The Central Role of Cytokines in PTSD and Major Depressive Disorder: Mechanisms and Clinical Implications

ABSTRACT: Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are debilitating psychiatric conditions that are frequently comorbid and linked to chronic immune dysregulation. Increasing evidence implicates cytokine-mediated inflammation in the pathophysiology of these disorders. Cytokines, key signaling molecules of the immune system, influence central nervous system (CNS) function by crossing the blood-brain barrier or signaling via neural routes, thereby affecting neuronal circuits involved in mood regulation and cognition. Elevated levels of pro-inflammatory cytokines—such as interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ)—have been observed in both peripheral and central compartments of individuals with PTSD and MDD. These molecules contribute to microglial activation, synaptic remodeling, hippocampal atrophy, and altered neurotransmission. Furthermore, chemokines such as CXCL12 and CCL2 are implicated in stress-induced neuroplasticity impairments. Moderating factors, including genetic polymorphisms (e.g, FKBP5, CRP), early-life adversity, sex differences, and exposure type, influence individual vulnerability to immune-related neuropsychiatric outcomes. This review synthesizes current molecular and clinical evidence, highlighting how cytokine dysregulation bridges peripheral inflammation and CNS pathology. It also explores emerging therapeutic strategies targeting inflammatory pathways and discusses the promise of biomarker-based approaches and machine learning for patient stratification and personalized treatment.