Agitation and anxiety features define a more severe phenotype in unipolar depression

Agitated depression, conventionally associated with bipolar disorder, may also constitute a clinically significant subtype within unipolar major depressive disorder (MDD). Nevertheless, the interrelationship between agitation and anxiety symptoms and their clinical implications in unipolar depression remain largely unexamined.

We examined three large, independent cohorts of patients with MDD from the GSRD (n = 1588), STAR*D (n = 1532), and PANDORA (n = 244) studies. A composite agitation-anxiety score was computed by summing relevant items of the retrospective Montgomery-Äsberg depression rating scale (rMADRS) in GSRD, the Hamilton Depression Rating Scale 17-items (HAM-D) in PANDORA and the 30-item Inventory for Depressive Symptomatology, Clinician-rated (IDS-C₃₀) in STAR*D. Patients were then stratified into patients with agitation-anxiety (AA+) and without agitation-anxiety (AA-) based on the median scores of each cluster. Associations between agitation-anxiety features and depression severity, suicidal ideation, disease duration, treatment response, and family history of bipolar disorder were evaluated using univariate and multivariate analyses.

A total of 3364 participants were analyzed. AA+ patients showed significantly greater baseline depression severity (independent from agitation-anxiety items) across all datasets. Moreover, agitation-anxiety features correlated with higher rates of suicidal ideation (STAR*D, GSRD), longer disease duration (GSRD), and lower treatment response (STAR*D), independent of age and sex. No significant associations with family history of bipolar disorder were found.

Features of agitated depression define a more severe depressive phenotype within depressive episodes and may represent a clinically relevant dimension in unipolar MDD. A transdiagnostic approach may enhance future research and treatment strategies.