Ketamine for Treatment-Resistant Depression: Neurobiology and Applications

Ketamine for Treatment-Resistant Depression: Neurobiology and Applications provides a simple, evidence-based overview for neuropsychiatrists and translational researchers on this medication, its mechanisms of actions, eligibility of patients for treatment, and the preparation and implementation of ketamine clinics.

• Provides efficacy research on ketamine as a treatment for depression
• Identifies best practices for clinical use, both long-term and acute
• Discusses the molecular mechanisms and neurobiology of action

• Language: English
• Publisher: Academic Press
• Release date: Sep 16, 2020
• ISBN: 9780128210345

Book preview

Ketamine for Treatment-Resistant Depression

Neurobiology and Applications

Editors

Gustavo H. Vazquez

Professor, Lead, Ketamine Clinic, Mood Disorders Outpatient Unit, Queen’s University, Department of Psychiatry, Providence Care Hospital, Kingston, ON, Canada

Carlos A. Zarate

Chief Experimental Therapeutics & Pathophysiology Branch & Section Neurobiology and Treatment of Mood Disorders, Division of Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States

Elisa M. Brietzke

Professor, Kingston General Hospital, Providence Care Hospital, Queen’s University School of Medicine, Kingston, ON, Canada

Table of Contents

Cover image

Title page

Copyright

Contributors

Chapter 1. Ketamine, Clio, and the hippocratic triangle—fragments of the history of ketamine

Introduction

A note on methodology

The origin of the term dissociative anesthesia

A note on the history of dissociation

From Phencyclidine and ketamine to model psychosis

Dumb me, dumb me!

Final reflections

Chapter 2. Ketamine's potential mechanism of action for rapid antidepressive effects – a focus on neuroplasticity

Background

Ketamine restores molecular neuroplastic molecules to induce rapid antidepressant effects

Divergence of mechanisms for ketamine's rapid effects versus sustained effects

Conclusion

Chapter 3. Treatment resistant depression

Defining treatment-resistant depression

Staging models

Prevalence

Diagnosis and differential diagnosis

Etiopathology

Treatment strategies

Conclusion

Chapter 4. Suicide in psychiatric disorders: rates, risk factors, and therapeutics

Introduction

Risk factors

Therapeutics

Conclusions

Chapter 5. Overview of ketamine for major depression: efficacy and effectiveness

Historical background

The antidepressant properties of ketamine: evidence from animal studies

Open-label and nonrandomized studies on the antidepressant potential of ketamine

Ketamine for suicidality

Evidence from randomized controlled trials

Role of ketamine in electroconvulsive therapy for depression

Possible mechanisms for the rapid antidepressant effects of ketamine

Predictors of treatment response to ketamine

Limitations and caveats

Chapter 6. How to implement a ketamine clinic

Background

Administrative approval

Initiation of the clinic

Patient evaluation

The clinical setting for ketamine

Treatment protocol

Ketamine infusion frequency—acute and maintenance therapies

Sustainability of the infusion service

Conclusion

Chapter 7. Development of new rapid-action treatments in mood disorders

Introduction

Molecular targets for rapid-action treatments

Overview of underdevelopment rapid-action treatments

Conclusions

Chapter 8. Closing remarks

Introduction

State of the art and current challenges

Conclusion

Index

Copyright

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ISBN: 978-0-12-821033-8

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Contributors

Anees Bahji, MD

Resident, Department of Psychiatry, Queen's University School of Medicine, Kingston, ON, Canada

Doctor, Psychiatry, Department of Public Health Sciences, Queen's University, Kingston, ON, Canada

Ross J. Baldessarini, MD

Research Associate, Psychiatry, McLean Hospital, Belmont, MA, United States

Professor, (Neuroscience), Harvard Medical School, McLean Hospital, Belmont, MA, United States

Elisa M. Brietzke, MD, PhD ,     Professor, Kingston General Hospital, Providence Care Hospital, Queen's University School of Medicine, Kingston, ON, Canada

Casimiro Cabrera-Abreu, LMS, MSc, MRCPsych, FRCPC

Associate Professor, Psychiatry, Queen’s University, Kingston, ON, Canada

Attending Psychiatrist, Mood Disorders Research and Treatment Service, Providence Care Hospital, Kingston, ON, Canada

Mariel Cabrera-Mendez, MD ,     Research Assistant, Providence Care Hospital, Kingston, ON, Canada

Ranjith Chandrasena, MD, MSc ,     Professor, Chatham-Kent Health Alliance, Chatham, Ontario, Canada

Jonathan Fairbairn, BMSc, MD ,     Professor, Chatham-Kent Health Alliance, Chatham, Ontario, Canada

Fabiano A. Gomes, MD, PhD

Assistant Professor, Department of Psychiatry, Queen's University School of Medicine, Kingston, ON, Canada

Kingston General Hospital, Kingston, ON, Canada

Melody J.Y. Kang, BScH ,     Master of Science, Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada

Sidney H. Kennedy, MD ,     Dr. Psychiatry, University Health Network, Toronto, ON, Canada

Rodrigo B. Mansur

Department of Psychiatry, University of Toronto, Toronto, ON, Canada

Mood Disorders Psychopharmacology Unit (MDPU), University Health Network (UHN), Toronto, ON, Canada

Roger S. McIntyre, MD, FRCPC

Department of Psychiatry, University of Toronto, Toronto, ON, Canada

Mood Disorders Psychopharmacology Unit (MDPU), University Health Network (UHN), Toronto, ON, Canada

Brain and Cognition Discovery Foundation (BCDF), Toronto, ON, Canada

Leonardo Tondo, MD, MSc

Director, Psychiatry, Mood Disorder Lucio Bini Center, Cagliari, Italy

Research Associate, Psychiatry, McLean Hospital, Belmont, MA, United States

Professor, (Neuroscience), Harvard Medical School, McLean Hospital, Belmont, MA, United States

Sophie R. Vaccarino, HBSc

Research Assistant, Centre for Depression and Suicide Studies, Unity Health Toronto, Toronto, ON, Canada

MSc Candidate, Institute of Medical Science, University of Toronto, Toronto, ON, Canada

Gustavo H. Vazquez, MD, PhD, FRCPC ,     Professor, Lead, Ketamine Clinic, Mood Disorders Outpatient Unit, Queen's University, Department of Psychiatry, Providence Care Hospital, Kingston, ON, Canada

Carlos A. Zarate, MD ,     Chief, Experimental Therapeutics and Pathophysiology Branch, Section Neurobiology and Treatment of Mood Disorders, Division of Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States

Chapter 1: Ketamine, Clio, and the hippocratic triangle—fragments of the history of ketamine

Casimiro Cabrera-Abreu, LMS, MSc, MRCPsych, FRCPC ¹ , ² , and Mariel Cabrera-Mendez, MD ³       ¹ Associate Professor, Psychiatry, Queen’s University, Kingston, ON, Canada      ² Attending Psychiatrist, Mood Disorders Research and Treatment Service, Providence Care Hospital, Kingston, ON, Canada      ³ Research Assistant, Providence Care Hospital, Kingston, ON, Canada

abstract

The objective of this chapter is to highlight some intriguing aspects of the history of ketamine. First, we will review the methodologies used when writing a small fragment of the overall history of psychopharmacology. Second, and due to the recent explosion of papers on ketamine and related substances in the past decade, we have focused on two themes, the interplay of ketamine with the nosologic status of dissociation and the repeated encounters of Edward Domino with ketamine and some of its psychotropic effects. Finally, this chapter does not end offering some inchoate conclusions or pretentious sagely advice about the future of psychopharmacology and the glutamate antagonists but rather wishes to be a critical reflection on psychiatry's constant reinvention and shifting paradigms, as it has been fashionable to say since Kuhn.

Keywords

Dissociation; Dissociative anesthesia; Dizocilpine; History; Ketamine; Phencyclidine

Introduction

In 2003, Edward Shorter and Peter Tyrer, a historian of psychiatry and one of the associate editors at the time of the British Journal of Psychiatry, respectively, published an intriguing paper about the nature of cothymia and the accompanying drought in the discovery of new antidepressants. ¹ Their paper was boldly published during a period when the hegemony of the Diagnastic and Statistical Manual of Mental Disorders (DSM) classification system was undisputed and absolute; nobody who wished to publish in an August psychiatric journal dared not to use DSM. Tyrer, with his characteristic dry wit, touched upon this issue in a later paper with a similar subject. ² By the beginning of the next decade, Stephen E. Hyman ³ deplored the announcement of a number of pharmaceutical companies concerning the closure of several lines of investigation in the field of psychotropic medications; the stagnation in the production of novel antidepressants became alarming. It is therefore remarkable that in a time when the future of the psychopharmacology of depression appeared to be barren, a revival of an old substance from the field of anesthesia appeared to revolutionize the treatment of depression. ⁴ Ketamine was introduced in anesthesia about the time the first antidepressants were launched (the 1950 and 1960s) but had to wait 50 years to become the new enfant terrible of psychopharmacology.

In a recent paper, John Krystal and his collaborators, ⁴ incorporating the revolutionary halo carried by ketamine, hailed the introduction of ketamine for depression as a proverbial paradigm shift, á la Kuhn, ⁵ in psychopharmacology, comparable to the Psychopharmacological Revolution of the aforementioned 1950 and 1960s. This chapter covering the (admittedly fragmented and partial) history of ketamine unravels thus in the context of the triumphalist assumptions of the turn-of-the-century diagnostic psychiatry ⁶ culminating in the recent controversies (debacle?) of DSM-5. ⁷ The issue of the sociohistorical context is apposite and with ironic justice brings to mind the image of the set and setting of Hartogsohn. ⁸

The purpose of this chapter is to follow the tribulations of ketamine and some of its psychotropic effects and how they have been interpreted in the context of the changing nosologic and nosographical vicissitudes of North American psychiatry during the past 5   decades. Without doubt, Edward Domino has been an important figure throughout this period; some of his encounters with ketamine and its congeners will also be briefly reviewed.

A note on methodology

The issue of context highlighted earlier—where and when does this narrative take place—leads us to the problem of the historiographical (i.e., the methodology) tools used in this chapter. This is important because there appears to be a small cottage industry rapidly building up around the history of ketamine. ⁹–¹² Although essential reading, it is difficult not to think of Ben Shephard's ¹³ comments when describing the functional approach to history of busy psychiatrists [and academic researchers] at the time of writing the history of posttraumatic stress disorder, which according to him is comparable to that of the Communist Party in The Brezhnev epoch, The medical literature of the past is important and interesting when it buttresses and legitimizes present practice. When it doesn't, forget it. ¹³ Be as it may, the historical snapshots offered in this chapter supplement the contributions of those authors.

Since Kuhn's weaponization of Butterfield's concept of ‘whiggishness’ as a fundamental principle in the history of science, ¹⁴ a presentist, internalist, or hagiographic approach/methodology has been declared deficient or suboptimal ¹⁵ at the time of pursuing historical endeavors. This creates significant problems for the two authors, a clinical psychiatrist and an MD, none of whom have professional training in the methods of ‘History’ (with a capital H), who attempt to operate within the current fashion of the rigorous bounds imposed by the ‘evidence-based’ study of facts. The temptation of writing a history with a ‘king and battle bent,’ as Edwin Wallace IV once said ¹⁶ or á la Brezhnev, in the words of Ben Shephard, is considerable. One of the approaches followed in this chapter is inspired by the ‘Hippocratic triangle’ posited by Jacalyn Duffin ¹⁷ that includes the ‘clinician-historian’ and its study of history as an inherently flexible task or a set of tasks in which regular calibration and recalibration, from several sources, should be explicitly stated (which is also redolent of the methodology of Berrios). Needless to say, other subtle influences are at work when writing these lines. We can only hope that they will become more or less visible as the text unravels; that is, the intended purpose is that these ‘methodologies’ and influences will become evident when addressing different aspects of the history of ketamine.

Continuing with the issue of the techniques used to offer a glimpse of the history of ketamine and its use in patients with mental illness, it is de rigueur to return to Berrios. ¹⁵ , ¹⁸ In studying the history of mental illnesses, Berrios suggests specifying if we are tracking the history of some of (1) the terms (in this chapter, ‘dissociation’ is an essential term that drives the narrative) or the historical meanderings of (2) the concepts attached to those terms or, finally, (3) the behaviors of the patients.

The task of writing a history of ketamine and its use in mental illness becomes particularly complex when the nosology and nosography of mental illnesses is also in flux, and this is illustrated, for example, by the choice of terminology for the action of ketamine as an anesthetic; I am referring to the term ‘dissociative anesthesia.’ Paraphrasing Farrell ¹⁹ trying to write this history against a changing psychiatric culture [ …] is akin to measuring a developing weather front with a stepladder and a yardstick.

One of the most interesting aspects of the introduction of ketamine to treat depression (and acute suicidal ideation) is the potential implications that the polymorphic nature of the altered ‘states of consciousness’ induced by this substance can bring not only to the terrain of the pathophysiology of depression but also to our current understanding of the pathogenesis of other disorders.

The origin of the term dissociative anesthesia

The story of how the wave of psychotomimetic effects caused by ketamine and its study leads to the term ‘dissociative anesthesia’ has been covered several times; however, and for the purposes of this chapter, it deserves some attention. In an often-quoted paper titled Taming the Ketamine Tiger, Edward Domino ²⁰ described how he was asked to work with the forerunner of ketamine, phencyclidine (PCP), by his mentor, Dr. Maurice Seevers, ²¹ who was the Head of Pharmacology at the University of Michigan. Domino then recollects his discovery that PCP could produce ‘emergency delirium’ in dogs and how PCP acted as a remarkable anesthetic in monkeys. ²⁰ PCP was then utilized as an anesthetic in humans by Dr. Ferdinand Greifeinstein, ²² who was the Chair of Anesthesiology at Wayne State University, Detroit, Michigan and Detroit Receiving Hospital. However, and due to the unpredictable occurrence of side effects, in particular a state of prolonged emergency delirium, ²³ PCP was voluntarily discontinued as a general anesthetic in 1965. ²⁰ This setback did not deter the scientists at Parke-Davis; a second substance of the cyclohexylamine group, cyclohexamine (CI400), was released for use in anesthesia in 1960. ²⁴ The presence of agitation and hallucinations in a significant proportion of women who took cyclohexamine added to the fact that only 19 of the 29 women experienced analgesia, motivating the dismissal of cyclohexamine.

Another substance synthesized by Dr. Calvin Stevens, working for Parke-Davis, known as CI-581 (ketamine), called the attention of Dr. Alex Lane, who was the Head of Clinical Pharmacology at Parke-Davis. Dr. Lane approached Edward Domino, ²⁰ who agreed to conduct the study in humans. Domino then contacted Dr. Guenter Corssen, a professor in anesthesiology interested in intravenous anesthesia. According to Domino, the first time a human was given ketamine in an intravenous subanesthetic dose was on August 3, 1964,   at the Jackson Prison in the State of Michigan.

In his 2010 paper, Domino goes on to the describe some of the remarkable effects of ketamine, including the minimal occurrence of frank emergence delirium. Domino contacted his colleague Dr. Elliot Luby, who was a psychiatrist; Parke-Davis feared the schizophrenomimetic effects of ketamine would render it useless. The psychiatrists (in plural in the 2010 paper by Domino) working for Parke-Davis concluded that the emergence reaction of the subjects tested was similar to the emergence reaction of diethyl ether. Ketamine then received the green light. ²⁵

The choice of the term dissociative anesthetic is interesting. Domino describes how there was a good deal of discussion among Dr. Guenter Corssen, Dr. Peter Chodoff, and himself regarding the publication of the data. Corssen and Chodoff were both anesthesiologists. They initially agreed to use the term dreaming because it was similar to the effects of PCP. According to Domino, the Parke-Davis scientists did not like it. Domino shared his concerns with his wife, Antoinette (Toni) Domino. He told her the subjects were disconnected from their environment. According to Domino, Toni came up with the term dissociative anesthetic. ²⁰ In another paper, ²⁶ Domino recounts this story with slight variations; Toni, his wife, is the protagonist in both and, moreover, the person responsible for using the term ‘dissociation.’

Domino's version was, however, in contrast to Guenter Corssen's version, ²⁷ who gave a somewhat different reason for using the terms ‘dissociation’ and ‘dissociative.’ For Corssen the reason for choosing ‘dissociative’ stemmed from the actual physiologic impact of the new medication. In his paper, he describes how Domino and himself observed the way in which the visual and somatosensory stimuli traveled "unimpaired from the periphery to