Pharmacogenetics of antidepressants, mood stabilizers, and antipsychotics in diverse human populations

Abstract

An increasing focus on personalized medicine is driving a renewed effort to understand the impact of ethnic and genetic background on treatment outcomes. Since responses to psychopharmacological treatments continue to be sub-optimal, there is a pressing need to identify markers of tolerability and efficacy. Pharmacogenomic studies aim to find such markers within the human genome, and have made some progress in recent years. Progress has been slower in populations with diverse racial and ethnic backgrounds. Here we review 10 genome-wide association studies (GWAS) that assessed outcomes after antidepressant, antipsychotic, or mood stabilizer treatment. These studies used samples collected by the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), Sequenced Treatment Alternatives to Relieve Depression (STAR*D), and Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) studies. We highlight findings from African American and European American participants since they are the largest groups studied, but we also address issues related to Asian and Hispanic groups. None of the GWAS we reviewed identified individual genetic markers at genome-wide significance, probably due to limited sample sizes. However, all the studies found poorer outcomes among African American participants. Some of this disparity seems to be explained by psychosocial and economic disadvantages, but at least 2 studies found that widespread genetic differences between participants of European and African ancestry also play an important role. Non-European groups are underrepresented in these studies, but the differences that are evident so far suggest that poorer outcomes among African Americans are not inevitable and may be particularly suited to pharmacogenomic strategies. The vision of more personalized psychopharmacology may critically depend on larger studies in more diverse human populations.

Figure 1. African Ancestry and Response to Antidepressant Treatment

Note. STAR*D data for individuals who were not African-American or European-American race by self-report. Bars represent proportion of African Ancestry in this subsample divided into quartiles. Fourth quartile contains individuals with 13.7% or more African ancestry. Figures represent percent change (reduction) in depressive symptom scores from baseline to exit (e.g., 0.5 = 50% reduction in depressive symptoms). African Ancestry Estimates obtained from STRUCTURE analysis. For QIDS-C, n = 85; for QIDS-SR, n=82.