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

Psychiatry Res. 2025 Dec 30;357:116928. doi: 10.1016/j.psychres.2025.116928. Online ahead of print.

ABSTRACT

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

PMID:41485399 | DOI:10.1016/j.psychres.2025.116928