By: Akanksha
Australian researchers from the University of Sydney’s Brain and Mind Centre have identified a new subtype of depression termed “circadian depression,” linked to disruptions in the body’s 24-hour internal clock that regulates the sleep-wake cycle. This phenomenon may explain why two in five patients do not see a benefit from traditional antidepressant medication. The findings come as antidepressant prescriptions in England reach record highs — with one in seven adults prescribed the drugs last year — and follow a recent health safety alert warning that antidepressants could cause long-lasting sexual side effects and suicidal thoughts long after treatment has stopped.
Major depressive disorder (MDD) is a heterogeneous condition with highly variable presentations and patterns of treatment response, yet most proposed clinical subtypes show only modest differences in prognosis or treatment response. Consequently, international treatment guidelines largely emphasize dimensions such as severity, persistence, or recurrence, often resulting in repeated trial-and-error prescribing of common antidepressants. Accumulating evidence implicates circadian disruption as a pathophysiological mechanism causing depressive symptomatology and a marker for a distinct profile termed “circadian depression.”
To test the biological validity and clinical utility of this profile, researchers analyzed cross-sectional clinical and genetic data from 11,380 Australians of genetically-inferred European ancestry (75% female; mean age 43.8 15.3 years) with mostly severe and recurrent depression from the nationwide Australian Genetics of Depression Study (AGDA). Published in the British Journal of Psychiatry, the study identified circadian depression in 2,604 participants — affecting 23% (nearly a quarter) of the cohort (80% female; mean age 37.87 13.62 years).
As explained in The Guardian by the first author Dr. Emiliana Tonini of the University of Sydney’s Brain and Mind Centre, participants were classified as having circadian depression if they met at least three of six binary circadian features:
Hypersomnia: Endorsed by 84% (N=2,182) of circadian cases, defined using DSM-5 MDD criteria as reporting to “sleep much more than usual” during the worst depressive episode.
Sleep inertia: Endorsed by 83% (N=2,143) of circadian cases, serving as a marker of waking during the biological night and defined using the Morningness-Eveningness Questionnaire (MEQ) as feeling “very tired” in the first half-hour after morning waking.
Evening chronotype: Endorsed by 68% (N=1,774) of circadian cases, representing a genetically-influenced preference for daily sleep-wake timing and defined via MEQ as being a “night owl”.
Delayed sleep midpoint: Endorsed by 42% (N=1,099) of circadian cases, calculated on free days using age-adjusted cut-off (>6:00 am for ages 18-24; >5:30 am for 25-34; >5:00 am for 35-64; >4:30 am for 65+).
Seasonality: Endorsed by 41% (N=1,071) of circadian cases, reflecting sensitivity to photoperiodic day-length changes and measured via the Seasonal Pattern Assessment Questionnaire with a Global Seasonality Score cut-off of 11.
Social Jetlag: Endorsed by 35% (N=924) of circadian cases, representing the mismatch between biological and social time — which Tonini described in The Guardian as when “their sleep when they go to bed during the week or when they work is very different from the weekend or when they are free to organize their day.” Age-adjusted thresholds for the difference in sleep midpoint between free and working days were ≥ 2.5 hours (Ages 18-24), ≥ 2.25 hours (25-34), ≥ 2 hours (35-64), and ≥ 1.25 hours (65+).
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Compared to the non-circadian group (N=8,776), circadian cases had an earlier age of onset (18.68 ± 8.40 vs. 23.20 ± 11.84 years, p < 0.001), more often experiences 10 or more depressive episodes (52% vs 36%, p<0.001), and more frequently experienced weight gain during episodes (42% vs. 31%, p<0.001). Circadian cases also showed greater severity of hypo/manic-like experiences, psychotic-like experiences, psychological distress, somatic complaints and suicidality (all p<0.001).
“Individuals with circadian depression have more severe mental health symptoms,” Tonini said during a press briefing. “The age of onset of their depression was younger compared to those with non-circadian depression, but they also had more episodes and also more complex trajectories, more suicidality, more hypomaniac and psychotic-like symptoms as well.”
Using DNA genotyping and polygenic risk scores (PGS), researchers found that after Bonferroni correction, the circadian subtype was associated with higher PGS for attention deficit/hyperactivity disorder (ADHD) (OR-=1.11), major depression (OR = 1.11), bipolar disorder (BD) (OR=1.09), body mass index (OR=1.11), triglycerides (OR=1.10), interleukin-6 (OR=1.08), insulin resistance (OR=1.08), later sleep midpoint (OR=1.16), insomnia (OR=1.08), and evening chronotype (OR=0.68).
As Tonini told The Guardian, those with circadian depression had higher risk for ADHD and mood disorders, “but also a series of metabolic and inflammatory markers… This is important because that indicates there is an underlying biology that is quite distinct from other forms of depression.”
Unlike atypical depression, immuno-metabolic depression, bipolar depression, or melancholic depression — which can conflate factors like neuroticism, chronicity, or delayed mania emergence — the circadian subtype is defined specifically by 24-hour sleep-wake and circadian markers.
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The circadian subtype was associated with poorer self-reported efficacy for selective serotonin reuptake inhibitors (SSRIs; OR=0.88) and serotonin and norepinephrine reuptake inhibitors (SNRIs; OR=0.89), alongside 20 self-reported side effects — including weight gain, drowsiness, fatigue, agitation, suicidal thoughts, attempted suicide, and reduced sexual desire. Tricyclic antidepressants (TCAs) showed no significant efficacy difference (OR=0.94).
Prof. Ian Hickie, psychiatrist and co-director of the Brain and Mind Centre, told The Guardian: “What is critical about being in this circadian type is its poor response to the standard therapies, those which are typically recommended in the guidelines.”
In the University of Sydney press release Tonini stated: "Depression is not a uniform illness and understanding the characteristics of different subtypes means that we can give people earlier access to treatments that will be most effective for them.”
Co-senior author Dr. Jacob Crouse added in the press release: “because circadian depression is linked to people’s internal body clock, treatments targeting the circadian rhythm, such as light therapy and melatonin, may be much more relevant, and clinicians should reach for these much earlier in people with this presentation. For those who find that antidepressants are not working for them, it is important to speak to your clinician for advice about your individual circumstances.”
In The Guardian, Hickie emphasized that “chronobiological treatments – things focused on the sleep-wake cycle, particularly… to do with morning light exposure, daylight activity, regularity of sleep-wake cycles, regularity of food schedules, is critical.” In the press release, Hickie added, “We really want young people to receive the most appropriate treatment early in their course of illness. Most young people will be offered SSRIs first up, but for at least a quarter there are better circadian focused medical and behavioral options to help treat and manage their condition,” including melatonin-targeted antidepressants and cognitive behavioral therapy.
H2: What Are the Limitations and Criticisms of the Study?
In their research paper, the authors noted that data were cross-sectional and self-reported without directly capturing internal physiological circadian markers, and noted that participants “were limited to those of genetically inferred European ancestry, which may limit generalizability” and that “future studies are needed to replicate our findings in diverse samples.”
In The Guardian, Prof. Jayashri Kulkarni, director of the Monash Alfred Psychiatry Research Centre, called it a “really well-conducted study,” stating: “They have got a polygenic risk score, which means that they’ve actually managed to tie certain types of depression to a specific genetic profile. That will be important for onward treatment.” However, she noted the study omitted the hormonal impacts of menopause, “which is predominantly one of the things that women describe as causing sleep disturbance… That would be another factor that might be worth considering.”
Meanwhile, Prof. Andrew Coogan of Maynooth University told The Guardian that “the findings are not overly surprising,” citing a “lack of detail as to how the cluster of features of, and the criteria for, the proposed circadian subtype of depression was arrived at,” and concluding: “The results of this exploratory study are best interpreted as initial if interesting findings that warrant further examinations.” Similarly, Prof. David Curtis of University College London told the Daily Mail: “Depressed patients present with a variety of different symptoms and selecting some who report particular symptoms does not mean that one has identified a new subtype of depression. The term circadian is also misleading. Some typical features of depression are circadian in nature, including early morning waking and having worse moods in the morning.”
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References:
Tonini, Emiliana, Jacob J. Crouse, Mirim Shin, Joanne S. Carpenter, Brittany L. Mitchell, Enda M. Byrne, et al. “Clinical and Genetic Correlates of a Circadian Subtype of Depression in the Australian Genetics of Depression Study.” medRxiv, February 23, 2026.
University of Sydney. “Researchers Identify Circadian Subtype of Depression.” Press release, October 21, 2026. https://www.sydney.edu.au/news-opinion/news/2026/10/21/researchers-identify-circadian-subtype-of-depression-.html.
(Rh/APC)
