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In this real-world cohort, 15 of 38 patients (39%) achieved clinical response and 5 of 38 (13.2%) achieved remission after an acute series of ketamine or esketamine for bipolar depression. Mean MADRS scores decreased from 31.1 to 19.2, which was a 38.3% reduction in depressive symptom severity (coefficient = −5.93 per 4 treatments; 95% CI, −7.97 to −3.89; P<.001). Mean QIDS scores decreased from 17.8 to 10.7, a 40.0% reduction (95% CI, −4.90 to −2.28; P<.001).

No. No patients experienced mania or hypomania during the initial acute series phase, when treatments were given twice weekly for up to 8 treatments. In this study, affective switch was observed only later during continuation or maintenance treatment, not during the acute induction phase.

During follow-up, 13 of 45 patients (28.9%) experienced symptoms consistent with a hypomanic or manic episode, with 16 total episodes observed across 518 patient-months of follow-up (43.1 patient-years). This corresponded to 1 hypomanic or manic event per 2.7 patient-years. The mean time from first ketamine or esketamine treatment to the initial event was 297 days (SD 261), and the median time was 266 days (range 51–995 days).

Most episodes were not severe. Of the 16 manic or hypomanic events, 15 were mild or moderate: 8 were mild hypomania that resolved without intervention, and 7 were moderate hypomania that resolved with medication adjustment. One patient with preexisting bipolar disorder developed severe mania that led to psychiatric hospitalization.

Not completely. Of the 16 manic or hypomanic events, 14 events (87.5%) occurred while the patient was taking a mood stabilizer, antipsychotic, or lithium. During the acute series overall, 40 of 45 patients (88.9%) were on an antipsychotic, lithium, or a mood stabilizer/anticonvulsant.

IV ketamine was administered at 0.5 mg/kg over 40 minutes, with dose adjustment by ideal body weight for patients with body mass index 30 or higher. Intranasal esketamine was given at 56 mg or 84 mg. The acute treatment protocol generally involved twice-weekly treatment for up to 4 weeks, and patients with meaningful improvement could continue weekly for another 4 weeks before tapering to less frequent maintenance treatment, usually every 2 to 4 weeks.

They were usually used alongside other psychiatric medications rather than as monotherapy. During the acute series, 40 of 45 patients (88.9%) were taking an antipsychotic, lithium, or a mood stabilizer/anticonvulsant, and 23 of 45 (51.1%) were also taking an antidepressant. Lamotrigine was the most common mood stabilizer (19/45, 42%), and bupropion was the most common antidepressant (9/45, 20%).

The response and remission rates in this cohort were lower than those reported in prior randomized ketamine trials in bipolar depression. In this study, response and remission after the acute series were 39% and 13.2%, whereas two earlier randomized trials reported response rates of 44% and 43% and remission rates of 31% and 29% after a single infusion measured at 24 hours. The authors noted that their sample was drawn from real-world clinical practice, had greater heterogeneity and comorbidity, and used outcomes after an acute series rather than after a single infusion.

The main limitations were the small sample size, limited racial and ethnic diversity, retrospective assessment of manic or hypomanic symptoms through manual electronic medical record review, and lack of tightly controlled treatment schedules or concomitant medication management. Because treatment was naturalistic and nonrandomized, the study did not formally compare ketamine with esketamine. The authors also noted that some hypomanic events may have been missed if they did not come to medical attention.