Files
Division
East Florida
Hospital
HCA Florida Aventura Hospital
Specialty
Psychiatry
Document Type
Poster
Publication Date
2025
Keywords
treatment resistant depression, clinical trial, Liafensine
Disciplines
Mental Disorders | Psychiatry | Psychiatry and Psychology
Abstract
Background: Treatment-resistant depression (TRD) remains a significant unmet need, affecting about one third of patients with major depressive disorder who fail to respond to two or more antidepressant trials. There is a need for new pharmacological approaches. Liafensine (also known as DB104) is a first-in-class triple reuptake inhibitor targeting serotonin, norepinephrine, and dopamine transporters, whose development has recently incorporated a precision medicine approach. Mechanism of Action: Liafensine inhibits reuptake of all three major monoamines (serotonin, norepinephrine, and dopamine) distinguishing it from existing SSRIs, SNRIs, or other agents which typically target one or two systems. A genetic biomarker, ANK3 (also called DGM4), has been identified as predictive of treatment response. Approximately 20% of TRD patients carry the ANK3-positive genotype, which appears to correlate with improved efficacy in clinical trials. Clinical Evidence: -Phase 2b ENLIGHTEN trial → enrolled 189 ANK3-positive treatment-resistant depression patients. Patients were then randomized to receive either: liafensine 1 mg, liafensine 2 mg, or placebo daily, over 6 weeks. -The primary outcome (change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 6), → revealed a mean reduction of −15.4 in liafensine-treated patients vs −11.0 in placebo, resulting in a mean treatment difference of −4.4 points (95% CI, −7.6 to −1.3; p = .006). -Secondary outcomes (Clinical Global Impression-Severity, Clinical Global Impression-Improvement, Sheehan Disability Scale) were also positive for liafensine. Patients began to improve during the first week. -Research shows ideal dosing is low: both 1 mg and 2 mg daily showed similar efficacy, with better tolerability at 1 mg. -Limitations: relatively short trial duration (6 weeks), limited long-term data, and the fact that efficacy was only demonstrated in the ANK3-positive subgroup (populations without this biomarker in earlier trials did not show benefit). Conclusion: Research shows liafensine is a new drug therapy for treatment resistant depression when applied in a biomarker-guided fashion. The ENLIGHTEN trial shows clinically meaningful benefits with good safety in ANK3‐positive patients. Further longer-term trials and studies in diverse populations are needed to establish its place in practice.
Original Publisher
HCA Healthcare Graduate Medical Education
Recommended Citation
Narvaez, Karla; Masud, Saad; and Callahan, Richard, "Emerging Role of Liafensine in the Treatment of Treatment Resistant Depression: Insights from the Enlighten Trial" (2025). East Florida Division GME Research Day 2025. 45.
https://scholarlycommons.hcahealthcare.com/eastflorida2025/45