Reference: BMJ. 2022 Feb 2;376:e067194
Suicide is the 10th leading cause of death in the US, but evidence-based treatment for suicidal crisis is limited and inadequate. Other than safety monitoring, interventions like psychotherapy and medication generally take weeks to become effective. Ketamine, a dissociative agent typically used as an anesthetic (and its enantiomer esketamine) have recently gained attention for their role in the management of treatment-resistant depression. There is even some evidence now to support the use of ketamine for acute suicidal ideation, but the data have been muddied by poor methodology. A recent trial published in the BMJ sought to examine the immediate effects of IV ketamine on suicidal ideation.
French investigators randomized 156 adults voluntarily admitted to the hospital with suicidal ideation to receive either ketamine 0.5 mg/kg IV infusion or normal saline infusion at baseline and at 24 hours. Median patient age was 40 years, 68% were female, and follow-up lasted for 6 weeks. Both groups received usual care involved with psychiatric hospital admission (medication, individual therapy, group psychotherapy, and family meetings). Participants were stratified into 3 diagnostic categories — major depressive disorder (MDD), bipolar disorder, or other psychiatric disorder such as dysthymia, PTSD, generalized anxiety disorder, panic disorder, and agoraphobia. Exclusion criteria included current substance dependence, history of schizophrenia, or history of other psychotic disorder. The primary outcome was remission of suicidal ideation (SI) defined as score ≤ 3 points on the Beck Scale for Suicidal Ideation, clinician-rated version (range 0-38 points).
At day 3, more people who initially had SI were in remission in the ketamine group compared to the placebo group (63% vs. 31.6%, p < 0.001). Remission rates differed when stratified by diagnosis and were greatest in adults with bipolar disorder (84.6% vs. 28% p < 0.001). SI remission rates were also higher in the ketamine group but were not significant for those with MDD (42.3% vs. 35.7%, p = 0.6) or other disorders (61.9% vs. 30.8%, p = 0.07). Overall side effects of ketamine were nonsevere and included sedation (11%), depersonalization (9.6%), nausea (6.8%), and dizziness (4.1%). Over the course of the study, six patients (8.2%) in the ketamine arm and eight patients (9.8%) in the placebo arm attempted suicide. Sadly, one patient died by suicide in the ketamine arm. At 6 weeks, no significant difference was found in SI remission rates comparing ketamine vs. placebo (69.5% vs. 56.3%, p = 0.7).
These results may seem uplifting — a treatment for suicidal ideation which acts promptly and effectively with a low risk of adverse effects — but could it be too good to be true? The study is described as double-blind, but patients may have been able to determine their assigned group based on their subjective experience after infusion. Similarly, assessors may have inferred group assignment due to patient sedation or depersonalization following infusion. From an EBM perspective, we know that lack of blinding systematically overestimates benefit. An alternative control like midazolam, which has been used in other studies of ketamine, may have offered better blinding to both participants and outcome assessors. Although ketamine seemed to have some effect on suicidal ideation, this did not translate into fewer suicidal attempts. Authors did note that patients in the intervention group who attempted suicide were poor responders to ketamine at day 3 based on SI scores, a finding that deserves more scrutiny. All in all, these study results support another potential use for ketamine in mental health disorders and justify a larger trial designed to evaluate the effects of ketamine on suicide attempts as a primary outcome.
For more information, see the topic Suicidal Ideation and Behavior in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Nicole Jensen, MD, family physician at WholeHealth Medical. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, Deputy Editor at DynaMed; Carina Brown, MD, Assistant Professor at Cone Health Family Medicine Residency; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; and Sarah Hill, MSc, Associate Editor at DynaMed.