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Sleep and biorythm disturbances in schizophrenia, mood and anxiety
disorders: a review
Disturbi del sonno e dei bioritmi nella schizofrenia, nei disturbi d’ansia
e dell’umore: una review
FRANCESCO SAVERIO BERSANI1,3, ANGELA IANNITELLI1,3, FRANCESCA PACITTI2,
GIUSEPPE BERSANI3
1Department
of Neurology and Psychiatry, Sapienza University of Rome
Department of Health Sciences, University of L’Aquila
3
Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome
2
SUMMARY. Sleep problems and circadian rhythms disturbances are common in many psychiatric disorders, with the mostoften-reported sleep problem in most cases being insomnia. In this paper, the main findings about sleep disturbances (features and therapy) and other biorhythm disturbances (biological timekeepers, CLOCK genes, GSK3, melatonin, hypothalamo-pituitary-adrenal axis, body temperature) are reviewed in relation to schizophrenia, mood and anxiety disorders.
KEY WORDS: sleep disturbances, insomnia, circadian rhythms, biorhythms, GSK3, melatonin, schizophrenia, depression,
bipolar disorder, post traumatic stress disorder, general anxiety disorder, panic disorder.
RIASSUNTO. Disturbi del sonno e disordini dei ritmi circadiani sono frequenti in diversi disturbi psichiatrici. L’obiettivo dell’articolo è presentare una revisione delle principali nozioni relative ai disturbi del sonno (le loro caratteristiche e la loro terapia) e dei ritmi circadiani (timekeepers biologici, geni CLOCK, GSK3, melatonina, asse ipotalamo-ipofisi-surrene, temperatura corporea) in relazione alla schizofrenia, ai disturbi d’ansia e dell’umore.
PAROLE CHIAVE: disturbi del sonno, insonnia, ritmi circadiani, bioritmi, GSK3, melatonina, schizofrenia, depressione, disturbo bipolare, disturbo da stress post-traumatico, disturbo d’ansia generalizzato, disturbo di panico.
INTRODUCTION
Since the end of the 1970s, more than 50 epidemiological studies have assessed the prevalence of insomnia
symptomatology in the general population (1). Sleep
problems are common in many psychiatric disorders,
with he most-often-reported sleep problem in most cases being insomnia. In mania and possibly depression, insomnia can significantly worsen the disorders, and early
intervention to improve sleep may help abort a relapse.
Also, insomnia is often a prodromal warning sign of imminent relapse. In addition to increased insomnia, there
can also be an increased incidence of parasomnias, circadian rhythm disorders, and hypersomnia (2).
Sleep disturbances are related to disturbances of circadian rhythms; in mammals, including humans, the circadian pacemaker, or biological clock, is the site of gen-
eration and entrainment of circadian rhythms (3,4). It is
located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus, on top of the optic chiasma. In the
absence of temporal signals (eg, in caves or bunkers),
circadian rhythms persist and express their own period
that differs significantly from 24 hours. In these conditions, circadian rhythms are said to “free run.” In humans, the endogenous period of the circadian clock is
estimated to have a mean value of 24.2 hours, which indicates that each day our biological clock is delayed by
12 minutes compared with the environmental light/dark
cycle. In order to remain perfectly entrained to the 24hour cyclicity of the environment, the circadian clock
uses several internal and external synchronizers that are
able to modify the period and the phase of circadian
rhythms. The light/dark cycle is the dominant synchronizing agent for circadian rhythmicity (light is therefore
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Bersani FS et al.
called a zeitgeber - timekeeper), although social cues
and physical activity may be important too (5,6).
The SCN receive direct light information through
the retinohypothalamic tract, a visual tract not linked
to visual processes, and indirect light information
through the thalamus, using the retinogeniculohypothalamic tract (3) The circadian oscillator adjusts its
functioning by integrating various parameters of the
light signal: time of presentation, duration, irradiance,
and wavelength (7). The circadian pacemaker is sensitive to light throughout the 24-hour cycle in a dose-dependent manner (8). As in other species, light presented in the evening (ie, before the circadian temperature
minimum) stimulates the human circadian pacemaker
to phase-delay its rhythms (ie, schedules it later in
time), whereas a light stimulus given in the morning
(after this minimum) produces a phase advance. The
phase response curve describes the phase shifts as a
function of the circadian phase of light application.
Apart from phase-shifting effects, ocular light exposure at night also directly suppresses the production of
melatonin by the pineal gland (9).
The circadian pacemaker is also sensitive to the
phase shifting effects of various chemical or pharmacological components, including melatonin (Nacetyl-5methoxytryptamine), which acts on the circadian clock
through specific MT1 and MT2 melatonin receptors
located in the SCN (10). In normal subjects, the secretion of melatonin, the pineal hormone that regulates
the rhythm of many functions, exhibits a circadian pattern. Melatonin is involved in the synchronization of
the circadian clock by the day-night cycle by signaling
day-night information to the endogenous circadian
pacemaker. Furthermore, melatonin, through its hypothermic properties, is known to affect the circadian
rhythm of body temperature directly. A striking property of the endogenous melatonin signal is its synthesis
pattern, characterized by long-term elevated melatonin levels throughout the night (8).
All animals have circadian pacemakers/clocks, and
their period and timing appear to be also dependant on
particular genes (so-called clock genes), most of which
are common to fruit files, mice, and primates, and probably many other species (11). Mutations (polymorphisms) of these genes that lead to an altered circadian
rhythm are particularly easy to identify in fruit flies, and
similar variants of these genes have been found in people with certain disorders of circadian rhythm (11).
The products of some of these clock genes regulate
their own expression, and the outcome of this feedback loop is an oscillation in the levels of messenger ribonucleic acids (mRNAs) and proteins. In mammals,
Clock and Bmal1 encode transcription factors
CLOCK and BMAL1 (11-14), which form heterodimers that activate the transcription of three Period genes (PER1, 2 and 3) and two Cryptochrome
genes (CRY1 and 2) (11,15-17), Rorα and Rev-Erbα
(11,18-20) (Figure 1). PER and CRY proteins form
complexes (21) that are translocated back into the nucleus and inhibit their own expression (11,22-25). RORα and REV-ERBα act on Bmal1 to activate and repress transcription respectively (11,18,19). NPAS2 is
an alternate dimerization partner for BMAL1 that
may also regulate circadian rhythmicity in the forebrain, but it has not been consistently found in the
SCN (11,26,27). Clock proteins are phosphorylated by
casein kinase I epsilon (CKI ) and delta (CKI ), and
possibly also by the Drosophila shaggy homologue
glycogen synthase kinase 3 (GSK3) (28). They are targeted for degradation by components of ubiquitin ligase complexes like FBXL3 and β-TRCP1 (11,29,30),
which together regulate the period of circadian oscillation by controlling the rate of accumulation, association and translocation of PER and CRY (11,31-33).
These genes, protein products, and enzymes work
together to control clock functioning, and abnormalities such as clock gene mutations can have profound
consequences for the synchronization of emotional,
Figure 1. Simplified schematic diagram of the molecular mechanisms
of the circadian clock in mammals. See the main text for details. Positive and negative feedbacks are indicated by arrows with a + and a
- sign, respectively. C = CLOCK protein; N = NPAS2 protein; B =
BMAL1 protein. Source: Lamont et al. (11).
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Sleep and biorythm disturbances in schizophrenia, mood and anxiety disorders: a review
physiological, and behavioural processes; it seems that
both how long we sleep and our preferred sleep timing
(whether or not we are evening people “owls” o morning people “larks”) is partly dependant on genetic
makeup. with each other and the environment (2).
DEPRESSION
Sleep disturbances
Sleep disorders have long been considered as a cardinal symptom of endogenous depression (34); subjects with insomnia exhibit symptoms of depression in
40% to 60% of the cases and have a clinical depression
in 10% to 25% of cases (1). Depressive symptoms may
reflect sleep disturbances, including phase shift of
sleep-wake cycles (35), reduced amplitude, or disturbance of sleep-wake dependent processes (35,36).
Sleep in depressed patients resembles sleep in normal subjects whose circadian rhythms of REM sleep
are phase-advanced with respect to their sleep schedules. Polysomnographic recordings of depressed subjects have evidenced that the internal sleep organization is impaired, with, specifically, a reduced latency of
the first REM sleep episode of the night with increased
density of rapid eye movements, an increase in total
percentage of REM sleep, a reduction in deep Slow
Wave Sleep (SWS), and an increase in night awakenings. These observations, together with the fact that
most antidepressant drugs inhibit REM sleep, have led
to the theory that short REM sleep latency is enhanced in depressed patients and are part of the pathological processes associated with depression (37).
Alterations in REM and SWS appear linked to
sleep related dysfunctional arousal in primary limbic
and paralimbic structures (amygdale), and hypofunction in frontal cortical areas (38). Preliminary studies
in insomnia in depression indicate subcortical hyperarousal and failure of sleep to provide normal restoration of function in the prefrontal cortex, leading to
chronic sleep deprivation.
Depressed patients also complain of insomnia, notably of difficulty in falling asleep, frequent nocturnal
awakenings, early waking up, and nonrefreshing sleep.
However, one should dissociate insomnia from decreased REM sleep latency. Indeed, while short REM
sleep latency is a pathogenic process, insomnia induces
an improvement in mood. In insomniac patients who
are at risk for depression, sleep loss might represent an
efficient adaptive mechanism to counteract the underlying depressive mood, and therefore, prolonged sleeping
appears as an important risk factor for depression (39).
Treatment of sleep disturbances
From a clinical point of view, the subjective perception of sleep is more important than polysomnographic findings. In general, in most of the studies of sleep
complaints during antidepressant treatment, the comparator is sleep at baseline, and there is improvement
over weeks as the depression lifts. This is seen with
both drug and cognitive therapies. Differences between drugs have been reported early in treatments
but these differences are generally much smaller or absent after 2-6 weeks (40).
However, the ability of different drugs to improve
sleep early in treatment, is often important to patients,
particularly if insomnia is causing significant distress.
Also, early improvement of sleep symptoms may encourage the patients to carry on with medications to the
point where the mood lifting effects are apparent (2-3
weeks). 5HT2 blockers such as mirtazapine and agomelatine (5-HT2 antagonist and melatonin receptor agonist) can improve subjective sleep quickly in depression;
tricyclic antidepressant (TCAs) such as trimipramine
and doxepine also do this, because they are potent histamine H1 antagonists, but have more unwanted effects
such as carry-over sedation and dry mouth (2).
Objectively, SSRIs, alerting TCA and mixed uptake
blockers antidepressants decrease REM sleep and
REM latency but can increase waking in sleep early in
treatment for which a hypnothic is sometimes required
(nonbenzodiazepine anxiolytics may offer advantages
over traditional sedative hypnotics; long-term use of
long-acting benzodiazepines should be avoided
(41,42)). Mirtazapine, mianserin, trazodone and trimipramine have smaller effects on REM but decrease
waking in sleep in the first week of treatment (2).
Treatment with melatonin in depression give still unclerar results; melatonin, however, may be helpful when
insomnia is related to shift work and jetlag (43-46).
There has been some recent evidence suggesting that
electroconvulsive therapy, transcranial magnetic stimulation and antidepressant medications targeting the
dopaminergic and serotonergic neurotransmitter systems, including, monoamine oxidase inhibitors
(MAOIs), fluoxetine, imipramine, clozapine, risperidone, and haloperidol may have a common mode of action either via the direct inhibition or increased phosphorylation of the GSK3 enzyme (11,47-49). GSK3 is
involved in many cellular functions; therefore the therapeutic action may be via a number of possible routes,
including regulation of monaminergic signaling, neuroprotection, neuroplasticity, modulation of estrogen and
glucocorticoid activity, regulation of brain metabolism,
or regulation of the circadian system (11,50).
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Exposure to bright light at appropriate times, traditionally used to alleviate the depression associated with
seasonal affective disorder, can help realign the circadian
rhythm in patients whose sleep-wake cycle has shifted to
undesirable times (morning bright light therapy is more
effective than evening therapy; the duration of administration varies from half an hour to 2 hours) (41,42,51).
The rapid, usually short-lasting improvement following total sleep deprivation and rapid return of depressive symptoms after subsequent recovery sleep, is well
documented, and indicates that the depressive process
is strongly sleep-dependent (39). Prolonged manipulations of the sleep-wake cycle, such as phase advancing,
could maintain the effects of total sleep deprivation,
both in the presence or absence of combined antidepressant drug treatment. In insomniac patients at risk
for depression, sleep loss might represent an efficient
adaptive mechanism to counteract the underlying depressive mood and, therefore, prolonged sleeping appears as an important risk factor for depression, as discussed above. However, the antidepressant effect of
sleep deprivation is very short-lived and cannot be considered as long-term antidepressant therapy (52).
Other biorhythm disturbances
The list of physiological variables showing circadian abnormalities in depressed patients is quite extensive (53).
– Body temperature: several investigators have indeed
demonstrated that there is reduced amplitude of circadian rhythms in depressed patients. In major depression, a flattened core body temperature rhythm
has been interpreted as a reduction in circadian amplitude, with the expected drop in nighttime core
body temperature being diminished (54,55). Patients
with Seasonal Affective Disorder (SAD) also exhibit a significant delay in core temperature rhythm.
Lewy et al. (56) have hown that morning phototherapy was effective in treating patients with SAD by
phase advancing endogenous circadian rhythms of
core body temperature (39).
– Hormones: dysregulation of the hypothalamo-pituitary-adrenal axis is common among depressed individuals. A meta-analysis of cortisol data in depression revealed evidence of overall increased glucocorticoid secretion with the largest effect at the
nadir of the circadian rhythm (57). Furthermore,
there is an earlier onset of the first cortisol secretory episode in depression, ie, a phase advance of the
rhythm of secretion of the hormone. An early morning rise in adrenocorticotropic secretion and a nocturnal elevation of prolactin and growth hormone
release have been also found to occur earlier in de-
pressed patients than in control subjects (58). In the
course of a 4-year study in 8 patients with mania, the
same team reported early timing of the nadir of the
circadian curve of plasma cortisol and normal levels
of growth hormone and prolactin (58). These authors hypothesized that these effects were secondary to an alteration of the sleep-wake cycle. The
physiological nighttime drop in thyrotropin (TSH) is
not observed in depressed patients. Nocturnal secretion of THS is reduced in bipolar patients, and returns to normal after recovery (39).
– Melatonin: both decreases (59) and increases (60) in
melatonin levels have been reported in depressed patients. The most consistent finding has been a lower
blood concentration of melatonin in depressive patients compared with controls, including bipolar disorder (BD) and premenstrual dysphoric disorder.
Brown et al. (61) reported that patients with melancholia had lower serum melatonin concentrations
than healthy volunteers, as well as inverse correlations
of melatonin concentration with mood depression and
disturbance factors on the Hamilton scale (62). Lower
nocturnal concentrations of the main metabolite of
melatonin, 6-sulfatoxymelatonin, in melancholic patients were reported by Boyce et al. (63), although Rubin et al. (46) failed to confirm lower pineal function.
The latter authors also reported a phase advance of
melatonin rhythms (46), though a trend toward a later
nocturnal melatonin peak has been also reported in
patients with unipolar depression (64). A familial vulnerability has been hypothesized in the endogenous
melatonin signal in subjects prone to depression, and
an abnormality in the duration of the melatonin signal
in those with current major depression (65). Nevertheless, melatonin has never shown antidepressant efficacy in clinical trials and shows contradictory results in
terms of efficacy on other parameters (eg, sleep), as is
discussed later in this article.
– Clock genes: to date there has been no evidence of
clock gene mutations associated with major depressive disorder. The T3111C polymorphism of CLOCK
was investigated, based on its association with
eveningness, but no differences were found in allelic
frequencies between a group of 143 people with a
history of major depression and 195 controls (11,66).
BIPOLAR DISORDER
Sleep disturbances
Sleep in BD is state-dependant, with a manic phase
usually being preceded by a shortened duration of
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sleep (this can be a useful early warning). Some patients also have longer duration of sleep and an increased amount daytime sleepiness during a depressed
phase. Objective sleep changes are similar to those in
unipolar depression (2).
The relationship between the sleep-wake cycle and
changes in mood appears to be important in patients
with frequent and rapid changes in mood state, socalled “rapid cyclers,” with the switch from mania/hypomania to depression/euthymia occurring during or
after sleep, while positive changes in mood from depression to hypomania/mania are more likely to occur
after a period of wakefulness (67,68).
The main psychopharmacological approaches to
treat sleep disorders in bipolar patients should follow
some simple guidelines: avoid the use of antidepressant
medications, even those with good efficacy on sleep
problems; avoid long-term use of benzodiazepines, in
particular on patients with a history of substance abuse;
prescribe one or more mood stabilizers (69).
Although it has been known for many years that
lithium is effective as a mood stabilizer, its pharmacological mode of action has remained uncertain. However, recent evidence suggests that the therapeutic action of lithium may be related to direct effects on the
circadian clock. For example, lithium has been shown
to lengthen the period of circadian rhythms in rodents
(70), and can lengthen the period of neuronal firing of
cultured SCN neurons in a dose-dependent manner
(71). A delay of the circadian rhythm of temperature
and of REM sleep has also been shown in a BD patient
(72). This suggests that the therapeutic action of lithium could be due, in part, to correcting a phase advance
of the circadian system related to the illness.
One proposed molecular mechanism is via the inhibition of GSK3 (11,73). Although this enzyme has a number of functions that could potentially mediate the therapeutic effects of lithium (11,74), one likely possibility is
via its function as a central regulator of the circadian
clock. Numerous lines of evidence support this idea;
both lithium and GSK3 knockdown produce a lengthening of mPer2 period in mouse fibroblasts (11,75), and
GSK3 phosphorylates PER2 and REV-ERB and regulates their localization and stability, respectively (73).
Even more interesting are findings that inhibition of
GSK3 may be common to other mood-stabilizing
agents such as valproate, and may even be a target of
antidepressant therapies, including drugs which target
the serotonergic and dopaminergic systems as well as
electroconvusive therapy (11,50,76). There is also evi-
dence for effects of allelic frequency of the GSK -50 T/C
SNP. Bipolar patients with the T/T allele of GSK3 show
an earlier age on onset of BD and enjoy less improvement from lithium therapy than patients with the T/C or
C/C alleles (11,77,78). Together these results are persuasive, making GSK3 a promising target for the future development of pharmotherapeutic agents (11).
Circadian disturbances have been reported in BD
that suggest a phase advance of the master clock
(SCN), including a phase advance of the diurnal
rhythm of plasma cortisol (79), although negative results have been reported (80).
Beck-Friis et al. (43) reported that manicdepressive
patients had lower nocturnal melatonin concentrations
than healthy individuals. Lam et al31also reported a decreased baseline melatonin level in acutely ill bipolar patients. Nurnberger et al. (81) confirmed the presence of
melatonin secretion abnormalities in patients with BD I.
In contrast, Rubin et al. (46) found no association between melatonin concentration and bipolar depression.
The evidence for genetic abnormalities associated
with clock genes is strongest in BD. Much of the work
attempting to link BD to clock genes has focused on
the 3111T/C polymorphism of the human CLOCK
gene (11,82-85). The C/C allele of CLOCK has been
associated with greater severity of insomnia during antidepressant treatment, a higher recurrence rate of
bipolar episodes and reduced need for sleep. Support
for a role of Clock mutation in BD has recently come
from the animal literature, where behavioural studies
using CLOCK mutant mice suggest a phenotype similar to mania, with an increase in the reward value of
appetitive stimuli and reduced depressive and anxietylike behaviors (11,86).
An analysis of 46 single nucleotide polymorphisms
(SNP) in eight clock genes (BMAL1, CLOCK, PER
1,2,3,CRY 1,2,TIMELESS) using family-based samples
with BD or schizophrenia has been reported (11,87). A
Mendelian transmission distortion analysis revealed association of BMAL1 and TIMELESS with BD. However, these were modest associations found using a very
liberal analysis. Interestingly, an independent study using haplotype analysis seems to confirm the association
with BMAL1 and also finds one with PER3 (TIMELESS was not studied) (11,88). Studies examining other genes have found negative results: screening for human PER2 mutations at the CKI / binding site showed
no difference in frequency between BD patients and
controls (11,89), nor is there any evidence for linkage
or association of CRY1 (11,90).
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GENERALIZED ANXIETY
POST-TRAUMATIC STRESS DISORDER (PTSD)
Sleep disturbances
Sleep disturbances
Sleep onset insomnia is experienced by about 2030% of patients with generalized anxiety disorders
(GAD), and sometimes sleep is the main focus of anxiety. They may also have increased night-time awakening and report poor sleep quality. There are a few objective abnormalities apart from reduced sleep continuity. Some believe that primary insomnia is variant of
GAD where the main focus of the worry is on sleep
and the negative consequences of having too little of it.
This may explain why the selective serotonin reuptake
inhibitors (SSRIs) that often disrupt sleep early in the
treatment of depression can improve sleep in GAD
and in some case of insomnia (2).
There is a high incidence of almost all sleep disturbances in PTSD. Of the patients, 70-90% have difficulty falling or staying asleep (2), and nightmares are reported by 20-70% (94). Parasomnias such as sleepwalking and night terrors are more common than that
in the general population, and more recently a high incidence of sleep-disordered breathing and sleep movement disorders have also been reported (2).
In a study of car accident survivors, sleep complaints
at 1 month after the trauma were higher in the group
who had PTSD a year later, so there may be some predictive value in assessing sleep (95).
Objective measures of sleep disturbances are inconsistent, but most studies show decreased sleep efficiency. There is controversy about REM sleep, with some
reports of REM decreases and some of increases.
There does, however, seem to be a consistent trend for
more awakening during REM episodes, and this plus
the reduced sleep efficiency appears to indicate hyperarousal at night (2).
In large clinical trials, it has been shown that sleep
improves along with other symptoms after effective
antianxiety treatment involving both antidepressants
and benzodiazepines. Cognitive behavioural therapy
(CBT) focussing on sleep appears to be efficacious in
this group, similar to its actions in patients with primary insomnia (2).
Monk et al. (91) recently assessed that behavioural circadian regularity at the age of 1 month predicts anxiety levels during school-age years (more
regular=less anxious). Apart from this, there is relatively little evidence suggesting specific circadian
disturbances or a role for clock genes in anxiety disorders (11). This is perhaps not surprising, given the
heterogeneity of anxiety disorders and their comorbidity with other disorders such as depression (92).
In contrast to studies in humans, there are a few interesting results from research on animals. One
study showed a reduction of Per1 mRNA levels in
mouse cerebellum by antianxiety medications
(11,93), suggesting that altering circadian clock gene
levels could theoretically contribute to the therapeutic action of these drugs. Also of interest is the
reduction of anxiety observed in mice with a mutation of the Clock gene. For example, Clock mutant
animals are much more likely to spend time in open
spaces, which normal mice avoid (11,86). However,
as these mice also showed behaviours associated
with mania, it is unclear how to best classify this
phenotype (11).
Drug therapy used for PTSD symptoms such as SSRIs, trazodone and mirtazapine may improve sleep
and nightmares. More recently, there have been encouraging reports of sleep improvements after prazosin, a centrally acting α1-adrenoceptor antagonist,
and also with buspirone, gabapentin and tiagabine,
which need to be confirmed. Evidence suggests that
benzodiazepines, TCAs and monoamine oxidase inhibitors (MAOIs) are not useful for the treatment of
PTSD-related sleep disorders. CBT targeting insomnia
and imagery rehearsal therapy for nightmares have also demonstrated good outcomes (2).
PANIC DISORDER (PD)
There are no specific associations between PD and
sleep disorders except in those patients who experience night-time panic attacks. Up to 50% of PD patients have at least one of these nocturnal panic attacks, and 30% experience them regularly. In this
group, fear of falling asleep becomes a problem, and
they describe onset insomnia (2).
Nocturnal panic attacks are not different in characteristics form daytime ones. When they have occurred
during polysomnography, they usually follow a sudden
awakening at the transition between stages 2 and 3
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sleep, that is just as the patient is descending into deep
sleep. They are usually vividly recalled. Anecdotally,
we have seen several patients who have described panic attacks right at the onset of sleep, and in these patients there has been a very high degree of physical
awareness of heart rate and/or respiration. In healthy
people, there is a slowing of heart rate and a short period of very shallow respiration at sleep onset as the
autonomic system resets to its “sleep” settings. It may
be that these patients are abnormally aware of these
changes, or that their innate alarm system to carbon
dioxide alterations is abnormal, so that the small increase in CO2 levels that occurs in the transition activates the brain stem sensors in vulnerable patients, and
these provoke a panic attack (2).
Apart from the nights with panic attacks, patients
with PD do not show any differences in sleep architecture from healthy controls.
Findings about the relation of circadian rhythms
and PD are still fragmentary. 24 h hypothalamic-pituitary-adrenal functionality is disturbed in PD patients.
Several studies found that patients with PD had elevated overnight cortisol secretion and greater amplitude of ultradian secretory episodes (96, 97, 98). Alprazolam produces substantial improvement in clinical
status accompanied by nearly full resolution of pretreatment hypercortisolemia (99). Also melatonin has
been found to be elevated in patients with PD (100).
Seasons seem to play a role in panic exacerbation,
given the observation that panic attacks are more frequent during the summer (101-103).
Limpido et al. (104) found alterations of diurnal 24h cycle rhythm of sleep and wake cycles sleep, appetite,
and other bodily functions in patients with PD and
anxiety disorders in comparison to healthy controls.
SCHIZOPHRENIA
Sleep disturbances
Patients with schizophrenia can suffer from insomnia, which is mostly described at times of acute symptoms. These include poor sleep initiation and consolidation, impaired sleep homeostasis expressed as low
levels of SWS, with many subjects showing a total absence of stage 4 sleep, and shortened REM sleep latency with frequent sleep onset REM periods. Patients
with schizophrenia can also have prolonged sleep or
excessive napping in the day even though this is often
thought to be due to the adverse effects of sedating an-
tipsychotic medication (2). Recently, it has also been
found a reduced sleep spindles in electroencephalograms (105). Taken together, these observations suggest a deficient homeostatic regulation of sleep, although sleep deprivation can lead to SWS rebound on
recovery nights (106).
The disorder which has been most consistently described in schizophrenia is circadian rhythm disorder;
actigraphic recordings of schizophrenic patients have
revealed disturbed rest-activity cycles, showing either
phase delays, longer periods of activity, or circadian
rest-activity patterns. The study of schizophrenic patients by a forced desynchrony experiment revealed an
abnormal circadian propensity for sleep suggesting a
disturbed circadian regulation of sleep. The cause of
this is unknown, but it presumably reflects some biological perturbations in the brain such that the sleep
wake routine appears to lose its normal sensitivity in
zeitgebers (contributing to lead to important cognitive
impairment) (107,108), and in some cases, a free-running cycle can emerge, that normalizes once the acute
relapse is over. Environmental factors may also play a
part, because the lifestyle of many patients can lead
them, for example, to spend most of the time in dim
light indoors or in hospital, to not have regular periods
of activity, etc; however, it is possible that at times of
acute illness these patients are indeed less sensitive to
external cues and this is an area of active research endeavour at present (2).
Psychopharmacological treatment should be implemented through the administration of those medications with both antipsychotic and hypnotic action (especially 5HT2 blockers such as clozapine, olanzapine
and quetiapine), with special attention to side effects
(69,109-111). Recent studies found that atypical antipsychotics, including olanzapine, clozapine, quetiapine, and ziprasidone the interaction between atypical
antypsichotics can regulate GSK3 and inhibit its activity of central regulator of the circadian clock (112) (see
sections 2.2 and 3.2).
Treatment using normal environmental entraining
processes, for example, light and exercise can be difficult in these patients, because the impetus to change
lifestyle and engage in such programs is often low (2).
Circadian disturbances have been reported in schizophrenia patients, but the results are inconsistent (113).
One study has measured core body temperature variation and reported desynchronization of temperature,
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Bersani FS et al.
pulse and blood pressure rhythms, although this study
was conducted under ambulatory conditions and the
data influenced by masking effects (114). In some experiments, the analysis of melatonin secretion demonstrated blunted circadian variation, although uncontrolled light exposure prior to data collection may have
confounded these results (115-117); this may be explained by the precox pineal calcification that occurs in
patients with schizophrenia (118-121). Others have reported phase advances of body temperature (122), prolactin and melatonin (123). These advanced rhythms
are surprising considering that actigraphic recordings
have revealed disturbed rest-activity cycles that are often inconsistent with a phase advance, including phase
delays, longer periods of activity or, occasionally, 48
hour rest-activity patterns (124-126). Levels and ultradian rhythms of nerve growth factor are also affected
(127-130) and antipsychotics such as clozapine or
haloperidol may regulate them (131-133). Patients with
schizophrenia disorders also show a greater tendency
towards eveningness (later wake and bed times and being most alert later in the day) than controls (113,134).
Evidence linking circadian clock gene polymorphisms
or deregulation with schizophrenia is limited. In one
study, SNP analysis of the CLOCK gene demonstrated
that the T3111C polymorphism showed a transmission
bias in a sample of 145 Japanese schizophrenic subjects
relative to healthy controls (11,135). The authors suggested that this polymorphism, associated with aberrant
dopaminergic transmission to the SCN may underlie the
pathophysiology of schizophrenia. Since dopaminergic
signalling through D2 receptors appears to be associated
with increased CLOCK:BMAL1 (11,136) activity, this
provides an interesting link between the dopaminergic
hypothesis of schizophrenia (11,137) and circadian abnormalities in these patients. Post-mortem studies have
shown decreased expression of the PER1 mRNA in the
temporal lobe of schizophrenic subjects compared with
age-matched normal controls (11,138). Associations of
PER3 and TIMELESS have also been found with schizophrenia/schizoaffective disorder, as well as with BD. The
association with PER3 is interesting, given the evidence
of a relationship between PER3 with delayed sleep phase
disorder and evening chronotype. However, the function
of TIMELESS in mammals is not yet clear (11,139), making it difficult to interpret this finding. Finally, the CRY1
gene was hypothesized to be a candidate gene for schizophrenia based on its location near a linkage hotspot for
schizophrenia on chromosome 12q24 (11,140). The fact
that CRY1 is expressed in dopaminergic cells in the retina and that its expression influences the effects of psychoactive drugs lends further supports to this hypothesis.
Acknowledgments
This study has been supported by project grant CNR (RSTL
DG.RSTL.059.008). Dr. Iannitelli is a recipient of a fellowship by the
Italian Ministry of Health (Ricerca Finalizzata ex art. 12.2006).
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