In the first randomized controlled trial of serial ketamine infusions for treatment-resistant bipolar depression, adjunctive ketamine significantly reduced depressive symptoms compared with midazolam.

Results showed that, on day 14, Montgomery-Åsberg Depression Rating Scale (MADRS) scores were 7.3 points lower with ketamine than with midazolam, exceeding the prespecified 3.6-point threshold for clinical significance, with no cases of treatment-emergent mania, hypomania, or psychosis.

Based on the data, off-label serial intravenous (IV) ketamine infusions are “reasonable to consider clinically for carefully selected patients with treatment-resistant bipolar depression,” senior author Joshua Rosenblat, MD, psychiatrist at UHN Krembil Brain Institute and associate professor, Department of Psychiatry, University of Toronto, both in Ontario, Canada, told Medscape Medical News.

“While more research is still needed, the present level of evidence is sufficient to support off-label clinical use in this population,” Rosenblat said.

The study was published online on September 2 in JAMA Psychiatry.

Clinically Meaningful Improvement

IV ketamine has shown antidepressant efficacy in major depressive disorder, but evidence in bipolar depression remains limited, in part because concerns about triggering mania or psychosis have led to the exclusion of many patients with bipolar disorder from prior studies.

The Ket-BD trial enrolled 68 patients (mean age, 44 years; 56% women) with bipolar I or II disorder and a current moderate-to-severe major depressive episode who had failed at least two evidence-based pharmacologic treatments.

All participants were on stable doses of at least one mood stabilizer or antipsychotic. They were highly treatment resistant, having tried an average of about 11 medications over their lifetime and six during the current depressive episode; 25% had received electroconvulsive therapy, and 31% transcranial magnetic stimulation. The mean MADRS score at baseline was 32.6.

They were randomly assigned to four 40-minute IV infusions over 2 weeks of either ketamine, starting at 0.5 mg/kg with the option to increase to 0.75 mg/kg, or the psychoactive control midazolam, starting at 0.02 mg/kg with the option to increase to 0.03 mg/kg.

The primary outcome was the change from baseline to day 14 on the MADRS, with a 3.6-point between-group difference prespecified as the minimum clinically important difference.

The primary efficacy analysis included 63 participants. After adjusting for sex, bipolar type, and baseline depression severity, the mean MADRS score at day 14 was 7.3 points lower in the ketamine group than in the midazolam group (P = .003), corresponding to a moderate-to-large effect size (Cohen d = 0.7).

At the end of treatment, 35% of patients in the ketamine group achieved a response, defined as at least a 50% reduction in MADRS score compared with 12% in the midazolam group. Remission rates were 17.6% and 8.8%, respectively. The diagnosis of bipolar I vs bipolar II was not significantly associated with treatment response.

The antidepressant advantage persisted for 1 week after the final infusion, which was given on day 12, although symptoms subsequently began to return.

Manic symptoms remained low in both groups throughout the trial, and no cases of mania, hypomania, psychosis, or suicide attempts were observed. One participant in each treatment group developed mixed features characterized by subthreshold hypomanic symptoms.

Adverse events occurred primarily on infusion days. Ketamine produced more dissociation during infusions. After the first infusion, 47% of participants correctly guessed their treatment assignment. By the end of treatment, 66% guessed correctly.

Rosenblat said the key next steps are a larger phase 3 trial and studies of maintenance treatment beyond the acute course.

“These two next steps would help to more definitively determine if ketamine is efficacious for treatment-resistant bipolar depression and if booster doses are an efficacious or safe approach to relapse prevention,” he said.

Important Signal of Benefit

The trial adds important randomized evidence supporting ketamine for bipolar depression, said John Krystal, MD, chair of psychiatry at Yale School of Medicine in New Haven, Connecticut, and a pioneer in the development of ketamine as an antidepressant.

Krystal, who was not involved in the study, told Medscape Medical News that despite the trial’s relatively small size, the 7.3-point reduction in depression severity was large and clinically meaningful.

Still, he noted that response and remission rates were lower than those typically reported with ketamine in treatment-resistant major depression, though it remains unclear whether the difference reflects bipolar disorder itself or the effects of concomitant medications.

“Half of the patients in this study were on benzodiazepines, and these drugs have been reported to reduce ketamine efficacy. Many patients were also on mood-stabilizing medications, including lithium, valproate, and lamotrigine. While these medications have not been shown to impair ketamine response, it has been a concern,” Krystal said.

He also cautioned against drawing firm conclusions about safety from the absence of mania or psychosis. “With only 34 patients per group, this study would not be sufficient to indicate the safety of ketamine for patients with bipolar disorder. Further, the risk of mania was probably mitigated by co-treatment with mood-stabilizing medications,” Krystal said.

He added that, in his experience, ketamine-associated mania occurs in fewer than 3% of patients.

For patients whose depressive symptoms have not responded to standard treatments and whose manic symptoms are controlled with mood stabilizers, ketamine or esketamine “may offer a path toward better control of depression symptoms,” Krystal said. He emphasized, however, the need for close monitoring for emerging mania.

The study was generally methodologically sound and suggests that some patients with bipolar disorder may respond to ketamine, said Steve Strakowski, MD, professor of psychiatry at Indiana University School of Medicine in Indianapolis, who was not involved in the study.

He cautioned, however, that interpreting the findings is “complicated by combining bipolar I and II disorder, as they are really not the same.” He also noted that the antidepressant effect of ketamine was already waning within days of the final infusion.

“My overall impression: promising early study, needs replication and distinguishing by bipolar disorder type to move the field forward,” he said.

The study was funded by the Canadian Institutes of Health Research. Disclosures for the authors are available with the original study publication. Krystal disclosed involvement in Yale-held patents for Spravato development, co-founding Freedom Biosciences, and consulting for several companies developing antidepressants. Strakowski disclosed financial relationships with MapLight and research grants from Janssen Pharmaceuticals, Eli Lilly and Company, and Abbott Laboratories.