Adjunctive Ketamine Reduced Symptoms in Small Trial of Treatment-Resistant Bipolar Depression

The investigator-led Ket-BD trial evaluated adjunctive intravenous ketamine in adults with treatment-resistant bipolar I or II depression at three Ontario sites. Investigators randomized 68 outpatients aged 21–65 years with moderate to severe depression and at least two failed pharmacotherapy trials. Participants received four 40-minute infusions over two weeks of ketamine (0.5–0.75 mg/kg) or midazolam (0.02–0.03 mg/kg), alongside stable treatment with at least one mood stabilizer or antipsychotic. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score through day 14.

The final efficacy analysis included 63 participants after five withdrew before the primary endpoint: one receiving ketamine and four receiving midazolam. Adjusted day-14 MADRS scores were lower with ketamine, with a between-group difference of −7.3 points (95% CI, −12.0 to −2.5; P=.003; Cohen d=0.7). Neither group had observed mania, hypomania, psychosis, or suicide attempts. One participant in each group developed mixed features involving subthreshold hypomanic symptoms. After the first infusion, 31 of 66 participants (47%) correctly guessed treatment allocation.

These findings support a short-term antidepressant effect of adjunctive ketamine in this population. However, the small sample, withdrawals, and two-week primary endpoint limit conclusions about durability and uncommon adverse events, including mood switching. This report is based on the abstract; full text was unavailable.