Background In 2019, the FDA and EMA approved intranasal esketamine for treatment resistant depression (TRD). The current study re–evaluated its efficacy and safety. Methods 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–Asberg Depression Rating Scale (MADRS) score at less than or equal 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). Results We re–analysed IPD from 7 RCTs including 1,505 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. Conclusions 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. Funding French Programme Hospitalier de Recherche Clinique (PHRC). Registration PROSPERO: CRD42021290721
Naudet et al. (Thu,) studied this question.