A research team led by BBRF grantees has reported the first randomized, controlled trial in patients with major depressive disorder (MDD) to demonstrate that a pharmacological intervention—follow-on treatment with low-dose buprenorphine—can maintain and enhance the anti-suicidal effects of a single ketamine infusion over the course of a month.

Ketamine, an anesthetic delivered at very low, subanesthetic doses, has proven a powerful antidepressant therapy that can also reduce suicidal ideation and behavior. Ketamine’s remarkably rapid action—most who respond do so within hours—has made it an especially valuable option in patients experiencing a suicidal crisis.

Although it has likely saved many lives, the problem with ketamine is that its benefits are often not sustained longer than a week. For some of those whose depression and/or suicidal behavior soon returns, this has meant follow-on ketamine infusions. There is still a paucity of long-term safety data for this course, as well as a financial burden placed upon patients and the potential—always present for ketamine—for misuse or abuse.

Various attempts to extend ketamine’s therapeutic effects via drug therapy have not succeeded. Ketamine blocks activity at NMDA receptors in the brain, but other NMDA antagonists have not generated similar antidepressant action or extended that of ketamine. Another possible approach is to take advantage of ketamine’s hypothesized impact on mu-opioid receptors (MORs), one of three major types of cellular receptors for opioids, which are involved in the management of pain, mood, and various physical functions.

In 2016, Dr. Yoram Yovell, a 1995 BBRF Young Investigator, and colleagues in Israel, demonstrated in a clinical trial that buprenorphine, a partial stimulator of activity at MORs and used as a treatment for opioid use disorder, when given at low doses could reduce suicidal ideation in patients with MDD or borderline personality disorder following 2 weeks of hospitalization. Still, participants in that trial remained suicidal after 4 weeks of buprenorphine treatment.

To potentially build on the antisuicidal effects of both buprenorphine and ketamine, a team co-led by Jason M. Tucciarone, M.D., Ph.D., and Igor D. Bandeira, M.D., Ph.D., both of Stanford University, set out to evaluate whether patients initially treated with a single intravenous ketamine dose, followed by 4 weeks of daily low-dose buprenorphine, would show greater reductions in suicidality compared with individuals receiving ketamine followed by 4 weeks of placebo treatments. The paper reporting their results appeared in the American Journal of Psychiatry.

Dr. Tucciarone is a 2025 and 2022 BBRF Young Investigator. The team’s senior members were Alan F. Schatzberg, M.D., a BBRF Scientific Council member and winner of the 2005 BBRF Falcone Prize, and Carolyn I. Rodriguez, M.D., Ph.D., a BBRF Scientific Council member and 2014 and 2009 BBRF Young Investigator.

Both, along with the late Dr. Nolan R. Williams, were instrumental in advancing the hypothesis in 2018 that opioid system activation (including mu-opioid receptor pathways) is necessary for ketamine to relieve depression. Dr. Williams, a 2018 and 2016 BBRF Young Investigator, was 2024 winner of the BBRF Colvin Prize and 2019 winner of the BBRF Klerman Prize.

In the new research, 50 people with MDD and suicidal ideation were randomized to receive one intravenous dose of ketamine (0.5 mg/kg over 40 minutes), plus 4 weeks of buprenorphine beginning 2 days after the injection or 4 weeks of placebo. Their mean age was about 37 and 68% were female. The buprenorphine (or placebo) was taken by participants daily, at home, sublingually (the drug or placebo placed under the tongue and dissolving over a period of minutes). Buprenorphine dosage was increased incrementally from 0.2mg/day to a maximum of 0.8mg/day, based on tolerance. By the end of the 4 weeks, the average dose among those receiving buprenorphine was 0.77mg/day. In the end, 23 in the ketamine + buprenorphine group and 22 in the ketamine + placebo group completed at least 1 week of follow-on treatments and were included in study results.

Importantly, 62% of participants had treatment-resistant depression, having failed to respond to at least two prior antidepressant therapies. Their mean score on the MADRS depression symptom scale was 34.1 (at the low end of the “severe” range) and their mean score on a scale called SSI that measures severity of suicidal ideation was 15 (6 is the typical threshold for “clinically significant suicidal ideation”). On average, participants had made at least one suicide attempt.

As expected, a single ketamine infusion across both groups led to significant declines in depression symptoms, and also in SSI scores for suicidal ideation. The latter declined on average from 15 to about 6, when measured 2 days after the infusion. At this point, 54% of all participants—based on ketamine alone—met the criterion for “response” (a reduction of 50% or more in suicidal ideation). MADRS depression scores also declined considerably, from about 34 to about 21 on average, 2 days after the ketamine infusion, with 38% experiencing a decline of 50% or greater.

The real distinction between the two groups emerged over the course of one month. SSI suicidal ideation scores significantly decreased in both groups: 11.6 points on average in the group that received daily buprenorphine and 6.3 points in the placebo group. Differences began to become evident at day 10 of buprenorphine/placebo treatment. At this point, even though they had experienced a significant decline in suicidal ideation, the placebo group not only stopped improving, but began to show a worsening of suicidal ideation. In contrast, the group receiving active buprenorphine not only maintained their initial improvements but continued to improve. By the 31st and final day of the trial, 78% of those who had received ketamine + buprenorphine met the “response” criterion of 50% or greater improvement in SSI score; this compared to 48% in the placebo group.

Graphs tracking their depression and suicidal ideation symptoms make the distinction easier to appreciate. In both groups, an initial ketamine infusion precipitated a rapid and steep decline in depression symptoms—a bit more for those in the buprenorphine group, but only incrementally. Then, over the course of the following month, those who received buprenorphine and those who received placebo generally maintained that initial antidepressant effect, with symptoms in the placebo group rising just a bit but still about 10 points lower on the MADRS scale relative to where they started.

This was not the pattern with respect to suicidal ideation. Those in the buprenorphine group had a somewhat larger initial decline following ketamine, and then not only maintained that lower level of symptoms but continued to register lower levels of symptoms—just under 4 on the SSI scale by day 31. Meantime, those receiving placebo following ketamine, after seeing a lowering of their score to a bit over 6, ended above 8, on average, at day 31: a significant improvement on their initial score of 15, but nearly twice the score of those in the buprenorphine group at day 31.

The team drew a number of conclusions with potential clinical significance from the trial. First, ketamine alone was responsible for an important 32% reduction in suicidal ideation 4 weeks after infusion. Second, prior data suggested ketamine’s antisuicidal effects may be partly independent of its antidepressant effects, and the current study’s results were consistent with this hypothesis.

A third point: a mild and transient worsening of both depression and suicidal ideation symptoms in the weeks following discontinuation of the combined ketamine + buprenorphine treatment “points to the need to follow patients after stopping.” Importantly, after 4 weeks of buprenorphine participants did not demonstrate symptoms of opioid withdrawal—a potential side effect. Other points: Careful screening for a history of substance use disorder would be essential prior to the initiation of buprenorphine therapy for suicidal ideation. Further research will be needed to determine the maximum duration of buprenorphine treatment that can effectively reduce suicidal ideation while minimizing risks of tolerance or dependence upon the drug. Finally, larger trials will be needed to reproduce results of the current trial as well as to help determine if buprenorphine can generate significant antidepressant effects. Long-term studies might also compare ketamine + buprenorphine with repeated ketamine infusions for patients with persistent or recurring symptoms.

The team also included: Charles DeBattista, M.D., D.M.H., 1998 BBRF Young Investigator; and Jennifer Keller, Ph.D., 2009 BBRF Young Investigator.