Serial Ketamine Infusions Ease Treatment-Resistant Bipolar Depression, Trial Finds

People with treatment-resistant bipolar disorder often have few good options: existing treatments can take weeks to work or fail to bring full relief, pushing researchers to search for faster alternatives.

A study published in the journal JAMA Psychiatry, led by Dr. Joshua Rosenblat at the University Health Network in Toronto, reports that serial ketamine infusions can safely and effectively reduce severe depression symptoms in people with treatment-resistant bipolar disorder. Ketamine is a fast-acting anesthetic that has separately shown antidepressant effects, but doctors have long worried it could trigger mania or psychosis in bipolar patients, so the researchers designed a carefully controlled trial to test this directly.

The double-blind study enrolled 68 adults with treatment-resistant bipolar I or II depression. Over two weeks, participants received four infusions of either low-dose ketamine or midazolam, a sedative used as the comparison, while continuing their usual mood stabilizers or antipsychotics. Depression scores, measured on the Montgomery-Åsberg Depression Rating Scale (MADRS), fell more in the ketamine group; by day 14 the gap was statistically significant, with ketamine scores averaging 7.3 points lower than midazolam scores. About 35% of ketamine participants saw symptoms cut by at least half, versus 11.8% on midazolam. The difference stayed significant for a week after the last infusion, though symptoms gradually returned once treatment stopped.

No participant developed mania, hypomania or psychosis during the trial, and there were no suicide attempts. One participant in each group developed "mixed features" — some hypomanic symptoms without meeting full criteria for hypomania.

The study, "Serial Ketamine Infusions for Treatment-Resistant Bipolar Depression" by Diana K. Orsini and colleagues, was small and tracked outcomes for only two weeks plus a brief follow-up, so there is no data yet on whether repeated ketamine use is safe or effective over longer periods for this condition.