Registered clinical trials investigating ketamine and esketamine for treatment-resistant depression: A systematic review
Madeline Brendle, Anya Ragnhildstveit, Matthew Slayton, Leo Smart, Sarah Cunningham, Mackenzie H. Zimmerman, Paul Seli, Michael S. Gaffrey, Lynnette A. Averill, Reid Robison
Journal of Psychedelic Studies January 16, 2023 DOI: 10.1556/2054.2022.00234 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Qualitative Peer reviewed |
|---|---|
| Sample size | 56 |
| Population | Registered clinical trials on ketamine or esketamine for treatment-resistant depression |
| Interventions | Ketamine Esketamine |
| Topics | Depression Esketamine Ketamine |
| Citations | 7 |
| Key findings | Trials of ketamine and esketamine for treatment-resistant depression have increased since 2008, with a shift toward larger, later-phase esketamine trials, but many studies do not assess patient characteristics such as age, sex, and race. |
Abstract
Ketamine and esketamine have garnered interest in both psychiatric research and clinical practice for treatment-resistant depression (TRD). In this review, we examined registered trials investigating the therapeutic use of ketamine or esketamine for TRD, with the aim of characterizing emerging trends and knowledge gaps.The ClinicalTrials.gov electronic registry and results database was queried from inception to February 5, 2022, adhering to elements of the PRISMA guideline, we evaluated trial eligibility in the qualitative synthesis. Data regarding study design, drug regimens, and measures were subsequently abstracted and descriptively analyzed.The search returned 86 records, of which 56 trials were included in the final review. The number of trials investigating ketamine and esketamine for TRD increased since 2008, with higher peaks observed in 2015 (n = 9) and 2021 (n = 9). Most trials were Phase 2 (13, 23.2%) or Phase 3 (11, 19.6%), gathering preliminary data on efficacy and/or further data on safety and efficacy with variant dosing and pharmacological approaches. By and large, trials examined ketamine and esketamine as individual versus combination treatments (45% and 25%, respectively). The Montgomery-Asberg Depression Rating Scale (MADRS) was most commonly used to assess clinical outcomes (75%).There are increasingly large-scale and late-phase trials of esketamine over ketamine for TRD, coupled with efforts to centralize evidence on these medications. Yet several trials do not assess patient characteristics that may affect treatment response, such as age, sex, and race. By understanding these design limitations, scientists and clinicians can avoid research waste and funding bodies can judiciously direct support towards high priority research.
Comparable studies
Other systematic reviews and meta-analyses on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Adults with unipolar or bipolar major depression | 2020 | Systematic review and meta-analysis | n = 1,877 |
| The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. Participants in randomized controlled trials of ketamine for suicidal ideation | 2020 | Systematic review and meta-analysis | n = 197 |
| Efficacy of Esketamine Augmentation in Major Depressive Disorder Patients with major depressive disorder who are treatment-resistant or acutely suicidal | 2020 | Systematic review and meta-analysis | n = 774 |
| Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. Patients with treatment-resistant major depressive disorder | 2025 | Systematic review and meta-analysis | |
| EFFICACY AND SAFETY OF RACEMIC KETAMINE AND ESKETAMINE FOR DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS Adults with unipolar or bipolar major depression | 2022 | Systematic review and meta-analysis | n = 2,903 |