Low-Dose Buprenorphine Enhanced Ketamine’s Antisuicidal Effects in Major Depression

Low-dose buprenorphine significantly enhanced the antisuicidal effects of a single infusion of ketamine in patients with suicidal ideation and major depressive disorder (MDD), a randomized trial showed.

Among 45 patients who received ketamine, Scale for Suicide Ideation (SSI) total scores significantly decreased from days 1 to 31 for those who received buprenorphine and those who received placebo, with a larger reduction observed in the buprenorphine group (mean change -11.6 vs -6.3; Glass delta 0.76, 95% CI 0.11-1.39), reported Jason M. Tucciarone, MD, PhD, and Alan F. Schatzberg, MD, of Stanford University School of Medicine in California, at the American Psychiatric Association annual meeting.

Mixed-effects modeling showed a significant time-by-treatment interaction (P<0.001), the researchers noted in their study, which was also published in the American Journal of Psychiatry.

“These findings offer a potentially scalable and safe therapeutic option for a population at risk of suicide,” they concluded.

There are currently no FDA-approved treatments for reducing suicidal ideation in patients with MDD, and roughly 50,000 people die in the U.S. each year by suicide, noted Schatzberg during their presentation.

He said that researchers have long thought of suicide as “the end of a continuum of severity” of depression, but a lot of people who take their lives aren’t necessarily depressed.

Tucciarone pointed out that “some people are very high-functioning. They’re at work. They have families. They’re holding it down, but yet they harbor these horrible feelings” about suicide.

A previous meta-analysis showed that ketamine infusion rapidly reduced suicidal and depressive symptoms among patients with a major depressive episode. Meanwhile, a randomized trial from Israel found that low-dose buprenorphine reduced suicidal ideation in hospitalized patients with MDD or borderline personality disorder after 2 weeks of treatment.

Of note, ketamine’s antisuicidal benefits are transient, and this study is among the first to demonstrate that a pharmacologic intervention can effectively preserve and build on those antisuicidal effects in at-risk persons, Schatzberg said.

The study took place at a single U.S. outpatient center from November 2020 to March 2025, and included participants with a diagnosis of MDD who were currently experiencing a major depressive episode lasting 8 weeks or more. They were required to have a “documented inadequate response” to at least one antidepressant given at an appropriate dose and duration, or an intolerance to such medications.

They were randomly assigned 1:1 to receive sublingual buprenorphine (0.2 to 0.8 mg/day) or placebo for 4 weeks starting 48 hours after receiving a single intravenous ketamine infusion (0.5 mg/kg over 40 minutes).

Of 50 participants who received ketamine, 45 completed at least 1 week of follow-on treatment. Mean age was 37.6, 68% were female, 72% were white, and 62% met criteria for treatment-resistant depression. The mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 34.1, and the mean baseline SSI total score was 15.0. The average number of prior suicide attempts was 1.3.

In the study’s ketamine phase, which preceded randomization and receipt of buprenorphine or placebo, SSI scores dropped significantly from day 1 to day 3 after infusion (mean -9.1, P<0.001). At day 3, 54% of participants met the response criterion (≥50% reduction in SSI score). MADRS total scores also significantly decreased (mean -13.4, P<0.001), with 38% of participants meeting criterion for response.

In the buprenorphine extension phase, data from days 3 to 31 revealed worsening suicidal ideation among the placebo group, while the buprenorphine group showed continued improvement. The greatest difference between groups was seen at days 24 and 31. On day 31, 78% of participants given buprenorphine met the study’s response criterion versus 48% who received placebo (P=0.035). The number needed to treat was three.

Depression scores did not differ significantly between groups.

No serious treatment-related adverse events occurred. The most common side effects were dizziness, oral burning, headache, and nausea, which were more frequent in the buprenorphine arm than in the placebo arm.

The researchers advised caution in interpreting their results given the study’s relatively small sample size.

Future research should extend to “other symptom clusters” of people with suicidal ideation, including those with borderline personality and bipolar disorders, Tucciarone noted.