ATYPICAL depression was shown to represent a clinically and biologically distinct subtype of major depressive disorder, according to a large genetically informed study linking symptom patterns to genetic risk profiles and differential antidepressant response.
The findings came from the Australian Genetics of Depression Study, which analysed data from 14,897 participants with a history of major depression. Around 21% were classified as having atypical depression, defined by hypersomnia and weight gain during their most severe depressive episode. Although atypical depression has long been recognised in diagnostic systems, its clinical utility has remained controversial.
Clinical and Circadian Features of Atypical Depression
Participants with atypical depression showed an earlier age of onset and greater illness severity compared with those without atypical features. They also demonstrated marked circadian disruption, including stronger eveningness preference and reduced daylight exposure, highlighting the relevance of sleep–wake regulation in this depressive subtype.
These clinical differences supported the concept that atypical depression is more than a variation in symptom expression, instead suggesting distinct underlying biological processes.
Genetic Risk and Treatment Response in Atypical Depression
Using polygenic score analyses, researchers found that atypical depression was associated with higher genetic risk for several psychiatric traits, including major depression, attention-deficit/hyperactivity disorder, bipolar disorder, and neuroticism.
Individuals with atypical depression showed higher polygenic risk for metabolic and inflammatory traits, including body mass index, Type 2 diabetes, C-reactive protein, and insulin resistance, alongside lower scores for high-density lipoprotein cholesterol and morning chronotype.
Atypical depression was also linked to poorer self-reported effectiveness of selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors, together with higher rates of side effects, particularly weight gain. Reduced treatment effectiveness remained evident after body mass index adjustment.
Implications for Clinical Practice
The authors acknowledged limitations, including reliance on retrospective self-report, cross-sectional design, and restriction to individuals of European ancestry. However, the consistency of circadian and treatment-response findings strengthened confidence in the subtype’s validity.
Overall, the study supported atypical depression as a clinically meaningful subtype with distinct genetic architecture and antidepressant response patterns. The results suggested that recognising atypical depression may help guide treatment selection, physical health monitoring, and future research into circadian-based interventions.
Reference
Shin M et al. Atypical depression is associated with a distinct clinical, neurobiological, treatment response and polygenic risk profile. Biol Psychiatry. 2026; doi:10.1016/j.biopsych.2026.01.003.
