Comparative effectiveness of pharmacogenomic-guided versus unguided antidepressant treatment in major depressive disorder: new insights from subgroup and cumulative meta-analyses.

QUESTION How effective is pharmacogenomic (PGx)-guided antidepressant treatment compared with treatment-as-usual (TAU) in major depressive disorder (MDD), and how do ethnicity, disease severity and genetic panel scope influence outcomes? STUDY SELECTION AND ANALYSIS This systematic review and meta-analysis comprised 13 randomised controlled trials (2013-2024) comparing PGx-guided therapy with TAU in MDD. PubMed, Ovid Embase, Ovid Medline, Ovid PsycINFO and the Cochrane Library were searched up to December 2024. Outcomes included response and remission rates at 8 and 12 weeks. Subgroup analyses examined ethnicity and MDD severity. Cumulative meta-analyses assessed gene panel size. The pooled risk ratios (RRs) with 95% CIs were calculated to estimate the overall effect. FINDINGS PGx-guided treatment significantly improved response rates at 8 weeks (RR 1.23, 95% CI 1.05 to 1.43) and 12 weeks (RR 1.29, 95% CI 1.17 to 1.43). Remission was significant at 8 weeks (RR 1.37, 95% CI 1.19 to 1.57) but not at 12 weeks (RR 1.56, 95% CI 0.93 to 2.61). Benefits appeared stronger in the Asian country subgroup compared with non-Asian country subgroup (interaction p=0.02), but this requires validation due to the smaller Asian country sample size. No significant subgroup differences were observed between the MDD not-specified and MDD difficult-to-treat subgroups, despite the latter demonstrating significant improvements in both response and remission rates with PGx-guided treatment compared with TAU at 8 weeks. Cumulative analyses showed effect sizes plateaued, with broader panels offering minimal incremental gains. CONCLUSIONS PGx-guided treatment seems to offer moderate benefits for antidepressant efficacy, with potential advantages in Asian and difficult-to-treat subgroups. Genetic and ethnic variability in drug metabolism underscores the need for population-specific approaches. While multigene panels show clinical benefits plateau, suggesting cost-benefit optimisation is critical. Future research should address adverse events, the cost-effectiveness of expanded panels, long-term remission outcomes and treatment efficacy across more precisely stratified disease severity levels to maximise clinical relevance. PROSPERO REGISTRATION NUMBER CRD42024570014.