One in four people with mood disorders show internal circadian misalignment

Young people with emerging mood disorders often show signs of internal circadian misalignment—a disruption in the timing between key biological rhythms—and those with greater misalignment tend to report more severe depressive symptoms. That’s according to new research published in the Journal of Biological Rhythms, which used lab-based physiological measurements to examine how circadian signals like melatonin, cortisol, and core body temperature interact in the context of mental health.

Circadian rhythms are biological cycles that operate on a roughly 24-hour schedule. They govern various physiological and behavioral processes such as sleep, hormone secretion, body temperature, and alertness. These rhythms are largely regulated by the brain’s internal clock, located in the hypothalamus, which synchronizes with environmental cues like light and darkness.

When circadian rhythms function in harmony, processes like falling asleep and waking up tend to follow predictable patterns. But when these rhythms become misaligned—either with each other or with the external environment—it can affect sleep quality, energy levels, and even mental health. In recent years, scientists have become increasingly interested in how disruptions in circadian timing might be involved in mood disorders such as depression.

Previous research has linked circadian dysfunction to mood problems, but most studies have focused on individual markers—such as melatonin onset or sleep-wake cycles—rather than looking at the system as a whole. A few small studies have suggested that the timing between different biological rhythms may be out of sync in people with depression. However, these studies have been limited by small sample sizes and a narrow focus on just two markers at a time.

The current study was designed to test whether young people with mood disorders tend to show “internal misalignment”—that is, mismatches in the timing of several biological rhythms within the body. The researchers also wanted to know whether greater degrees of misalignment were associated with more severe depressive symptoms.

“We know from previous research that there is a lot of evidence for links between mood disorders (like depression and bipolar disorder) and disturbances in circadian rhythms (i.e. the 24-hour ‘body clock’), including abnormal sleep-wake patterns, altered energy and fatigue, and differences in 24-hour rhythms of things like hormone secretion (such as melatonin and cortisol) and core body temperature,” said study author Joanne Carpenter, a research fellow at the Youth Mental Health and Technology Team at the Brain and Mind Centre at the University of Sydney.

“However, most of the previous research in this area looks at how well the body clock is aligned with the environment around us. For instance, the hormone melatonin (the ‘darkness hormone’) usually starts being produced by our bodies a couple of hours before our normal bedtime, but in those with mood disorders, this might occur later than normal, putting them ‘out of sync’ in the same way that we might get out of sync by travelling across time zones.”

“What intrigued us was that the findings were not always consistent across studies or in studies that used different markers as outputs of the body clock. Most of the research on the body clock in mood disorders has only really looked at the timing of one biological measure at a time, so we were interested in looking at multiple outputs of the body clock to see whether the timing of these rhythms was just out of sync with the environment, or also out of sync with each other.”

The researchers collected data from 69 young people (ages 16 to 35) who were seeking mental health care and compared them to 19 healthy control participants. The group with mood disorders included individuals with depression, bipolar disorder, anxiety, or other psychiatric conditions. Participants were excluded if they had sleep disorders, neurological conditions, recent travel across time zones, or were using certain medications.

Each participant underwent multiple assessments. They wore wrist-based actigraphy monitors for several days to record sleep-wake patterns. Then, they spent a night in a sleep lab, where researchers tracked the timing of three key circadian markers: the onset of melatonin secretion under dim light conditions, the peak of salivary cortisol levels after waking, and the lowest point of core body temperature. These are all known to be regulated by the body’s internal clock. Participants also completed clinical assessments, including the Hamilton Depression Rating Scale to measure the severity of depressive symptoms.

Using this data, the researchers calculated “phase angles”—the time differences between each pair of rhythms (for example, how many hours after melatonin onset the core body temperature reached its lowest point). They defined internal circadian misalignment as any phase angle that fell more than two standard deviations away from the average values found in the control group.

About 23% of the young people with mood disorders showed signs of internal circadian misalignment. These individuals had unusual timing relationships between at least one pair of biological markers—most commonly involving melatonin and core body temperature.

Interestingly, those with internal misalignment did not differ from other participants in terms of diagnosis, medication use, or overall sleep duration. However, they did tend to show later melatonin onset times relative to other rhythms, suggesting a delayed signal from one part of the circadian system.

Across the full group of young people with mood disorders, the researchers found that certain types of misalignment were associated with more severe depressive symptoms. Specifically, those whose core body temperature dropped earlier in the night—relative to either melatonin onset, cortisol peak, or sleep timing—tended to report higher levels of depression. These associations held even after accounting for age and sex.

“This highlights that — at least for some people — a poorly synchronised clock may be relevant to their mood, and so it may be really important for us to look at how we can target this in treatment and prevention strategies,” Carpenter told PsyPost.

While the researchers initially hypothesized that delayed rhythms would be most strongly linked to depression, they found that earlier-than-expected temperature drops may also be involved. This suggests that disruptions in either direction—whether rhythms are too early or too late—can contribute to mood disturbances. The specific patterns of misalignment varied widely across individuals, highlighting the complexity of circadian disruptions in mood disorders.

“We were interested to find that the specific nature of the circadian abnormalities was not the same for everyone with mood disorders, with a lot of variation in individual patterns (e.g., one individual may have a late melatonin rhythm and an early temperature rhythm, whereas another may have the opposite),” Carpenter said. “This challenges us to think more about what the different causes might be for clocks to get out of sync in different ways, and whether we might need different approaches to correcting specific circadian problems.”

The study offers some of the strongest evidence to date that internal circadian misalignment may play a role in mood problems among young people. Still, several limitations suggest the findings should be interpreted with caution.

For instance, the study was cross-sectional, meaning it only provides a snapshot in time. It cannot determine whether circadian misalignment causes depression, results from it, or whether both are influenced by other factors. Longitudinal studies will be needed to clarify whether correcting circadian misalignment can improve mental health outcomes.

“We only measured these circadian rhythms and mood symptoms at one point in time, so we can’t say from this whether there is any causal relationship with the internal jet lag leading to the mood symptoms or vice versa,” Carpenter noted. “We also don’t yet know much about whether those who are out of sync can be re-synchronised with specific treatments or if this would help these individuals to have better mood outcomes.”

The lab-based methods used to measure circadian rhythms are not easily scalable for widespread clinical use. Each participant had to spend a night in a dimly lit lab while providing saliva samples and wearing temperature sensors. While this approach provides high-quality data, it is labor-intensive and difficult to replicate outside of research settings.

“Measuring circadian rhythms in this way (an in-lab overnight study) takes a lot of time and resources and can be quite a burden to participants,” Carpenter said. “There is a lot of promise for digital and wearable innovation (e.g., activity tracking watches, mobile apps) that may lead to easier or better ways to study circadian rhythms. We are excited to see these develop and hope that it may help this research to be better translated to real-world applications.”

Despite these caveats, the findings from this study support the idea that internal circadian misalignment is common in young people with mood disorders and tends to be linked to greater depressive symptoms. While the exact patterns of misalignment vary, the results indicate that disrupted timing between biological rhythms—especially melatonin, cortisol, and core body temperature—may play an important role in emotional well-being.

“We hope that this will lead to further investigation of how internal circadian alignment changes over time in those with mood disorders — do people become more in or out of sync over time, what drives those changes, and how does it relate to their mood?” Carpenter explained. “Ultimately, we hope that this will lead to avenues for better identifying those with circadian disturbances and informing how circadian-focused strategies or treatments can help improve our approaches to prevention and intervention.”

The study, “Evidence for Internal Misalignment of Circadian Rhythms in Youth With Emerging Mood Disorders,” was authored by Joanne S. Carpenter, Jacob J. Crouse, Mirim Shin, Emiliana Tonini, Gabrielle Hindmarsh, Zsofi de Haan, Frank Iorfino, Rebecca Robillard, Sharon Naismith, Elizabeth M. Scott, and Ian B. Hickie