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.
The treatment of urothelial cancer (UC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICIs). However, while ICIs have achieved better therapeutic results than traditional chemotherapeutic agents, immune-related adverse events (irAEs) can lead to poor treatment outcomes. This exploratory study was designed to seek tumour single-nucleotide polymorphisms (SNPs) related to irAEs in patients with UC treated with ICIs. Tumour specimens were collected at several hospitals in Madrid (Spain) from 102 patients treated with nivolumab, atezolizumab, avelumab or pembrolizumab. DNA was extracted from formalin-fixed paraffin-embedded tumour biopsies, and 49 SNPs genotyped using a MassARRAY platform. Among the 49 SNPs analyzed, rs1738074 was associated both with overall toxicity (p < 0.001), and with the appearance of specific toxicities such as dermatitis and pneumonitis (p = 0.005 and p = 0.036, respectively). In effect, 100% of patients with pneumonitis were homozygous for the variant allele (p = 0.020). Other SNPs were also linked to a higher risk of irAEs: rs2301756 to pneumonitis (p = 0.005), rs55733913 and rs2117997 to dermatitis (p = 0.026, p = 0.021, respectively) and rs4988956 to hepatitis (p = 0.027). Contrarily, two SNPs, rs11571302 and rs66502444, showed a possible protective role against asthenia (p = 0.012, p = 0.030, respectively). This exploratory study highlights the possible useful role of tumour SNPs as biomarkers to predict the risk of UC patients developing irAEs. Further studies are needed to validate the utility of SNPs as biomarkers of ICI-induced toxicity.
Maternal and neonatal health (MNH) urgently requires precision medicine interventions, as morbidity, mortality, and health disparities hinder the achievement of Sustainable Development Goal 3. Clinical implementation of artificial intelligence (AI)-powered Pharmacogenomics (PGx) requires validated, transparent algorithms and frameworks. The “pregnancy black box”-which refers to a data void due to historical exclusion of pregnant and postpartum women from clinical trials-continues to create bias in AI models. The review establishes a path for upcoming research, including methods to reduce algorithmic bias via AI-driven data augmentation, resolution of ethical challenges, and creation of international registries. Ultimately, leveraging AI for remote monitoring is crucial for enhancing equitable access in lower-resource environments. The proposed roadmap provides organizations with a robust framework to develop AI-driven PGx systems, which will enable safer and more tailored pharmacotherapy for mothers and their newborns.
Clopidogrel therapy is recommended to prevent recurrent ischemic stroke. However, clopidogrel resistance exists. This study examines which enzymes are involved in clopidogrel resistance. The study group includes 402 neurology patients who had experienced a recurrent ischemic stroke while receiving clopidogrel monotherapy. Patients were genotyped for CYP2C19, CYP2C9, CYP2B6, CYP3A4, CYP3A5, CYP1A2, ABCB1 and CES1A1. Phenotype frequencies were compared with those of a Global(G), European(E) and a local patient control(C) group. Only for ABCB1 a significant difference in phenotype distribution was seen (pG = 0.003, pE = <0.001, pC = 0.019). In patient with ABCB1 rapid efflux activity (3435TT), no other enzyme was significantly associated. In patients with ABCB1 normal efflux activity (3435CT/CC), CYP2C19 intermediate and poor metabolism were significantly associated (pE = <0.001, pG = <0.001, pC = 0.002). In patients with normal CYP2C19 metabolism, CYP2C9 intermediate and poor metabolism were significantly associated (pG = <0.001, pE = <0.001, pC = <0.001). Besides CYP2C19 clinical guidelines, also for ABCB1 and CYP2C9 guidelines are needed to prevent clopidogrel resistance.
Pharmacogenetics uses genetic testing to improve the safety and effectiveness of prescribed medicines, yet implementation at scale remains limited due to the absence of interoperable health IT solutions that integrate results into prescribing workflows. This study aimed to develop and validate open data standards for pharmacogenetic results to enable interoperability across healthcare systems. A baseline data model was constructed using the open standard openEHR by synthesising literature, genomic sequencing outputs, and international data specifications, and refined through iterative workshops with the Global Alliance for Genomics and Health. The model underwent two rounds of structured peer review involving 24 experts from 10 countries. Mapping to HL7 FHIR was evaluated using both manual and automated approaches, including the FHIR-Connect tool. The resulting standardised pharmacogenetic data model separates test results from therapeutic implications and incorporates recognised terminologies such as SNOMED CT and HGNC. It achieved international consensus and is published on the openEHR Clinical Knowledge Manager platform. Mapping to HL7 FHIR demonstrated bidirectional information flow within healthcare systems, with automated mapping enabling scalable and reusable transformations. This work provides a framework for storing and exchanging pharmacogenetic test results, supporting semantic harmonisation, interoperability, and integration with clinical decision support systems. Open data standards for pharmacogenetic test results therefore offer a foundation for scalable implementation of pharmacogenetics in routine clinical practice.
Cardiovascular disease and hypercholesterolemia present significant global health and economic burdens. While statins are the standard treatment, individual variability and toxicities necessitate personalized approaches. This narrative review (2013-2025) evaluated the economic landscape of pharmacogenomics (PGx)-guided statin therapy and factors influencing its cost-effectiveness. Out of 219 studies, only four relevant evaluations were identified, all focusing on North American (United States & Canada) cohorts and published before 2019. Most models relied on literature-based simulations and utility data, introducing significant parameter uncertainty. Nevertheless, PGx-guided strategies generally proved cost-effective or dominant, particularly at higher willingness-to-pay thresholds, such as $50,000/QALY. In conclusion, PGx-guided therapy offers a viable pathway for improving clinical outcomes and economic efficiency. However, a paucity of raw clinical data and geographic diversity currently limit its standardized adoption. Future research must leverage real-world evidence from ongoing trials to inform robust, value-based healthcare policy.
This study assessed the cost-effectiveness of encorafenib plus cetuximab (EC) and EC combined with mFOLFOX6 versus standard of care (SOC) as first-line treatment for BRAF V600E-mutant metastatic colorectal cancer from a Chinese healthcare perspective. Using a partitioned survival model with data from the BREAKWATER trial, we found that compared to SOC, the incremental cost-effectiveness ratios for EC and EC plus mFOLFOX6 were 77,589.95 per quality-adjusted life year (QALY) and 82,419.06 per QALY, respectively, both exceeding the willingness-to-pay threshold of $40,343.68/QALY. At this threshold, SOC had a 95.43% probability of being cost-effective against EC, and 99.64% against EC plus mFOLFOX6. We conclude that neither EC nor EC plus mFOLFOX6 is cost-effective in China at current prices, suggesting the price negotiations would be necessary to improve their economic value.
Intensive care units (ICU) patients are highly vulnerable to inaccurate drug dosing. Pharmacogenomics (PGx) studies the role of inherited genetic variation in drug metabolism and dose efficacy. To assess the prevalence of PGx variants that may influence therapeutic effect in the ICU, we carried out whole genome sequencing (WGS) of 210 Qataris in ICU care at Hamad Medical Corporation (HMC), Doha, Qatar and assessed the WGS for predicted deleterious variants of genes that metabolize 30 drugs commonly prescribed in the ICU. PGx variation was evaluated using two complementary approaches. First, variants with established functional interpretation were assessed using CPIC guidelines and star-allele haplotypes inferred by PharmCAT to estimate the prevalence of alleles associated with abnormal drug metabolism. Second, a broader exploratory analysis examined computationally predicted deleterious single-nucleotide variants in pharmacogenes that currently lack CPIC guidelines or defined star alleles, with these findings interpreted as descriptive of genomic variation rather than clinical metabolizer phenotypes.Of the ICU patients that received the 5 most commonly prescribed drugs (warfarin, phenytoin, midazolam, vancomycin, levetiracetam), 93% had deleterious metabolism-related variants. Ninety-one % of ICU patients carried at least one variant in a gene with known PGx relevance that could potentially impact the metabolism or activity of at least one medication they received. Most patients had ≥14 deleterious variants of genes that affect the metabolism of administered drugs. Comparison of the deleterious variants related to metabolism of ICU drugs with African/African American and European populations revealed significant population specificity in ICU related PGx variants. Together, these data suggest that population specific, PGx based on the individual’s genome likely plays a significant role in effective, safe dosing in the ICU setting.
We performed a retrospective cohort study to evaluate risk of antidepressant discontinuation as a function of CYP2C19 and CYP2D6 phenotype. Patients who participated in an elective genomic screening and had a diagnosis of depression or anxiety with a corresponding antidepressant were analyzed. This resulted in 5 808 patients comprising 8 571 antidepressant orders. Of the total antidepressant orders, 51% of the antidepressants ordered before pharmacogenetic testing were discontinued. A multivariate analysis - accounting for age, medication tenure, allergies, PHQ-9, malaise/fatigue, and medication indication - revealed a significant association between metabolizer status and discontinuation for CYP2C19 increased metabolizers (ultrarapid plus rapid metabolizers) compared to normal metabolizers (n = 4 635) (HR = 1.17 [1.08, 1.27], p < 0.001) for CPIC guideline-recommended medications (i.e., citalopram, escitalopram, sertraline). Stratifying risk by individual drug maintained significant associations for escitalopram (HR = 1.27 [1.1, 1.46], p < 0.05) and sertraline (HR = 1.15 [1.01, 1.31], p < 0.05). While the CYP2D6 decreased metabolizer group (intermediate plus poor metabolizers) did not reach statistical significance for guideline recommended medications (i.e., paroxetine, venlafaxine, vortioxetine), the individual effect for venlafaxine showed an increased risk of discontinuation (HR = 1.23 [1.01, 1.5], p < 0.05). These results suggest phenotypic variations may have variable impact on risk of discontinuation amongst different antidepressant medications, but for escitalopram, sertraline, and venlafaxine, the risk of discontinuation in particular phenotypes should be considered at the time of therapy initiation.
Tumor necrosis factor inhibitors (TNFi) have transformed the management of rheumatoid arthritis (RA); however, up to 40% of patients fail to achieve an adequate clinical response. Current clinical predictors remain insufficient, highlighting the need for pharmacogenetic biomarkers to guide biologic therapy selection. In this study, we investigated genetic variants associated with TNFi treatment response, with a particular focus on body mass index (BMI)-dependent effects, using a large real-world cohort. A total of 519 patients with RA were identified from the Taiwan Precision Medicine Initiative (TPMI), an electronic health record-linked biobank. Eligible patients had received TNFi therapy for at least 6 months and had available genotyping data. Ninety-seven candidate single nucleotide polymorphisms (SNPs) previously reported to be associated with TNFi response were identified through a systematic literature search. Five variants located in immune-metabolic genes (FTO, ZNF618, RANK, CD84, and LOC105375523) were further analyzed using univariable and multivariable logistic regression models. Subgroup analyses stratified by BMI were performed to explore potential effect modification. Three variants-FTO rs7195994, ZNF618 rs16911006, and LOC105375523 rs834811-were significantly associated with TNFi response in initial analyses. In multivariable models, only FTO rs7195994 remained an independent predictor of non-response (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.22-0.87; p = 0.019). Among patients with BMI < 27 kg/m², carriers of the rs7195994 risk allele had a 49% lower likelihood of achieving treatment response (OR 0.51, 95% CI 0.28-0.92; p = 0.0249), whereas no significant association was observed in patients with higher BMI. These findings identify FTO rs7195994 as a novel, BMI-modulated pharmacogenetic marker of TNFi non-response in RA. Incorporating BMI-stratified genetic profiling into clinical decision-making may facilitate early identification of patients unlikely to benefit from TNFi therapy, thereby supporting precision treatment strategies. Further validation in multiethnic populations and functional studies is warranted.
Pharmacogenetic (PGx) testing of cytochrome P450 (CYP) enzymes CYP2D6 and CYP2C19 is increasingly utilised to personalise psychopharmacological treatment, but clear criteria for patient selection are lacking. We developed and conducted a pilot evaluation of a clinical decision-making tool, the CYPRI (CYP Pharmacogenetic Risk Index), which uses routinely available clinical and pharmacological data to estimate the likelihood of a clinically relevant and actionable PGx testing result. A pilot observational study involving 34 patients was conducted at Psychiatric Hospital Bohnice in Prague, Czech Republic. A significant correlation was observed between the CYPRI score and the IMPACT score (ordinal logistic regression: t = 3.279, p = 0.0011; Kendall's τ = 0.46, p = 0.0011). Discriminative ability was high, with an area under the curve (AUC) of 0.83 (95% CI: 0.69-0.97), based on ROC analysis performed using two outcome categories (0-2 vs. ≥ 2 points of IMPACT score). The optimal cut-off was 4. The CYPRI score offers a straightforward method to prioritise patients for PGx testing, potentially enhancing cost-effectiveness and clinical outcomes in psychiatric care.
Oral esketamine displays therapeutic potential for treatment-resistant depression. However, treatment is complicated by a low and variable bioavailability. Genetic polymorphisms in the cytochrome P450 (CYP) enzymes responsible for esketamine's metabolism may influence bioavailability. In a subsample of patients included in a placebo-controlled trial investigating repeated, low dose oral esketamine (N = 18), blood samples were collected four hours after dosing. CYP2B6 516 G > T, CYP3A4*22, and CYP3A5*3 genotyping was performed, and the plasma levels of esketamine and its metabolites were measured. CYP2B6 516 G > T carriers (Mdn = 5.1 µg/L) demonstrated higher esketamine plasma levels compared to non-carriers (Mdn = 2.1 µg/L) (U = 45.00, p = 0.032). No significant associations were observed for CYP3A4*22 carriership (n = 2) or CYP3A5*3 heterozygosity (n = 2), nor for esketamine's metabolites. In summary, CYP2B6 516 G > T is associated with higher esketamine plasma concentrations. Further research with more participants is warranted to draw conclusions about CYP3A4*22 and CYP3A5*3. Clinical trial registration: NTR6161 (Dutch Trial Register).
The aim of this study was to elucidate cardiovascular prescriber access, uptake, and attitudes toward CYP2C19 and CYP2D6 genetic testing to guide prescribing of commonly used medications such as clopidogrel, antiarrhythmics, proton pump inhibitors, and antidepressants. A survey, designed in collaboration with the European Society of Cardiology (ESC) WG on Cardiovascular Pharmacotherapy and external experts was disseminated to ESC members using SurveyMonkey. 265 prescribers from 68 countries participated. Most respondents thought testing would be beneficial, though CYP2C19 testing was perceived as more beneficial (73%) and desirable than CYP2D6 (61%). Access to CYP2C19 testing was more common (30%) than CYP2D6 testing (19%), but mostly outside of public funded health systems. Uptake in those who had access was higher for CYP2C19 (67%), than for CYP2D6 (33%). Confidence in interpreting results to prescribe was also higher with CYP2C19 (69%) than with CYP2D6 (53%), but most respondents wanted information prior to prescribing. One third of respondents highlighted the need for a turnaround time that matched their clinical practice. Unsolicited Pharmacogenomic (PGx) information from a patient was uncommon, but most prescribers acted on the information. A minority of respondents had undertaken PGx testing themselves, but most wanted testing for relevant medications. Respondents' experiences as patients made them more likely to believe that PGx testing was warranted. A minority ( ~ 15%) were aware of either local prescriber guidance or patient information materials regarding PGx testing. Prescribers want access to pharmacogenomics data regarding CYP2C19 and CYP2D6 for prescribing cardiovascular medicines. However, there are barriers which hamper implementation. Prescribers lived experience with medication use as patients impacted their views of PGx. 265 prescribers responded to the ESC survey from 68 countries. Most prescribers wanted access to pharmacogenomic testing for CYP2C19 and CYP2D6 for their patients and for themselves. Though most prescribers thought these pharmacogenomic tests would be useful and could improve the risk/benefit profile of relevant medications, prescribers responded more positively to CYP2C19 compared with CYP2D6 testing. Guidance and information for both prescribers and patients were lacking.
Pharmacogenomics (PGx) is a key component of precision medicine, yet most PGx studies exclude pregnant people and children. The VICE (Vanderbilt Integrated Center of Excellence)-MPRINT (Maternal and Pediatric Precision in Therapeutics): Maternal and Pediatric Pharmacogenetics Trial is a single-center, randomized control trial to assess how PGx testing and return of results influence patients' understanding and perceived utility of PGx testing in a pregnancy and pediatric cohort. Pregnant individuals and families or guardians of children with a chronic health condition aged 0-16 were recruited. We assessed participants' knowledge and attitudes regarding PGx testing at baseline and after receiving results with patient-friendly interpretations. Cases received an educational video about PGx testing with return of results. Controls received PGx test results alone. We aimed to determine perspectives regarding PGx in these understudied populations with the goal of promoting research and clinical implementation of PGx for pregnant women and children.
Cardiovascular diseases are the leading cause of death in Chile and worldwide, representing a major public health challenge that demands urgent preventive and therapeutic strategies. In atrial fibrillation, anticoagulation is essential, and in Chile acenocoumarol rather than warfarin, used in most countries, is the standard agent. Its dosing shows substantial interindividual variability due to CYP2C9 and VKORC1 polymorphisms. We developed a cohort-based Markov model to compare standard care, genotype-guided dosing, and genotype-guided dosing adjusted for population-level adherence in 123 Chilean patients with atrial fibrillation and 123 matched simulated individuals. Outcomes were measured as quality-adjusted life years (QALYs) and direct medical costs, with cost-effectiveness assessed at a willingness-to-pay (WTP) threshold of US$17,093, estimated using the international approach of approximating the country’s GDP per capita rather than a Chilean policy-based value. Genotype-guided dosing achieved the highest effectiveness (2938.34 QALYs) with an incremental cost-effectiveness ratio of US$436.86/QALY versus standard care, remaining cost-effective in sensitivity analyses up to test prices far exceeding the current US$190. The adherence-adjusted strategy was weakly dominated. These results strongly support implementing pharmacogenetic testing for acenocoumarol dosing to optimize anticoagulation safety, efficacy, and cost-effectiveness in Chile.
Modest outcomes from pharmacogenomic (PGx) testing in depression may be influenced by low rates of actionable gene-drug interactions. This 12-week pilot pragmatic randomized clinical trial evaluated the effectiveness of selectively targeting PGx testing to depressed Veterans receiving psychiatric polypharmacy with an antidepressant on the Sanford Pharmacogenomics Panel. 60 Veterans were randomized to having their PGx test results available immediately or delayed until the end of the 12-week trial. Patient Health Questionnaire-9 (PHQ-9) scores were assessed monthly by blinded raters, with medication changes assessed via the electronic medical record. 30% of subjects had an actionable gene-drug interaction, compared to 20% in prior PGx research in Veterans. There were no significant differences in PHQ-9 scores, proportion of patients with medication changes, or time to first medication change. This study showed that targeted PGx testing can increase rates of actionable genotypes in patients with depression.
Variants in cytochrome P450 enzymes are known risk factors for developing adverse drug reactions (ADR). Most antidepressants (AD) are simultaneously metabolized by major or minor pathway of CYP2C19 and CYP2D6, resulting in a complex interplay of metabolites. This study is one of the first to investigate and demonstrate the combined CYP 2C19/2D6 functional metabolic status as a possible risk factor for ADR in AD treatment of major depressive disorder. Most prescribed AD venlafaxine underwent subgroup analysis. More ADR in non-normal metabolizers (nNM) for one or both CYP enzymes compared with normal metabolizers (p = 0.039) were observed. Both slow (PM and IM) and rapid metabolizers (RM and UM) were affected. There were non-significant trends for CYP2C19 RM and UM with ADR in venlafaxine, which may be avoided in CYP2C19 nNM. More research is required to identify risk variants for personalized and safe AD treatment.
