Precision Medicine in Depression: Response to Antidepressants is Associated with the Interplay Between Genetic variants and Gene Expression Levels in Patient-Derived Neurons

Despite the abundance of approved antidepressants, the majority of depressed patients do not respond to their first prescribed antidepressant, with >30% not responding to subsequent drugs. Multiple studies have been conducted with the aim of identifying variations in genes that are associated with drug response. However, these studies yielded mostly inconsistent results, with robust effects largely related to drug pharmacokinetics. Similarly, differences in gene expression levels between responders and non-responders to antidepressants have largely been poorly reproducible. This is likely due to the fact that a systemic readout of gene expression levels from patients’ blood does not reflect the effects of drugs on the target organ, the brain. In this study, we looked at both genetic variation as well as gene expression levels directly in neurons derived from patients with a known response profile to various antidepressants. We found that the interplay between genetics and neuronal gene expression in genes implicated in mechanisms of drug response is associated with patient response to specific drugs. For example, gene expression levels of the catechol-O-methyltransferase (COMT) gene are associated with response to citalopram in patients with the low activity genotype, and with response to bupropion in patients with mid- or high-activity genotypes. This interplay was assessed also for the DRD2 and BDNF genes in patients treated with either citalopram or bupropion. Our findings indicate the utility of patient-derived neurons in mechanistic disease and drug modeling, and the potential of combining genetics and target organ gene expression levels as biomarkers for drug response.