This double-blind RCT (Ket-BD) evaluated adjunctive IV ketamine (0.5–0.75 mg/kg, 4 infusions over 2 weeks) vs. midazolam (active control) in 68 adult outpatients aged 21–65 with treatment-resistant bipolar I or II depression (TRBD), all on a stable mood stabilizer or antipsychotic, across 3 sites in Ontario, Canada.
Ketamine produced a significantly greater reduction in MADRS score at day 14 vs. midazolam (between-group difference = −7.3 points; 95% CI, −12.0 to −2.5; P = .003; Cohen d = 0.7). No mania, hypomania, psychosis, or suicide attempts occurred in either group; 1 case of mixed features was seen per arm.
- Small sample (n=68 randomized, 63 analyzed), limiting generalizability. - Blinding was partially compromised: 47% of participants correctly guessed treatment allocation after the first infusion. - Short follow-up (14 days) leaves durability of antidepressant effect unknown.
For patients with bipolar I or II depression who have failed ≥2 evidence-based pharmacotherapies, adjunctive IV ketamine (on a mood stabilizer backbone) showed a clinically meaningful antidepressant effect with no treatment-emergent mania or psychosis in this trial. Clinicians should note the small sample size and brief observation window before broad adoption.
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