Pharmacotherapy for Depression and Treatment-Resistant Depression Downloaded from

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4 Published by World Scientific Publishing Co. Pte. Ltd. 5 Toh Tuck Link, Singapore USA office: 27 Warren Street, Suite , Hackensack, NJ UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. PHARMACOTHERAPY FOR DEPRESSION AND TREATMENT-RESISTANT DEPRESSION Copyright 2010 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the Publisher. For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy is not required from the publisher. ISBN ISBN X Typeset by Stallion Press enquiries@stallionpress.com Printed in Singapore.

5 I dedicate this book to my children Yanni and Ellie. I am extremely grateful to my wife Stefania and our son Giovanni for their incredible support of my work. George Maurizio

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7 George I. Papakostas About the Authors George I. Papakostas is Associate Professor of Psychiatry at Harvard Medical School and Director of Treatment-Resistant Depression Studies in the Department of Psychiatry at Massachusetts General Hospital in Boston, Massachusetts, USA. The focus of Dr. Papakostas research includes the pharmacotherapy of major depressive disorder including treatment-resistant depression, the study of the placebo effect and its relevance to clinical trial design in major depressive disorder, and the study of clinical and biologic predictors, moderators, and mediators of treatment outcome in major depressive disorder. Dr. Papakostas has received numerous national and international research awards from sources including the American College of Neuropsychopharmacology, the Collegium Internationale Neuropsychopharmacologium, the New Clinical Drug Evaluation Unit of the National Institute of Mental Health, the American Psychiatric Association, the World Federation of Societies of Biological Psychiatry, the American Academy of Clinical Psychiatrists, the International College of Psychosomatic Medicine, and the American Foundation for Suicide Prevention. He is the author or co-author of over 150 clinical and scientific publications and book chapters, his publications appearing in prominent journals, including the American Journal of Psychiatry, Biological Psychiatry, the Journal of Clinical Psychiatry, and the Journal of Clinical Psychopharmacology. He is also on the editorial board of the journal Psychiatry Research, and a field editor for psychopharmacology for the World Journal of Biological Psychiatry. Dr. Papakostas is often invited throughout the United States vii

8 viii Pharmacotherapy for Depression and Treatment-Resistant Depression and abroad to lecture on a wide range of topics pertaining to the treatment of depression. To date, he has delivered more than 100 lectures at national or international meetings in more than 30 countries. Dr. Papakostas attended Medical School at the New York University School of Medicine. He completed his residency in adult psychiatry at Massachusetts General Hospital and McLean Hospital, and a fellowship in Clinical Neuropsychopharmacology at Massachusetts General Hospital that was funded by the American College of Neuropsychopharmacology. Maurizio Fava Dr. Fava obtained his medical degree from the University of Padova School of Medicine, USA, and completed a residency training in endocrinology at the same university. After completing a residency training in psychiatry at the Massachusetts General Hospital (MGH), he has been Director of the MGH Depression Clinical and Research Program since 1990 at the same hospital. Under Dr. Fava s direction, the MGH Depression Clinical and Research Program has become one of the most highly regarded depression programs in the country. Dr. Fava has authored or co-authored more than 400 original articles published in medical journals with international circulation. He has also edited five books, and published more than 50 chapters and 500 abstracts. Dr. Fava is also a well-known national and international speaker, and has also been the recipient of many honors and awards. He is currently Executive Vice Chair for the MGH Department of Psychiatry, Executive Director, MGH Clinical Trials Network and Institute, and Director of the MGH Depression Clinical and Research Program, and Professor of Psychiatry at Harvard Medical School.

9 Preface Major depressive disorder (MDD) is a highly prevalent and, often, chronic illness, which has been shown to result in considerable patient suffering and distress, as well as significant disability, morbidity and mortality. Despite more than half a century of intensive research, contemporary therapies for MDD demonstrate, at best, modest overall efficacy, most often resulting in either a complete lack of or insufficient symptom improvement. In addition, the tolerability profile of all contemporary pharmacotherapies for MDD, although greatly improved since their first appearance in the mid-1950s, can often contribute to poor treatment adherence, as well as patient discomfort and disability. Furthermore, many patients who experience robust antidepressant effects may still suffer a relapse or recurrence of MDD shortly after the full eradication of symptoms, and despite full compliance with their treatment. As a result, patients with depression often describe feelings as if they are caught in a vicious cycle, with only brief periods of complete symptom recovery that are not sufficient in duration to allow for a return to the pre-morbid level of functioning. When depression strikes, clinicians, patients, their families and their loved ones are on the front line. Supporting them are those working vigorously to enhance our ability to effectively treat depression: those working in academic clinical care and research centers, government sources including the National Institutes of Health, the pharmaceutical industry, as well as private donors and fundraisers. This book is intended as a review on the state of our knowledge regarding pharmacologic treatments for depression. It is divided into four parts. The first three parts focus on ix

10 x Pharmacotherapy for Depression and Treatment-Resistant Depression Life-Cycle of Depression Step-wise Contributing Factors MDD Episode (1) Relapse and Recurrence (4) Treatment- Resistance (2) Residual Symptoms (3) 1: Relative high prevalence of MDD in the general population. 2: Limited efficacy of first-line treatments for MDD contributing to TRD. 3: Modest efficacy of subsequent treatment strategies for MDD contributing to residual symptomatology. 4: History of treatment-resistance, presence of residual symptoms, and partial or non-adherence to treatment (poor tolerability) contributing to depressive relapse or recurrence. contemporary pharmacologic treatment strategies for MDD, as well as non-pharmacologic strategies for treatment-resistant MDD. These include a description of first-line pharmacotherapy strategies (Part I), next-step treatment strategies (Part II), and pharmacologic strategies to help maintain treatment gains (Part III). The final part of the book (Part IV) focuses on describing emerging leads that may help improve our ability to treat MDD (novel treatments and biological markers in depression). When writing this book, it was our intention to combine a comprehensive and detail-oriented approach, so that this work may have broader appeal to all those who have an interest in the field,

11 Preface xi including clinicians, researchers, those who fund research, and those who provide direction and leadership. Thus, it was our hope that this work could, simultaneously, provide the readers with either an overview of our current state of understanding of the treatment of MDD, or with more selective knowledge that would enhance their understanding of a specific topic or topic area. Ultimately, such knowledge may lead to novel hypotheses and insights that, in turn, could help improve the standard of care for depression. G. I. Papakostas and M. Fava

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13 About the Authors Preface Contents 1. Major Depressive Disorder and Treatment-Resistant Depression Major Depressive Disorder Definition Prevalence and disease burden Treatment-Resistant Depression (TRD) Definition and staging Prevalence Pseudo-resistance Demographic and Clinical Risk Factors for Resistant Depression Studies focusing on SSRI therapy Studies focusing on therapy with older antidepressants Studies focusing on therapy with newer antidepressants Summary and Conclusion of Chapter vii ix xiii

14 xiv Pharmacotherapy for Depression and Treatment-Resistant Depression Part I: First-Line Pharmacotherapy Strategies Monoaminergic-Based Strategies: Single-Acting Agents Monoamine Precursors for Depression Selective Serotonin Reuptake Inhibitors (SSRIs) Neuropharmacology Efficacy (general) Efficacy in patients with medical conditions Diabetes mellitus Coronary artery disease and myocardial infarction Pulmonary and sleep disorders Cerebrovascular illness andstroke Movement disorders Epilepsy Dementia Renal insufficiency Hepatitis, cirrhosis, and interferon therapy Human immunodeficiency virus Malignancy Transplant recipients Side effect profile General Central nervous system Cardiovascular Hematologic Endocrine Metabolic Immunologic Dermatologic Risk of malignancy... 62

15 Contents xv Risk of teratogenicity Risk of transmission during breastfeeding Discontinuation syndrome Dosing Initial and optimal dose Serotonin transporter occupancy as a function of dose Plasma levels and clinical efficacy Cytochrome enzyme genotype and plasma levels P-glycoprotein interactions Drug interactions Serotonin Receptor Antagonists and Agonists Trazodone and nefazodone Neuropharmacology Efficacy Side effect profile Dosing Other 5HT-2 active agents Ritanserin Fenfluramine and dexfenfluramine Agomelatine HT-1 active agents Agonists Antagonists Agents acting on 5HT-3 and 5HT Serotonin Reuptake Enhancers α-2 Adrenergic Receptor Agonists and Antagonists Norepinephrine Reuptake Inhibitors (NRIs) Reboxetine Atomoxetine Viloxazine... 85

16 xvi Pharmacotherapy for Depression and Treatment-Resistant Depression 2.7 Selective β Adrenergic Receptor Agonists Dopamine-Selective Agents Receptor agonists Reuptake inhibitors Receptor antagonists Monoaminergic-Based Strategies: Dual-Acting Agents Tricyclic Antidepressants (TCAs) Neuropharmacology Classification Efficacy Side effect profile Dosing Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) Venlafaxine Neuropharmacology Efficacy Side effect profile Dosing Desvenlafaxine Duloxetine Efficacy Side effect profile Dosing Milnacipran HT-2 and α-2 Adrenergic Receptor Antagonists Mirtazapine Neuropharmacology Efficacy Side effect profile Dosing Mianserin

17 Contents xvii 3.4 Norepinephrine-Dopamine Reuptake Inhibitors Bupropion Neuropharmacology Efficacy Side effect profile Dosing Nomifensine Monoaminergic-Based Strategies: Triple-Acting Agents Monoamine Oxidase Inhibitors (MAOIs) Neuropharmacology Efficacy Side effect profile Dietary restrictions and drug interactions Dosing Serotonin-Norepinephrine-Dopamine Reuptake Inhibitors Catechol-O-Methyltransferase (COMT) Inhibitors Polypharmacy from the Onset of Treatment Adjunctive Treatment with Monoaminergic Agents Tryptophan Pindolol Typical antipsychotic agents HT2 and α-2 adrenergic receptor antagonists Other antidepressants Atypical antipsychotic agents Dopaminergic agents Other monoaminergic agents

18 xviii Pharmacotherapy for Depression and Treatment-Resistant Depression 5.2 Adjunctive Treatment with Neuroendocrine Agents Thyroid hormones Estrogen Other neuroendocrine agents Other Agents Lithium GABA-ergic agents Folates and s-adenosylmethionine (SAMe) Anticonvulsants Miscellaneous other agents Summary and Conclusion of Part I Part II: Next-Step Treatment Strategies Polypharmacy Strategies for Treatment-Resistant Depression Adjunctive Treatment with Monoaminergic Agents Pindolol HT2 and α-2 adrenergic-receptor antagonists Tricyclic antidepressants Selective 5HT1A agonists Other antidepressants Atypical antipsychotic agents Dopaminergic agents Other monoaminergic agents Adjunctive Treatment with Neuroendocrine Agents Thyroid hormones Androgens Estrogens

19 Contents xix Steroids and steroid synthesis inhibitors Melatonin Other Agents Lithium ω-3 fatty acids Modafinil Glutamatergic agents Anticonvulsants Inositol Folates, s-adenosyl methionine (SAMe) and B-vitamins Cholinergic agents Miscellaneous other agents Monotherapy Strategies for Resistant Depression Increasing the Dose of Antidepressants Switching Antidepressants Due to Lack of Efficacy Switching from a TCA to an SSRI or MAOI and vice versa Switching to a TCA or an MAOI following the failure of multiple antidepressants Switching from one SSRI to another, or to a non-ssri antidepressant Other switch strategies Non-pharmacologic Approaches for Resistant Depression Device-Based Therapies Electroconvulsive therapy Vagus nerve stimulation Transcranial magnetic stimulation Deep brain stimulation

20 xx Pharmacotherapy for Depression and Treatment-Resistant Depression Transcranial direct current stimulation (tdcs) Bright light therapy Acupuncture Psychotherapy Exercise Yoga and Meditation Summary and Conclusion of Part II Part III: Maintaining Treatment Gains Pharmacotherapy of Relapse/Recurrence Prevention and Treatment Antidepressant Continuation and Maintenance Therapy Studies Tricyclic antidepressants (TCAs) Monoamine oxidase inhibitors (MAOIs) Selective serotonin reuptake inhibitors (SSRIs) Newer antidepressants Summary of continuation and maintenance trials Special Topics in the Pharmacotherapy of Relapse Prevention Long-term efficacy differences among antidepressants Optimal duration of long-term therapy Long-term dosing and risk of relapse Continuing adjunctive agents during long-term therapy Instituting antidepressants among non-medicated remitters

21 Contents xxi Timing of symptom improvement and risk of relapse Treatment-resistance and risk of relapse Treatment of Depressive Relapse/Recurrence Pharmacologic Strategies to Enhance Antidepressant Tolerability Adjunctive Therapy Sexual dysfunction Fatigue and hypersomnia Insomnia, anxiety, and activation Akathisia and bruxism Gastrointestinal symptoms Weight gain Anticholinergic and other side effects Cognitive side effects Switching Antidepressants Due to Intolerance Summary and Conclusion of Part III Part IV: Future Directions in Treatment Development Agents Operating on Non-monoaminergic Neurotransmitter Systems GABA-ergic Treatments Benzodiazepines Clinical evidence Treatment limitations Neuropharmacology of GABA-A receptors Conclusion Barbiturates Other GABA-ergic agents

22 xxii Pharmacotherapy for Depression and Treatment-Resistant Depression 11.2 Glycine and Glutamate-Based Treatments Neuropharmacology NMDA-active agents Other glutamatergic agents Glycinergic agents Agents with Combined GABA-ergic and Glutamatergic Activity Anticonvulsants Other Anticonvulsants Neurokinin-Receptor Antagonists Neuropharmacology Clinical evidence Nicotinic Receptor Based Treatments Neuropharmacology Nicotinic-receptor agonists Cholinesterase inhibitors Nicotinic-receptor antagonists Cannabinoids and Endocannabinoids Opioidergic Therapies Opioid-receptor antagonists Opioid-receptor agonists Mixed agonists/antagonists Other Neurotransmitter Systems Neuroendocrine-Based Agents Hypothalamic-Pituitary-Gonadal Axis (HPG) Estrogen Progesterone Androgens Dehydroepiandrosterone (DHEA) Other gonadotropic agents Hypothalamic-Pituitary-Adrenal Axis (HPA) Corticosteroids Steroid synthesis inhibitors

23 Contents xxiii Steroid- and CRF-receptor antagonists Hypothalamic-Pituitary-Thyroid Axis (HPT) Melatonin and Melatonergic Agents Other Hormones Metabolic-Based and Other Agents Metabolic-Based Agents Elements of the one carbon cycle S-adenosylmethionine (SAMe) Folates and other B-vitamins Agents acting on neuronal second messenger systems Anatomy of the second messenger system Phosphodiesterase inhibitors Inositol Other agents Essential fatty acids Overview Clinical studies Carnitine Minerals, trace elements, and vitamins (non-b vitamins) Agents with Unknown Mechanism of Action Herbal remedies Hypericum perforatum Ginseng Kava kava Valerian root and Ginkgo bilboa Modafinil Pivagabine

24 xxiv Pharmacotherapy for Depression and Treatment-Resistant Depression 14. Biological Predictors, Moderators, and Mediators of Efficacy Definition and Significance of Mediators of Outcome Genetic Markers Studies involving SSRI therapy Genes coding for TPH and 5HTT Genes coding for 5HT-receptors Genes coding for NET or NE-receptors Genes coding for MAO and COMT Genes coding for other proteins Studies involving therapy with other antidepressants Studies comparing antidepressants Neurophysiology Brain functioning and metabolism Positron emission tomography Functional magnetic resonance imaging Magnetic resonance spectroscopy Electroencephalography Traditional electroencephalography Quantitative electroencephalography Loudness Dependence of Auditory Evoked Potentials (LDAEP)

25 Contents xxv Brain functional asymmetry (dichotic listening) Molecular Biology Receptor and transporter kinetics Intracellular signal transduction Inflammatory markers Summary and Conclusion of Part IV Appendix A Appendix B Appendix C Appendix D Bibliography 409 Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Index 695