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EV0651

Pharmacogenetics in psychiatry: bridging the gap between clinical potential and real-world implementation

PHARMACIGENETICS IN PSYCHIATRY: BRIDGING THE GAP BETWEEN CLINICAL POTENTIAL AND REAL-WORLD IMPLEMENTATION

Pharmacogenetic testing reliably changes which medication is prescribed, but does not yet reliably change whether the patient improves.

The aim is to examine whether the evidence provides equal support for efficacy and safety, given that the uptake of pharmacogenetic (PGx) testing remains low despite the role of genetic variability in CYP2D6, CYP2C19, and pharmacodynamic targets in determining drug response. The methods comprised a narrative review and conceptual synthesis of studies, meta-analyses, and guidelines (CPIC, DPWG, ISPG); implementation barriers were examined, prioritizing large pragmatic trials, recent meta-analyses, and guideline-endorsed gene–drug pairs. The strongest evidence concerns safety: the PREPARE study (N = 6,944, open-label, multispecialty) reported a 30% reduction in clinically relevant adverse drug reactions, with an odds ratio of 0.70 (95% confidence interval 0.54 to 0.91). Regarding prescribing, in the PRIME Care pragmatic randomized controlled trial (N = 1,944), 60% of participants received a medication with no predicted gene–drug interaction, compared with 26% in the comparison group; however, the primary endpoint was not met. Evidence for efficacy is weaker: a meta-analysis of 13 randomized controlled trials (11 industry-funded) found a relative risk of achieving remission of 1.41 (95% confidence interval 1.15 to 1.74), while the NIH-funded ADOPT PGx 2026 trial did not meet its primary endpoint. Implementation barriers included the absence of validated pharmacodynamic markers (CPIC 2023: level C, no recommendation for SLC6A4 and HTR2A), genotype–phenotype discordance due to phenoconversion and differences in panel coverage, and classification of the same CYP2D6 activity score (AS 1.0) as an intermediate metabolizer by DPWG but a normal metabolizer by CPIC. Clinician preparedness is also limited: 73% of primary care physicians in the United States considered their training inadequate for interpreting PGx results, and 94% of French psychiatrists found the guidelines unclear. In conclusion, PGx is currently most justifiable for tolerability and dose selection; confidence is highest for CYP2D6 and CYP2C19 in relation to specific antidepressants and antipsychotics, as well as for HLA-B*15:02 and HLA-A*31:01 testing before carbamazepine treatment. Closing the gap requires preemptive testing, decision support, therapeutic drug monitoring, and validated pharmacodynamic markers.

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