The immunological perspective of major depressive disorder: unveiling the interactions between central and peripheral immune mechanisms (2025)

Table of Contents

Introduction

  • Antidepressant has many issues:
    • slow onset of action
    • wide individual variation
    • incosistent long-term efficacy
  • patients with chronic inflammatory diseases have an increased risk of MDD
  • patients wiht MDD show abnormalities in immune activity
  • peripheral and brain inflammatory processes disrupts neurotransmission, impairs neuroplasticity and causes neuropathological changes inside the brain

Peripheral immune and interactions between peripheral and central immune mechanisms

Systemic inflammation

  • systemic inflammation is tipically assessed through inflammatory cytokines.
  • TNF-α enhance IDO activity affecting tryptophan metabolism toward kynurenine (KYN) pathway, reducing serotonin synthesis.
  • KYN activates microglia
  • TNF-α induces depressive like symptoms, anti-TNF-α drugs show efficacy in treating MDD
  • IL-1 promotes activation of the HPA axis
  • IL-6 levels are increased in patients with MDD
  • peripheral inflammatory factors permeate BBB, interfering with neurotransmitter metabolism and neural signal transmission
  • However low dose IL-2 mitigated inflammatory responses, and depressive symptoms in animal models, and, in a clinical phase II study it enhanced response to antidepressant treatments.