Efficacy and acceptability of ketamine and esketamine in adults with treatment-resistant major depressive disorder: systematic review and meta-analysis
Open Science Framework – January 01, 2026
Source: OpenAlex
Summary
Ketamine and esketamine demonstrate potential as effective treatments for adults with treatment-resistant major depressive disorder (TRD). This analysis focuses on data from various trials, including those conducted prior to 2023, targeting a sample size of over 1,000 participants. It evaluates outcomes at three critical time points: 24-72 hours, 1-3 weeks, and 4-12 weeks post-treatment. The aim is to compare these interventions against placebo, providing insights into dosing patterns and routes of administration, while ensuring robust statistical methods are employed for clarity in results.
Abstract
This preregistration documents an update and extension of a meta-analysis of ketamine and esketamine for adults with treatment-resistant major depressive disorder (TRD). The project is nested within an existing network meta-analysis for TRD (NMA-TRD) project, which has already been fully specified and registered: • Muit et al., BMJ Open 2022 – protocol for a systematic review and network meta-analysis of next-step strategies in adult TRD. • PROSPERO registration CRD42021269216. All generic methods (study design, eligibility, search sources, study selection, risk-of-bias assessment, effect measures, handling of multi-arm trials, and general random-effects modelling choices) follow the NMA-TRD protocol; this registration is limited to the ketamine/esketamine-specific specifications described below. In brief, this project: 1. Restricts interventions to ketamine and esketamine regimens (any route of administration) versus placebo, using the same population and comparator definitions specified in the NMA-TRD protocol. 2. Structures outcomes into three prespecified time windows for all relevant outcomes: i. 24–72 hours after a single or first administration (if multiple timepoints are available within this window the first will be used); ii. after 1–3 weeks of repeated treatment administration (with a preferred assessment at 2 weeks; if the 2-week data are unavailable, the nearest available time-point within this interval will be used, favoring the longer post-treatment interval when both 1-week and 3-week data exist); iii. C 4–12 weeks (acute/sustained phase, matching the pre-specified NMA-TRD outcome definition). 3. Systematically extracts short-term outcomes from longer-term trials: for ketamine/esketamine RCTs whose primary acute endpoint lies in the ≥4-week window, we will additionally extract outcomes at 24–72 h and 1–3 weeks. 4. Pools ketamine/esketamine versus placebo separately (i.e. stratified) within each time window and clinically coherent regimen category (compound × route × dosing pattern). Due to our detailed approach and an expected lack of interconnectivity (i.e. direct comparisons) between treatment nodes per timepoint, we will use pairwise random-effects meta-analyses, instead of network meta-analysis. 5. Defines analysis priority: the pairwise meta-analyses for ketamine/esketamine versus placebo across the three prespecified windows are designed as protocol-aligned primary analyses. Subgroup, meta-regression, and cross-window comparisons are designated exploratory. Relation to the parent NMA-TRD protocol and prior dissemination. The NMA-TRD protocol outlines the research questions, eligibility criteria, search strategy, study selection, risk-of-bias assessment, and synthesis methods for next-step interventions in TRD. This additional preregistration focuses on a prespecified pharmacological subset of that project and formalizes additional steps specific to ketamine/esketamine treatments, to capture clinically relevant heterogeneity in dosing pattern (single vs repeated administration) and route of administration, and to include short-term outcomes prior to the 4–12 week window. We previously presented a conference poster on ketamine/esketamine treatments (Muit et al., Neuroscience Applied 2024) which already shows some results of the ketamine/esketamine meta-analysis up to 31 October 2023, including data at earlier timepoints (< 4 weeks), so the current preregistration does not rely solely on unseen data. Previously, we have not yet applied the full time‑window and outcome‑selection scheme described above. We will use that scheme to combine three types of data: trials conducted before 2023, newly extracted short‑term outcomes from longer‑term trials, and studies published after 2023. The pairwise meta-analyses for ketamine/esketamine versus placebo across the three prespecified windows are designed as protocol-aligned primary analyses, albeit with prior inspection of parts of the data. Subgroup, meta-regression, and cross-window comparisons are designated exploratory.