Role of chronotype in depression

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

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.

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.

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.