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REPEATED KETAMINE INFUSIONS FOR TREATMENT-RESISTANT BIPOLAR DEPRESSION: A RANDOMIZED, MIDAZOLAM-CONTROLLED CLINICAL TRIAL

Diana Orsini — Sara Di Luch1, George Tomlinson1, Gabrielle Lovell1, Shreya Vasudeva1, Nelson Rodrigues1, Danica Johnson1, Alastair Flint1, Roger McIntyre1, Rodrigo Mansur1, Keyvan Karkouti1, Amer Burhan2, Erica Kaczmarek1, Noah Chisamore1, Joshua Rosenblat1 1University of Toronto, 2Ontario Shores Centre for Mental Health Sciences Diana Orsini, University of Toronto

2026 ASCP Annual Meeting

Background

Antidepressant efficacy of intravenous (IV) ketamine has been demonstrated in major depressive disorder (MDD); however, it is not known whether an acute course of IV ketamine is also effective for bipolar depression.

Methods

We conducted a multi-site, randomized, midazolam-controlled clinical trial to assess the antidepressant efficacy, safety and tolerability of adjunctive IV ketamine compared with midazolam for treatment resistant bipolar I/II depression (TRBD). Participants were randomized to receive four flexibly dosed 40-minute infusions over two weeks of either ketamine (0.5-0.75 mg/kg) or midazolam (0.02-0.03 mg/kg). The primary outcome was change in depression symptom severity measured by the Montgomery–Åsberg Depression Rating Scale (MADRS) score from baseline to end of treatment (day 14).

Results

A total of 68 participants were randomized with 5 withdrawn (1 ketamine, 4 midazolam) before day 14. Based on the primary efficacy analysis, controlling for sex, bipolar type and baseline MADRS, the mean MADRS score at day 14 was significantly lower in the ketamine group compared to the midazolam group (between group difference = 7.3 points; 95% CI: -12.0 to -2.5; p = 0.003). No cases of mania, hypomania, psychosis or suicide attempts were observed in either group. One case of mixed features (subthreshold hypomanic symptoms) was observed in each group. After the first infusion, 47% of participants correctly guessed treatment allocation.

Conclusions

An acute course of IV ketamine was well tolerated and associated with significant antidepressant effects for TRBD. (Funded by Canadian Institute of Health Research; Registered: NCT05004896, clinicaltrials.gov)

Learning Objective 1: Describe the need for clinical trials investigating novel interventions for treatment resistant bipolar depression

Learning Objective 2: Evaluate the antidepressant efficacy, safety and tolerability of an acute course of intravenous ketamine compared with midazolam in individuals with treatment resistant bipolar depression

References

Fancy F, Haikazian S, Johnson DE, Chen-Li DCJ, Levinta A, Husain MI, Mansur RB, Rosenblat JD. Ketamine for bipolar depression: an updated systematic review. Ther Adv Psychopharmacol. 2023 Sep 26;13:20451253231202723. doi: