ANK3 Biomarker Unlocks Liafensine’s Potential in Treatment-Resistant Depression
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Published: JAMA Psychiatry, September 10, 2025 (pubmed)
Study: ENLIGHTEN Trial – ANK3 as a Novel Genetic Biomarker for Liafensine in TRD
🔎 Background
Liafensine, a triple reuptake inhibitor (serotonin, norepinephrine, dopamine), had previously failed in large trials without biomarker selection. However, retrospective analyses suggested that patients with a specific genetic marker—ANK3 (rs12217173)—may preferentially respond. This trial prospectively tested that hypothesis.
🧪 Study Design
Type: Multicenter, randomized, double-blind, placebo-controlled phase 2b trial
Sites: 58 sites across the US, Canada, and China
Participants: 189 patients with TRD positive for ANK3 biomarker
Intervention: Liafensine 1 mg daily, 2 mg daily, or placebo for 6 weeks
Primary Outcome: Change in MADRS score (Montgomery-Åsberg Depression Rating Scale) at day 42
📊 Key Results
Primary outcome:
- Liafensine (1 mg + 2 mg combined): −15.4 MADRS
- Placebo: −11.0 MADRS
- Mean difference: −4.4 points (p = .006), effect size = 0.42
Both doses effective:
- 1 mg: −4.4 vs placebo (p = .02)
- 2 mg: −4.5 vs placebo (p = .02)
Secondary outcomes:
- Significant improvements in CGI-S, CGI-I, and Sheehan Disability Scale
- Response and remission rates higher in liafensine group
Safety:
- Generally well tolerated, with no signals of sedation, dissociation, metabolic dysfunction, or abuse liability
- Most common AEs: nausea, headache, constipation
- Discontinuation rates lower at 1 mg compared with 2 mg
🔬 Mechanism of Precision
- The ANK3 gene encodes a scaffolding protein critical for neuronal signaling and transporter regulation. Its identification as a predictive biomarker allowed the enrichment of this trial with only ANK3-positive patients, marking the first successful biomarker-guided antidepressant trial in psychiatry.
🩺 Clinical Implications
Proof of concept: Demonstrates that precision medicine in psychiatry is achievable—similar to oncology, where drug development is tied to biomarkers.
Efficacy signal: Liafensine may become the first biomarker-based antidepressant, offering a new mechanism for TRD beyond esketamine or atypical antipsychotic augmentation.
Practical dosing: 1 mg appears preferable for balancing efficacy and tolerability.
Future direction: Phase 3 trials in ANK3-positive patients could establish liafensine as a new standard for TRD.
✅ Clinical Takeaway
Liafensine demonstrated statistically significant and clinically meaningful benefit in ANK3-positive patients with TRD, with a favorable safety profile. This is the first prospective biomarker-guided trial in psychiatry and signals a new era of precision medicine for depression.
📚 References
- Wang G, Aguado M, Spear MA, Alphs L, Chen C, Huang H, Lu XX, Doostzadeh J, Wu S, Wang S, Patel A, Nemeroff CB, Wang Z, Li A, Luo W. ANK3 as a Novel Genetic Biomarker for Liafensine in Treatment-Resistant Depression: The ENLIGHTEN Randomized Clinical Trial. JAMA Psychiatry. 2025 Sep 10:e252416. doi: 10.1001/jamapsychiatry.2025.2416. Epub ahead of print. PMID: 40928787; PMCID: PMC12423948. (Pubmed)
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