Evidence is presented that peripheral NIMETOX pathways may lead to neuroinflammation, microglial activation, and neuronal damage and that increased lipid load impairs these central pathways, as well as evidence that peripheral NIMETOX pathways may lead to neuroinflammation, microglial activation, and neuronal damage.
Abstract
Current state-of-the-art neuroimmune, metabolic, and oxidative stress (NIMETOX) knowledge that has been developed in clinical major depressive disorder (MDD) research over the past three decades is explored in this review. Between 1990 and 2000, the acute phase of severe MDD was characterized by the activation of T helper (Th)1 cells and M1 macrophages, leading to immune dysregulation that affects nutritional immunity and alters protein, tryptophan, iron, and lipid metabolism. The latter comprises lower high-density lipoprotein cholesterol, reverse cholesterol transport (RCT), ω3 polyunsaturated fatty acids, heightened lipid peroxidation and atherogenicity. Additionally, immune alterations regulate stress-responsive systems and modify the biological basis of depressive symptoms through neurotoxic effects and reduced neuroprotection. The incremental information acquired from 2000 to 2026 revealed that the acute phase of severe MDD is characterized by immune sensitization, imbalances between the compensatory immunoregulatory system (CIRS) and the immune-inflammatory response system (IRS) and that there are multiple interactions between increased atherogenicity, metabolic syndrome, oxidative stress, and lower antioxidant activity and RCT. Additionally, the NIMETOX pathway may be fuelled by increased expression of TLR4 and NF-κB intracellular signaling driven by increased lipopolysaccharides, lipids, and oxidatively modified epitopes. This paper presents evidence that peripheral NIMETOX pathways may lead to neuroinflammation, microglial activation, and neuronal damage and that increased lipid load impairs these central pathways. This paper assesses the field’s future advancements by conducting a comprehensive examination of the reviewed knowledge base, deep phenotyping, panomics methodologies, and machine learning techniques, including the nomothetic precision approach.
BACKGROUND
Aberrations in neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways are implicated in major depressive disorder (MDD). First-episode simple dysmood disorder (FE-SDMD) without metabolic syndrome offers a unique model to investigate early lipid alterations using a systems biology approach.
METHODS
Plasma samples were collected from 88 university students (44 FE-SDMD, 44 healthy controls). Participants underwent psychiatric assessments, including adverse childhood experiences (ACEs), negative life events (NLEs), depression, anxiety, suicidal behaviors, and insomnia. Untargeted lipid profiling was performed using LC-QTOF-MS, while indices of oxidative and nitrosative stress (ONS) and lecithin-cholesterol acyltransferase (LCAT) activity were assessed. Data was analyzed using machine learning approaches with recursive feature elimination and cross-validation.
RESULTS
FE-SDMD was characterized by increased ceramides (CER), diacylglycerides (DAG), triacylglycerides (TG), sphingomyelins (SM), bis-monoacylglycerol phosphates (BMP), cholestone, and fatty-acyl amino acids (FAAA). DAG, CER, and BMP were the strongest predictors of depression severity and physiosomatic symptoms, whereas cholestone, CER, and SM predicted suicidal behaviors. These lipid modules, together with lowered LCAT and increased ONS, explained substantial variance in depression severity (46.4%), physiosomatic symptoms (42.4%), cognitive-affective symptoms (37.9%), suicidal behaviors (30.1%), insomnia (32%), and anxiety (19.5%). ACEs and NLEs were strongly associated with CER (p < 0.001), DAG (p < 0.01), and cholestone (p < 0.01), revealing coordinated lipidomic networks within a systems biology framework.
CONCLUSION
Early-stage MDD is characterized by lipid dysregulations, which are linked to psychosocial stress exposure, oxidative stress and attenuated reverse cholesterol transport. These lipid modules identify biologically functional pathways associated with early disease and may inform the development of future therapeutic strategies.
V. Sirivatanapa, Pannipa Janta, A. Almulla et al.· Journal of Affective Disorde...· 0 citations
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
A comprehensive understanding of neuroinflammatory mechanisms may provide new opportunities for developing targeted therapeutic interventions and improving clinical outcomes in psychiatric disorders, including patient stratification and enable precision psychiatry.
P. Karwa, Vaibhav Parekar, Sarthak Buttepatil et al.· Current pharmaceutical desig...· 0 citations
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
Depression is increasingly recognized as a multifactorial disorder involving immune, metabolic, and neurobiological disturbances that extend beyond classical monoaminergic hypotheses. Among xenobiotic-based experimental approaches, lipopolysaccharide (LPS) has become a valuable tool for investigating how peripheral inflammatory stimuli are translated into central neurobiological dysfunction. This narrative review aimed to integrate current evidence regarding the mechanisms by which LPS-induced neuroimmune activation contributes to depression-related phenotypes and to discuss the translational relevance of these findings. Literature searches were performed in PubMed, ScienceDirect, and Google Scholar, focusing on studies addressing inflammatory signaling, oxidative imbalance, inflammasome activation, neurotransmitter dysfunction, and experimental modeling strategies. Current evidence suggests that LPS-induced neuroinflammation involves a dynamic interaction between peripheral immune signaling, mitochondrial dysfunction, redox imbalance, and glial activation, establishing self-amplifying mechanisms capable of sustaining chronic inflammatory states. Such alterations profoundly affect kynurenine metabolism, glutamatergic homeostasis, and reward-related neurotransmission, thereby contributing to synaptic dysfunction and behavioral impairment. Experimental findings obtained from animal, cellular, and computational platforms further support the emergence of integrated therapeutic strategies targeting multiple neuroimmune pathways. Collectively, these observations reinforce the concept that neuroinflammation represents a central biological interface linking xenobiotic exposure to depressive-like behavior.
Alissa Maria de Oliveira Martins, Maxsyara Felismino da Silva Soares, Lucas Nóbrega de Oliveira et al.· Journal of Xenobiotics· 0 citations
Major depressive disorder (MDD) is a prevalent psychiatric condition characterized by substantial biological heterogeneity. Evidence suggests that the endocannabinoid system (ECS), which regulates stress responses, emotional processing, and neuroimmune signaling, may contribute to depression pathophysiology. However, clinical studies examining circulating endocannabinoids (eCBs) and N-acylethanolamines (NAEs) in MDD have produced inconsistent findings. We therefore conducted a systematic review and meta-analysis to quantify peripheral alterations in eCBs and NAEs in individuals with MDD. Following PRISMA guidelines, case-control and cross-sectional studies comparing circulating levels of eCBs and NAEs between patients with MDD and healthy controls were identified. Standardized mean differences (SMDs) with 95 % confidence intervals (CIs) were calculated using a random-effects model. Between-study heterogeneity was assessed by using Cochran's Q test and further explored in subgroups analysis. Nine studies, including 514 individuals with MDD and 417 healthy controls, met the inclusion criteria. Patients with MDD exhibited significantly higher circulating levels of anandamide (AEA; SMD = 0.32, 95 % CI: 0.10---0.54, p = 0.005) and palmitoylethanolamide (PEA; SMD = 0.35, 95 % CI: 0.04---0.65, p = 0.03) compared with controls, whereas no significant differences were observed for 2-arachidonoylglycerol (2-AG) or oleoylethanolamide (OEA). Subgroup analyses indicated that the elevation in AEA levels were more pronounced among medicated patients and individuals with psychiatric comorbidities. These findings suggest selective alterations in ECS-related lipid mediators in individuals with MDD and support dysregulation of the ECS-NAE signaling axis in depression. Circulating lipid signaling molecules such as AEA and PEA may represent potential peripheral biomarkers of MDD, although longitudinal and mechanistic studies are needed to clarify the influence of treatment and comorbidities.
Muhammad Yaseen, Wei-Jen Chen, Jane-Pei-Chen Chang et al.· Brain, behavior, and immunit...· 0 citations
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