Neuroinflammation in major depressive disorder: Mechanisms, biomarkers, and emerging therapeutic targets

Neuroinflammation in Major Depressive Disorder: Mechanisms, Biomarkers, and Therapeutic Implications

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.

Neuroinflammation as a Pharmacological Target in Psychiatric Disorders.

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.

β-hydroxybutyrate in depression: Neuropharmacological mechanisms and therapeutic potential.

Therapeutic Potential of Ketamine in Major Depressive Disorder: Pharmacological Insights and Clinical Evidence.

When conventional treatments are ineffective for treating treatment-resistant depression, ketamine offers quick and strong results, marking a paradigm change in psychiatric care.

269. Resolution of inflammation in metabolic mood disorders

Abstract Background Major Depressive Disorder (MDD) frequently co-occurs with obesity, insulin resistance, and other metabolic disorders, conditions that share a state of chronic low-grade inflammation. A substantial subgroup of depressed patients exhibits elevated inflammatory biomarkers such as CRP and IL-6, which predict poorer antidepressant response and increased treatment resistance. Existing anti-inflammatory approaches (e.g., cytokine antagonists, COX-2 inhibitors) provide only modest benefits because they block inflammatory signals without restoring endogenous mechanisms that actively resolve inflammation. Specialized pro-resolving mediators (SPMs), including resolvins, lipoxins, and Annexin-A1, represent an active resolution pathway implicated in both mood regulation and metabolic homeostasis. Preliminary evidence shows impaired resolution signaling in depression-prone FSL rats, suggesting a mechanistic link between unresolved inflammation, metabolic vulnerability, and depressive symptoms. Aims & Objectives This project aims to determine whether enhancing inflammatory-resolution pathways using a novel pro-resolving drug (Compound X) improves depressive-like behavior, metabolic dysfunction, and inflammatory biomarkers. A four-phase translational program evaluates: (1) baseline disturbances in resolution pathways in depression models, (2) the antidepressant-like efficacy of Compound X under normal and high-fat diet conditions, (3) Compound X as an augmentation strategy versus classical anti-inflammatory drugs, and (4) a clinical proof-of-concept trial in patients with inflammation-associated depression. Method We combine mechanistic, behavioral, metabolic, molecular, and clinical approaches. Preclinically, depression-prone FSL rats will be investigated under standard or high-fat diets. Compound X will be tested as monotherapy and in combination with low-dose antidepressants to model treatment resistance. Behavioral readouts include forced swim test, sucrose preference, social interaction, and anxiety-related assays. Metabolic outcomes include OGTT, insulin sensitivity, body weight, liver enzymes, and lipidomics. Inflammatory and resolution markers (CRP, cytokines, SPMs, ChemR23, Annexin-A1) will be assessed by ELISA, Olink panels, lipidomics, and molecular profiling. A double-blind randomized trial (60–90 patients with CRP ≥3 mg/L or metabolic syndrome) will evaluate Compound X added to standard antidepressants over 8 weeks. Results We expect (1) impaired resolution signaling in depressed and metabolically challenged animals, (2) antidepressant-like and metabolic-improving effects of Compound X, especially under high-inflammation conditions, (3) restoration of central and peripheral resolution biomarkers, (4) superior augmentation effects compared with classical anti-inflammatory strategies, and (5) clinical improvement in depressive symptoms and inflammatory/metabolic markers in the patient subgroup with elevated inflammation. Discussion & Conclusions This project addresses a major therapeutic gap by directly targeting the resolution of inflammation rather than suppression of inflammatory pathways. Demonstrating that Compound X improves depressive and metabolic outcomes would establish resolution pharmacology as a novel treatment avenue for inflammation-associated depression and facilitate biomarker-guided precision psychiatry.

686. Glutamate dysfunction in treatment-resistant depression: translational and clinical insights

Abstract Background Treatment-resistant depression (TRD) represents a major clinical challenge and is associated with substantial symptom burden, functional impairment, and poor prognosis. Beyond traditional monoaminergic models, converging evidence indicates that dysfunction of the glutamatergic system plays a central role in the pathophysiology of TRD, contributing to impaired neuroplasticity and altered stress-related neural circuitry. Aims & Objectives This lecture aims to provide an integrated overview of the clinical relevance of glutamatergic dysfunction in TRD, combining translational neurobiological evidence with findings from clinical trials and real-world studies. Particular attention is given to the implications of glutamate-based mechanisms for diagnostic refinement, symptom profiling, and personalized treatment strategies. Method A narrative synthesis of evidence from translational research, randomized controlled trials, and real-world observational studies is presented. Key neurobiological findings related to glutamate-mediated synaptic plasticity, excitation–inhibition balance, and NMDA- and AMPA-receptor–dependent mechanisms are discussed alongside clinical data from studies evaluating glutamatergic agents, with a focus on adjunctive intranasal esketamine in routine clinical practice. Results Translational evidence indicates that alterations in glutamatergic signaling contribute to disrupted cortico-limbic network functioning and impaired adaptive stress responses in TRD. Clinically, glutamatergic abnormalities are associated with specific symptom dimensions, including anhedonia, cognitive impairment, affective instability, and sleep–wake dysregulation. Real-world studies of intranasal esketamine demonstrate rapid reductions in depressive severity, improvements in functional outcomes, and an acceptable tolerability profile in heterogeneous and comorbid patient populations. Discussion & Conclusions Glutamatergic dysfunction represents a clinically meaningful dimension of TRD that extends beyond categorical diagnostic boundaries. Integrating mechanistic insights with real-world effectiveness data supports a dimensional and personalized approach to the assessment and management of treatment-resistant mood disorders. Identification of glutamate-related clinical phenotypes may improve prognostic stratification and inform treatment selection in clinical practice.