Psychiatric Annals

CME Article 

Neurobiological Mechanisms of Ketamine: Depression, Suicide, Trauma, and Chronic Stress Pathologies

Lynnette A. Averill, PhD; Christopher L. Averill, MS; Chadi G. Abdallah, MD

Abstract

The serendipitous discovery of ketamine's robust antidepressant effects has served as a major catalyst to usher in new era of drug development and a paradigm shift in our understanding of the neurobiology of chronic stress pathology (CSP). This review provides a selective synthesis of (1) the historical foundations of N-methyl-D-aspartate receptor modulators and the path to discovering ketamine's use in psychiatry; (2) ketamine's clinical efficacy, specifically its rapid-acting antidepressant and rapid-acting antisuicidal effects; (3) a model of synaptic loss and dysconnectivity thought to underlie CSP; (4) clinically relevant biomarkers and mechanisms of action; and (5) how ketamine may be both an effective treatment to reverse and normalize CSP as well as a tool to further our understanding of depression, trauma, suicidality, and CSP. We conclude with a brief discussion of outstanding questions and the continued struggle between optimism and concern regarding ketamine's widespread utility as a pharmacologic agent. [Psychiatr Ann. 2020;50(2):48–53.]

Abstract

The serendipitous discovery of ketamine's robust antidepressant effects has served as a major catalyst to usher in new era of drug development and a paradigm shift in our understanding of the neurobiology of chronic stress pathology (CSP). This review provides a selective synthesis of (1) the historical foundations of N-methyl-D-aspartate receptor modulators and the path to discovering ketamine's use in psychiatry; (2) ketamine's clinical efficacy, specifically its rapid-acting antidepressant and rapid-acting antisuicidal effects; (3) a model of synaptic loss and dysconnectivity thought to underlie CSP; (4) clinically relevant biomarkers and mechanisms of action; and (5) how ketamine may be both an effective treatment to reverse and normalize CSP as well as a tool to further our understanding of depression, trauma, suicidality, and CSP. We conclude with a brief discussion of outstanding questions and the continued struggle between optimism and concern regarding ketamine's widespread utility as a pharmacologic agent. [Psychiatr Ann. 2020;50(2):48–53.]

Careful observations by clinicians and scientists have allowed serendipity to lead the landscape of breakthrough discoveries in the field of psychopharmacology.1 Along with the discovery of monoaminergic antidepressants, anxiolytics, antipsychotics, and other drugs of clinical utility, it was chance that led to early reports that the antibiotic cycloserine, later found to be an N-methyl-D-aspartate receptor (NMDAR) modulator, may elicit unintended antidepressant effects.2 Despite these early suggestive results, it would be another four decades before serendipity struck again, showing the potential clinical utility of targeting NMDARs in the treatment of depression.3 In a mechanistic pilot study, Berman et al.3 discovered that ketamine, an NMDAR antagonist with downstream glutamatergic consequences, can induce rapid and robust antidepressant effects in patients with depression.

Around the turn of the century, mounting preclinical evidence suggested that NMDAR modulation may be key in the development of new antidepressants, and the depression-glutamate link was being explored.4,5 In this context, the Berman et al.3 finding and its replication by Zarate et al.6 generated tremendous interest and investment into the study of glutamate neurotransmission as a key target for the development of new rapid-acting antidepressants (RAADs). Focusing on glutamate neurotransmission, the work of the past 20 years has largely centered on the dialectic between glutamate inhibition and activation, and the role that either might play in the development and pharmacodynamics of novel antidepressants.7,8 Although a struggle between optimism and concern persists, the accidental discovery and repeated replication of ketamine's RAAD effects continue to serve as the foundation for a paradigm shift in our understanding of depression, suicide, and chronic stress pathology (CSP).9

The current review will provide a concise synthesis of the clinical efficacy of ketamine's RAAD and rapid-acting anti-suicidal (RAAS) effects, will present a model of CSP founded in synaptic loss and dysconnectivity, and will discuss clinically relevant ketamine biomarkers and mechanisms of action. We describe how ketamine may serve an important dual purpose (1) as a tool to advance our understanding of depression, suicide, and CSP and (2) as a treatment to reverse and normalize stress- and trauma-induced neural alterations, with special relevance for patients with treatment-resistance to traditional monoaminergic antidepressants.

Ketamine's Clinical Efficacy

Considerable evidence supports the clinical efficacy of ketamine's RAADs, with the overwhelming majority of studies using the original treatment regimen used by Berman et al.3 (ie, 0.5 mg/kg infused intravenously over approximately 40 minutes),10 which appears to be the optimal dose.11 Although evidence is still accumulating, significant improvements are also noted in posttraumatic stress disorder (PTSD)12 and suicidal ideation,13 even after adjusting for parallel improvements in depressive symptoms. Studies have repeatedly reported that ketamine was associated with significant clinical response and remission relative to both placebo and active (eg, midazolam) comparators in patients with either major depressive disorder or bipolar depression,14 PTSD,12 and suicidal ideations,13 regardless of treatment-resistance or medication status at the time of the investigations.

Studies support a relatively consistent time course of ketamine-induced RAAD and RAAS effects—and unfortunately of relapse—with significant improvement within 4 hours, peak response at 24 hours, and 1 to 2 weeks of sustained clinical benefit before a resurgence of symptoms.8,15 Evidence suggests repeated dosing and optimized standard pharmacologic intervention may extend the durability of effects.16 Although the typical mode of ketamine administration is via intravenous infusion, which could be considered a limitation by some, given the logistical and infrastructure requirements, intranasal administration of esketamine (the S-enantiomer of ketamine) has demonstrated RAAD and RAAS effects.17 In fact, intranasal esketamine, in conjunction with an oral antidepressant, recently received US Food and Drug Administration approval for treatment-resistant depression, potentially offering broader access to ketamine for patients, although some barriers and unanswered questions remain.18

Synaptic Dysconnectivity Model of Chronic Stress Pathology

The CSP model proposes synaptic dysconnectivity as a common neural pathology underlying depression, suicide, PTSD, and other chronic stress-related psychiatric disorders.7,19 This pathway of synaptic alterations could be a predisposing factor as well as a consequence of psychiatric symptoms.7,8,20 In this model, chronic, repeated exposure to trauma and/or uncontrollable stress leads to extensive neuronal atrophy within limbic and cortical regions implicated in the regulation of mood, behavior, and cognition for which glutamate synapses are the primary foundation for synaptic connectivity.8,20 This remodeling appears to be consistent with variable alterations in synaptic connectivity—specifically, reductions in the prefrontal cortex (PFC) and hippocampus, and increases in select nuclei of the amygdala and the nucleus accumbens (NAc).7,8,20 It is hypothesized that the pattern and location of these synaptic alterations interact with individual and environmental characteristics (eg, sex, early life stress, genetics/epigenetics, concurrent trauma/stress exposure, poor social support, psychiatric, or medical comorbidities) to affect the clinical presentation and constellation of symptoms experienced.7,8

The synaptic alterations seen in the PFC and hippocampus are thought to be secondary to sustained elevations in extracellular glutamate caused by stress-induced astroglial loss and changes in glutamate release and reuptake. This, then triggers reductions in branching and spine density, and dendritic retraction in the PFC as well as altered synaptic strength and excitotoxicity.21,22 Glutamate release and glucocorticoid signaling alterations, combined with astroglial deficits and reduced glutamate uptake are thought to paradoxically maintain elevated levels of extracellular glutamate despite chronic stress-induced reductions in synaptic glutamate neurotransmission.21,22 Interestingly, the opposite is found in the NAc, where neuronal hypertrophy and synaptic hyperconnectivity are upregulated, putatively a consequence of monoamine dysregulation.7,20 Further, ketamine studies have demonstrated opposing effects of the reversal and normalization of synaptic dysconnectivity, with demonstrated reductions and increases in the NAc and PFC, respectively.7,8

There are some important factors that must be considered carefully with the CSP model. The duration of stress “response” versus stress “exposure” and the distinction between “acute” and “chronic” is paramount. Although there is considerable heterogeneity in stress response and resilience, exposure to ongoing, repeated manageable, escapable, and predictable stress may lead to “acute” transient stress responses, whereas for example a single, isolated extreme stressor (eg, a sexual assault) may lead to a sustained or “chronic” stress response.7,8 It is suspected that this acute versus chronic stress response will lead to different glutamatergic alterations and variable synaptic changes. Acute stress response prompts a glutamate surge in the PFC that leads to a transient elevation in glutamate release and sustained elevations in synaptic strength, and NMDA and AMPA receptors.7,8 Conversely, chronic stress response promotes reductions in prefrontal glutamate neurotransmission, synaptic strength, and NMDA and AMPA receptors with sustained elevations in extracellular glutamate.8,20

Further, it is hypothesized that there are two independent pathways that could differentially lead to hypoconnectivity in the PFC and hippocampus but hyperconnectivity in the NAc and amygdala.7,20 Patients with amino acid-based pathology will demonstrate amino acid impairment, synaptic loss and excitotoxicity in the PFC, are resistant to monoaminergic antidepressants, and have gray matter deficits in the hippocampus and PFC.20 Patients with monoamine-based pathology on the other hand are thought to have localized NAc elevations in synaptic gain and brain-derived neurotrophic factor (BDNF), lack of amino acid impairment, enhanced response to monoaminergic antidepressants, and increased volume in the NAc.20 Although the CSP and dual pathology models have most commonly been considered in studies of major depression, both may translate well to other trauma- and stress-related psychiatric disorders, including PTSD.20

Antidepressants have been shown to reverse CSP in animals and humans and can effectively reduce the impact of trauma- and stress-related psychiatric symptoms in humans.7,8,22 This synaptic model of CSP provides the basis for a common schema that may help to explain the psychopathology of multiple disorders, and describes synaptic connectivity as a potential target that is shared across antidepressants, while explaining some of the observed variance between individuals, disorders, and medications.8,20 This model suggests targeting synaptic loss and dysconnectivity may lead to novel, mechanistically unique RAADs with potential to improve the lives of millions across the world struggling with trauma- and stress-related psychopathology, including suicidality.

Neurobiological Mechanisms of Ketamine and Raad Effects

Much of the research that followed the Berman et al.3 article was initially focused on the idea that inhibition of glutamate transmission (ie, via glutamate release inhibitors or NMDAR antagonists) would mitigate excitotoxicity and lead to RAAD effects. Of these approaches, NMDAR antagonism has shown promise in human studies.23 Surprisingly, however, more recent evidence suggests that the RAAD effects of ketamine and other NMDAR antagonists may work through transient activation, rather than inhibition, of glutamate neurotransmission.7

Early preclinical studies showed long-term administration of various traditional, slow-acting antidepressants (SAADs) altered NMDAR binding, and that NMDAR antagonists had antidepressant-like effects.5 Coupled with concurrent findings of gray matter structural alterations in human studies of stress-related psychopathology and parallel findings of stress-induced dendritic atrophy in rodents, this early research led to the hypothesis that down-regulation of excess glutamate may be the catalyst leading to the RAAD effects of ketamine, and that this may be a common pathway across antidepressant drugs.7 Conversely, in this same period, Duman et al.24 raised the neurotrophic hypothesis of depression, whereas BDNF deficits in chronic stress and depression were shown to normalize after administration of either SAADs or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) potentiators; AMPAR not only increased BDNF expression, but also exhibited RAAD properties in rodents.7 Although neuronal plasticity was strongly implicated in both the pathophysiology of depression and the pharmacodynamics of both SAADs and RAADs, it was not initially clear whether the search for novel antidepressants should focus on glutamate activators, inhibitors, or both.7

Over the past three decades, accumulating evidence demonstrated a ketamine-induced glutamate surge, which is hypothesized to precipitate transient postsynaptic activation leading to increased synaptic connectivity in the PFC and subsequently RAAD properties. In this context, it is important to pay attention to the difference between presynaptic glutamate release and postsynaptic glutamate activation. It is thought that postsynaptic activation is required for BDNF induction, increased synaptic strength, and the RAAD effects of ketamine.7,8 For this reason, mechanisms that are independent of presynaptic glutamate release have been proposed for ketamine. Additionally, other agents such as AMPAR potentiators and NMDAR partial agonists may evoke RAAD effects by targeting postsynaptic glutamate activation directly7,8 (Figure 1). Although the importance of postsynaptic glutamate activation to ketamine's RAAD effects have been repeatedly shown in preclinical studies, the mechanisms by which ketamine induces this surge are not clearly understood. The dominant hypothesis is that subanesthetic doses of ketamine may preferentially inhibit NMDARs on interneurons, disinhibit pyramidal neurons, and provoke a paradoxical surge in glutamate release.7,8 Alternatively, the ketamine metabolite (2R,6R)-hydroxynorketamine was shown to directly increase presynaptic glutamate release without possessing NMDAR antagonistic properties.25 Other hypotheses suggest that inhibition of NMDAR signaling on pyramidal neurons would increase eukaryotic elongation factor 2 signaling and BDNF translation in the absence of induced presynaptic glutamate release, leading to increased synaptic connectivity and protein synthesis; however, the same study demonstrated that postsynaptic glutamate activation is required to evoke post-ketamine RAAD effects.8,20

The mechanism of action of rapid-acting antidepressants (RAADs). The figure depicts the targets of a glutamatergic synapse that might lead to the RAAD effects of ketamine and its metabolite hydroxynorketamine (HNK). Ketamine is thought to block interneuron NMDAR signaling leading to glutamate release disinhibition and transient surge in postsynaptic AMPA and NMDA receptors activity, ultimately resulting in increased protein synthesis and synaptic strength in the prefrontal cortex. The latter is thought to be necessary and sufficient to exert RAAD effects. AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF, brain-derived neurotrophic factor; CB1, cannabinoid receptor; EAAT, excitatory amino acid transporter; eEF2, eukaryotic elongation factor 2; Gln, glutamine; GluN1, NMDA subtype 1; GluN2B, NMDA subtype 2B; Glu, glutamate; Gly, Glycine; GlyT, Glycine transporter; M-AChR, muscarinic acetylcholine receptor; mGluR2/3, metabotropic glutamate receptor subtype 2 and 3; mTORC1, mechanistic target of rapamycin complex 1; N-AChR, nicotinic AChR; TrkB, tyrosine kinase B receptor; VSOAC, volume-sensitive organic osmolyte/anion channel. Adapted with permission from the Emerge Research Program (http://emerge.care).

Figure 1.

The mechanism of action of rapid-acting antidepressants (RAADs). The figure depicts the targets of a glutamatergic synapse that might lead to the RAAD effects of ketamine and its metabolite hydroxynorketamine (HNK). Ketamine is thought to block interneuron NMDAR signaling leading to glutamate release disinhibition and transient surge in postsynaptic AMPA and NMDA receptors activity, ultimately resulting in increased protein synthesis and synaptic strength in the prefrontal cortex. The latter is thought to be necessary and sufficient to exert RAAD effects. AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; BDNF, brain-derived neurotrophic factor; CB1, cannabinoid receptor; EAAT, excitatory amino acid transporter; eEF2, eukaryotic elongation factor 2; Gln, glutamine; GluN1, NMDA subtype 1; GluN2B, NMDA subtype 2B; Glu, glutamate; Gly, Glycine; GlyT, Glycine transporter; M-AChR, muscarinic acetylcholine receptor; mGluR2/3, metabotropic glutamate receptor subtype 2 and 3; mTORC1, mechanistic target of rapamycin complex 1; N-AChR, nicotinic AChR; TrkB, tyrosine kinase B receptor; VSOAC, volume-sensitive organic osmolyte/anion channel. Adapted with permission from the Emerge Research Program (http://emerge.care).

RAAD-Related Biomarkers

In addition to its clinical promise as a RAAD, ketamine is also valuable to the field as a methodological tool to increase our understanding of the neurobiology of mood and trauma-related disorders and to elucidate the mechanisms underlying CSP and its therapeutic reversal.7,8 Ketamine appears to influence glutamate neurotransmission and support RAAD effects in two primary ways: first, as an acute surge of glutamate that triggers transient prefrontal activation of glutamate neurotransmission and second, as a sustained elevation in prefrontal synaptic connectivity.7,8,19,26 Brief bursts of prefrontal glutamate precipitate multiple intracellular processes that ultimately result in increased synaptic connectivity in the PFC approximately 24 hours after ketamine administration (the peak response time of the drug).19,26 It is suspected the pathway of ketamine's RAAD action begins with postsynaptic activation leading to BDNF release and elevations in synaptic strength and protein synthesis.15,26 Resting-state functional connectivity magnetic resonance imaging studies have demonstrated reductions in PFC connectivity in stress-related disorders27 and suicidality,28 suggesting this may be a viable biomarker of CSP and potential treatment target.

Human mechanistic studies further support this notion by coupling PFC global connectivity to glutamate neurotransmission, ketamine administration to increased PFC connectivity, and this ketamine-induced normalization in connectivity to the RAAD effects and treatment response.29 Further, evidence suggests ketamine may influence gray matter volume, increasing and decreasing in the hippocampus and NAc, respectively, at the peak of treatment response.30 These ketamine-induced neural alterations in glutamate neurotransmission, functional connectivity, and grey matter volume provide opportunity to examine putative biomarkers underlying CSP and RAAD treatment response. Advancing our understanding of the neurobiological underpinnings of stress-related psychopathology including suicidality, as well as markers of treatment response, may provide the needed foundation for improved psychopharmacologic options with robust RAAD and RAAS properties.

Conclusions

The past two decades have seen an expanding interest and optimism regarding ketamine and the possibility of a novel class of drugs with RAAD and RAAS effects. Although there is great optimism regarding the RAAD and RAAS effects of ketamine, this is tempered by concerns regarding some of the limitations of the drug, and the difficulty in translating its findings to other NMDAR modulators. First, there is concern regarding the side-effect profile, namely the addiction liability and the psychotomimetic symptoms (eg, perceptual and cognitive disturbances) during infusion. These are limiting factors in consideration of at-home dosing/self-administration for patients. Next, although the evidence supporting ketamine's RAAD and RAAS effects is promising, there are considerable challenges in effectively blinding either patients or research study staff during clinical trials given the side-effect profile. This has been partially addressed in studies using an active comparator such as midazolam.14 To date, although evidence is mounting, there is not yet a solidly reproducible biomarker(s) of target validation (eg, sustained synaptic remodeling), treatment engagement (eg, transient postsynaptic glutamate activation), or treatment response, which highlight the need for in vivo human robust and reproducible markers of prefrontal synaptic connectivity and glutamate activation.7,8 Further, questions remain regarding long-term safety and outcomes.

Successful identification and development of these synaptic biomarkers are critical to optimize dosing and administration of potential novel RAADs prior to conducting large and expensive clinical trials. Further, given the robust and rapid onset of synaptic remodeling and behavioral (mood, cognition, including psychotomimetic) effects, future investigations can benefit from using ketamine as a tool to carefully examine synaptic biomarkers that appear to be relevant to CSP and many neuropsychiatric disorders and to normal brain functions.

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Authors

Lynnette A. Averill, PhD, is an Assistant Professor, National Center for PTSD - Clinical Neurosciences Division, VA Connecticut Healthcare System; and an Assistant Professor, Department of Psychiatry, Yale University School of Medicine. Christopher L. Averill, MS, is a Research Scientist, National Center for PTSD - Clinical Neurosciences Division, VA Connecticut Healthcare System; and a Research Associate, Department of Psychiatry, Yale University School of MediArticles--cine. Chadi G. Abdallah, MD, is the Deputy Director of Research, National Center for PTSD - Clinical Neurosciences Division, VA Connecticut Healthcare System; and an Associate Professor, Department of Psychiatry, Yale University School of Medicine.

Address correspondence to Chadi G. Abdallah, MD, Department of Psychiatry, Yale University School of Medicine, 950 Campbell Avenue, 151-E, West Haven, CT 06516; email: chadi.abdallah@yale.edu.

Disclosure: Chadi G. Abdallah has served as a consultant, speaker, and/or a member of the advisory boards for Genentech, Janssen, Lundbeck, and FSV7; and is the Editor of the journal Chronic Stress for Sage Publications, Inc. The remaining authors have no relevant financial relationships to disclose.

10.3928/00485713-20200109-02

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