Atypical Depression Is Associated With a Distinct Clinical, Neurobiological, Treatment Response and Polygenic Risk...

Atypical depression is considered a distinct clinical subtype of major depression, yet its predictive validity and clinical utility remain contested. We investigated associations between atypical depression and clinical characteristics, genetic profiles, and antidepressant responses.

Among 14,897 participants from the Australian Genetics of Depression Study (75% female; mean age 43.7 years), 3098 (21%) were classified phenotypically as having atypical depression based on self-reported weight gain and hypersomnia during their worst depressive episode. Demographic variables and clinical features were compared. Bonferroni-corrected regression models were used to evaluate associations between atypical depression and polygenic scores (PGSs) for mental disorders, metabolic-inflammatory-circadian traits, and self-reported antidepressant response and side effects.

Atypical depression cases had an earlier age of onset, greater illness severity, stronger eveningness, and reduced daylight exposure. Atypical depression cases had higher PGSs for major depression (odds ratio [OR] = 1.10 [95% CI, 1.06-1.15]), attention-deficit/hyperactivity disorder (OR = 1.08 [1.04-1.13]), bipolar disorder (OR = 1.07 [1.02-1.12]), neuroticism (OR = 1.07 [1.02-1.12]), body mass index (OR = 1.35 [1.29-1.42]), type 2 diabetes (OR = 1.22 [1.16-1.28]), C-reactive protein (OR = 1.12 [1.07-1.17]), and insulin resistance (OR = 1.11 [1.06-1.16]) but lower PGSs for high-density lipoprotein cholesterol (OR = 0.91 [0.87-0.95]) and chronotype (indicating eveningness) (OR = 0.94 [0.90-0.98]). Atypical depression was associated with poorer self-reported effectiveness of selective serotonin reuptake inhibitors (OR = 0.88 [0.81-0.96]) and serotonin-norepinephrine reuptake inhibitors (OR = 0.85 [0.77-0.94]), as well as more side effects, particularly weight gain (OR = 2.89 [2.66-3.15]).

This large, genetically informative study supports the neurobiological and clinical validity of atypical depression, demonstrating distinct clinical and genetic risk profiles alongside differential antidepressant responses. These findings support the use of the atypical subtype to guide treatment selection and physical health management.