Dimensional and Categorical Solutions to Parsing Depression Heterogeneity in a Large Single-Site Sample

Background: Recent studies have reported significant advances in modeling the biological basis of heterogeneity in major depressive disorder, but investigators have also identified important technical challenges, including scanner-related artifacts, a propensity for multivariate models to overfit, and a need for larger samples with more extensive clinical phenotyping. The goals of the current study were to evaluate dimensional and categorical solutions to parsing heterogeneity in depression that are stable and generalizable in a large, single-site sample.

Methods: We used regularized canonical correlation analysis to identify data-driven brain-behavior dimensions that explain individual differences in depression symptom domains in a large, single-site dataset comprising clinical assessments and resting-state functional magnetic resonance imaging data for 328 patients with major depressive disorder and 461 healthy control participants. We examined the stability of clinical loadings and model performance in held-out data. Finally, hierarchical clustering on these dimensions was used to identify categorical depression subtypes.

Results: The optimal regularized canonical correlation analysis model yielded 3 robust and generalizable brain-behavior dimensions that explained individual differences in depressed mood and anxiety, anhedonia, and insomnia. Hierarchical clustering identified 4 depression subtypes, each with distinct clinical symptom profiles, abnormal resting-state functional connectivity patterns, and antidepressant responsiveness to repetitive transcranial magnetic stimulation.

Conclusions: Our results define dimensional and categorical solutions to parsing neurobiological heterogeneity in major depressive disorder that are stable, generalizable, and capable of predicting treatment outcomes, each with distinct advantages in different contexts. They also provide additional evidence that regularized canonical correlation analysis and hierarchical clustering are effective tools for investigating associations between functional connectivity and clinical symptoms.