One-Third of Patients with Treatment-Resistant Depression May Benefit from Targeting Brain Immune-Inflammatory Pathways
Background
Major Depressive Disorder (MDD) is a highly prevalent and debilitating mental illness worldwide. For decades, the dominant hypothesis in psychiatry has been that a deficiency in monoamine neurotransmitters, such as serotonin and norepinephrine, is the core cause of depression. Existing antidepressants, including Selective Serotonin Reuptake Inhibitors (SSRIs), are based on this hypothesis, but approximately one-third of patients do not achieve adequate treatment response. This gap suggests the existence of pathophysiology that cannot be explained solely by the monoamine hypothesis.
With the accumulation of neuroimmunological research, there is a growing trend to reconstruct the biological mechanisms of depression from the perspective of immune-brain interactions. In particular, evidence is accumulating that activation of glial cells in the brain and chronic low-grade inflammation disrupt neurotransmitter systems, and the view that neuroinflammation may be a core mechanism of the disease itself, rather than a simple accompanying phenomenon, is gaining traction.
Key Findings
In this review article published in Translational Psychiatry on July 3, 2026, the Santerre, Shcherbik, and Sawaya research team systematically summarized the mechanistic basis of the neuroinflammation hypothesis, biomarker stratification strategies, and therapeutic approaches.
Immunological Pathways of Monoamine Disruption. The research team presents three specific mechanisms by which inflammation disrupts the monoamine system. First, inflammatory cytokines activate indoleamine 2,3-dioxygenase (IDO1), which shifts tryptophan metabolism to the kynurenine pathway, depleting the substrate for serotonin synthesis. Second, cytokines such as tumor necrosis factor-alpha (TNF-ฮฑ) and interleukin-6 (IL-6) induce AMPA receptor internalization, impairing glutamatergic signaling and synaptic plasticity. Third, the bidirectional feedback regulation between the hypothalamic-pituitary-adrenal (HPA) axis and the immune system is disrupted, leading to chronic cortisol excess and a self-perpetuating inflammatory cycle.
Multilayered Evidence of Glial Cell Activation. Activation of three lineages of glial cells โ microglia, astrocytes, and oligodendrocytes โ has been identified as a neurobiological feature of depression. Postmortem brain tissue analysis, positron emission tomography (PET) measuring translocator protein (TSPO) density, and brain tissue transcriptomic analysis consistently show microglial activation. The research team evaluated this finding as evidence supporting the view that it is a pathology of depression itself, rather than a result of comorbid physical illness, while also noting that it is not yet in a fully definitive stage.
Biomarker Stratification. C-reactive protein (CRP), IL-6, and TNF-ฮฑ in peripheral blood are elevated in a significant proportion of patients with MDD, and these elevated levels predict poor response to conventional antidepressants while also serving as an indicator to identify patients who are likely to respond preferentially to anti-inflammatory strategies.
Significance and Prospects
This review clearly states that there is a 'substantial subgroup' of depression patients who belong to the immune-inflammatory subtype, and that a different approach is needed for them than the existing monoamine-targeted treatment. A precision psychiatry paradigm that stratifies patients with CRP and other peripheral inflammatory markers and then applies anti-inflammatory strategies may be the key to overcoming treatment-resistant depression.
However, the research team also addressed methodological limitations in a balanced manner. The lack of cellular type specificity of TSPO PET, negative results in some clinical intervention studies, and the incomplete correlation between peripheral markers and central inflammation remain as challenges to be solved. In addition, the causal direction of whether microglial activation is the cause of depression or a result of early pathology is still debated. Despite these limitations, elucidating the immune-brain axis mechanism provides a basis for new drug targets and biomarker-based personalized treatment design for treatment-resistant patients.
Major depressive disorder is among the most prevalent and disabling conditions in global medicine, yet its biological underpinnings remain incompletely understood, and current pharmacological treatments fail to produce adequate responses in approximately one-third of patients. A rapidly accumulating body of evidence has not simply challenged the long-dominant monoamine deficiency hypothesis but has provided a mechanistic framework that may explain many of the observed monoaminergic alterations in depressive cohorts, including IDO1-driven serotonin depletion, cytokine-mediated AMPA receptor internalization, and HPA-immune feedback dysregulation. Neuroinflammation, particularly glial activation across microglial, astrocytic, and oligodendrocyte lineages, and its downstream consequences for tryptophan metabolism, glutamatergic transmission, synaptic plasticity, and neurotrophic signaling, represents a central pathophysiological mechanism in a substantial subgroup of depressed patients. Peripheral inflammatory markers, including C-reactive protein, interleukin-6, and tumor necrosis factor-alpha, are elevated in a significant proportion of individuals with major depressive disorder, and these elevations predict poor response to conventional antidepressants while identifying patients who may respond preferentially to anti-inflammatory strategies. Post-mortem studies, positron emission tomography imaging of translocator protein density, and transcriptomic analyses of brain tissue have collectively provided consistent, though not yet fully definitive, evidence that microglial activation is a neurobiological feature of depression rather than a consequence of comorbid physical illness. This review synthesizes current mechanistic understanding of the neuroinflammatory hypothesis of depression, examines the evidence base from epidemiological, biomarker, neuroimaging, and interventional studies, including null findings and methodological limitations, evaluates emerging therapeut
Currently, treatment-resistant depression patients undergo a trial-and-error process of sequentially trying various antidepressants, but measuring blood inflammatory markers such as CRP and IL-6 at the initial consultation stage can pre-select patients who may benefit from anti-inflammatory combination therapy. In fact, clinical trials are underway to expand the indications of existing anti-inflammatory drugs such as TNF-ฮฑ inhibitors, IL-6 receptor-blocking antibodies, and minocycline for depression, and this review systematically supports the mechanistic basis of these attempts.
From a pharmaceutical industry perspective, IDO1 inhibitors and TSPO ligand-based dual diagnostic and therapeutic strategies may emerge as a new axis in the psychiatric pipeline. Given that past clinical trials that administered anti-inflammatory drugs to all MDD patients without biomarker stratification have shown mixed results, inflammation subtype selection will be a key variable determining success in future trial designs.