developmental delay. However, in a small study of infants born to women who received monoamine oxidase

134 Treating Depression Effectively inhibitor (MAOI) therapy, there was an increased risk of congenital malformations. Therefore, it is best to avoid MAOIs in pregnant women. In another study, there was no effect on global intelligence quotient (IQ), language development or behavioral development in preschool children exposed to TCAs or fluoxetine in the first trimester or throughout pregnancy. There were also no significant differences in mood, temperament, arousal or activity levels, distractibility or behavioral problems in these groups of children. Because pregnancy is a hypermetabolic state, it is not surprising that higher doses of antidepressants are often required, particularly in the later stages of pregnancy, to maintain adequate plasma levels and prevent recurrence of symptoms. In a retrospective review of dosing for fluoxetine, paroxetine and sertraline during pregnancy, the dose at delivery was approximately 1.8 times higher than the initial dosage, and the mean time for dose increase was 27 weeks into the pregnancy. There were no significant differences in dosage changes across SSRIs. It should be noted, however, that all SSRIs cross the placental barrier, and caution is advised. Similar findings have also been reported with TCAs. Pregnancy is not protective with respect to risk of relapse into a major depressive episode. Over 60% of women who discontinued antidepressant therapy during pregnancy experienced a relapse, compared to 26% in women who maintained medication throughout pregnancy. The consequences of antidepressant discontinuation during pregnancy are substantial. As of 2006, five prospective controlled trials identified significant withdrawal symptoms in neonates. These were generally similar to those encountered in adults following abrupt SSRI discontinuation, and included neurobehavioral, motor, gastrointestinal and respiratory effects – respiratory distress was particularly prevalent. The majority of cases involved paroxetine, and included several reports of neonatal seizures. Up to 75% of pregnant women who discontinue antidepressant treatment experience a relapse of major depression by the end of pregnancy, with most relapses occurring in the first trimester. Inadequate antenatal care, poor nutrition, obstetric complications and postpartum depression (PPD), as well as the increased risk of exposure to tobacco, alcohol or drugs, are all potential consequences of relapse. Untreated depression during pregnancy has been associated with low birth weight, neonatal distress, prematurity and a threefold increase in the risk of PPD. The Motherisk Program is a Canadian resource center that deals specifically with the effects of medication on fetal development and other


Table 10.3 Recommendations for the treatment of depression during pregnancy Therapeutic choice

Recommendations

Evidence

First

Fluoxetine

Level 1

Second

Citalopram; escitalopram; fluvoxamine; paroxetine; sertraline; venlafaxine

Level 2

Third

Tricyclic antidepressants (TCAs) Electroconvulsive therapy (ECT) Interpersonal psychotherapy (IPT)


pregnancy-related concerns (www.motherisk.org). The National Women’s Health Information Center at www.4woman.gov is a US website that may provide additional information.

Electroconvulsive therapy (ECT) There are no prospective, controlled studies of ECT during pregnancy, although it is known that pregnancy may alter the seizure threshold, and that fetal arrhythmias may occur as a consequence of ECT. Most of these effects can be minimized by modifying the standard ECT technique when treating pregnant patients; however, the patient’s ability to understand and evaluate the risks to both herself and her fetus should be considered in the decision to use ECT. For a summary of the recommendations for the treatment of depression during pregnancy, see Table 10.3.

Postnatal mood disorders Prevalence Postnatal mood disturbance occurs frequently, and may be considered along a continuum of severity from ‘maternity blues’, a mild self-limiting disorder occurring in over 50% of new mothers in the first two weeks after delivery, to ‘PPD’ and ‘postpartum psychosis’ (PPP). PPD, termed MDD with postpartum onset in DSM-IV-TR, requires onset within the first four weeks after delivery. However, depression occurring within three months of delivery is considered to be PPD by many clinicians.


Table 10.4 Risk factors associated with postpartum depression 1. 2. 3. 4. 5. 6. 7. 8.

Previous episode of postpartum depression Previous history of a mood disorder or other psychiatric disorder Depressive symptoms during pregnancy Family history of depression Inadequate social support Chronic stressors Lower socioeconomic status Depression and high levels of expressed emotion in one’s partner

It affects 10% to 15% of new mothers. Screening for known risk factors should be part of antenatal care (Table 10.4). The Postpartum Depression Checklist and the Edinburgh Postnatal Depression Scale have been developed as diagnostic aids (Table 10.5).

Psychotherapy for PPD Women who are at risk for PPD may benefit from counseling, enhanced social support and education prior to delivery. CBT for six sessions was as effective as fluoxetine in one small comparative trial, and equivalent to paroxetine in another. IPT with specific modifications to help resolve marital disputes and major role transition issues after childbirth was also effective. There was also a significant benefit to involving both parents in psychoeducation, compared with psychoeducation only for mothers.

Pharmacotherapy for PPD There are some indications that antidepressant medication decreases recurrence rates for PPD. Fluoxetine, nortriptyline, paroxetine, sertraline and venlafaxine have all shown efficacy. Women with a history of PPD who began antidepressant treatment within 24 hours of delivery had a relapse rate of 6.7%, compared with a rate of 62% in women who deferred prophylaxis in one study, although nortriptyline was not superior to placebo in the prevention of recurrent PPD in another study. Estrogen was also significantly more effective than placebo in improving symptoms in women with severe depression, although the effect was only significant after one month of treatment (onset within three months postpartum). High-dose estrogen therapy has been evaluated as a prophylactic treatment, but its efficacy is mitigated by a number of considerations, such as


Table 10.5 Edinburgh Postnatal Depression Scale (EPDS) Instructions How are you feeling? Because you have recently had a baby, we would like to know how you are feeling now. Please circle the answer that comes closest to how you have felt in the past 7 days, not just how you feel today. Never/ Sometimes Often not often

Most of the time

1. I have been able to laugh and see the funny side of things

3

2

1

0

2. I have looked forward with enjoyment to things

3

2

1

0

3. I have blamed myself unnecessarily when things went wrong

0

1

2

3

4. I have been worried and anxious for no good reason

0

1

2

3

5. I have felt scared or panicky for no very good reason

0

1

2

3

6. Things have been getting on top of me

0

1

2

3

7. I have been so unhappy that I have had difficulty sleeping

0

1

2

3

8. I have felt sad or miserable

0

1

2

3

9. I have been so unhappy that I have been crying

0

1

2

3

0

1

2

3

10. The thought of harming myself has occurred to me

A score of 12 or more is indicative of probable major or minor depression.

interference with breast milk production and coadministration of anticoagulants. In a large, naturalistic follow-up of women with PPD, some of whom requested progesterone, it was found that the relapse rate in the progesteronetreated group was 7%, compared with 67% in the non-progesterone group. Further controlled studies are needed to confirm these impressive findings. It should also be noted that women who suffer from bipolar disorder have a high risk of relapse (35% to 50%) in the postpartum period. Lithium, given in the third trimester or 48 hours postpartum, has been shown to be prophylactic. Recommendations for the treatment of PPD are summarized in Table 10.6.


Table 10.6 Recommendations for the treatment of postpartum depression Recommendations

Evidence

Women with risk factors for postpartum depression (PPD) should be monitored closely during and following pregnancy

Level 3

If there is a history of previous PPD, antidepressant prophylaxis should be considered

Level 3

First choice

Level 2 Level 2

Fluoxetine; paroxetine; sertraline Interpersonal therapy (IPT)

Second choice CBT-focused counseling Level 2 Patient and partner psychoeducation as adjunctive treatment Level 3 Third choice

Estrogen or progesterone Progesterone

Level 2 Level 3

Postpartum psychosis Prevalence Postpartum psychosis (PPP) is a rare disorder, occurring in two out of 1000 deliveries within the first four weeks postpartum.

Treatment This is a psychiatric emergency that invariably requires hospitalization (on a voluntary or involuntary basis). In the majority of cases (70%), PPP is associated with bipolar disorder, and should be managed accordingly using antipsychotic, mood-stabilizing and, if warranted, antidepressant medications. ECT is also effective, and can be first choice for speed of response. The risk of recurrence of psychotic episodes following a subsequent pregnancy or at other times is greater than 50%. Transdermal estrogen started 48 hours after delivery was not effective in reducing relapse in a high-risk group of women.

Pharmacotherapy and breast-feeding The desire to breast-feed, and the increased risk of recurrence in the postpartum period, present an added clinical dilemma, as all antidepressants are excreted in breast milk. There are limited data on the safety of antidepressants during breast-feeding. However, it does appear that some TCAs, MAOIs and SSRIs have no adverse effects on breast-fed infants.


Table 10.7 Recommendations for the treatment of depression during breast-feeding Recommendations

Evidence

Data regarding antidepressants during breast-feeding are limited; long-term developmental effects are unknown

Level 2

Current safety data do not contraindicate the use of several TCAs (amitriptyline, desipramine and nortriptyline) as well as citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine

Level 2

Most studies of SSRIs report very low (fluoxetine) to nearly undetectable (sertraline and paroxetine) levels of the antidepressant in the nursing infant, but the levels of the drug and its metabolite vary with maternal dosing. Some studies report that there is a gradient effect, with greater concentrations occurring in the later portions of breast milk (hind milk) than in the early portions (fore milk); this has been reported for paroxetine and sertraline. The use of sertraline, paroxetine, fluvoxamine and citalopram as well as venlafaxine in nursing mothers has not been associated with infant harm, although side-effects in infants have been reported. In the case of fluoxetine, at a standard dose of 20 mg daily, plasma levels were approximately 10% of maternal levels. Long-term studies, however, are not available and more studies are required to investigate possible long-term developmental effects (Table 10.7).

Depression and menopause Prevalence Controversy over the existence of ‘involutional melancholia’ has spanned several centuries. More recently, the influence of estrogen on serotonin (5HT) receptors has been a topic of growing interest. There is also evidence that

depressive

symptoms

increase

around

the

perimenopause.

Approximately 30% of women in this age group endorse symptoms associated with major depression or a primary anxiety disorder, and the association between physical symptoms and mood disorder is doubled in those women with artificial or surgically induced menopause, compared with other menstrual status groups. Given the increased likelihood of depression during the perimenopausal period it is advisable to screen women aged 45 to


Table 10.8 Risk factors for depression in menopause • • • • • •

History of postpartum depression History of major depressive episodes History of premenstrual dysphoric disorder Prolonged perimenopause (>27 months) Surgically induced menopause Thyroid dysfunction

55 years for depressive symptoms, particularly those who carry identified risk factors (Table 10.8). Problems inherent in defining a menopause-related disorder include lack of adequately standardized diagnostic tools, variability in age and definitions of menopause and variability in psychosocial and biological factors among women. Careful monitoring of symptomatology and endocrinological status may, however, assist in diagnosis and treatment. Considerations for treatment include whether the menopause is naturally or surgically induced, the role of hormone replacement therapy (HRT) and the nature and severity of symptoms. It is also important to determine whether a patient with a previous history of depression is having a recurrence or is suffering from menopause-related depression.

Treatment There is considerable controversy about the influence of menopausal status on antidepressant response, although the consensus is that premenopausal women respond better than postmenopausal women to SSRIs, while men and postmenopausal women respond equally well to TCAs. In a pooled dataset from eight controlled trials, venlafaxine was superior to SSRIs in women 50 years of age and older, but comparable to SSRI plus hormone replacement therapy in this older age group. The availability of desvenlafaxine succinate (DVS) as a treatment for vasomotor symptoms and as a dual-action 5HT and norepinephrine (NE) reuptake inhibitor antidepressant will provide an additional therapeutic option in this population. There is also evidence that women have a better response than men to augmentation with triiodothyronine (T3). Studies of estrogen augmentation in women with postmenopausal depression are inconclusive. Estrogen replacement therapy may provide some relief of vasomotor, minor cognitive and mood symptoms. In a small placebo-controlled trial


Table 10.9 Recommendations for the treatment of postmenopausal depression Therapeutic choice

Recommendations

Evidence

First

Standard pharmacological or psychological treatments (in the absence of specific trials in this population)

Level 3

Second

Estrogen supplementation alone or estrogen augmentation of antidepressant

Level 2

involving perimenopausal women with minor and major depression, transdermal estrogen was significantly more effective than placebo. There are, however, case reports of mania occurring during estrogen treatment. This association may indicate that estrogen has a destabilizing effect in vulnerable patients. In a preliminary report, estradiol effectively treated perimenopausal depression. The use of estrogen replacement must be considered in the context of other data on long-term safety for such interventions (Table 10.9). Most estrogen augmentation studies involved TCAs, although recent studies examined estrogen augmentation of fluoxetine or sertraline, with contradictory conclusions. Treatment of women suffering from affective changes in the menopausal period is comparable to that of MDD: SSRIs can be of benefit for women on HRT, and some observations suggest that TCAs may be better tolerated and more effective than SSRI monotherapy. Mirtazapine has also proved to be an effective monotherapy. Interestingly, the decline in HRT prescription has been correlated with increases in prescriptions of SSRI antidepressants in women over 50 years old. This suggests that antidepressants are being prescribed for physiological symptoms formerly controlled by HRT, and possibly that HRT contributed antidepressant effects that were previously underrecognized.

Conclusions It is important to recognize the influence of the reproductive system on depression in women. There is substantial evidence to support the role of various SSRIs in PMDD, including the use of intermittent-dosing regimens. Clinicians should pay attention to various ‘at risk’ stages in women’s lives, diagnose depression and provide evidence-based treatments. During pregnancy and breast-feeding this often requires discussion of the risks of

142 Treating Depression Effectively untreated depression on mother and infant compared to any medicationrelated concerns, so that optimally informed decisions can be made. The evidence concerning antidepressant response in postmenopausal women is inconsistent, with some suggestion that SSRIs are less effective than in premenopausal women.

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144 Treating Depression Effectively Nulman I, Rovet J, Stewart DE et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout foetal life: a prospective controlled study. Am J Psychiatry 2002; 159: 1889–95. O’Hara MW, Stuart S, Gorman LL, Wenzel A. Efficacy of interpersonal psychotherapy for postpartum depression. Arch Gen Psychiatry 2000; 57: 1039–45. Rabheru K. The use of electroconvulsive therapy in special patient populations. Can J Psychiatry 2001; 46: 710–19. Rasgon NL, Altshuler LL, Fairbanks LA et al. Estrogen replacement therapy in the treatment of major depressive disorder in perimenopausal women. J Clin Psychiatry 2002; 63 (Suppl 7): 45–8. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry 2001; 9: 393–9. Simon GE, Cunningham ML, Davis RL. Outcomes of prenatal antidepressant exposure. Am J Psychiatry 2002; 159: 2055–61. Soares CN, Poitras JR, Prouty J. Effect of reproductive hormones and selective estrogen receptor modulators on mood during menopause. Drugs Aging 2003; 20: 85–100. Spinelli MG, Endicott J. Controlled clinical trial of interpersonal psychotherapy versus parenting education program for depressed pregnant women. Am J Psychiatry 2003; 160: 555–62. Stewart DE. Antidepressant drugs during pregnancy and lactation. Int Clin Psychopharmacol 2000; 15 (Suppl 3): S19–24. Thase ME, Reynolds CF III, Frank E et al. Do depressed men and women respond similarly to cognitive behavior therapy? Am J Psychiatry 1994; 151: 500–5. Wisner KL, Parry BL, Piontek CM. Clinical practice. Postpartum depression. N Engl J Med 2002; 347: 194–9. Wisner KL, Hanusa BH, Perel JM et al. Postpartum depression: a randomized trial of sertraline versus nortriptyline. J Clin Psychopharmacol 2006; 26: 353–60. Yonkers KA, Kando JC, Cole JO, Blumenthal S. Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication [see comments]. Am J Psychiatry 1992; 149: 587–95. Yonkers KA, Holthausen GA, Poschman K et al. Symptom-onset treatment for women with premenstrual dysphoric disorder. J Clin Psychopharmacol 2006; 26: 198–202.

Chapter 11

Depression in children and adolescents Introduction Clinicians have very little evidence-based information to guide their choice of treatments for depression in children and adolescents. Until recently, they were often forced to rely on adult-based evidence in selecting antidepressant treatments. Emerging results from pharmacotherapy trials conducted in young populations provide information on the relative advantages and hazards of antidepressant medications.

Risk factors for depression in children and adolescents Prepubertal boys and girls are equally affected by depression, but the prevalence changes in teens and young adults, with depression affecting girls twice as frequently as boys. There is some evidence to suggest that girls who experience puberty much earlier than their peers are biologically and psychologically predisposed to developing depression. Other risk factors are summarized in Table 11.1. Prepubertal children who rapidly experience a major depressive episode (MDE) are also at considerable risk of developing bipolar disorder in their teens or in adulthood. Early-onset major depressive disorder (MDD) is often associated with high rates of comorbid anxiety disorders, including obsessive compulsive disorder (OCD).

Psychotherapies in children and adolescents There is good evidence to support the benefits of cognitive behavior therapy (CBT) in 8- to 11-year-old children, although diagnostic criteria for MDD may


Table 11.1 Risk factors for developing depression early in life* • • • • • • • • • •

Learning and developmental disorders Attention deficit/hyperactivity disorder (ADHD) Anxiety disorders Parental separation and divorce History of head injury Abuse, neglect, trauma or bereavement Early-onset puberty First-degree relative with depression Chronic medical illness Drug misuse

*Adapted with permission from Garland and Solomons, 2002.

not have been met in some studies. Similarly, adolescents (12–19 years old) have benefited significantly from individual and group CBT; also, there are trials to support interpersonal psychotherapy (IPT) in this age group. In general, these studies support the use of CBT or IPT in mild-to-moderate forms of childhood or adolescent depression. However, the efficacy of psychotherapies in severe depression has yet to be established, since at least one trial (Treatment for Adolescents with Depression Study, TADS) found that fluoxetine was superior to pill placebo while CBT alone was not; however, the combination treatment appeared to be most effective in this severely ill sample (Table 11.2). Although there is strong evidence linking the development of depression in children to family relationships, it is surprising that the role of family therapy in reducing symptoms of depression has not been rigorously investigated. It is also recognized that many children with depression grow up in healthy families.

Table 11.2 Recommendations for psychotherapy in children and adolescents Therapeutic choice

Recommendations

Evidence

First

CBT for mild-to-moderate but not severe depression IPT for mild-to-moderate but not severe depression

Level 1 Level 2

Depression in children and adolescents 147

Pharmacotherapy in children and adolescents There have been relatively few pharmacokinetic and pharmacodynamic studies of antidepressants in children and adolescents, although metabolism usually takes place at similar or faster rates than in adults. While the ‘start low, go slow’ axiom is particularly appropriate here, children may ultimately require doses that are higher than usual adult doses on a mg/kg basis. Time to response or remission may also take longer (six to eight weeks) in younger age groups compared with adults; therefore, a longer than usual trial may be warranted. Most standard antidepressant drugs have not received the approval of governmental regulatory bodies, such as the Food and Drug Administration (FDA) in the USA, for use in children because efficacy studies have not been carried out. In an attempt to correct this, the FDA requested manufacturers to carry out such trials, and results of several controlled trials evaluating antidepressant efficacy and safety in these age groups have become available. There is enough evidence to state that tricyclic antidepressants (TCAs) should not be prescribed for the treatment of depression in children or adolescents. This is based on consistently negative results and concerns about side-effects, particularly cardiac arrhythmias. Monoamine oxidase inhibitors (MAOIs) are rarely prescribed in these age groups, although case series support their effectiveness in otherwise treatment-resistant patients.

SSRIs and dual-action antidepressants Several published studies have shown evidence of efficacy for selective serotonin reuptake inhibitors (SSRIs) (including fluoxetine, sertraline, citalopram) in the treatment of childhood depression, albeit with low effect sizes. However, emerging data in 2003 regarding reports on increased suicidal ideation in children and adolescents during treatment with paroxetine and venlafaxine led to a reevaluation of recommendations for SSRI or serotonin and norepinephrine reuptake inhibitor (SNRI) therapy in the treatment of childhood depression (see Table 11.3). In 2003, advisory letters naming paroxetine and venlafaxine were sent to physicians warning against the use of these agents in the treatment of childhood depression. The FDA commissioned a reanalysis of the pediatric trials which found a small but statistically significant excess of suicidal behaviors (including ideation and attempts) during antidepressant treatment compared


Table 11.3 Dosing of SSRIs in adolescents* Medication

Initial dose (mg)

Citalopram Escitalopram Fluoxetine Fluvoxamine Sertraline

10 5 5 50 50

Target dose (mg)

Dose range (mg)†

20 10 20 200 50

10–40 5–20 10–60 100–300 50–200

*Adapted with permission from Kutcher, 1997. † High ends of range may exceed recommended upper limits in formularies and should be used with caution.

to placebo; however, there was not a single completed suicide in the entire database. This small effect translated to about 1–3 patients with increased risk of suicidal ideation/behaviors for every 100 patients treated with antidepressants, compared to placebo. Although the pattern was similar for all antidepressants, only venlafaxine was statistically associated with increased risk, while paroxetine showed a trend to statistical significance. Complicating this safety concern was the fact that the overall meta-analysis of published and unpublished trials with the newer antidepressants (which included patients with mild–moderate severity) showed no convincing evidence of efficacy compared to placebo, with the exception of fluoxetine. Consequently, only fluoxetine was approved by the FDA for use in youths with depression. In addition, recommendations were given for patient and family education and close monitoring of clinical status (both depressive symptoms and potential side-effects of medication) to optimize safety. Atomoxetine is an inhibitor of the norepinephrine (NE) transporter that has recently become available to treat attention deficit/hyperactivity disorder (ADHD) in some countries, including the USA. Based on its mode of action, it may also have antidepressant effects, although these have not been the focus for regulatory approval. There does not appear to be the same potential for abuse with this type of agent compared to psychostimulants, presumably because dopamine release is not increased. Bupropion may be considered for children with comorbid depression and ADHD, where its dopamine and/or NE uptake blocking effects may help both syndromes (Tables 11.4 and 11.5). Duloxetine, mirtazapine and agomelatine have yet to be evaluated in younger age groups.


Table 11.4 Dosing of dual-action antidepressants* Medication Bupropion Mirtazapine

Initial dose (mg)

Target dose (mg)

Dose range (mg)†

150 30

200–450 30–45

100 15

*Adapted with permission from Shugart and Lopez, 2002. †High end of range may exceed recommended upper limits in formularies and should be used with caution.

Table 11.5 Recommendations for pharmacotherapy of MDD in children and adolescents Therapeutic choice

Recommendations

Evidence

First

Fuoxetine

Level 1

Second

Citalopram; escitalopram; sertraline

Level 2

Third

Bupropion; MAOIs

Level 3

Not recommended

TCAs Paroxetine Venlafaxine Nefazodone

Level 1 Level 2 Level 3 Level 3

Maintenance therapy There have been very few antidepressant maintenance trials in children and adolescents; sertraline was effective in one trial that lasted 20 weeks. Safety concerns about the SSRI class need to be resolved before other agents can be recommended. So far, recommendations about maintenance therapy in this population are derived from trials in adult populations, although the same case can be made for children as for adults, that the goals of therapy are to obtain and maintain remission. As in adults, discontinuation should follow a tapering regimen.

Electroconvulsive therapy (ECT) in children and adolescents Based on limited data, the use of ECT in teenagers with depression or mania is effective and relatively well tolerated. Rates of improvement and

150 Treating Depression Effectively side-effects appear comparable to those reported for adults. There are insufficient data on the use of ECT in children, and there is insufficient clinical experience with children to inform the development of guidelines. In practice, ECT should be reserved for the treatment of adolescents who are suffering from a treatment-resistant depressive or manic illness of such severity that the medical condition of the patient is compromised, or when the patient is at imminent risk for suicide. In such cases, it is prudent to obtain a second opinion from a psychiatrist who is not involved in the care of the patient. Practical aspects for the use of ECT are summarized in Table 11.6. A comprehensive medical and psychiatric history and physical examination should also be conducted. Informed consent from both patient and legal guardian should be obtained prior to the use of ECT. Guidelines for the use of ECT in adolescence are currently under development by the American Academy of Child and Adolescent Psychiatry. Resistance to ECT can be defined as an absence of response after 12 treatments, of which six were bilateral. There is evidence to show that relapse rates following ECT are high in patients who are restarted on an

Table 11.6 Suggestions for the use of ECT in children and adolescents 1.

2.

3.

4.

5.

Choice of anesthetic: Thiopentone, methohexitone and propofol (associated with shorter seizures in young people) are preferred in combination with suxamethonium as the muscle relaxant Device and dosing: As young people have low seizure thresholds, machines that are capable of delivering low doses should be used. Brief-pulse, not sine-wave, machines are preferred Electrode position: There are no data correlating improvement with electrode placement. Unilateral placement may be as effective and may result in fewer cognitive side-effects but bilateral may be associated with a more rapid onset of improvement. Change position to unilateral if the patient becomes confused following bilateral treatment, or change from unilateral to bilateral after six to eight treatments if there is no improvement Electroencephalogram (EEG) monitoring and recording seizure length: This is particularly important in this population, and prolonged seizures (> 2 minutes) should be terminated with diazepam or additional general anesthetic Number of treatments: Similar to those for adults, usual range being six to 12 treatments. The absence of any signs of improvement after six to eight treatments is an indication to discontinue


Table 11.7 Recommendations for the use of ECT in children and adolescents Recommendations

Evidence

ECT is third-line treatment for adolescents but may be considered earlier in acutely suicidal, psychotic or treatment-resistant patients

Level 3

There is weak evidence to support ECT use in prepubertal children

Level 4

antidepressant that was previously ineffective. Therefore, treatment with an antidepressant from a different class should be considered. The effectiveness of maintenance ECT to prevent relapse or recurrence has not been evaluated in children and adolescents (Table 11.7). In adolescents, side-effects with ECT are common in the postictal period but are usually transient. Headaches occur most frequently and should be treated conservatively. When the cognitive effects of ECT were evaluated, there were no long-lasting effects on various neurocognitive functions, although short-term effects (lasting up to two months) on memory have been noted. See Chapter 8 for a more detailed discussion of ECT.

Conclusions The controversy about risks and benefits of treatment for depression in children and adolescents will require further study before it can be resolved. There is also a need to compare the relative effectiveness of antidepressants and evidence-based psychotherapies as well as to evaluate the benefits of maintenance treatments in children and adolescents. Regardless of treatment choice, close monitoring during therapy of depression is important, especially at the beginning of treatment when symptom severity is highest and sideeffects may be experienced before any benefits of treatment are noticed. Currently, for depression of mild to moderate severity in children and adolescents, clinical management or evidence based psychotherapy alone is recommended. Fluoxetine is indicated (in addition to psychotherapy) when the depression is more severe or chronic, or comorbidity is present, or when there is limited response or access to psychotherapy. Other SSRIs can be used if these first line recommendations are not effective. Other newer antidepressants and ECT should be reserved as third line treatments.


Bibliography Baumgartner JL, Emslie GJ, Crismon ML. Citalopram in children and adolescents with depression or anxiety. Ann Pharmacother 2002; 36: 1692–7. Bridge JA, Salary CB, Birmaher B et al. The risks and benefits of antidepressant treatment for youth depression. Ann Med 2005; 37: 404–12. Cohen D, Taieb O, Flament M et al. Absence of cognitive impairment at long-term follow-up in adolescents treated with ECT for severe mood disorder. Am J Psychiatry 2000; 157: 460–2. Curry JF. Specific psychotherapies for childhood and adolescent depression. Biol Psychiatry 2001; 49: 1091–100. Daviss WB, Bentivoglio P, Racusin R et al. Bupropion sustained release in adolescents with comorbid attention-deficit/hyperactivity disorder and depression. J Am Acad Child Adolesc Psychiatry 2001; 40: 307–14. Emslie GJ, Heiligenstein JH, Wagner KD et al. Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry 2002; 41: 1205–15. Emslie G, Kratochvil C, Vitiello B et al. Treatment for adolescents with depression study (TADS): safety results. J Am Acad Child Adolesc Psychiatry 2006; 45: 1440–55. Garland EJ, Solomons K. Early detection of depression in young and elderly people. BC Medical Journal 2002; 44: 469–72. Geller B, Reising D, Leonard HL et al. Critical review of tricyclic antidepressant use in children and adolescents. J Am Acad Child Adolesc Psychiatry 1999; 38: 513–16. Ghaziuddin N, King CA, Naylor MW et al. Electroconvulsive treatment in adolescents with pharmacotherapy-refractory depression. J Child Adolesc Psychopharmacol 1996; 6: 259–71. Harrington R, Whittaker J, Shoebridge P, Campbell F. Systematic review of efficacy of cognitive behaviour therapies in childhood and adolescent depressive disorder. BMJ 1998; 316: 1559–63. Kutcher S. Psychopharmacologic Treatment of Depressive Disorders. Philadelphia: Saunders, 1997. Lam RW, Kennedy SH. Prescribing antidepressants for depression in 2005: recent concerns and recommendations. Can J Psychiatry 2004; 49: Insert 1–6. March J, Silva S, Petrycki S et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA 2004; 292: 807–20. Nutt DJ, Bell C, Masterson C, Short C. Mood and Anxiety Disorders in Children and Adolescents. London: Martin Dunitz, 2001.

Depression in children and adolescents 153 Park RJ, Goodyer IM. Clinical guidelines for depressive disorders in childhood and adolescence. Eur Child Adolesc Psychiatry 2000; 9: 147–61. Shugart MA, Lopez EM. Depression in children and adolescents. When ‘moodiness’ merits special attention. Postgrad Med 2002; 112: 53–61. Vasa RA, Carlino AR, Pine DS. Pharmacotherapy of depressed children and adolescents: current issues and potential directions. Biol Psychiatry 2006; 59:1021–8.

Chapter 12

Depression in late life

Introduction Most recommendations for the treatment of depression are based on evidence derived from studies of middle-life populations. Historically, this information has been applied to special populations, including the elderly, without adequate evaluation of efficacy, tolerability or safety. Yet there are age-related differences in the prevalence of depression, its clinical presentation and various aspects of treatment. The goal of this chapter is to provide a critical evaluation of the available data on epidemiology and treatment options as they pertain to managing depression in older adults. The assessment and management of depression in the elderly involves several challenges. The very old are more sensitive to adverse effects of pharmacotherapy, for reasons ranging from pharmacokinetic and pharmacodynamic properties of the agents to inherent biological differences in an aging body and brain. Although several of the stereotypes about depression in this group, compared to younger adults (e.g. poorer response to treatment and greater risks of chronicity), have turned out to be largely unjustified, depression in the elderly continues to cause substantial morbidity and mortality. Frequent medical comorbidity and the not uncommon need for complex multidrug regimens contribute to underdetection of mood disorders in the elderly. Reluctance to voice concerns about one’s mental health or to utilize mental health services are also significant issues among the elderly, who often grew up with more stigmatized beliefs about mental illnesses and psychiatric treatments than subsequent generations. Biased assumptions persist among healthcare providers, who sometimes view depression as normal in the context of medical or mental impairment

156 Treating Depression Effectively or declining socioeconomic power and reduced independence, which can result in an overlooked diagnosis and a missed opportunity to make a difference with treatment.

Epidemiology The belief that depression is a natural or even inevitable consequence of aging is unfounded. Multiple studies suggest that the current and lifetime prevalences of major depressive disorder (MDD) in later life (age 65 years and over) are significantly lower than at younger ages. For example, oneyear prevalence rates for men and women, respectively, in the Epidemiologic Catchment Area (ECA) study were only 0.4 per 100 and 1.4 per 100, i.e. about one-third of the rates seen in younger or mid-life groups. Of course, higher rates are observed in specific treatment settings, including hospital wards and nursing homes. Patients at particular risk include those with chronic debilitating illnesses, including dementia. There also appears to be a late-life onset variant of dysthymia that is thought to be linked to the cumulative burden of illness on brain function. As the most serious outcome of depression, suicide rates in the elderly differ from those of mid-life adults. Specifically, elderly white men have the highest suicide rates of all sociodemographic groups. There has, nevertheless, been a reduction in overall suicide rates in the elderly during the past few decades.

Treatment Psychotherapy Various psychotherapies have been adapted for treatment of late-life depression, including several forms of cognitive behavior therapy (CBT), interpersonal psychotherapy (IPT) and psychodynamic psychotherapy (see Table 12.1). One meta-analysis found that CBT was an effective treatment as compared to waiting list or no-treatment control groups, but psychodynamic psychotherapy was not. Before concluding that psychodynamic psychotherapy is not a useful treatment for depressed elders, it is important to keep in mind the potential impact of the ‘allegiance effect’ to bias studies: in this case few of the studies of psychodynamic therapy were conducted or supervised by advocates of this form of treatment. Results of another meta-analysis of a broader grouping of time-limited psychotherapy studies suggested efficacy because response rates to psychotherapy were significantly higher

Depression in late life 157

Table 12.1 Recommendations for psychotherapy in late-life MDD Therapeutic choice

Recommendations

Evidence

First

CBT and IPT for mild-to-moderate depression

Level 2

than those observed in placebo-control groups in double-blind trials of antidepressant medications. However, as there were no direct comparisons between psychological and pharmacological treatments included in this meta-analysis, confidence in the conclusion is limited by the simple fact that studies of psychotherapy and pharmacotherapy may enroll different types of elderly depressed patients. Only a small number of controlled studies of psychotherapy in older depressed patients have included both an active comparator (pharmacotherapy) and a double-blind placebo. In the first study, patients with bereavementrelated major depressive episodes were randomly assigned to either an antidepressant or a psychotherapy, singly or in combination. Overall, nortriptyline was significantly more effective than placebo, whereas IPT was not. The combination tended to be more effective than nortriptyline alone. In the second study, patients who were depressed following myocardial infarction were randomized to either citalopram or placebo and to either IPT or clinical management using a factorial design. After 12 weeks of study therapy, the effects of the selective serotonin reuptake inhibitor (SSRI) were clinically and statistically significant; non-significant trends actually favored clinical management alone over IPT. In the only relevant published placebo-controlled study of treatment of late-life dysthymia and minor depression, a study based in primary care comparing paroxetine and problem-solving therapy, results overall favored the pharmacotherapy. However, the inconsistency of the effect of this brief psychosocial intervention was noteworthy, varying from the least to the most effective treatment group across the clinical sites of the trial.

Maintenance psychotherapy Reynolds and colleagues have conducted the only long-term studies evaluating the role of IPT, alone and in combination with antidepressants, for the prevention of recurrent depression in later life. The first study, which utilized nortriptyline, was open to patients aged 60 and older. The second study, which used paroxetine, was limited to patients 70 and older. In both trials

158 Treating Depression Effectively patients had initially received acute-phase therapy with the combination of IPT and antidepressants, and did not relapse during four months of continuation therapy. The randomized experiments thus did not begin until patients had fully recovered from the index episode of depression. In both studies, patients who were withdrawn from both medication and psychotherapy had the poorest outcomes, with those remaining on both therapies having the lowest risk of recurrence. In the first study, the advantage of combined treatment (as compared to the monotherapies) was particularly evident among those patients aged 70 and above, who were less likely to remain well on monotherapies than the patients aged 60–69. In the second study, IPT did not perform as well as in the first; patients on IPT alone were nearly as likely to suffer recurrences as patients on placebo.

Pharmacotherapy Antidepressant pharmacotherapy has become the cornerstone of management of depression in late life. Evidence from a number of meta-analyses documents convincingly that antidepressant medications are effective treatments of late-life depression. The newer medications were found to be as effective as tricyclic antidepressants (TCAs) in these analyses, and generally are associated with fewer discontinuations due to severe adverse events and a lower burden of side-effects. Thus, because the SSRIs are the most widely used antidepressants across all age groups, they also are generally used first in late-life depression. Although not available in the USA, moclobemide has been studied extensively in this population, and, where available, is a first line treatment in depressed elders. Among the newer medications, no significant differences in efficacy across classes of antidepressants were revealed in these meta-analyses. However, results from a pooled analysis of eight randomized controlled trials (RCTs) suggested that therapy with the dual-action agent venlafaxine might result in higher remission rates than observed with the SSRIs. Although none of the studies included in the pooled analysis were specifically designed to examine treatment outcomes in the elderly, this finding held true across age groups, with the difference being particularly large among postmenopausal women not taking hormone replacement. The safety and tolerability of venlafaxine has not been studied extensively in frail elders, although one published trial that compared venlafaxine and sertraline observed that the SSRI was significantly better tolerated than the immediate-release formulation of the serotonin and norepinephrine reuptake inhibitor (SNRI). Clinical experi-


ence with the extended-release formulation of venlafaxine therapy with healthier older depressed patients has been reassuring. A similar conclusion was reached in a post hoc analysis of the older participants of double-blind studies of duloxetine, the second SNRI to be widely introduced. There is also evidence that escitalopram may have stronger antidepressant effects than citalopram and, possibly, other SSRIs in controlled studies of depressed patients, but the impact of such differences specifically in older patients has not yet been examined. These differences are hypothesized to be the result of stereochemically mediated differences in binding at the serotonin transporter. Without consensus about a specific pharmacotherapy of first choice for treatment of late-life depression, medications are more likely to be determined by individual physicians’ experiences and differences in side-effect profiles. This is appropriate because vulnerability to the adverse effects of pharmacotherapy is a major concern when treating the elderly and concerns are not restricted to any specific antidepressant class. Anticholinergic effects (constipation, urinary retention, dry mouth, blurred vision and cognitive impairment) and postural hypotension, which can cause falls and, secondarily, hip fractures, are of particular concern when TCAs are used to treat the elderly. For those at risk for dementia, anticholinergic effects can unmask cognitive difficulties, and, in the extreme, can provoke a delirium. TCAs also have quinidine-like effects on cardiac conduction, which can worsen otherwise benign bundle branch blocks, can cause tachycardia and can have a relatively high lethality index, which makes them dangerous in overdose. Within the TCA class, nortriptyline and desipramine are generally preferred for the treatment of depression in late life, because these medications tend to cause fewer anticholinergic and antihistaminic side-effects. Moreover, blood level/treatment response relationships for TCAs have been relatively well studied, which permits somewhat greater precision in titrating to higher doses. Nevertheless, the overall side-effect burden of the secondary amine TCAs is still greater than that of the SSRIs. For example, nortriptyline has anticholinergic effects that are an order of magnitude stronger than those of paroxetine, which is the most anticholinergic of the SSRIs. Thus, even the secondary amine TCAs are now widely considered to be a second or third line therapy for depression in late life. Although the SSRIs are now generally preferred over the TCAs because of safety considerations, there are some other concerns that are relevant to treat-


Table 12.2 Recommendations for pharmacotherapy in late-life MDD Therapeutic choice

Recommendations

Evidence

First

Moclobemide Citalopram; bupropion; escitalopram; fluvoxamine; paroxetine; sertraline; venlafaxine; mirtazapine

Level 1 Level 2

Second

Fluoxetine; nortriptyline Desipramine; trazodone

Level 1 Level 2

Third

Amitriptyline; imipramine Clomipramine; doxepin; maprotiline Phenelzine; tranylcypromine


Maintenance-phase treatment Elderly patients should continue maintenance pharmacotherapy for at least two years

Level 1

ment of the frail elderly. Foremost among these are bradycardia, the syndrome of inappropriate excretion of antidiuretic hormone (SIADH) and balance difficulties, which can cause falls. To these more serious side-effects must be added the common treatment-emergent complaints, such as sexual dysfunction, nausea, diarrhea and other gastrointestinal complaints and insomnia. Venlafaxine (which, at lower doses, can be thought of as an SSRI) has similar side-effects, with an additional concern of elevated blood pressure at higher doses (Table 12.2). Among the other newer antidepressants, bupropion, moclobemide, nefazodone and mirtazapine are distinguished from the SSRIs and venlafaxine by a relatively low incidence of sexual side-effects. Mirtazapine has beneficial effects on sleep, which can be a bonus for many older depressed patients, whereas bupropion and moclobemide are essentially non-sedating. Mirtazapine is the most antihistaminic of all the newer antidepressants, and, as a result, can cause oversedation and weight gain. Interestingly, in one recent clinical trial, response to mirtazapine was superior to response to paroxetine among patients who expressed the APOE4 gene, which is implicated in the risk of dementia and cerebrovascular disease. Nefazodone is seldom used today because it has been associated with a rare incidence of liver failure. The non-selective monoamine oxidase inhibitors (MAOIs), tranylcypromine and phenelzine, are considered third-choice therapies for late-life


depression, largely because of the need for dietary restrictions to avoid the socalled ‘cheese effect’, i.e. a hypertensive crisis triggered by ingestion of the amino acid tyramine. The MAOIs can also cause a range of troublesome sideeffects, with orthostatic hypotension being the most serious in late-life patients. Nevertheless, these medications were found to be significantly more effective than the RIMA (reversible inhibitor of monoamine oxidase A) moclobemide in one meta-analysis. This analysis was not confined to studies of late-life depression, however, in which the tolerability advantage of moclobemide may have been more salient. It remains to be seen whether the new transdermal formulation of selegiline is useful in late-life depression. Although selegiline is approved in low (MAO-B) selective doses for treatment of Parkinson’s disease (i.e. 5–10 mg/day orally), antidepressant activity requires much higher, non-selective oral doses (i.e. >30 mg/day). Transdermal administration eliminates inhibition of MAO-A in the gut and, by skipping first-pass metabolism, minimizes MAO-A inhibition in the liver. Thus, transdermal delivery permits a high, non-selective level of MAO inhibition in the brain, with much less risk of dietary interactions. There are, however, two remaining issues that have dampened clinical enthusiasm: (1) the US Food and Drug Administration (FDA) has approved therapy without dietary restrictions only at the initial, minimum therapeutic dose (6 mg/24 hours), while higher doses (i.e. 9–12 mg/24 hours) are often needed for patients with difficult-to-treat depression; and (2) relative freedom from dietary interactions does not convey any protection from the potential for drug–drug interactions, which can include potentially lethal cases of serotonin syndrome when high doses of selegiline are used in close temporal proximity to SSRIs or SNRIs. Washouts of at least one week are thus necessary when switching from reuptake inhibitors and, because of the long elimination half-life of its metabolite (norfluoxetine), at least five weeks are needed following cessation of fluoxetine therapy. Pharmacokinetic factors and propensity to cause drug–drug interactions are also important when considering which newer antidepressant to prescribe. SSRIs vary in their effects on the various cytochrome P450 (CYP) isoenzymes, thus resulting in significant differences in propensity to cause drug–drug interactions (see Chapter 6). This is particularly important in elderly patients who have often been prescribed multiple medications for various comorbid physical conditions. Sertraline, citalopram, escitalopram, venlafaxine, mirtazapine and also agomelatine are considered to have lower potential for this type of drug–drug interaction.


Maintenance pharmacotherapy The need for maintenance treatment after successful antidepressant therapy in the elderly is at least as important as it is for younger adults. Moreover, elderly patients may be even more likely to relapse after discontinuing antidepressants, so most antidepressant responders should receive maintenance pharmacotherapy for at least two years (see Chapter 2). In a four-year outcome study of elderly patients with MDD, higher anxiety scores at the time of response and longer time to treatment response were risk factors for recurrence. Therefore, treatment of residual anxiety symptoms may improve the long-term treatment outcome. With one exception, controlled studies of the SSRIs have documented sustained efficacy. There are few studies to compare the effectiveness of specific maintenance treatments in the elderly, and none specifically contrasting various types of newer antidepressants (e.g. SSRI vs. SNRI) and none comparing a newer antidepressant against an older standard such as nortriptyline. Phenelzine was superior to nortriptyline in a placebo-controlled, one-year maintenance study of elderly patients with depression, although high dropout rates compromised this study. As noted earlier, there is evidence from the first study of Reynolds and colleagues that nortriptyline is an effective maintenance pharmacotherapy, especially at higher serum levels and in combination with IPT. The TCA dosulpin has also been shown to be effective for prevention of recurrent depression in late-life depression.

Electroconvulsive therapy (ECT) Electroconvulsive therapy (ECT) is a safe, rapidly effective and well-tolerated treatment for severe forms of MDD (see Chapter 8). It has been repeatedly shown to be a useful treatment in late-life depression, even in the presence of significant medical comorbid conditions. In some regions, ECT is used preferentially for the treatment of patients who are less able to tolerate prolonged response times to pharmacotherapy (i.e. intensely suicidal patients or those who are essentially starving to death from disinterest in food). ECT is the treatment of first choice for severe depressive episodes with psychotic features, and should always be considered when multiple antidepressant trials have been ineffective. Good ECT practice in the elderly requires careful pre-anesthetic medical consultation and management, minimization of concomitant pharmacotherapy that may adversely affect cognition and vigilant monitoring of intra- and post-ECT cardiac status.


Factors influencing the choice of bilateral versus unilateral electrode placement are similar to those in younger groups, balancing the higher probability of response, fewer missed seizures (and thus less required exposure to anesthetics) and longer times to relapse in bilateral placements with correspondingly greater likelihood of confusion, memory impairment or delirium.

Conclusion Although prevalence rates for depression in late life are lower compared to middle life depression, comorbid depression and medical illness is a frequent problem in the elderly and often adds complexity to pharmacotherapy. In general the same treatments that work in middle late life are effective in the elderly, although there is a substantially smaller evidence base. The use of ECT is disproportionately higher in this population compared to younger age groups.

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Depression in late life 165 Regier DA, Boyd JH, Burke JD Jr et al. One-month prevalence of mental disorders in the United States. Based on five Epidemiologic Catchment Area sites. Arch Gen Psychiatry 1988; 45: 977–86. Reynolds CF III, Kupfer DJ. Depression and aging: a look to the future. Psychiatr Serv 1999; 50: 1167–72. Reynolds CF III, Miller MD, Pasternak RE et al. Treatment of bereavement-related major depressive episodes in later life: a controlled study of acute and continuation treatment with nortriptyline and interpersonal psychotherapy. Am J Psychiatry 1999; 156: 202–8. Reynolds CF III, Perel JM, Frank E et al. Three-year outcomes of maintenance nortriptyline treatment in late-life depression: a study of two fixed plasma levels. Am J Psychiatry 1999; 156: 1177–81. Reynolds CF 3rd, Dew MA, Pollock BG et al. Maintenance treatment of major depression in old age. N Engl J Med 2006; 354: 1130–8. Rocca P, Calvarese P, Faggiano F et al. Citalopram versus sertraline in late-life nonmajor clinically significant depression: a 1-year follow-up clinical trial. J Clin Psychiatry 2005; 66: 360–9. Schatzberg AF, Kremer C, Rodrigues HE et al. Double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients. Am J Geriatr Psychiatry 2002; 10: 541–50. Sheikh JI, Cassidy EL, Doraiswamy PM et al. Efficacy, safety, and tolerability of sertraline in patients with late-life depression and comorbid medical illness. J Am Geriatr Soc 2004; 52: 86–92. Steffens DC, Skoog I, Norton MC et al. Prevalence of depression and its treatment in an elderly population: the Cache County study. Arch Gen Psychiatry 2000; 57: 601–7. Tew JD Jr, Mulsant BH, Haskett RF et al. Acute efficacy of ECT in the treatment of major depression in the old-old. Am J Psychiatry 1999; 156: 1865–70. Whyte EM, Basinski J, Farhi P et al. Geriatric depression treatment in nonresponders to selective serotonin reuptake inhibitors. J Clin Psychiatry 2004; 65: 1634–41. Williams JW Jr, Barrett J, Oxman T et al. Treatment of dysthymia and minor depression in primary care: a randomized controlled trial in older adults. JAMA 2000; 284: 1519–26. Wilson KC, Mottram PG, Ashworth L, Abou-Saleh MT. Older community residents with depression: long-term treatment with sertraline. Randomised, double-blind, placebocontrolled study. Br J Psychiatry 2003; 182: 492–7.

Chapter 13

Psychiatric and physical comorbidities in depression

General principles Major depressive disorder (MDD) is such a common condition in the general population that its co-occurrence with other Axis I (psychiatric), Axis II (personality) and Axis III (physical) disorders is to be expected. However, MDD occurs much more often than would be expected by chance in many conditions (Figures 13.1 and 13.2). Clinicians can expect

General population

5

Schizophrenia

25

Alcohol abuse

26

Drug abuse

35

Personality disorders

35

Attention deficit disorder

40

Anxiety disorders

50

Bulimia nervosa

65

Anorexia nervosa

84 0

20

40

60

% of sample with MDD

Figure 13.1 Prevalence of MDD in other Axis I disorders.

80

100


General population

5

Alzheimer's disease

11

HIV/AIDS

12

Heart disease

17

Stroke

23

Myocardial infarct

25

Diabetes

27

Cancer

42

Parkinson's disease

51 0

10

20

30

40

50

60

% of sample with MDD

Figure 13.2 Prevalence of MDD in chronic disease. HIV, human immunodeficiency virus; AIDS, acquired immune deficiency syndrome.

that many patients with MDD will have comorbid conditions. Left untreated, depression can contribute to poor compliance for treatment of other medical conditions, increase length of hospital stays and increase mortality. There are many common diagnostic and treatment issues associated with comorbid depression, regardless of the specific comorbid condition. The diagnosis of depression is often difficult to make in the presence of comorbidity. Depressive symptoms frequently accompany other illnesses, and the primary condition may have symptoms that are common to MDD. For example, anxiety symptoms such as panic attacks can occur or worsen during a major depressive episode (MDE). Mood instability is a common symptom in personality disorders and can be misdiagnosed as depressive mood. In physical illnesses such as cancer, fatigue and lack of energy may not be a valid symptom of depression. In these situations, other depressive symptoms such as anhedonia, loss of interest and feelings of guilt may be helpful in making a diagnosis of comorbid MDD. Despite the high frequency of comorbidity, there are very few controlled studies of treatment. MDD with comorbidity is usually more difficult to treat, runs a more chronic course, has greater impairment of function and is associated with greater risk of suicide compared with MDD alone. Unfortunately, most randomized controlled trials of MDD specifically exclude comorbid

Psychiatric and physical comorbidities in depression 169

conditions, so results cannot be generalized to patients with comorbidity. Many studies focus only on depressive symptoms and do not include formal comorbid depressive disorders. Psychotherapeutic interventions are often targeted at the primary condition, which may also reduce secondary depressive symptoms. Similarly, studies of antidepressants for comorbidity can be complicated by other medications used in treating the primary disorder. Not surprisingly, response and remission rates with monotherapy treatments are generally lower in patients with comorbidity. Combined treatment with pharmacotherapy and psychotherapy is usually indicated for optimal outcome. In the following sections, evidence-based treatment recommendations for both psychotherapy and pharmacotherapy are summarized for Axis I, II and III comorbidities.

Axis I comorbidities Depression is frequently comorbid with other psychiatric disorders (see Figure 13.1). Among the Axis I disorders, anxiety disorders (panic disorder, generalized anxiety disorder, post-traumatic stress disorder, obsessive compulsive disorder and social anxiety disorder) and eating disorders are most commonly associated with MDD. In some conditions, such as schizophrenia, it is very difficult to separate symptoms of depression from symptoms of the primary condition, such as negative symptoms. Specific symptom scales (such as the Calgary Depression Scale) can be useful in making an MDD diagnosis.

Treatment In the treatment of Axis I comorbidities, some of the same medication principles apply as for people with medical illnesses. For example, people with anxiety disorders are often hypersensitive to somatic sensations. Thus, lower initial doses and slower dose titration are helpful strategies to minimize their experience of medication side-effects. In most cases, however, full therapeutic doses are required for optimal response. Evidence based treatments of selected Axis I comorbidities are summarized in Table 13.1.

Axis II comorbidities Personality disorders and dimensions also have a complex relationship with MDD. An estimated 30–50% of patients with MDD have a diagnosable


Table 13.1 Recommendations for the treatment of MDD with comorbid Axis I (psychiatric) disorders

Condition

Treatment choice Psychotherapy Pharmacotherapy

Anxiety disorders

CBT (Level 3)

SSRIs and novel agents (Level 3) • panic disorder: start with lower initial doses • OCD: aim for higher doses

Substance use disorders

Motivational interviewing (Level 3)

Fluoxetine; imipramine; desipramine (Level 2) Avoid benzodiazepines (Level 3) Avoid interactions: MAOIs with opiates; SSRIs with MDMA; fluoxetine/paroxetine and codeine (opiate withdrawal); bupropion SR (increased seizure risk)

Eating disorders

CBT (Level 2)

Bulimia nervosa: fluoxetine (Level 2); phenelzine (cautions apply) (Level 2) Anorexia nervosa: TCAs and SSRIs (Level 3)

Schizophrenia

Adjunctive CBT treats negative and positive symptoms (Level 2)

Imipramine; sertraline (Level 2) Other SSRIs (Level 3) SSRIs may help negative symptoms (Level 2) Atypical antipsychotics (olanzapine; risperidone) treat depressive symptoms in acute psychosis (Level 1) Clozapine reduces suicide events (Level 2)

Attention deficit disorder

CBT may be useful as adjunctive treatment (Level 3)

Bupropion SR (Level 3) Atomoxetine (Level 4) Fluoxetine; sertraline as adjunctive treatment for depressive symptoms only (Level 3)

Dementia

BT (Level 2)

Citalopram; fluoxetine; sertraline (Level 2) Amitriptyline; clomipramine (Level 2) ECT (Level 3)

SSRI, selective serotonin reuptake inhibitor; OCD, obsessive compulsive disorder; MAOI, monoamine oxidase inhibitor; CBT, cognitive behavior therapy; BT, behavior therapy; TCA, tricylic antidepressant; ECT, electroconvulsive therapy; MDMA, methylenedioxymethamfetamine (Ecstasy).

personality disorder. There is some evidence that premorbid personality dimensions such as neuroticism confer vulnerability to depression. However, MDD can also result in regression and exacerbation of premorbid personality dimensions. In many studies, effective treatment of MDD leads to an


Table 13.2 Recommendations for the treatment of MDD comorbid with Axis II (personality) disorders Recommendations

Evidence

Psychotherapy Combined psychotherapy and pharmacotherapy may have superior outcomes Level 3 The combination of Cognitive Behavioral Analysis System of Psychotherapy Level 2 (CBASP) and pharmacotherapy was particularly effective in a group of patients with ‘chronic depression’, many of whom met criteria for Axis II disorders Dialectical behavior therapy is beneficial for mood symptoms associated with Level 2 borderline personality Pharmacotherapy Fluoxetine (in borderline personality) Monoamine oxidase inhibitors (MAOIs) Olanzapine and risperidone (as adjunctive treatment)


improvement in personality traits, and patients may no longer meet criteria for a personality disorder once they have recovered from an MDE. Evidence based treatments of Axis II comorbidities are summarized in Table 13.2.

Treatment Most attention has been focused on depression in relation to borderline personality disorder. In two clinical trials, one in the USA and one in New Zealand, the presence of a Cluster B diagnosis before treatment predicted a positive antidepressant response to fluoxetine compared to those without a comorbid diagnosis, although a subsequent meta-analysis suggested a therapeutic disadvantage for pharmacotherapy in depressed patients with comorbid personality disorders. In addition, electroconvulsive therapy (ECT) outcome in depressed patients with comorbid borderline personality disorder was significantly worse than in depressed patients with or without other personality disorders. The role of psychotherapy is of particular importance, either alone or combined with pharmacotherapy, in treating axis II comorbidities. Psychoeducational and skills-oriented approaches to psychotherapy have been recommended for patients with chronic depression and comorbid personality disorders. Modified forms of cognitive behavior therapy (CBT), including dialectical behavior therapy (DBT), have been developed for patients with borderline personality disorder. The Cognitive Behavioral Analysis System of

172 Treating Depression Effectively Psychotherapy was specifically developed for the treatment of chronic depression, and was found to have significant effects on psychosocial functioning independent of change in depressive symptoms. Evidence based treatments of Axis II comorbidities are summarized in Table 13.2.

Axis III comorbidity Depression is common, and increasingly recognized as an important risk factor in the mortality and functional impairment of patients with comorbid physical illness (see Figure 13.2). Depression can worsen outcomes in medical conditions by several potential mechanisms: (1) behavioral inactivation and lack of motivation seen in depression may affect adherence to medications or other important treatments (such as exercise for diabetes); (2) there may be an increase in negative behaviors associated with depression (e.g. poor diet, smoking, etc.); (3) interpersonal problems experienced by people with depression may affect ability to engage with health professionals and rehabilitation programs; and (4) biological manifestations of depression, such as immune dysfunction, decreased heart rate variability, impaired circadian rhythms and disrupted sleep patterns, may specifically affect physical health. There is particular interest in the relationship between cardiovascular disease and depression. Depression is a significant risk factor for developing coronary artery disease (CAD), and depressed patients are four times as likely to have a myocardial infarction (MI). Depression is also associated with increased mortality in patients with CAD, possibly due to alterations in the hypothalamic–pituitary–adrenal axis, increased platelet activation and coagulability, increased levels of proinflammatory cytokines or decreased heart rate variability. In the first six months after an MI, there is a three- to fourfold increase in mortality among those patients with MDD, which makes it second only to heart failure as a poor prognostic indicator.

Treatment Despite the high prevalence and importance of depression in physical illness, there are very few large randomized controlled trials (RCTs) of medically ill patients with defined comorbid depression (with the exception of CAD – see below). In general, antidepressants appear to be effective treatments in patients with MDD and general medical illnesses. A systematic review conducted through the Cochrane collaboration showed that antidepressants are effective for depression comorbid with a wide range of medical


Table 13.3 Recommendations for MDD comorbid with Axis III (physical) disorders

Condition

Treatment choice Psychotherapy Pharmacotherapy

General medical disorders

Social support; psychotherapy (elderly) (Level 1)

Selective serotonin reuptake inhibitors (SSRIs); novel antidepressants; tricyclic antidepressants (TCAs); psychostimulants (Level 1)

Cardiac disease

Cognitive behavior therapy (CBT) (Level 2) Interpersonal psychotherapy (IPT) no more effective than placebo, therefore not recommended

Citalopram; sertraline (Level 1) Nortriptyline (Level 2)

Cancer

No studies found

Fluoxetine; mianserin; paroxetine (Level 2) Amitriptyline; desipramine (Level 2)

Diabetes

CBT (Level 2)

Fluoxetine; sertraline (Level 2) Nortriptyline (Level 2) and other norepinephrine-acting TCAs may worsen glucose control, therefore not recommended

HIV/AIDS

IPT; group social support; CBT (Level 2)

Fluoxetine (Level 1) Paroxetine; desipramine; imipramine (Level 2) Sertraline (Level 3)

Parkinson’s disease

No studies found

Nortriptyline; desipramine (Level 2) Paroxetine; sertraline (Level 3)

Stroke disease

CBT no more effective than placebo, therefore not recommended (Level 2)

Citalopram; fluoxetine; nortriptyline; sertraline (Level 1) Psychostimulants (Level 3)

conditions, and are generally well tolerated by patients with medical illness. Evidence-based treatment recommendations for comorbid medical conditions are summarized in Table 13.3. There are numerous studies of psychological treatment for cancer. While several studies have shown reductions in depressive and anxiety symptoms

174 Treating Depression Effectively with CBT and other treatments, none has specifically examined patients with a comorbid diagnosis of MDD. There is limited information on antidepressant effects in cancer patients with comorbid depression, although positive results with mianserin, fluoxetine and paroxetine have been reported. Three large RCTs have examined the treatment of depression in patients with CAD. In the SADHART study (Sertraline AntiDepressant Heart Attack Randomized Trial), sertraline was compared with placebo in the treatment of MDD post-MI. The antidepressant was effective in reducing symptoms of depression, and overall showed better outcomes than placebo on a number of cardiovascular system measures. Although sertraline did not significantly reduce mortality or other cardiac events, this study was not adequately powered to detect these differences. Another study, ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients), examined CBT (augmented by sertraline for severe depression non-responders after five weeks) for post-MI MDD. CBT modestly improved depressive symptoms compared to usual care (which may have included antidepressants), but did not affect cardiac outcomes. A post hoc analysis, however, found that the subgroup taking sertraline did show reductions in mortality and cardiac events. The third RCT compared citalopram, interpersonal psychotherapy (IPT) and the combination in patients with CAD and MDD. Citalopram, but not IPT, was superior to pill placebo in reducing symptoms of depression. There was no added benefit of IPT over clinical management in this study. In summary, selective serotonin reuptake inhibitors (SSRIs) such as sertraline and citalopram are effective for MDD comorbid with CAD, with some evidence suggesting that both depression and cardiac outcomes may be improved with treatment. CBT, but not IPT, also appears to have benefit for these patients. There are some important considerations with the use of specific medications for depression comorbid with other medical illnesses (see Table 13.4). For example, nortriptyline is effective in treating people with diabetes and depression but it has been found to worsen glucose control, while fluoxetine not only improved mood but also improved glycemic control. The effect of psychotropic medication-related weight gain on insulin resistance is always an important issue to be considered. On the other hand, amitriptyline and dual-action antidepressants also play an important role in treating chronic painful physical conditions. One important caution in using antidepressants in physically ill patients is the risk of adverse events of particular antidepressants and potential interactions with other drugs.


Table 13.4 Safety concerns for the use of antidepressants in physically ill patients Avoid antidepressants with: • • •

potential interactions with the physical illness, e.g. tertiary amine TCAs in cardiac disease or bupropion in epilepsy side-effects that may exacerbate the physical illness, e.g. nortriptyline or mirtazapine in diabetes potential interactions with other drugs used to treat the physical illness, e.g. fluvoxamine with quinidine.

Start low, go slow and keep going, i.e. start with lower than usual doses of medications and titrate up slowly but continue to full therapeutic doses as needed.

Conclusions Comorbidities are the rule rather than the exception among patients with mood disorders, yet few clinical trials have been carried out to assess outcomes in patients with psychiatric and physical comorbidities. A notable exception is the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, where real-world patients received sequenced treatments. A valuable contribution from this project will be results comparing treatment outcomes for patients with and without Axis I, II or III comorbidities. In general, comorbidity with depression tends to predict less favorable therapeutic outcomes. For optimal patient care, it is important that treatment selection is informed by careful assessment of all three axes. In medically ill patients, it is important to evaluate the impact of antidepressant treatment not only on mood symptoms but also on other physical outcome criteria.

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176 Treating Depression Effectively Gill D, Hatcher S. Antidepressants for depression in people with physical illness (Cochrane Review). Cochrane Database Syst Rev 2000; (4): CD001312. Glassman AH, O’Connor CM, Califf RM et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002; 288: 701–9. Hirschfield RM, Dunner DL, Keitner G et al. Does psychosocial functioning improve independent of depressive symptoms: a comparison of nefazodone, psychotherapy and their combination. Biol Psychiatry 2002; 51: 123–33. Howland RH, Thase ME. Refractory and chronic depression: the role of axis II disorders in assessment and treatment. In: Depression and Personality: Conceptual and Clinical Challenges. Rosenbluth M, Kennedy SH, Bagby RM, eds. Washington, DC: American Psychiatric Publishing, 2005: 157–85. Keller MB, McCullough JP, Klein DN et al. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 2000; 342: 1462–70. Koerner K, Linehan MM. Research on dialectical behavior therapy for patients with borderline personality disorder. Psychiatr Clin North Am 2000; 23: 151–67. Kool S, Schoevers R, de Maat S et al. Efficacy of pharmacotherapy in depressed patients with and without personality disorders: a systematic review and meta-analysis. J Affect Disord 2005; 88: 269–78. Krishnan KR, Delong M, Kraemer H et al. Comorbidity of depression with other medical diseases in the elderly. Biol Psychiatry 2002; 52: 559–88. Lesperence F, Frasure-Smith N, Koszycki D et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007; 297: 367–79. Linehan MM. Commentary on innovations in dialectical behaviour therapy. Cogn Behav Ther 2000; 7: 478–81. Mulder RT, Joyce PR, Luty SE. The relationship personality disorders to treatment outcome in depressed patients. J Clin Psychiatry 2003; 64: 259–64. Newport DJ, Nemeroff CB. Assessment and treatment of depression in the cancer patient. J Psychosom Res 1998; 45: 215–37. Rocca P, Marchiaro L, Cocuzza E, Bogetto F. Treatment of borderline personality disorder with risperidone. J Clin Psychiatry 2002; 63: 241–4. Writing Committee for the ENRICHD Investigators. Effects of treating depression and low perceived social support on clinical events after myocardial infarction. The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA 2003; 289: 3106–16. Zanarini MC, Frankenburg FR. Olanzapine treatment of female borderline personality disorder patients: a double-blind, placebo-controlled pilot study. J Clin Psychiatry 2001; 62: 849–54.

Index

Page references in italics refer to Figures and Tables adherence 16, 16 adolescence see children and adolescents α2-adrenoceptor antagonism 55 agomelatine 56 in anxious depression 67, 68 in melancholia 65 in winter depression 67 agomelatine 75, 82, 83 in children and adolescents 148 in elderly people 162 optimization 96 side-effects 85, 86 alcohol abuse\130 allegiance effect 156 all-or-none thinking 33 allosteric serotonin reuptake inhibitor (ASRI) 53, 81 amine uptake blocking agents 51–5 amitriptyline 51, 79 comorbidities 174 in psychotic major depression 66 anhedonia 35, 64, 168 anticonvulsants, ECT and 109 antidepressant, choice of 14–16 classification by mechanism of action 75, 76 evolution of 49–50, 49 psychotherapy in combination with 42–4 anxious depression 67–8, 68 anxiety disorder 44 aripiprazole 98

assertiveness 35 atomoxetine in children and adolescents 148 attention deficit hyperactivity disorder (ADHD) 148 atypical depression 17, 78, 129 management 63, 63 atypicals as augmentation therapies 98 augmentation therapy 45, 98 automatic negative thoughts 33, 34 Beck Depression Inventory 17, 29 Beck’s model of cognitive therapy 30 befloxatone 51 behavior therapy 35 vs. cognitive therapy 39 behavioral rehearsal 35 benzodiazepines in anxious depression 68 ECT and 109 bereavement 3, 5 bibliotherapy 39–40 bipolar disorder 5 postpartum depression and 136 bradycardia 160 breastfeeding 138–9 bupropion 52, 75, 82 in children and adolescents 148 in combination 100 in elderly people 160 optimization 96 in pregnancy 133

178 Index bupropion (cont.) in premenstrual dysphoric disorder 131 side-effects 82, 84, 86 switching 94 in winter depression 67 burden of illness 1 buspirone 99 Calgary Depression Scale 169 cancer 168, 172–3 carbamazepine, ECT and 109 cheese reaction 51 children and adolescents, depression in ECT 149–51 maintenance therapy 149 pharmacotherapy 147–9, 148 psychotherapies 145–6, 146 risk factors 145, 146 chlomipramine 52 chlorpromazine 51 choice of antidepressants, factors influencing 75 chronic depression 68–70, 69 citalopram 52, 53, 81 augmentation 94, 98, 99 in children and adolescents 147 comorbidities 174 in elderly people 157, 159, 161 in postpartum psychosis 139 in pregnancy 133 in premenstrual dysphoric disorder 131, 132 remission after 93 in winter depression 67 clomipramine 53, 79 augmentation 99 in anxious depression 68 in melancholia 64 clonazepam in anxious depression 68 cognitive behavior therapy (CBT) 13, 32 in adolescents 146 in Axis II comorbidity 171 in children\145–6 in depression during pregnancy 133 in elderly people 156 interpersonal psychotherapy vs. 38 in postpartum depression 136 women and 130

Cognitive Behavioral Analysis System of Psychotherapy (CBASP) 13, 35–6, 44, 69, 171–2 cognitive therapy 31, 32–4 vs. behavioral therapy 39 vs. interpersonal psychotherapy 38 phases of treatment 33–4, 34 response/remission in 45 in switching 94 cognitive triad 33 collaborative empiricism 33 combination strategies 100, 101 combination therapy 98 comorbidity 167–75 Axis I 169 Axis II 169–72 Axis III 172–4 gender and 130 management 10, 11–12 compliance 16, 16 conflict resolution 35 continuation phase psychotherapy 41–2 coronary artery disease (CAD) 172 cost of depression 1 course of depression 1 cross-over 97 Daily Record of Dysfunctional Thoughts 34 deep brain stimulation 114–15 dehydroepiandrosterone 122 delayed onset of antidepressant action 56–7, 56–7 dementia 156 depression neurocircuitry 114 desipramine 53, 79 in combination 97, 100 overdose 88 in premenstrual dysphoric disorder 131 switching 98 desvenlafaxine succinate (DVS) 81 in menopause 140 diabetes 174 diagnosis 2–4 diagnostic instruments 4–5 dialectical behavior therapy (DBT) 171 diaphragmatic breathing 35

Index 179 disability adjusted life years (DALYs) 1, 2 discontinuation and discontinuationemergent symptoms 88 docosahexanoic aicd (DHA) 120 dosulphin in elderly people 162 double depression 68 drug–drug interactions 86–7 DSM-IV-TR (SCID) 5 dual-action antidepressants 53–5, 75, 79 in children and adolescents 147–8, 149 during pregnancy 133 duloxetine 53, 54, 75, 79, 81 in children and adolescents 148 drug–drug interactions 86 in melancholia 65 optimization 96 side-effects 86 dysthymic disorder 68 eating disorders 130 Edinburgh Postnatal Depression Scale (EPDS) 137 eicosapenaenoate (EPA) 120, 121 elderly people, depression in 155–63 ECT 162–3 epidemiology 156 maintenance pharmacotherapy 162 maintenance psychotherapy 157–8 pharmacotherapy 158–62, 160 psychotherapy 156–7, 157 treatment 156–63 electroconvulsive therapy (ECT) 55, 105–10 adverse effects 108 in Axis II comorbidity 171 bilateral (BL-ECT) 107 in children and adolescents 149–51, 150–1 in combination with antidepressants 109 efficacy and indications 105–6 in elderly people 162–3 gender differences in response 131 indications 107 maintenance 109, 109 management of seizure activity 108 in postpartum psychosis 138

in pregnancy 135 prevention of relapse following 110 in psychotic major depression 66 treatment parameters 106–8 unilateral (UL-ECT) 107 electroencephalogram (EEG) 107 emotional reasoning 33 enzyme inhibitors 50 eosinophilia myalgia syndrome 121 escitalopram 52, 53, 81 in elderly people 161 in melancholia 65 in pregnancy 133 in premenstrual dysphoric disorder 131, 132 in winter depression 67 estrogen replacement therapy 140–1 evening primrose oil, in premenstrual dysphoric disorder 132 evidence based antidepressant selection 61–70, 62 exercise 125, 126 fatigue 3 first generation antidepressants 75–80 fluoxamine 86 fluoxetine 53, 54, 57 in adolescents 146 in anxious depression 68 in atypical depression 63 in Axis II comorbidity 171 in breastfeeding 139 in children and adolescents 147, 148, 151 in chronic depression 68 in combination 98, 100, 122 comorbidities 174 discontinuation 88 drug–drug interactions 86 in melancholia 65 in menopause 141 optimization 97 in postpartum depression 136 in postpartum psychosis 139 in pregnancy 133, 134 in premenstrual dysphoric disorder 131

180 Index fluoxetine (cont.) in recurrent brief depression 69 side-effects 85, 86 switching 97 washout period 78, 97 in winter depression 67 fluparoxan 55 fluvoxamine in anxious depression 68 discontinuation 88 in minor depressive disorder 69 in postpartum psychosis 139 in pregnancy 133 side-effects 85 gender differences in depression 129–30 in treatment response 130–1 graded task assignment 35 grief, unresolved 36 group therapy, gender and 130 guided discovery 33 Guillain-Barré syndrome 52 haloperidol 98 Hamilton Depression Rating Scale (HDRS/HAM-D) 17, 18–19, 38, 65 hepatitis 52 HIV 38 hopelessness 10 hormone replacement therapy (HRT) 140–1 Hospital Anxiety and Depression Scale (HADS) 17, 24–5 hyperforin 120 hypericin 120 Hypericum perforatum 119–20 side-effects 120 idazoxan 55 imipramine 51–2, 79 in atypical depression 63 in anxious depression 68 vs. cognitive therapy 41 vs. interpersonal psychotherapy 38, 42 interpersonal psychotherapy and 45 inositol 120–1 insomnia 3

interpersonal deficits 36 interpersonal psychotherapy (IPT) 13, 36–7 in children and adolescents 146 cognitive behavioral therapy vs. 38 cognitive therapy vs. 38 in elderly people 156, 157, 158 gender and 130 phases of treatment 36, 37 involuntary admission 11 involutional melancholia 139 lesion based neurosurgery 115 light therapy 67, 123–4, 125, 126 efficacy 123 maintenance and prevention 124 side-effects 124, 124 treatment parameters 123 α-linolenic acid 120 lithium augmentation 94, 97, 98 in combination 125 ECTs and 109, 110 in postpartum depression 137 lorazepam in anxious depression 68 maintenance response to treatment 17, 20 major depressive disorder (MDD) management goals 9–10, 9 phases 9–10, 10 MAO-A 78, 161 maprotiline 52 in minor depressive disorder 69 in premenstrual dysphoric disorder 131 maternity blues 135 major depressive disorder prevalence in other Axis disorders 167 prevalence in chronic disease 168 subtypes of 6 treatment options for subtypes 63–8 measurement-based care 17 meditation 40 melancholia 64–5, 64, 65 memory retrieval 33 menopause 139–41

Index 181 prevalence of depression 139–40 risk factors 140 treatment 140–1 metachlorophenylpiperazine 55 methylphenidate 99 mianserin 55 in combination 100 comorbidities 174 mifepristone (RU486) in psychotic major depression 66 milnacipran 53, 75, 79, 81 side-effects 86 mind-reading 33 mindfulness based cognitive therapy (MBCT) 40, 45 Mini International Neuropsychiatric Interview (MINI) 5, 10, 14 minor depressive disorder (mDD) 69, 70 mirtazapine 53, 55, 58, 82, 83 in anxious depression 68 in children and adolescents 148 in chronic depression 68 in combination 100 in elderly people 160, 162 in menopause 141 in pregnancy 133 in recurrent brief depression 69 remission 95 side-effects 85, 86 switching to 94 moclobemide 51, 53, 75 in anxious depression 68 in atypical depression 63 in chronic depression 68 in elderly people 158, 160, 161 in melancholia 64, 65 washout period 78, 97 in winter depression 67 modafinil 99 monoamine oxidase inhibitors (MAOIs) 63, 75–8, 97 in breast-feeding 138 in children and adolescents 147 in chronic depression 68 dosing 76 in elderly people 161 irreversible 50 in pregnancy 133–4

reversible 51 side-effects 71 in tuberculosis 49, 50 type A 50 type B 50 washout period before 78 Montgomery Asberg Depression Rating Scale (MADRS) 17, 21–3, 65 Mood Disorders Questionnaire 5 Motherisk Program 134–5 myocardial infarction (MI) 172 nefazodone 55 in combination with CBASP 44 in chronic depression 68 in elderly people 160 in pregnancy 133 nomifensine 52 norepinephrine reuptake inhibitor (NRI) 52 in menopause 140 in pregnancy 133 norepinephrine transporter blockade 96 norfluoxetine 53 in elderly people 161 nortriptyline 42, 52, 79 comorbidities 174 ECT and 110 in elderly people 157, 158, 159, 162 IPT and 42 optimization 96 in postpartum depression 136 in pregnancy 133 switching to 94 obsessive compulsive disorder (OCD) 145 olanzapine augmentation 98 in psychotic major depression 66 omega-3 fatty acids 120–1 omega-6 fatty acids 120 optimization 96 overdose, safety in 88 overgeneralization 33 panic attacks 168 pargyline 50

182 Index Parkinson’s disease 50, 78, 114 in elderly people 161 paroxetine 52, 53, 57 in anxious depression 68 vs. behavioral therapy 39 in children and adolescents 147, 148 in chronic depression 68 comorbidities 174 discontinuation 88 drug–drug interactions 86 in elderly people 157, 158 interpersonal therapy and 42 in melancholia 64, 65 in minor depressive disorder 69 in postpartum depression 136 in postpartum psychosis 139 in pregnancy 133, 134 in premenstrual dysphoric disorder 131, 132 in psychotic major depression 66 in recurrent brief depression 70 side-effects 85, 86 Patient Health Questionnaire (PHQ) 17, 26–7 perphenazine in psychotic major depression 66 personality disorder 44 personalization 33 phenelzine in atypical depression 63, 78 in elderly people 161, 162 switching 97 phospholipids 120 physical symptoms, unexplained 3, 5 pindolol 57 augmentation 99 in combination 125 placebo 37 postnatal mood disorders 70, 135–7 prevalence 135–6 postpartum depression (PPD) 134, 135–7 pharmacotherapy 136–7 prevalence 135–6 psychotherapy 136 risk factors 136 postpartum psychosis (PPP) 135, 138–9 pharmacotherapy and breast-feeding 138–9

prevalence 138 pregnancy, depression during 132–5 pharmacotherapy 133–5 prevalence 132–3 psychotherapy 133 premenstrual dysphoric disorder 131–2 pharmacotherapy 131–2 prevalence 131 psychotherapy for 131 symptoms 132 prevalence 1, 2 PRIME-MD (Primary Care Evaluation of Mental Disorders) 4–5, 17 problem-solving therapy 35 in elderly people 157 in minor depressive disorder 69 progressive deep muscle relaxation 35 protriptyline 52 psychoanalytic psychotherapy 30 psychotic major depression 65–6, 66 psychodynamic psychotherapy, in elderly people 156 psychoeducation 17, 29 psychotherapy 12–14, 15, 29–30 along, indications for 31–2 antidepressants in combination with 42–4, 43 depression-focused, effectiveness of 37–9 gender differences in response 130 in Axis II comorbidity 171 maintenance phase models 42, 42 preventive effects 40–1 treatment overview and limitations 30–1 quetiapine as augmentor 98 in psychotic major depression 66 randomized controlled trials (RCTs) 30 rapid eye movement (REM) 3, 85 reboxetine 52, 75, 83 in pregnancy 133 in recurrent brief depression 69 side-effects 83 receptor-acting drugs 55–7 recurrence rates 1

Index 183 recurrent brief depression (RBD) 69–70, 70 remission 17 repetitive transcranial magnetic stimulation (rTMS) 110–12 combination with antidepressants 112 efficacy and indications 110–11 treatment parameters 111 RIMA (reversible inhibitor of monoamine oxidase A) 161 risperidone augmentation 98 in psychotic major depression 66 role disputes 36 role playing 35 role transitions 36 S-adenosyl methione (SAMs) 121 schemas 32 schizophrenia 49, 51 second generation antidepressants 80–3, 87 selective abstraction 33 selective serotonin reuptake inhibitor (SSRI) 51, 52–3, 61, 75, 80–1 in anxious depression 67 in breast-feeding 138 in children and adolescents 147–8, 148 discontinuation 88 dosing 81 in elderly people 159, 160 metabolism and weight change 85–6, 85 in menopause 141 in minor depressive disorder 69 in pregnancy 133, 134 in premenstrual dysphoric disorder 131 sexual function 86, 86 side-effects 81, 82, 83–6 sleep, alertness and neurocognition 84–5 selegiline (L-deprenyl) 78 in elderly people 161 in Parkinson’s disease 50 self-help manuals 34 sequential combined treatment 44–5

serotonergic syndrome 122 serotonin and norepinephrine reuptake inhibitor (SNRI) 53, 81–3 in children and adolescents 147 dosing 83 in elderly people 157, 158, 159 in pregnancy 133 metabolism and weight change 85–6, 85 sexual function 86, 86 side-effects 83–6, 84 sleep, alertness and neurocognition 84–5 switching 94 serotonin metabolism, gender and 130 serotonin syndrome 51 sertraline 52 in anxious depression 68 in atypical depression 63 in children and adolescents 149 in chronic depression 68 in combination 100 comorbidities 174 in elderly people 158, 161 in melancholia 64 in menopause 141 in minor depressive disorder 69 in postpartum depression 136 in postpartum psychosis 139 in pregnancy 133, 134 in premenstrual dysphoric disorder 131, 132 in psychotic major depression 66 side-effects 86 switching 94 in winter depression 67 severity of depression 64, 64 six-month prevalence 1, 2 sleep deprivation 124–5, 126 combination and maintenance 125 efficacy 124–5 treatment parameters 125 sleep disturbance 3, 57 slow wave sleep (SWS) 3 social isolation 37 socioeconomic costs 1 Socratic questioning 33 somatization disorders 130

184 Index St John’s wort 119–20 in premenstrual dysphoric disorder 132 STAR*D (Sequenced Treatment Alternatives to Relieve Depression) results 93–5 Structured Clinical Interview 5 substance abuse 130 suicide 1, 88 in the elderly 156 gender and 130 risk assessment 10–11, 13–14 support interventions 14, 15–16 switching 45, 96–7 practical aspects 97–8 syndrome of inappropriate excretion of antidiuretic hormone (SIADH) 160 therapeutic alliance 11–12, , 14 third generation antidepressants 80–3, 87 thought stopping 35 tianeptine 83 tranylcypromine 89 in combination 100 in elderly people 161 overdose 88 in recurrent brief depression 69 remission 95 switching 97 in treatment resistant depression 78 in winter depression 67 trazodone 55, 83 in pregnancy 133 Treatment of Depression Collaborative Research Project (TDCRP) 38 treatment outcome, monitoring 16–17 treatment resistant depression 64, 64, 95–6 vagus nerve stimulation and 112–13 tricyclic antidepressants (TCAs) 51–2, 55, 63, 79–80 in breast-feeding 138 in children and adolescents 147 in chronic depression 68 discontinuation 88 dosing 77 in elderly people 158, 159

limitation of 79–80 in melancholia 64 in menopause 141 in pregnancy 133, 134 in schizophrenia 49 side-effects 80, 85 triiodothyronine 94 in menopause 140 tryptophan 121–2 in augmentation 99 depletion 125 tuberculosis 49, 50 tyramine 51 unipolar depression 5 vagus nerve stimulation 112–13 valproic acid, ECT and 109 venlafaxine 53, 54, 79, 81, 89 in anxious depression 67, 68 in children and adolescents 147, 148 in chronic depression 68 in combination 100 discontinuation 88 dose–response relationship 96 drug–drug interactions 87 in elderly people 158, 159, 160, 161 in melancholia 65 in menopause 140 overdose 88 in postpartum depression 136 in postpartum psychosis 139 in pregnancy 133 remission 95 side-effects 86 switching 94 winter depression 70, 123–4, 129 treatment 67, 67 women, depression in 129–42 reproductive cycle 129, 129 work loss 1, 3 yoga 40 zimelidine 52 ziprasidone 98

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