The serendipitous discovery of ketamine’s rapid-acting and robust antidepressant effects has been hailed as “arguably the most important discovery [in neuropsychiatric research] in half a century.”1 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.2-4 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 (Figure 1).5,6
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.7 A recent trial 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.8
Based on the promising results of intranasal esketamine trials the FDA has designated it as a “breakthrough therapy.”2 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.
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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