S. Poletti

Mapping generalizable brain-based depression subtypes across clinical, cognitive, and neurotransmitter dimensions

Identifying generalizable brain-based biotypes across independent cohorts is critical for parsing heterogeneity in Major Depressive Disorder (MDD), yet robust subtypes spanning micro- and macroscales remain poorly defined. We applied stability-based clustering to cortical thickness data from 1,531 MDD individuals in UK Biobank (UKB), with external validation in 144 inpatients from IRCCS Ospedale San Raffaele (HSR). Two distinguishable clusters emerged (accuracy=87.5%), with one showing widespread cortical thinning, anergy-related symptoms, childhood trauma, and diabetes comorbidity. This profile generalized with 96.5% accuracy in a hold-out UKB sample and 80.6% in HSR. Mapping clusters cortical profiles onto Neurosynth meta-analytic activation patterns revealed a ventral-dorsal gradient linked with emotion regulation, interoceptive, and motivational processes. Spatial correlations with 19 neurotransmitter receptors and transporters obtained from positron emission tomography identified dopamine transporter as the dominant contributor in UKB, and histamine receptor H3 in HSR. These findings provide a reproducible framework linking MDD subtypes to multiscale biological complexity.

History of childhood trauma enhances the detrimental effects of recent stressors on brain structure and function in major depressive disorder.

CLOCK 3111T/C Polymorphism and Sex Moderate the Effect of Childhood Trauma on White Matter Microstructure in Bipolar Disorder

Background. Bipolar disorder (BD) is characterized by circadian rhythm disruptions, contributing to mood instability and recurrence. These rhythms are regulated by clock genes in the suprachiasmatic nucleus, including the CLOCK 3111T/C (rs1801260) polymorphism that has been linked to delayed sleep phase, insomnia, and altered circadian expression. Both circadian disruption and adverse childhood experiences (ACEs) correlate with white matter (WM) abnormalities. We hypothesized that rs1801260 moderates ACE effects on WM microstructure in BD. Methods. We enrolled 137 BD patients in depressive episodes. Participants underwent 3T MRI, rs1801260 genotyping and completed the Childhood Trauma Questionnaire. Moderation (PROCESS) tested genotype–ACE interactions on whole-brain fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) values; voxel-wise TBSS (FSL Randomize) localized effects, with sex-stratified and GLZ analyses for genotype–sex interactions. Results. Significant rs1801260 × ACE interactions emerged for FA and RD across physical abuse, physical neglect, and emotional neglect. Higher ACEs were associated with lower FA/higher RD only in CLOCK rs1801260*C carriers, mainly females. TBSS showed physical abuse × rs1801260 interaction in the corpus callosum, internal capsule and corona radiata. A GLZ model with separate slopes confirmed physical abuse × sex × rs1801260 interactions on FA/RD, with effects specific to female CLOCK rs1801260*C carriers but genotype-independent in males. Conclusions. rs1801260 moderates the impact of early-life stress on WM integrity in BD, particularly in emotion-regulation tracts, with CLOCK rs1801260*C carriers showing greater vulnerability. Effects are genotype-specific in females but genotype-independent in males, possibly reflecting sex-dimorphic neurodevelopment driven by estrogen–androgen modulation of clock genes, HPA axis, and myelination.