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SAN FRANCISCO — Buprenorphine — a medication commonly used to treat opioid use disorder — prolonged the reduction in suicidal ideation following treatment with ketamine in patients with major depressive disorder (MDD).

Results of the randomized controlled trial showed that after a single infusion with ketamine, patients given low doses of buprenorphine experienced significant decreases in suicidal ideation, with a 76% reduction at week 4 compared with 43% for placebo.

This is the second trial that has shown that buprenorphine at low doses reduces suicidal ideation in MDD.

“However, unlike earlier reports, the degree of reduction was enhanced markedly by pretreating with intravenous ketamine,” principal investigator Alan Schatzberg, MD, said in a press briefing.

“The similarities of the buprenorphine findings and the availability of both drugs for clinical use could rapidly increase the potential adoption of the sequence as a treatment strategy to reduce suicidality,” he added.

The findings also suggest a different biological mechanism between depression symptoms and suicidal symptoms.

“We have long thought of suicide as the end of a continuum of severity in depression. And that’s wrong,” Schatzberg, professor in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, Stanford, California, told Medscape Medical News.

The findings were presented on May 18 at the American Psychiatric Association (APA) 2026 Annual Meeting and were simultaneously published online on May 18 in the American Journal of Psychiatry.

Few Treatment Options

Every 11 minutes in the US, a person dies by suicide, making it an urgent public health crisis. Despite this significant burden, there are currently no FDA-approved treatments for reducing suicidal ideation in MDD and only a limited number of interventions that have shown anti-suicidal effects.

Ketamine has recently been shown to reduce suicidal thoughts. However, its effects are transient, and data on the efficacy of repeated infusions are lacking. Growing evidence suggests ketamine’s antidepressant and anti-suicidal effects may be, in part, mediated through the mu-opioid receptor.

Buprenorphine, which is primarily used to treat opioid use disorder, acts as a partial agonist to this receptor and was shown in a previous study to reduce suicidal ideation at low doses.

The goal of the trial was to determine whether buprenorphine could prolong ketamine’s reductions in suicidal ideation.

Adults with MDD and a score ≥ 6 on the Scale for Suicidal Ideation (SSI) were randomly assigned to receive low doses of buprenorphine (0.2-0.8 mg/d) or placebo for 4 weeks, administered 48 hours after a single infusion of ketamine (0.5 mg/kg over 40 minutes).

Exclusion criteria included a history of opioid use disorder, substance use disorder within 6 months of screening, or severe psychiatric comorbidities. Participants, treating investigators, and outcome assessors were blinded to treatment assignment.

The primary outcome was the change in SSI score, measured weekly over a period of a month. A total of 50 patients received a ketamine infusion (68% female; mean age, 38 years; 72% White), and 45 patients completed at least 1 week of treatment.

Secondary outcomes included changes in depression scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale.

Sustained Reductions in Suicidal Ideation

After the single ketamine infusion, SSI total scores decreased significantly (mean, -9.1; P < .001), and at day 3, 54% of participants showed a response (50% or more reduction in SSI score). MADRS total scores also significantly decreased from day 1 to day 3.

Over 4 weeks, the buprenorphine group showed significantly greater reductions in suicidal ideation than the placebo group (mean change, -11.6 vs -6.3; P < .001 for both).

At week 4, there was a 76% reduction in suicidal ideation in the ketamine and buprenorphine group compared with a 43% reduction in the ketamine and placebo group.

Linear mixed-effects models showed a significant time-by-treatment interaction (P < .001). At day 31, the number needed to treat was 3, which is considered clinically meaningful.

There were no serious treatment-related adverse events among participants. In addition, patients did not show a typical opioid withdrawal syndrome following discontinuation of buprenorphine.

Although both groups improved on depression scores, there were no statistically significant differences between the groups.

The study’s limitations included the failure to assess treatment expectancy and insufficient statistical power to determine whether response to ketamine predicted response to buprenorphine.

However, these findings raise the possibility that ketamine’s effects on suicidal ideation are mediated through mechanisms different from those responsible for the drug’s antidepressant effects, potentially involving the mu-opioid system, the study’s lead author Jason Tucciarone, MD, PhD, assistant professor in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, said at the briefing.

Further research is needed with larger sample sizes to assess whether longer durations of treatment are required and whether longer durations of posttreatment discontinuation follow-up are necessary, he added.

“We really think that these findings offer a scalable and safe therapeutic option for folks at risk of suicide,” he concluded.

‘A Big Deal’

This research adds to the ongoing debate over whether suicidality is a distinct clinical entity separate from depression, Charles Nemeroff, MD, PhD, who was not involved in the trial, told Medscape Medical News.

Given the lack of options available to reduce suicidality, Nemeroff, who is professor and Matthew P. Nemeroff Endowed Chair in the Department of Psychiatry and Behavioral Sciences at The University of Texas at Austin, said the results are significant.

“The idea that you could extend the benefit of suicidality reduction or antidepressant effect, that you could actually extend it with buprenorphine, is a big deal,” he said. “If there was a follow-up, larger study that showed that this regimen was in fact very effective in reducing suicidality, I would definitely consider it for my patients.”

Studies of treatments for suicidal ideation are notoriously difficult to conduct, and treatments are urgently needed, Cristina Cusin, MD, who also was not involved in the study, told Medscape Medical News.

Cusin, associate professor of psychiatry and director of the MGH Ketamine Clinic in Boston, struck a cautious note, noting key limitations such as the small sample size and limited generalizability.

In addition, the patients enrolled were “not very treatment resistant according to common research definition,” with 38% having failed only one prior antidepressant and with an average number of past treatments of 2.3, she said.

“Ethically, I have some concerns, and, in my practice, I would not consider a trial of ketamine or buprenorphine in patients who have failed only one or two antidepressants. I would consider ketamine after three to four trials, including adequate augmentations and combinations, or after interventions that are relatively benign like TMS [transcranial magnetic stimulation], for example,” Cusin added.

The trial was funded by the American Foundation for Suicide Prevention, in addition to other grants. Cusin declared having no relevant disclosures. Nemeroff disclosed consulting for pharmaceutical companies. Tucciarone disclosed serving as a consultant for Headlamp Health. Schatzberg disclosed serving as a consultant for pharmaceutical companies (see study).