Structural network alterations and peripheral immune-inflammatory dysregulation define distinct subtypes of major depressive disorder with prognostic implications.

BACKGROUND

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.

METHODS

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.

RESULTS

Genetically predicted MDD was associated with lower levels of circulating IGF-1 (pFDR = 0.013). Levels of IL-5 and leptin were negatively associated with GMV alterations in the right cingulate gyrus and bilateral putamen, respectively (pFDR < 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 (n = 49) and a hyperconnectivity subtype (n = 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 (p = 0.032).

CONCLUSIONS

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.