Structural network alterations and peripheral immune-inflammatory dysregulation define distinct subtypes of major depressive disorder with prognostic implications.
Authors
Affiliations (4)
Affiliations (4)
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, China.
- Mental Health Center, National Center for Mental Disorders, West China Hospital of Sichuan University, Chengdu, China.
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
- West China Biomedical Big Data Center, West China Hospital of Sichuan University, Chengdu, China.
Abstract
Immune-inflammatory dysregulation and cortical structural vulnerability have been increasingly implicated in major depressive disorder (MDD). However, how they interact with each other, and whether immune heterogeneity in MDD is systematically organized by structural networks, remain unclear. Genome-wide association studies data of MDD, gray matter volume (GMV) phenotypes, and 19 immune-related traits were utilized to assess causal relationships. A prospective cohort comprising 122 patients with MDD and 66 healthy controls underwent structural magnetic resonance imaging and assessment of 40 inflammatory and immune-related markers. Individualized structural covariance network analysis, machine-learning approaches, and survival analyses were used to identify neurobiological subtypes and evaluate treatment outcomes. Genetically predicted MDD was associated with lower levels of circulating IGF-1 (<i>p</i><sub>FDR</sub> = 0.013). Levels of IL-5 and leptin were negatively associated with GMV alterations in the right cingulate gyrus and bilateral putamen, respectively (<i>p</i><sub>FDR</sub> < 0.05). Structural covariance abnormalities were predominantly localized to connectivity between the default mode and limbic networks and within the limbic network in MDD, and they were classified into a hypoconnectivity subtype (<i>n</i> = 49) and a hyperconnectivity subtype (<i>n</i> = 73). The hypoconnectivity subtype exhibited greater anxiety and anhedonia symptoms, whereas the hyperconnectivity subtype showed broadly elevated inflammatory and immune state and achieved antidepressant response more rapidly during follow-up (<i>p</i> = 0.032). This study supports a bidirectional immune-brain framework in MDD and suggests that structure-derived subtypes classify different immune signaling heterogeneity, which may provide a biologically informed basis for stratification and prognosis in MDD.