In this study of euthymic patients with BD, correlates of poor sleep quality independent from residual depressive symptoms were examined in multiple domains that might be expected to affect sleep quality, including sociodemographic factors, medical and anxiety disorder comorbidities, features of BD, severity/symptom measures, chronotype and sleepiness, personality, life story/trauma, and behavioral factors. When domain-wide predictors were included in a final model, independent predictors of poor sleep quality in the BD sample included rapid cycling, high neuroticism, and undesirable events in the past 6 months, and those in the HC sample included social stress.
We can conceptualize poor sleep quality during euthymia in five ways: (1) as a causative trigger for a new mood episode, (2) as a prodromal sign or early symptom of a new mood episode, (3) as a residual symptom of a remitted mood episode, (4) as a distinguishing characteristic of a bipolar phenotype, and (5) as a comorbid sleep disorder/condition. By restricting the analysis to patients in a euthymic period, we designed our approach to study sleep quality as a characteristic of bipolar disorder. Though these subjects were in a traditionally defined ‘euthymic’ period, there was a range of subsyndromal symptoms in this population, consistent with a number of other studies indicating that subsyndromal depressive symptoms are common and predict recurrence (Perlis et al. 2006). The prevalence of subsyndromal symptoms such as poor sleep quality has led some groups to refer to periods without major mood episodes as ‘interepisode’ rather than euthymia (Harvey 2008). In our study, poor sleep quality was correlated with subsyndromal depressive symptoms in euthymic participants when not adjusted for other factors. However, when depressive symptoms were included with other factors affecting sleep quality, the correlation with depressive symptoms was lost, indicating that we found factors that affect sleep quality independently of subsyndromal symptoms. We continue to describe the cohort as euthymic to remain consistent with the bulk of the literature; however, the term interepisode should be considered. Whether poor sleep quality in this population is best categorized as prodromal or residual, treatment targeting the sleep quality outside of targeting depressive symptoms may reduce the substantial impairment and disruption in social and occupational functioning.
We found some consistencies between factors associated with poor sleep quality and psychological and environmental factors that are important predictors of sleep quality in the general population. In the HC group, social undermining predicted poor sleep, whereas in the BD group, association was found between poor sleep and neuroticism and stressful life events. Neuroticism is measured in the widely used five-factor model of personality developed by Costa and McCrae, which also measures extraversion (E), openness (O), agreeableness (A), and conscientiousness (C) (Costa and McCrae 1992). Neuroticism (N) measures the tendency to experience negative affects including fear, sadness, embarrassment, anger, and disgust. Individuals with BD have been shown to have elevated N and O, and low A, C, and E (Barnett et al. 2011). N marks a trait that has been associated with many psychiatric illnesses in addition to BD, including major depressive disorder, anxiety disorders, and personality disorders (Barnett et al. 2011; Costa et al. 2005; Middeldorp et al. 2011; Bagby et al. 2008; Bienvenu et al. 2004). Personality traits have high heritability and may predispose individuals to psychiatric illness; however, there is some indication that personality traits may be affected by psychiatric illness as well (Costa et al. 2005; Christensen and Kessing 2006). We believe that the association between poor sleep quality and neuroticism reported here is a general phenomenon which may be enhanced and exaggerated in BD patients, perhaps due to genetic predisposition, but is not unique to BD or to psychiatrically ill populations.
We found that poor sleep quality was associated with stressful events in euthymic BD and social stress in the HC group, which has also been found in general population samples (Fernandez-Mendoza et al. 2010b; LeBlanc et al. 2007). This is particularly important for BD because social stress has been shown to be greater in BD patients even when euthymic and was shown to be bi-directionally related to disturbed sleep (Eidelman et al. 2012). Affect reactivity in response to stress has also been shown to be greater in euthymic BD than in unipolar depressive disorder or controls (Knowles et al. 2007). Negative mood and sleep have also been shown to have a bi-directional relationship in a euthymic bipolar population; that is, negative mood in the evening may disturb sleep, and disturbed sleep may cause negative mood in the morning (Talbot et al. 2012). Close attention to the role of stress and mood reactivity is warranted in future studies of sleep quality in euthymic BD.
A history of rapid cycling was related to poor sleep quality in the euthymic BD group. Rapid cycling may be associated with sleep quality due to frequent cycling and short euthymic periods between episodes, and similar to stress reactivity, rapid cycling can be conceptualized as both a cause of poor sleep quality and a result of underlying poor sleep quality. In fact, rapid cycling may describe a distinct phenotype with biologically different properties driving both the mood and sleep disturbance. For example, rapid cycling has been linked to panic disorder in familial and genetic studies (MacKinnon and Zamoiski 2006;MacKinnon et al. 2003a, b) and has also been linked to low-activity risk alleles of the catechol-O-methyl transferase gene (Papolos et al. 1998;Kirov et al. 1998;Joyce et al. 1995) as well as abnormalities in the hypothalamic-pituitary-thyroid axis (Chakrabarti 2011). In addition, the hypothalamic-pituitary-adrenal (HPA) axis is an important modulator of sleep and the immune system and is abnormally activated in chronic insomnia (Vgontzas and Chrousos 2002;Vgontzas et al. 2004
2007;Basta et al. 2007). One pilot study has shown abnormally high cortisol and high cortisol response to the dexamethasone suppression test in five patients with rapid cycling, regardless of mood state (Watson et al. 2005). Underlying HPA axis dysfunction at baseline or in response to stress may link sleep quality, rapid cycling, and stress reactivity in BD. Rapid cycling is associated with the severity of BD illness and poor outcome (Schneck et al. 2004), and as has been shown in other studies, both rapid cycling and mixed episodes were highly correlated with suicide attempts (Coryell et al. 2003). In this sample, though both rapid cycling and mixed episodes were associated with suicide attempts, rapid cycling and mixed episodes were distinct from each other.
We did not find medical comorbidities, smoking, alcohol or drug use, or anxiety disorders to be significantly associated with sleep quality in HC or BD, when adjusting for other contributing factors. However, we had very few participants who reported active substance use, in part because active substance dependence was an exclusion criterion of the study. In our sample, HCs were younger and had a very low rate of CV disease. Cardiovascular disease and obesity have been associated with insomnia and overall poor sleep quality (Vgontzas et al. 2009a, b, c). In the BD sample, we found a significant association between sleep quality and cardiovascular disease in bivariate correlations and a trend toward association with obesity, but neither was significant in the final model. The domain-wide model identified cardiovascular disease as a stronger predictor of poor sleep quality than obesity.
Diagnosis of anxiety disorder did not affect sleep quality in the BD sample. Though this appears contradictory to the literature showing anxiety affects sleep quality (Fernandez-Mendoza et al. 2012a;Singareddy et al. 2012;Fernandez-Mendoza et al. 2012b), several factors may account for this lack of association. First, anxiety disorder comorbidity was half as common in this sample as other samples that were not restricted to euthymic patients, and in the Prechter cohort, if baseline mood is not restricted to euthymia, rates of anxiety disorders are very similar to published reports (Otto et al. 2006;Saunders et al. 2012). Because anxiety disorders are associated with worse course and severity of illness in BD (Goes et al. 2011;McLean et al. 2011;Saunders et al. 2012), they were underrepresented in our sample, which was restricted to euthymia. Two additional factors include the following: we did not have a systematic assessment of post-traumatic stress disorder (PTSD) included in anxiety disorders on all of our subjects, and we did not have a measurement of general anxiety outside of the specific anxiety disorders noted above. Future study of a measure of general anxiety may elucidate the relationship between anxiety and sleep in BD.
Though we did not have a measure of PTSD for all participants, we did examine the relationship between childhood trauma (CTQ), adult trauma (LEC), and poor sleep. Childhood trauma, but not adult trauma, was higher in the BD group, and associated with sleep quality in bivariate analysis, but recent undesirable events (LEOS) were a stronger predictor of poor sleep quality than childhood trauma in this sample. Recent stresses may have a stronger effect on sleep than childhood traumatic events due to the proximal temporal relationship. An alternate explanation is that individuals with BD who have recurring difficulties from trauma are continuing to have persistent depressive symptoms and may not be represented in this sample.
In the life story/trauma domain, raw scores for social support were lower in the BD group than in the HC group, but this difference was not significant after adjustment for age, sex, BMI, and marital and employment/student status; however, social undermining remained significantly higher in the BD group than in the HC group. This could be due to several reasons - the HC group is much younger, which was likely the reason for fewer marriages in this group. Thus, the BD group may have more individuals who are married, but fewer are employed or students, and may have a restricted social circle, and the marriage may not be a supportive one, but more of the HC are students with a social network.
We expected to find significant differences in sleep quality between women who had undergone menopause and those who have not, as previous population-based studies have shown (Chung and Tang 2006;Blumel et al. 2012;Monterrosa-Castro et al. 2012). One explanation is that the influence of BD on sleep quality may be more important than the effect of menopause; thus, no difference was detected in BD between women pre- and post-menopause. However, in this study, we had only self-reports of menopause, which may mean that peri-menopausal women are included in the pre-menopausal sample.
Limitations of this study include the subjective and retrospective nature of the PSQI. The PSQI measures an aggregate of sleep quality that includes many dimensions that are influenced by many factors, including the use of medications to promote sleep (Buysse et al. 1989). The use of medication may affect the presentation of BD, and thus, it is important to ask how the use of medication may have affected the variables examined in this study. Rapid cycling has been linked to antidepressant use in some studies (Fountoulakis et al. 2013); however, in this sample of euthymic BD subjects, antidepressants were used by a quarter of the participants (n = 31) at baseline, and the use was not correlated to the PSQI score (r = .03, p = .76), neuroticism (r = .08, p = .40), rapid cycling (r = .07, p = .46), or stressful events (r = .01, p = .95). An additional limitation includes the lack of objective physiological measures of physical health other than BMI. The contribution of cardiovascular or physiological measures that may contribute to poor sleep quality is likely underestimated in this study. In addition, our control group was younger than the BD group. However, we adjusted for age when comparing the HC and BD groups. The study strengths include a large sample of patients with well-characterized BD, as well as dimensional measures of sleep, personality, psychosocial stress, and behavioral measures.