Suicidal ideation (SI) in major depressive disorder (MDD) is a major clinical concern, yet pharmacologic options that specifically target SI remain limited. Intravenous ketamine can rapidly reduce SI, but its effects are often transient, and repeated infusions may raise concerns related to cost, access, long-term safety, and misuse potential. Because ketamine’s antidepressant and antisuicidal effects may involve mu-opioid receptor pathways, a study recently published in the American Journal of Psychiatry evaluated whether low-dose sublingual buprenorphine could extend ketamine’s antisuicidal benefit.

This randomized, double-blind, placebo-controlled trial enrolled adults aged 18–70 years with MDD, a current major depressive episode, and clinically significant SI, defined as a Scale for Suicide Ideation (SSI) score ≥6. Participants first received a single open-label intravenous ketamine infusion (0.5 mg/kg over 40 minutes). Forty-eight hours later, they were randomized to 4 weeks of low-dose sublingual buprenorphine or matched placebo. Buprenorphine was started at 0.2 mg/day and titrated weekly as tolerated to 0.6–0.8 mg/day. The primary outcome was change in SSI total score through day 31. Secondary outcomes included depressive symptoms measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAM-D).

Of 50 participants who received ketamine, 45 completed at least 1 week of follow-on treatment and were included in the primary analysis. The sample had substantial illness burden, with a mean baseline SSI score of 15.0, mean MADRS score of 34.1, and 62% meeting criteria for treatment-resistant depression. Ketamine rapidly reduced SI by 48 hours, with SSI scores decreasing by a mean of 9.1 points; 54% of participants achieved a ≥50% reduction in SSI score.

During the follow-on phase, SI improved in both groups but to a greater extent with buprenorphine. From day 1 to day 31, SSI scores decreased by 11.6 points with ketamine plus buprenorphine compared with 6.3 points with ketamine plus placebo. The time-by-treatment interaction was significant (p<0.001), with group differences emerging by day 10 and persisting through day 31. At day 31, 78% of participants receiving buprenorphine met SSI response criteria compared with 48% receiving placebo, corresponding to a number needed to treat of approximately 3.

Depressive symptoms also improved in both groups, but differences between buprenorphine and placebo were not statistically significant. MADRS scores decreased by 15.8 points with buprenorphine and 8.5 points with placebo, while HAM-D findings were similar. These results suggest that buprenorphine’s benefit may have been more specific to SI than to overall depressive symptoms.

Low-dose buprenorphine was generally well tolerated, with no serious treatment-related adverse events. Common adverse events included dizziness, oral burning, headache, nausea, constipation, and dry mouth. During the 2-week discontinuation phase, clinician-rated opioid withdrawal symptoms were minimal to none, and patient-rated withdrawal symptoms were minimal and not significantly different from placebo. SI and depression scores increased modestly after buprenorphine discontinuation, underscoring the need for follow-up after stopping treatment.

This small, single-site trial provides preliminary evidence that low-dose sublingual buprenorphine may help sustain and enhance ketamine’s rapid antisuicidal effects in adults with MDD. The findings are promising, but the approach remains investigational. Larger and longer-term trials are needed to confirm efficacy, clarify safety, determine optimal treatment duration and tapering strategies, and assess generalizability to patients with substance use disorders or other psychiatric comorbidities.

Reference: Tucciarone et al. Am J Psychiatry 2026. Epub ahead of print. Abstract