Prefrontal Structural Asymmetry Mediates Body Mass Index and Treatment Response in Major Depressive Disorder

Elevated body mass index (BMI) predicts poor treatment response in major depressive disorder (MDD), yet the neurobiological mechanisms underlying this association remain poorly understood. Cortical thickness asymmetry has been proposed as a structural correlate of affective regulation and may represent a pathway through which metabolic factors influence treatment outcomes. We investigated whether BMI-related alterations in prefrontal cortical asymmetry mediate antidepressant treatment resistance in MDD.

We analyzed baseline structural MRI (sMRI) and 12-week clinical outcome data from 312 adults with MDD across a discovery cohort (n = 107) and an independent replication cohort (n = 205). Treatment response was operationalized as absolute reduction in Hamilton depression rating scale (HAMD-17) scores. Cortical thickness asymmetry indices were derived from regional parcellations. Associations between BMI and asymmetry were examined using linear regression models; mediation analyses tested whether BMI-related asymmetry statistically mediates the link between higher BMI and reduced treatment response. Sex-stratified analyses were conducted to identify divergent pathways.

Across both cohorts, higher BMI was consistently associated with greater leftward cortical thickness asymmetry in the prefrontal cortex (PFC). This structural asymmetry significantly mediated the relationship between BMI and poorer treatment response. Sex-stratified analyses revealed additional female-specific mediation through prefrontal opercular regions, with no corresponding effect in males. Transcriptomic annotation of implicated regions identified enrichment for genes involved in metabolic and cytoplasmic signaling pathways.

BMI-associated leftward prefrontal asymmetry statistically mediates antidepressant resistance in MDD via both a sex-shared structural pathway and a female-specific opercular circuit. These findings suggest that metabolic factors may influence treatment outcomes partly through hemispheric structural imbalance in prefrontal regions and position cortical thickness asymmetry as a candidate neuroimaging biomarker for patient stratification in precision psychiatry.