The Role of Chronopsychiatry in Precision Medicine: Circadian Dysregulation as Diagnostic Marker and Therapeutic Target

Abstract

Purpose of Review

Chronopsychiatry refers to a research and clinical approach which studies psychiatric illness through the lens of circadian rhythms and aims to reset the body’s biological clock to counteract circadian rhythm abnormalities in psychiatric disorders. This review highlights the use of circadian biomarkers collected from wearable devices and other methods to help the development of personalized treatment plans based on patients’ individual circadian functioning. Circadian biomarkers, such as activity, heart rate, skin temperature, and light exposure recorded over 24 h, has shown promise in diagnosing and assessing the severity of various neuropsychiatric disorders. 

Recent Findings

Wearable devices capable of recording multiple circadian parameters have greatly aided data collection, and when integrated into treatment, have shown promise for revolutionizing circadian medicine. Therapies that entrain or shift the circadian system can help stabilize sleep-wake rhythms or better align rhythms with the environment.

Summary

These approaches support the emerging field of precision psychiatry, moving beyond a one-size-fits-all approach and addressing the heterogeneity and complexity of psychiatric disorders.

Introduction

Why Biological Rhythms Matter in 21 st Century Mental Health

In a society increasingly characterized by artificial environmental cue modification, i.e. via light pollution and ubiquitous electronic use, healthy circadian functioning is particularly vulnerable. The human circadian system is multilayered, with both central and peripheral components, as well as intrinsic and extrinsic inputs. Centrally, circadian rhythms are coordinated within the suprachiasmatic nucleus (SCN) of the hypothalamus, utilizing a pathway which starts with external light cues. These light cues regulate the signaling of cells containing melanopsin receptors in the retina which travel from the eye to the SCN via the retinal hypothalamic tract, thus entraining the SCN to external light/dark rhythms. The SCN in turn functions as a central pacemaker, coordinating circadian processes throughout the brain and body [1].

Additionally, virtually every cell in the human body contains its own peripheral circadian clock, which functions via a timed transcription-translation feedback loop involving core circadian genes, including Circadian Locomotor Output Cycles Kaput (CLOCK), Brain and Muscle ARNT-Like1 (BMAL1), Period Circadian Regulator (PER), and Cryptochrome (CRY1, CRY2) [2]. Clocks in the periphery are also entrained to various non-photic environmental stimuli, such as food intake, exercise, and stress [3]. For example, meal timing affects peripheral clocks in the liver, adipose tissue, and gut, independent of the SCN which is primarily synchronized by light. Unusual biological feeding times (i.e. eating late at night) can increase metabolic risk [4]. Exercise can also serve as a time-cue, synchronizing internal circadian rhythms and improving sleep [5]. The circadian clock in the SCN allows the human body to continue operating with close to a 24 h period even in the total absence of external light signals. For example, these free-running circadian rhythms are still observed in blind individuals with no entrainment to light [6].

Since the circadian clock is embedded in nearly every cell of the human body, circadian rhythms play a fundamental role in every aspect of human health, including the regulation of sleep, metabolism, immunity, and digestion. In addition, maintaining healthy circadian function is essential for brain development and plasticity, emotional stability, impulsivity, reward seeking, and cognitive performance. Exposure to timed signals, primarily light, helps synchronize human rhythms, which are increasingly affected by social and environmental factors such as shift work, electronic devices, light pollution, and travel across time zones. Because of these social and environmental factors, circadian dysfunction has become widespread, with these disturbances increasingly linked to psychiatric disorders and mood dysregulation [7]. Moreover, disruption of the internal clock resulting in circadian dysregulation can also serve as a trigger for the onset of neuropsychiatric conditions and can precipitate mood and psychotic episodes [8].

Chronopsychiatry and Precision Medicine

Chronopsychiatry, a field which explores psychiatric processes through the lens of circadian rhythm patterns and disturbances, offers the potential for precise psychiatric assessment and treatment by utilizing patients’ circadian patterns in order to individually characterize and treat psychiatric processes. The precision potential of chronopsychiatry stems from the uniqueness of human circadian response. Individuals respond differently to various circadian environmental cues based on biological factors related to the strength of entrainment and features of the internal biological clock. Individualized circadian profiling could provide a valuable measure of circadian health, an important component of overall psychiatric health (Fig. 1).

Fig. 1.

Circadian dysregulation, biomarkers, and interventions in psychiatric disorder. Figure created using biorender (https://biorender.com/)

Specifically, circadian rhythms may be described through the key measures of amplitude, phase, and period. Period is the duration of one complete circadian cycle, which is approximately 24 h. Period is characterized by an inherent discordance between an individual’s intrinsic circadian system, which has exhibited a period of 24.2 h in the absence of external light cues, and the exact 24-hour period of the external daily cycle. This mismatch is resolved on a daily basis through the process of entrainment to light cues, as described above, which allows humans to successfully remain synchronized with the 24-hour clock [9]. Amplitude refers to the difference between the peak and trough of an individual’s circadian rhythm. This can be determined via objective measures such as day-night differences in melatonin, body temperature, thyroid stimulating hormone (TSH), or plasma cortisol [10]. Amplitude differences can be observed in psychiatric disease states; for example, lower amplitudes of various measures are observed in patients with major depressive disorder [11]. Phase refers to the timing of an individual’s peaks and troughs throughout the 24-hour cycle. For example, individuals with an early phase, called an advanced phase, experience their circadian peaks earlier in a 24-hour cycle, while individuals with a late phase, called a delayed phase, experience peaks later in the cycle [12].

Phase is particularly relevant in mood disorders, for example in bipolar disorder, where phase advance is associated with mania and phase delay with depressive episodes. Moon et al. explored this effect, showing that circadian phase advances about 7 h during acute manic episodes, and then resolves to a normally timed phase after treatment of the manic episode. Depressive episodes, conversely, displayed a 6–7 h phase delay, which also corrected following resolution of the depressive episode [13]. Related to the concept of phase is the notion of chronotype, which characterizes an individual’s preference for morning or evening activity. Individuals with a late chronotype tend to report higher energy and better concentration in the evenings, with a preference for later sleep/wake times, while individuals with an early chronotype report better productivity in the morning, with a preference for earlier sleep/wake times [14]. Notably, late chronotype has been associated with a higher risk for mood disorders [15].

The parameters of circadian period, amplitude, and phase, along with characterization of chronotype, may be measured in individuals for the purpose of precise circadian profiling. However, this is rarely done in practice due to the difficulty of accurately measuring circadian biomarkers. Sleep and circadian phenotyping are often incomplete, leading to data gaps. Data collection is limited by participant compliance, the need for constant routine protocols with strict light control, and repeated biological sampling. Data interpretation is complicated by heterogeneity in analysis, which limits accurate estimation of circadian rhythm parameters. Factors such as medication timing, seasonal variations, and small sample sizes also complicate data comparison. Instead of using precise biomarkers, most circadian data gathering has traditionally relied on questionnaires. For example, the Munich ChronoType Questionnaire (MCTQ), developed in 2003, assesses characteristics such as sleep times and wake times, ease of waking up, and ease of falling asleep in order to determine an individual’s chronotype, with individuals described as either “larks” (those with a preference for morning activity) or “owls” (those with a preference for evening activity) [16]. The Morningness-Eveningness Questionnaire (MEQ) is another commonly used measure that assesses energy and alertness throughout the day, determining an individual’s degree of “morningness” vs. “eveningness” [17]. While these questionnaire-based measures have made critical contributions to circadian science, they are limited by the subjective nature of self-report data. Circadian biomarkers offer a more objective alternative for characterizing individual circadian profiles, and will be explored in more depth in this review (Fig. 2).

Fig. 2.

Circadian rhythm alterations, measurements, and treatments. Panels A-C depict circadian rhythm alterations commonly seen in psychiatric disease. Paned D depicts types of biodata which can be used to assess circadian rhythm; these data are grouped according to method of measurement. Panel E depicts techniques for treating altered circadian rhythms. Image created and licensed for publication by BioRender

Methods

Initial literature search was conducted through PubMed, searching for key terms “circadian rhythm” AND “actigraphy” OR “melatonin” OR “cortisol” OR “polysomnography”, with a subsequent search for “chronopsychiatry” OR “interpersonal and social rhythms therapy” OR “chrononutrition” OR “sleep deprivation” OR “bright light therapy”, initially filtering for articles published from 2022 to 2025. The results of these searches were reviewed, with some articles selected for their potential relevance to chronopsychiatry to include in this review. Reference lists from these selected articles were also used to identify other relevant articles for inclusion in the review.

Circadian Biomarkers: Tools for Objective Psychiatric Assessment

Psychiatric diagnosis is based in large part on clinical interviews and exams. Objective tests (i.e. labs and/or imaging) in psychiatric assessment are less common, with neuroimaging techniques such as Positron Emission Tomography (PET) and Functional Magnetic Resonance Imaging (fMRI) used generally for research rather than clinical diagnosis. While current psychiatric assessment techniques are mostly subjective, the availability of blood tests and other biological diagnostics presents an opportunity for the emergence of reliable biomarkers to diagnose and inform treatment regimens for patients. Circadian biomarkers present one such opportunity. These are biological markers characterized by rhythmic expression across various systems, including genetic, epigenetic, proteomic, metabolomic, histopathologic, neuroimaging, neurophysiological, and neurochemical domains, and include varied indicators such as Dim Light Melatonin Onset (DLMO), cortisol rhythm, body temperature, and circadian gene polymorphisms. These biomarkers can be used in precisely identifying psychiatric pathology and determining optimal treatment strategies (Table 1).

Table 1.

Acquisition, Relevance, and limitations of major circadian biomarkers in neuropsychiatric disorders

Circadian Biomarkers	Method of Acquisition	Relevance	Limitation	References
Polysomnography	Multi-lead recording during sleep hours, including electroencephalogram	Gold standard for recording sleep. Reveals sleep abnormalities such as the structure of REM and NREM sleep phases, as well as, sleep latency, onset and offset.	Requires specialized expertise for recording; difficult to interpret signals/artifacts; recording is only possible in clinical settings; data is only available from one night’s recording.	[46–49]
Rest-Activity Rhythms	Actigraphs/Wearables/Smart Phones.	Non-invasive; circadian parameters recorded for longer days. Recorded in natural settings.	Heterogeneity of data acquisition and analysis algorithms. Difficult to stage quiet wake and sleep.	[18–26]
Heart Rate; Heart Rate Variability	ECG/Fitness Trackers/Smart Phones/Chest Straps	Detects circadian rhythms of the autonomous nervous system; shows phase shifts and reduced amplitude in BD and MDD.	Heterogeneity of acquiring and analyzing algorithms recorded from different devices; data is affected by posture/movement.	[34, 79]
Melatonin (DLMO)	Saliva/Plasma under dim light conditions	Gold standard technique for recording circadian factors. Can reveal advanced and/or delayed rhythms in MDD and BD.	Repeated sampling; patient burden, high cost, high sensitivity.	[40, 43]
Cortisol Diurnal Rhythm	Saliva/Plasma/Sweat/Urine	Can reveal rhythmic changes in patients with mood disorders, particularly changes to the Cortisol Awakening Response (CAR) time in the morning.	Cortisol response is dependent on multiple factors, including stress, sleep, medication and food.	([41]–[42])
Core/Peripheral Body Temperature	Wearables/Sensors	Reveals phase/amplitude of body temperature rhythms; Delayed/advanced phase circadian rhythms are seen in MDD and BD.	Peripheral temperature is variable with environmental and physiological influences.	[42–44]

Multimodal Circadian Measurement via Actigraphy

Patterns of sleep/wake activity throughout the 24-hour cycle comprise one source of circadian rhythm data, and may be obtained via actigraphy. An actigraphy device, worn on the non-dominant wrist, measures activity-related changes in gravitational acceleration detected by sensors and translates the measured movement into estimates of sleep and wakefulness, analyzed by a mathematical algorithm. This method provides information about a subject’s sleep and activity patterns over multiple days in their home environment [18], including measures of total sleep time and sleep fragmentation. Actigraphic data may also include measurement of intra-daily stability, i.e. the fluctuation of activity levels throughout a 24-hour cycle; inter-daily variability, i.e. the consistency in activity and sleep/wake patterns across multiple days; and identification of “least active periods”, referring to periods of time when an individual tends to display more rest and less activity [19]. Actigraphy devices can also synthesize these various data in order to provide total assessment of circadian rhythmic patterns using Non-Parametric Circadian Rhythm Analysis (NPCRA) [20].

Circadian data available via actigraphy has been studied in the context of various psychiatric diagnoses. Specific sleep and activity patterns measured by actigraphy, such as sleep onset and offset, sleep mid-point, total sleep time, sleep fragmentation, and sleep variability, have been associated with psychiatric diagnoses, and could be used to support a clinical diagnostic formulation. For example, insomnia, poor sleep quality, and later sleep onset are associated with unipolar depression, while hypersomnia, longer sleep duration, and motor retardation are associated with atypical depression and bipolar depression [21]. More generally, circadian analysis of rest-activity rhythms over the 24 h cycle have found lower stability and greater variability in subjects with bipolar disorder compared to healthy subjects [22]. Actigraphic evidence of sleep disturbance may also serve as a biomarker for early prognosis or prediction in depressive disorders [23–25]. And actigraphy also yields insight regarding suicidal ideation, with patients who show evidence of excessive daytime sleepiness also exhibiting more severe depression symptoms, increased suicidal ideation and greater susceptibility to seasonal light/dark variations [26].

Advances in sensor technology and AI-based algorithms have resulted in modern wearables which incorporate actigraphic technology, like Fitbit, Apple Watch, Oura Ring, GENEActiv, and WHOOP. These devices provide personalized information and can aid in studying sleep data stratified by genetic criteria, sex, and geography [27–29]. Actigraphy-derived sleep and activity information from these wrist or finger-based devices has proven useful in providing circadian diagnostic markers that associate with various psychiatric symptoms [30], for example by effectively distinguishing manic and depressive mood states in bipolar disorder. For example, Clemens et al. found that reduced overall activity and less stable circadian rhythms were associated with depressive episodes, while increased activity and higher inter-daily stability were associated with manic/hypomanic days in patients with bipolar disorder [31].

Other actigraphy studies have used circadian assessment to predict mood episodes in patients with mood disorders. One prediction model used sleep-wake data from wearable devices to show that circadian phase delays and advances could predict the onset of depressive and manic episodes, respectively, in individual subjects [32]. Another recent study showed that patients with bipolar disorder who exhibited variability in total sleep time could be predicted to have a shorter estimated time between mood episodes [33].

Actigraphy can measure heart rate, which may also be used to characterize circadian rhythm. When heart rate is mapped over a 24-hour period, it may be analyzed by fitting a cosinor curve to the heart rate data, which is referred to as the individual’s heart rate circadian rhythm (HRCR). The HRCR curve may then be analyzed using standard circadian parameters, such as period, phase, and amplitude. Individuals with major depressive disorder display differences in their HRCR compared to control subjects. For example, individuals with depression have a dampened amplitude of HRCR, meaning a smaller distance between the highest and lowest points of their HRCR curve (i.e. less heart rate increase during the day, less heart rate decrease during the night). Similarly, when analyzing raw heart rate data, patients with depression also have a lower interval between their daytime and nighttime heart rates, also indicating a dampened heart rate circadian rhythm in these individuals [34].

Some studies have combined actigraphy with other data sources (i.e. measuring metabolites in blood samples) in order to correlate sleep/wake activity data with other biomarkers relevant to psychiatric disease risk. For example, Yavuz et al. measured actigraphic data and tryptophan metabolite levels in patients with bipolar disorder. They found that reduced sleep efficiency, with longer total time in bed and increased wakefulness after sleep onset, along with elevated kynurenine (KYN)/tryptophan (TRP) ratio and increased expression of 3-hydroxyanthranilic acid (3-HAA), predicted familial risk of bipolar disorder [35].

Wearable actigraphy devices can also assess psychiatric treatment efficacy, as in one study which measured circadian phase shifts and treatment response following lithium treatment in patients with bipolar disorder [36]. This approach can help categorize responders and non-responders to lithium; for example, Scott et al. demonstrated that individuals with bipolar I disorder who respond well to lithium tend to have less interdaily and intradaily fragmentation of circadian rest-activity rhythms, higher peaks of activity during the 24-hour cycle, and generally less disorganized circadian rhythms compared to non-responders [22].

More broadly, wearable devices can be used with other personal data collecting sources (such as smartphones) to enable digital phenotyping, which has proven more reliable than questionnaire-based diagnosis, especially in schizophrenia and bipolar disorder [37]. Data from wearables, along with phone usage patterns, screen time, and social media interactions from smartphones, can be used to develop a digital phenotype for a patient, helping clinicians assess the patient’s condition in real time [38]. This type of data is particularly useful for assessing a patient’s circadian changes and sleep-wake patterns, along with factors that could be influencing these patterns such as light at night.

Endocrine Markers

The primary endocrine markers of circadian rhythms are cortisol and melatonin. Melatonin is a hormone produced by the pineal gland that regulates sleep and is among the most widely used sleep-promoting supplements. In contrast, cortisol is released by the adrenal cortex with a morning peak to assist in waking. Together, the circulating levels of these two hormones through the 24-hour cycle, offer a window into endocrine circadian function. These levels can be measured using a variety of methods. Melatonin can be measured at 2–8 h intervals throughout the 24-hour cycle via the metabolite 6-sulphatoxymelatonin (aMT6s), which is present in the urine. It can also be measured serially from saliva or blood samples [39]. Notably, serial saliva samples are often used in practice to determine a subject’s Dim Light Melatonin Onset (DLMO), the point in time when a subject starts to release melatonin in the evening under dim light conditions [40]. Cortisol may also be measured using a variety of methods, with urine, saliva, and blood all providing reliable measurements for 24-hour monitoring, as well as samples taken from sweat and/or interstitial fluid [41]. Abnormal circadian cortisol patterns are known to correlate with symptoms of anxiety, depression, and irritability, while normalization of circadian cortisol rhythms has been correlated with improvement in these symptoms [42]. Melatonin pattern disturbances have also been implicated in mood symptomatology; for example, with melatonin rhythm disturbances preceding next-day mood symptoms in subjects with bipolar disorder [43].

New technologies allow easier and more precise tracking of endocrine markers. Although blood, saliva, and urine have traditionally been used to measure cortisol and melatonin, newer alternatives such as molecularly imprinted polymer (MIP) electrochemical fingertip sweat sensors [44], skin temperature sensors, and contact lenses [45] now offer additional options for assessment of circadian endocrine patterns that can be performed outside the laboratory setting, making them more practical options for use in psychiatric diagnostic and maintenance settings.

Sleep Related Brain Activity Via Polysomnography

Polysomnography (PSG) is a multi-sourced recording of sleep-related brain, respiratory, cardiac, and muscle rhythm, which provides a rich collection of sleep data for individuals [46]. While not directly measuring circadian rhythm variation, PSG can be used to inform an individual’s circadian profile by providing precise data about the timing of sleep onset and sleep phases during the night. PSG has been used for decades to study primary sleep disorders; however, PSG findings have also been correlated with various psychiatric phenomena, and thus represent a largely untapped source of biodata for precisely assessing and treating psychiatric symptomatology. For example, sleep parameters such as shorter Rapid Eye Movement (REM) sleep and reduced sleep stage 1 (N1) sleep latency are associated with seasonal vulnerability in major depressive episodes [47]. Sleep parameters have also been associated with psychotic disorders; for example, reduced sleep spindle density with altered spindle morphology during non-REM sleep, as evidenced by the electroencephalogram (EEG) component of a PSG, is associated with schizophrenia [48, 49]. While not directly informing the circadian profiles of individuals with these disorders, PSG may continue to provide useful insight into sleep-related phenomena which may be found in concert with circadian rhythm disruptions.

Circadian Therapeutic Treatments

As discussed above, chronopsychiatric data can provide precise information about a subject’s circadian profile, which may lend helpful objective data to an overall psychiatric assessment. With this information in mind, practitioners may also be able to identify chronotherapeutic targets for personalized treatment plans. A variety of chronotherapies have been implemented with success, particularly in the treatment of mood disorders, such as bright light therapy, dark therapy, sleep deprivation, time-restricted feeding, interpersonal and social rhythm therapy, and light restriction therapy. These therapies, discussed at length below, can improve management of mood disorder symptoms when used alongside other psychiatric interventions (Table 2).

Table 2.

Major Interventions, Mechanisms, and limitations of psychiatric therapies

Intervention	Mechanism	Key Outcome in Disease	Limitation	Reference
Bright Light Therapy	Promotes phase shifts and normalization of circadian rhythms by modulating SCN; regulates melatonin and monoamines, modulates sleep-wake timing.	Phase shifts in MDD; reduction of mood episodes in patients with BD.	Heterogeneity of light intensity, dosing and time of day (AM/PM); Requires daily adherence and must be monitored properly.	[66–78]
Sleep Deprivation/Wake Therapy	Total/partial sleep deprivation produces antidepressant effects; helps to reset circadian rhythm by promoting phase advance.	Rapid effects in bipolar disorder and MDD when combined with medication. Can alleviate symptoms of treatment resistant depression.	Effects are short-lived; High relapse rate after sleep recovery; Close monitoring required.	[62, 63]
Interpersonal Social Rhythm Therapy (IPSRT)	Regularizes daily routines (activity, sleep, diet); reduces disturbances in social rhythms to stabilize mood.	Prevents relapse of mood episodes; promotes mood stability over time.	Requires prolonged participation and adherence from patients.	[50–54]
Time Restricted Eating (TRE)	Aligns light-dark cycle with metabolic cues, thereby stabilizing circadian rhythms.	Can improve metabolic health and mood in MDD and BD.	Adherence to time and diet can be challenging. Difficult to implement in medically underweight patients.	[56–61]
Lithium	Mood stabilizer: modulates circadian clock genes and stabilizes circadian rhythms.	Lengthens circadian period and amplitude; prevents relapse in BD; stabilizes sleep-wake cycle.	May cause adverse effects on thyroid and kidney. Lithium levels in serum must be regularly monitored. Non-responders/partial- responders require combination therapy.	[33, 49]

Interpersonal and Social Rhythm Therapy (IPSRT)

Interpersonal and social rhythm therapy (IPSRT) is a psychotherapeutic modality which helps patients with mood disorders improve their symptoms by understanding and improving their biological and social rhythms. This therapy aims to help patients create and maintain daily schedules, thus preventing rhythmic disruptions that can lead to mood disturbances. IPSRT has been shown to stabilize daily rhythm disruptions and boost mood and quality of life in bipolar disorder (BD) and major depressive disorder (MDD) by improving emotion regulation [50, 51]. It has also been reported to be effective in patients with BD type II depression, specifically by reducing suicidal thoughts in this population [52]. Regularizing the timing of daily routines, such as mealtimes, exercise, sleep, and wake times, can reduce the risk of mood episode relapse. Social impairment seen in schizophrenia spectrum disorders can also improve through IPSRT [53]. Telehealth social rhythm therapy (SRT) was also shown to reduce suicide risk and mood symptoms in adolescents and young adults with bipolar disorder [54], thus demonstrating the wide applicability of this modality and its usefulness in virtual healthcare settings.

Chrononutrition

Chrononutrition is a nutrition approach informed by the timing of an individual’s food intake [55]. This approach incorporates awareness of the circadian nature of digestion and metabolism and fosters a bidirectional exploration of the impact of meal timing on circadian health, as well as the importance of circadian rhythm in nutrition and metabolism. This line of thinking has produced an innovative dietary approach known as time-restricted eating (TRE) or time-restricted feeding (TRF), which involves limiting an individual’s daily eating window to a predetermined time of day. Studies have indicated that TRE generally enhances circadian gene expression [56] and sleep quality [57]; however, specific effects on psychiatric disorders remain unclear.

While this technique is still being explored, some studies have examined associations between TRE and psychiatric phenomena. For example, a recent report from Li et al., 2024 advocated for careful selection of TRE eating windows, showing that extended eating windows (> 12 h) are linked to a higher risk of depression. Importantly, they also showed that excessively shortened eating windows (< 10 h) are also linked with higher depression risk, and that the optimal TRE window for psychiatric benefit lies between these two extremes, in the 10–12 h range [58]. Another recent pilot study showed that an early TRE window can advance sleep timing in participants with delayed phase, or in late sleepers [59]. In animals, one study showed that TRE prevents depression- and anxiety-like behaviors in rat models of shift work [60]. The mechanism behind these associations is not fully understood; however, data from a recent publication shows that TRE synchronizes peripheral clocks in different organs, such as the liver, kidney, and muscles, with brain cells in the suprachiasmatic nucleus, helping to reverse systemic circadian disruptions via corrective peripheral input [61].

Sleep Deprivation Therapy and Sleep Phase Advance

In sleep deprivation therapy, patients are kept awake for periods ranging from 4 h to as long as 40 h for the alleviation of depression symptoms. Sleep deprivation therapy has proven effective in rapidly treating both unipolar and bipolar depression. However, patients tend to resume their prior sleeping patterns following the sleep deprivation period, leading to a resurgence of depression symptoms. Lasting benefits have been noted only when sleep deprivation therapy is paired with bright light therapy (see below) and sleep phase advance techniques, in which patients receive support in achieving and maintaining an advanced sleep schedule [62]. Notably, sleep deprivation therapy regimens are most appropriately conducted inpatient, due to the risk of triggering mania symptoms, as well as safety risks inherent to sleep deprivation [63]. Alternatively, bipolar mania, which is often associated with a phase advance, may be treated via dark therapy, which aims to minimize melanopsin-mediated light signaling to the SCN by utilizing blue light-blocking eyewear for 14 h daily [64] or by spending extended periods in darkness [65].

Bright Light Therapy

Bright light therapy (BLT) involves daily, early morning exposure to high-intensity light that stimulates retinal cells, thereby activating the circadian system, phase advancing the circadian system, increasing brain arousal, and alleviating depression symptoms [66–68]. BLT has been used as a cost-effective and safe treatment for both non-seasonal depression and seasonal affective disorder (SAD) for 30 years, leading to improved depression ratings and increased patient responsiveness to active treatments [69, 70]. This treatment has been reported to reduce irritability in bipolar depression compared to pharmacotherapy alone [71]. Whether used alone or with medication, BLT has been shown to improve the quality of life for patients with major depressive disorder (MDD) by alleviating depression symptoms, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) score [72].

Recent research on BLT has established its efficacy across specific subgroups and settings. For example, individuals who experience recurrent depression with seasonal patterns have demonstrated improvement with BLT [73]. BLT is effective across diverse populations, regardless of geographical location; for example, a recent study in people from Asia demonstrated that BLT is effective in treating MDD [74], while another study demonstrated the effectiveness of BLT in advancing sleep phase for Brazilian athletes prior to the 2016 Rio Olympic Games [75]. Additionally, BLT helps reduce depressive symptoms associated with schizophrenia, although one study found that the effect did not last beyond two weeks in patients [76]. A recent study in patients with bipolar disorder (BD) already receiving antidepressants showed that BLT enhanced the therapeutic response to medications [77]. BLT has also demonstrated promise as part of new, innovative delivery systems. For example, Visser et al. explored a novel BLT technique which they termed Light Café, a social setting for receiving BLT under the guidance of trained administrators, and alongside other participants also undergoing BLT. This setting offers several benefits beyond traditional self-administered BLT, including social support, lifestyle reinforcement from peers, and the availability of professionals to determine each patient’s personalized BLT timings, based on their individual circadian rhythms and treatment goals [78].

From Circadian Assessment to Chronotherapy: Chronopsychiatry in Practice

As reviewed above, a variety of tools are available for precisely characterizing and targeting circadian rhythm as a psychiatric treatment. However, these types of chronopsychiatric interventions have not been widely adapted in clinical practice. Below, we provide several example vignettes which make use of the techniques described above for the purpose of individualized chronopsychiatric intervention. Of note, the vignettes below could be limited in implementation by logistical concerns (i.e. insurance coverage, availability of testing); however, we suggest them as possibilities for the future of chronopsychiatric care.

Vignette 1

A 49 year old male with symptoms of depression is assessed by an outpatient psychiatrist. The psychiatrist finds that one of this patient’s symptoms is self-described “poor sleep.” The patient shares that he wears an Apple Watch which records his daily sleep and wake times. Using this Apple Watch data, the psychiatrist observes that the patient has a delayed sleep phase, with sleep times often occurring around 2AM and wake times around 9AM. The psychiatrist counsels the patient to use bright light therapy upon awakening every morning, in order to advance his sleep phase and help alleviate depression symptoms.

Vignette 2

A 30 year old woman with bipolar disorder goes to her therapist for a routine appointment. Although the patient feels she is doing well, the therapist decides to assess her circadian rhythm by having her wear a clinical actigraphy device for four weeks. Later, when reviewing the patient’s actigraphy data, her therapist observes high inter-daily circadian variability of rest/activity rhythms, with 24-hour peaks and troughs often occurring at different times on different days. She informs the patient that this indicates circadian rhythm instability, a common symptom of individuals with bipolar disorder, and recommends for the patient to start interpersonal social rhythms therapy as a means of stabilizing her circadian rhythms. She advises the patient that this may help prevent the onset of mood episodes.

Vignette 3

A 28 year old man with bipolar disorder schedules an appointment with his psychiatrist because he feels “hypomanic”, describing a sense that his thoughts are racing and he has more energy than usual. The psychiatrist decides to assess the patient’s circadian rhythm by having him complete an at-home DLMO testing kit, in which the patient collects his own saliva every 30 min during the afternoon/evening in order to calculate the time of his Dim-Light Melatonin Onset (DLMO). Using these results, the psychiatrist learns that the patient’s DLMO has been occurring early at 6pm, indicating a circadian phase advance. She counsels the patient that this type of phase advance can indicate an oncoming manic episode. She recommends that he begin wearing blue-light blocking glasses from 6PM-8AM daily, in an effort to delay his circadian phase and prevent the development of a manic episode.

Conclusion

Circadian assessment tools are plentiful and have the potential to generate precise, individualized circadian profiles for patients as part of a complete psychiatric assessment. This in turn may promote the development of personalized, chronotherapeutic treatment plans. Many circadian assessment tools are easily accessible to patients (i.e. wearable actigraphy and biosensors), and could theoretically be incorporated into clinical practice. However, concerns remain regarding the accuracy and reliability of such devices, and further validation and standardization is still required in order to enable more widespread use.

In the meantime, conventional methods for sleep and chronopsychiatric assessment remain, including polysomnography and clinical lab sampling, and though these methods require laboratory visits and potential overnight stays, they present ready options for clinicians who wish to incorporate objective circadian data into their psychiatric formulations. Likewise, conventional chronotherapeutic techniques are also available for clinical use, such as bright light therapy, sleep phase advance, and IPSRT.

We suggest that a comprehensive diagnostic approach which utilizes circadian data alongside other methods of psychiatric assessment, as well as a treatment approach which incorporates chronotherapeutics when appropriate, is essential for improved prediction, understanding, and treatment of neuropsychiatric disorders.

Key References

• Maruani J, Vissouze L, Ambar Akkaoui M, Zehani F, Frija J, Lejoyeux M, et al. (2025) Sleep biomarkers of seasonal vulnerability in major depressive episodes: a clinical study using actigraphy and polysomnography. Int J Clin Health Psychol 25 [2]:100595.

  • The authors identify polysomnography features associated seasonal vulnerability in major depressive disorder.
• Leseur J, Boiret C, Romier A, Bazin B, Basquin L, Stern E, et al. (2024) Comparative study of sleep and circadian rhythms in patients presenting unipolar or bipolar major depressive episodes. Psychiatry Res 334:115811.

  • The authors demonstrate the potential of actigraphy in precision medicine; in this case, by using actigraphy to identify sleep patterns associated with specific psychiatric phenotypes (unipolar vs bipolar depressive episodes).
• Clemens J, Mühlbauer E, Reinhard I, Bauer M, Neubauer AB, Ritter P, et al. (2025) Circadian rhythm parameters differentiate euthymic, manic and depressive mood states in bipolar disorders: an explorative pilot study. Int J Bipolar Disord 13(1):30.

  • This study broadly establishes how circadian parameters may be used as objective data for identifying psychiatric phenomena (in this case, mood states).
• Titone MK, Goel N, Ng TH, MacMullen LE, Alloy LB (2022) Impulsivity and sleep and circadian rhythm disturbance predict next-day mood symptoms in a sample at high risk for or with recent-onset bipolar spectrum disorder: an ecological momentary assessment study. J Affect Disord 298(Part A):17–25.

  • The authors use dim light melatonin onset (DLMO) to objectively assess circadian rhythm, then found a relationship between circadian rhythm and psychiatric phenomena (i.e. impulsivity and mood symptoms) in their subjects, thus demonstrating a path toward psychiatric assessment informed by objective circadian data.

Author Contributions

A.Bs, K.L. and C.A.M all wrote and edited the manuscript.

Funding

Work from our lab was funded by a University of Pittsburgh Physician-Scientist Institutional Award from the Burroughs Wellcome Fund to K.L. as well as the Baszucki Brain Research fund, National Institute of Mental Health (NIMH) (MH106460; MH111601), National Institute on Drug Abuse (NIDA) (DA039865; DA046346), and the WoodNext Foundation and Baszucki Brain Research Fund to C.M.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Human and Animal Rights and Informed Consent

Ethical approval and consent are not relevant to this article type.

Competing interests

The authors declare no competing interests.