Genomic studies of treatment resistance in major depressive disorder

Abstract

Treatment-resistant depression describes the subset of individuals with major depressive disorder who do not reach symptomatic remission despite multiple adequate treatment trials. While treatment resistance has a substantial impact on functioning, quality of life, and healthcare costs, little is known about the underlying neurobiology. While at least some treatment-resistant depression (TRD) risk is likely to be heritable, based primarily on evidence from antidepressant pharmacogenomics, studies to date have failed to reliably identify rare or common genetic variation associated with this phenotype. Challenges in the study of TRD include misclassification arising from medication intolerance or inadequate treatment trials, the heterogeneity of the concept itself, and most notably the absence of well-characterized cohorts with DNA available for study. New strategies to identify large cohorts from biobanks or disease registries and efforts to meta-analyze multiple cohorts may facilitate the identification of risk variants. In addition, further studies to understand the potential utility of pharmacogenomic testing among individuals with TRD or to stratify risk for TRD are needed.