Prospective study of chronotype and incident depression among middle- and older-aged women in the Nurses’ Health Study II
Introduction
The past decade has provided increasing evidence for links between the circadian system and mood, including data linking non-visual photoreception pathways in rodents to impaired mood (LeGates et al., 2012), and the beneficial role of timed light exposure therapy and sleep deprivation on mood, likely by resetting circadian rhythms (McClung, 2007, 2013, 2015; Wirz-Justice, 2003). Circadian rhythms regulate physiology and behavior – from gene expression and immune function to sleep and cognition – and the disturbance of those rhythms has also been put forward as one of the correlates of mood disorders (Wirz-Justice, 2006). The circadian system entrains to the light/dark cycle of the 24 h day (Duffy and Wright, 2005; Pittendrigh, 1981; Roenneberg and Merrow, 2007) and thereby gives rise to an individual's chronotype, with genetic variation being at least in part contributing to inter-individual differences in chronotype (Roenneberg et al., 2007a). This phenotype has also been shown to be associated with e.g. the period length of circadian clock gene expression in human fibroblasts (Brown et al., 2008). And while the implications of the circadian system and circadian photoreception pathways with mood seem established, it is unclear to what extent inter-individual differences in chronotype per se are linked to depression.
Previous work has mainly relied on cross-sectional data sets, with limited information on potential confounding factors. One of the largest datasets, FINRISK, included behavioral information on an established scale of Morningness/Eveningness (Horne and Ostberg, 1976) that correlates well with other proxies for chronotype, such as sleep timing (Kitamura et al., 2014) or dim light melatonin onset (Kantermann et al., 2015; Megdal and Schernhammer, 2007; the key circadian phase marker; Arendt, 2006); the FINRISK analysis showed that morningness was associated with lower levels of depressive symptoms, and lower odds of diagnosed depression and anti-depressant medication use (Konttinen et al., 2014; Merikanto et al., 2013, 2015). Studies around the world, in adult and adolescent populations have reported similar findings (Alvaro et al., 2014; Chan et al., 2014; de Souza and Hidalgo, 2014; Hidalgo et al., 2009; Jeong et al., 2015; Kitamura et al., 2010; Levandovski et al., 2011; Pabst et al., 2009), independent of whether they used sleep timing or morningness/eveningness as a proxy for chronotype. Patients with major depressive disorder have been reported to be more likely to be late chronotypes, as compared to individuals suffering from dysthymia or anxiety disorders. Those results suggest that depression might also alter an individual's chronotype (Antypa et al., 2016; Lemoine et al., 2013; Müller et al., 2015; Selvi et al., 2010), or possibly that changes in chronotype is related to depression severity. Indeed, recent findings in adolescents show no significant differences in chronotype between healthy controls and patients with remitted depression (Keller et al., 2017). Prospective analyses are crucial to better understand the directionality of the association of chronotype with depression, and the present study addresses this gap. We hypothesized that late chronotypes would be at higher risk and early chronotypes would be at lower risk for incident depression as compared to intermediate chronotypes.
Section snippets
Methods
The Nurses' Health Study II (NHSII) is a large, prospective cohort study of women's health, which started in 1989 when 116,434 registered US nurses (aged 25–42 years) responded to a baseline questionnaire. Biennial follow-up questionnaires have since been mailed to obtain updated information on medical history, lifestyle factors, and newly diagnosed diseases. Follow-up rates are high with approximately 90% participation at each two-year cycle (Schernhammer et al., 2011). This study was approved
Statistical analyses
We defined definite morning types as ‘early chronotypes’, definite evening types as ‘late chronotypes’, and others as ‘intermediate chronotypes’, and used Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (95%CI) across the three chronotype categories. Intermediate chronotypes served as the referent group in all analyses. We included the following covariates in multivariable (MV) adjusted models: menopausal status (pre/post-menopausal), marital status
Results
Across four years of follow-up, we observed 2,518 cases of incident depression. Table 1 shows the baseline characteristics of women free of depression and depressive symptoms at baseline in 2009. Late chronotypes were less likely to be married, and more likely to live alone, to be smokers, and more frequently reported extreme sleep durations.
In age-adjusted models, early chronotypes had a significantly reduced risk of depression as compared to intermediate types (Table 2, HR = 0.86,
Discussion
In this study of more than 30,000 middle-aged and older women, chronotype was associated with incident depression, even after accounting for potential confounders of the association. Sensitivity analyses excluding women with potentially disturbed circadian rhythms, such as shift workers or women who had a history of extreme sleep durations, similarly showed that early chronotypes were at lower risk of newly-occurring depression, as compared to intermediate. Thus, our findings indicate that
Funding
This work was supported by Center for Disease Control and Prevention/The National Institute for Occupational Safety and Health grants 5R01OH009803 and 5R21OH011052. The Nurses’ Health Study II is supported by the National Cancer Institute grant UM1CA176726.
Conflicts of interest
None.
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