Ketamine and Suicidal Ideation: Direct Effect or Epiphenomenon?

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To the Editors
Suicide is a major clinical and public health problem in patients with mental illness, and the development of individual- and population-level interventions to prevent suicide is a research priority.1 Two medications, clozapine and lithium, have been shown in randomized controlled trials and cohort studies to reduce suicide attempts and/or death by suicide.2 Although lithium's effects on suicidality have been ascribed to antidepressant activity,3 other evidence indicates antisuicidal effects are independent of its effect on preventing depressive recurrences.4 It has been proposed that lithium's antisuicidal effects might be due to reduced impulsivity rather than any direct effect on mood.2 Clozapine's antisuicidal effects also seem independent of direct effects on mood; in this case, improved control of psychotic symptoms and more frequent clinical contact have been suggested as being mechanistically relevant.5
In this context, it is relevant to consider the distinctive clinical effects of ketamine: to what extent does its rapid antisuicidal action depend on improvement in depressed mood? The answer to this question will help define ketamine's place in psychopharmacotherapy and may also shed light on the pathophysiological overlap between depression and suicide. In a recent review in this journal, Lee et al6 proposed that reduced suicidal thinking with ketamine may derive from a procognitive mechanism also associated with mood improvement due to common effects on prefrontal cortical network activity. Because the review considered only patients with depression, addressing the question of whether this is a direct effect or an epiphenomenon of improved mood is confounded. One way to disentangle this would be to examine changes in suicidal thinking in ketamine responders and nonresponders, using individual patient data, as previously used to address this issue with lithium.4 Another approach would be to evaluate ketamine's antisuicidal effects in patients without significant coexisting depression (eg, borderline personality disorder,7 autistic spectrum disorder,8 or chronic pain9).
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