Prevalence of Abnormal CYP2D6 Phenotypes in those with Treatment Resistant Depression

This work was sponsored by University of Arizona, College of Medicine - Phoenix Treatment-resistant depression (TRD) affects approximately 30% of patients with depression, and genetic variations in drug-metabolizing enzymes have been implicated in treatment failure. However, the role of abnormal CYP2D6 gene variants in TRD remains unclear. In this retrospective analysis of 356 patients from a large southwestern US hospital system, we investigated the difference in abnormal CYP2D6 variants between those with TRD and those with depression (Non-TRD). TRD was defined as patients who had undergone adequate trials of two different antidepressants and whose symptoms persisted beyond the treatment window, required augmentation, or resulted in a suicide attempt. Non-TRD was defined as those who had been diagnosed with a depressive disorder but did not meet the definition of TRD as reported in their psychiatric treatment record. Our analysis found a significantly greater prevalence of abnormal CYP2D6 variants in those with TRD (47.12%) compared to those with Non-TRD (31.51%) (p=.04). These findings suggest that abnormal CYP2D6 variants play a role in anti-depressant failure, increasing the risk of TRD in affected patients. Our study provides further evidence of the complex genetic factors that influence treatment response in depression. Prospective studies are needed to confirm these findings and to explore the clinical implications for patients with TRD. Such studies could include a more specific definition of categories, such as surveys to determine the extent of TRD and confirm depression remission. Ultimately, a better understanding of the genetic basis of TRD could lead to more personalized treatment approaches and improved outcomes for patients with this challenging condition.