Aug 2026· African Journal of Biomedical Research· Vol 29· 0 citations
TL;DR
Inflammation contributes to MDD in some patients, but single-marker diagnosis and routine anti-inflammatory treatment are not currently justified, and biomarker-stratified trials are needed to develop precision therapies.
Abstract
Background: Major depressive disorder (MDD) is heterogeneous, and low-grade systemic inflammation may contribute to illness in a clinically relevant subgroup.
Methods: This narrative review examined human studies published between January 2010 and June 2026, prioritizing systematic reviews, meta-analyses, cohort studies, central biomarker research, and randomized trials.
Results: Approximately one-quarter of patients with depression have CRP levels above 3 mg/L, supporting an inflammatory phenotype rather than a universal inflammatory model. Immune signals may affect brain function through blood–brain barrier, neural, neurovascular, and metabolic pathways, influencing neurotransmission, stress regulation, oxidative balance, and neuroplasticity. CRP is the most accessible clinical marker, but no biomarker reliably identifies inflammatory depression. Anti-inflammatory treatments show inconsistent benefits, with the strongest signals observed in biomarker-selected patients.
Conclusion: Inflammation contributes to MDD in some patients, but single-marker diagnosis and routine anti-inflammatory treatment are not currently justified. Biomarker-stratified trials are needed to develop precision therapies.
Major depressive disorder (MDD) affects an estimated 280 million people worldwide and remains a leading cause of disability. The monoamine hypothesis, and later the neuroplasticity hypothesis, transformed treatment but leave a substantial share of patients with delayed response, partial remission, or outright treatment resistance. Over the past two decades, evidence has accumulated that a subset of MDD is driven by chronic, low-grade neuroinflammation rather than, or in addition to, monoaminergic deficits.
This review synthesizes current evidence on the neuroimmune mechanisms involved in MDD microglial activation, pro-inflammatory cytokine signaling, blood–brain barrier disruption, oxidative stress, kynurenine pathway dysregulation, and impaired neuroplasticity and examines how these mechanisms are captured by peripheral, central, neuroimaging, and emerging molecular biomarkers. It then reviews therapeutic strategies that target inflammation directly (minocycline, celecoxib, TNF-α antagonists), indirectly (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), ketamine), or through lifestyle modification (exercise, diet, sleep), with attention to why inflammation-stratified trials have outperformed unstratified ones.
Across mechanisms, biomarkers, and treatment response, a consistent pattern emerges: neuroinflammation does not simply co-occur with depression, it may mark a biologically distinct, identifiable subtype roughly a quarter to a third of patients with elevated high-sensitivity C-reactive protein (hsCRP) or IL-6 for whom anti-inflammatory or immune-modulating strategies produce disproportionate benefit. Overall, the findings suggest that neuroinflammation represents a promising and increasingly actionable target for biomarker-guided, personalized psychiatric care.
Zvikomborero Murimbechi· World Journal of Advanced Re...· 0 citations
BACKGROUND
Growing evidence indicates that immune dysfunction contributes to the heterogeneity of major depressive disorder, yet it remains unclear when inflammation is clinically relevant, how it manifests in symptomatology and brain structure, and for whom immune-related mechanisms may be most important. Clarifying these questions is essential for patient stratification and the development of immunomodulatory treatments.
METHODS
Clinical, biochemical, and neuroimaging data from 176 hospitalized adults with DSM-5 major depressive disorder was involved. Peripheral inflammation was assessed using routinely available markers, including C-reactive protein (CRP) and the neutrophil-to-lymphocyte ratio (NLR), and a high-inflammation subgroup was defined using literature-based thresholds (CRP > 3.0 mg/L and/or NLR > 3.53). Depressive symptoms, functioning, and illness severity were evaluated from structured clinical records. Voxel-based morphometry analyses were conducted to investigate associations between inflammatory markers and gray matter volume.
RESULTS
Approximately one-third of patients met criteria for an inflammation-associated subtype. In univariate analyses, CRP was nominally higher in patients with anhedonia and suicide attempt, though neither association survived FDR correction. After adjusting for age, sex, and BMI, CRP was independently associated with suicide attempt (OR = 1.221, p = 0.004) and suicidal plan (OR = 1.173, p = 0.021), while the anhedonia association was no longer significant. CRP correlated with higher CGI-S (ρ = 0.193, pFDR = 0.041) and predicted both GAF and CGI-S in covariate-adjusted models. NLR showed no significant associations with any symptom or clinical severity measure. The high-inflammation subgroup was characterized by older age, higher BMI, and later age at illness onset, without significant differences in symptoms, CGI-S, or GAF after covariate adjustment. Exploratory VBM analyses revealed CRP-related gray matter increases in the left middle and inferior temporal gyrus and decreases in occipital and inferior parietal regions, while NLR was associated with increased volume in the right thalamic nuclei and decreased volume in the right superior temporal gyrus; subgroup contrasts indicated greater occipital and cuneus volume in the low-inflammation group and greater temporal pole volume in the high-inflammation group, with all findings reported at uncorrected thresholds.
CONCLUSIONS
Our findings suggest that CRP, a routinely available inflammatory marker, is independently associated with suicidality and clinical severity in severely depressed inpatients, even after accounting for confounders. The divergent neuroanatomical correlates of CRP and NLR, though exploratory, point to distinct inflammatory pathways with regionally specific brain signatures. These findings support the potential utility of CRP in identifying a clinically relevant inflammatory dimension within severe depression. Prospective studies with larger samples are needed to replicate these associations, clarify the temporal dynamics of inflammation in depression, and evaluate whether inflammatory stratification can guide treatment selection.
I. K. Sabitay, Muhammed Ballı, S. S. Kirlioglu Balcioglu et al.· Brain, behavior, and immunit...· 0 citations
Major depressive disorder (MDD) is one of the leading psychiatric causes of disability worldwide and is characterized by marked heterogeneity, high recurrence risk, and low treatment rates. Traditional models have emphasized monoaminergic neurotransmitter imbalance, hypothalamic-pituitary-adrenal axis dysfunction, structural and functional brain remodeling, and inflammatory activation. Although these perspectives have substantially advanced our understanding of MDD, they do not fully account for its complex pathogenesis, and further investigation may support the development of novel prevention and treatment strategies. Increasing evidence indicates that MDD is closely associated with endocrine and metabolic abnormalities. This review summarizes evidence suggesting that endocrine and metabolic dysregulation may provide mechanistic insights into symptom burden, variability in disease progression, and treatment difficulties in certain patients. Particular attention is given to five interrelated domains: shared genetic and environmental susceptibility, dysfunction of the hypothalamic-pituitary-target gland axes, chronic low-grade inflammation and immune imbalance, impaired insulin signaling, and disruption of cerebral energy metabolic homeostasis. The review further explores potential clinical implications, including targeted endocrine and metabolic assessment, metabolism-related pharmacological strategies, modulation of the gut-brain axis, and lifestyle interventions. Rather than simply describing associative findings, this review aims to identify endocrine and metabolic abnormalities with potential predictive, modifiable, and clinically meaningful value, thereby providing a cautious and evidence-based framework for future risk assessment, disease-course interpretation, and adjunctive treatment of depression.
Ee Chang, Yiran Zhu, Wei Wei et al.· Neurobiology of Disease· 1 citation
Major depressive disorder (MDD) and metabolic syndrome (MetS) frequently exhibit high comorbidity, with the latter characterized primarily by insulin resistance, dyslipidemia, and abdominal obesity. Growing evidence suggests that immune-inflammatory dysregulation constitutes a shared pathobiological basis for both conditions. This review focuses on the roles of innate and adaptive immune responses in this context, including glial cell activation, blood-brain barrier disruption, microglial polarization, and T/B cell functional imbalance, which collectively contribute to a systemic chronic low-grade inflammatory state. We further integrate the bidirectional regulatory effects of key immune signaling pathways—such as TLR4–NF-κB, PI3K–Akt–mTOR, and JAK–STAT—in central neuroinflammation and peripheral metabolic dysfunction. These intertwined mechanisms influence mood regulation and synaptic plasticity while exacerbating insulin resistance and lipid abnormalities. Additionally, we discuss the potential value of immune markers, including GFAP, CTRP3, IL-6, and IFN-γ, in disease subtyping and risk assessment, and evaluate the prospects of novel anti-inflammatory intervention strategies for precision therapy. Finally, we highlight the current limitations in translational research and advocate for systematically integrated multi-omics and longitudinal cohort studies to advance precise interventions and personalized management of depressive-metabolic comorbidity.
Xinxin Wang, Bo Zhang, Ran Xia et al.· Discover Neuroscience· 0 citations
Background Depression is increasingly recognized as a multisystem disorder involving interconnected neuroinflammatory, neuroendocrine, metabolic and gut–brain mechanisms rather than isolated neurotransmitter abnormalities. Emerging evidence suggests that dysregulation of cytokine activity, hypothalamic–pituitary–adrenal (HPA) axis function, oxidative stress, mitochondrial dysfunction and gut microbiota collectively contribute to depressive pathophysiology. This review aimed to synthesise current evidence on these biological interactions and evaluate the potential role of nutritional modulation in influencing these pathways. Summary A PRISMA-informed systematic review was conducted using PubMed, Scopus, Web of Science, Embase, PsycINFO and Google Scholar for studies published between 2010 and 2025. Thirty-five eligible studies were included. The evidence demonstrates a self-reinforcing biological network in which chronic stress activates the HPA axis, leading to glucocorticoid receptor resistance, increased pro-inflammatory cytokines, neuroinflammation, oxidative stress and gut microbiota dysbiosis. These interconnected mechanisms contribute to depressive symptoms and may perpetuate disease progression. Nutritional interventions, including Mediterranean dietary patterns, omega-3 fatty acids, dietary fibre, probiotics, polyphenols and selected micronutrients, consistently showed potential to reduce inflammation, regulate HPA axis activity, improve gut microbial balance and mitigate oxidative stress. Key Message Depression should be conceptualised as a complex multisystem disorder driven by dynamic interactions among immune, endocrine, metabolic and microbiota-related pathways. Nutritional modulation represents a promising adjunctive strategy capable of targeting these interconnected biological mechanisms. Future longitudinal and interventional studies integrating multi-omics approaches are needed to validate causal pathways and develop personalised nutrition-based interventions for depression.
Saranya Ts, Şebnem Yücel, Sandeep Kumar Gupta et al.· Annals of Neurosciences· 0 citations
This review addresses the high prevalence of depression and anxiety in systemic sclerosis (SSc), as well as the core biological, psychological and social mechanisms underlying such psychiatric comorbidities, The prevalence of clinically significant depression or anxiety disorders reaches 30%–50% among patients with SSc who satisfy corresponding diagnostic criteria. Established risk factors encompass multi-organ involvement (e.g., lung fibrosis, digital ulcers), chronic pain, physical disability and disease-related stigma. Three key pathophysiological mechanisms drive this comorbidity: immune dysregulation induces neuroinflammation via pro-inflammatory cytokines (IL-6, TNF-α), pathogenic autoantibodies and gut-brain axis disruption; cerebral microvascular damage and chronic hypoxia impair emotion-regulating neural circuits; tissue fibrosis and persistent stress over activate the HPA axis, forming a pathogenic cycle connecting systemic inflammation, glucocorticoid resistance and negative mood. Clinical management of SSc should extend beyond conventional antidepressants and cognitive behavioral therapy to include integrated rheumatology-psychiatry care, IL-6/JAK-targeted biologics and transcutaneous vagus nerve stimulation (tVNS), all designed to ameliorate patients’ physical and psychiatric symptoms simultaneously. In conclusion, psychiatric comorbidity in SSc stems from the intricate interplay of biological, psychological and social factors. Elucidating these mechanisms facilitates the development of targeted therapeutic strategies that address both systemic SSc manifestations and associated mental health conditions, thereby enhancing patients’ health-related quality of life and long-term psychiatric outcomes.
Jia-Xin Chen, Ronghong Guo, Xian-Zhe Zhou et al.· Frontiers in Immunology· 0 citations
