A large Australian study finds that nearly one in four participants with a history of depression fit a proposed circadian profile marked by disrupted sleep patterns, greater symptom severity, and reduced perceived antidepressant effectiveness, offering new clues to why conventional treatments may work less well for some patients.
Study: Clinical and genetic correlates of a circadian subtype of depression in the Australian Genetics of Depression Study. Image credit: PeopleImages/Shutterstock.com
A recent study published in the British Journal of Psychiatry has identified a potential subtype of depression linked to disrupted circadian rhythms, more severe symptoms, and poorer responses to common antidepressants. The findings, based on a large Australian cohort, also reveal distinct genetic associations that could help researchers better understand differences in depression and treatment response.
The role of circadian disruption in major depressive disorder
Major depressive disorder (MDD) presents with a wide spectrum of symptoms and treatment responses, likely stemming from diverse underlying biological mechanisms. Despite attempts to define clinical subtypes, most have shown only limited value in predicting prognosis or guiding treatment.
Current treatment guidelines primarily focus on severity, persistence, or recurrence, which often leads to repeated trial-and-error use of antidepressants. This approach underscores a significant research gap: the lack of robust, actionable biomarkers or clear clinical criteria to guide personalized treatment. Advancing early identification of distinct illness pathways remains a critical unmet need for improving outcomes in MDD.
Emerging evidence implicates circadian disruption as a key mechanism in a subset of depressive syndromes. The concept of 'circadian depression' has been introduced to describe cases marked by disrupted 24-hour sleep–wake cycles, reduced daytime activity, low energy, and episodic weight gain.
Clinically, this proposed subtype has been associated with earlier depression onset, bipolar-like features, poorer responses to common antidepressants, and cardiometabolic or inflammatory conditions. Objective markers, such as actigraphy-derived circadian measures, are heritable, and genetic predisposition to bipolar disorder or MDD is associated with delayed circadian rhythms. Gene variants affecting circadian regulation and evening chronotype have also been tied to poor antidepressant response. However, research gaps remain regarding precise diagnostic criteria for circadian depression and the development of targeted interventions for this subgroup.
Assessing clinical, genetic, and circadian factors for depression
The current study analyzed data from the Australian Genetics of Depression Study (AGDS), a nationwide cohort designed to investigate genetic and psychosocial factors in depressive disorders and antidepressant response. Eligible participants had a diagnosis of depression, were of genetically inferred European ancestry, and had complete polygenic risk score data and information on at least three circadian criteria. The final sample included 11,380 adults (75% female; mean age 43.8) recruited between September 2016 and September 2018.
Participants completed an online survey assessing depressive symptoms, antidepressant use, sleep and circadian behaviors, and other mental health diagnoses. MDD was evaluated using the Composite International Diagnostic Interview Short Form in line with DSM-5 criteria.
Circadian subtype classification was determined by six criteria: seasonality (Global Seasonality Score ≥11), delayed sleep midpoint (later than age-based cut-offs), social jetlag (greater difference in sleep midpoints between free and workdays by age group), evening chronotype (self-identified as 'Definitely an evening type'), hypersomnia (sleeping much more than usual during the worst depressive episode), and morning tiredness (very tired in the first half-hour after waking). Participants meeting at least three criteria were classified as having the 'circadian subtype'; those meeting fewer were assigned to the 'non-circadian' group.
Antidepressant efficacy was self-reported and rated on a three-point scale and compared across selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), amitriptyline, and mirtazapine, using the highest class rating when multiple medications were reported. Polygenic scores were calculated using genome-wide association study (GWAS) results for mental, physical, circadian, sleep, metabolic, and inflammatory traits.
Clinical utility of the circadian subtype in depression
Of 11,380 participants, 2,604 were classified as having a circadian subtype. Of these, 80% were female, with a mean age of 37.9 years. Hypersomnia was most common at 84%, followed by morning tiredness at 83%, evening chronotype at 68%, delayed sleep midpoint at 42%, and seasonality at 41%. Social jetlag was least common at 35%. The most frequent combination was hypersomnia, morning tiredness, and evening chronotype (18%).
Compared with the non-circadian subtype group (8,776), participants with the circadian subtype were younger, with a mean age of 37.9 years versus 45.6 years. They were more often female, 80% compared to 73%, and had an earlier onset of depression, 18.7 years compared to 23.2 years. This group also had greater severity of manic-like, psychotic-like, and suicidal ideation, as well as higher psychological and somatic distress. The most pronounced differences were in age and age at onset.
The circadian subtype showed higher polygenic scores indicating genetic predisposition for attention-deficit hyperactivity disorder (ADHD), major depression, anxiety, and bipolar disorder. Although an increased polygenic score for schizophrenia was seen, it was not statistically significant after correction. No genetic association was observed for neuroticism or autism.
The circadian subtype was also associated with higher polygenic scores for body mass index, triglycerides, interleukin-6, and insulin resistance, suggesting shared genetic predispositions involving metabolic and inflammatory traits. There were trends toward greater genetic predisposition to migraine, C-reactive protein, type 2 diabetes, coronary artery disease, fasting insulin, and lower high-density lipoprotein, but these did not remain significant after correction. No other physical health genetic risks were associated.
The circadian subtype had a stronger genetic predisposition toward an evening chronotype, along with increased polygenic scores for insomnia and delayed sleep timing. There were also trends for weaker rest-activity rhythms and shorter sleep duration, though these were not statistically significant after correction.
Participants with the circadian subtype reported lower perceived effectiveness of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. No statistically significant differences were detected for mirtazapine or amitriptyline. This group also reported more side effects from antidepressants, such as drowsiness, fatigue, agitation, weight gain, and suicidal thoughts. The study found no significant association with rash, other side effects, or weight loss. However, these findings were based on retrospective self-reports.
Circadian patterns may help explain differences in depression
The findings suggest that people with depression who experience disrupted circadian rhythms may have more severe symptoms, different genetic risk profiles, and poorer responses to common antidepressants.
Nonetheless, several limitations merit consideration. Reliance on self-report measures may introduce recall bias, and the cross-sectional design precludes causal inference. The absence of objective physiological circadian measurements also limits confirmation that the identified group has underlying circadian dysfunction. The sample’s restriction to individuals of European ancestry may limit generalizability, and grouping antidepressants into broad categories may obscure important differences.
Future work should replicate these findings in more diverse populations, incorporate objective circadian assessments, refine the circadian subtype criteria, and evaluate the predictive value and pathophysiological relevance of this proposed subtype. The researchers also suggested investigating whether circadian-targeted interventions, such as light-based therapies and regular sleep–wake schedules, could improve treatment outcomes, although these approaches were not tested in the current study.
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