A systematic review and meta-analysis of 24 randomized controlled trials with 1,877 participants compared racemic ketamine and esketamine for unipolar and bipolar major depression. Racemic ketamine showed greater treatment response (rate ratio 3.01 versus 1.38) and remission rates (rate ratio 3.70 versus 1.47) than esketamine, and had lower dropout rates (rate ratio 0.76 versus 1.37). Intravenous ketamine appears more efficacious than intranasal esketamine for depression.
Ketamine appears to help treat bipolar depression, though evidence is preliminary. A systematic review of six studies involving 135 adults (53% female, average age 44.7 years) found that 61% of those receiving intravenous racemic ketamine (0.5 mg/kg, added to a mood stabilizer) achieved at least a 50% reduction in depression severity, compared to 5% receiving placebo. Response rates across studies ranged from 52% to 80%. Ketamine was reasonably well tolerated, but two participants developed manic symptoms (one on ketamine, one on placebo), and some experienced significant dissociative symptoms 40 minutes after infusion in two trials. Longer-term outcomes and alternative formulations need further study.
A multi-centre trial across four Canadian institutions will compare intravenous ketamine infusions with electroconvulsive therapy (ECT) for treating major depressive episodes in 240 patients with major depressive or bipolar disorder. Patients are randomized to either ECT or ketamine three times per week for three to four weeks; non-responders cross over to the other treatment. Responders enter a six-month maintenance phase. The primary outcome is change in depression severity scores assessed by blinded raters. The study aims to identify clinical, molecular, and imaging predictors of response to each treatment.
Ketamine's rapid antidepressant effects in major depressive disorder and bipolar disorder, including treatment-resistant depression, may stem from restoring deficits in neuroplasticity. A literature search of 139 publications—from cell cultures, animal models, and patients—found accumulating evidence that ketamine increases molecules involved in neuroplasticity, paired with rapid mood improvements. Key molecules include glutamate, AMPA receptors, mTOR, BDNF/TrkB, VGF, eEF2K, p70S6K, GSK-3, IGF2, Erk, and microRNAs. The studies suggest a robust relationship between mood improvements and ketamine-induced increases in molecular neuroplasticity, especially intracellular signaling molecules.