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

Abstract Introduction Approximately 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. Methods 26 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. Results Concurrent 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). Discussion Our 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.