Ketamine works in treatment-resistant bipolar depression without triggering mania

The edition in brief

Ketamine's antidepressant effect is established in major depressive disorder and has been avoided in bipolar depression on the assumption that it would precipitate mania. Ket-BD tested that. This double-blind midazolam-controlled trial at three Ontario sites randomised 68 outpatients aged 21 to 65 with bipolar I or II disorder, a current moderate-to-severe depressive episode (MADRS 21 or above) and at least two failed pharmacotherapy trials, to four flexibly dosed 40-minute infusions of ketamine 0.5 to 0.75 mg/kg or midazolam 0.02 to 0.03 mg/kg over two weeks, on top of a stable mood stabiliser or antipsychotic. At day 14 the adjusted between-group MADRS difference was -7.3 points (95% CI -12.0 to -2.5, p=0.003, Cohen's d 0.7). No mania, hypomania, psychosis or suicide attempt occurred in either group; one case of subthreshold mixed features occurred in each. A network meta-analysis of 95 trials and 5,898 patients ranked pharmacological options for antipsychotic-induced weight gain: semaglutide -10.98 kg (95% CI -13.33 to -8.62), liraglutide -5.43 kg, topiramate -3.95 kg, metformin -3.86 kg and exenatide -2.97 kg, all at moderate certainty. Only semaglutide and metformin achieved clinically meaningful weight change of 5% or more. An individual participant data meta-analysis of five paliperidone discontinuation trials found rapid relapse was not over-represented after discontinuation, arguing against a pharmacological withdrawal effect; baseline symptom severity predicted rapid relapse instead. A pragmatic SMART trial in 316 anxious youths found fluoxetine, CBT and their combination produced similar symptom reduction.