Pharmacogenomics in the clinic: Genetic polymorphism contributing to venlafaxine-associated heart failure

Pharmacogenomic tests are now commercially available, but it is difficult to know which patients and drugs should trigger consideration for pharmacogenomic evaluation. Venlafaxine is a widely used serotonin-norepinephrine reuptake inhibitor indicated for the treatment of major depression disorder, anxiety and pain disorders [1]. Genetic variation is thought to play an important role in patient risk for cardiotoxicity by both acute and prolonged exposure to venlafaxine. Polymorphisms and drug-drug interactions with CYP2D6, and to some extent CYP2C19, have been shown to significantly influence the pharmacokinetics and metabolic clearance of venlafaxine and the formation of its active metabolite, O-desmethylvenlafaxine (ODV) [2-5]. Venlafaxine and ODV are both potent inhibitors of serotonin and norepinephrine reuptake. Other hepatic enzymes (CYP3A4, CYP2C19 and CYP2C9) metabolize venlafaxine and ODV to minor, less active metabolites (Figure 1). Several case reports have shown an association between cardiomyopathy and a poor CYP2D6 metabolizer status in patients taking venlafaxine [6-8]. While cardiac events with venlafaxine are considered rare even at high doses, evidence suggests drug-induced cardiomyopathy and heart failure in instances of overdose and regular dosing of venlafaxine. Resolution of symptoms upon cessation of venlafaxine therapy further supports cardiovascular adverse events related to venlafaxine. The exact mechanism of cardiotoxicity remains unknown; however, some hypotheses have been made.One theory is the hypertrophic effects of dose-related sustained hypertension. Likewise,myocardial damage due to increased levels of catecholamine with inhibition of dopamine and norepinephrine reuptake is reported by the current literature [9]. The surge in catecholamine levels eventually leads to the development of cardiomyopathy resulting in left ventricular dysfunction. Patient genotyping allows for a fairly reliable estimation of CYP2D6 and CYP2C19 phenotypic status with respect to venlafaxine and ODV exposure, especially among 'poor' and 'extensive (normal)' metabolizers [4,5]. However, there are few case reports speculating on the clinical significance for an 'intermediate' CYP2D6 metabolizer; Vinetti et al. report an intermediate CYP2D6 metabolizer who presented with severe acute cardiomyopathy following a venlafaxine overdose [8]. We report a patient who developed nonischemic cardiomyopathy after 4 years of venlafaxine treatment for depression and anxiety, and who is a CYP2D6 intermediate metabolizer and CYP2C19 extensive metabolizer.