Chadi G. Abdallah, MD

This activity offers CE credit for:
	1. Physicians (CME)
	2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to provide a comprehensive understanding of psychopharmacologic treatments for stress-induced psychopathology and the need for novel, rapid-acting agents.

At the end of this CE activity, participants should be able to:

• Summarize recent research on ketamine’s rapid-acting antidepressant and rapid-acting anti-suicidal effects

• Recognize the pros and cons of administering ketamine in research or clinical settings

• Understand how ketamine can be used as a treatment to restore and normalize stress-induced neural alterations

• Describe how ketamine can be used as a tool to study potential biomarkers of stress-related psychopathology and treatment response

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

 This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 

. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer-review process.

The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.

Lynnette A. Averill, PhD, has no conflicts to report.

Christopher L. Averill, has no conflicts to report.

Chadi G. Abdallah, MD, reports that he has served as a consultant and/or on advisory boards for Genentech and Janssen, and is editor of Chronic Stress for Sage Publications, Inc; he is also an inventor on a filed patent for using mTOR inhibitors to augment the effects of antidepressants.

Derek Tracy, MB, BCh, BAO, MSc, FRCPsych, (peer/content reviewer) has no conflicts to report.

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The serendipitous discovery of ketamine’s rapid-acting and robust antidepressant effects has been hailed as “arguably the most important 

 [in neuropsychiatric research] in half a century.”

 However, the optimism regarding ketamine’s rapid-acting antidepressant (RAAD) effects in stress-related psychopathology, including suicidality, is tempered by concerns about long-term safety; the lack of a reproducible biomarker of target engagement/validation; and the need to extend the durability of clinical benefits, reduce adverse effects, and limit abuse potential. Nonetheless, the discovery-and replication-of ketamine’s antidepressant effects has prompted a paradigm shift in our understanding of the neurobiology underlying stress-related psychopathology and in our approach to drug development for associated symptom constellations.

The bleak landscape of traditional antidepressants

Since the early 1950s, tricyclics, monoamine oxidase inhibitors, and SSRIs have been used to treat depression and other stress-related disorders. These drugs were developed under a monoaminergic hypothesis that postulates psychopathology is due to a functional deficiency in monoaminergic neurotransmitters (eg, serotonin, dopamine, norepinephrine). Thus, the mechanism of action for traditional antidepressants is to elevate synaptic availability of these neurotransmitters.

Although these drugs work very well for some patients, they have limitations. Approximately two-thirds of patients do not achieve symptom remission with a single medication trial, and among the one-third who do, rates of sustained remission are low. Furthermore, even when these agents are effective, they are slow-acting antidepressants (SAADs) with a delayed onset of action; thus, it can take weeks to months before patients experience clinical benefit.

This latency period significantly increases the risk of suicide and self-harm as well as other destructive behaviors, including self-medication with drugs and alcohol. With each failed medication trial, the likelihood of finding an effective treatment declines, further increasing risk. Moreover, SAADs often fall short of treating the full spectrum of symptoms for many patients; consequently, even when some improvement is noted, refractory symptoms persist, including suicidal ideation and cognitive impairment.

The landscape is perhaps even bleaker for bipolar disorder or PTSD because there are significantly fewer FDA-approved pharmacologic options for these disorders. With the exception of clozapine, which is approved by the FDA to target suicide risk in patients with schizophrenia, no medications are specifically indicated for suicidality.

Ketamine’s RAAD effects in stress-related symptoms and suicidality

Multiple studies have supported the short-term efficacy of ketamine-and more recently, one of its two enantiomers, S+ (esketamine)-for stress-related psychopathology. Significant benefits have been demonstrated for suicidal ideation and PTSD, even after adjusting for simultaneous reductions in depressive symptoms. Ketamine was associated with increased clinical response and remission relative to comparators (eg, saline/placebo, midazolam) in individuals with either MDD or bipolar depression, suicidality, and PTSD, regardless of treatment-resistant status and of whether study participants were medicated.

 In addition, the suspected neurobiological effects of ketamine were further supported by the relatively consistent response across studies: improvement within 4 hours, peak response at about 24 hours, and efficacy for approximately 7 to 10 days, as well as the maintenance of efficacy through repeated treatment (

Similar onset and duration of clinical benefit have been shown for suicidal ideation: rapid-acting antisuicidal (RAAS) effects occurred within 24 hours and persisted approximately 1 week.

 that compared the RAAS effects of ketamine with those of the active comparator midazolam found ketamine was superior in promoting rapid and robust improvements in suicidal ideation. These improvements were maintained for up to 6 weeks with an additional optimized standard pharmacologic intervention.

Based on the promising results of intranasal esketamine trials the FDA has designated it as a “

 While these results are encouraging, further investigation will be required to establish ketamine’s efficacy and safety as well as to determine how best to extend the durability of effects and to reduce adverse effects and risk of abuse.

Clinical anecdotes from subjective reports

Findings indicate that ketamine’s robust RAAD and RAAS effects have a positive downstream effect in which the improvement in symptoms, especially in lassitude and negative mood and cognitions, kick-starts therapeutically beneficial practices. In addition to self-initiated engagement outside the study, the behavioral activation of participating in a clinical trial (eg, the structure provided by study visits, required outing, engaging with research staff) seems to be highly therapeutic as well.

One man in his early 50s who had struggled with treatment-resistant MDD for several decades reported a single infusion of ketamine gave him the boost he needed to re-engage in hobbies and to feel invigorated for both work and family life. The day after his infusion, he reported that he had slept well, cooked his family breakfast, practiced an instrument, and planned to walk his dog in the evening-all of which he enjoys but has not had the motivation for recently. Although he reported a re-emergence in some symptoms at 2-week and 4-week follow-up, he experienced ketamine-promoted re-engagement in mood-enhancing activities, which helped extend the effects.

A Vietnam Veteran with treatment-resistant PTSD and chronic suicidal ideation, said he had attempted to take his own life on three occasions since the late 1960s, when he experienced significant trauma in combat. Following the ketamine infusion, he was “totally stunned to wake up without a single idea about suicide” and reported a significant reduction in negative mood and cognitions, specifically guilt, shame, and related self-talk. He was able to talk with his spouse about things he had never discussed previously, which not only was cathartic for him, but also brought them closer together. He reported a slight re-emergence in overall symptoms, including suicidal ideation at the 4-week follow-up visit, but noted the “memory of hope and better days” kept him pushing forward.

An Army Veteran in his mid-40s endorsed only relatively minor improvements on formalized measures of PTSD symptoms. However, he noted that his quality of life and level of irritability improved significantly after he received a single open-label dose of ketamine (0.5 mg/kg). The treatment increased his cognitive flexibility, reduced his rigidity, and diminished the sense that any minor disruption in his plans was “catastrophic” and would throw his entire day (sometimes up to a week) into unrest. He reported that following the infusion, he was much more able to “roll with the punches” and “take things as they come.” At a 4-week follow-up visit, he indicated this change in emotion, cognition, and behavior had been maintained despite other symptoms that resurfaced.

As in the last vignette, some of the meaningful improvements reported by participants are not necessarily captured by routinely used clinician-administered or self-report measures. For example, another interesting, and challenging, phenomenon is that sometimes patients report guilt, shame, and/or frustration that their symptoms improved so dramatically in such a brief period. They feel something must be wrong with them if they can feel so much better, if it is this “easy.” Some patients report they unintentionally “blunt” the clinical benefit of ketamine because they are worried about when it will end and are “waiting for the other shoe to drop.”

A clear informed consent process is paramount, for both research and clinical settings. Ideally, the participant’s mental health care provider should be involved early, and patients should be encouraged to discuss the pros and cons of ketamine with family members or other close confidants. Overall, we have found that patients are glad they participated and are willing to seek out alternative routes for additional doses, either through research or clinical settings, or to explore other treatment options. We have not had patients who reported seeking out illegal means of obtaining ketamine.

One of the most common questions asked by potential study participants and treatment providers is, “What do we do if ketamine works-what’s next?” Until recently, ketamine has been given only in the context of research studies. However, as evidence of its effects has continued to build along with data that suggest the drug is well-tolerated-despite concerns about unknown long-term effects, short duration of effects, and abuse potential-medical professionals with prescribing privileges have started offering the drug as an off-label treatment. Ketamine “boutique” clinics are opening across the country.

A current challenge is that most health insurance companies do not cover the high costs of off-label ketamine dosing. Patients for whom the medication is effective are concerned about how to continue treatment, especially if they do not have the finances for private-pay options. Similarly, health care providers are concerned about the options for those who respond to ketamine as well as for those who do not.

 from the American Psychiatric Association Research Task Force on Novel Biomarkers and Treatments provides a good summary of the promise and limitations of off-label ketamine treatment.

 Although no clinical practice guidelines exist for the off-label administration of ketamine, the consensus statement offers an overview of appropriate training for prescribers, treatment setting and available facilities and resources (eg, blood pressure monitor, crash cart), and patient considerations (eg, safety eligibility such as cardiovascular risk factors or history of psychosis) as well as the challenges and limitations of the drug, including abuse potential, adverse-effect profile, and limited durability of effect (

A synaptic model of chronic stress pathology

Psychopharmacologic drug development and neuropsychiatry are undergoing a paradigm shift from the monoamine neurotransmitter systems toward the glutamatergic system and glutamate modulators for the treatment of stress-related psychopathology. Ketamine, a noncompetitive, high-affinity, N-methyl-d-aspartate receptor (NMDAR) antagonist, has served as the poster child for this new generation of research and drug development. Landmark preclinical and clinical studies that provided the first solid evidence of RAAD-like effects began an avalanche of research, including trials of ketamine and other glutamatergic drugs as well as those that support a glutamate- or synaptic-based hypothesis of chronic stress pathology (CSP).

 of SAADs altering NMDAR binding led to the hypothesis that the downregulation of NMDAR function may be a common pathway of antidepressant action.

 of gray matter volume loss in stress-related psychopathology, which appeared to parallel dendritic atrophy observed with chronic stress in rodents.

 These converging data suggested that downregulation of excess glutamate may exert antidepressant effects, which led to the question of whether ketamine’s RAAD effects may be due to the blockage of NMDARs and subsequent inhibition of glutamate neurotransmission.

In contrast to this inhibition model, mounting 

 also hinted at a neurotrophic hypothesis of stress-related psychopathology, in which chronic stress and depression are associated with a deficit in brain-derived neurotrophic factor (BDNF).

 Other findings suggested that administration of sub-anesthetic ketamine produces transient activation of glutamate neurotransmission. This Î±-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–dependent activation was found to increase BDNF levels and promote RAAD-like effects in rodent models.

It makes sense to consider psychopathology through the lens of the glutamatergic system because glutamate is the most prevalent excitatory neurotransmitter in the brain. Furthermore, synaptic glutamate neurotransmission is cardinal in emotion, cognition, and behavior-all phenomena inextricably linked to psychopathology. 

 support dysregulated glutamate neurotransmission in cortical and limbic areas as well as variance in glutamate content in individuals with stress-related psychopathology relative to those who are psychiatrically healthy.

 It is hypothesized that the pattern and location of these synaptic alterations interact with individual and environmental characteristics to affect the clinical presentation and constellation of symptoms. Focus on glutamate-related neural remodeling and synaptic plasticity has led to a synaptic hypothesis of CSP.

Chronic stress has been associated with both synaptic potentiation and neuronal hypertrophy in brain regions including the amygdala and nucleus accumbens, as well as synaptic depression and neuronal atrophy in the prefrontal cortex, and hippocampus. The synaptic alterations in the hippocampus and prefrontal cortex are thought to be secondary to stress-induced changes in glutamate release and reuptake and astroglial loss, resulting in sustained elevations in extracellular glutamate. This precipitates reduced spine density, dendritic retraction, and branching in the prefrontal cortex as well as altered synaptic strength and excitotoxicity. The dysregulation in glutamate release and glucocorticoid signaling, together with reduced glutamate uptake and astroglial deficits, are suspected to paradoxically maintain elevated levels of extracellular glutamate despite chronic stress- induced reductions in synaptic glutamate neurotransmission.

Stress-induced synaptic hyperconnectivity in the nucleus accumbens is associated with dysregulation in monoaminergic neurotransmitters, whereas hypoconnectivity in the prefrontal cortex is associated with glutamate excitotoxicity and dysregulation. MRI studies have demonstrated that the reversal of synaptic deficits produces antidepressant-like effects and both RAADs and SAADs can reduce synaptic connectivity in the 

 while alternately increasing connectivity in the prefrontal cortex. MRI findings have also shown reduced volume in the hippocampus and prefrontal cortex of individuals with SAAD/monoaminergic treatment-resistant depression, particularly those with impaired glutamate and Î³-aminobutyric acid levels.

The synaptic model of CSP has some important components:

 The duration of stress response-as opposed to the duration of stress exposure-is critical, and the distinction between acute and chronic stress is paramount. Although there is significant individual variability in stress response and resilience, exposure to a single extreme stressor or trauma may lead to a sustained or “chronic” threat response, whereas ongoing or repeated escapable, manageable, or predictable stress exposure may lead to acute transient responses.

It is thought that acute stress exposure triggers a glutamate surge in the prefrontal cortex that results in a brief elevation in extracellular glutamate and sustained elevations in synaptic strength and NMDA and AMPA receptors. Chronic stress exposure, on the other hand, promotes reductions in prefrontal glutamate levels, synaptic strength, and NMDA and AMPA receptors with sustained elevations in extracellular glutamate.

 Two independent pathways-hyperconnectivity in the nucleus accumbens and hypoconnectivity in the prefrontal cortex and hippocampus-may contribute to stress-related psychopathology. Patients with monoamine-based pathology show localized nucleus accumbens elevations in synaptic gain and BDNF, lack of amino acid impairment, enhanced response to monoaminergic SAADs, and increased volume in the nucleus accumbens. Patients with amino acid–based pathology demonstrate prefrontal cortex synaptic loss and excitotoxicity, amino acid impairment, and resistance to monoaminergic SAADs and have gray matter deficits in the hippocampus and prefrontal cortex (

Research on glutamate release inhibitors, NMDAR antagonism, and glutamate neurotransmission activation has yielded promising results, yet ketamine and other glutamatergic drugs have notable limitations for mainstream use that require further study. Moreover, it is yet to be determined whether synaptic loss and dysconnectivity represent predisposing risk factors, an outcome of stress exposure, or factors that perpetuate psychopathology. The synaptic model posits that CSP is a common pathway across many psychopathologies and that targeting synaptic loss and dysconnectivity may provide mechanistically novel RAADs with the potential to improve the lives of patients with stress-related psychopathology, including suicidality.

Based on this synaptic model of CSP, ketamine’s suspected mechanism of action provides a unique opportunity to:

•Investigate our ability to reverse neural alterations in CSP and the cognitive, emotional, and behavioral implications of doing so

• Explore ketamine-affected biomarkers of CSP

Two ketamine-induced alterations in glutamate neurotransmission may underlie its RAAD effects: (1) an acute burst of glutamate leading to transient prefrontal activation of glutamate neurotransmission and (2) a sustained increase in prefrontal synaptic connectivity. Brief surges of prefrontal glutamate precipitate multiple intracellular processes that ultimately lead to increased synaptic connectivity in the prefrontal cortex approximately 24 hours after a subanesthetic dose of ketamine. 

 shows the suspected pathway of ketamine’s action beginning with postsynaptic activation leading to a glutamate surge and BDNF release, activation of mammalian target of rapamycin signaling, and elevations in synaptic strength and protein synthesis.

Evidence from MRI studies has repeatedly demonstrated reduced prefrontal cortex global brain connectivity in stress-related disorders and suicidality, which suggests that this may be a viable biomarker of CSP.

 Human mechanistic studies further support this notion by directly coupling prefrontal cortex global brain connectivity to glutamate neurotransmission, ketamine administration to increased prefrontal cortex global brain connectivity, and this ketamine-induced normalization in connectivity to the RAAD effects and treatment response.

 Ketamine has been seen to influence gray matter volume-with increases in the hippocampus and decreases in the nucleus accumbens-at the peak of treatment response.

 These ketamine-induced neural alterations in glutamate neurotransmission, global brain connectivity, and gray matter volume provide the opportunity to examine putative biomarkers underlying CSP and RAAD treatment response.

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Dr Averill is Clinical Research Psychologist, Clinical Neuroscience Division, Veterans Affairs National Center for PTSD, West Haven, CT; Associate Research Scientist, Department of Psychiatry, Yale School of Medicine, New Haven, CT; and Clinical Director, Emerge Research Program, Department of Psychiatry, Yale School of Medicine. Mr Averill is Neuroimaging & Technology Manager, Emerge Research Program, Clinical Neuroscience Division, Veterans Affairs National Center for PTSD, West Haven, CT and Department of Psychiatry, Yale University School of Medicine. Dr Abdallah is Assistant Professor of Psychiatry, Yale University School of Medicine, and Director of Neuroimaging, Clinical Neuroscience Division, Veterans Affairs National Center for PTSD.

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Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders

Articles

This CME provides a comprehensive understanding of psychopharmacologic treatments for stress-induced psychopathology and the need for novel, rapid-acting agents.

Author | Chadi G. Abdallah, MD

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