Treatment-Resistant Depression: A Psychiatry Perspective on Pathophysiological Mechanisms, Biomarkers, and Novel Therapeutic Frontiers
INNOVAPATH June 22, 2026 Muhammad Bilal Akram, Ali Sher, Areena Fatima et al.
Treatment-resistant depression (TRD) affects many people with major depressive disorder who do not get better after adequate medication. TRD is a varied condition driven by complex interactions among brain, immune, and social factors. Better understanding of its causes—including brain inflammation, problems with how brain cells communicate, and hormone imbalances—has helped identify possible markers for diagnosis and new treatments. This perspective discusses these underlying mechanisms, highlights promising biomarkers for diagnosis and treatment planning, and covers emerging therapies such as fast-acting antidepressants, brain stimulation, and psychedelic-assisted therapy. Combining these advances into medical care may allow more personalized and effective management of TRD.