Role of chronotype in depression

Abstract

Depression is a widespread and debilitating mental health disorder affecting millions globally. Chronotype has been increasingly recognized as a significant factor associated with depression. This review aims to comprehensively dissect the role of chronotype in depression, providing insights into the underlying mechanisms linking chronotype to depression, as well as the potential therapeutic implications. Converging evidence indicates that evening chronotype is notably associated with an elevated risk of depression, more severe symptoms, and a higher rate of suicidality, while morning chronotype may exert a protective effect. These findings highlight that chronotype plays a crucial role in the development, manifestation, and management of depression. Nevertheless, some methodological issues of the existing studies (e.g., reliance on self-reported chronotype assessments) should be noted and discussed. Further investigations are warranted to elucidate the intricate mechanisms underlying the relationship between chronotype and depression, establish causal links, and optimize the clinical application of chronotype-based interventions for depression.

Key Words: Depression; Chronotype; Circadian rhythm; Underlying mechanism; Therapeutic implication

Core Tip: Growing evidence highlights the role of chronotype in depression. This review summarizes the association between chronotype and depression, dissecting the underlying mechanisms including neurotransmitter system dysregulation, circadian rhythm disruption, sleep disturbance, and genetic factors. It also explores the therapeutic implications of light therapy, cognitive behavioral therapy, and pharmacotherapy in the context of different chronotypes. The findings emphasize that evening chronotype is linked to an elevated risk, severe symptoms, and higher suicidality in depression, while morning chronotype may exert a protective effect. These insights could guide future research and personalized clinical strategies.

INTRODUCTION

Depression is one of the most prevalent mental health disorders worldwide, affecting over 300 million people and representing a leading cause of disability globally[1]. Characterized by marked and persistent depressed mood and loss of interest or pleasure, accompanied by cognitive, behavioral, and physiological impairments, depression imposes a significant burden on individuals, families, and society[2]. Despite advances in understanding its etiology and treatment, the underlying mechanisms of depression remain incompletely understood, and a substantial proportion of patients do not achieve full remission with current therapies.

Chronotype, also known as diurnal preference, refers to individual differences in the preferred sleep-wake cycle timing. It reflects an individual’s diurnal or nocturnal preference and is an integral part of the circadian rhythm[3-5]. Moreover, it describes the temporal patterns of human behavior, specifically when individuals tend to wake up, engage in activities, and go to sleep within a 24-hour period. It is a complex trait that is influenced by genetic, environmental, and social factors, which remains relatively stable within the individuals over time[6].

In recent years, the relationship between chronotype and depression has attracted growing attention from researchers. Disturbances in chronotype are common among patients with depression and may represent potential pathophysiological mechanisms of depression. Chronotype in depression are associated with disease onset, severity of symptoms, comorbidities, antidepressant response, recurrence, cognition, social function, and physical health. Understanding the role of chronotype in depression is crucial for the development of more effective prevention and treatment strategies.

CLASSIFICATION OF CHRONOTYPE

Chronotype can be broadly classified into morning chronotype (characterized by activity preference in the morning, including absolute morning chronotype and moderate morning chronotype); evening chronotype (with activity peaks in the evening, including absolute evening chronotype and moderate evening chronotype); and intermediate chronotype (falling between the two extremes, comprising most individuals)[7,8]. It has been reported that the intrinsic circadian pacemaker in evening chronotypes is significantly delayed compared to that in morning chronotypes. The rhythms of melatonin and core body temperature are, on average, 2-3 hours later in evening chronotypes[9]. To date, the distribution of different chronotypes in the population is not uniform, with a certain percentage of individuals falling into each category[10]. However, this individual preference in the timing of sleep and activity varies systematically throughout the lifespan for males and females[11]. Generally, chronotypes of individuals tend to be earliest in young children, shifts to the latest in adolescents, and then gradually advances again in middle and older ages[10,12]. Moreover, large cross-sectional studies have identified sex differences in chronotype, showing that adult males tend to exhibit later chronotypes than females until approximately 50 years of age[12-14].

The assessment of chronotype is typically done through self-reported questionnaires such as the morningness-eveningness questionnaire (MEQ)[7] and its reduced version (rMEQ)[15], and the Munich chronotype questionnaire[16,17]. The higher the score on the MEQ, the stronger the preference for the morning chronotype; conversely, the lower the score, the stronger the preference for the evening chronotype. Other relatively objective tools can be used to assess chronotype, including core body temperature monitoring[18], dim light melatonin onset[19], sleep diaries[20], and wrist actigraphy[18,21] (Table 1).

Table 1 Comparison of chronotype assessment tools.

Assessment tool	Advantages	Limitations	Applications
Self-reported questionnaires	Low cost, easy to administer, suitable for large samples	Susceptible to recall bias, subjective interpretation	Epidemiological studies, clinical screening
Core body temperature monitoring	Objective, non-invasive, reflects circadian rhythm directly	Requires continuous monitoring equipment, time-consuming	Circadian rhythm research, clinical trials
Dim light melatonin onset	Gold standard for circadian phase assessment	Requires controlled laboratory environment, labor-intensive	Mechanistic studies, precision medicine
Wrist actigraphy	Provides objective data on sleep-wake cycles and activity rhythms	Data analysis requires specialized software, limited to motor activity	Long-term monitoring in clinical settings, personalized treatment
Sleep diaries	Captures detailed daily sleep-wake patterns	Reliant on participant compliance, potential recording errors	Diagnosis of sleep disorders, behavioral interventions
Genetic markers	Identifies genetic basis of chronotype	Limited to research settings, complex interpretation	Genetic epidemiology, molecular mechanism studies

CHRONOTYPE AS A POTENTIAL RISK FACTOR FOR DEPRESSION

Numerous studies have consistently reported a significant association between the evening chronotype and an increased risk of depression (Table 2). In children and adolescents, controlling for pubertal status, age and gender, a greater evening chronotype is associated with higher earlier depression symptoms and history of depression diagnosis[22]. Among Korean high-school students, the evening chronotype was demonstrated to be associated with an increased risk for depression[23]. Among Chinese college students during the corona virus disease 2019 (COVID-19) pandemic, those with evening chronotype were more likely to suffer from depressive symptoms[24]. A study of young male military recruits in compulsory service also showed that the evening chronotype was associated with depressive symptoms[25]. In a perinatal depression study, perinatal women with evening chronotype showed a higher risk for developing perinatal depression symptoms[26]. Among the general adult population, participants with evening chronotype had a higher risk of depression as well[27]. A study on a rural population showed that social jetlag, defined as the mismatch between an individual’s internal biological clock and external social schedules, correlated positively with chronotype and may be a risk factor for developing depression[28]. A 17-year cohort study on data from the Finnish Hospital personnel cohort study, which involved 10637 participants including local government employees and nurses, physicians, and administrative staff from Finnish Hospital, revealed that evening chronotypes were more vulnerable to self-reported mood disorders than morning chronotypes[29]. Another large cohort study using a large Dutch cohort also demonstrated a significant association between the evening chronotype and depression[30]. In analyzing the data in the United Kingdom Biobank (n = 496820) and the older Finnish twin cohort (n = 23854), the evening chronotype predicted increased incidence of psychiatric disorders, including major depressive disorder (MDD)[31]. Crucially, evening chronotypes without sleep inertia were at no higher risk as compared to morning chronotypes[31].

Table 2 Summary of key studies: Association between chronotype and depression.

Population	Study design	Key findings	Ref.
Children and adolescents	Longitudinal study	Evening chronotype was associated with earlier depressive symptoms and history of depression diagnosis	Koo et al[23]
Korean high school students	Cross-sectional study	Evening chronotype was significantly associated with increased depression risk	Koo et al[23]
Chinese college students during COVID-19 pandemic	Cross-sectional study	Evening chronotype was more prevalent among students with depressive symptoms, with sleep quality mediating this association	Zhang et al[24]
Young male military recruits	Cross-sectional study	Evening chronotype was associated with depressive symptoms and higher symptom severity	Tonon et al[25]
Perinatal women	Cohort study	Perinatal women with evening chronotype showed a higher risk of developing depressive symptoms	Garbazza et al[26]
General adults	Cross-sectional study	Evening chronotype was linked to increased depression risk, while morning chronotype showed a protective effect	Mao et al[27]
Rural population	Cross-sectional study	Social jetlag correlated with chronotype and served as a risk factor for depression; evening chronotypes had more severe depression	Levandovski et al[28]
Finnish Hospital personnel	17-year cohort study	Evening chronotypes were more vulnerable to self-reported mood disorders than morning chronotypes	Cheng et al[29]
Large Dutch cohort	Cohort study	A significant association was found between evening chronotype and depression	Antypa et al[30]
United Kingdom biobank and older Finnish twin cohort	Genome-wide association + cohort study	Evening chronotype predicted increased incidence of psychiatric disorders, including MDD; evening chronotypes without sleep inertia had no higher risk than morning chronotypes	Burns et al[31]
General adults (genetically predicted)	Mendelian randomization study	Genetically predicted morning chronotype was associated with a 23% lower risk of depression	Daghlas et al[33]
Korean adults	Cross-sectional study	Evening chronotype was associated with increased depression risk in women but not men; women with evening chronotype had 1.5-fold higher depression risk than men	Kim et al[35]
Adults from NHANES 2017-2020	Cross-sectional study	Evening chronotype was associated with higher levels of depressive symptoms	Seizer et al[41]
Patients with depression	Cross-sectional study	Evening chronotype was linked to higher suicidality, more severe symptoms, lower remission rates, and poorer response to antidepressants in depression patients	Mokros et al[44]; Rasmussen et al[45]; Chan et al[46]

COVID-19: Corona virus disease 2019; MDD: Major depressive disorder; NHANES: The National Health and Nutrition Examination Survey of the United States.

The morning chronotype, however, may have a protective effect against depression. Both population-based observational and mendelian randomization studies have demonstrated this association[27,32-34]. Particularly, individuals with a genetically predicted earlier diurnal preference had a 23% lower likelihood of developing depression[33].

In addition, gender differences have been noted in the relationship between chronotype and depression[35]. The association between the evening chronotype and depression may be stronger in women, potentially mediated by hormonal fluctuations and social stressors. Estrogen enhances the expression of clock genes (e.g., PER3), making women more sensitive to circadian misalignment, a condition in which the internal circadian clock is not synchronized with external cues (e.g., light-dark cycles, social schedules) or with an individual’s behavioral patterns (e.g., irregular sleep-wake times, shift work)[36]. Testosterone in males correlates with delayed sleep timing in adolescents[14,37]. Women with morning chronotype exhibit earlier increases in estradiol during the menstrual cycle compared to those with intermediate type, whereas higher testosterone levels in males predict evening chronotype tendency[36-38]. Socially, caregiving responsibilities in women may exacerbate sleep disruptions in evening chronotypes[39], amplifying depression risk. The onset time of melatonin secretion in women is earlier than that in men, and the amplitude is also greater[40]. Consequently, the evening chronotype confers a 1.5-fold higher depression risk in women than in men[35]. However, the interplay between sex hormones, circadian regulation, and social roles in this relationship remains unclear and warrants mechanistic exploration.

CHRONOTYPE AND DEPRESSION SEVERITY

In addition to elevating depression risk, chronotype has been shown to influence depression severity. During the COVID-19 pandemic, Chinese college students with evening chronotype were more likely to experience more severe depressive symptoms[24]. In addition, association between the evening chronotype and severity of depressive symptoms was found in the young male military recruits in compulsory service[25]. The severity of perinatal depressive symptoms was also modulated by chronotype[26]. In the aforementioned rural population study, evening chronotypes exhibited more severe depression than intermediate and morning chronotypes[28]. Within the United States population surveyed by the National Health and Nutrition Examination Survey from 2017 to 2020, the evening chronotype was associated with a higher level of depression[41], which substantiates the findings of previous studies. Due to a late chronotype and a delayed bedtime, the opportunities for individuals to ruminate increase, which may exacerbate depression[42].

Suicidal thoughts and behavior often reflect the severity of depression. Growing evidence suggests a relationship between the evening chronotype and suicidal thoughts and behaviors in those with depression[43-45]. Notably, depression patients with evening chronotype not only exhibit higher suicidality, but also have more severe depressive symptoms and a higher non-remission rate than those with morning chronotype[46,47]. Even when undergoing antidepressant treatment, depression patients with evening chronotype still reported more depressive symptoms and suicidality[48]. Interestingly, dysregulation of eating pattern (assessed via the Biological Rhythms Interview of Assessment in Neuropsychiatry) may exacerbate suicidal ideation in patients with depression[49]. However, a narrative review shows an absence of a direct correlation between the evening chronotype and suicidality, but the evening chronotype promote a chain of effects that could be involved in an increased risk of suicidal behaviors[50].

POTENTIAL MECHANISMS LINKING CHRONOTYPE TO DEPRESSION

Interplay between neurotransmitter systems and circadian rhythms

Neurotransmitter systems, including serotonin, dopamine, and norepinephrine (NE), interact bidirectionally with circadian rhythms, potentially linking chronotype to depression (Table 3).

Table 3 Neurotransmitter systems and their interactions with circadian rhythms, chronotype, and depression.

Neurotransmitter	Key mechanisms in circadian regulation	Circadian rhythm associations	Chronotype-specific differences	Link to depression
5-HT[51-61]	Regulates nonphotic phase shifts in the SCN; activity of 5-HT and SERT mRNA expression follow robust circadian rhythms	5-HT turnover peaks in hippocampus during ZT18-ZT22; disrupted 5-HT circadian alignment in evening chronotypes	Evening chronotypes exhibit heightened 5-HT misalignment; morning light enhances 5-HT signaling in evening types	5-HT dysregulation correlates with depression severity and prevalence; stress-induced 5-HT dysfunction increases depression susceptibility
DA[62-72]	Modulates reward processing and circadian timing via retinal and SCN signaling; DA transporter sensitivity shows diurnal variation	Evening chronotypes have blunted daytime DA peaks; chronic misalignment exacerbates DA-driven anhedonia	Evening chronotypes exhibit altered DA transporter sensitivity; DA fluctuations align with chronotype-dependent motivation deficits	DA dysregulation underlies anhedonia in depression; bidirectional feedback loop with circadian arousal patterns
NE[22,73-75]	Regulated by the LC in a diurnal pattern tied to sleep-wake cycles; influences circadian plasticity (e.g., PER3 expression)	NE turnover peaks during ZT22-ZT2; evening chronotypes show blunted NE peaks and elevated nighttime levels	LC dysfunction in evening types disrupts NE circadian release; NE dysregulation interacts with pubertal sleep shifts in adolescents	NE imbalance exacerbates stress responses and depressive symptoms; bright light therapy modulates NE release in the SCN

5-HT: 5-hydroxytryptamine; DA: Dopamine; mRNA: Message RNA; NE: Norepinephrine; SCN: Suprachiasmatic nucleus; SERT: Serotonin transporter; LC: Locus coeruleus.

Firstly, the serotonergic system exemplifies this interplay. Serotonin [5-hydroxytryptamine (5-HT)], regulates nonphotic circadian phase shifts in the suprachiasmatic nucleus (SCN)[51-53], while its own activity, including neurotransmitter levels, metabolite variation, and transporter expression, follows robust circadian rhythms[54-58]. Presynaptic and postsynaptic 5-HT signaling in the SCN inhibits light-driven phase resetting[59], creating a feedback loop that aligns chronotype with mood regulation. Stress may disrupt this balance: Cortisol-induced 5-HT dysregulation impairs circadian synchronization and increases susceptibility to MDD[60,61]. Evening chronotypes exhibit heightened 5-HT circadian misalignment, which correlates with depression severity and prevalence[28,61].

Secondly, dopamine links reward processing to circadian regulation. Its dysregulation underlies depressive anhedonia while influencing sleep wake timing via signaling in the retina and SCN[62-67]. Diurnal dopamine fluctuations align with chronotype: Evening chronotypes show blunted daytime peaks and altered transporter sensitivity, increasing depression risk[68-70]. Chronic circadian misalignment exacerbates dopamine dysfunction, worsening anhedonia and motivational apathy[71]. Conversely, depression disrupts dopamine-mediated arousal patterns, creating a bidirectional feedback loop[72].

Thirdly, NE, central to stress and arousal, is regulated by the locus coeruleus (LC) in a diurnal pattern tied to sleep wake cycles[73]. Evening chronotypes often exhibit LC dysfunction, characterized by blunted NE peaks and elevated nighttime levels, which exacerbate depressive symptoms[74]. NE directly influences circadian plasticity; for example, acute NE exposure shifts PER3 expression in human fibroblasts[74]. In adolescents, NE dysregulation interacts with pubertal sleep shifts to increase depression vulnerability[22]. Bright light therapy modulates NE release in the SCN, enhancing circadian synchronization and reducing depression severity[75].

Notably, the effects of single neurotransmitters may not operate in isolation. For example, a short light-dark cycle (22 hours) increases NE, dopamine, and serotonin turnover in the prefrontal cortex, inducing depressive states and desynchronizing SCN oscillations[76]. These findings highlight how neurotransmitter dysregulation and circadian misalignment form interdependent pathways in depression.

Circadian rhythms, driven by endogenous oscillators (e.g., SCN and pineal gland) and exogenous cues (e.g., light, and sleep-wake cycles)[77,78], are critical for mental health. Circadian rhythm disruptions, which are often linked to abnormal chronotypes, can lead to disturbances in sleep-wake cycle, hormone secretion, and other physiological processes, increasing the risk of depression[79].

Moreover, nocturnal light exposure impairs SCN synchronization with the light-dark cycle, disrupting melatonin and cortisol rhythms[80]. Morning light deprivation in evening chronotypes further disrupts SCN resetting, reinforcing the link between evening chronotype and depression[81]. These hormonal changes intersect with dopamine and NE dysregulation, creating a bidirectional loop[82]. Glucocorticoid abnormalities and thyrotropin rhythm disruptions also contribute to depression pathogenesis[83,84].

Depression itself may exacerbate circadian dysfunction. Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis blunts cortisol rhythms, while prefrontal cortex alterations impair emotional regulation[85]. Conversely, circadian disruption via chronotype abnormalities perpetuates physiological and mood dysregulation. This interplay positions circadian misalignment as a key mechanistic node connecting chronotype to depression[79,85].

In summary, neurotransmitter dysregulation and circadian rhythm disruption represent interconnected rather than independent pathways in depression. Serotonin and dopamine directly modulate circadian circuitry, while NE links stress responses to chronotype. Disruptions in these systems create feedback loops with hormonal and behavioral processes, amplifying depression risk, particularly in evening chronotypes. Future research into these neurochemical-circadian interactions may yield targeted therapies for depression.

Sleep disturbances

Sleep disturbances or sleep problems, including insomnia symptoms, poor sleep quality, and daytime functional impairments, are common in both evening chronotypes and depression patients, which may also be the underlying mechanism linking chronotype and depression[5,24,47,86]. The discrepancy between the biological clock and the social clock may be the key factor causing the significant association between the evening chronotype, sleep disturbances, and depression[87]. It has also been discovered that sleep quality plays a mediating role in the relationship between chronotype and depression[24,88,89]. Therefore, greater evening chronotype is associated with poorer sleep quality, which may lead to severer depression[5,24,47,86]. Conversely, the improvement of sleep disturbances reduces the severity of depression or prevents its relapse/recurrence[86]. Nevertheless, whether the improvement in sleep disturbances will alter an individual’s chronotype has not yet been studied, which would be an intriguing direction for future research.

Genetic factors

Clock genes exist in every cell, with their expression regulated by circadian rhythms. They also impact individual circadian rhythms and chronotype. These genes control multiple transcriptional-translational feedback loops that form the molecular clock[90]. A total of 351 distinct genome-wide significant loci associated with chronotype were discovered in a sample of 697828 individuals[91]. Additionally, this genome-wide association study of chronotype demonstrated associations between chronotype polygenic score and circadian and sleep-wake characteristics[92]. Marginal and conditional mendelian randomization analyses also revealed that the causal effect of the evening chronotype on depression was driven by certain genetic architecture[31].

Multiple clock genes may contribute to both specific chronotype and the susceptibility to depression. Two large population studies indicated that individuals with genetically proxied earlier diurnal preference were associated with lower risk of depression, while individuals with eveningness-related genes were more likely to be depressed[92,93]. Other studies have suggested that several clock genes are closely related to depression[94-99]. In addition, the abnormal processing of pre-miR-182, a modulator of circadian rhythms[100], was revealed in patients with MDD carrying the T allele of the rs76481776 polymorphism, which may contribute to their dysregulation of circadian rhythms[101]. Depression-like behavioral state was observed in core clock gene Arntl knockout mice[102]. Crucially, clock genes interact with various systems and processes, including monoamine and glutamatergic transmission, HPA axis function, metabolism, and immune function, thereby playing a potential role in MDD[103].

The clock genes have also been reported to be involved in the regulation of antidepressant effect[104], suggesting the dual significance of clock genes in pathophysiology and treatment of depression. Specially, an animal experiment demonstrated a potential involvement of the circadian clock in rapid antidepressant responses with ketamine and sleep deprivation[105]. In this experiment, there is downregulation of clock genes including Ciart, Per2, Npas4, Dbp, and Rorb[105].

Importantly, although chronotype has a certain genetic basis, social and environmental factors can also affect its manifestation[106]. For example, work schedules, lifestyle habits, and light exposure can all interact with genetic factors to influence an individual’s chronotype and, consequently, their susceptibility to depression. Evening chronotype individuals may be more likely to engage in unhealthy lifestyle behaviors, such as staying up late, which can further increase their risk of depression.

In summary, the specific chronotype and its corresponding risk of depression may be modulated by certain clock genes. However, the specific molecular mechanisms and the interaction between genes and the environment still need further in-depth studies.

THERAPEUTIC IMPLICATIONS

Light therapy

Light therapy has been shown to be an effective treatment for depression[107]. By exposing individuals to specific wavelengths and intensities of light at certain times of the day, light therapy can help reset the circadian rhythm and improve depressive symptoms. This may be beneficial for depression patients with evening chronotypes. The evening preference of patients with depression can be changed by adjunctive bright light therapy, and such change predicted a higher likelihood of depression remission over 5 months of follow-up[108]. Additionally, adjunctive dim red light treatment also has some therapeutic effect on depression patients with evening chronotype, but shorter time to remission and higher probability of achieving remission were found in patients receiving adjunctive bright light therapy[109]. Light therapy has also been combined with sleep deprivation (wake therapy)[110,111], or combined with sleep deprivation and sleep advance/stabilization[112] for comprehensive chronotherapy in patients with depression, with the underlying mechanism lying in improving depression by regulating chronotype. Light therapy can be combined with antidepressants for patients with depression, which is more effective than either treatment alone[113]. Nevertheless, a retrospective study found that there was no significant relationship between the therapeutic effect of light therapy on patients with seasonal affective disorder at fixed time schedule and chronotypes[114], suggesting the potential differences in the pathogenesis between seasonal affective disorder and depression.

Light therapy at different time periods can have different effects on different chronotypes. Greater evening chronotype was associated with a better response to morning light therapy[115] and chronotherapy[116,117]. While stronger morning chronotype was associated with a better response to light therapy in the afternoon[115].

However, chronotype manifests substantial interindividual stability[39]. Individual disparities in chronotype, which is reflected by the entrained phase manifested in sleep timing, arise from the intricate interplay of genetic, physiological, and environmental determinants[118]. Therefore, it should be noted that although light therapy is a safe and effective treatment for depression, once the light exposure intervention ceases, individuals may revert to their pre-intervention chronotype. The robustness of the new better chronotype and antidepressant effect after light therapy warrants further investigation.

Cognitive behavioral therapy for chronotype adjustment

Evening chronotypes may be trained to gradually shift their bedtime and wake-up time earlier to improve their sleep quality and reduce depressive symptoms. Cognitive behavioral therapy (CBT) can be used to help individuals modify their behavior and lifestyle to better match their natural chronotype or reset their chronotype to a more optimal state, thereby having a positive impact on mental health and performance. In a randomized controlled trial, nonpharmacological interventions (adjusting light exposure via sleep schedule changes, standardizing meal times, controlling caffeine intake, and regular exercise) advanced the sleep-wake timings of night owls by approximately 2 hours. This change reduced self-reported depression and stress, and improved cognitive (reaction time) and physical (grip strength) performance without affecting sleep duration[119].

The relationship between chronotype, treatment time of day, and outcomes in patients with depression is an area that has not been fully studied. In a study involving 227 outpatients with MDD, 14 sessions of group-based CBT delivered at different times of the day (morning, afternoon, or evening) led to significant increases in morningness in the afternoon and evening CBT groups, but not in the morning group[120]. The afternoon CBT group demonstrated a significant interaction between changes in morningness-eveningness scores and post-treatment depression severity. These findings suggest that CBT timing may influence an individual’s chronotype, and changes in chronotype could potentially interact with treatment outcomes. However, it is noteworthy that the lack of a control group in this study limits the certainty of these conclusions. In addition, findings from a study of 419 adult insomnia outpatients receiving group CBT for insomnia (CBT-I) demonstrated significantly increased sleep efficiency (SE) and reduced depressive symptoms severity[121]. Controlling for baseline factors, stronger evening chronotype and smaller improvements in SE were unique predictors of less reduction in depressive symptoms. While all chronotypes benefited from sleep improvements, evening chronotypes with limited SE gains showed less relief from depression. These findings highlight that the evening chronotype and insomnia symptoms may independently impact mood, suggesting that integrating circadian factors into CBT-I could potentially enhance its effectiveness in reducing depressive symptoms.

Pharmacotherapy considerations

Some antidepressants may have different effects on individuals with different chronotypes. Depression patients with evening chronotype commonly had lower selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-norepinephrine reuptake inhibitors efficacy than those with morning chronotype, and reported taking a higher number of antidepressants[48,122]. Specifically, with regard to 10 common antidepressants, sertraline, escitalopram, venlafaxine, amitriptyline, mirtazapine, desvenlafaxine, citalopram, fluoxetine, duloxetine, and paroxetine, a stronger self-reported evening chronotype was significantly associated with poorer therapeutic response to escitalopram, citalopram, fluoxetine, sertraline, and desvenlafaxine[122]. Additionally, this chronotype was linked to a higher incidence of side effects, with insomnia being the most prevalent complaint[122]. Treatment outcomes with SSRIs for patients with depression may be affected by their habitual light exposure patterns[48]. The evening chronotype was also associated with a worse response to agomelatine[123]. However, a shift toward morning chronotype was observed after treatment with agomelatine, which was greater in responders than non-responders. In a study involving 139 adult patients with comorbid MDD and insomnia disorder, participants with evening chronotype were also at increased risk for poor response to antidepressant treatment (escitalopram, or sertraline, or desvenlafaxine) augmented with either CBT-I or a control therapy for insomnia[124]. Notably, a repeated-measures study using wrist activity monitors demonstrated an association between the antidepressant effects of ketamine and circadian timekeeping (amplitude and timing), suggesting that its efficacy may also be modulated by chronotype[125]. In contrast, a multicenter, parallel, controlled study reported no significant effect of chronotype on depression remission rates after antidepressant treatment[126]. This discrepancy may reflect differences in study design, sample characteristics, or treatment duration.

Intake of SSRIs may elevate the light sensitivity of the human circadian system. When an acute dose of citalopram was given, a 47% increase in melatonin suppression was observed[127]. This change may aid the recovery process for some patients with depression, while causing more significant disruptions in others.

Antidepressant timing is also a critical clinical consideration. Different administration times (morning vs evening) of imipramine, either at acute or chronic doses, significantly influence its antidepressant efficacy in rats, with greater effects observed in the morning[128]. The antidepressant activities of fluoxetine, venlafaxine, and bupropion are also associated with circadian fluctuation, and antidepressants with different modes of action have different chronopharmacological profiles[129]. Plasma and brain concentrations of all the aforementioned antidepressants are higher in the morning than in the evening when administered to C57BL/6 mice[129]. On the contrary, fluvoxamine administered in the evening shows a better antidepressant effect[57]. For milnacipran, both morning and evening administration exhibits antidepressant effects, but morning dosing preferentially acts on the serotonergic system, whereas evening dosing preferentially targets the noradrenergic system[130]. Activating SSRIs (e.g., fluoxetine) are best taken in the morning to avoid sleep disruption, whereas antidepressants with a sedative profile (e.g., mirtazapine and fluvoxamine) are optimally dosed at bedtime to leverage their hypnotic effects[131]. Aligning medication schedules with circadian rhythms could optimize drug-receptor interactions and enhance efficacy. For example, evening chronotypes may benefit from evening-administered sedative antidepressants to synchronize with their delayed sleep-wake cycle. However, research remains limited on how to tailor antidepressant timing to chronotype, representing a key gap in personalized medicine.

Other potential interventions

Growing evidence indicates that regular exercise may regulate clock gene expression, synchronize circadian rhythms, and improve sleep, metabolism, and immunity, thus preventing and treating circadian-related diseases[132]. Exercise is an effective treatment for depression[133]. Thus, tailoring exercise to patients with depression based on their chronotypes may be a clinically relevant and interesting research direction, although the evidence is rare. Nocturnal exercise is not recommended in depression patients with evening chronotype, because it often delays circadian phase[132].

In addition to scheduling morning exercise, the combined implementation of maintaining earlier wake-up/sleep times, fixing meal times, avoiding caffeine after 15:00, and maximizing morning outdoor light exposure can collectively induce phase advance of participants’ chronotypes and improve self-reported depression[103]. However, the specific contributions of each individual measure remain unclear. Further in-depth research is warranted to dissect the independent and synergistic effects of each component strategy on chronotype regulation and depression in diverse populations.

The therapeutic implications/strategies for depression based on chronotype are summarized in Table 4.

Table 4 Therapeutic implications/strategies for depression based on chronotype.

Therapeutic approach	Core mechanism	Chronotype-specific considerations	Limitations/challenges
Light therapy	Resets circadian rhythms by modulating light exposure at specific times	Evening chronotypes show better response to morning light therapy; morning chronotypes may benefit from afternoon light	Short-term effects were demonstrated; long-term stability unconfirmed; chronotype may revert after intervention; optimal timing, intensity, and wavelength remain undefined
CBT	Modifies behavior/Lifestyle to align with chronotype or shift sleep-wake timing	Evening chronotypes may require gradual sleep-wake advancement protocols; CBT timing (e.g., afternoon sessions) may influence chronotype shifts	Lack of long-term data on mood stability; need for personalized CBT components (e.g., sleep restriction)
Pharmacotherapy	Antidepressant efficacy varies with chronotype due to interactions between circadian rhythms and neurotransmitters	Evening chronotypes may be suitable for sedative antidepressants (e.g., mirtazapine) dosed at bedtime; morning chronotypes may benefit from activating SSRIs (e.g., fluoxetine) in the morning	Limited research on chronotype-pharmacokinetics interactions; inconsistent findings across studies; need for personalized dosing based on genes (e.g., PER3 and CYP450)
Lifestyle interventions	Regular exercise and structured routines synchronize circadian rhythms	Avoid nocturnal exercise in evening chronotypes; prioritize morning physical activity	Limited evidence on chronotype-tailored exercise protocols; the synergy between interventions remains unclear
Combined interventions	Multimodal approaches targeting circadian alignment and neurotransmitter systems	Tailor combinations to chronotype (e.g., morning light + CBT for evening chronotypes)	Complexity of implementing multimodal protocols; long-term adherence and efficacy data are needed; individual variability

CBT: Cognitive behavioral therapy; SSRIs: Selective serotonin reuptake inhibitors.

DISCUSSION

The findings synthesized in this review underscore the intricate relationship between chronotype, depression, and therapeutic interventions, offering both novel insights and highlighting critical areas for future research. The consistent association between evening chronotype and an elevated risk of depression, along with its link to greater symptom severity and suicidal ideation, indicates that chronotype is not merely a phenotypic trait but a significant risk factor and potential biomarker in depression[22-30,43-47]. This has far-reaching implications for preventive strategies. By identifying individuals with evening chronotype, especially during relatively vulnerable life stages such as adolescence or the perinatal period, targeted early interventions could be implemented to mitigate the risk of developing depression[22,26].

The proposed mechanisms linking chronotype to depression, including neurotransmitter system dysregulations, circadian rhythm disruptions, sleep disturbances, and genetic factors, paint a complex and interconnected picture. The bidirectional regulation between neurotransmitters like serotonin, dopamine, and NE and chronotype suggests that dysregulation in one system can cascade into the other, contributing to the development and maintenance of depression[51-61,63-76]. For example, the disruption of the serotonin system, which is crucial for both mood regulation and circadian rhythm modulation, may explain why evening chronotype, with their altered serotonergic profiles, are more susceptible to depression[54,60,61]. Understanding these mechanisms at a molecular and systems level could open up new avenues for drug development, potentially targeting the specific dysregulations associated with different chronotypes.

In terms of therapeutic implications, light therapy, CBT for chronotype adjustment, and pharmacotherapy all show promise, but also come with caveats. Light therapy is particularly beneficial for depression patients with evening chronotype, though the long-term stability of its effects on chronotype and depression remission remains unclear[107-109]. Individual responses to light therapy at different times underscore the need for chronotype-based personalized protocols[115-117]. Morning light exposure aligns with evening chronotypes’ delayed circadian phase to enhance phase advance, with greater evening chronotype correlating with stronger antidepressant responses to morning sessions[115-117]. By contrast, morning chronotypes benefit more from afternoon light therapy[115]. While current protocols commonly use 10000 Lux white or 480 nm blue light for 30-60 minutes in the morning, optimal timing (e.g., precise hours relative to sleep-wake cycles) and dose parameters (intensity, wavelength) remain undefined. Short-wavelength light may more potently activate melanopsin pathways, but long-term safety and subtype-specific efficacy data are limited. Dynamic monitoring of circadian markers (e.g., salivary melatonin) or wearable actigraphy could refine personalized protocols. Therefore, integrating real-time circadian data with dose optimization light therapy strategies represents a critical future direction for enhancing treatment precision of depression.

CBT can effectively shift the sleep-wake timings of evening chronotypes, but more research is needed to determine the optimal combination of behavioral strategies and the long-term impact on mental health outcomes[119-121]. Specific components within CBT, such as sleep restriction therapy and stimulus control therapy, are crucial for resetting the circadian phase in evening chronotypes. Combining CBT with morning light exposure as an adjunctive strategy can achieve a greater phase advance than either intervention alone[119]. However, long-term data are lacking regarding whether these adjustments can maintain mood stability and reduce the recurrent risk of depression in the long run.

Regarding pharmacotherapy, the differential effects of antidepressants on different chronotypes highlight the critical need for personalized medicine in depression treatment[48,122-126]. Current research is predominantly focused on SSRIs, with limited understanding of how chronotype influences broader treatment outcomes such as medication side effects, functional recovery, and long-term recurrent risk[127], while the impact of antidepressant administration timing on therapeutic efficacy across chronotypes remains largely unaddressed. Future studies should therefore explore the effects of a wider range of antidepressants and different dosing timings (morning vs. evening) on treatment responses in distinct chronotypes, as well as potential interactions between medications, chronotype, genetic polymorphisms (e.g., CYP450 enzymes and clock genes), and environmental factors (e.g., light exposure). Key priorities include: (1) Elucidating how chronotype modulates antidepressant pharmacokinetics and side effect profiles through mechanistic studies; (2) Establishing evidence-based, chronotype-tailored dosing guidelines via randomized controlled trials; and (3) Characterizing the longitudinal impact of chronotype on recurrent risk, functional recovery, and quality of life during maintenance therapy through large-scale cohort research. Such investigations will be essential to integrating circadian biology into clinical practice and optimizing personalized treatment strategies for depression.

Therefore, to better implement individualized treatment for patients with depression, clinicians could first assess patients’ chronotypes using the validated and user-friendly rMEQ in clinical practice. In addition to self-report measures, where feasible, objective tools such as wrist actigraphy can be used to measure activity patterns and circadian amplitude, providing more accurate chronotype characterization. Correspondingly, combining self-report measures with objective tools (e.g., 7-day wrist actigraphy) for accurate chronotyping in clinical practice may be a better approach. By determining the patient’s chronotype, clinicians may probabilistically predict treatment response and potential side effects, thereby selecting a more appropriate antidepressant. Nonpharmacological interventions tailored to chronotype, such as morning light therapy for evening chronotypes to enhance circadian alignment and chronotype-timed CBT, may optimize outcomes. While existing evidence supports these approaches, large-scale longitudinal studies are warranted to establish chronotype-guided protocols for optimizing antidepressant efficacy and minimizing side effects.

Notably, several limitations persist in the current research landscape. First, most studies on the relationship between chronotype and depression are observational, which makes it challenging to establish causal relationships. Prospective longitudinal studies and mendelian randomization designs[33,34] are needed to strengthen causal inference, although experimental studies with forced desynchrony protocols in humans are limited by ethical concerns due to potential induction of depressive symptoms[77]. Second, the effect size of this relationship is not consistent across the above studies. Not only may some variability relate to instrument measurement, but the sample characteristics such as age distribution and differences in subject populations (clinical or general) can also affect the effect size. Conducting meta-analysis or meta-regression to quantify effect sizes across diverse contexts would be warranted to further clarify this inconsistency. Third, the assessment of chronotype still relies heavily on self-reported questionnaires, which may be subject to recall bias and individual interpretation[7,15-17]. Although objective measures exist, their widespread use is limited by practical and cost-effectiveness issues[18-21]. For instance, dim light melatonin onset is a well-established, reliable measure of the timing or phase of the internal circadian clock[134], but rarely used in epidemiological or clinical studies due to the need for a light-controlled environment and intensive labor[135]. Thus, developing more accurate, accessible, and real-time methods for chronotype assessment is essential for advancing this field. Fourth, existing research has insufficiently explored sex differences in the relationship between chronotype and depression. While a study analyzing data from the 2016 Korea National Health and Nutrition Examination Survey indicated that an evening chronotype was associated with an increased risk of depression in women but not in men[35], overall evidence remains scarce. Future investigations should focus on disentangling the sex-specific biological mechanisms underlying the relationship between chronotype and depression, which will be instrumental in formulating personalized prevention and treatment approaches tailored to different genders.

CONCLUSION

In conclusion, the role of chronotype in depression is a burgeoning area of research with significant potential to transform our understanding, prevention, and treatment of this debilitating disorder. By addressing the current limitations through interdisciplinary research efforts, integrating genetic, molecular, physiological, and behavioral perspectives, we can hope to develop more effective, personalized, and targeted strategies for managing depression, ultimately improving the lives of millions of affected individuals worldwide.

ACKNOWLEDGEMENTS

We would like to express our sincere gratitude to Sallie SN, a native English speaker from the United States and a current postdoctoral fellow at Department of Psychiatry, University of Cambridge, for her invaluable assistance in refining the grammar, sentence structure, word usage, and overall readability of our manuscript.