The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis

Samuel T. Wilkinson, M.D., Elizabeth D. Ballard, Ph.D., Michael H. Bloch, M.D., M.S., Sanjay J. Mathew, M.D., James W. Murrough, M.D., Ph.D., Adriana Feder, M.D., Peter Sos, M.D., Ph.D., Gang Wang, M.D., Carlos A. Zarate, Jr., M.D., Gerard Sanacora, M.D., Ph.D.

American Journal of Psychiatry, 2018, 175, (2) 150–158.

Doi : 10.1176/appi.ajp.2017.17040472

 

Objective : Suicide is a public health crisis with limited treatment options. The authors conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation.

Method : Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment. The analysis included only participants who had suicidal ideation at baseline (N=167). A one-stage, individual participant data,
meta-analytic procedure was employed using a mixedeffects, multilevel, general linear model. The primary outcome measures were the suicide items from clinician-administered (the Montgomery-Åsberg Depression Rating Scale [MADRS] or the Hamilton Depression Rating Scale [HAM-D]) and
self-report scales (the Quick Inventory of Depressive Symptomatology–Self Report [QIDS-SR] or the Beck Depression Inventory [BDI]), obtained for up to 1 week aftervketamine administration.

Results : Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures. Effect sizes were moderate to large (Cohen’s d=0.48–0.85) at all time points after dosing. A sensitivity analysis demonstrated that compared
with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI. Ketamine’s effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms.

Conclusions : Ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation. Ketamine’s effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in transdiagnostic samples are required to
confirm that ketamine exerts a specific effect on suicidal ideation. Additional research on ketamine’s long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.

Suicide is a public health crisis and ranks among the top three causes of mortality worldwide for individuals ages 15–44 (1, 2). Unfortunately, the suicide rate has increased over the past two decades despite renewed efforts to address this crisis (3). Studies suggest that approximately 90% of individuals who commit suicide suffer from a treatable psychiatric disorder, most commonly a mood disorder(4). Nevertheless, current treatment options for patients at acute risk for suicide are limited and generally consist of hospitalization plus pharmacotherapy, psychotherapy, ECT, or a combination thereof. The National Action Alliance for Suicide Prevention has highlighted the importance of identifying fast-acting interventions for suicidal individuals as a critical research goal to reduce the suicide rate (5). Treatment with lithium and clozapine, as well as dialectical behavioral therapy and cognitive-behavioral therapy (CBT), have been shownto reduce suicide deaths (2, 6, 7) and rates of suicide attempts (8, 9). However, while these treatments and interventions function to reduce suicide risk long-term, they have not been shown to be effective in acute settings.

Since 2000, several small clinical trials have demonstrated that subanesthetic doses of ketamine have rapid-acting antidepressant properties (10–14) as well as potential antisuicidal properties (15–18) in patientswithmood disorders (both major depressive disorder and bipolar depression). Given ketamine’s rapid antidepressant effects, there is considerable interest regarding its potential ability to stabilize patients with mood disorderswho are at imminent risk of suicide. Here, we report on a systematic reviewandmeta-analysis using patient-level data of explicit measures of suicidal ideation to assess ketamine’s potential antisuicidal effects.

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