269. Resolution of inflammation in metabolic mood disorders

Abstract

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.