Nearly 1 in 4 patients with severe or recurring depression may have “circadian depression,” a subtype marked by disrupted internal biological rhythms and a weaker response to antidepressants, a new national analysis suggested.

About 23% of individuals in the study fit this body-clock profile, which includes oversleeping, morning fatigue, seasonal mood changes, and more weight gain during depressive episodes.

The researchers — who first proposed the subtype in 2021 — said these patients might benefit from interventions that target the body’s 24-hour clock, such as light therapy and melatonin.

“What has been missing is matching these treatments to the people who might respond optimally to them,” said Jacob Crouse, PhD, co-senior investigator of the new study and senior research fellow at Brain and Mind Centre, The University of Sydney in Sydney, Australia.

“This should be prompting clinicians to be curious about querying these experiences in their patients and proactive about whether they should play a role in personalization of care,” he told Medscape Medical News.

The study was published online on October 20 in the British Journal of Psychiatry.

Defining the Body-Clock Profile

Major depressive disorder is a variable condition, with patients presenting with vastly different symptoms, treatment responses, and underlying biology, the authors noted.

Yet current international guidelines largely categorize depression by broad dimensions like severity or persistence — often resulting in trial-and-error prescribing rather than targeting specific illness pathways.

In a 2021 review in Neuroscience & Biobehavioral Reviews, Crouse and colleagues argued that identifying depression subtypes based on underlying biology or treatment relevance could lead to more personalized prevention and treatment. They described a new phenotype driven by disruption in the 24-hour circadian rhythm cycle, which had been linked to mood disorders.

They proposed that circadian depression would present as disrupted sleep, low energy, and weight gain, tend to start early in life, and respond poorly to standard antidepressants. Researchers described it as a hypothesis in need of testing, not an established diagnosis.

The new study was designed to test their theory. Investigators analyzed questionnaire and genetic data from the Australian Genetics of Depression Study. The nationwide cohort of 11,380 participants (75% women; mean age, 43.8 years) predominantly comprised adults with severe, recurrent illness who reported their symptom trajectories, sleep habits, and medication history.

Of the overall cohort, 2604 participants (23%; circadian group) had dysregulated 24-hour body clocks based on meeting at least three of six provisional criteria: seasonal mood and behavior fluctuations, delayed sleep schedules, an evening chronotype (“night owl”), marked morning exhaustion, hypersomnia during depressive episodes, and social jetlag (substantial shifts in sleep timing between workdays and free days).

“The typical person who fits is a young person who comes to our service with depression, oversleeping, weight gain — particularly in winter — and profound daytime fatigue,” Ian Hickie, MD, co-director of the Brain and Mind Centre, said. “They’ve tried conventional antidepressants but had a poor response and considerable side effects. Conventional psychological therapy also didn’t help.”

Earlier Onset, Less Responsive

For those in the circadian group, depression began at an earlier average age compared with the noncircadian group (18.7 vs 23.2 years; P < .001) and were more likely to report weight gain during depressive episodes than those in the noncircadian group (41% vs 31%; P < .001).

Individuals with this subtype were also more likely to be female (80% vs 73%; P < .001) and reported more recurrent depressive episodes, suicidal ideation, hypomanic- and psychotic-like experiences, psychological distress, and physical complaints (P < .001 for all).

Genetic analyses revealed that participants with the circadian profile carried higher polygenic risk scores for neurodevelopmental disorders like attention-deficit/hyperactivity disorder, as well as distinct metabolic markers, increased insulin resistance, and heightened risk for cardiovascular and inflammatory health problems.

Perhaps the most crucial takeaway for clinical practice is that the circadian profile was less responsive to common first-line serotonin-based antidepressants (SSRIs; odds ratio [OR], 0.88; P < .001) and serotonin-norepinephrine reuptake inhibitors (SNRIs; OR, 0.89; P = .023). These participants also reported significantly more medication side effects.

Because this subtype appears driven by circadian disturbance rather than just serotonin pathways, clinicians should consider earlier use of therapies that stabilize the internal clock, such as light therapy, melatonin, or behavioral sleep interventions, the researcher suggested.

Although previous trials support bright light therapy for nonseasonal depression, the study did not test specific treatments. To guide personalized decisions, investigators recommended assessing metabolic health and collecting at least 2 weeks of wearable sleep-wake data.

Clinicians should also account for diagnostic overlap: 12% of the circadian group reported a bipolar disorder diagnosis, and 36% met criteria for atypical depression.

Bipolar disorder often initially presents as depression, Hickie told Medscape Medical News.

“Circadian-focused therapies are particularly relevant to those diagnosed with bipolar depression and our previous simulation modelling work has demonstrated they may be to preventing further episodes of mania,” Hickie said.

A ‘Compelling Idea’

The researchers acknowledged several limitations, including the lack of direct internal clock measurements and cross-sectional design that cannot establish causality. Retrospective reports also leave uncertainty over whether medication outcomes reflected true nonresponse or poor adherence.

Additionally, they noted, the sample was restricted to individuals of genetically inferred European ancestry, limiting generalizability.

The research presents a “plausible and compelling idea,” said Brant P. Hasler, PhD, associate professor of psychiatry, clinical and translational science, and psychology in the Center for Sleep and Circadian Science at the University of Pittsburgh in Pittsburgh, who was not involved in the study.

“The size of the sample, the consideration of clinical course…and the examination of polygenic risk scores are all clear strengths,” Hasler told Medscape Medical News.

However, he cautioned that self-reported sleep does not always align with biology. Multiple studies have found individuals meeting the diagnostic criteria for delayed sleep-wake phase disorder — extreme night owls with sleep complaints — “do not reliably have delayed circadian rhythms based on our gold standard biomarker in humans,” he said.

This disconnect makes clinical implementation challenging because chronotherapies like bright light therapy are most effective when timed to an individual’s internal clock rather than just their sleep schedule, Hasler added.

Diagnostic Hurdle

Robert D. Levitan, MD, professor of psychiatry and physiology at the University of Toronto in Toronto, Ontario, Canada, praised the study for capturing patients whom clinicians regularly encounter. The sample size is larger than previous research and features robust phenotyping, he said.

Drawing on his own clinical trials of light therapy for seasonal and nonseasonal depression, Levitan questioned whether some of these patients had “soft bipolar” presentations — depression resembling bipolar depression without the highs — or whether circadian disruption was truly the primary driver of their illness.

Future trials should compare SSRIs or SNRIs with circadian therapies and a treatment for bipolar depression, such as lamotrigine, he suggested.

Crouse agreed that diagnostic overlap remains a hurdle. He described the core characteristics for “circadian depression” as an initial proof of concept. Because symptoms like oversleeping and waking exhausted could easily stem from other causes, he noted, the criteria require refinement before clinicians can use them for formal diagnosis.

To test and refine the concept, the team is now seeking independent replication in the ongoing MELODY trial, a randomized, placebo-controlled study investigating whether targeting sleep and circadian rhythm dysfunction can improve major depression and mood disorders in young people.

“We acknowledge that better measurement tools like wearables or simple measures of circadian physiology will get us closer to identifying a distinct subtype,” Crouse said. “Nevertheless, we think our proposed construct is a critical step toward identifying these people.”

Disclosure information for study authors is available in the original study publication. Hasler reported receiving research funding from Quest Diagnostics, Inc. Levitan declared having no relevant financial relationships.

Carla Cantor is a freelance science, health, and mental health writer and a former director of communications for Columbia Psychiatry and the New York State Psychiatric Institute. She mentors families through NAMI Family Match, a free peer-support program of the National Alliance on Mental Illness.