CYP2D6 and CYP2C19 variability: Increased antidepressant trials, side effects?
In a retrospective analysis of individuals with obsessive-compulsive disorder (OCD) previously treated with multiple trials of antidepressants, neither CYP2D6 nor CYP2C19 metabolism status was associated with overall differences in duration of illness, current symptom severity, treatment response, or side effects. However, patients classified as CYP2D6 non-extensive metabolizers were more likely to have undergone four or more previous antidepressant drug trials and experience significant side effects with venlafaxine as compared with CYP2D6 extensive metabolizers.
OCD occurs in roughly 1% to 2% of the population, with more than half of patients classified as having severe disease. First- and second-line drug therapies for OCD include SSRIs, clomipramine, and some antipsychotic agents. Many antidepressants are metabolized by CYP450 enzymes that are subject to variability influenced by genetics and environmental factors. However, few data are available to inform clinicians about use of pharmacogenetic testing to guide antidepressant therapy in patients with OCD.
In the current study, investigators identified 184 individuals diagnosed with OCD according to Diagnostic and Statistical Manual of Mental Disorders-IV criteria who had received one or more trials of SSRIs, venlafaxine, mirtazapine, duloxetine, or clomipramine. Patients were assigned as drug “overall responders” or “overall nonresponders” based on categorization of patient-reported improvements with previous medications. Individuals were also classified as experiencing “significant side effects” or being “without significant side effects” based on patient report. Genotyping was performed using TaqMan single nucleotide polymorphism assays by Applied Biosystems, Foster City, CA, with use of published CYP2D6 activity and inhibitor scores.
Out of 184 patients genotyped, 35% and 5%, respectively, were classified as CYP2C19 intermediate (*1/*2, *1/*3) and poor metabolizers (*2/*2, *2/*3, *3/*3). A total of 8% and 2% of patients were classified as CYP2D6 ultrarapid and poor metabolizers, respectively. There were no overall differences in duration of illness, severity of current symptoms, treatment response, or significant side effects based on CYP2C19 or CYP2D6 metabolism status (P = NS for all comparisons). However, significantly more patients classified as CYP2D6 non-extensive metabolizers underwent 4 or more drug trials than those classified as extensive metabolizers (P = 0.007). Additionally, investigators observed an association with CYP2D6 non-extensive metabolizer status and venlafaxine side effects as compared with extensive metabolizers (P = 0.022).
This trial represents one of the first and largest investigations of effects of CYP2D6 and CYP2C19 variability on treatment response in patients with OCD. “Our positive findings regarding potential impact of CYP2D6 metabolizer status on success of medications (as indicated by number of medications tried) and venlafaxine tolerability should serves as stimulus for further research,” investigators concluded.
Trial findings add to a growing body of literature exploring clinical effects of CYP2D6 and CYP2C19 variability in psychiatric conditions as clinicians await clear guidance for incorporating genotype-guided antidepressant therapy in practice. Current Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide CYP2C19- and CYP2D6-guided dosing recommendations for tricyclic antidepressants and recommendations for genotype-guided therapy of SSRIs are underway.
Limitations of the current study included the potential for patient recall bias, heterogenous samples with small group sizes, and investigation of only the most relevant and common polymorphisms, which may have excluded rare genotype variants. Investigators also did not examine specific side effects or perform plasma levels for correlating phenotype assessment.
Brandl EJ et al. Influence of CYP2D6 and CYP2C19 gene variants on antidepressant response in obsessive-compulsive disorder. Pharmacogenomics J. 2014;14:176-81.