Orexin receptor antagonists for major depressive disorder: perspectives from a systematic review and meta-analysis

A recent report by Dr. Hashimoto in Molecular Psychiatry highlighted that, because the orexin system in mesolimbic pathways modulates reward and motivation, it is important to monitor mood changes in individuals with insomnia treated with orexin receptor antagonists (QXR-ANTs) [1].Orexin receptors comprise two subtypes: OX1R and OX2R.Recent double-blind, randomized, placebo-controlled trials (DBRPCTs) showed that seltorexant, a selective OX2R antagonist, alleviated overall symptoms in individuals with major depressive disorder (MDD) [2].Nevertheless, other QXR-ANTs (filorexant and tebideutorexant) did not improve symptoms in individuals with MDD in DBRPCTs, leaving their therapeutic value uncertain [3,4].Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy, acceptability, tolerability, and safety of QXR-ANTs in individuals with MDD.This study followed Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines (Table S1) [5].The PICO framework was defined as follows: Patients, adults with MDD; Intervention, pooled QXR-ANTs; Comparison, placebo; Outcome, improvement in overall symptom scores (17 items in the Hamilton Depression Rating Scale [HDRS17] [6] and Montgomery-sberg Depression Rating Scale [MADRS] [7], primary), response rate ( 50% reduction in HDRS17 or MADRS total score from baseline), remission rate (HDRS17 total score 7 or MADRS 12), all-cause discontinuation, adverse event-related discontinuation, and incidence of individual adverse events.We searched PubMed, the Cochrane Library, and Embase databases for studies published before October 26, 2025.The detailed strategy is provided in