This retrospective, matched, case-control study was conducted to compare rates of severe adverse events (SAE) within the first three treatment cycles in DPYD and UGT1A1 variant carriers who received genotype-guided treatment compared to variant carriers who received standard treatment with fluoropyrimidines (FP) and irinotecan. Subjects were matched by at-risk phenotype, chemotherapy regimen, and age. Sixteen subjects received genotype-guided treatment (12 with FP) and were matched to 75 subjects who received standard treatment. The primary endpoint of SAE attributed to the FP or irinotecan was significantly lower in variant carriers receiving genotype-guided treatment (12.5% vs. 50.7%; OR: 0.15; 95% CI: 0.03–0.68). Treatment modifications were also significantly reduced for genotype-guided treatment (12.5% vs. 54.6%; p < 0.05). Six (37.5%) subjects with genotype-guided treatment received and tolerated dose escalation. This real-world study of genotype-guided treatment in DPYD and UGT1A1 variant carriers provides additional evidence of the clinical benefit of genotype-guided treatment to improve patient safety.
Pharmacogenomic (PGx) testing may improve antidepressant prescribing, but uptake in primary care is limited. The Consolidated Framework for Implementation Research (CFIR) can help identify determinants of implementation. To synthesise barriers and facilitators to implementing PGx-guided antidepressant prescribing in primary care using CFIR, we searched MEDLINE, EMBASE, Scopus, CINAHL, APA PsycINFO, and Web of Science to March 2025. Qualitative and mixed-methods studies were screened by two independent reviewers and analysed using a CFIR-informed framework. Thirteen studies (n = 979 records screened) involving clinicians, administrators, policymakers, and patients were included. Barriers included limited perceived evidence, cost and reimbursement uncertainty, intervention complexity, workflow disruption, and low clinician confidence. Facilitators included perceived relative advantage, pharmacist-led support, interprofessional collaboration, reimbursement, clinical integration, adaptable delivery models, and training. Our findings suggest that PGx testing is viewed as promising in primary care, but implementation is constrained by interrelated issues of clinical utility, cost, workflow integration, and immature implementation processes.
Cytochrome P450 2D6 (CYP2D6) is a polymorphic enzyme that influences antidepressant metabolism. This retrospective cohort study investigated the association between CYP2D6 genotype and treatment outcomes in 99 hospitalized patients with major depressive disorder (MDD) in Belgrade, Serbia. Patients were classified as poor (PM, n = 5), intermediate (IM, n = 21), or normal metabolizers (NM, n = 73). Effectiveness and tolerability were assessed from admission to discharge (~4 weeks). Hamilton Depression Rating Scale (HAM-D) score reduction was the primary outcome; tolerability was measured using the Toronto Side Effects Scale (TSES). Compared with NMs, HAM-D score reductions were 4.3 and 9.0 points lower in IMs and PMs. TSES scores were 1.3 and 2.3 points higher in IMs and PMs, respectively. Central nervous system and gastrointestinal effects were more frequent in IMs and PMs; sexual dysfunction did not differ. Reduced CYP2D6 activity was associated with poorer outcomes, indicating the potential usefulness of CYP2D6 genotyping in MDD.
We evaluated the effect of CYP2C19 genotype on SSRI response in 114,627 research participants. We graded metabolizer status (0 for ultrarapid metabolizers to 4 for poor metabolizers), and regressed drug response outcomes on these grades. Among participants taking escitalopram or citalopram, slower metabolizers experienced side effects significantly more often than faster metabolizers (OR = 1.04 per grade, 95%CI = [1.02-1.06] and OR = 1.05 per grade, 95%CI = [1.02-1.07]) and were more likely to discontinue treatment due to side effects (OR = 1.05, 95%CI = [1.03-1.08], e.g. 29.7% of poor vs. 21.6% of ultrarapid metabolizers, and OR = 1.07, 95%CI = [1.04-1.11], e.g. 25.7% vs. 20.2%). Slower metabolizers taking escitalopram were more likely to suffer from sleep problems and sexual problems. Slower metabolizers taking sertraline reported tremor more often than faster metabolizers. Overall, we find substantial differences in side effect risk with different CYP2C19 genotypes, supporting the notion that individuals seeking depression treatment may benefit from pharmacogenetic-guided treatment selection to minimize side effects and reduce discontinuations.
Direct-to-consumer (DTC) pharmacogenomic (PGx) testing is expanding rapidly in the UK, yet no dedicated regulatory framework currently governs these services. Although a 2021 parliamentary inquiry recommended stronger safeguards and clearer technical standards for genomic testing, these proposals have not been applied to PGx. This study explores public attitudes toward DTC PGx testing, focusing on expectations for pre-test information, quality standards, and NHS data use. We conducted focus groups with members of the public, both with and without prior experience of purchasing DTC PGx tests, or other online health tests. Focus groups were audio-recorded with consent, transcribed, and analysed thematically. We identified three themes: (mis)understanding towards and awareness of DTC PGx testing; altruistic motivation and equity concerns; and (mis)trust. Participants were generally enthusiastic about PGx testing, as long as issues of equity, data protection, and regulation were addressed, with data sharing concerns being particularly prominent.
