Clinical Summary: Efficacy and Safety of Ketamine/Esketamine in Bipolar Depression in a Clinical Setting
Patients with bipolar disorder spend far more time depressed than manic, yet bipolar depression remains difficult to treat and antidepressants carry both limited efficacy and concern for affective switch. This report addresses a practical question many clinicians face in refractory bipolar depression: whether ketamine or esketamine can improve depressive symptoms in routine care without triggering early mania.
Key Findings
- Among 38 patients with efficacy data who completed an acute series, 15/38 (39%) achieved clinical response (≥50% improvement on MADRS) and 5/38 (13.2%) achieved remission (≤10 on MADRS).
- For the whole group, mean MADRS scores decreased from 31.1 to 19.2 (coefficient=−5.93 per 4 treatments, 95% CI, −7.97 to −3.89, P<.001), a mean reduction in symptom severity of 38.3%.
- Mean QIDS scores decreased from 17.8 to 10.7 (coefficient=−3.59 per treatment, 95% CI, −4.90 to −2.28, P < .001), a mean reduction of 40.0%.
- No patients experienced any mania or hypomania during the initial acute series phase, but 13/45 (28.9%) patients experienced symptoms consistent with a hypomanic or manic episode during maintenance treatment, with 16 total episodes across 518 total patient-months of follow-up (43.1 patient-years), equivalent to 1 event per every 2.7 patient-years.
- The mean time between the first treatment of ketamine/esketamine and the initial hypomanic/manic event was 297 days (SD 261), the median time was 266 days (range 51–995 days), and 15/16 episodes were mild or moderate while 1 episode led to psychiatric hospitalization.
Ketamine and esketamine produced meaningful acute antidepressant improvement in a real-world treatment-resistant bipolar depression cohort, with no observed mania or hypomania during the acute twice-weekly treatment phase. The main clinical safety signal was delayed hypomanic/manic symptoms during maintenance treatment, which were usually manageable but require ongoing monitoring.
Practice Implications
- Consider ketamine or esketamine for refractory bipolar depression when standard options have failed, while setting expectations that acute-series outcomes in routine care were 39% response and 13.2% remission rather than the higher rates reported in small controlled trials.
- Monitor for affective switch beyond induction, not just during the first 2–4 weeks, because no manic/hypomanic episodes occurred during the acute series but events emerged later with a mean onset of 297 days and median onset of 266 days.
- Do not assume concurrent mood-stabilizing treatment eliminates switching risk: 14 (87.5%) of 16 manic/hypomanic episodes occurred while patients were on a mood stabilizer, antipsychotic, or lithium.
- Discuss maintenance-phase surveillance with patients and families, including sleep reduction, racing thoughts, increased energy, and goal-directed activity, since 8/16 episodes resolved without intervention, 7 required medication adjustment, and 1 required hospitalization.
