CYP2D6 metabolizer status and HTTLPR variant of SLC6A4 associated with antidepressant-induced mania in bipolar disorder

Abstract

IntroductionApproximately 12% of individuals with bipolar disorder (BD) treated with an antidepressant experience antidepressant-induced mania (AIM). Numerous clinical risk factors have been identified but the only genetic risk factor found is the “S” allele or “SS” genotype of HTTLPR, a polymorphism in the promoter region of SLC6A4. We sought to investigate whether metabolizer status of five Cytochrome P450 genes, which encode for enzymes involved in the degradation of medications in the liver played a role in AIM. Methods26 AIM+/25AIM− individuals were identified from the Toronto BD sample, via a blind retrospective analysis of two questionnaires and life charts. Genotyping was performed using pre-plated Taqman assays and metabolizer status was assigned based on the Clinical Pharmacogenetics Implementation Consortium guidelines. ResultsConcurrent use of mood stabilizer had a protective effect against AIM (p = 0.0001). No significant association between metabolizer status and AIM for the CYP genes was observed. When we grouped poor metabolizers (PM) and intermediate metabolizers (IM) we identified a nominal trend (p = 0.14) towards them being at a greater risk of experiencing AIM. In an additive model, combining CYP2D6 metabolizer status and HTTLPR, PM and IM with the “S” allele were 9× more likely to experience AIM (p = 0.002). DiscussionOur results provide further support for concurrent mood stabilizers having a protective effect against AIM. They also suggest that PM and IM of CYP2D6 may be at a greater risk of AIM. Lastly, combining the risk-allele of the HTTLPR with the risk metabolizer statuses increases the overall risk of AIM.