In depressed patients, the most common sleep difficulty is inability to initiate or maintain sleep, although less frequently, hypersomnia is present. Of all depressive symptoms, depressed patients report sleep complaints as the primary presenting problem to health care practitioners (American Psychiatric Association and American Psychiatric Association, Task Force on DSM-IV 1994). Depressed patients also have well-documented alterations in immunity, including decreased NK activity, decreased proliferative response to antigenic challenge, and increased levels of inflammatory cytokines. Emerging evidence indicates that poor sleep in depression is related to, and may mediate immune alterations in these patients. Similar to primary insomnia patients, self-reported sleep quality negatively correlates with NK activity in depression, whereas other depression-related symptoms such as weight loss, poor concentration, or diurnal variation in moods are not related to NK activity (Irwin et al. 2003). Likewise, EEG studies reveal that disturbances of sleep continuity (e.g., prolonged sleep latency, declines of total sleep time) correlate with alterations of innate and cellular immune function among depressed patients (Irwin, Smith, and Gillin 1992; Cover and Irwin 1994). Moreover in bereaved subjects, causal statistical analyses have shown that disordered sleep mediates the relationship between severe life stress and decreased NK responses (Hall, Baum, Buysse, Prigerson, Kupfer, and Reynolds 1998). Depressed patients have increased levels of inflammatory markers such as IL-6, soluble intercellular adhesion molecule (sICAM) and C-reactive protein (Liukkonen et al. in press; Miller, Stetler, Carney, Freedland, and Banks 2002; Motivala, Sarfatti, Olmos, and Irwin 2005). As mentioned earlier, low-grade inflammation, as reflected by systemic elevations in these measures, promotes atherosclerosis and cardiovascular disease.
The elevation of inflammatory markers in depressed patients is consistent both in depressed patients recovering from an acute coronary artery event (Lesperance, Frasure-Smith, Theroux, and Irwin 2004) as well as with depressed patients who are otherwise healthy (Miller et al. 2002; Motivala et al. 2005). The relation between depression and inflammatory markers do not appear to be due to factors such as smoking or obesity (Lesperance et al. 2004; Motivala et al. 2005), but may be related to poor sleep. Motivala and colleagues (2005) found that in depressed patients, polysomnographic assessment of prolonged sleep latency and increases of rapid eye movement (REM) density were associated with elevated levels of IL-6 and sICAM (Fig. 10.2). Moreover, these sleep measures were better predictors of IL-6 and sICAM than depression or depressive symptoms, providing initial evidence that sleep disturbance has a key role in alterations of inflammatory markers in depression. To our knowledge, this study is the only one to date that examined the relationship between sleep and cytokines in depression, although corroborating results can be found in other populations. For example, caregivers of patients with Alzheimer's disease face heavy demands, and this population is chronically stressed with significant depressive symptoms (Sanders and Adams 2005). Like patients with major depression, caregivers of dementia patients sleep less and have more fragmented sleep than noncaregiver controls.
Figure 10.2. Depressed subjects (n = 22) have significantly higher circulating levels of IL-6 (p < 0.01) and sICAM (p < 0.02) than nondepressed controls (n = 18).
Furthermore, longer sleep onset time correlates with higher IL-6 in this sample (Kanel et al. 2006). Links between sleep and immunity are only beginning to be examined in depressed patients; thus, diurnal variation in cytokine expression in this population is unclear and the impact of experimental sleep deprivation paradigms on cytokines are also unknown in this population.
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