Professional Documents
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An Integrated Model
Jessica C. Levenson, University of Pittsburgh Medical Center
Robin Nusslock, Northwestern University
Ellen Frank, University of Pittsburgh Medical Center
Bipolar disorder contributes substantially to the global mated at 2.1% in the United States (Merikangas et al.,
burden of disease. Both sleep disturbance and life 2007). Bipolar episodes are likely to recur, and the dis-
events predict symptoms of mania, although the under- order is associated with the highest rates of suicide
lying mechanisms associated with these relationships among all psychiatric disorders (Miklowitz & Johnson,
have been difficult to elucidate. In this report, we
2006).
Both sleep disturbance and life events predict symp-
explore the relationships among life events, sleep dis-
toms of mania, although the underlying mechanisms
turbance, and mania in an effort to provide support for
associated with these relationships have been difficult to
the hypothesis that some life events lead to a disrup-
elucidate. Examining the role of sleep disturbance and
tion of sleep that may ultimately lead to the develop-
life events may help us better understand the underlying
ment of mania. We present an integrated conceptual mechanisms of bipolar disorder, especially when we
model that draws on research examining the mecha- consider evidence implicating these factors in the devel-
nisms by which life events disrupt sleep in various pop- opment of bipolar episodes (e.g., Altman et al., 2006;
ulations, and we evaluate the role of these mechanisms Harvey, 2008; Harvey et al., 2005; Johnson, 2005;
in individuals with mania. Suggestions for future work Miklowitz & Johnson, 2009; Proudfoot, Doran, Mani-
in this area are also presented. cavasager, & Parker, 2010). Because our understanding
Key words: bipolar disorder, life events, mania, of how sleep disturbance and life events contribute to
sleep, social rhythms. [Clin Psychol Sci Prac 20: 195 bipolar episodes is not fully developed, recent work has
210, 2013] focused specifically on elucidating the mechanisms by
which these factors are involved in the etiology of bipo-
Bipolar disorder contributes substantially to the global lar disorder (Miklowitz & Johnson, 2006; Plante &
burden of disease and has been ranked as the sixth Winkelman, 2008). Studying sleep in relation to manic
leading cause of disability worldwide (Fajutrao, episodes is highly relevant, because sleep disturbance is
Locklear, Priaulx, & Heyes, 2009; Murray & Lopez, the most common prodrome of mania (Jackson, Cava-
1996). The disorder is characterized by manic, hypo- nagh, & Scott, 2003). Further study that clarifies the
manic, mixed, and major depressive episodes (Ameri- role of these factors in the development of mania is war-
can Psychiatric Association [APA], 2000). The lifetime ranted and may contribute to the development of new
prevalence rate of bipolar I and II disorders is esti- treatment strategies or the improvement of existing ones
that target these biological and psychosocial factors.
Sleep disturbance and life events are also predictors
Address correspondence to Ellen Frank, Western Psychiatric
of onsets of bipolar depression, and considerable
Institute and Clinic, 3811 OHara Street, BT 812, Pittsburgh,
research has been conducted on the relationship
PA 15213. E-mail: franke@upmc.edu.
2013 American Psychological Association. Published by Wiley Periodicals, Inc., on behalf of the American Psychological Association.
All rights reserved. For permissions, please email: permissionsuk@wiley.com. 195
between life events and depressive episodes (e.g., Hor- mania with interpersonal and social rhythm therapy
esh & Iancu, 2010; Johnson, 2005; Johnson et al., (IPSRT; Frank, 2005).
2008); however, little is known about the predictors of According to the two-process model (Borbely,
hypersomnia, a sleep disturbance that often character- 1982), sleep is regulated by a homeostatic sleep-
izes bipolar depression (Kaplan & Harvey, 2008). Fur- dependent process (Process S) and a sleep-independent
thermore, the types of life events and sleep disturbance circadian process (Process C). Still, factors other than
that individually predict bipolar depression onset, as homeostatic and circadian processes may affect sleep
well as the mechanisms underlying the effect of life (Harvey, 2008), such as environmental stressors or
events on sleep that, in turn, lead to a bipolar sleep-altering drugs.
depressive episode may differ from those relevant to Sleep in mood disorders may be disturbed in a num-
mania. It may be problematic, at this point in time and ber of ways. In unipolar depression, altered REM sleep
without a more complete understanding of the hetero- and decreased delta sleep appear to be the most com-
geneity of sleep disturbance that characterizes bipolar mon changes to sleep architecture (Hetta, Rimon, &
depression, to generate a model that is appropriate to Almqvist, 1985), while increased sleep-onset latency
both mania and bipolar depression. Thus, we limit this and decreased sleep efficiency are also common. Unipo-
report to the exploration of the relationships among lar depression and mania share the sleep abnormality of
sleep disturbance, life events, and mania. Still, an reduced delta sleep (Hetta et al., 1985), and one study
understanding of the mechanisms by which life events (Hudson et al., 1992) found that several polysomnogra-
disrupt sleep in the onset of bipolar depression is cen- phy (PSG) measures differentiated inpatients with mania
tral to our understanding of bipolar disorder more gen- and unipolar depression from healthy controls, includ-
erally. Future work should aim to generate a ing decreased total recording period, sleep efficiency,
mechanistic model relevant to bipolar depression, and and REM latency, as well as increased number of awak-
then evaluate whether there are mechanisms that over- enings, percentage of stage 1 sleep, and REM density.
lap between the two models. The two patient groups were similar to each other on
We propose that some life events lead to disturbed nearly all indices of sleep. Still, those with mania had
sleep, which ultimately predicts the onset of mania. significantly less total sleep time than those with unipo-
This hypothesis is supported by evidence presented in a lar depression, which may speak to the fact that a
conceptual model that outlines three mechanisms decreased need for sleep is considered the classic sleep
underlying this relationship: disruptions to circadian disturbance characteristic of mania or it may speak to
and social rhythms, disruptions to the behavioral activa- potential differences between the groups in the homeo-
tion system, and emotional hyperarousal. static and circadian mechanisms underlying sleep.
CLINICAL PSYCHOLOGY: SCIENCE AND PRACTICE V20 N2, JUNE 2013 196
studies have found that changes in sleep duration, may promote the occurrence of life events themselves.
particularly decreased sleep, predict increased mood Later we will consider these other effects.
(Bauer et al., 2006, 2008) among inpatients with bi- Overall, evidence supports the role of sleep distur-
polar disorder whose episode was of less than two bance in the onset of manic episodes. Still, the relation-
weeks duration (Barbini, Bertelli, Colombo, & ships among these variables are not entirely clear
Smeraldi, 1996), and among individuals with rapid- because of the role of homeostatic, circadian, and envi-
cycling bipolar disorder (Leibenluft, Albert, Rosenthal, ronmental processes that may affect sleep.
& Wehr, 1996). Experimental work in this area has
shown the depressiogenic effect of sleep and the LIFE EVENTS AND MANIA
antidepressant effect of wakefulness. For example, the Research has generally supported a positive association
addition of dark therapy (DT) to treatment as usual between life events and affective episodes (Alloy et al.,
(TAU) was associated with a faster reduction of manic 2005; Brown, 1989; Brown & Harris, 1978; Johnson,
symptoms than TAU alone among patients in the first 2005; Johnson & Roberts, 1995; Paykel, 2001, 2003).
two weeks of a manic episode (Barbini et al., 2005). It Stress has been operationalized by some as the level of
is unclear whether these improvements are the result of threat severity (Brown, 1989; Brown & Harris,
increased sleep or increased time in the dark, suggesting 1978) or negative consequences associated with an
the possible importance of sleep rhythms and/or event. Still, recent research has suggested that some
behavioral deactivation (discussed below) in this effect. events that are not typically considered stressful nev-
The antidepressant effect of sleep deprivation may be ertheless may be important for the development of
strong enough to cause a switch into mania or hypoma- mania (discussed below). Investigating this area requires
nia (Colombo, Benedetti, Barbini, Campori, & Smer- an awareness of the lack of differentiation between epi-
aldi, 1999) in a relatively short amount of time sode types that exists in the literature, and the fact that
(Salvadore et al., 2010). One relevant hypothesis states psychopathology itself can lead to subsequent life
that factors that trigger manic episodes may do so via events (Johnson, 2005; Johnson & McMurrich, 2006;
their ability to cause sleep deprivation (Wehr, 1989; Paykel, 2001). These are notable limitations because
Wehr, Sack, & Rosenthal, 1987), with sleep reduction predictors of mood episodes may not be common to
(insomnia or sleep deprivation) as the final common both mania and depression and, if the direction of cau-
pathway leading to mania in some cases (Wehr et al., sality is not considered, life events that are dependent on
1987). To support this theory, a recent review (Salva- the current mood state may be mistaken for life events
dore et al., 2010) proposed mechanisms by which sleep that have caused the mood state (Bender, Alloy, Sylvia,
deprivation leads to a switch into mania. Sleep depriva- Urosevic, & Abramson, 2010; Hammen, 2006).
tion may bring about its rapid antidepressant effects by Early work in this area was largely atheoretical and
activating the locus coeruleus noradrenergic system dur- focused on establishing a link between life events and
ing REM sleep periods, times when the system would bipolar episodes. Many studies in this area found a
typically be inactive. The release of norepinephrine at positive association between mood episodes and the
this time would result in expression of certain plasticity presence of stressful life events (or higher levels of life
genes, such as brain-derived neurotrophic factor stress), with regard to both the first of a mood episode
(BDNF), camp-response element binding (CREB), and (Ambelas, 1979, 1987; Joffe, MacDonald, & Kutcher,
tyrosine kinase receptor B (TrkB), and, consequently, a 1989; Kennedy, Thompson, Stancer, Roy, & Persad,
rapid antidepressant response (Salvadore et al., 2010). 1983; Kessing, Agerbo, & Mortensen, 2004) or prior
Some life events may promote sleep deprivation (e.g., to a relapse or recurrence (Aronson & Shukla, 1987;
spending the night in the emergency room with a friend Ellicott, Hammen, Gitlin, Brown, & Jamison, 1990;
who has been in a car accident), so this mechanism may Hammen & Gitlin, 1997; Hunt, Bruce-Jones, & Silver-
be important to the genesis of mania as a product of life stone, 1992; Pardoen et al., 1996).
events. Of course, in other instances, sleep disturbance But some of these early studies are characterized by
may affect mood even without a preceding life event or retrospective designs and used case reports to identify
Increased
Change in CRH/Corsol
Light Exposure (HPA Axis)
Via SRD
Via Stress
Life Event
Via BAS/Reward
Sleep Disturbance
Dysregulaon
Dysregulaon of
Reward-Related
Via Stress
Brain Funcon
Emoonal Physiological
Arousal (ANS) Arousal
Poor Coping
Skills
Figure 1. Integrated conceptual model: mechanisms explaining the role of life events in the onset of sleep disturbances.
CLINICAL PSYCHOLOGY: SCIENCE AND PRACTICE V20 N2, JUNE 2013 198
in a manic state with a high level of goal seeking rhythms (Ehlers et al., 1988, p. 948). Once social rhy-
spends all night gambling at a casino. This, in turn, thms are dysregulated, biological rhythm dysregulation
leads to sleep deprivation and the loss of large amounts can result (including disrupted sleep rhythms), leading
of money while pursuing a big win at the slot to somatic symptoms and affective episodes. Empirical
machines. Accordingly, Urosevic et al. (2010) showed support for this theory is still growing, but the role of
that individuals with bipolar spectrum disorders gener- disturbed circadian rhythms or sleep in the effect of life
ated more reward-relevant events than healthy controls. events on bipolar disorder has been discussed and sup-
Last, it is unclear whether disturbed sleep is a pro- ported by other researchers as well (Altman et al.,
drome or a cause of mania (Plante & Winkelman, 2006; Johnson, 2005; Russell & Browne, 2005). As
2008). Paying close attention to the timing of symptom mentioned above, some of these SRD events may, in
onset may help us to determine whether sleep distur- fact, directly prohibit sleep, such as accompanying a
bance predicts mood symptoms, whether it appears friend to the emergency room at midnight or taking an
simultaneous to the onset of a mood disturbance, or overnight flight.
whether it is the result of a mood disturbance. Each of One study noted that SRD events occurring prior
these plausible scenarios may indicate the role of differ- to a bipolar episode were associated with manic but
ent mechanisms underlying the development of a not bipolar depressive episode onset (Malkoff-Schwartz
mood episode and the causes and consequences of it. et al., 1998) and that individuals with mania were
These are methodological complications to consider more likely to report an SRD event than cycling indi-
when investigating this area, and further work is viduals or those with unipolar depression (Malkoff-
needed to untangle cause and effect. In this work, Schwartz et al., 2000). Those experiencing mania were
however, we will focus on the effect of life events on also more likely to report an SRD event during a
sleep in the onset of mania. preonset period than during a control period (Malkoff-
Schwartz et al., 1998). While these studies did not
Sleep, Social Rhythm Disruption, and Bipolar Disorder examine the effect of life events on sleep per se, one
Some recent work in the life events literature has could argue that, given the definitions used for SRD
focused on events that involve a disruption of social events in this study, social rhythm disruption may be
rhythms (SRD events). Losing a job, for example, may used as a proxy for sleep disturbance. In those with
have financial implications, involving some level of soft bipolar diagnoses (bipolar II disorder and/or
threat (Brown, 1989; Brown & Harris, 1978), but it cyclothymia), life events, particularly SRD events, pro-
can also alter the sleep, wake, and meal times of an spectively predicted depressive symptoms and episodes,
individuals daily schedule, that is, his or her social although their ability to predict (hypo) manic symp-
rhythms (Ehlers, Frank, & Kupfer, 1988; Ehlers, toms and episodes was less consistent (Sylvia, Alloy,
Kupfer, Frank, & Monk, 1993; Malkoff-Schwartz Hafner, Gauger, & Verndon, 2009).
et al., 1998, 2000). Alternatively, a change in ones It may be possible to identify a couple of potential
work shift may not cause significant stress as job secu- mechanisms underlying the effect of life events on sleep
rity is not in jeopardy, but nonetheless can lead to a disruption in mania from a study of unipolar depres-
disruption of rhythms-based needing to go to and/or sion. This may not be altogether unexpected given the
return from work at a different time. sleep architecture shared by individuals with unipolar
Exploration of the social zeitgeber (timegiver) theory depression and mania, and the fact that the social zeit-
of affective disorders (Ehlers et al., 1988, 1993) explains geber hypothesis was originally applied to unipolar
how SRD events lead to mania through a disruption of depression (Ehlers et al., 1988; Healy & Williams,
sleep and circadian rhythms. This theory asserts that 1989). In a study that showed that depressed adults had
some life events prompt a disturbance in social zeitge- more disturbed sleep following SRD events than
bers and subsequently disrupt social rhythms. Social normal controls (Haynes, McQuaid, Ancoli-Israel, &
zeitgebers include personal relationships, social Martin, 2006), the authors suggested that the sleep/
demands, or tasks that serve to entrain biological wake systems of these patients, already susceptible to
CLINICAL PSYCHOLOGY: SCIENCE AND PRACTICE V20 N2, JUNE 2013 200
(Alloy & Abramson, 2010; Depue & Iacono, 1989; more reward activation (e.g., goal striving) and reward
Urosevic, Abramson, Harmon-Jones, & Alloy, 2008). deactivation (e.g., failures) events as compared to
This model proposes that individuals with bipolar dis- healthy controls. The high achievement motivation
order are prone to experience an excessive increase in (Johnson, 2005) and reward sensitivity among individu-
approach- or reward-related affect to reward-relevant als with bipolar disorder can lead to working exces-
cues, which, in the extreme, is reflected in hypo/manic sively long hours and neglecting important social
symptoms (Alloy & Abramson, 2010; Depue & Iacono, routines (Nusslock et al., 2009). In extreme cases, this
1989; Urosevic et al., 2008). Compared to relevant can involve extreme sleep loss and disruption of circa-
control groups, bipolar individuals display elevated dian rhythms. In line with this view, the two most
scores on self-report measures of both BAS sensitivity common prodromes of a manic episode are increased
and sensitivity to reward-relevant cues (Alloy & reward-directed activity and decreased need for sleep
Abramson, 2010; Alloy et al., 2006, 2008; Carver & (Lam & Wong, 1997).
Johnson, 2009; Gruber & Johnson, 2009; Johnson There is also an important coupling between
& Carver, 2006; Meyer, Johnson, & Carver, 1999; reward-processing and social/circadian rhythm variables
Meyer, Johnson, & Winters, 2001; Salavert et al., at the biological level of analysis. Growing evidence
2007). Among bipolar spectrum individuals, elevated suggests that activity in the reward system may be
self-reported BAS sensitivity prospectively predicts partly determined by timing information from the
shorter time to onset of hypo/manic episodes (Alloy SCN, such that reward motivation is greatest when the
et al., 2008) and a greater likelihood of converting environment is most likely to produce rewards
from cyclothymia/bipolar II disorder to bipolar I disor- (daytime for diurnal species; see Murray et al., 2009;
der (Alloy et al., 2011). Individuals with both bipolar I Murray & Harvey, 2010; for review). Positive affect,
disorder and a bipolar spectrum disorder display subjective alertness, and heart rate responses to reward-
elevated reward/approach-related brain activity, as related stimuli show a circadian rhythm and reach their
indexed by both electroencephalography (Harmon- zenith in the late afternoon, whereas negative affect
Jones et al., 2008; Nusslock et al., 2012), and fMRI does not show such daily variation (Clark, Watson, &
(Nusslock et al., 2012). Finally, and relevant to the Leeka, 1989; Goel, Van Dongen, & Dinges, 2011;
present report, both reward-striving and reward- Hasler, Mehl, Bootzin, & Vazire, 2008; Murray, Allen,
attainment relevant life events have been shown to & Trinder, 2002; Murray et al., 2009). Animal studies
trigger hypo/manic episodes (Johnson, Meyer, Winett, report circadian genes from the clock pathway influ-
& Small, 2000; Johnson & Sandrow, 2000; Nusslock, ence behavioral indices of reward function (Andretic,
Abramson, Harmon-Jones, Alloy, & Hogan, 2007). Chaney, & Hirsh, 1999; McClung et al., 2005) and
The social zeitgeber and BAS/reward models of mice carrying a mutation of the CLOCK gene exhibit
bipolar disorders can be integrated in a complimentary manic-like behavior (e.g., hyperactivity, greater valuing
fashion given that many reward-relevant events (e.g., of cocaine; Roybal et al., 2007). Finally, recent
goal striving, goal attainment) can disrupt social research has examined the relationship between
rhythms. Highly reward-sensitive individuals may also reward-related brain function in humans and circadian
be more vulnerable to social rhythm disruption in genes (Forbes et al., 2011).
response to reward-relevant events, and greater social Despite the relationship between reward and social
rhythm disruption in response to reward-relevant rhythm/sleep-related variables, there are many unan-
events predicts increases in bipolar episodes and first swered questions as to how these variables interact to
onset of a bipolar spectrum diagnosis (Boland, Bender, generate vulnerability to manic episodes. Under certain
LaBelle, Abramson, & Alloy, 2012). Furthermore, indi- circumstances, SRD events likely precede manic symp-
viduals with bipolar disorder may generate the very toms such as excessive goal-striving behaviors and
reward-relevant events that disrupt social rhythms and approach-related affect, as proposed by the social zeit-
trigger bipolar episodes. As noted above, Urosevic geber perspective (Ehlers et al., 1988, 1993). Under
et al. (2010) reported that bipolar individuals generate other circumstances, excessive goal-striving-related
CLINICAL PSYCHOLOGY: SCIENCE AND PRACTICE V20 N2, JUNE 2013 202
dysfunctional attitudes about sleep, but they did differ A second possibility is that euthymic individuals with
from a group of healthy controls on these measures. bipolar disorder may experience decreased sleep as a
Although the findings pertaining to rumination and result of hyperarousal following a stressful life event,
worry did not remain significant after controlling for and the change in sleep duration itself may lead to
symptoms of depression and anxiety, the authors sug- increased mood. It may be these individuals who expe-
gest that the shared transdiagnostic processes common rience a stressful life event that results in insomnia, ulti-
to both disorders may reflect shared comorbid anxiety mately leading to the onset of mania, as described by
and depressive symptoms (Gruber et al., 2008). The Wehr et al. (1987). Other individuals may know the
authors note that dysfunctional beliefs about sleep may appropriate strategies for facilitating sleep but still find
be important in maintaining insomnia in individuals themselves awake, or they may desire to continue
with bipolar disorder and that the individuals with engagement in activities that maintain elevated energy
bipolar disorder may have anxiety and fear about sleep, levels and prohibit sleep. These individuals may be fur-
as do individuals with primary insomnia. ther into a manic episode and their sleep disturbance
Extending these findings, we could hypothesize that may be better characterized as decreased need for sleep
the stress and anxiety associated with a stressful life rather than difficulty initiating sleep.
event itself can produce hyperarousal, worry, and
disturbed sleep in these patients. Like those with DISCUSSION
insomnia, patients with bipolar disorder may have the This review has highlighted several lines of evidence
experience of internalized emotions, leading to physio- suggesting that both sleep disturbance and life events
logical arousal, even if the reaction pertains to a stress- predict manic symptoms and episodes. Sleep plays a key
ful life event, rather than inadequate sleep. When role in the development of mania, based on both
combined with poor coping strategies, sleep distur- homeostatic and circadian processes. In addition, the
bance may be even more likely to occur, which may association between various types of life events and
in turn predict elevated mood. This is reminiscent of mania is generally positive. Furthermore, life events
Haynes and colleagues (2006) suggestion that patients may contribute to the development of disturbed sleep
with unipolar depression have sleep/wake systems that in their own right. Figure 1 shows the four mechanisms
are less likely to self-correct after SRD, making dysre- underlying this effect that have been proposed based on
gulation more likely, and of the evidence for increased the empirical and theoretical work reviewed here.
mood that results from decreased sleep (e.g., Barbini Events involving social rhythm disruption, or those that
et al., 1996; Bauer et al., 2006, 2008). Hyperarousal prohibit sleep directly, may lead to sleep and circadian
may be a normal reaction to a stressful event, but those rhythm disruption via a change in the amount of light
who later develop insomnia or mania may be less capa- exposure. Increased light exposure that accompanies a
ble of reversing this reaction than healthy individuals, change in social rhythms may increase CRH/cortisol
which may lead to the development of more symptoms release, thereby disrupting sleep. Life events involving
of mania. threat or stress may also increase cortisol release directly,
When considering these mechanisms, it is also subsequently disrupting sleep via HPA axis dysregula-
important to note the heterogeneity among individuals tion. Third, reward-striving and reward-attainment
with mania. Some may actually desire to sleep but can- relevant life events have been shown to trigger hypo/
not, while others are content in their sleeplessness manic episodes, and there is an important coupling
while engaging in activating or rewarding endeavors. between reward and sleep-related variables. Future
We may not be able to determine whether the arousal research is needed to establish under which circum-
mechanism mentioned here applies to both of these stances reward-related events precipitate abnormalities
groups, given the limited data available. Some individ- in social/sleep-related variables, and vice versa, as well
uals early in a manic episode may desire to sleep but as the biological mechanisms through which reward and
may not possess the skills needed to lower their arousal sleep-related processes interact to generate manic epi-
at bedtime, similar to some individuals with insomnia. sodes. Last, some individuals internalize the emotions
CLINICAL PSYCHOLOGY: SCIENCE AND PRACTICE V20 N2, JUNE 2013 204
physical arousal. Learning skills to counteract the effects REFERENCES
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