Neuroinflammation and treatment resistance in major depressive disorder

Major depressive disorder (MDD) is increasingly recognized as a multi-system disease that extends beyond neurotransmitter dysregulation. Treatment-resistant depression (TRD), which affects approximately one-third of patients who do not achieve remission with monoaminergic antidepressants, poses a significant global challenge because of its association with a heightened risk of suicide and impaired social functioning. Low-grade chronic inflammation, a hallmark of TRD, increases blood-brain barrier (BBB) permeability. These inflammatory signals can affect the central nervous system, induce alterations in neural circuits, and contribute to depressive symptom development. A shift is necessary in the treatment of patients with TRD, moving from conventional symptom-based diagnosis to personalized medicine based on biological subtypes using inflammatory markers. In the future, complex interventions that facilitate a restorative immune environment in the brain-such as enhancing the M2 phenotype and restoring homeostasis in the nervous, immune, and endocrine systems-are anticipated to become central to next-generation antidepressant therapies. This review provides a comprehensive overview of the molecular and cellular mechanisms through which peripheral and central inflammation contribute to the pathophysiology of TRD.