طول مدت خواب، بی خوابی و نشانگرهای التهاب سیستمیک: نتایج حاصل از مطالعه افسردگی و اضطراب در کشور هلند (NESDA)

Systemic inflammation has emerged as a potential pathway linking depressive and anxiety disorders with disease risk. Short and long sleep duration, as well as insomnia, are common among psychiatric populations and have previously been related to increased inflammation. The aim of the present study was to investigate associations between sleep duration and insomnia with biomarkers of inflammation and to explore whether these associations varied by psychiatric diagnostic status. To this end, self-reported measures of sleep duration, insomnia symptoms, and markers of inflammation, including C-reactive protein (CRP), interleukin-(IL)-6, and tumor necrosis factor (TNF)-α, were obtained in 2553 adults (aged 18–65 years) diagnosed with current/recent or remitted depressive and/or anxiety disorders and healthy controls enrolled in the Netherlands Study of Depression and Anxiety (NESDA). Regression analyses revealed associations between sleep duration and levels of CRP and IL-6 with higher levels observed in long sleepers. These associations remained statistically significant after controlling for age, gender, education, body mass index, smoking, alcohol consumption, medical comorbidities, medication use, psychotropic medication use, and psychiatric diagnostic status. There were no clear associations between insomnia symptoms and levels of inflammation. Relationships between sleep duration and inflammation did not vary as a function of psychiatric diagnostic status. These findings suggest that elevated levels of systemic inflammation may represent a mechanism linking long sleep duration and disease risk among those with and without depressive and anxiety disorders.

Depression and anxiety disorders are highly prevalent and comorbid psychiatric disorders with substantial consequences for physical health, including increased incidence and progression of a number of age-related diseases such as cardiovascular disease, diabetes, and the metabolic syndrome (Eaton et al., 1996, Lett et al., 2004, Raikkonen et al., 2007 and Suls and Bunde, 2005). The biological mechanisms linking these psychiatric conditions to physical health remain unclear; however, low-grade chronic inflammation has emerged as a key biological pathway. Several meta-analytic reviews support elevations in inflammatory markers, such as pro-inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and acute phase proteins, such as C-reactive protein (CRP), in depressed compared to non-depressed patients (Dowlati et al., 2010, Howren et al., 2009 and Zorrilla et al., 2001). Elevations are also observed in those with clinical anxiety (O'Donovan et al., 2010 and Vogelzangs et al., 2013); however, this link is less well characterized (O'Donovan et al., 2013). Not all studies have been consistent, however, which may reflect the heterogeneity that exists within the diagnostic categories of Depressive and Anxiety Disorders (Goldberg, 2011 and Insel and Wang, 2010). Accordingly, researchers have begun to focus attention on symptoms relevant across psychiatric conditions (i.e., transdiagnostic processes); sleep disturbance has emerged as one such symptom (Harvey et al., 2011). Growing evidence suggests that disturbed sleep is associated with elevations in systemic levels of inflammation. For instance, in several though not all laboratory studies (reviewed in Solarz et al. (2012)) healthy sleepers subjected to total and partial sleep restriction show significant elevations in inflammatory activity compared to an undisturbed sleep condition (Irwin et al., 2006, Shearer et al., 2001, Vgontzas et al., 1999 and Vgontzas et al., 2004). Further, compared to nondepressed controls, depressed patients displayed higher nocturnal levels of IL-6, a difference that is partially accounted for by a longer time to sleep onset in the depressed patients (Motivala et al., 2005). Whether these associations extend beyond the laboratory setting remains unclear. In this regard, greater inflammation has been documented in patients with insomnia compared to non-disturbed sleepers (Burgos et al., 2006). Further, short (e.g., sleeping less than 5 or 6 h per night) and/or long sleep duration (e.g., sleeping more than 9 or 10 h per night) have been associated with higher levels of inflammation compared to those reporting typical sleep duration (i.e., 7–8 h per night) in several large epidemiologic investigations (Dowd et al., 2011 and Miller et al., 2009). While curvilinear associations are not supported in all studies, these findings map onto prevalence rates of several chronic diseases and early mortality observed at higher frequency among short and long sleepers (Ayas et al., 2003a, Ayas et al., 2003b, Cappuccio et al., 2010a, Cappuccio et al., 2010b, Hall et al., 2008 and Heslop et al., 2002). For instance, Hall et al. found that compared to normal sleepers (7–8 h) both short (<6 h per night) and long (>8 h) showed significantly increased odds of meeting diagnostic criteria for the metabolic syndrome, independent of other sociodemographic characteristics and health behaviors (Hall et al., 2008). Despite converging evidence for a link between psychopathology, namely depression and to some extent anxiety, sleep, and markers of inflammation, no study has sought to systematically examine their inter-relationships in a large sample. The goals of the present study are to 1) estimate the associations between poor sleep, as characterized by short and/or long sleep duration and insomnia symptoms, with markers of systemic levels of inflammation (CRP, IL-6, and TNF-α) in a large sample of patients with current and past psychopathology (depressive and/or anxiety disorder) and never diagnosed controls and 2) determine whether psychopathology status moderates the sleep-inflammation link. The proposed study utilizes data from the Netherlands Study of Depression and Anxiety (NESDA) which have previously demonstrated differential elevations in markers of inflammation in patients with psychopathology compared to healthy controls (Vogelzangs et al., 2013 and Vogelzangs et al., 2012). Given that sleep is a modifiable health behavior, understanding the extent to which sleep drives inflammatory activity in the context of psychopathology may have important implications for treatment.

Baseline characteristics of the present sample grouped by sleep duration category and insomnia status are presented in Table 1. Consistent with previously published findings (van Mill et al., 2010), short sleepers (i.e., sleeping ≤ 6 h per night) were more likely to be men, older, less educated, heavier, current smokers, consume fewer than 1 alcoholic drink per week, have diabetes, cardiovascular disease and a greater number of medical conditions, use statins, anti-inflammatory medications and benzodiazepines, and to have a current psychiatric diagnosis, particularly comorbid depressive and anxiety disorders compared to normal sleepers (i.e., participants sleeping 7–9 h per night). Long sleepers (i.e., sleeping ≥ 10 h per night), compared to normal sleepers, were more likely to be women, younger, less educated, be a current smoker, consume fewer than 1 drink per week, less physically active, a higher number of medical conditions, to use SSRI medication and have a current depressive or a comorbid depressive and anxiety disorder diagnosis. Participants with insomnia (IRS ≥ 9), as compared to those without insomnia (IRS < 9), were older, less educated, heavier, more likely to be a heavy drinker of alcohol, have cardiovascular disease and more other medical conditions, more likely to take statins and anti-inflammatory medications, use antidepressants, use benzodiazepines, and to be diagnosed with depressive disorders or comorbid depressive and anxiety disorders. Associations between inflammatory markers and study covariates, including sociodemographic characteristics, health indicators, and psychotropic medication use are provided in Table 2. Analyses revealed that participants with higher levels of inflammation were older, more likely to be men, less educated, more likely to be current smokers, reported no alcohol consumption or heavy alcohol consumption, reported more chronic diseases, were more likely to have cardiovascular disease and diabetes, and more likely to use benzodiazepines and antidepressants. Pearson correlations revealed that levels of inflammatory markers were low to modest but significantly inter-correlated (p's < 0.001) (CRP-IL-6, r = 0.31; CRP-TNF-α: r = 0.12; IL-6-TNF-α: r = 0.12).