Serial ketamine infusions for treatment-resistant bipolar depression may offer a faster therapeutic option for patients who have not improved with established medications. A new randomized clinical trial provides controlled evidence that four intravenous infusions can reduce depressive symptoms when added to ongoing mood-stabilizing treatment.
Bipolar Depression Remains A Difficult Treatment Target
Depressive episodes often account for much of the disability associated with bipolar disorder. Yet treatment choices can be complicated because conventional antidepressants may provide limited benefit and can raise concerns about mood destabilization in some patients.
Individuals are considered treatment resistant when depressive symptoms persist despite adequate trials of evidence-based therapies. For these patients, clinicians must balance the need for symptom relief against the possibility of triggering hypomania, mania, mixed symptoms, or psychosis.
Ketamine has demonstrated rapid antidepressant activity in major depressive disorder, but bipolar depression has remained comparatively understudied. Much of the previous evidence came from small studies, single infusions, or trials with limited control conditions.
Testing Serial Ketamine Infusions For Treatment-Resistant Bipolar Depression
The Ket-BD trial evaluated adults with bipolar I or bipolar II disorder who were experiencing a moderate to severe depressive episode. All participants had failed at least two evidence-based medication trials.
Researchers enrolled 68 outpatients across three clinical sites in Ontario, Canada. Participants were randomly assigned to receive four 40-minute infusions of either ketamine or midazolam over two weeks.
Ketamine doses ranged from 0.5 to 0.75 mg/kg, while midazolam served as an active comparison treatment. Participants continued a stable dose of at least one mood stabilizer or antipsychotic throughout the trial.
An Active Control Strengthened The Comparison
Using midazolam rather than saline helped address one of the challenges in ketamine research. Ketamine can produce noticeable short-term perceptual or dissociative effects, making it easier for participants to guess their treatment assignment.
Midazolam can also produce noticeable sensations, offering a more credible comparison. Even so, 47% of participants correctly identified their assignment after the first infusion, meaning blinding may not have been complete.
The primary outcome was the change in Montgomery-Åsberg Depression Rating Scale scores from baseline through day 14. Researchers also monitored participants closely for treatment-emergent mania, hypomania, mixed features, psychosis, and suicidal behavior.
Depressive Symptoms Declined Over Two Weeks
After accounting for sex, bipolar subtype, and baseline depression severity, participants receiving ketamine had significantly lower depression scores at day 14 than those receiving midazolam.
The adjusted difference between groups was 7.3 points on the depression scale, favoring ketamine. The reported effect size was moderate to large, suggesting that the difference was clinically meaningful rather than only statistically detectable.
Five participants withdrew before the primary endpoint, including one from the ketamine group and four from the midazolam group. The final efficacy analysis included 63 participants.
Mood Switching Was Not Observed During Treatment
No cases of mania, hypomania, psychosis, or suicide attempts occurred in either group during the trial. One participant in each group developed mixed features involving subthreshold hypomanic symptoms.
These findings offer encouraging short-term safety information, particularly because mood switching is a central concern when treating bipolar depression. However, the sample was too small and the observation period too brief to rule out uncommon or delayed adverse outcomes.
Ketamine May Engage Rapid Plasticity Pathways
Ketamine affects glutamate signaling through pathways involving NMDA and AMPA receptors. Researchers have proposed that these effects support synaptic plasticity and help neural networks adapt more rapidly than they typically do with conventional antidepressants.
The precise mechanism remains unsettled. NMDA receptor inhibition, downstream AMPA activity, brain-derived neurotrophic factor signaling, and changes in synaptic protein production may all contribute. Most detailed mechanistic evidence still comes from preclinical research or studies of major depressive disorder.
Repeated Dosing Sets This Trial Apart
The study examined a clinically recognizable series of infusions rather than a single administration. It also included both bipolar I and bipolar II depression, required continued mood-stabilizing treatment, and used an active control.
Still, the trial does not establish how long the antidepressant effect lasts, whether maintenance infusions are beneficial, or which patients are most likely to respond. Broader studies will also be needed to assess longer-term safety, cognitive outcomes, and practical treatment schedules.
A Stronger Foundation For Bipolar Ketamine Research
Serial ketamine infusions for treatment-resistant bipolar depression are not yet a universal solution. The treatment requires medical supervision, careful diagnostic assessment, and ongoing monitoring for cardiovascular, dissociative, and mood-related effects.
The findings nevertheless strengthen the case for larger and longer trials. For patients with persistent bipolar depression, this controlled study moves ketamine closer to an evidence-based adjunctive option while keeping the need for cautious implementation firmly in view.
Citations
Orsini DK, Di Luch S, Tomlinson G, et al. “Serial Ketamine Infusions for Treatment-Resistant Bipolar Depression: A Randomized Clinical Trial.” JAMA Psychiatry. Published September 2, 2026.
Workman ER, Niere F, Raab-Graham KF. “Ketamine and Rapid Antidepressant Action: New Treatments and Novel Synaptic Signaling Mechanisms.” Neuropsychopharmacology. 2023.
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