A conceptual framework based on current and emerging treatments for treatment-resistant depression: mechanistic evolution, clinical evidence, and future directions.

Abstract

Treatment-resistant depression (TRD) represents an unmet challenge, accounting for disproportionate morbidity, disability, and healthcare burden in depression. Limitations of monoaminergic antidepressants have prompted a conceptual shift toward models emphasizing impaired neuroplasticity, synaptic dysfunction, and network dysregulation. This expert review synthesizes preclinical, translational, and clinical literature on depression pathophysiology from monoamine-based frameworks to models centered on synaptogenesis, glutamatergic signaling, neurotrophic regulation, inflammation, and brain networks. The authors outline a conceptual progression from monoaminergic models to neuroplasticity and synaptic remodeling and ultimately to network connectivity models of depressive illness, interpreting TRD treatments within this mechanistic framework. The authors review established and emerging treatments, including pharmacologic therapies, neuromodulation, antidepressants, and experimental plasticity-based interventions. Relevant literature was identified through PubMed and Google Scholar searches using terms related to treatment-resistant depression, neuroplasticity, ketamine, and neuromodulation, covering foundational studies through 2026. TRD is conceptualized as impaired neural adaptability rather than neurotransmitter deficiency. Treatments reopening plasticity windows and recalibrating dysfunctional networks, such as ketamine, neuromodulation, and psychedelics, represent a paradigm shift in antidepressant development. The framework presented here is a conceptual synthesis rather than treatment guidelines, and prospective studies are needed to determine how mechanistically informed models can be validated and applied clinically.