Ketamine for suicidal ideation in adults with psychiatric disorders: A systematic review and meta-analysis of treatment trials

Abstract

Objective: Ketamine may reduce suicidal ideation in treatment-resistant depression. But it is not known how quickly this occurs and how long it persists. We undertook a systematic review and meta-analysis to determine the short- and long-term effectiveness of ketamine for suicidality. Method: CENTRAL, EMBASE, Medline, and PsycINFO were searched until 12 December 2018. Randomised controlled trials of ketamine or esketamine reporting data on suicidal ideation, self-harm, attempted or completed suicide in adults diagnosed with any psychiatric disorder were included. Two reviewers independently extracted data, and certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation tool. Standardised mean difference was used for continuous outcomes. Results: Twenty-five reports from 15 independent trials, with a total of 572 participants diagnosed with predominately affective disorders, were included. The evidence was rated moderate to low. In most trials, ketamine was administered at 0.5 mg/kg via a single intravenous infusion over a 30- to 45-minute period. Only a single trial of intranasal esketamine was identified. At 4 hours post-infusion, treatment with ketamine was associated with a significant reduction in suicidal ideation scores (standardised mean difference = −0.51, 95% confidence interval = [−1.00, −0.03]), which persisted until 72 hours post-infusion (time points between 12 and 24 hours: standardised mean difference = −0.63, 95% confidence interval = [−0.99, −0.26]; between 24 and 72 hours: standardised mean difference = −0.57, 95% confidence interval = [−0.99, −0.14]), but not thereafter. However, there was marked heterogeneity of results. In a single trial of esketamine, marginal effects on suicidal ideation were observed. In terms of actual suicidal behaviour, there were virtually no data on effects of ketamine or esketamine. Conclusion: A single infusion of ketamine may have a short-term (up to 72 hours) beneficial impact on suicidal thoughts. While confirmation of these results in further trials is needed, they suggest possible use of ketamine to treat acute suicidality. Means of sustaining any anti-suicidal effect need to be found.

Ketamine treatment for individuals with treatment-resistant depression: longitudinal qualitative interview study of patient experiences

“…6 The use of ketamine to try and reduce these phenomena has also received recent attention. [7][8][9] Reviews of trials have demonstrated that a single intravenous treatment with ketamine can have beneficial effects on suicidal ideation, but again with transitory benefits, 10,11 possibly of shorter duration than the effects on depression. There is no evidence regarding actual suicidal acts.…”

“…10 Most earlier trials of ketamine treatment for depression or suicidal ideation in the context of TRD involved single infusions. 4,5,10 Because of the often temporary benefits of a single dose of ketamine, in clinical practice multiple doses may be given and patients might be transferred to other modes of ketamine treatment (e.g. oral, intramuscular) once they have shown improvement with intravenous treatment.…”

Ketamine and esketamine for suicidal ideation: Recent progress and practical issues

“…Despite findings of different meta-analyses showing antidepressant and antisuicidal effects of ketamine (e.g., Wilkinson et al, 2018), quality of evidence needs to be carefully judged to interpret results, draw conclusions and generate appropriate recommendations. The meta-analysis of Witt and colleagues (2020) tested the efficacy of ketamine for suicidal ideation in adults with major depressive or bipolar disorders. The authors estimated a moderate reduction in suicidal ideation 4 hours after ketamine’s infusion, which persisted until 72 hours.…”

“…To date, no head-to-head trial of esketamine versus ketamine in depression or suicidal ideation has been conducted. Notably, the single trial based on esketamine included in the meta-analysis of Witt et al (2020) estimated a significant improvement in suicidal ideation at 4 hours, but not at subsequent endpoints (Canuso et al, 2018). The different protocols and comparator treatments used in each trial may limit strict comparisons across trials.…”

“…The manufacturer recently filed a Supplemental New Drug Application to FDA for esketamine for the indication of a rapid reduction of depressive symptoms in adults with active suicidal ideation, following the announcement of positive results from two phase III clinical trials (ASPIRE I [clinicaltrial.gov identifier: NCT03039192] and ASPIRE II [clinicaltrial.gov identifier: NCT03097133], including 226 and 230 participants, respectively). Because of the timing of these trials, they were not able to be included in the meta-analysis of Witt et al (2020). Results for both trials revealed a significant effect on depression scores at 24 hours though not on suicidal ideation.…”