Sleep Problems in Euthymic Bipolar Disorders: A Review of Clinical Studies

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1 Send Orders for Reprints to Current Psychiatry Reviews, 2015, 11, Sleep Problems in Euthymic Bipolar Disorders: A Review of Clinical Studies M.K. Steinan *, K. Krane-Gartiser, G. Morken and J. Scott Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Østmarka Department of Psychiatry, St. Olavs University Hospital, Trondheim, Norway Abstract: Sleep disturbance is of considerable interest to researchers in bipolar disorders (BD) and clinicians are increasingly aware of the impact of sleep disruptions on the course of BD (prediction of relapse) and treatment selection (sleep problems are frequently medication-refractory). The aim of this paper is to synthesize the data on the nature and prevalence of sleep problems in euthymia as observed by clinicians and reported by their patients and to explore the potential influence of study design on research findings in BD. A literature search identified 11 publications that included (i) euthymic cases and (ii) reported the prevalence of self- or observer-rated sleep problems. Study samples included from 20 to >700 euthymic BD cases, and about 60% of studies included a comparison group. Broadly conceptualized sleep problems were reported in >50% of the BD cases on average, but specifically defined sleep disorders such as insomnia were reported in about 20% BD cases. This review highlights that sleep disturbances are a major clinical issue in BD even in individuals who are currently euthymic. The reported rates of insomnia and hypersomnia may indicate disturbances in the arousal or circadian systems may be key factors in increasing the rates of sleep difficulties. However, there were only a few high quality clinical studies that report self- or observer-rated prevalence data, and so developing consensus on definitions of different sleep problems in BD or greater application of the criteria used in sleep and circadian rhythm research would be potentially useful steps to allow greater cross-study comparisons of findings. Keywords: Bipolar disorders, euthymia, inter-episode, sleep disorders, sleep problems. INTRODUCTION Bipolar Disorders (BD) are chronic, recurring conditions that are estimated to affect 1-4% of the global population [1]. They are characterized by alternating phases of major depressive episodes and (hypo)manic or mixed episodes with intermittent periods of euthymia or remission (when the individual has few or no symptoms of BD for two or more months) and sleep disturbance is one of the most common symptoms in BD regardless of phase of illness. Decreased need for sleep is one of the most recognized prodromal symptoms of mania and one of its diagnostic criteria [2, 3], and improvement in sleep is an important therapeutic target in mania, as this often heralds the beginning of restabilization of the individuals mental state [2, 3]. Likewise, sleep problems are reported in 50-90% of patients with syndromal or sub-syndromal depressive symptoms in BD [4] and sleep disturbance is frequently the last symptom to resolve as a depressive episode concludes [5]. It is also noteworthy that symptoms of sleep disturbance may fail to fully remit, even though euthymia is achieved [6]. However, the first issue in exploring the sleep disturbances that are observed in clinical practice rather than measured in research settings is that the former cover a broader spectrum of issues. Namely, the term specific sleep disturbance usually *Address correspondence to this author at the Østmarka Department of Psychiatry, St. Olavs University Hospital, Trondheim, Norway; Tel/Fax: ; mette.steinan@ntnu.no refers to a well-defined sleep problem, often meeting the diagnostic criteria of a specific sleep disorder such as insomnia, hypersomnia, or delayed sleep phase. However, the term non-specific sleep disturbances usually refers to more general and broadly assessed sleep complaints, such as poor quality of sleep, non-restorative or insufficient sleep [7]. This is highly relevant studies of clinical as compared to research samples, and Grandner highlights that though it can be difficult to gain conceptual or methodological clarity regarding the meaning of non-specific sleep disturbances, the term can capture sleep problems in a global way and is generally the only way to assess sleep at a broader, population level [7]. Despite differences in actual range of sleep problems reported in research as compared to clinical settings, it does appear that changes in sleep pattern predict new BD episodes, and are a prognostic marker for episode outcomes for all polarities [3, 5, 6, 8]. For example, several clinical studies have explored the sleep profiles of BD cases and identified several individual characteristics associated with the presence or absence of sleep problems. Also, a number of research studies have employed actigraphy or other objective measures to record sleep patterns and their associations with circadian or other systemic disturbances [6, 8-10]. However, there is some debate about how to interpret the sleep findings reported for BD cases during a current episode, as the sleep pattern that is observed may be a state marker, rather than an indicator of any underlying predisposition to abnormal sleep homeostasis or disrupted circadian rhythms /15 $ Bentham Science Publishers

2 236 Current Psychiatry Reviews, 2015, Vol. 11, No. 4 Steinan et al. One way in which researchers have tried to further understand the importance of sleep parameters in BD is to examine sleep abnormalities in the inter-episode period in cases meeting criteria for euthymia. Many of these studies have used electronic monitoring, and two recent meta-analyses of actigraphy studies demonstrated that, compared with controls, euthymic or remitted BD cases showed significant differences in a number of key sleep parameters [11, 12]. Namely, sleep in BD cases was characterized by a longer sleep onset latency, changes in sleep duration, more waking after sleep onset, and reduced sleep efficiency [11, 12]. However, there are two limitations that decrease the applicability of this data to clinical practice. First, the meta-analysis was hampered by the differences in methodologies employed in the studies, such as the nature of the control groups and the type of actigraphy measures that were reported in each publication etc. Second, and particularly important for day to day clinical practice, the studies mainly focused on statistical differences in mean scores or ratings of sleep parameters using electronic monitoring and sophisticated analyses of the recordings obtained. Whilst these findings are very important for research, the technology is not used routinely and most clinicians will not employ this approach to detect sleep problems in BD. For clinicians, it would be useful to clarify: (a) What proportion of euthymic BD cases who are seen in clinical practice will report the presence of any sleep problems? And: (b) What are the likely prevalence rates of specific or nonspecific sleep disturbances that can be detected through clinical interview or simple self- or observer ratings? This review seeks to address these questions in order to provide clinicians with an indication of the current state of the clinical evidence and the gaps in the knowledge base. METHOD Original articles that reported sleep problems in euthymic BD were eligible for inclusion in the review. A systematic literature search was conducted using PubMed, EMBASE and Ovid using the following terms for BD (bipolar disorder*, manic depression), and for sleep problems (sleep abnormality*, sleep problem*, sleep disorder*, insomnia*, hypersomnia*). Hand searching of reference lists was also used to identify additional citations. The search inclusion criteria were: (i) publication occurred between January 1 st 1990 and March 31 st 2015; (ii) the publication included a categorical rating of a sleep problem and the prevalence of such problems was reported or could be estimated from the data provided; (iii) the publication recorded how the diagnosis of BD was determined; and (iv) some or all of the cases in the sample were euthymic or in remission at baseline assessment (and data for euthymia cases were reported separately). The exclusion criteria were (i) the sample were all aged <18 years or >65 years; (ii) only objective recordings of sleep parameters were provided (e.g. actigraphy and polysomnography); (iii) only mean scores on continuous measures of sleep were reported and there was no indication of the proportion of cases that would be clinically defined as having any sleep abnormality. Two researchers (MKS and KKG) independently undertook the same preliminary search to confirm that the search strategy was reliable. Of 525 articles identified through the search (two papers were identified through hand searches of citations), 46 were duplicates. After removal of the latter, 470 publications were selected for preliminary screening, of which 41 were found to report on sleep in euthymic BD cases. A review of the abstracts revealed that 23 studies were potentially relevant for this review and detailed examination of these papers determined that 11 studies met eligibility criteria (see Fig. 1 for the PRISMA flow diagram). We excluded 12 full-text articles due to their failure to report diagnosis of BD or prevalence of sleep problems. RESULTS Overview of Studies As shown in Table 1, the 11 studies that met eligibility criteria were published between 2004 and 2013 and the majority originated in the USA (6 studies). Four studies had a sample size <100 BD cases [13-16], four included samples of [17-20], and the remaining three studies included samples of 209, 403 and 2014 (of which 36% were euthymic BD cases) respectively [21-23]. The gender distribution demonstrated that the proportion of females in the study samples ranged from 50-85% (median about 64%), and the mean age of the samples ranged from years (median about 43 years). Two of the studies recruited participants through the multi-center STEP-BD trial [21, 22], six recruited from an identified clinical service (mainly outpatient clinics, but 2 studies did not specify whether participants were in- or out-patients) [13, 14, 17, 18, 20, 23], and three studies recruited samples via advertisements or a study-specific referral pathway [15, 16, 19]. Out of the eleven studies, four were of BD only samples [17, 18, 21, 22], whilst seven studies used a comparison group [13-16, 19, 20, 23]. The latter usually comprised of healthy controls, but one study compared BD cases to individuals with insomnia and to individuals defined as good sleepers [14]. The diagnosis of BD was confirmed according to DSM- IV criteria; two studies used clinician confirmed diagnosis [13, 18], the STEP-BD Affective Disorder Evaluation [24] was used for two studies [21, 22], the Structured Clinical Interview for DSM-IV (SCID) [25] for six of the studies ([14-17, 19, 20] and the Mini-International Neuropsychiatric Interview (MINI) [26] for one study [23]. Most studies were of BD I cases exclusively [13-15, 17], or BD I was in the majority in the study sample (between 56% - 91%) [16, 18, 19, 21, 23]. In two of the studies, percentage of subtype was not specified [20, 22]. Eight studies used symptom rating scales to report the current severity of depressive BD symptoms (Hamilton Depression Rating Scale (HRSD), Montgomery Asberg Depression Rating Scale (MADRS), Inventory of Depressive Symptomatology (IDS-C/IDS-SR), and the Clinical Monitoring Form for STEP-BD (CMF) [14-19, 21, 22]. Seven of these used symptom rating scales to report the current severity of (hypo)manic BD symptoms

3 Sleep Problems in Euthymic Bipolar Disorders Current Psychiatry Reviews, 2015, Vol. 11, No Included Eligibility Screening Identification Records identified through database searching (n = 523) Records after duplicates removed (n = 479) Records screened (n = 41) Full-text articles assessed for eligibility (n = 23) Studies included in the review (n = 11) Additional records identified through other sources (n = 2) Records excluded (n =18) Full-text articles excluded due to failure to report diagnosis of BD or prevalence of sleep problems (n = 12) Fig. (1). PRISMA flow diagram for selection of publications on sleep problems in euthymic bipolar disorders. (Young Mania Rating Scale and Clinical Monitoring Form for STEP-BD) [14-18, 21, 22]. Three studies assessed euthymia by clinical evaluation [13, 14, 20], whilst the other eight studies used criteria based on scores below a predetermined cutoff on symptom rating scales such as the HRSD, MADRS, IDS-C / IDS-SR, and Young Mania Rating Scale (YMRS) [15-19, 21-23]. The defined sleep abnormalities varied from sleep problems/disturbances based on self- report inventories (n=7 studies) [15, 17, 19-23], clinical evaluations of sleep (n=2) [13, 18] and sleep disorders such as insomnia diagnosed according to clinically recognized diagnostic criteria (n=2) [14, 16]. Three of the studies assessed for sleep disorders and excluded candidates who met criteria for major sleep disorders such as obstructive sleep apnea, narcolepsy, periodic limb movement disorder or restless legs syndrome [15, 16, 19]. Findings from Cross-Sectional Assessments a) Studies of BD Cases The four studies of BD samples only reported crosssectional assessments of sleep variables based on a range of psychometric inventories (CMF, HRSD, and MADRS) and reported sleep disturbance in 15-58% BD cases [17, 18, 21, 22]. In addition, Gruber et al. found that BD I and II cases had significantly higher Total Sleep Time (TST) than BD NOS [21]. The gender and age distributions were very similar across the four studies but an examination of the locations showed that three studies were undertaken in the USA and one in Brazil [17]. The USA studies reported sleep disturbance in 15-24% of the BD cases, whilst the Brazilian study reported sleep problems in 58%. b) Studies with a Non-BD Comparison Group Seven studies reported cross-sectional assessments of sleep using psychometric inventories such as the Sleep History Questionnaire (SHQ), Insomnia Diagnostic Interview (IDI), Pittsburgh Sleep Quality Index (PSQI), Duke Structured Interview for Sleep Disorders (DSID), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS). Mood was assessed using the Beck Depression Inventory II (BDI- II), Hamilton Rating Scale for Depression (HRSD), and the Inventory of Depressive Symptomatology Clinician Version (IDS-C) and Self Report Version (IDS-SR) [13-16, 19, 20, 23]. Six studies compared BD cases to healthy controls, whilst Harvey et al. compared BD cases with a group of insomnia cases and a group of good sleepers, both without BD [14]. Overall, sleep problems were reported in % of BD cases (median rate 55%) [13-16, 19, 20, 23] compared with

4 238 Current Psychiatry Reviews, 2015, Vol. 11, No. 4 Steinan et al. Table 1. Overview of studies of bipolar disorders meeting eligibility criteria for inclusion in the review of sleep problems in euthymia. 1st Author, Year, Country Reported Sleep Problem BD Subtype BD cases: Mean Age & % F (Female) Sample Recruitment Criteria for Euthymia Comparison Group Cross-sectional Longitudinal Assessments Findings Measurements Sleep Variables Findings BD only studies Gruber, 2009, USA (21) Sleep duration: Normal, Short (<6hs), or Long (>9hs) Total sample =2024: 63% BD I, 26% BD II, 8% BD NOS 38 ± 13.1y 56% F STEP-BD: multicenter study 728 (36% of sample) met CMF criteria for euthymia None CMF (max & min sleep time in last week): TST + sleep variability In euthymic BD: Normal sleep= 38% Short sleep= 34% Long sleep= 27% TST: BDI & BDII > BD NOS Giglio, 2009, Brazil (17) Sleep problems 190 BD I 43 ± 11.1y 57% F Patients HRSD <7, YMRS<7 None Score 1 on HRSD items 4, 5, 6 58%= sleep problems Brill, 2011, USA (18) Sleep disturbance 106 : 56% BD I, 22% BD II, 23% BD NOS 43 ± 14.6y 65% F Outpatient chart review STEP-BD interview score <11 for depression & <10 for mania None CGI-S, Clinician evaluation & description of patient sleep 24% = clinically significant ongoing sleep disturbance: 27% BD I, 22% BD II & 17% BD NOS Sylvia, 2012, USA (22) Sleep disturbance 483 (BD I or BD II) 43 ± 13y 64% F STEP-BD: multicenter study MADRS 10, YMRS 12 None Score 2 on MADRS item 4 15% = at least mild sleep disturbance Studies with comparison groups Millar, 2004, UK (13) Insomnia 19 BD I 47 ± 10.6y 58% F Outpatients Remitted (did not meet DSM episode criteria) 19 healthy controls SHQ Sleep disturbance: 100% BD cases versus 21% controls 5days Actigraphy, Sleep Logs & x2 daily Mood Ratings TST, SOL, SE, WASO BD versus controls: Less stable sleep patterns & significantly higher variance in SOL, TST & WASO Harvey, 2005, UK (14) Insomnia 20 BD I 40 ± 15.2y 50% F Outpatients Clinical diagnosis of euthymia confirmed by HDRS & YMRS 20 good sleepers (i.e. no sleep difficulties) & 20 with insomnia IDI, PSQI BD: 55%= Insomnia (IDI) 70%=PSQI>5 (versus 0% of good sleeper & 100% of insomnia groups) 8days Actigraphy & Sleep Diary SOL, WASO, TST, Daytime Activity BD versus insomnia & good sleeper groups: Longer SOL on self-report, but not on actigraphy; Longer TST; Lower daytime activity Kaplan, 2011, USA (19) Hypersomnia 56: 91% BD I 36 ± 12.4y 80% F Advert IDS-C 11, YMRS 7 55 healthy controls DSID, Sleep items from BDI-II, IDS-C, IDS-SR Hypersomnia= 25% BD cases (3 of 6 measurements) & significantly more than controls 7days Sleep Diary TIB, TST BD versus controls: TIB >9 hours: 29% v 8% TST>9 hours: 4% v 0% Gershon, 2012, USA (15) Sleep & affect coupling 32 BD I 35 ± 10.5y 63% F Advert IDS-C 23, YMRS healthy controls DSID, ISI, PSQI Sleep disturbance: 38% score >7 on ISI 53% score >5 on PSQI (Not reported for controls) 8 weeks: Actigraphy, Sleep & Affect Diaries SOL, WASO, TWT, TIB, TST, nwak, SE BD versus controls: significantly more TWT & TIB. Longer WASO, Lower SE, & Increased negative affect Kaplan, 2012, USA (16) Insomnia 27: 85% BD I 33 ± 10.3y 85% F Advert & referrals IDS-C 11, YMRS 7 27 healthy controls DSID Insomnia (diagnostic criteria) 22% BD versus 0% Controls = 2 nights PSG, Actigraphy & Sleep diary SOL, WASO, nwak, TST, SE BD versus controls: No significant differences Rocha, 2013, Brazil (23) Sleep quality 105: 90% BD I 10% BD II 47 ±18.5y 77% F Patients HDRS < 7, YMRS < healthy controls PSQI BD versus controls: Poor Sleep Quality (PSQI>5) 83% v 21%. No difference in sleep duration. Walz, 2013, Brazil (20) Daytime sleepiness, Sleep disturbance 81 (BD I, BD II or BD NOS) 44 ± 12.3y 72% F Outpatients Not in episode (using SCID criteria) 79 controls ESS PSQI BD versus controls: Sleep Disturbance (PSQI>6) 78% v 21% Daytime Sleepiness (ESS>10) 40% v 18%

5 Sleep Problems in Euthymic Bipolar Disorders Current Psychiatry Reviews, 2015, Vol. 11, No % of healthy controls (median 21%). Higher rates of sleep problems tended to be found in studies of non-specific disturbances. Of the specific sleep disorders, the reported rate of insomnia was 22% and 70% in the two studies that assessed this diagnosis [14, 16], whilst the prevalence of hypersomnia in one study was 25% [19]. Two studies were from the UK [13, 14], two from Brazil [20, 23] and three from the USA [15, 16, 19]. Country of origin did not appear to influence findings, although the study samples were younger (33-36 years) and adverts were more often used in the three studies from USA [15, 16, 19], compared to the other studies [13, 14, 20, 23]. However, the difference in prevalence rates of sleep difficulties appears to be mainly linked to the assessment of sleep employed. Three of the four studies using PSQI report rates >70% for sleep disturbance [14, 20, 23], and the one study using SHQ report sleep disturbance in 100% of the BD cases [13]. In contrast, the lowest prevalence (22%) is reported by Kaplan et al. who used diagnostic criteria to classify cases of insomnia [16]. Findings from Prospective Longitudinal Studies Five studies undertook longitudinal sleep measurements based on sleep diaries and actigraphy [13-16, 19]. The median duration of recording was about seven days, but varied from two nights of polysomnography [16] undertaken in a sleep laboratory up to eight consecutive weeks of actigraphy and sleep and mood diaries [15]. Using self-report measures, Millar et al. found Sleep Onset Latency (SOL) in BD cases was significantly longer than that reported by healthy controls [13] and Harvey et al. found significantly longer SOL in BD cases compared to both an insomnia and a good sleeper group [14]. The same two studies found self-reported Total Sleep Time (TST) to be significantly different in the BD and comparison groups: Millar et al. found that the sleep diary reports suggested that the BD group slept longer than healthy controls, whilst Harvey et al. found the BD group reported that they slept less than the good sleepers [13, 14]. Interestingly, actigraphy recordings from the latter study showed that, objectively, the BD group slept significantly longer than the good sleeper and the insomnia groups. Gershon et al. also found nonsignificantly longer TST for the BD group compared with healthy controls on actigraphy measurements [15], and Kaplan et al. also found a similar non- significant increase in TST according to sleep diary reports [16]. Gershon et al. also found that compared to healthy controls, the BD group spent longer Time In Bed (TIB) [15] and Kaplan et al. reported that 29% of the BD group had a TIB > 9 hours compared to only 8% of the controls [19]. Although four studies of actigraphy and sleep diaries report that BD cases have increased Wake After Sleep Onset (WASO) than other comparison groups [13-16], these differences only reached statistical significance in the selfreport data presented by Harvey et al. [14]. Few studies examined stability of sleep patterns over time, but Millar et al. found the BD group to have less stable sleep patterns than the healthy controls; they had significant higher variance on SOL, TST and WASO [13]. Other Reported Findings As well as reporting sleep problems, a small number of the studies included in this review also examined the associations between sleep and metabolic measures such as Body Mass Index (BMI) and links to daytime mood and functioning. a) Body Mass Index Only one study reported BMI data. Brill et al. noted that half of the BD cases had a BMI >30, but this study did not find a significant association between BMI and self-ratings of sleep disturbance or duration. [18]. b) Consequences of Sleep Disturbance Gershon et al. reported that cases and controls who had increased WASO and lower Sleep Efficiency (SE) reported higher levels of negative affect, and that this association was more significant in the BD cases [15]. Gruber et al. noted that BD cases categorized as Short Sleepers showed more consistent impairment across a range of measures of functioning than Normal Sleepers [21]; whilst Harvey et al. noted that BD cases with insomnia showed reduced daytime activity relative to the comparison groups [14]. In addition, Walz et al. found that 40% of BD cases experienced daytime sleepiness, compared to only 18% of healthy controls [20]. Methodological Considerations There are many potential explanations of differences in the reported rates of sleep problems in the studies reviewed, not least the sampling strategies employed, which ranged from the inclusion of samples participating in randomized controlled trials (such as STEP-BD), convenience samples of outpatient clinic attendees through to individuals with BD who were recruited through advertisements. However, the majority of the studies used recognized diagnostic criteria for BD, and most described a definition of euthymia and/or an assessment procedure to ensure that cases were currently remitted or between major episodes. As such, the main sources of heterogeneity in methodologies probably are the definitions of sleep problems employed and the variations in use of medications. These two issues are therefore briefly discussed. a) Definitions of Sleep Problems As shown in Table 2, the methods for assessing sleep problems were markedly different across the studies. Five studies used specific sleep inventories to define sleep problems, such as the SHQ [13], ISI [14] and PSQI [14, 15, 20, 23], and the definition of disturbance was based on a score on the scale that exceeded a pre-determined cutoff. Three studies defined sleep problems by using one or more selected sleep items on depression rating scales such as the HRSD [17], MADRS [22], BDI-II, IDS-C and IDS-SR [19]. Lastly, the remaining studies used a clinical assessment to state whether a sleep problem was present or absent.

6 240 Current Psychiatry Reviews, 2015, Vol. 11, No. 4 Steinan et al. Table 2. Brief overview of measures of sleep and/or sleep problems employed in studies of euthymia. 1st Author, Year, Country Scales Used Sleep Assessment Description of Assessment (Items used in Assessment, Cutoff Scores and/or Sleep Problem Assessed, etc.) Millar, 2004, UK (13) Sleep History Questionnaire (SHQ) Clinical assessment of history of any sleep problems. Harvey, 2005, UK (14) Insomnia Diagnostic Interview (IDI); Pittsburgh Sleep Quality Index (PSQI) PSQI > 5 Clinical assessment (IDI) and specific sleep inventory assess sleep quality. Giglio, 2009, Brazil (17) Hamilton Depression Rating Scale (HRSD) Score 1 on items 4,5,6 The items assess the presence/severity of early, middle &/or late insomnia. Gruber, 2009, USA (21) Clinical Monitoring Form for STEP-BD (CMF) Clinical assessment of presence or absence of sleep problem over previous week. Brill, 2011, USA (18) Patient chart review Clinical assessment of presence or absence of sleep problem. Kaplan, 2011, USA (19) Beck Depression Inventory II (BDI-II); Inventory Depressive Symptomatology Clinician Version (IDS-C) and Self Report Version (IDS-SR) BDI-II: item 16; IDS-C & IDS-SR: item 4 BDI-II item indicates change in sleep pattern (cf. usual), IDS-C & IDS-SR items assess hypersomnia. Gershon, 2012, USA (15) Duke Structured Interview for Sleep Disorders (DSID); Insomnia Severity Index (ISI); Pittsburgh Sleep Quality Index (PSQI) ISI > 7 PSQI > 5 Both clinical assessment (DSID) & specific sleep inventories assess severity of insomnia & sleep quality. Kaplan, 2012, USA (16) Duke Structured Interview for Sleep Disorders (DSID) Clinical assessment of presence or absence of sleep problem. Sylvia, 2012, USA (22) Montgomery Asberg Depression Rating Scale (MADRS) Score 2 on item 4 Selected item on a depression rating scale, the item indicates reduced sleep (duration/depth) compared to normal state. Walz, 2013, Brazil (20) Pittsburgh Sleep Quality Index (PSQI); Epworth Sleepiness Scale (ESS) PSQI > 6 ESS > 10 Specific inventories of sleep quality & daytime sleepiness. Rocha, 2013, Brazil (23) Pittsburgh Sleep Quality Index (PSQI) PSQI > 5 Specific inventory of sleep quality. It is also noteworthy that the longitudinal studies relied on self-ratings and/or objective recordings, rather than observer ratings [13-16, 19]. Whilst it might be expected that the use of sleep diaries and actigraphy ratings might influence the reported rates of different sleep problems between studies, what is intriguing is that subjective or objective ratings of the same variable (such as TST) may show different levels of significance within a study. Perhaps, the most obvious example of this is in the study by Harvey et al. that showed that BD cases self-reported sleeping for significantly less time than the good sleepers, whilst actigraphy recordings showed that they actually slept significantly longer then the good sleepers [14]. Whilst this might be interpreted as indicating that self-report is unreliable, it is important to recognize that actigraphs are motion sensors, and although they are sensitive to movement they are not fool proof and so it is not certain that someone who is not moving is asleep [27]. Furthermore, other studies have noted similar findings and it may be that the self-ratings reflect not only the individuals estimate of the duration of their sleep, but also taps into some aspect of the quality of sleep or the perception of feeling rested (or not) after sleep [11, 28, 29]. b) Use of Medications Most (but not all) studies acknowledge the importance of assessing medication use when reviewing sleep disturbance. However, only about half of the studies in this review reported information on prescribing either for BD in general or for any sleep problems that were currently experienced. The reported rates of prescribing of sleep medication varied widely, ranging from 0-78% in BD cases and 0-16% in controls. It is unclear whether age, gender or BD subtype influenced the actual rates of current or past use of sleep medications, as there were no obvious patterns. However, as Brill et al. highlight, it is important to consider this issue in the context of prevalence rates of sleep problems. In their study, Brill et al. reported sleep disturbances in 24% of 106 BD cases, but they then speculated that up to 31% more BD cases in their sample might have had a sleep problem if they were not protected from manifesting this because they were being prescribed sleep medications (n=9) or a sedating antipsychotic medication (n=24)[18]. This highlights the importance of reporting the use of sleep medication, but also the benefits of considering the classes of medications prescribed for BD as well. For example, Sylvia et al. examined the

7 Sleep Problems in Euthymic Bipolar Disorders Current Psychiatry Reviews, 2015, Vol. 11, No odds of reporting sleep disturbances in cases prescribed different medications (such as mood stabilizers) and noted that whilst the odds ratios (OR) were non-significant for lithium, valproate, atypical antipsychotics or lamotrigine, there was a nearly three-fold (OR 2.73) increase in the prevalence of sleep disturbances in those being prescribed a range of other anticonvulsants such as oxycarbazepine, gabapentin, etc. Other possible potential explanations of differences in the reported rates of sleep problems in the reviewed studies can be cultural, as the two Brazilian studies using PSQI as sleep assessment reported higher rates of sleep disturbance compared to the two American studies using the same instrument. Rocha et al. [23] reported 83% BD with poor sleep quality at PSQI>5 and Walz et al. [20] reported 78% at PSQI>6, compared to Harvey et al. [14] and Gershon et al. [15] reporting 70% and 53% at PSQI>5. It is possible that cultural factors influenced these findings, but age and gender can also help explain the differences. The participants in the two Brazilian studies have both a higher percentage of women (72% and 77%) compared to the American participants (50% and 63%) and are older (mean age 44 and 47 years) than the American sample (mean age 35 and 40 years) [14, 15, 20, 23]. CONCLUSION As the aim of the review was to identify the prevalence of any defined sleep problem in euthymic BD, ranging from sleep disturbance through to specific sleep disorders, we excluded publications that did not report categorical as well as dimensional ratings (such as mean scores on the PSQI). This led to the exclusion of a small number of wellconducted studies e.g. [29, 30], but did not dramatically change the conclusions that can be drawn with regard to the prevalence of sleep problems in euthymic BD. As shown in this review, the median rate of any sleep problem in such cases is about 55%. It is more difficult to give an accurate estimate of the rates of specific sleep disorders such as insomnia and hypersomnia, as sleep diagnostic tools were only employed in three studies, but we note that these disorders were diagnosed in at least 20% of those study participants. It is important to highlight the reported rate of hypersomnia for two reasons. First, it draws attention to a disorder that is frequently overlooked in both clinical and treatment studies [10, 31]. Second, the fact that both hypersomnia and insomnia are common may indicate that the shared underlying pathophysiology relates to dysregulation or variability in sleep or circadian rhythms rather than e.g. arousal (which may explain insomnia but would not explain delayed sleep offset) [8, 31]. However, examination of such variability or dysregulation is best undertaken in prospective longitudinal studies that use objective actigraphic monitoring (with or without sleep diaries), and few such studies have been undertaken to date [13] as most of the published actigraphy studies have examined mean levels for TST, WASO, etc. Unsurprisingly, the actigraphy studies included in this review confirm the findings from the recent meta-analysis of remitted BD cases and reinforce the notion that, even in euthymia, BD may be differentiated from healthy controls on parameters such as SOL, TST, WASO, and SE [11]. However, as highlighted in the section on methodological considerations, there is some heterogeneity in the findings between studies and between self-ratings and electronic recordings within studies. Sleep disturbance in euthymic BD should matter to clinicians because we repeatedly find a high prevalence of different sleep problems in the group. Clinicians have always paid attention to changes in sleep patterns in euthymic BD because it so often is one of the first signs of a new affective episode, but with more than half of the euthymic patients having sleep problems on a regular basis, the problem should receive more attention in the clinic. The studies we reviewed in this paper found statistically significant differences between people with BD and healthy controls in several objective sleep measurements, which may or may not be clinically meaningful, but it does not have to be complicated for the clinician to evaluate sleep problems in the clinic. The use of self- report instruments can give a good overview and be easily implemented. ISI and PSQI were used in several of the studies we reviewed, both are validated self-report instruments that assess sleep quality in a few minutes, and if combined with sleep and/or mood diary, they give the clinician a good understanding of the actual sleep problems for the patient. This again could be useful in registering changes in sleep patterns and for selecting and evaluating treatment. It is important to highlight that whilst euthymia is a proxy measure of disease-free periods, it is not advisable to extrapolate from the findings on sleep in euthymia to the potential causal role of sleep or circadian problems in BD. All the studies included in this review described that the cases recruited to the sample had an established BD and most individuals were assessed some 10 or more years after the first onset of mood episodes. As such, the sleep problems could be a cause or consequence of the disease process and at this stage might be best regarded as markers of the course of illness or potentially could be used to monitor treatment response. Only studies of high risk populations that examine transition to BD in those with or without sleep problems can provide reliable and valid insights into the causal role of sleep-wake dysregulation as a predictor of the development of BD. FUTURE DIRECTIONS FOR RESEARCH Although the recognition and management of sleep problems in BD is becoming increasingly recognized as an important consideration for clinical case management [10, 31], the overall quality of the studies reviewed is modest and therefore the prevalence findings we report must be regarded as general estimates. At present, there are three main issues that need to be resolved in order to address the gaps in our understanding and improve our confidence in the estimated prevalence rates. The first issue is that it would be helpful if researchers could agree on a set of reliable and valid definitions of sleep problems that could be operationalized and applied to clinical studies of sleep in BD. Whilst the use of diagnostic assessments for sleep disorders would be the ideal, it is clear from research in euthymia and cases in a current BD episode that it is also possible to use sub-scale or symptom item ratings from other rating scales as proxy

8 242 Current Psychiatry Reviews, 2015, Vol. 11, No. 4 Steinan et al. measures of sleep disorders such as insomnia or hypersomnia as described in the International Classification of Sleep Disorders and in DSM [32]. However, this approach can only be recommended if researchers reach a consensus on these definitions as currently different studies have created their own proxy measures. The second issue is that future studies need to undertake a priori power calculations to ensure that the sample sizes are sufficient to allow full exploration of the range of sleep profiles that may be observed in different BD subtypes (and ideally across different phases of the disorder from euthymia to depression and/or hypomania or mania). The studies also need to have adequate statistical power to determine the proportion of variance in sleep patterns/problems that might be explained by other known influences such as age, gender, BMI and/or the confounding effects of BD treatments and the use of night sedation [11, 33]. As a minimum it would help if these variables were routinely reported so that clinicians can judge how the samples included in any research study compare to the cases they see in their own clinical setting. Finally, it is clear that there are new ways in which data can and should be examined in order to better understand whether the prevalence of problems within individuals changes over time or with phase of illness; whether variability in sleep is a more sensitive marker of BD than mean scores on specific parameters; how the differences in subjective and objective ratings of the same variables can best be understood, and importantly the nature of any associations between sleep and metabolic problems or sleep and day-to day-functioning. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS Declared none. REFERENCES [1] Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiat 2007, 64(5): [2] Jackson A, Cavanagh J, Scott J. A systematic review of manic and depressive prodromes. 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9 Sleep Problems in Euthymic Bipolar Disorders Current Psychiatry Reviews, 2015, Vol. 11, No [30] Eidelman P, Talbot LS, Gruber J, Harvey AG. Sleep, illness course, and concurrent symptoms in inter-episode bipolar disorder. J Behav Ther Exp Psychiatry 2010, 41(2): [31] Bellivier F, Geoffroy PA, Etain B, Scott J: Sleep- and circadian rhythm-associated pathways as therapeutic targets in bipolar disorder. Expert Opin Ther Targets 2015: [32] Manber R, Blasey C, Arnow B, et al. Assessing insomnia severity in depression: comparison of depression rating scales and sleep diaries. J Psyc Res 2005, 39(5): [33] Boudebesse C, Geoffroy PA, Henry C, et al. Links between sleep and body mass index in bipolar disorders: An exploratory study. Eur Psychiatry Received: April 30, 2015 Revised: October 19, 2015 Accepted: October 25, 2015