Efficacy and safety of ketamine maintenance therapy in treatment-resistant depression: A systematic review of treatment protocols and clinical outcomes.
A. M. Al-Garni, Gustavo Vazquez, Tariq Alotibi, Carolina Hernandorena, Yuliya Knyahnytska
Journal of Affective Disorders October 1, 2025 DOI: 10.1016/j.jad.2025.120475 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Randomized Peer reviewed |
|---|---|
| Population | Patients with treatment-resistant depression |
| Interventions | Ketamine maintenance therapy psychotherapy |
| Topics | Depression Esketamine Ketamine |
| Key findings | Across 11 studies, ketamine maintenance therapy for treatment-resistant depression was associated with lower relapse rates with regular dosing than variable protocols (27.3% vs 45.6%), better response among patients under 45 and those with depression duration under 2 years, and improved maintenance with concurrent psychotherapy (hazard ratio 0.72 for relapse). Adverse events were generally mild to moderate, with a 7.2% discontinuation rate. |
Abstract
Introduction: Treatment-resistant depression (TRD) represents a significant therapeutic challenge, as conventional treatments demonstrate limited efficacy. Although ketamine's acute antidepressant effects are well-documented, the role of maintenance therapy remains understudied. We conducted a systematic review to assess the efficacy, safety, and optimal implementation strategies of ketamine maintenance therapy in TRD.
Methods: Following PRISMA guidelines, we searched major databases for studies published between January 2020 and November 2024 that examined ketamine maintenance therapy in TRD. Studies were assessed using the Cochrane Risk of Bias 2 tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies.
Results: Eleven studies met inclusion criteria. Regular maintenance dosing showed superior outcomes compared to variable protocols (relapse rates: 27.3 % vs 45.6 %). Younger age (<45 years) and shorter duration of depression (<2 years) predicted better response rates. Concurrent psychotherapy improved treatment maintenance (HR: 0.72 for relapse). Adverse events were generally mild to moderate, resulting in a 7.2 % discontinuation rate.
Conclusions: Ketamine maintenance therapy shows promise as a treatment option for TRD, with regular dosing schedules and early intervention associated with optimal outcomes. While safety profiles are reassuring, standardized protocols and careful patient selection remain essential. Future research should focus on determining the optimal maintenance duration and identifying reliable biomarkers for treatment response.
Comparable studies
Other systematic reviews and meta-analyses on ketamine for depression, most cited first.