Elsevier

Journal of Affective Disorders

Volume 204, 1 November 2016, Pages 32-39
Journal of Affective Disorders

Research paper
Influence of lithium on sleep and chronotypes in remitted patients with bipolar disorder

https://doi.org/10.1016/j.jad.2016.06.015Get rights and content

Highlights

  • Lithium acts at a physiological and molecular level on biological rhythms.

  • Euthymic BD I patients receiving lithium, compared to those not receiving lithium, have better sleep efficiency and longer sleep duration.

  • Women receiving lithium have better sleep quality, longer sleep duration and less frequent use of night sedation.

  • Euthymic patients receiving and not receiving lithium have similar chronotype profiles.

Abstract

Background

Lithium (Li) is the first-line treatment for bipolar disorder (BD), but its mechanisms of action remain unknown. Although the chronobiological action of Li is well documented in animals, its effects on sleep and chronotypes in remitted BD patients have never been investigated.

Methods

OPTHYMUM is a multicenter, cross-sectional, observational study conducted in France. We compared the sleep (Pittsburgh Sleep Quality Index, PSQI) and chronotypes (Composite Scale of Morningness, CSM) of 525 euthymic adult bipolar outpatients with (n=149) and without (n=376) current Li treatment. We used a general linear mixed-effects Poisson model to correct for age, gender, BD subtype, and mood symptoms.

Results

In patients with BD type I, women taking Li had significantly lower PSQI (−23% [−37; −7]), but men did not (−4% [−20; +16]). Patients with BD I taking Li had better sleep efficiency (−40% [−61; −7]) and tended to better sleep duration scores (−42% [−68; +3]). A Li effect exists in women for both sleep duration and the use of night sedation (resp. −70% [−90; −10] and −37% [−60; +0.01]) but not in men (resp. −12% [−63;+113] and +9% [−31;+72]). No such associations were observed for BD II. No lithium effect was detected in the CSM score.

Limitations

No controls for other medications but no between-group differences for sedative or antidepressant intakes.

Conclusions

Euthymic BD I patients with Li have better sleep efficiency and longer sleep duration than those without Li. Women with Li have better sleep quality, longer sleep duration and less frequent use of night sedation.

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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