Efficacy and Safety of Triple Monoamine Reuptake Inhibitors for Major Depressive Disorder: Meta-analysis of Randomised Controlled Trials
Z. Kahveci, D. KaraçamIntroduction
Major depressive disorder (MDD) is a leading cause of disability, and current antidepressants show limited efficacy and tolerability. Triple reuptake inhibitors (TRIs; serotonin–norepinephrine–dopamine) may improve outcomes, particularly anhedonia. Several TRIs (toludesvenlafaxine, amitifadine, liafensine, GSK372475) have been tested in randomized controlled trials (RCTs), but results remain uncertain.
Objectives
To evaluate the efficacy and safety of TRIs versus placebo in adults with MDD.
Methods
Systematic searches of PubMed, Embase, and CENTRAL were conducted (Figure 1). Eligible studies were RCTs ≥6 weeks in adults with MDD, comparing TRIs to placebo/antidepressants, reporting depressive symptom scales or response/remission. Data extraction and risk-of-bias assessment were performed independently.
Results
Five RCTs met criteria. Continuous outcomes (Hedges g) showed substantial heterogeneity (Figure 3). Neutral-effect agents (amitifadine, GSK372475) pooled to SMD −0.08 [−0.37, 0.22], while toludesvenlafaxine showed large effects (Mi 2022 SMD −1.03 [−1.46, −0.60]; Mi 2023 SMD −1.90 [−2.11, −1.69]); subgroup difference significant. Tolerability was generally favorable for toludesvenlafaxine; GSK372475 showed limited efficacy and more adverse events.
Binary outcome (response; RR>1 favors TRI): pooled RR = 1.36 [0.86–2.16] (Figure 2), with high heterogeneity (I²=84.5%). Benefit was driven by toludesvenlafaxine, while other TRIs showed neutral or imprecise effects.
Image 1: Long description.