Not Sleeping?????? This article may explain why not, and an OFTEN "hidden" cause.
James MacLachlan
Bipolar Disorder
by Ellen Leibenluft, M.D.
Psychiatric Times May 1996 Vol. XIII Issue 5
At this time, both patients and professionals seem to have an
unprecedented interest in circadian
rhythms. Phototherapy and melatonin, two interventions that manipulate
the circadian system, are
being used widely for seasonal affective disorder, jet lag and some
forms of insomnia. Scientists
continue to make tremendous strides in understanding the regulation of
the circadian system in
humans and animals. We now know that the body's clock is located in the
suprachiasmatic nucleus
(SCN) of the hypothalamus, and that the SCN regulates the pineal gland's
secretion of the hormone
melatonin (Klein and colleagues).
In humans as well as animals, light suppresses melatonin secretion;
recent evidence shows that even
ordinary room light can have this effect. Because light suppresses
melatonin secretion, the hormone is
typically secreted at night. Furthermore, the SCN can "remember" the
day-length to which it has
been recently exposed, so the timing of nocturnal melatonin secretion is
determined by the "lights on"
and "lights off" times of the preceding days. In 1994, scientists cloned
genes regulating circadian
rhythms in mice, making the circadian system the first complex
behavioral system whose genetic
underpinnings could begin to be unraveled in mammals (Vitaterna and
coworkers).
In mood disorder research, interest in circadian rhythms is not new. For
at least 50 years,
investigators have questioned whether abnormalities in circadian rhythm
regulation might be involved
in the pathogenesis of mood disorders, including rapid-cycling bipolar
disorder. These questions
were motivated by three clinical observations. The first of these was
that the sleep duration of
patients often changes dramatically as they cycle between mania.i.mania;
and depression, bipolar
depression is typically associated with hypersomnia.i.hypersomnia; while
mania is characterized by
extreme and sometimes total insomnia.
The second observation was that approximately 60 percent of depressed
patients experience
remission after a night of total or partial sleep deprivation (SD). In
bipolar.i.bipolar; patients, SD may
actually cause a switch into hypomania or mania. However, this "upward"
switch usually lasts only
until the patient undergoes recovery sleep, leading to the formulation
that SD, or extended
wakefulness, is antidepressant, (or manicogenic), while sleep is
depressogenic, (Wehr). The
antidepressant effects of SD are conceptually important because they
show that changes in sleep
duration are more than just symptoms of the illness, and also play a
pathogenic role.
Using a longitudinal analysis of mood and sleep in a sample of patients
with rapid-cycling bipolar
disorder, we recently demonstrated that decreased sleep duration
precedes, rather than simply
follows, a switch into hypomania.i.hypomania; or mania (Leibenluft and
coworkers, in press).
Furthermore, in this sample, decreased sleep duration was more
consistently associated with a shift
to an earlier wake-up time than it was with a shift to a later bedtime.
Pharmacologically, it is easier to
manipulate the time a patient goes to sleep than to change the time he
or she wakes up; perhaps for
this reason, clinicians have generally attended less to wake-up time
than to sleep-onset time.
However, these data indicate that interventions designed to shift
patients' wake-up time may deserve
further study.
The third observation implicating abnormal circadian rhythms in the
pathogenesis of mood disorders
concerns diurnal variation. In its classic, typical form, diurnal
variation is defined as a gradual
improvement in the patient's depressed mood as the day wears on. Like
sleep deprivation, typical
diurnal variation demonstrates that extended wakefulness is associated
with an antidepressant
response. We recently extended the concept of diurnal variation to
bipolar patients with data
demonstrating that rapid-cycling patients are more likely to switch "up"
(i.e., from depression or
euthymia into hypomania) during the day, and to switch "down" (from
hypomania or euthymia into
depression) overnight, while they sleep (Susana Feldman-Naim, M.D., and
coworkers, unpublished
data). Thus, once again, extended wakefulness is associated with an
antidepressant response, while
sleep appears to be depressogenic.
Specific theories have been advanced as to how circadian rhythm
dysfunction might lead to
rapid-cycling bipolar disorder. In 1968, Halberg suggested that some,
but not all, circadian rhythms
in such patients were not synchronized with the 24-hour day-night cycle
(Halberg). According to
Halberg's hypothesis, the interaction between the unsynchronized,
"free-running" rhythms and the
normally synchronized (entrained) rhythms causes switches back and forth
between mania and
depression.
Kripke and colleagues then presented data demonstrating what appeared to
be a free-running
temperature rhythm in five of seven rapid-cycling patients. In these
patients, the period (time taken to
complete one cycle) was abnormally short, in essence showing that
patients with rapid mood cycles
had rapid physiological cycles. However, subsequent investigators have
not generally found either
free-running or unusually fast circadian rhythms in patients with
rapid-cycling bipolar disorder.
In the 1970s and '80s Wehr and collaborators, working at the National
Institute of Mental Health,
continued to study biological rhythms in this patient population. Using
both cross-sectional and
longitudinal designs, they showed that the phase (timing) of patients'
sleep, temperature and motor
activity rhythms varied systematically as they cycled between hypomania
or mania and depression.
Specifically, the timing of these rhythms appeared to be earlier in
manic than in depressed patients,
and earlier in depressed patients than in controls (Wehr and colleagues
1980). We now have
preliminary data indicating a similar pattern in the time of onset of
nocturnal melatonin secretion.
These new data show that, in rapid-cycling bipolar patients, the time of
nocturnal melatonin onset
may be approximately 90 minutes earlier when they are hypomanic,
compared to when they are
depressed (Leibenluft and colleagues 1993). It is as if rapid-cycling
patients might have an
endogenous form of jet lag, internally traveling back and forth over one
or two time zones as they
cycle between hypomania and depression. Indeed, several studies show
that bipolar patients are at
risk to develop an affective episode when they travel across time zones
(Young).
What might cause these shifts in the phase (time) of onset of nocturnal
melatonin secretion? It is
possible that phase shifts.i.phase shifts; in nocturnal melatonin
secretion precede the patients' mood
switches and play a pathogenic role in mood cycling. However, it is also
possible that the phase
shifts are epiphenomena caused by the patient's symptoms. Specifically,
the phase shifts may be
secondary to the changes in the sleep-wake cycle.i.sleep-wake cycle;
that occur with mood cycling.
The phase of circadian rhythms is determined by zeitgebers
("time-givers").
While light is the most potent zeitgeber, physical activity, eating and
social routines can probably also
affect the timing of circadian rhythms. The timing of all these
zeitgebers is often different when a
patient is hypomanic, compared to when he or she is depressed, and
shifts in the timing of zeitgebers
would cause phase shifts in circadian rhythms.
However, a third possibility also exists. We suggest that phase shifts
in melatonin secretion and other
circadian rhythms are not the primary cause of mood cycling, but they
are also not irrelevant
epiphenomena. We hypothesize that phase shifts in melatonin secretion
are secondary to the patient's
symptoms or to more fundamental causes of bipolar illness, but they
nonetheless have pathogenic
significance and contribute to the development of a full-blown affective
episode.
This formulation is analogous to that of Wehr and coworkers (1987) in
describing the contribution of
sleep deprivation to the development of manic episodes. These authors
suggested that insomnia,
which is itself a symptom of mania, contributes to the development of a
manic episode because it
causes sleep deprivation. In other words, insomnia is both a symptom and
a cause of mania. If one
treats the insomnia early and aggressively, one can truncate an episode,
or prevent mild or moderate
symptoms from snowballing into a severe and destructive episode.
Similarly, it is possible that the
shifts in circadian rhythms, while not the initial cause of a mood
switch, contribute to the severity and
duration of an episode, and thus play a role in determining the course
of illness.
We are currently testing this hypothesis by determining whether
interventions designed to prevent
phase shifts in nocturnal melatonin secretion have therapeutic effects
in rapid-cycling bipolar patients.
One such experimental treatment involves the use of phototherapy. Data
indicate that midday bright
light may increase the amplitude of nocturnal melatonin secretion. Since
increasing the amplitude of a
rhythm makes it more resistant to phase shifts, midday light might be
expected to stabilize the time of
nocturnal melatonin secretion. In other words, midday phototherapy
administered to these patients
might prevent the shifts in timing of nocturnal melatonin secretion that
we believe have pathogenic
significance. After encouraging results with a small number of patients,
we are now conducting a
formal, controlled trial of this intervention. Interestingly, morning
bright light, which shifts patients'
circadian rhythms, may have caused several of our rapid-cycling bipolar
patients to cycle more
dramatically.
Thus, even if circadian abnormalities are neither the sole nor the
primary cause of bipolar illness, it is
possible that circadian interventions can have therapeutic utility.
Compared to psychotropic
medications, circadian interventions are relatively flexible therapeutic
modalities; they have a rapid
onset and offset of action, and their clinical effects may be altered by
changing the time that they are
administered. This flexibility may be particularly useful in
rapid-cycling bipolar patients, whose
frequent mood cycles may require rapid alterations in their therapeutic
regimen. Further research will
indicate what, if any, role circadian dysfunction plays in the
pathogenesis of rapid-cycling bipolar
disorder, and whether circadian interventions can be helpful to these
often treatment-resistant
patients.
Ellen Leibenluft, M.D., is chief, Unit on Rapid-Cycling Bipolar
Disorder, Clinical
Psychobiology Branch, National Institute of Mental Health.
References
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the 32nd Annual Meeting of
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9. Wehr TA, Muscettola G, Goodwin FK. Urinary
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