Pharmacogenomics for stratified antidepressant treatment in major depressive disorder: evidence, limits and a roadmap for clinical use

Major depressive disorder (MDD) is treated largely by trial and error, despite marked interindividual variation in antidepressant exposure, efficacy and tolerability. Pharmacogenomics (PGx) has therefore been proposed as a route to stratified antidepressant treatment. This Review asks whether current evidence supports that claim by distinguishing actionable drug-gene guidance, clinical utility in broad trial populations and subgroup evidence for stratified care. Contemporary guidance supports genotype-informed prescribing for selected antidepressants, most consistently through CYP2D6 and CYP2C19 and, for selected serotonin reuptake inhibitors, CYP2B6, whereas SLC6A4 and HTR2A are not clinically actionable for antidepressant prescribing. Randomized and pragmatic trials show that PGx reduces drug-gene mismatched prescribing more reliably than symptom outcomes in unselected MDD samples. Meta-analyses suggest small-to-moderate short-term response or remission gains, with larger signals in treatment-exposed, severe or difficult-to-treat patients. PGx is therefore not simply weakly useful for everyone; its strongest current role is selective, subgroup-enriched prescribing where exposure mismatch is plausible. A practical roadmap is to restrict current interpretation to guideline-supported CYP2D6/CYP2C19/CYP2B6 gene-drug pairs, prioritize testing before affected antidepressants or after nonresponse, intolerance or polypharmacy, avoid broad proprietary class assignment, and validate stratified claims in prospective enriched trials.