An actigraphy study investigating sleep in bipolar I patients, unaffected siblings and controls
Introduction
Bipolar disorder is a chronic psychiatric disorder characterized by severe fluctuations in mood, which affects 1–2% of the general population (Belmaker, 2004). According to the DSM-V criteria, one prominent manifestation of a mood episode is a shift in sleep-wake behavior (American Psychiatric Association, 2013). The majority of patients experience insomnia or hypersomnia during depression and a reduced need for sleep during mania (Harvey, 2008). These disturbances are thought to be a hallmark of a current mood episode, and often precede mood episodes, suggesting utility as a marker of prodromal symptoms (Jackson et al., 2003).
Studies focusing on bipolar patients have tried to delineate whether these sleep disturbances can be considered as more than a state marker of the disorder and represent a general deregulation of the endogenous circadian cycle independent from current episodes. In accordance with that idea, phase advances, phase delays and general phase instabilities have been reported for several measures of rhythmicity, such as body temperature, nocturnal cortisol levels and peak melatonin time in euthymic bipolar patients (Milhiet et al., 2011, Nurnberger et al., 2000). Sleep (the most evident behavioral reflection of circadian rhythms) has also been reported to be disturbed during non-clinical phases of the disorder. According to Harvey et al. (2005), 70% of euthymic patients reported clinically significant sleep problems, with 55% of patients also meeting the criteria for insomnia. Several other studies using self-report measures identified worse sleep quality and more disturbed sleep-timing preferences in non-clinical bipolar patients compared to controls (Cretu et al., 2016, Rocha et al., 2013, Seleem et al., 2015). Actigraphy has proven to be an indispensable tool in the objective assessment of sleep-wake parameters (Sadeh et al., 1995). Actiwatches are wrist-worn devices that continuously record movement and allow for measurements in a natural environment over several weeks. Validation showed better performance compared to observational measurements, sleep logs and diaries (Ancoli-Israel et al., 2003). When assessed in a bipolar sample, actigraphy showed high correlations with polysomnography and high to moderate correlations with subjective measures of sleep (Boudebesse et al., 2014). Nevertheless, studies using actigraphy in the analysis of sleep in bipolar disorder have come up with conflicting results. While some studies found differences between bipolar patients and controls on several sleep parameters (e.g. sleep duration, sleep onset latency, sleep efficiency) (Geoffroy et al., 2014, Harvey et al., 2005, Millar et al., 2004, Salvatore et al., 2008), other studies failed to replicate these findings (Jones et al., 2005, Kaplan et al., 2012, St-Amand et al., 2013). These contradictory results can potentially be explained by differences in methodology. Measurement periods varied between 2 and 54 nights and different diagnostic criteria may have resulted in heterogeneous patient samples. Moreover, sample sizes were generally small (<36 cases and controls), raising the possibility that some studies were underpowered. Recently, two meta-analyses concluded that bipolar patients differed from controls on measures of sleep duration, sleep onset latency and wake after sleep onset (Geoffroy et al., 2015a, Ng et al., 2014). Sleep efficiency of bipolar patients was significantly lower in only one of the two meta-analyses. According to the authors, the number of actigraphy studies in bipolar disorder is limited and lags behind similar research in depression and ADHD. Furthermore, Geoffroy et al. pointed to heterogeneity in methodologies and found that age matching, level of depressive symptoms and actigraphy device potentially influence the actigraphy analyses and should be taken into account in future research (Geoffroy et al., 2015a, Geoffroy et al., 2015b). Moreover, associations between objective sleep parameters and bipolar illness characteristics have so far not been studied. If sleep disturbances indeed reflect a continuous aberration of the circadian rhythm, it is conceivable that these disturbances correlate with an unfavorable course of the disorder.
Although the presence of sleep disturbances in bipolar patients has gained increasing attention, the question whether disturbances in sleep patterns can be considered as a heritable trait of bipolar disorder, has scarcely been investigated. As of yet, only two studies objectively studied the difference in sleep-wake behavior between bipolar patients and their relatives. Jones et al. (2006) studied children of bipolar patients and concluded that sleep onset latency and sleep fragmentation were lower in children of bipolar parents compared to control children. However, when affected bipolar offspring was excluded the effects were no longer significant. Pagani et al. (2016) analyzed 26 pedigrees ascertained for bipolar I disorder and showed that bipolar patients slept longer and woke up later compared to their non-affected relatives. The authors also provided evidence that a number of sleep measures are heritable. Extending this pedigree study by also including independent control subjects gives the opportunity to study the sleep-wake pattern in individuals who are genetically susceptible for the disorder, but lack the direct illness and its sequelae such as medication use. If first-degree relatives indeed show disturbed sleep patterns similar to probands, it would support the hypothesis that the sleep-wake pattern is a trait of bipolar disorder.
The current study aims at extending previous research in a large, homogenous sample of bipolar I patients using an elaborate collection of objective measures of sleeping behavior. First, the question will be addressed whether euthymic bipolar patients show differences in sleep pattern compared to controls and whether the non-affected siblings display similar patterns of sleeping behavior. Sleep duration, timing of sleep onset, timing of sleep offset, sleep onset latency, sleep efficiency, wake after sleep onset (WASO) and sleep inertia will be measured objectively using actigraphy. Subsequently, the association with current mood symptom level and life-time illness characteristics (i.e. age at onset, number of mood episodes, presence of psychotic symptoms and history of suicidal behavior) will be analyzed.
Section snippets
Sample
The current study is a follow up of the Dutch Bipolar Cohort (DBC) study, which is a collaboration between the University Medical Center Utrecht (UMCU), various health care institutes in the Netherlands and the University of California Los Angeles (UCLA). In short, the DBC study is designed to provide a deep-phenotype characterization of bipolar I patients and their first-degree relatives. The cohort included 1700 bipolar I patients, 586 relatives and 265 controls. After completion of the DBC
Participants
A total of 107 patients, 74 siblings and 80 controls were included with a mean measurement period of 14.4 days. Patients, siblings and controls had an equal male-female ratio, but groups differed on mean age, with siblings being significantly older than controls (F[2,258]=6.66, p=0.001). All groups reported similarly low levels of manic symptoms. Current depressive symptoms were significantly higher in patients (F[2,257]=35.72, p<0.001). The total number of workdays during the measurement
Discussion
Investigating a large bipolar I sample with a long actigraphy measurement period of 14 days, the current study aimed to expand previous findings on sleep disturbances in bipolar disorder. We found a longer sleep duration and later timing of sleep offset in patients compared to non-affected siblings, but these findings were attributable to differences in current depressive symptoms. Euthymic bipolar patients and healthy controls did not differ on any of the sleep parameter, nor was there a
Conclusion
In a large homogeneous sample of bipolar I sample, we did not identify persisting sleep disturbances in bipolar patients other than related to increased depressive symptoms. The meta-analysis points in the direction of longer sleep duration, WASO and sleep onset latency and lower sleep efficiency in bipolar patients. The majority of these differences in the meta-analysis were however small, the overall number of participants limited and the question remains whether they reflect clinically
Role of funding source
This study was funded by the National Institute of Mental Health (NIMH), Grant number: R01 MH090553 (to RO). The NIMH had no role in the design and conduct of the study, collection, management, analysis, or interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.
Contributors
RO was the principal investigator for the DBC study and MB was the principal investigator for the actigraphy protocol. RK was the leading on-site investigator. The UMCU study team consisted of SV, AV, LA and AB responsible for the recruitment and assessment of participants. Recruitment and assessment of participants at the UMCG site was done by RS, RR and SK. LP and JT developed the scripts for actigraphy data processing. Data management and analyses were done by SV, LP, and YJ. SV wrote the
Acknowledgments
None to report.
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