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

This systematic review (2018) and meta-analysis (n=176) examined the effects of ketamine on suicidal ideation using patient-level data from various studies that applied a single-dose intravenous administration route to treat any type of psychiatric disorder. Ketamine significantly reduced suicidal ideation for up to one week after the infusion.

Abstract

“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 mixed-effects, 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 after ketamine 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.”

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

Summary

Suicide is a public health crisis and ranks among the top three causes of mortality worldwide for individuals ages 15 – 44. Current treatment options for individuals at acute risk for suicide are limited and do not reduce suicide deaths or rates of suicide attempts.

A systematic review and meta-analysis of clinical trials using patient-level data of explicit measures of suicidal ideation shows that ketamine has potential antisuicidal effects in patients with mood disorders.

Study Identification and Selection

Two reviewers searched MEDLINE for studies on ketamine and suicide. They identified several systematic reviews and meta-analyses.

This meta-analysis looked at how single-dose intravenous ketamine affected suicidal ideation in people with depression.

Statistical Analysis

We collected data on suicidal ideation, overall severity of depressive symptoms, treatment assignment, potential moderators of treatment effect, and age, gender, race, inpatient versus outpatient status, use of concomitant medications for each patient.

We excluded patients who had no suicidal ideation at baseline. Suicidal ideation was defined as active or passive and was operationalized a priori as a score on a clinician-administered scale or a self-report scale.

We used a standard one-stage hierarchical modeling approach to assess whether ketamine would resolve suicidal ideation more rapidly than the control treatment. A general linear mixed model was used, and a group-by-time interaction was included.

In crossover trials, ketamine treatment was associated with a reduction in suicidal ideation. The effect of ketamine on suicidal ideation was calculated using mean differences between baseline and each time point.

Included Studies

We identified 11 eligible trials from 153 citations and included participants from 10 of these studies. The remaining study had no participants with baseline suicidal ideation, so it was not included in the analysis.

Characteristics of the Included Sample

298 patients participated in 10 included ketamine trials; 167 patients met criteria for baseline suicidal ideation. Included patients had more severe depressive symptoms at baseline than excluded patients as measured by the MADRS, the HAM-D, the QIDS-SR, and the BDI.

Ketamine did not affect mean age, gender distribution, diagnoses, inpatient versus outpatient status, proportion receiving concomitant psychotropic medications, or baseline MADRS score.

The Effects of Ketamine on Clinician-Administered Suicidal Ideation Item Scores

Ketamine reduced suicidal ideation more rapidly than control treatments on the MADRS and HAM-D, with significant benefits appearing as early as day 1 after treatment and extending up to day 7. None of the baseline variables significantly moderated ketamine’s effects on suicidal ideation.

Ketamine reduced suicidal ideation significantly more rapidly than control treatments on both the MADRS and HAM-D, and was associated with a significantly greater proportion of patients being free from suicidal ideation compared with control treatments at all postinfusion time points.

Suicidal Ideation

Ketamine significantly reduced suicidal ideation more rapidly than the control treatments, with significant benefits noted at each individual time point. The effects of ketamine remained significant after baseline covariates were adjusted for in the model.

Ketamine was associated with a significantly greater proportion of patients being free from suicidal ideation at postinfusion days 1, 2, and 3 compared with the control treatments, but not at day 7 (Figure 3B).

Correlation Between Suicidal Ideation and Severity of Depressive Symptoms

Changes in suicidal ideation and overall severity of depressive symptoms were strongly correlated at all time points, with the strongest correlations at day 1 and day 7.

Independence of Improvement Measures for Suicidal

The time-by-treatment interaction remained significant regardless of whether clinician-administered or self-report outcome measures were used. Significant differences were observed between groups at all postinfusion time points on clinician-administered outcome measures.

Durability of Effect

86.0% of patients who received ketamine had a resolution of suicidal ideation by 24 hours after infusion, compared with 52.9% of patients who received control treatments.

Midazolam Versus Saline as Control Treatment

We calculated effect sizes separately for saline and midazolam as control treatments, and found no group-by-time interaction nor a main effect of group for suicidal ideation in the linear mixed model.

DISCUSSION

This study used individual participant-level data from all single-dose comparison intervention trials of intravenous ketamine to examine the effects of ketamine on suicidal ideation. It found that ketamine significantly reduced suicidal ideation and that patients treated with ketamine were significantly more likely to be free of suicidal ideation.

In a study of 131 patients, 54.9% were free of suicidal ideation 24 hours after a single ketamine infusion, and 60.0% were free of suicidal ideation at 1 week postinfusion. This suggests that ketamine’s effects on suicidal ideation may hold considerable promise.

Pseudospecificity

There is considerable interest regarding whether ketamine’s antisuicidal properties occur independently of its general antidepressant effects, particularly because this may have an impact on the path toward FDA approval for ketamine or related compounds in treating suicidal ideation or behavior.

Ketamine reduces suicidal ideation partially independently of mood symptoms in patients with major depressive disorder or bipolar depression. However, further research is required to determine whether ketamine is effective in patients with other psychiatric diagnoses and levels of treatment resistance.

Limitations

Although the included studies had small sample sizes, three of the four scales yielded consistent findings, and all but one study excluded patients who had no suicidal ideation at baseline. The short follow-up of the studies precludes further guidance on sustained effects beyond 7 days after treatment.

Future Work

Despite robust findings, more studies are needed to determine whether ketamine can be used to treat patients at risk of suicide. These studies should also explore the effects of combining ketamine with established somatic/pharmacologic or psychotherapeutic modalities to extend beneficial response. Future clinical studies should assess details of suicidal ideation, including frequency, intensity, duration, and past suicidal behaviors. Also, midazolam may attenuate the effect size of ketamine, but our study did not find a significant difference between the two control conditions.

CONCLUSIONS

This study found that a single ketamine infusion rapidly reduced the severity of suicidal thinking in patients with some level of active or passive suicidal ideation. Further research is needed to determine the optimal patient selection, dosing frequency, clinical monitoring, and follow-up assessment.