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<p>Major Depressive Disorder (MDD) stands as a foremost contributor to global disability, with a substantial proportion of patients failing to achieve remission through conventional antidepressant therapies. This review positions neuroinflammation as a central pathophysiological mechanism and examines immunotherapy as a promising frontier for a biologically defined subset of patients. We synthesize current evidence detailing how peripheral immune activation, driven by pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, disrupts neural homeostasis through blood-brain barrier (BBB) compromise, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and a shift in tryptophan metabolism toward the neurotoxic kynurenine pathway. We further analyze the heterogeneous immunomodulatory effects of conventional antidepressants—including tricyclic antidepressants and selective serotonin reuptake inhibitors—and critically assess inflammatory cytokines as predictive biomarkers for differential treatment responses. While elevated inflammation is generally linked to resistance to traditional monoaminergic drugs, it may predict enhanced responsiveness to glutamatergic agents such as ketamine or to direct anti-cytokine strategies. Finally, we systematically evaluate the rationale and emerging evidence for cytokine-targeted immunotherapies, including anti-IL-6 receptor agents, TNF-α inhibitors, and NLRP3 inflammasome blockers. We conclude that realizing the full potential of immunotherapy in MDD necessitates a paradigm shift toward biomarker-guided patient stratification, standardized inflammatory profiling, and rigorously designed clinical trials to establish both efficacy and safety.</p>

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Immunotherapy for depression: targeting cytokine pathways in major depressive disorder

  • 期刊论文

  • 发表日期：

    2026年4月29日

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  • Chenyang Long,
  • Guirui Zhang,
  • Zihao Jiang,
  • Feifeng Yang,
  • Jin Wang

摘要

Major Depressive Disorder (MDD) stands as a foremost contributor to global disability, with a substantial proportion of patients failing to achieve remission through conventional antidepressant therapies. This review positions neuroinflammation as a central pathophysiological mechanism and examines immunotherapy as a promising frontier for a biologically defined subset of patients. We synthesize current evidence detailing how peripheral immune activation, driven by pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, disrupts neural homeostasis through blood-brain barrier (BBB) compromise, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and a shift in tryptophan metabolism toward the neurotoxic kynurenine pathway. We further analyze the heterogeneous immunomodulatory effects of conventional antidepressants—including tricyclic antidepressants and selective serotonin reuptake inhibitors—and critically assess inflammatory cytokines as predictive biomarkers for differential treatment responses. While elevated inflammation is generally linked to resistance to traditional monoaminergic drugs, it may predict enhanced responsiveness to glutamatergic agents such as ketamine or to direct anti-cytokine strategies. Finally, we systematically evaluate the rationale and emerging evidence for cytokine-targeted immunotherapies, including anti-IL-6 receptor agents, TNF-α inhibitors, and NLRP3 inflammasome blockers. We conclude that realizing the full potential of immunotherapy in MDD necessitates a paradigm shift toward biomarker-guided patient stratification, standardized inflammatory profiling, and rigorously designed clinical trials to establish both efficacy and safety.