Efficacy and safety of esketamine for "treatment resistant depression": registered report for a systematic review with an individual patient data meta-analysis of randomized, double-blind, placebo-controlled trials.

Intranasal esketamine plus an antidepressant reduced depression scores by about 3 points on the MADRS scale after 4 weeks, a statistically significant but small improvement that falls below the 6.5-point threshold for clinical significance used in the pivotal trials. A continuation trial showed reduced relapse risk, but a monotherapy trial had a larger effect with concerns about bias. Esketamine increased risks of sedation, dissociation, and other adverse events without increasing serious adverse events. No moderation by age or treatment resistance level was found. The clinical relevance of the benefit is unclear given the adverse event risks.

Study at a glance

Abstract

In 2019, the FDA and EMA approved intranasal esketamine for treatment-resistant depression (TRD). The current study re-evaluated its efficacy and safety. This registered report presents a systematic review and individual patient data (IPD) meta-analysis of double-blind, randomised, placebo-controlled trials (RCTs) assessing intranasal esketamine for TRD. Two reviewers independently screened studies from multiple databases and obtained IPD via the Yale Open Data Access Project. Two independent researchers selected studies and assessed risk of bias. The primary outcome was the Montgomery-Åsberg Depression Rating Scale (MADRS) score at ≥ 4 weeks in initiation trials, benchmarked against the 6.5-point clinical significance threshold used in the design of pivotal trials. Evidence certainty was rated using GRADE. Secondary outcomes included additional efficacy and safety endpoints. A two-step IPD meta-analysis was conducted, with separate analyses by trial phase (initiation vs. continuation) and treatment type (combination vs. monotherapy). A one-stage meta-analysis explored moderators (e.g. age and resistance level). We re-analysed IPD from 7 RCTs including 1505 patients. In five initiation trials of esketamine plus an antidepressant, esketamine reduced MADRS scores at 4 weeks (mean difference (MD) = - 2.94, 95% CI [- 5.39 to - 0.48]; GRADE: moderate certainty). A continuation trial showed reduced relapse risk (HR = 0.38 [0.26-0.57]), though FDA concerns about one centre could not be addressed due to data privacy restrictions. A monotherapy trial (aggregate data only) showed a larger effect (MD = - 6.32 [- 8.62 to - 4.03]), but there were concerns over selection bias and unblinding. Esketamine increased sedation (RR = 3.70 [2.02-6.78]), dissociation (RR = 2.36 [2.10-2.65]), and adverse events (IRR = 3.91 [2.37-6.45]), with no increase in serious adverse events (IRR = 1.35 [0.54-3.40]). No treatment effect moderation was found by age or resistance level, with most patients displaying low-stage TRD. Based on the IPD used for approval, esketamine in combination with an antidepressant showed an advantage over placebo that was statistically significant but small. The clinical relevance of this benefit is unclear, particularly given the risks of adverse events. PROSPERO: CRD42021290721.