The use of buprenorphine helps prolong the antisuicidal benefits derived from treatment with ketamine in patients with major depressive disorder (MDD), suggests a study.
“This randomized controlled trial (RCT) provides the first evidence that low-dose buprenorphine can effectively extend the antisuicidal effects of a single intravenous ketamine infusion over 4 weeks in individuals with MDD,” the investigators said.
In this single-centre RCT, adults with MDD and a total score of ≥6 on the Scale for Suicide Ideation (SSI) were randomized to receive either sublingual buprenorphine (0.2 to 0.8 mg/day) or a matched placebo for 4 weeks, beginning 48 h after a single open-label intravenous ketamine infusion (0.5 mg/kg over 40 min). The change in SSI total score, assessed weekly from day 1 through 31, was the primary outcome.
Fifty participants (68 percent female) received ketamine from November 2020 to March 2025. Of these, 45 completed at least 1 week of follow-on treatment. [Am J Psychiatry 2026;183:409-419]
SSI total scores decreased significantly in both treatment groups, but participants who received buprenorphine showed greater improvements (mean change, ‒11.6; n=23) than those treated with placebo (mean change, ‒6.3; n=22; Glass delta, 0.76, 95 percent confidence interval, 0.11‒1.39).
A significant time-by-treatment interaction was noted in mixed-effects modelling (p<0.001). No significant between-group difference was observed in terms of depression scores. Moreover, serious treatment-related adverse events did not occur.
“These findings offer a potentially scalable and safe therapeutic option for a population at risk of suicide,” the investigators said.
Antisuicidal effect
Previous studies suggest that the antisuicidal effects of ketamine is partially independent of its antidepressant effects, consistent with the current observations. [Am J Psychiatry 2016;173:491-498; Am J Psychiatry 2018;175:150-158]
This can be potentially explained by the rapid effects of ketamine on symptoms associated with suicidal ideation, including anhedonia, hopelessness, rumination, and impaired decision making. Such symptoms could indicate changes in glutamatergic neurotransmission, dopamine turnover, opioid activity, and associated neurocircuitry in relevant brain regions. [Am J Psychiatry 2020;177:902-916]
“There is continuing debate over whether ketamine’s antidepressant properties are primarily through glutamatergic synaptic plasticity or engagement of opioid receptor pathways,” the investigators said. [Int J Neuropsychopharmacol 2025;28:pyaf073]
In a recent study using functional magnetic resonance spectroscopy, pretreatment with naltrexone reduced ketamine-induced glutamatergic activation and its subsequent antidepressant effects, “providing direct evidence that opioid system activation may be mechanistically necessary for ketamine’s therapeutic action.” [Nat Med 2025; 31:2958–2966]
“Previous efforts to extend ketamine’s therapeutic benefits using pharmacological agents such as lamotrigine, lithium, and riluzole failed to show a statistically significant advantage over placebo,” according to the investigators. [Pharmaceuticals (Basel) 2023;16:1164; Neuropsychopharmacology 2019;44:1812-1819; J Psychiatr Res 2014;58:197-199; Neuropsychopharmacology 2012;37:1526-1533]
“Currently, there are no pharmacologic treatments approved by the US Food and Drug Administration for reducing suicidal ideation in MDD,” they noted.
“Active suicidal ideation is also a key driver of care, where its presence may warrant higher-level interventions, such as inpatient or intensive outpatient treatment,” the investigators said. “These gaps underscore the pressing need for effective and targeted approaches to address suicidal ideation in individuals with MDD.” [Am J Psychiatry 2016;173:491-498]