Treatment-resistant depression

Approximately 30% of patients with major depressive disorder do not respond to two or more adequate antidepressant trials, qualifying as treatment-resistant depression (TRD). Current interventions such as esketamine, ECT, and deep brain stimulation show partial efficacy but lack predictive biomarkers for patient selection. Understanding why standard monoaminergic treatments fail and identifying alternative neurobiological targets (glutamatergic, GABAergic, neuroinflammatory pathways) remains a critical unsolved problem.