Clinical heterogeneity in major depressive disorder underlies comorbidity with functional disorders.

Observed Findings

• Two of five identified depression symptom classes showed significantly increased prevalence of all three functional disorders (FM, ME/CFS, IBS).
• The 'severe typical' depression class was equally associated with fibromyalgia and ME/CFS diagnoses.
• The 'anhedonia/weight gain' depression class showed different levels of association with different pairs of functional disorders.
• Not all individual depression symptoms were equally associated with functional disorder diagnoses, suggesting heterogeneous mechanisms.
• The five-class solution best balanced statistical fit and interpretability compared to models with different numbers of classes.

Inferred Conclusions

• MDD-FD comorbidity is not explained by a single shared mechanism but likely reflects multiple distinct pathways.
• Specific depression symptom profiles are more strongly associated with functional disorders than others, suggesting symptom heterogeneity is clinically meaningful.
• The anhedonia/weight gain symptom profile may represent a biologically distinct subtype with specific relationships to different functional disorders.
• Identifying mechanisms underlying depression symptom heterogeneity is essential for understanding FD comorbidity.

Remaining Questions