A meta-analysis of trial data suggests intranasal esketamine plus an antidepressant offers a statistically significant but small benefit in while increasing side effects.
Evidence
This systematic review and individual patient data meta-analysis re-analyzed 7 randomized, double-blind, placebo-controlled trials in 1505 patients with treatment-resistant depression, separating initiation, continuation, and monotherapy studies.
Caveat
The main efficacy signal in combination trials was below the pivotal trials' clinical-significance threshold, and adverse events increased while some evidence was limited by unaddressed center concerns and monotherapy bias risks.
Simplified
BACKGROUND: In 2019, the FDA and EMA approved intranasal esketamine for (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-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).
RESULTS: 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.
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.
STUDY REGISTRATION: PROSPERO: CRD42021290721.
Key numbers
0.38
for Relapse
Efficacy observed in continuation trials for esketamine.
3 points
Mean Difference on
Primary outcome of efficacy in the meta-analysis.
7 times
Increase in Adverse Events
Comparative increase in adverse events reported in trials.
Full Text
We can’t show the full text here under this license.
