The Genetics of Treatment-Resistant Depression: A Critical Review and Future Perspectives

Background: One-third of depressed patients develop treatment-resistant depression with the related sequelae in terms of poor functionality and worse prognosis. Solid evidence suggests that genetic variants are potentially valid predictors of antidepressant efficacy and could be used to provide personalized treatments. Methods: The present review summarizes genetic findings of treatment-resistant depression including results from candidate gene studies and genome-wide association studies. The limitations of these approaches are discussed, and suggestions to improve the design of future studies are provided. Results: Most studies used the candidate gene approach, and few genes showed replicated associations with treatment-resistant depression and/or evidence obtained through complementary approaches (e.g., gene expression studies). These genes included GRIK4, BDNF, SLC6A4, and KCNK2, but confirmatory evidence in large cohorts was often lacking. Genome-wide association studies did not identify any genome-wide significant association at variant level, but pathways including genes modulating actin cytoskeleton, neural plasticity, and neurogenesis may be associated with treatment-resistant depression, in line with results obtained by genome-wide association studies of antidepressant response. The improvement of aggregated tests (e.g., polygenic risk scores), possibly using variant/gene prioritization criteria, the increase in the covering of genetic variants, and the incorporation of clinical-demographic predictors of treatment-resistant depression are proposed as possible strategies to improve future pharmacogenomic studies. Conclusions: Genetic biomarkers to identify patients with higher risk of treatment-resistant depression or to guide treatment in these patients are not available yet. Methodological improvements of future studies could lead to the identification of genetic biomarkers with clinical validity.