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
Abstract
Background: In 2019, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved a nasal spray formulation of esketamine for “treatment resistant depression” (TRD). However, the evidence base for its use proved to be controversial. This registered report aims to independently reappraise the efficacy of esketamine in TRD, by i) exploring the possibility of data integrity issues, ii) re-analyzing and iii) pooling the trial data. Main secondary objectives are to reappraise the safety of esketamine in the treatment of TRD and to explore whether esketamine’s efficacy and safety vary with level of treatment resistance and patient age. Methods: This systematic review and meta-analysis of individual patient data will include all double-blind, randomised, placebo-controlled trials of intranasal esketamine (with the following approved doses: 56 mg or 84 mg or “flexible” doses) for the indication of TRD. Systematic searches will be conducted by two independent researchers using PubMed, the Cochrane library, Embase, ClinicalTrials.gov, Clinicaltrialsregister.eu, FDA, EMA and the manufacturer website. Selection, coding and risk of bias assessment of the different study characteristics will be performed by two independent researchers in a blinded manner. The primary outcome will be the MADRS score at the end of treatment in initiation trials. Other efficacy and safety outcomes will be considered as secondary outcomes. For efficacy and safety outcomes a two-step approach will be adopted. First, we will perform a reanalysis of each study. Then, a fixed effect meta-analysis, or a random effect meta-analysis (in case of heterogeneity), will be used to employed the different efficacy indexes derived from these re-analyses. Initiation and continuation design will be analysed separately. In order to explore the impact of resistance stage and age, a one stage IPD meta-analysis using a mixed model will be performed. If applicable (> 10 studies), we will use a funnel plot to look at small study effects. We will use GRADE to rate the overall certainty of evidence.
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