Associations of antidepressants and antipsychotics with lipid parameters: Do CYP2D6/CYP2C19 genes play a role? A UK population-based study

ABSTRACT 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.