JAMA Psychiatry

Genetic biomarker identifies responders to novel agent in treatment-resistant depression

September 12, 2025

Liafensine, a triple reuptake inhibitor, significantly improved outcomes in ANK3-positive patients with treatment-resistant depression (TRD), demonstrating both efficacy and tolerability. These findings support ANK3 as a predictive biomarker and mark the first successful prospective biomarker-guided study in psychiatry.

Study details: The ENLIGHTEN randomized, double-blind, placebo-controlled phase 2b study (NCT05113771) evaluated liafensine in patients with TRD who tested positive for ANK3. A total of 189 ANK3-positive patients were randomized to receive liafensine (1 mg or 2 mg daily) or placebo for 6 weeks. Primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Secondary endpoints included change from baseline to day 42 in Clinical Global Impression–Severity (CGI-S) score, CGI-Improvement (CGI-I) score at day 42, and change from baseline to day 42 in Sheehan Disability Scale (SDS) score.

Results: Liafensine demonstrated a 4.4-point MADRS improvement over placebo at day 42 (P=0.006), a statistically and clinically meaningful effect. Secondary endpoints also favored liafensine. Treatment completion rates were higher in the liafensine groups (84.0%) vs. placebo (76.6%), and discontinuation due to adverse events was lower with liafensine (4.0% vs 14.1%).

Source:

Wang G, et al. (2025, September 10). JAMA Psychiatry. ANK3 as a Novel Genetic Biomarker for Liafensine in Treatment-Resistant Depression: The ENLIGHTEN Randomized Clinical Trial. https://pubmed.ncbi.nlm.nih.gov/40928787/