Ketamine for Treatment-Resistant Depression

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Design and Participants: This multicenter trial evaluated oral extended-release ketamine in an enriched patient population with TRD. Adults with TRD and Montgomery-Asberg Depression Rating Scale (MADRS) scores of 20 or more received open-label R-107 tablets 120 mg/day for 5 days and were assessed on day 8 (enrichment phase). On day 8, responders (MADRS≤12 and reduction ≥50%) were randomized 1:1:1:1:1 to receive double-blind 30, 60, 120, or 180 mg, or placebo, twice per week for an additional 12 weeks. Nonresponders on day 8 exited. The primary endpoint was least-square mean MADRS change for each treatment vs placebo at 13 weeks, starting with 180 mg, using a fixed sequence step-down closed-test procedure. Fisher’s test, ANOVA, and ANCOVA were used.

Results: Enriched responders (N=168) were aged mean 45 years (SD=14), and 55% were male. The least-square mean score difference for 180 mg and placebo was −6.1 (95% CI=1.0-11) at 13 weeks. Compared to placebo, greater reductions in day 92 scores were for females (−10 [−19-−1.5]) vs males (−4.2 [−11-2.4]); patients 65 years and older (−6.9 [−12-−1.6]) vs younger than 65 years (0.1 [−23-24]); those taking antidepressants (−6.5 [−13-−0.6]) vs not taking (−2.5 [−13-7.7]); and those with greater than median body weight (−7.1 [−14-−0.1]) vs below median (−5.3 [−13-2.5]). Relapse rates showed a dose response from 71% for placebo to 43% for 180 mg. Tolerability was excellent, with no blood pressure changes and minimal sedation or dissociation. The most common adverse events were headache, dizziness, and anxiety.

Commentary: Treatment-resistant depression is defined as depression that has not responded to at least two adequate trials of antidepressants. In patients with serious illness, TRD can negatively affect quality of life and increase suffering. There has been increasing interest in alternative agents such as ketamine and psilocybin, which have much more rapid antidepressant effects compared with traditional antidepressants, which would be invaluable to patients with a short prognosis. This study shows efficacy of an oral extended-release ketamine pill, with fewer side effects compared to injected or intranasal formulations. Oral ketamine can be administered at home—a significant advantage in seriously ill patient populations. However, as this particular study design eliminated nonresponders before the randomization phase, it likely overestimates population treatment response, and more research is needed.

Bottom Line: Oral extended release ketamine shows promise as a therapy for TRD, however more studies are needed to confirm efficacy in patients with TRD who also have a serious illness.

Reviewer: Mei-Ean Yeow, BMBCh FACP FAAHPM, Mayo Clinic, Rochester, MN

References:

1. Nikolin S, Rodgers A, Schwaab A, et al. Ketamine for the treatment of major depression: a systematic review and meta-analysis. EClinicalMedicine. 2023;62, 102127.

2. Kim J, Farchione T, Potter A, Chen Q, Temple R. Esketamine for treatment-resistant depression—first FDA-approved antidepressant in a new class. N Engl J Med. 2019;38(1):1-4.

Source: Glue P, Loo C, Fam J, et al. Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial. Nat Med. 2024;30(7):2004-2009. doi:10.1038/s41591-024-03063-x.

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