REVIEW URRENT C OPINION
Circadian rhythms and sleep in bipolar disorder: implications for pathophysiology and treatment Isabella Soreca
Purpose of review Multiple lines of evidence support the conceptualization of bipolar disorder as a disorder of circadian rhythms. Considering bipolar disorder in the framework of circadian disturbances also helps understand the clinical phenomenology pointing toward a multisystemic involvement. Recent findings Patients with bipolar disorder show altered rhythmicity in body temperature and melatonin rhythms, high day-to-day variability in activity and sleep timing, persistent disturbances of sleep or wake cycles, including disturbances of sleep continuity. The internal clocks are, indeed, responsible for regulating a variety of physiologic functions, including appetitive behaviors, cognitive functions and metabolism. Summary An underlying circadian pathology in bipolar disorder is a unifying explicatory model for the high psychiatric and medical comorbidity observed during the long-term course of the disorder. This model also provides a rationale for therapeutic interventions aimed at re-entraining the internal clock. Keywords bipolar disorder, circadian rhythms, sleep
INTRODUCTION Bipolar disorder ranks as the 4th cause of disability worldwide (2008 WHO estimates), leading to billions of dollars in annual healthcare costs related to loss of productivity, reduced occupational functioning and medical comorbidity [1]. Although functional impairment and medical burden are thought to be primarily linked to affective episodes and interepisodic mood disturbances, leading to cognitive impairment and unhealthy behavior, recent evidence suggest that sleep and circadian disturbances contribute, at least in part, to functional and medical outcomes in bipolar disorder [2]. Sleep disturbances have, indeed, been described across all mood states as well as during interepisodic intervals. The two-process model of sleep regulation first proposed by Borbely et al. [3] postulates that sleep onset is the result of the complex interaction between two constituent processes, a sleep or wakedependent homeostatic Process S and a circadian Process C. The interaction between these two processes generates the timing of sleep, waking and daytime vigilance [3]. The specific symptoms of mania and depression (disturbances in sleep, appetite, energy, concentration), as well as the alternating between the opposite polarities are suggestive of a disruption of circadian rhythms as core to bipolar
disorder pathology, of which sleep disturbances are one of the manifestations. Though less specific, the sleep disturbances described in patients with bipolar disorder during remission may also represent an epiphenomenon of an underlying circadian pathology. The conceptualization of bipolar disorder as a disorder of circadian pathology may help explain the multisystemic involvement observed with the longitudinal progression of the disorder [2,4]. This review will discuss circadian and sleep disturbances in bipolar disorder: we will examine how they inform pathophysiology of affective disorders, discuss the implications of circadian and sleep disturbances on the multisystemic involvement, encompassing multiple comorbidities, with a specific focus on medical outcomes. Finally, we will briefly touch on chronotherapeutic tools for the treatment of bipolar disorder. Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA Correspondence to Isabella Soreca, MD, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, USA. Tel: +1 412 586 9173; e-mail: [email protected] Curr Opin Psychiatry 2014, 27:467–471 DOI:10.1097/YCO.0000000000000108
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KEY POINTS Several lines of evidence support circadian rhythm disturbance as a core component in bipolar disorder. The sleep–wake cycle alterations observed in the euthymic phase of bipolar disorder may be an epiphenomenon of an underlying disruption of endogenous rhythms. The multisystemic involvement in bipolar disorder, with high rate of psychiatric and medical comorbidity, may be a downstream effect of the underlying circadian pathology. Behavioral interventions targeted at re-entraining social rhythms can ameliorate symptoms, improve functioning and reduce medical risk factors.
BIPOLAR DISORDER AS A DISORDER OF CIRCADIAN RHYTHMS Every living organism has internal biological clocks that are synchronized with external environmental cues, of which the light–dark cycle is the most important and powerful synchronizer. An intact and functioning biological clock is critical for survival [5,6], as it contributes to regulating and coordinating physiologic states and behavioral output. So, if an intact and well functioning circadian system is critical for survival, how does the circadian system become perturbed in bipolar disorder and how did it survive selective pressure? The internal clock entrains to environmental cues, thus assuring behavioral responses that are adaptive to the specific characteristics of the environment. The lack of strong self-sustained circadian activity is advantageous in these two extreme and unpredictable conditions: Arctic animals are released from circadian constraints and are able to feed when the opportunity arises [7]. Migratory birds can reduce avian jet lag when traveling across multiple time zones if their oscillatory rhythm is weak and therefore more easily pushed forward by light [7]. These two examples help us understand how a weak circadian system may represent vestiges of early adaptive traits in hunter-gatherer societies, who migrated to follow seasonally available wild plants and game. A low amplitude (i.e., weak) circadian rhythm may have provided an adaptive advantage allowing more flexible behavioral responses to the rapidly changing environmental challenges. These responses may have involved the ability to rapidly switch from rest to behavioral activation when prey became suddenly available or to promptly arouse from sleep in response to a predator or impending natural disaster. However, in modern society, the multitude of competing entraining 468
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stimuli, including artificial illumination, is such that a weak circadian system is no longer adaptive. Bipolar disorder would, therefore, result from the interaction of internal triggers (weak circadian rhythms) and multiple competing social zeitgebers (literally, time-giver stimuli) that would promote inappropriate behavioral activation (mania) or inhibition (depression) [8]. In line with this hypothesis, Malkoff-Schwartz et al. [9], in their seminal study, found that the onset of manic episodes was preceded by stressful life events, especially those involving social rhythm disruption, significantly more often than depressive episodes. Several lines of evidence from human and animal models of bipolar disorder converge toward an altered circadian rhythmicity in bipolar disorder. Abnormalities in core body temperature rhythms [10], the melatonin secretion curve [11,12] and instability of daily rest or activity patterns [13,14] have all been reported in euthymic patients with bipolar disorder. In mice, disruption of the genetic machinery responsible for creating and sustaining circadian rhythms is associated with disrupted rest-activity behaviors and both mania and depression-like behavior [15]. Genetic studies suggest an association between polymorphisms in the circadian clock genes and clinical phenotypes [16], including chronotype [17], and response to lithium prophylaxis [18]. Sleep–wake cycles are a key component of circadian rhythms. Sleep is regulated by the interaction of homeostatic factors (e.g., sleep pressure, related to time spent awake) and circadian aspects (e.g., melatonin release during the dark phase). Not surprisingly, sleep disturbances are a key diagnostic criterion for affective episodes. Specifically, reduced need for sleep is one of the diagnostic criteria for manic episode, while insomnia or hypersomnia may be present during a depressive episode, with up to 100% of patients reporting some degree of sleep disturbances [19]. Sleep disturbances are not only prominent during florid mania [20], but can be part of the prodromal syndrome of a manic episode and predict relapse [21]. Early polysomnographic (PSG) investigations found that patients with bipolar disorder in a manic episode show disturbed sleep continuity, decreased total time spent asleep, increased percentage of stage 1 sleep, shortened rapid eye movement latency and increased rapid eye movement density compared with healthy counterparts [20,22], similar to what observed in severe major depressive disorders. The ability to maintain high energy levels despite lack of sleep appears to be the aspect of greater specificity in describing mania [23]. However, some evidence suggests that reduced sleep during the manic phase may not be caused by a decreased need for sleep, but is rather, an Volume 27 Number 6 November 2014
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epiphenomenon of general hyperactivity, leading to decreased tendency to sleep. Few case reports and small studies using ‘dark therapy’ have, in fact, reliably induced sleep in patients who were acutely manic, when placed in a sensory and light deprived environment [24–26]. This would suggest that the short sleep duration during mania could actually be resulting from a vicious behavioral cycle, in which patients experience increased energy and hyperactivity, leading to excessive exposure to light cues (including artificial light and computer, TV, or phone screens at night-time) which, in turn, maintains reduced sleep time and altered mood. Sleep disturbances in the depressive phase have been more intensely investigated with the goal of identifying specific biomarkers that would help differentiate bipolar and unipolar depression. Results from PSG sleep studies have, however, generated conflicting results suggesting, in general, sleep abnormalities in bipolar disorder that are largely overlapping with those found in unipolar depression. The most consistent sleep findings in bipolar depression appear to be decreased rapid eye movement (REM) latency and more sleep fragmentation compared with unipolar depressed patient and healthy controls [19,27]. However, Kupfer and Ehlers [28] hypothesized that although REM sleep abnormalities may be primary in unipolar depression, they may be a result of a primary deficit in slow-wave sleep in bipolar disorder. In line with this hypothesis, in their longitudinal study of adolescent with major depression, Rao et al. [29] reported that patients who later developed bipolar disorder had a relatively intact REM sleep profile, but showed increased stage 1 and decreased stage 4 sleep. This would suggest that the REM sleep findings in adult depressed patients with bipolar disorder may result from the interaction of developmental processes and illness course. Sleep disturbances in the remitted phase of bipolar disorder have been more widely investigated with the intent to parse out the effects of the symptomatic episodes from possible trait characteristics. A variety of methods have been employed, including self reports, PSG recordings and actigraphy. In general, the consensus is that patients with bipolar disorder in the euthymic phase continue to show prominent alterations in sleep duration, sleep continuity and day-to-day variability in sleep timing [13,30,31].
MULTISYSTEMIC INVOLVEMENT IN BIPOLAR DISORDER: MEDICAL BURDEN AS A CONSEQUENCE OF UNDERLYING CIRCADIAN PATHOLOGY The relationship between sleep and cardiovascular disease (CVD) risk has now been established by a
wealth of epidemiologic and experimental data [32–34]. A more recently discovered pathway to CVD risk is the disruption of the circadian rhythms. From the first observations that shift workers have increased risk for obesity, diabetes and hypertension [35]; several experimental studies in animal models have shown that the effect of circadian misalignment on CVD risk is independent of that of sleep deprivation [36]. Along this line, experimental studies have shown that meal timing also affects insulin resistance, an important risk factor for metabolic syndrome, diabetes and CVD [37,38]. Patients with bipolar disorder have high rates of obesity and the metabolic syndrome [39–41]. Considering the wealth of data documenting CVD morbidity and mortality in bipolar disorder [42,43], there has been surprisingly little research investigating the causes and mechanisms, other than the reported effects of psychotropic medications on CVD risk. Although medications undoubtedly play a major role, a number of neurobiological and behavioral characteristics linked to the disorder may independently increase the CVD risk. For example, recent evidence points toward several chronobiological factors affecting CVD risk, namely evening chronotype [44], sleep duration [45 ,46], birth seasonality [47 ] and instability of daily rest-activity patterns [45 ]. Each of these sleep and circadian characteristics is associated with bipolar disorder, as reviewed above. &
&
&
CHRONOTHERAPEUTIC STRATEGIES Chronotherapeutics refer to a set of treatments based on current knowledge of chronobiology that uses controlled exposure to environmental stimuli in order to entrain the circadian system [48]. The chronotherapies used in bipolar disorder include bright light therapy, dark therapy, wake therapy (total or partial sleep deprivation), or a combination of these. In addition, behavioral interventions aimed at strengthening the daily behavioral patterns, namely interpersonal and social rhythm therapy (IPSRT) and cognitive behavioral therapy for insomnia (CBT-I), have also been successfully applied in the treatment of bipolar disorder. Bright light therapy was originally developed and tested for the treatment of major depressive disorder and seasonal affective disorder, and subsequently tested as adjunct treatment for bipolar depression. A few small studies and case reports point toward the efficacy of mid-day light therapy in ameliorating bipolar depression and rapid cycling [24,49]; however, other studies have reported negative results [50]. One study reported a significant reduction of depressive symptoms and suicidality in
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treatment-resistant bipolar depression with a combination of bright light therapy, sleep deprivation and lithium [51 ]. Dark therapy is achieved by extending rest or sleep in a dark room or by wearing amber tinted lenses, blocking up to 90% of the blue light wavelength to which circadian photoreceptors are particularly sensitive [52]. A few small studies and case reports have shown efficacy of dark therapy in stabilizing rapid cycling bipolar disorder [24,26]; and reducing manic symptoms [25,26,53]. Sleep deprivation has rapid but transient mood enhancing effects in bipolar depression, which can be used as a primer for pharmacologic treatments’ antidepressant effect [54]. IPSRT is a behavioral treatment geared toward increasing the regularity of patients’ daily routines [55]. IPSRT has been shown to delay time to relapse in patients with bipolar disorder who have achieved acute stabilization form a mood episode, mediated, in part, by increased regularity of patients’ social routines [56]. Interestingly, the advantages of behavioral treatments that target social rhythm regularity seem to extend beyond their ability to reduce symptoms and prevent recurrences, with new evidence pointing toward improving occupational functioning [57] and facilitating weight loss (Frank et al. submitted). An adaptation of CBT-I, based on stimulus control [58] and sleep restriction [59], has also been tested for the treatment of sleep disturbances in bipolar disorder. Preliminary evidence suggests that CBT-I is a well tolerated and effective treatment for sleep disturbances in patients with bipolar disorder [60 ].
Acknowledgements None.
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&
CONCLUSION In summary, multiple lines of evidence support the conceptualization of bipolar disorder as a disorder of circadian rhythms. Considering bipolar disorder in the framework of circadian disturbances also helps understand the clinical phenomenology pointing toward a multisystemic involvement. Internal clocks are, indeed, responsible for regulating a variety of physiologic functions, including appetitive behaviors, cognitive functions and metabolism. An underlying circadian pathology in bipolar disorder provides a unifying explicatory model for the high psychiatric and medical comorbidity observed during the chronic course of the disorder. This model also provides a rationale for therapeutic interventions aimed at re-entraining the internal clock, reducing symptoms and enhancing health span and lifespan in patients with bipolar disorder. 470
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Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Roshanaei-Moghaddam B, Katon W. Premature mortality from general medical illnesses among persons with bipolar disorder: a review. Psychiatr Serv 2009; 60:147–156. 2. Soreca I, Frank E, Kupfer DJ. The phenomenology of bipolar disorder: what drives the high rate of medical burden and determines long-term prognosis? Depress Anxiety 2009; 26:73–82. 3. Borbely AA, Acherman P, Trachsel L, Tobler I. Sleep initiation and initial sleep intensity: interactions of homeostatic and circadian mechanisms. J Biol Rhythms 1989; 4:149–160. 4. Leboyer M, Soreca I, Scott J, et al. Can bipolar disorder be viewed as a multisystem inflammatory disease? J Affect Disord 2012; 141:1–10. 5. DeCoursey PJ, Walker JK, Smith SA. A circadian pacemaker in free-living chipmunks: essential for survival? J Comp Physiol A 2000; 186:169–180. 6. DeCoursey PJ, Krulas JR, Mele G, Holley DC. Circadian performance of suprachiasmatic nuclei (SCN)-lesioned antelope ground squirrels in a desert enclosure. Physiol Behav 1997; 62:1099–1108. 7. Koukkari WL, Sothern RB. Introducing biological rhythms: a primer on the temporal organization of life, with implications for health, society, reproduction and the natural environment. New York: Springer; 2006. 8. Ehlers CL, Frank E, Kupfer DJ. Social zeitgebers and biological rhythms. A unified approach to understanding the etiology of depression. Arch Gen Psychiatry 1988; 45:948–952. 9. Malkoff-Schwartz S, Frank E, Anderson BP, et al. Social rhythm disruption and stressful life events in the onset of bipolar and unipolar episodes. Psychol Med 2000; 30:1005–1016. 10. Souetre E, Salvati E, Wehr TA, et al. Twenty-four-hour profiles of body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects. Am J Psychiatry 1988; 145:1133–1137. 11. Nurnberger JI, Adkins S, Lahiri DK, et al. Melatonin suppression by light in euthymic bipolar and unipolar patients. Arch Gen Psychiatry 2000; 57:572– 579. 12. Kennedy SH, Kutcher SP, Ralevski E, Brown GM. Nocturnal melatonin and 24-h 6-sulphatoxymelatonin levels in various phases of bipolar affective disorder. Psychiatry Res 1996; 63:219–222. 13. Geoffroy PA, Boudebesse C, Henrion A, et al. An ASMT variant associated with bipolar disorder influences sleep and circadian rhythms: a pilot study. Genes Brain Behav 2014; 13:299–304. 14. Jones SH, Hare DJ, Evershed K. Actigraphic assessment of circadian activity and sleep patterns in bipolar disorder. Bipolar Disord 2005; 7:176–186. 15. McClung CA. Circadian genes, rhythms and the biology of mood disorders. Pharmacol Ther 2007; 114:222–232. 16. Rybakowski JK, Dmitrzak-Weglarz M, Dembinska-Krajewska D, et al. Polymorphism of circadian clock genes and temperamental dimensions of the TEMPS-A in bipolar disorder. J Affect Disord 2014; 159:80–84. 17. Etain B, Jamain S, Milhiet V, et al. Association between circadian genes, bipolar disorders and chronotypes. Chronobiol Int 2014; 31:807–814. 18. Rybakowski JK, Dmitrzak-Weglarz M, Kliwicki S, Hauser J. Polymorphism of circadian clock genes and prophylactic lithium response. Bipolar Disord 2014; 16:151–158. 19. Harvey AG. Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation. Am J Psychiatry 2008; 165:820–829. 20. Hudson JI, Lipinski JF, Keck PE, et al. Polysomnographic characteristics of young manic patients. Comparison with unipolar depressed patients and normal control subjects. Arch Gen Psychiatry 1992; 49:378–383. 21. Perlman CA, Johnson SL, Mellman TA. The prospective impact of sleep duration on depression and mania. Bipolar Disord 2006; 8:271–274. 22. Hudson JI, Lipinski JF, Frankenburg FR, et al. Electroencephalographic sleep in mania. Arch Gen Psychiatry 1988; 45:267–273. 23. Kessler RC, Rubinow DR, Holmes C, et al. The epidemiology of DSM-III-R bipolar I disorder in a general population survey. Psychol Med 1997; 27:1079–1089. 24. Wirz-Justice A, Quinto C, Cajochen C, et al. A rapid-cycling bipolar patient treated with long nights, bedrest, and light. Biol Psychiatry 1999; 45:1075– 1077.
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Circadian rhythms and sleep in bi polar disorder Soreca 25. Gomez-Bernal G. Dark therapy for schizoaffective disorder. A case report. Med Hypotheses 2009; 72:105–106. 26. Phelps J. Dark therapy for bipolar disorder using amber lenses for blue light blockade. Med Hypotheses 2008; 70:224–229. 27. Fossion P, Staner L, Dramaix M, et al. Does sleep EEG data distinguish between UP, BPI or BPII major depressions? An age and gender controlled study. J Affect Disord 1998; 49:181–187. 28. Kupfer DJ, Ehlers CL. Two roads to rapid eye movement latency. Arch Gen Psychiatry 1989; 46:945–948. 29. Rao U, Dahl RE, Ryan ND, et al. Heterogeneity in EEG sleep findings in adolescent depression: unipolar versus bipolar clinical course. J Affect Disord 2002; 70:273–280. 30. Geoffroy PA, Boudebesse C, Bellivier F, et al. Sleep in remitted bipolar disorder: a naturalistic case-control study using actigraphy. J Affect Disord 2014; 158:1–7. 31. Boudebesse C, Geoffroy PA, Bellivier F, et al. Correlations between objective and subjective sleep and circadian markers in remitted patients with bipolar disorder. Chronobiol Int 2014; 31:698–704. 32. Hall MH, Muldoon MF, Jennings JR, et al. Self-reported sleep duration is associated with the metabolic syndrome in midlife adults. Sleep 2008; 31:635–643. 33. Arora VM, Chang KL, Fazal AZ, et al. Objective sleep duration and quality in hospitalized older adults: associations with blood pressure and mood. J Am Geriatr Soc 2011; 59:2185–2186. 34. Gangwisch JE, Malaspina D, Babiss LA, et al. Short sleep duration as a risk factor for hypercholesterolemia: analyses of the National Longitudinal Study of Adolescent Health. Sleep 2010; 33:956–961. 35. Esquirol Y, Perret B, Ruidavets JB, et al. Shift work and cardiovascular risk factors: new knowledge from the past decade. Arch Cardiovasc Dis 2011; 104:636–668. 36. Challet E. Circadian clocks, food intake, and metabolism. Prog Mol Biol Transl Sci 2013; 119:105–135. 37. Morgan LM, Shi JW, Hampton SM, Frost G. Effect of meal timing and glycaemic index on glucose control and insulin secretion in healthy volunteers. Br J Nutr 2012; 108:1286–1291. 38. Baron KG, Reid KJ, Kern AS, Zee PC. Role of sleep timing in caloric intake and BMI. Obesity (Silver Spring) 2011; 19:1374–1381. 39. Soreca I, Fagiolini A, Frank E, et al. Relationship of general medical burden, duration of illness and age in patients with bipolar I disorder. J Psychiatr Res 2008; 42:956–961. 40. Fagiolini A, Frank E, Scott JA, et al. Metabolic syndrome in bipolar disorder: findings from the Bipolar Disorder Center for Pennsylvanians. Bipolar Disord 2005; 7:424–430. 41. Birkenaes AB, Opjordsmoen S, Brunbirg C, et al. The level of cardiovascular risk factors in bipolar disorder equals that of schizophrenia: a comparative study. J Clin Psychiatry 2007; 68:917–923. 42. Chang CK, Hayes RD, Perera G, et al. Life expectancy at birth for people with serious mental illness and other major disorders from a secondary mental healthcare case register in London. PLoS One 2011; 6:e19590. 43. Laursen TM, Munk-Olsen T, Gasse C. Chronic somatic comorbidity and excess mortality due to natural causes in persons with schizophrenia or bipolar affective disorder. PLoS One 2011; 6:e24597. 44. Soreca I, Fagiolini A, Frank E, et al. Chronotype and body composition in bipolar disorder. Chronobiol Int 2009; 26:780–788. 45. Boudebesse C, Geoffroy PA, Henry C, et al. Links between sleep and body & mass index in bipolar disorders: an exploratory study. Eur Psychiatry 2014. [Epub ahead of print] This study suggests that underlying circadian disturbances may be a pathway to cardiovascular risk in patients with bipolar disorder. In euthymic patients with bipolar disorder, the authors find an association between higher BMI and day-today variability in rest-activity patterns.
46. Soreca I, Wallace ML, Frank E, et al. Sleep duration is associated with dyslipidemia in patients with bipolar disorder in clinical remission. J Affect Disord 2012; 141:484–487. 47. Soreca I, Cheng Y, Frank E, et al. Season of birth is associated with adult body & mass index in patients with bipolar disorder. Chronobiol Int 2013; 30:577– 582. Spring birth is associated with higher adult BMI and waist circumference in patients with bipolar disorder, but not in patients with unipolar depression. These results suggest that early environmental factors, yet to be identified, interact with specific neurobiological features of bipolar disorder to determine stable traits and disease risk factors in adult life. 48. Wirz-Justice A, Benedetti F, Terman M. Chronotherapeutics for affective disorders: a clinician’s manual for light and wake therapy. 2nd revised ed. Basel, New York: Karger; 2013. 49. Leibenluft E, Turner EH, Feldman-Naim S, et al. Light therapy in patients with rapid cycling bipolar disorder: preliminary results. Psychopharmacol Bull 1995; 31:705–710. 50. Dauphinais DR, Rosenthal JZ, Terman M, et al. Controlled trial of safety and efficacy of bright light therapy vs. negative air ions in patients with bipolar depression. Psychiatry Res 2012; 196:57–61. 51. Benedetti F, Riccaboni R, Locatelli C, et al. Rapid treatment response of && suicidal symptoms to lithium, sleep deprivation, and light therapy (chronotherapeutics) in drug-resistant bipolar depression. J Clin Psychiatry 2014; 75:133–140. In this study, 143 patients with bipolar disorder, who were admitted to the hospital for depression and suicidality, were treated with a combination of 36-h sleep deprivation, bright light therapy in the morning and lithium. The authors report a rapid response (50% reduction in depression scores) within 1 week, which was sustained at 1-month follow-up. Bipolar depression is difficult to treat and current pharmacologic options are often partially effective and have a long latency of response. This study suggests that a combination of chronotherapeutic strategies could significantly shorten patients’ suffering. 52. Kayumov L, Casper RF, Hawa RJ, et al. Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work. J Clin Endocrinol Metab 2005; 90:2755– 2761. 53. Barbini B, Benedetti F, Colombo C, et al. Dark therapy for mania: a pilot study. Bipolar Disord 2005; 7:98–101. 54. Benedetti F. Antidepressant chronotherapeutics for bipolar depression. Dialogues Clin Neurosci 2012; 14:401–411. 55. Frank E, Swartz HA, Boland E. Interpersonal and social rhythm therapy: an intervention addressing rhythm dysregulation in bipolar disorder. Dialogues Clin Neurosci 2007; 9:325–332. 56. Frank E, Kupfer DJ, Thase ME, et al. Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Arch Gen Psychiatry 2005; 62:996–1004. 57. Frank E, Soreca I, Swartz HA, et al. The role of interpersonal and social rhythm therapy in improving occupational functioning in patients with bipolar I disorder. Am J Psychiatry 2008; 165:1559–1565. 58. Morin AK, Jarvis CI, Lynch AM. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy 2007; 27:89–110. 59. Spielman AJ, Saskin P, Thorpy MJ. Treatment of chronic insomnia by restriction of time in bed. Sleep 1987; 10:45–56. 60. Kaplan KA, Harvey AG. Behavioral treatment of insomnia in bipolar disorder. & Am J Psychiatry 2013; 170:716–720. CBT-I has not been extensively studied for the treatment of sleep disturbances in bipolar disorder. One of the concerns is that one component of CBT-I is based on partial sleep restriction to build adequate sleep pressure. Sleep restriction may cause hypomanic or manic switch in patients with bipolar disorder. This study suggests that the amount of sleep restriction indiced with CBT-I is safe in patients with bipolar disorder.
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Circadian rhythms and sleep in bipolar disorder: implications for pathophysiology and treatment Isabella Soreca
Purpose of review Multiple lines of evidence support the conceptualization of bipolar disorder as a disorder of circadian rhythms. Considering bipolar disorder in the framework of circadian disturbances also helps understand the clinical phenomenology pointing toward a multisystemic involvement. Recent findings Patients with bipolar disorder show altered rhythmicity in body temperature and melatonin rhythms, high day-to-day variability in activity and sleep timing, persistent disturbances of sleep or wake cycles, including disturbances of sleep continuity. The internal clocks are, indeed, responsible for regulating a variety of physiologic functions, including appetitive behaviors, cognitive functions and metabolism. Summary An underlying circadian pathology in bipolar disorder is a unifying explicatory model for the high psychiatric and medical comorbidity observed during the long-term course of the disorder. This model also provides a rationale for therapeutic interventions aimed at re-entraining the internal clock. Keywords bipolar disorder, circadian rhythms, sleep
INTRODUCTION Bipolar disorder ranks as the 4th cause of disability worldwide (2008 WHO estimates), leading to billions of dollars in annual healthcare costs related to loss of productivity, reduced occupational functioning and medical comorbidity [1]. Although functional impairment and medical burden are thought to be primarily linked to affective episodes and interepisodic mood disturbances, leading to cognitive impairment and unhealthy behavior, recent evidence suggest that sleep and circadian disturbances contribute, at least in part, to functional and medical outcomes in bipolar disorder [2]. Sleep disturbances have, indeed, been described across all mood states as well as during interepisodic intervals. The two-process model of sleep regulation first proposed by Borbely et al. [3] postulates that sleep onset is the result of the complex interaction between two constituent processes, a sleep or wakedependent homeostatic Process S and a circadian Process C. The interaction between these two processes generates the timing of sleep, waking and daytime vigilance [3]. The specific symptoms of mania and depression (disturbances in sleep, appetite, energy, concentration), as well as the alternating between the opposite polarities are suggestive of a disruption of circadian rhythms as core to bipolar
disorder pathology, of which sleep disturbances are one of the manifestations. Though less specific, the sleep disturbances described in patients with bipolar disorder during remission may also represent an epiphenomenon of an underlying circadian pathology. The conceptualization of bipolar disorder as a disorder of circadian pathology may help explain the multisystemic involvement observed with the longitudinal progression of the disorder [2,4]. This review will discuss circadian and sleep disturbances in bipolar disorder: we will examine how they inform pathophysiology of affective disorders, discuss the implications of circadian and sleep disturbances on the multisystemic involvement, encompassing multiple comorbidities, with a specific focus on medical outcomes. Finally, we will briefly touch on chronotherapeutic tools for the treatment of bipolar disorder. Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA Correspondence to Isabella Soreca, MD, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, USA. Tel: +1 412 586 9173; e-mail: [email protected] Curr Opin Psychiatry 2014, 27:467–471 DOI:10.1097/YCO.0000000000000108
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KEY POINTS Several lines of evidence support circadian rhythm disturbance as a core component in bipolar disorder. The sleep–wake cycle alterations observed in the euthymic phase of bipolar disorder may be an epiphenomenon of an underlying disruption of endogenous rhythms. The multisystemic involvement in bipolar disorder, with high rate of psychiatric and medical comorbidity, may be a downstream effect of the underlying circadian pathology. Behavioral interventions targeted at re-entraining social rhythms can ameliorate symptoms, improve functioning and reduce medical risk factors.
BIPOLAR DISORDER AS A DISORDER OF CIRCADIAN RHYTHMS Every living organism has internal biological clocks that are synchronized with external environmental cues, of which the light–dark cycle is the most important and powerful synchronizer. An intact and functioning biological clock is critical for survival [5,6], as it contributes to regulating and coordinating physiologic states and behavioral output. So, if an intact and well functioning circadian system is critical for survival, how does the circadian system become perturbed in bipolar disorder and how did it survive selective pressure? The internal clock entrains to environmental cues, thus assuring behavioral responses that are adaptive to the specific characteristics of the environment. The lack of strong self-sustained circadian activity is advantageous in these two extreme and unpredictable conditions: Arctic animals are released from circadian constraints and are able to feed when the opportunity arises [7]. Migratory birds can reduce avian jet lag when traveling across multiple time zones if their oscillatory rhythm is weak and therefore more easily pushed forward by light [7]. These two examples help us understand how a weak circadian system may represent vestiges of early adaptive traits in hunter-gatherer societies, who migrated to follow seasonally available wild plants and game. A low amplitude (i.e., weak) circadian rhythm may have provided an adaptive advantage allowing more flexible behavioral responses to the rapidly changing environmental challenges. These responses may have involved the ability to rapidly switch from rest to behavioral activation when prey became suddenly available or to promptly arouse from sleep in response to a predator or impending natural disaster. However, in modern society, the multitude of competing entraining 468
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stimuli, including artificial illumination, is such that a weak circadian system is no longer adaptive. Bipolar disorder would, therefore, result from the interaction of internal triggers (weak circadian rhythms) and multiple competing social zeitgebers (literally, time-giver stimuli) that would promote inappropriate behavioral activation (mania) or inhibition (depression) [8]. In line with this hypothesis, Malkoff-Schwartz et al. [9], in their seminal study, found that the onset of manic episodes was preceded by stressful life events, especially those involving social rhythm disruption, significantly more often than depressive episodes. Several lines of evidence from human and animal models of bipolar disorder converge toward an altered circadian rhythmicity in bipolar disorder. Abnormalities in core body temperature rhythms [10], the melatonin secretion curve [11,12] and instability of daily rest or activity patterns [13,14] have all been reported in euthymic patients with bipolar disorder. In mice, disruption of the genetic machinery responsible for creating and sustaining circadian rhythms is associated with disrupted rest-activity behaviors and both mania and depression-like behavior [15]. Genetic studies suggest an association between polymorphisms in the circadian clock genes and clinical phenotypes [16], including chronotype [17], and response to lithium prophylaxis [18]. Sleep–wake cycles are a key component of circadian rhythms. Sleep is regulated by the interaction of homeostatic factors (e.g., sleep pressure, related to time spent awake) and circadian aspects (e.g., melatonin release during the dark phase). Not surprisingly, sleep disturbances are a key diagnostic criterion for affective episodes. Specifically, reduced need for sleep is one of the diagnostic criteria for manic episode, while insomnia or hypersomnia may be present during a depressive episode, with up to 100% of patients reporting some degree of sleep disturbances [19]. Sleep disturbances are not only prominent during florid mania [20], but can be part of the prodromal syndrome of a manic episode and predict relapse [21]. Early polysomnographic (PSG) investigations found that patients with bipolar disorder in a manic episode show disturbed sleep continuity, decreased total time spent asleep, increased percentage of stage 1 sleep, shortened rapid eye movement latency and increased rapid eye movement density compared with healthy counterparts [20,22], similar to what observed in severe major depressive disorders. The ability to maintain high energy levels despite lack of sleep appears to be the aspect of greater specificity in describing mania [23]. However, some evidence suggests that reduced sleep during the manic phase may not be caused by a decreased need for sleep, but is rather, an Volume 27 Number 6 November 2014
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epiphenomenon of general hyperactivity, leading to decreased tendency to sleep. Few case reports and small studies using ‘dark therapy’ have, in fact, reliably induced sleep in patients who were acutely manic, when placed in a sensory and light deprived environment [24–26]. This would suggest that the short sleep duration during mania could actually be resulting from a vicious behavioral cycle, in which patients experience increased energy and hyperactivity, leading to excessive exposure to light cues (including artificial light and computer, TV, or phone screens at night-time) which, in turn, maintains reduced sleep time and altered mood. Sleep disturbances in the depressive phase have been more intensely investigated with the goal of identifying specific biomarkers that would help differentiate bipolar and unipolar depression. Results from PSG sleep studies have, however, generated conflicting results suggesting, in general, sleep abnormalities in bipolar disorder that are largely overlapping with those found in unipolar depression. The most consistent sleep findings in bipolar depression appear to be decreased rapid eye movement (REM) latency and more sleep fragmentation compared with unipolar depressed patient and healthy controls [19,27]. However, Kupfer and Ehlers [28] hypothesized that although REM sleep abnormalities may be primary in unipolar depression, they may be a result of a primary deficit in slow-wave sleep in bipolar disorder. In line with this hypothesis, in their longitudinal study of adolescent with major depression, Rao et al. [29] reported that patients who later developed bipolar disorder had a relatively intact REM sleep profile, but showed increased stage 1 and decreased stage 4 sleep. This would suggest that the REM sleep findings in adult depressed patients with bipolar disorder may result from the interaction of developmental processes and illness course. Sleep disturbances in the remitted phase of bipolar disorder have been more widely investigated with the intent to parse out the effects of the symptomatic episodes from possible trait characteristics. A variety of methods have been employed, including self reports, PSG recordings and actigraphy. In general, the consensus is that patients with bipolar disorder in the euthymic phase continue to show prominent alterations in sleep duration, sleep continuity and day-to-day variability in sleep timing [13,30,31].
MULTISYSTEMIC INVOLVEMENT IN BIPOLAR DISORDER: MEDICAL BURDEN AS A CONSEQUENCE OF UNDERLYING CIRCADIAN PATHOLOGY The relationship between sleep and cardiovascular disease (CVD) risk has now been established by a
wealth of epidemiologic and experimental data [32–34]. A more recently discovered pathway to CVD risk is the disruption of the circadian rhythms. From the first observations that shift workers have increased risk for obesity, diabetes and hypertension [35]; several experimental studies in animal models have shown that the effect of circadian misalignment on CVD risk is independent of that of sleep deprivation [36]. Along this line, experimental studies have shown that meal timing also affects insulin resistance, an important risk factor for metabolic syndrome, diabetes and CVD [37,38]. Patients with bipolar disorder have high rates of obesity and the metabolic syndrome [39–41]. Considering the wealth of data documenting CVD morbidity and mortality in bipolar disorder [42,43], there has been surprisingly little research investigating the causes and mechanisms, other than the reported effects of psychotropic medications on CVD risk. Although medications undoubtedly play a major role, a number of neurobiological and behavioral characteristics linked to the disorder may independently increase the CVD risk. For example, recent evidence points toward several chronobiological factors affecting CVD risk, namely evening chronotype [44], sleep duration [45 ,46], birth seasonality [47 ] and instability of daily rest-activity patterns [45 ]. Each of these sleep and circadian characteristics is associated with bipolar disorder, as reviewed above. &
&
&
CHRONOTHERAPEUTIC STRATEGIES Chronotherapeutics refer to a set of treatments based on current knowledge of chronobiology that uses controlled exposure to environmental stimuli in order to entrain the circadian system [48]. The chronotherapies used in bipolar disorder include bright light therapy, dark therapy, wake therapy (total or partial sleep deprivation), or a combination of these. In addition, behavioral interventions aimed at strengthening the daily behavioral patterns, namely interpersonal and social rhythm therapy (IPSRT) and cognitive behavioral therapy for insomnia (CBT-I), have also been successfully applied in the treatment of bipolar disorder. Bright light therapy was originally developed and tested for the treatment of major depressive disorder and seasonal affective disorder, and subsequently tested as adjunct treatment for bipolar depression. A few small studies and case reports point toward the efficacy of mid-day light therapy in ameliorating bipolar depression and rapid cycling [24,49]; however, other studies have reported negative results [50]. One study reported a significant reduction of depressive symptoms and suicidality in
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Sleep disorders
treatment-resistant bipolar depression with a combination of bright light therapy, sleep deprivation and lithium [51 ]. Dark therapy is achieved by extending rest or sleep in a dark room or by wearing amber tinted lenses, blocking up to 90% of the blue light wavelength to which circadian photoreceptors are particularly sensitive [52]. A few small studies and case reports have shown efficacy of dark therapy in stabilizing rapid cycling bipolar disorder [24,26]; and reducing manic symptoms [25,26,53]. Sleep deprivation has rapid but transient mood enhancing effects in bipolar depression, which can be used as a primer for pharmacologic treatments’ antidepressant effect [54]. IPSRT is a behavioral treatment geared toward increasing the regularity of patients’ daily routines [55]. IPSRT has been shown to delay time to relapse in patients with bipolar disorder who have achieved acute stabilization form a mood episode, mediated, in part, by increased regularity of patients’ social routines [56]. Interestingly, the advantages of behavioral treatments that target social rhythm regularity seem to extend beyond their ability to reduce symptoms and prevent recurrences, with new evidence pointing toward improving occupational functioning [57] and facilitating weight loss (Frank et al. submitted). An adaptation of CBT-I, based on stimulus control [58] and sleep restriction [59], has also been tested for the treatment of sleep disturbances in bipolar disorder. Preliminary evidence suggests that CBT-I is a well tolerated and effective treatment for sleep disturbances in patients with bipolar disorder [60 ].
Acknowledgements None.
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CONCLUSION In summary, multiple lines of evidence support the conceptualization of bipolar disorder as a disorder of circadian rhythms. Considering bipolar disorder in the framework of circadian disturbances also helps understand the clinical phenomenology pointing toward a multisystemic involvement. Internal clocks are, indeed, responsible for regulating a variety of physiologic functions, including appetitive behaviors, cognitive functions and metabolism. An underlying circadian pathology in bipolar disorder provides a unifying explicatory model for the high psychiatric and medical comorbidity observed during the chronic course of the disorder. This model also provides a rationale for therapeutic interventions aimed at re-entraining the internal clock, reducing symptoms and enhancing health span and lifespan in patients with bipolar disorder. 470
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Conflicts of interest There are no conflicts of interest.
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