A conceptual framework based on current and emerging treatments for treatment-resistant depression: mechanistic evolution, clinical evidence, and future directions.
Expert review of neurotherapeutics July 1, 2026 Stephen Rush, Henry A Nasrallah
Treatment-resistant depression may stem from impaired neural adaptability rather than a simple chemical imbalance. This expert review synthesizes research showing a shift from monoamine-based models of depression toward frameworks centered on neuroplasticity, synaptic growth, glutamatergic signaling, and brain network dysfunction. The authors describe how treatments such as ketamine, neuromodulation, and psychedelics may work by reopening windows of plasticity and recalibrating dysfunctional neural networks, representing a paradigm shift in antidepressant development. The review is a conceptual synthesis, not treatment guidelines, and prospective studies are needed to validate and apply these mechanistically informed models clinically.