IV Ketamine Shows Rapid Benefits for Suicide Risk, Depression in Major Depressive Episodes

Intravenous (IV) ketamine rapidly reduced both suicidal and depressive symptoms in patients experiencing a major depressive episode, with benefits appearing within hours of treatment and persisting for weeks in some patients, new research shows.¹

The systematic review and meta-analysis published today in JAMA Psychiatry analyzed data from 26 randomized clinical trials involving 1166 patients with a major depressive episode, including major depressive disorder (MDD) and bipolar depression. Of the participants, 626 received ketamine infusions, and 540 received control treatments such as saline placebo or midazolam. The researchers reported standardized mean differences (SMDs) with 95% CIs and stated that statistical significance was defined as a 2-sided P < .05.

Researchers reported that patients receiving a single ketamine infusion experienced significantly greater reductions in suicidal symptoms compared with control groups at 24 hours, with an SMD of –0.69 (95% CI, –0.98 to –0.40). Improvements remained significant at 1 month after treatment, with an SMD of –0.70 (95% CI, –1.17 to –0.24). Repeated ketamine infusions also reduced suicidal symptoms at the end of treatment, with an SMD of –0.72 (95% CI, –1.00 to –0.43).

The antidepressant effects were similarly rapid and robust. Compared with controls, patients receiving a single ketamine infusion had significantly lower depressive symptom severity at 4 hours after treatment, with an SMD of –1.74 (95% CI, –2.43 to –1.06). Significant improvements were also observed at 24 hours (SMD, –1.15; 95% CI, –1.58 to –0.72), 3 days (SMD, –0.97; 95% CI, –1.73 to –0.20), and 1 week (SMD, –0.89; 95% CI, –1.65 to –0.13). Patients receiving repeated ketamine infusions also experienced reduced depressive symptoms at the end of treatment, with an SMD of –0.81 (95% CI, –1.16 to –0.46).

The investigators said the findings underscore ketamine’s potential role as a rapid-acting intervention for patients with severe depression or suicide risk, particularly because traditional antidepressants often require several weeks before clinical benefits emerge.

Current therapies for treatment-resistant depression often fall short because they “are limited by delayed onset of action, inadequate efficacy, and/or intolerable adverse effects,” resulting in remission rates of less than 15% among patients with TRD.² The investigators added that “there is an urgent need for more effective interventions that rapidly reduce depressive symptoms and suicide risk.”

Ketamine, a noncompetitive N-methyl-D-aspartate glutamate receptor antagonist, has increasingly been used off-label for depression and suicidal ideation over the past 2 decades.¹ Although intranasal esketamine has received FDA approval for treatment-resistant depression and depression associated with suicidal risk,³ IV racemic ketamine has not been approved by the FDA for depressive symptoms.¹ However, the authors noted that France became the first country to approve IV racemic ketamine for adults with severe suicidal symptoms in March 2026.

Among the 26 included trials, 18 studies evaluated single ketamine infusions and 8 studies examined repeated infusions. Most studies included patients with MDD, although several involved bipolar depression or mixed mood disorders with suicidal ideation. Comparator groups most commonly received saline infusions or midazolam.

The analysis also evaluated safety outcomes and found that ketamine was generally well-tolerated in controlled clinical settings. Serious adverse events, including hospitalizations and deaths reported during the trials, were determined to be unrelated to the treatment interventions. More common adverse events, including headache and transient dissociative symptoms, typically resolved during the course of the studies.

The authors cautioned that important questions remain regarding long-term efficacy and safety. Most trials focused on short-term outcomes ranging from several hours to several weeks after treatment, leaving limited evidence about the durability of response, maintenance strategies, relapse prevention, and the long-term effects of repeated ketamine exposure.

The researchers also acknowledged heterogeneity among the included studies, including differences in dosing protocols, patient populations, and outcome measures. Although the pooled data consistently favored ketamine overall, some individual trials reported mixed findings or nonsignificant differences between ketamine and control groups.

Still, the investigators concluded that both single and repeated IV ketamine infusions appear efficacious in rapidly reducing suicidal and depressive symptoms during the acute phase of major depressive episodes. They suggested the findings support consideration of ketamine as an off-label treatment option for patients at risk of suicidal behaviors or for those who have not responded adequately to conventional depression therapies.

References

1. Shim SR, Jeong HS, Bommersbach TJ, et al. Ketamine infusions and rapid reduction of suicidal and depressive symptoms in major depressive episode: a systematic review and meta-analysis. JAMA Psychiatry. Published online May 6, 2026. doi:10.1001/jamapsychiatry.2026.0612
2. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178(5):383-399. doi:10.1176/appi.ajp.2020. 20081251
3. Grossi G. Esketamine approved by FDA as first monotherapy for treatment-resistant depression. AJMC^®. January 21, 2025. Accessed May 6, 2026. https://www.ajmc.com/view/esketamine-approved-by-fda-as-first-monotherapy-for-treatment-resistent-depression