Am J Psychiatry
Buprenorphine extends ketamine effect on suicidal ideation
Clinical Takeaway: The combination uses two existing drugs and offers a possible bridge for patients with persistent suicidal ideation while slower-acting therapies take effect. Replication in larger trials is needed.
A single ketamine infusion can reduce suicidal ideation within hours, but the effect typically fades within a week. Prior attempts to extend it with lamotrigine, lithium, riluzole, and d-cycloserine have largely failed. This trial tested whether buprenorphine, a partial opioid receptor agonist, could sustain ketamine's antisuicidal effect, building on evidence that ketamine itself acts in part through the opioid system.
At four weeks, 78% of patients on buprenorphine after ketamine had a meaningful reduction in suicidal ideation, compared with 48% on placebo after ketamine. The buprenorphine group's average score fell below the threshold for clinically significant ideation; the placebo group's stayed above it.
Notably, the antidepressant effect did not separate between groups. Both arms showed substantial improvement on depression scales after ketamine, but buprenorphine did not significantly enhance that effect, suggesting the antisuicidal and antidepressant actions of the regimen may run through distinct mechanisms. After buprenorphine was stopped, suicidal ideation scores rose slightly but remained below the clinical threshold two weeks later, and withdrawal symptoms were minimal.
Researchers randomized 50 adults with major depressive disorder and clinically significant suicidal ideation to receive a single ketamine infusion followed by either low-dose, sublingual buprenorphine or matched placebo, beginning 48 hours after the infusion. If replicated in larger trials, the regimen could fill a real treatment gap.
"There is divergence between the antisuicide effect, to some extent, and the antidepressant effect of ketamine. It is somewhat separate, suggesting there's a different biology and a different pharmacology," said senior author Alan Schatzberg, MD, the Kenneth T. Norris, Jr. Professor in Psychiatry and Behavioral Sciences at Stanford University School of Medicine.
Source: Tucciarone JM. Am J Psychiatry. 2026 May 18. Low-dose buprenorphine following ketamine treatment for suicidal ideation in major depressive disorder: a randomized, double-blind, placebo-controlled trial