Antidepressant Dosing in Major Depression: A Pharmacogenomic Approach

Major depressive disorder (MDD) is the most predominant mental disorder in the United States, with serious and costly health risks if not successfully managed. Pharmacotherapy is a standard option for MDD treatment, but patients often require extensive therapy adjustments to find a suitable regimen. Pharmacogenomics may enable greater precision in antidepressant therapy. Genotypic variations in CYP2D6 and CYP2C19 metabolic enzymes are reliable predictors of serum drug concentration, but the complex dose-response relationship of antidepressants prevents such variations from predicting therapy success. Additionally, ABCBl has been examined for its role in P-glycoprotein efflux of antidepressants in the brain, yet it is still inconclusive as to which variations are correlated with drug response. Current genotypic guidelines are largely proactive and clinical trials utilizing genotypic dosing have shown significant reductions in side effects and health care costs. Further studies of genotypic targets are needed and, if the possible clinical benefits are confirmed, the use of genotyping will be an important tool in optimizing antidepressant therapy

The Effect of CYP3A5 Polymorphism on Kidney Transplant Recipients Given Tacrolimus

Tacrolimus, an immunosuppressant agent indicated for organ transplants, is commonly administered to reduce the risk of renal graft rejection in patients with chronic kidney disease (CKD) and end stage renal disease (ESRD). Due to its narrow therapeutic index and high inter-patient variability, studies have suggested that CYP3A5-based dosing provides specialized regimens which may significantly improve the chances of achieving therapeutic concentrations. According to the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations, extensive (CYP3A5*1/*1) and intermediate metabolizers (CYP3A5*1/*3) require a higher initial dose while poor metabolizers (CYP3A5*3/*3) require a lower initial dose in order to achieve target tacrolimus concentrations. Studies concluded that CYP3A5 expressers present a greater risk for chronic nephrotoxicity and acute transplant rejection, supporting the need to closely monitor patients for severe adverse events. Further trials considering CYP3AS polymorphisms are needed to determine whether this genotype dosing improves clinical outcomes, which includes reducing rejection and toxicity, before testing can be recommended