A Proposed Circadian Subtype of Depression Fit 23 Percent of Patients. They Reported Less Benefit From SSRIs.
In 11,380 adults with depression, those meeting three of six sleep and body-clock criteria had earlier onset, more severe symptoms and poorer self-reported response to SSRIs and SNRIs, a British Journal of Psychiatry study published Oct. 20 found. The data are cross-sectional and self-reported.
About 23 percent of adults with depression in a large Australian cohort met criteria for a proposed circadian subtype, and they reported poorer response to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, according to a study published online Oct. 20 in the British Journal of Psychiatry.
The open-access paper, with first author Emiliana Tonini of the University of Sydney's Brain and Mind Centre and last author Ian B. Hickie, analyzed 11,380 participants in the Australian Genetics of Depression Study, a nationwide cohort. "Pending independent replication, investigation of its biology and predictive utility are warranted," the authors write.
How was the subtype defined?
Patients qualified if they met at least three of six features: seasonality, a delayed sleep midpoint, social jet lag between workdays and free days, evening chronotype, hypersomnia during the worst episode and marked morning tiredness. News-Medical's summary of the paper reports that hypersomnia (84 percent) and morning tiredness (83 percent) were the most common features in the subtype, followed by evening chronotype (68 percent). Delayed sleep midpoint (42 percent), seasonality (41 percent) and social jet lag (35 percent) were less common.
Of the 11,380 participants, 2,604 met the definition. The cohort was 75 percent female (80 percent in the subtype), of genetically inferred European ancestry, and diagnosed with major depressive disorder by the Composite International Diagnostic Interview Short Form.
What was different about these patients?
Patients with the circadian subtype were younger (mean age 37.9 versus 45.6 years) and had earlier onset (mean 18.7 versus 23.2 years). They reported more (hypo)manic-like and psychotic-like experiences, more suicidal ideation and distress, and more weight gain during episodes.
They also rated SSRIs (odds ratio 0.88) and SNRIs (odds ratio 0.89) as less effective and reported more side effects, including drowsiness, fatigue, weight gain and sweating. There was no significant difference for mirtazapine or amitriptyline. Polygenic risk scores were higher for attention-deficit/hyperactivity disorder, major depression, anxiety, bipolar disorder, body mass index, triglycerides, interleukin-6 and insulin resistance, as well as for later sleep timing and insomnia.
A self-reported pattern in a cross-sectional cohort is a hypothesis about treatment, not a reason to change it. It is a reason to ask about sleep timing.
What are the limits?
The design is cross-sectional, so it cannot show cause. Medication response was rated retrospectively by patients on a three-point scale, antidepressants were grouped broadly, and there were no objective circadian measures such as actigraphy or melatonin timing. All participants were of European ancestry, which limits generalizability. In a sensitivity analysis excluding participants without major depressive disorder, three genetic findings and one treatment finding lost significance.
The study team has suggested treatments aimed at the body clock. Jacob Crouse, one of the researchers, was quoted by ScienceAlert as saying that treatments targeting the circadian rhythm, "such as light therapy and melatonin, may be much more relevant" for this presentation, and Hickie was quoted describing the experience as "When it's off, you feel jet-lagged all the time." Those therapies were not tested in this study.
What it means in clinic
The six criteria are questions a clinician can already ask: when the patient falls asleep and wakes on workdays and free days, whether they consider themselves an evening type, whether they sleep much more during episodes, how they feel on waking and whether symptoms change with the seasons. For a patient who reports poor response to an SSRI or SNRI and fits this pattern, documenting sleep timing gives a clearer baseline for any later discussion of sleep-wake interventions or referral to sleep medicine. The subtype is a research construct for now, and the authors themselves call for replication. For another recent psychiatry development, see our coverage of the monthly subcutaneous olanzapine approval.
Reported, fact-checked and edited by The Script Pad's editorial staff. See How we use AI.
This article is for professional education and does not replace clinical judgment. Treatment decisions should be based on the individual patient and current guidelines.
