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Ketamine for Treatment-Resistant Depression Sanjay J Ketamine for Treatment-Resistant Depression Sanjay J. Mathew • Carlos A. Zarate Jr. Editors Ketamine for Treatment- Resistant Depression The First Decade of Progress Editors Sanjay J. Mathew Carlos A. Zarate Jr. Psychiatry and Behavioral Sciences Experimental Therapeutics and Baylor College of Medicine Pathophysiology Branch Michael E. Debakey VA Medical Center National Institute of Mental Health Houston , Texas National Institutes of Health USA Bethesda , Maryland USA ISBN 978-3-319-42923-6 ISBN 978-3-319-42925-0 (eBook) DOI 10.1007/978-3-319-42925-0 Library of Congress Control Number: 2016960037 © Springer International Publishing Switzerland (outside the USA) 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper This Adis imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is Gewerbestrasse 11, 6330 Cham, Switzerland Comme ntary First conceptualized by Hippocrates, depression and mania are mankind’s oldest known brain disorders. These illnesses are common, often disabling, and associated with a signifi cantly elevated risk of suicide. Indeed, major depressive disorder (MDD) is the most common psychiatric disorder in developed countries, with a prevalence of approximately 17 % (Wittchen et al. 2011; Kessler et al. 2003). In 2004, the World Health Organization (WHO) ranked MDD third among the leading causes of global disease burden (Collins et al. 2011). Today, available medications for MDD act almost exclusively on monoamine neurotransmitter systems (dopamine, norepinephrine, and/or serotonin). Unfortunately, conventional antidepressants have low rates of treatment response; one-third of patients with MDD will respond to their fi rst antidepressant, but approximately two-thirds will achieve an initial response only after trying several classes of antidepressants and augmentation strategies (Trivedi et al. 2006). Even when these agents are effective, they are associated with a delayed onset of action of several weeks. This latency period signifi cantly increases risk of suicide and self- harm and is a key public health issue. The situation for bipolar disorder (BD) is perhaps even bleaker. Lithium, discovered in the late 1940s, remains the only drug specifi cally indicated for BD; BD is otherwise managed in clinical practice with a wide array of drugs, including anticonvulsants, antidepressants, and antipsychotics. Thus, there is a strong need to identify and rapidly test novel antidepressants with different biological targets beyond the classic monoaminergic receptors and their downstream targets; these agents would also be expected to act faster and more effectively. Into this void came the N-methyl-D-aspartate (NMDA) antagonist ketamine. The chapters in this book chart the rapid and remarkable fi eld of research into ketamine and other glutamatergic modulators. In the early 1990s, a seminal rodent behavioral despair model study of depression fi rst demonstrated that the NMDA receptor complex played a major role in antidepressant action (Trullas and Skolnick 1990) (see the overview of the history of ketamine use and its clinical indications by Dr. Chang and colleagues in Chap. 1 ). A decade later, the fi rst report was published of rapid antidepressant effects associated with ketamine in patients with MDD v vi Commentary (Berman et al. 2000). Since 2006, when ketamine began to be systematically stud- ied (Zarate et al. 2006)—particularly in treatment-resistant depression—the number of studies investigating ketamine as well as other glutamatergic modulators in MDD has multiplied exponentially (see Chap. 3 by Dr. Blier for a summary of ketamine’s clinical effectiveness in depressive disorders). This book is the fi rst-ever scholarly compendium of scientifi c information about the use of ketamine in treatment-resistant depression and related conditions, an area in which there is surging worldwide interest. It is worth noting that one author recently observed that the discovery of subanesthetic NMDA receptor antagonists as rapid and robust antidepressants revolutionized the fi eld of mood disorders research, noting that their discovery was “arguably the most important discovery [in psychiatric research] in half a century” (Duman and Aghajanian 2012). In this book, we have brought together an international group of clinicians and researchers from a broad swath of interrelated disciplines to offer the most up-to-date information about clinical and preclinical fi ndings in ketamine research. The discovery of ketamine’s rapid and robust antidepressant effi cacy has pro- vided hope for patients with treatment-resistant depression as well as the health professionals who work in this fi eld. Ketamine is a paradigm-shifting agent for several reasons. First, its use as a proof-of-concept agent has led to the identifi cation of novel glutamate-based mechanisms of disease and treatment response in depres- sive disorders. Second, it may hold promise as a fi rst-in-class rapid-acting antide- pressant medication. Indeed, the initial clinical studies with ketamine bolstered the view that rapid antidepressant effects are achievable in humans. These fi ndings facilitated the development of new treatments for depression that target alternative neurobiological systems. New therapeutics could signifi cantly lower morbidity and mortality for both MDD and BD and commensurately minimize or prevent disrup- tion to personal, family, and occupational life and functioning as well as lower risk of suicide. An additional area of considerable importance is—as ably reviewed by Drs. Ballard and Price in Chap. 4 of this book—that ketamine appears to have signifi cant anti-suicidal effects. This is an area of public health where swift onset and signifi - cant response are absolutely vital and where ketamine may have an immediate impact. Notably, ketamine has also shown preliminary effi cacy in other disorders such as obsessive-compulsive disorder, post-traumatic stress disorder, and alcohol/ substance abuse, which may ultimately extend its utility in clinical practice; this evidence is reviewed by Drs. Rodriguez and Dakwar in Chap. 9 . Synergistically, ketamine has also been used in conjunction with electroconvulsive therapy (ECT) to increase its effectiveness; Drs. Loo and Galvez review this evidence in Chap. 8 . As any reader of this book can observe by simply fl ipping through the evidence contained in this volume, research over the past decade—and particularly over the last fi ve years—has made great advances toward improving our understanding of ketamine’s underlying mechanisms of action (Drs. Lapidus and Wolf present an overview of the basic and clinical pharmacology of ketamine in Chap. 2 ) as well as compiling mounting evidence of its superior antidepressant effi cacy. Importantly, this work has provided a sort of scaffolding on which our knowledge has grown Commentary vii exponentially with every preclinical and clinical study (see Chaps. 6 by Drs. Hermes and Sanacora and 7 by Averill and colleagues for an overview of ketamine’s mecha- nisms of rapid antidepressant activity gleaned from preclinical and clinical studies, respectively). This burgeoning evidence is essential for the future development of targeted therapies that are more effective, act more rapidly, and are better tolerated than currently available treatments. Despite these promising fi ndings, however, there has been reluctance to consider ketamine for the widespread treatment of depression because of the dissociative side effects associated with its use at even low doses and because of its abuse poten- tial (see Chap. 5 by Drs. Rybakowski and colleagues for a thorough review of ket- amine’s overall safety, tolerability, and neurocognitive effects). As the chapters in this book underscore, ketamine’s antidepressant mechanism has been an active topic of preclinical and clinical investigation. Signifi cantly, as this book was going into publication, ongoing investigations building on much of the previous work out- lined in these chapters unearthed another potential paradigm-shifting fi nding. Specifi cally, a team led by Todd Gould at the University of Maryland in collabora- tion with NIH investigators suggested that the antidepressant effects of ketamine are produced not by the drug itself, but by one of its metabolites: (2 R ,6 R )- hydroxynorketamine (HNK) (Zanos et al. 2016); this metabolite is currently being developed as a treatment. This discovery is an excellent
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