BackgroundAntipsychotic-induced weight gain is a contributing factor in the reduced life expectancy reported amongst people with psychotic disorders. CYP2D6 is a liver enzyme involved in the metabolism of many commonly used antipsychotic medications. We investigated if CYP2D6 genetic variation influenced weight or BMI among people taking antipsychotic treatment.MethodsWe conducted a systematic review and a random effects meta-analysis of publications in Pubmed, Embase, PsychInfo, and CENTRAAL that had BMI and/or weight measurements of patients on long-term antipsychotics by their CYP2D6-defined metabolic groups (poor, intermediate, normal/extensive, and ultra-rapid metabolizers, UMs).ResultsTwelve studies were included in the systematic review. All cohort studies suggested that the presence of reduced-function or non-functional alleles for CYP2D6 was associated with greater antipsychotic-induced weight gain, whereas most cross-sectional studies did not find any significant associations. Seventeen studies were included in the meta-analysis with clinical data of 2,041 patients, including 93 poor metabolizers (PMs), 633 intermediate metabolizers (IMs), 1,272 normal metabolizers (NMs), and 30 UMs. Overall, we did not find associations in any of the comparisons made. The estimated pooled standardized differences for the following comparisons were (i) PM versus NM; weight = –0.07 (95%CI: –0.49 to 0.35, p = 0.74), BMI = 0.40 (95%CI: –0.19 to 0.99, p = 0.19). (ii) IM versus NM; weight = 0.09 (95% CI: –0.04 to 0.22, p = 0.16) and BMI = 0.09 (95% CI: –0.24 to 0.41, p = 0.60). (iii) UM versus EM; weight = 0.01 (95% CI: –0.37 to 0.40, p = 0.94) and BMI = –0.08 (95%CI: –0.57 to 0.42, p = 0.77).ConclusionOur systematic review of cohort studies suggested that CYP2D6 poor metabolizers have higher BMI than normal metabolizers, but the data of cross-sectional studies and the meta-analysis did not show this association. Although our review and meta-analysis constitutes one of the largest studies with comprehensively genotyped samples, the literature is still limited by small numbers of participants with genetic variants resulting in poor or UMs status. We need further studies with larger numbers of extreme metabolizers to establish its clinical utility in antipsychotic treatment. CYP2D6 is a key gene for personalized prescribing in mental health.

Background: Dyslipidaemia is an important cardiovascular risk factor for people with severe mental illness, contributing to premature mortality. The link between antipsychotics and dyslipidaemia is well established, while evidence on antidepressants is mixed. Aims: To investigate if antidepressant/antipsychotic use was associated with lipid parameters in UK Biobank participants and if CYP2C19 and CYP2D6 genetic variation plays a role. Methods: Review of self-reported prescription medications identified participants taking antidepressants/antipsychotics. Total, low-, and high-density lipoprotein cholesterol (L/HDL-C) and triglycerides derived from blood samples. CYP2C19 and CYP2D6 metabolic phenotypes were assigned from genetic data. Linear regression investigated aims, adjusted for key covariates. Results: Of 469,739 participants, 36,043 took antidepressants (53% female, median age 58, 17% taking cholesterol-lowering medications) and 3255 took antipsychotics (58% female, median age 57, 27% taking cholesterol-lowering medications). Significant associations were found between use of each amitriptyline, fluoxetine, citalopram/escitalopram, sertraline, paroxetine and venlafaxine with higher total cholesterol, LDL-C, and triglycerides and lower HDL-C, compared to participants not taking each medication. Venlafaxine was associated with the worst lipid profile (total cholesterol, adjusted mean difference: 0.21 mmol/L, 95% confidence interval (CI): 0.17 to 0.26, p < 0.001). Antipsychotic use was significantly associated with lower HDL-C and higher triglycerides. In participants taking sertraline, CYP2C19 intermediate metabolisers had higher HDL-C (0.05 mmol/L, 95% CI: 0.01 to 0.09, p = 0.007) and lower triglycerides (−0.17 mmol/L, 95% CI: −0.29 to −0.05, p = 0.007), compared to normal metabolisers. Conclusions: Antidepressants were significantly associated with adverse lipid profiles, potentially warranting baseline and regular monitoring. Further research should investigate the mechanistic pathways underlying the protective effects of the CYP2C19 intermediate metaboliser phenotype on HDL-C and triglycerides in people taking sertraline.

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Background Dyslipidaemia is an important risk factor for cardiovascular morbidity in people with severe mental illness and which contributes to premature mortality in this population. The link between antipsychotics and dyslipidaemia is well-established, whilst evidence on antidepressants is mixed. Aims To investigate (1) if antidepressant/antipsychotic use was associated with lipid parameters in UK Biobank participants, and (2) if CYP2D6 and CYP2C19 genetic variation plays a role. Methods Review of self-reported prescription medications identified participants taking antidepressants/antipsychotics. Total, low-, and high-density lipoprotein (L/HDL-C) cholesterol and triglycerides derived from blood samples. CYP2D6 and CYP2C19 metabolic phenotypes were assigned from genetic data. Linear regression investigated study aims. Results Of 469,739 participants, 36,043 took antidepressants and 3,255 antipsychotics. Significant associations were found between use of amitriptyline, fluoxetine, citalopram/escitalopram, sertraline, paroxetine, and venlafaxine with worse levels of each lipid parameter (i.e., higher total cholesterol, LDL-C, and triglycerides and lower HDL-C). Venlafaxine was associated with the worst lipid profile (total cholesterol, mean difference: 0.21 mmol/L, 95% confidence interval [CI]: 0.17 to 0.26, p<0.001). Antipsychotic use was associated with lower HDL-C and higher triglycerides (0.31 mmol/L, 95% CI 0.28 to 0.35, p<0.001). In participants taking sertraline, the CYP2C19 intermediate metaboliser phenotype was associated with higher HDL-C (0.05 mmol/L 95% CI: 0.01 to 0.09, p=0.007) and lower triglycerides (-0.17 mmol/L 95% CI: -0.29 to -0.05, p=0.007). Conclusions Antidepressants are significantly associated with adverse lipid profiles, potentially warranting baseline and regular monitoring of lipids. Further research should investigate why the CYP2C19 intermediate metaboliser phenotype may be protective for HDL-C and triglycerides in people taking sertraline.