Drugs Modulating Neuroplasticity and Neurotrophicity: Amdiglurax, Liafensine, and Genetic Precision Approaches in Treatment Resistant Depression

Treatment-resistant depression (TRD) affects approximately 30% of patients with major depressive disorder who fail to respond adequately to at least two antidepressant trials, representing 2.8 million adults in the United States alone and imposing an economic burden exceeding $43 billion annually [1]. Emerging pharmacological agents targeting neuroplasticity and neurotrophic pathways—including the hippocampal neurogenesis stimulator amdiglurax and the triple monoamine reuptake inhibitor liafensine—represent paradigm shifts in depression treatment [2,3]. The recent identification of ANK3 as a predictive genetic biomarker for liafensine response marks the first successful prospective biomarker-guided clinical trial in psychiatry, demonstrating statistically significant improvements in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (4.4point reduction, p=0.006) in ANK3-positive patients with TRD [4]. This review synthesizes contemporary evidence on neuroplasticity-modulating antidepressants, rapid-acting glutamatergic agents, and precision medicine approaches, emphasizing the mechanistic role of brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR) signaling, and synaptic plasticity in antidepressant efficacy [5,6]. Understanding these neurobiological mechanisms and implementing pharmacogenomic stratification strategies may optimize treatment selection, reduce trial-and-error prescribing, and improve outcomes for this highly morbid patient population [7].