Adequate opioid prescribing is critical for therapeutic success of pain management. Despite the widespread use of opioids, optimized opioid therapy remains unresolved with risk of accidental lethal overdosing. With the emergence of accumulating evidence linking genetic variation to opioid response, pharmacogenetic based treatment recommendations have been proposed. The aim of this review is to evaluate pharmacogenetic evidence and provide an overview on genes involved in the pharmacokinetics and pharmacodynamics of opioids. For this review, a systematic literature search of published articles was used in PubMed®, with no language restriction and between the time period of January 2000 to December 2020. We reviewed randomized clinical studies, study cohorts and case reports that investigated the influence of genetic variants on selected opioid pharmacokinetics and pharmacodynamics. In addition, we reviewed current CPIC clinical recommendations for pharmacogenetic testing. Results of this review indicate consistent evidence supporting the association between selected genetic variants of CYP2D6 for opioid metabolism. CPIC guidelines include recommendations that indicate the avoidance of tramadol use, in addition to codeine, in CYP2D6 poor metabolizers and ultrarapid metabolizers, and to monitor intermediate metabolizers for less-than-optimal response. While there is consistent evidence for OPRM1 suggesting increased postoperative morphine dosing requirements in A118G G-allele carriers, the clinical relevance remains limited. There is emerging evidence of clinical relevance of CYP2D6 and, to a lesser extent, OPRM1 polymorphism in personalized opioid drug dosing. As a result, first clinics have started to implement pharmacogenetic guidelines for CYP2D6 and codeine.

The P‐glycoprotein efflux pump, encoded by the ABCB1 gene, has been shown to alter concentrations of various antidepressants in the brain. In this study, we conducted a systematic review and meta‐analysis to investigate the association between six ABCB1 single‐nucleotide polymorphisms (SNPs; rs1045642, rs2032582, rs1128503, rs2032583, rs2235015, and rs2235040) and antidepressant treatment outcomes in individuals with major depressive disorder (MDD), including new data from the Canadian Biomarker and Integration Network for Depression (CAN‐BIND‐1) cohort. For the CAN‐BIND‐1 sample, we applied regression models to investigate the association between ABCB1 SNPs and antidepressant treatment response, remission, tolerability, and antidepressant serum levels. For the meta‐analysis, we systematically summarized pharmacogenetic evidence of the association between ABCB1 SNPs and antidepressant treatment outcomes. Studies were included in the meta‐analysis if they investigated at least one ABCB1 SNP in individuals with MDD treated with at least one antidepressant. We did not find a significant association between ABCB1 SNPs and antidepressant treatment outcomes in the CAN‐BIND‐1 sample. A total of 39 studies were included in the systematic review. In the meta‐analysis, we observed a significant association between rs1128503 and treatment response (T vs. C‐allele, odds ratio = 1.30, 95% confidence interval = 1.15–1.48, P value (adjusted) = 0.024, n = 2,526). We did not find associations among the six SNPs and treatment remission nor tolerability. Our findings provide limited evidence for an association between common ABCB1 SNPs and antidepressant outcomes, which do not support the implementation of ABCB1 genotyping to inform antidepressant treatment at this time. Future research, especially on rs1128503, is recommended.

There has been a worldwide substantial increase in accidental opioid-overdose deaths. The aim of this review, along with preliminary results from our pilot study, is to highlight the use of pharmacogenetics as a tool to predict causes of accidental opioid-overdose death. For this review, a systematic literature search of PubMed^® between the time period of January 2000 to March 2023 was carried out. We included study cohorts, case–controls, or case reports that investigated the frequency of genetic variants in opioid-related post-mortem samples and the association between these variants and opioid plasma concentrations. A total of 18 studies were included in our systematic review. The systematic review provides evidence of the use of CYP2D6, and to a lower extent, CYP2B6 and CYP3A4/5 genotyping in identifying unexpectedly high or low opioid and metabolite blood concentrations from post-mortem samples. Our own pilot study provides support for an enrichment of the CYP2B6*4-allele in our methadone-overdose sample (n = 41) compared to the anticipated frequency in the general population. The results from our systematic review and the pilot study highlight the potential of pharmacogenetics in determining vulnerability to overdose of opioids.

Objective: The genetic architecture of antidepressant response is poorly understood. This study investigated whether polygenic risk scores (PRSs) for major psychiatric disorders and a personality trait (neuroticism) are associated with antidepressant treatment outcomes. Methods: We analysed 148 participants with major depressive disorder (MDD) from the Canadian Biomarker Integration Network for Depression-1 (CAN-BIND-1) cohort. Participants initially received escitalopram (ESC) monotherapy for 8 weeks. Nonresponders at week 8 received augmentation with aripiprazole (ARI), while responders continued ESC until week 16. Primary outcomes were remission status and symptom improvement measured at weeks 8 and 16. At week 16, post-hoc stratified analyses were performed by treatment arm (ESC-only vs. ESC + ARI). Eleven PRSs derived from genome-wide association studies of psychiatric disorders (e.g., MDD and post-traumatic stress syndrome (PTSD)) and neuroticism, were analysed for associations with these outcomes using logistic and linear regression models. Results: At week 8, a higher PRS for PTSD was nominally associated with a lower probability of remission (odds ratio (OR) = 0.08 [0.014–0.42], empirical p -value = 0.017) and reduced symptom improvement (beta (standard error) = −29.15 (9.76), empirical p -value = 0.019). Similarly, a higher PRS for MDD was nominally associated with decreased remission probability (OR = 0.38 [0.18–0.78], empirical p -value = 0.044). However, none of the results survived multiple testing corrections. At week 16, the stratified analysis for the ESC-only group revealed that a higher PRS for MDD was associated with increased remission probability (empirical p- value = 0.034) and greater symptom improvement (empirical p -value = 0.02). In contrast, higher PRSs for schizophrenia (empirical p -value = 0.013) and attention-deficit hyperactivity disorder (empirical p -value = 0.032) were associated with lower symptom improvement. No significant associations were observed in the ESC + ARI group. Conclusions: These findings suggest that PRSs may influence treatment outcomes, particularly in ESC monotherapy. Replication in larger studies is needed to validate these observations.