Genetic Framework Identifies Depression Drug Targets and Repurposing Opportunities
A genetic framework using Mendelian randomization identified and prioritized drug targets for major depression from over 525,000 cases. The study found drugs targeting genetically supported proteins are 2.6 times more likely to succeed and prioritized 54 repurposing opportunities using existing medications for other conditions.
A new research framework using genetic methods has identified and prioritized drug targets for major depression, revealing potential repurposing opportunities for medications already approved for other conditions. The study found that drugs targeting genetically supported proteins are 2.6 times more likely to succeed in drug development, underscoring the value of genetic evidence in depression drug discovery.
The researchers leveraged genome-wide association study summary statistics from more than 525,000 major depression cases and derived exposure data from 10 datasets measuring protein quantitative trait loci and gene expression levels in blood, cerebrospinal fluid, and brain tissues. They performed cis-Mendelian randomization on 3,469 druggable targets — genes encoding proteins targeted by existing compounds or experimentally predicted to be druggable. To strengthen causal inference, the team implemented robust Mendelian randomization estimators, colocalisation, external replication, and assessed directional consistency across tissues.
The researchers integrated cis-Mendelian randomization effect directions with drug mechanisms and clinical annotations to infer potential therapeutic effects. Validation analyses showed that 82% of drugs approved for depression or anxiety had at least one significant Mendelian randomization target, compared to 51% for compounds in clinical trials.
For repurposing purposes, the team prioritized 54 targets of compounds developed for other conditions with estimated beneficial effects on major depression. Ten high-priority targets of brain-penetrating compounds included ACE and NISCH (cardiovascular drugs), NDUFA2, NDUFB6, and NDUFS1 (metformin), CDK4, NTRK3, and MET (oncology inhibitors), and GLS and NOS2 (enzyme inhibitors).
The study found genetic evidence for established and novel major depression targets across the drug development pipeline. The novel targets point to mechanisms beyond monoaminergic systems, most with approved drugs for other conditions, offering immediate repurposing opportunities for depression treatment.