Research paperInfluence of lithium on sleep and chronotypes in remitted patients with bipolar disorder
Introduction
Bipolar disorder (BD) is a severe mental disorder characterized by recurrent manic and depressive episodes; it usually starts in early adulthood and affects1–4% of the general population worldwide (Merikangas et al., 2007). Patients with BD suffer from enduring sleep and circadian rhythm abnormalities, even during remission phases but with milder manifestations (Geoffroy et al., 2015a, Geoffroy et al., 2015b). These sleep and circadian abnormalities may reflect core features related to the underlying neurobiology and genetic susceptibility of BD (Etain et al., 2011, McClung, 2011, McClung, 2007, Murray and Harvey, 2010). The severity and poor prognosis of BD are related to the high rate of recurrences despite medications, with a mean recurrence rate of 60–80% within two years of an index episode (Gitlin et al., 1995, Perlis et al., 2006); disruptions in sleep homeostasis and circadian rhythm irregularities have been associated with the risk of subsequent episodes (Jackson et al., 2003, Plante and Winkelman, 2008, Sylvia et al., 2012). In this context, there is an increasing interest in the adjunctive use of chronobiotics (such as melatonin agonists) in BD (Anderson et al., 2015, Geoffroy et al., 2015a, Geoffroy et al., 2015b) and chronotherapeutics (such as cognitive behavioural therapies) to specifically target sleep and circadian problems (Frank et al., 2005, Geoffroy et al., 2015a, Geoffroy et al., 2015b, Kaplan and Harvey, 2013).
Lithium salt (Li) is the cornerstone of BD treatment in all international therapeutic guidelines (Goodwin et al., 2016, Grunze et al., 2010, Grunze et al., 2009, Yatham et al., 2013). Indeed, Li is the first-line treatment of BD for preventing relapses and recurrences of any episodes of either polarity (Goodwin, 2009, Grunze et al., 2010, Grunze et al., 2009, Yatham et al., 2009). Furthermore, it is the only treatment shown to decrease the risk of suicide in BD (Yerevanian and Choi, 2013). Although mechanism of action of Li is not fully understood, its therapeutic benefit has been related to its ability to act on circadian rhythms (Moreira and Geoffroy, 2016). Indeed, a link between the action of Li on both acute and relapsing mood symptoms and its stabilization action of circadian rhythms has long been suggested in humans (Geoffroy et al., 2014a, Geoffroy et al., 2014b, Klemfuss, 1992) and in rodents (Roybal et al., 2007). Li acts at a physiological level on the period, phase, amplitude and coupling of biological rhythms, and at a molecular level on circadian gene expression and protein production (Alda, 2015, Can et al., 2014, Kripke et al., 1979, Kripke and Wyborney, 1980a, Subramanian et al., 1998, Welsh and Moore-Ede, 1990, Yin et al., 2006). Further, Li appears to interact with environmental light through the retinal-hypothalamic pineal pathway to influence circadian rhythms (Hallam et al., 2005a, Hallam et al., 2005b, Pablos et al., 1994, Seggie et al., 1987, Werstiuk et al., 1984).
Although a number of studies have demonstrated the functions of lithium on circadian rhythms (Geoffroy et al., 2014a, Geoffroy et al., 2014b), its actions in remitted patients with BD have not been studied to date. The OPTHYMUM study is an observational study that aimed to examine residual symptoms in patients with BD who were recruited in the euthymic phase. In this large sample, we compared sleep and circadian phase preferences (i.e., chronotype) in Li-treated patients and patients effectively treated with other mood stabilizer medications (including second-generation antipsychotics). The objective was to test the hypothesis that Li treatment is associated with better sleep quality and a more stable chronotype.
Section snippets
Study design
The OPTHYMUM study is a multicenter, cross-sectional, non-interventional research study conducted in France in adult outpatients diagnosed with BD who were enrolled by active psychiatrists in hospital and office-based settings between April and October 2012. The study design was published in detail in a previous work (Samalin et al., 2014). The examination of sleep and circadian rhythms as residual symptoms was one of the primary objectives of OPTHYMUM; these were measured in real-life
Results
The sample consisted of 525 outpatients with BD (376 individuals receiving and 149 not receiving current Li treatment; Table 1). Patients receiving Li were older, had longer duration of illness and had more bipolar type I disorder compared to patients not receiving Li (Table 1). There were no statistically significant differences between the groups in terms of gender, BMI and the presence of residual mood symptoms (YMRS and BDRS scores). In the comparison of groups regarding Li treatment, the
Discussion
Considering the well documented disrupted circadian rhythms and sleep abnormalities observed in euthymic bipolar patients, our study confirmed the hypothesis that Li is associated with better sleep quality but not a more stable chronotype in subgroups of patients. Specifically, we observed that: i) euthymic BD I patients taking Li had better sleep efficiency and longer sleep duration than patients not receiving Li, and ii) women taking Li seemed to sleep better than men receiving Li treatment
Conclusion
Euthymic patients with BD type I and treated with Li have better sleep efficiency and longer sleep duration than those not receiving Li. Women treated with Li seem to sleep better, have longer sleep duration and use less night sedation. While this study cannot definitively confirm a causality link between lithium's effects and sleep in BD, these findings support the scientific rationale about the possible therapeutic action of Li through the stabilization of sleep and sleep-wake patterns in BD
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