Some people with depression sleep far more than average, wake up exhausted, habitually stay up late, and experience mood shifts with the seasons. A new study suggests that these symptoms may cluster in a distinct subtype of depression that's tied to the body's internal clock.

While research has long linked a scrambled circadian rhythm to a risk of mood disorders, neuroscientists are now proposing that these disruptions define a specific form of depression that they call "circadian depression." First conceptualized in 2021, the body-clock subtype may affect about 1 in 4 people with severe, recurrent or persistent depression, the researchers estimate.

In their new study, published Wednesday (Oct. 21) in The British Journal of Psychiatry, the team identified the subtype in about 2,600 people out of over 11,000 evaluated.

"Circadian depression is a biologically informed subtype," said study co-author Emiliana Tonini, a neuroscientist at the University of Sydney. "Unlike subtypes defined mainly by symptoms, the core feature here is a disturbed circadian system, which common antidepressants may not fully address," Tonini told Live Science in an email.

The researchers think treatments that target the sleep-wake system, such as the sleep hormone melatonin or bright light therapy, might be beneficial for people with this subtype. However, because the subtype is still a proposal and not formally established yet, other experts say that further research is needed before the findings can inform clinical practice.

More than just bad sleep

Tonini and her team analyzed data from 11,380 adults ages 18 to 90 who took part in the Australian Genetics of Depression Study (AGDS), a nationwide study exploring how genes and life experiences influence depression and responses to treatment. They classified participants under the "circadian" umbrella if they had at least three of six features: seasonal mood swings, late sleep schedules, social jet lag (a mismatch between sleep routine during workdays and free days), night-owl habits, excessive sleep (hypersomnia), and fatigue upon waking.

A total of 2,604 people fit the proposed subtype. Compared with others in the AGDS cohort, this group was younger and developed depression earlier in life — around 19, compared with about 23 for the rest of the cohort.

The group also skewed female, and individuals reported greater psychological distress, frequent suicidal thoughts and more physical complaints than people who didn't fit the proposed subtype. Some experienced weight gain during depressive episodes and symptoms resembling hypomania, a revved-up state of elevated mood and energy that's milder than full-blown mania.

However, having this constellation of symptoms doesn't mean someone's biological clock is disrupted, said Brant Hasler, a psychologist and sleep researcher at the University of Pittsburgh who was not involved in the study. The researchers relied on the participants' self-reports of their sleep patterns; that data correlates only modestly with direct measures of circadian timing, such as measurements of melatonin in saliva, he said in an email.

"One can identify as an evening-type, and report later sleep timing, and still have physiological circadian timing that is not particularly delayed," he said.

So, in addition to checking symptoms, the team hunted for genetic clues underlying the proposed subtype. They analyzed DNA from participants' saliva samples and calculated "polygenic risk scores," which add up the influence of thousands of different genetic variants to estimate how likely someone is to develop a given condition.

"Mental health conditions are shaped by hundreds or thousands of variants that each add a small amount of risk, so everyone carries a unique 'portfolio' of risk," Tonini explained.

People in the circadian group had a higher genetic risk for depression, anxiety, attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder, the analysis suggested. They also had a greater genetic risk of higher body weight, insulin resistance, inflammation, insomnia and late-night sleep habits, compared with the other study participants.

This suggests "circadian depression is more than just 'depression with bad sleep,'" Tonini said. "It involves a mix of metabolic, inflammatory, circadian, and mood-related processes."

Could this change depression treatment?

The researchers looked at the participants' past experiences with antidepressants, finding that the circadian group reported less benefit from common medications, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Common examples include the SSRI Lexapro and the SNRI Cymbalta.

The circadian group also experienced more side effects from these treatments, such as drowsiness, nausea, anxiety and weight gain.

"If circadian disruption is a core biological mechanism in these individuals, treatments that fail to address those abnormalities may naturally be less effective," said Dr. Ruth Benca, a psychiatrist and sleep researcher at Wake Forest University School of Medicine who was not involved in the study. However, Benca cautioned that body-clock disruption may not be the only reason standard drugs fall short for these patients.

"People with more pronounced circadian disturbances often have more severe illness and other psychiatric conditions, which can contribute to treatment resistance," Benca told Live Science in an email.

Even so, tracking sleep, measurements of circadian rhythm, and seasonal shifts in mood could help clinicians identify at-risk patients earlier and select more effective treatments sooner in the course of illness, Benca suggested. "Potential approaches include behavioral routines, structured sleep schedules, or chronotherapy," in which the timing of medication or light exposure is strategically coordinated with internal body rhythms, she added.

Clinical trials are still needed to draw firm conclusions about potential treatments, Tonini noted. The findings also must be validated in broader populations, since the study drew on a single Australian cohort and its genetic analysis included only people of European ancestry.

For now, "the study is an important step toward a more personalized treatment approach," she said.

This article is for informational purposes only and is not meant to offer medical advice.

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People who are the exact same chronological age can undergo very different molecular changes as they grow older, a new study finds.

"Molecular aging is dynamic and unique to each person," said study co-author Julia El-Sayed Moustafa, a computational genomics researcher at King's College London. Even if you and your friend were born the same day, the activity of some of your genes might ramp up while the same genes in your friend dial down. The same is true for metabolites, which are small molecules produced during the body's chemical processes essential for health.

Genetics, environmental exposures and daily biological rhythms may help to explain some of those differences, the researchers say.

The findings, published Thursday (Sept. 3) in the journal Science, may complicate efforts to capture aging with a single metric. For example, "biological age" scores estimate the body's true cellular and physical health, judging how much "older" it is than your chronological age. Scientists have developed "aging clocks" that use molecular markers, such as chemical tags on DNA, to estimate biological age.

But this new study suggests that "biological aging is less like a fixed score and more like a changing set of molecular trajectories," said Raghav Sehgal, an associate research scientist at the Yale School of Medicine who was not involved in the new research. "No single number can fully capture the many systems that age at different rates," he told Live Science in an email.

More than a snapshot

In the study, researchers followed 335 women ages 32 to 80 from the long-running TwinsUK cohort for eight years. The cohort includes identical and fraternal twin pairs, along with detailed health and biological data gathered to investigate how genetics and environment can influence health.

Each woman had at least three clinic visits between 2009 and 2017, with a median of six years between their first and last visits. At each visit, researchers took blood samples and measured gene activity and levels of metabolites.

"Most aging studies take only a 'snapshot,' comparing different people at one point in time," El-Sayed Moustafa said. "In this study, we have multiple measurements, so we can see how gene activity and metabolite levels change over time within the same person."

Of more than 16,000 genes and 915 metabolites analyzed, 5,061 genes and 181 metabolites changed significantly over time. Of those genes, the vast majority — 5,036 — showed a consistent increase or decrease across the group. The same was true of 45 metabolites.

Many of these genes were involved in pathways linked to immune function, metabolism and age-related conditions, including heart disease and neurodegenerative disorders.

That said, "even when most people's genes or metabolites moved in one direction, we still found groups moving the opposite way," said study co-author Kerrin Small, a professor of genomics at King's College London. So even if, on average, certain genes' activity trended in the same direction, there were individuals who broke from the pattern.

Among 136 metabolites, for example, the levels changed from person to person. A metabolite that increased in one woman could fall in another, while some showed little change over time. One consistent pattern was that each woman's overall metabolite profile also became less similar to her earlier profile.

What might shape those changes?

Several factors appeared to shape these molecular changes. Identical twins tended to have more similar gene-expression patterns than fraternal twins did, suggesting that genetics plays a strong role. Different immune cell types also showed distinct patterns of gene activity with age, suggesting age-related changes in the immune system are not uniform.

The molecular signals also varied with the time of day and season in which the blood samples were collected. About a quarter of the genes and metabolites showed seasonal shifts, including changes linked to energy production and immune activity, while up to 40% of the metabolites varied with the body's 24-hour internal clock.

The researchers also found an unexpected decline in blood levels of per- and polyfluoroalkyl substances (PFAS), including PFOA and PFOS. Often called "forever chemicals," PFAS are synthetic compounds used in a variety of products, such as nonstick cookware and food packaging. Their decline in the study was likely due to restrictions on their use in the U.K., the study authors suspect. Blood levels of PFAS were also associated with changes in some genes and metabolites, although the study could not show that the chemicals themselves caused those changes.

The team found more than 100,000 associations between genes and metabolites, suggesting that changes in certain genes go hand-in-hand with changes in specific metabolites. This highlights how interconnected the body’s biological processes are and how complex aging really is.

"I would not call aging unpredictable, but it is certainly more individualized and context-dependent," Sehgal said. Understanding these individual trajectories could one day help researchers distinguish healthy aging from molecular changes linked to disease, but that application is still a long way off.

The study was observational, included only women and relied solely on blood samples, so larger and more diverse studies are still needed to see whether these patterns hold in broader populations. The researchers now plan to track molecular changes over about 15 years, up from eight in the current study. In the future, Sehgal suggested, aging assessments could combine broad, biological-age scores with more personalized measures of immune, metabolic, brain and cardiovascular aging.