A conceptual framework based on current and emerging treatments for treatment-resistant depression: mechanistic evolution, clinical evidence, and future directions.
Stephen Rush, Henry A Nasrallah
Expert review of neurotherapeutics July 1, 2026 Peer reviewed DOI: 10.1080/14737175.2026.2675008 via PubMed
Summary
Treatment-resistant depression (TRD) is increasingly viewed as a result of impaired neuroplasticity rather than just neurotransmitter deficiencies. This review discusses the shift from traditional monoamine-based models to those focusing on synaptogenesis and glutamatergic signaling. It highlights treatments like ketamine and neuromodulation that aim to enhance neural adaptability and recalibrate dysfunctional brain networks. The authors emphasize the need for prospective studies to validate these mechanistic models in clinical settings.
Study at a glance
| Design | review |
|---|---|
| Key finding | TRD is conceptualized as impaired neural adaptability, with treatments like ketamine representing a paradigm shift in antidepressant development. |
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.