Mechanisms and management of treatment-resistant depression in clinical psychiatry

Abstract

Treatment-resistant depression (TRD) is a severe and persistent form of major depressive disorder characterized by inadequate response to at least two antidepressant treatments of adequate dose and duration. It affects a substantial proportion of patients and is associated with chronic symptoms, functional impairment, and elevated suicide risk. The underlying mechanisms are multifaceted, involving disrupted neurocircuitry, impaired neuroplasticity, neuroinflammation, and dysregulation of the hypothalamic-pituitary-adrenal axis. Structural and functional brain imaging studies have identified consistent abnormalities in the prefrontal-limbic networks, particularly in regions such as the subgenual anterior cingulate cortex and dorsolateral prefrontal cortex. Inflammatory markers including interleukin-6 and C-reactive protein are frequently elevated in TRD populations, linking immune system activation to poor antidepressant response. Diagnosis of TRD is complicated by the absence of universal criteria, variability in clinical assessment, and confounding psychiatric or medical comorbidities. Misclassification is common due to incomplete treatment histories and inconsistent use of structured diagnostic tools. Recent advances in treatment include glutamatergic agents such as esketamine, non-invasive neuromodulation techniques like theta burst stimulation, and the emergence of digital monitoring tools to guide personalized care. Psychedelic-assisted therapy is also gaining clinical interest, supported by preliminary evidence of rapid and sustained antidepressant effects. As research progresses, there is increasing emphasis on integrating biomarkers, neuroimaging, and functional outcomes into future diagnostic and therapeutic frameworks.