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Major depressive disorder on a neuromorphic continuum.

ABSTRACT: The heterogeneity of major depressive disorder (MDD) has hindered clinical translation and neuromarker identification. Biotyping facilitates solving the problems of heterogeneity, by dissecting MDD patients into discrete subgroups. However, interindividual variations suggest that depression may be conceptualized as a "continuum," rather than as a "category." We use a Bayesian model to decompose structural MRI features of MDD patients from a multisite cross-sectional cohort into three latent disease factors (spatial pattern) and continuum factor compositions (individual expression). The disease factors are associated with distinct neurotransmitter receptors/transporters obtained from open PET sources. Increases cortical thickness in sensory and decreases in orbitofrontal cortices (Factor 1) associate with norepinephrine and 5-HT_2A density, decreases in the cingulo-opercular network and subcortex (Factor 2) associate with norepinephrine and 5-HTT density, and increases in social and affective brain systems (Factor 3) relate to 5-HTT density. Disease factor patterns can also be used to predict depressive symptom improvement in patients from the longitudinal cohort. Moreover, individual factor expressions in MDD are stable over time in a longitudinal cohort, with differentially expressed disease controls from a transdiagnostic cohort. Collectively, our data-driven disease factors reveal that patients with MDD organize along continuous dimensions that affect distinct sets of regions.

SUBMITTER: Li J

PROVIDER: S-EPMC11897166 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature

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Major depressive disorder on a neuromorphic continuum.

Li Jiao J Long Zhiliang Z Ji Gong-Jun GJ Han Shaoqiang S Chen Yuan Y Yao Guanqun G Xu Yong Y Zhang Kerang K Zhang Yong Y Cheng Jingliang J Wang Kai K Chen Huafu H Liao Wei W

Nature communications 20250311 1

The heterogeneity of major depressive disorder (MDD) has hindered clinical translation and neuromarker identification. Biotyping facilitates solving the problems of heterogeneity, by dissecting MDD patients into discrete subgroups. However, interindividual variations suggest that depression may be conceptualized as a "continuum," rather than as a "category." We use a Bayesian model to decompose structural MRI features of MDD patients from a multisite cross-sectional cohort into three latent dise ...[more]

PMID: 40069198

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Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Dataset Information

Major depressive disorder on a neuromorphic continuum.

Publications

Major depressive disorder on a neuromorphic continuum.

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