Andrew N. Wilner, MD, FAAN, FACP
From
Sleep Medicine
October 28, 2005 (Volume 7, Number 2)
A Preliminary Study of Sleep-Disordered Breathing in Major Depressive
Disorder
Deldin PJ, Phillips LK, Thomas RJ
Sleep Med. 2005;Oct 28; [Epub ahead of print]
The incidence of sleep-disordered breathing was evaluated with a home
monitoring device in patients with major depressive disorder compared with
controls.
The investigators studied 19 people (15 women, 4 men; mean age, 34; body
mass index, 26) with major depression and 15 controls (10 women, 5 men, mean
age 34, body mass index 24). At baseline, patients with depression had
statistically higher scores on the Beck Depression Inventory (BDI) (P
< .01) and the Spielberger Trait Anxiety Inventory (STAI-T) (P <
.01) than controls. Patients with major depression also had significantly
higher scores on the Pittsburgh Sleep Quality Index (PSQI) (P = 0.001)
and lower sleep efficiency (P = .010) than controls. However, scores on
the Epworth Sleepiness Scale (ESS) did not significantly differ between the 2
groups. A home polysomnography system (Stardust) recorded body position,
oximetry, heart rate, respiratory rate and effort, and nasal airflow. Airflow
was measured with a nasal cannula pressure transducer rather than a thermistor.
Respiratory parameters that differed significantly between people with major
depressive disorder and controls included major flow limitation events (P
= .02), the percentage of major flow limitation events accompanied by a
desaturation of at least 3% (P = .01), and average oxygen saturation (P
= .02). In addition, 5 of 19 (26%) of the depressed patients had greater than 5
major flow limitation events/hour. Antidepressant medication or sedative
hypnotics did not appear to be responsible for these differences.
Compared with controls, patients with major depressive disorder have
symptoms of sleep-disordered breathing, increased PSQI scores, lower sleep
efficiency, an increased number of major flow limitations, major flow
limitations with oxygen saturation, and decreased oxygen saturation.
Patients with obstructive sleep-disordered breathing may have symptoms of
depression that respond to treatment of their breathing disorder. Conversely,
patients with depression may have sleep-disordered breathing. This pilot home
study reveals significant differences in reported and measured sleep variables
between patients with major depression and controls. These findings suggest
that patients with major depressive disorder should be screened for symptoms of
obstructive sleep-disordered breathing and studied with polysomnography when
indicated. If significant breathing limitations are discovered, these should be
treated along with the depression. The hypothesis that treatment of minor
breathing disorder symptoms may improve depressive symptoms in patients with
major depressive disorder should be tested. Future studies should include a
larger number of patients and matched controls. Although the use of a nasal
cannula pressure transducer is innovative, standard polysomnographic techniques
would allow a more direct comparison of the magnitude of sleep-disordered
breathing in patients with major depressive disorder to other populations.
January 2006 (Volume 7, Number 1)
An Efficacy, Safety, and Dose-Response Study of Ramelteon in Patients With Chronic Primary Insomnia
Erman M, Seiden D, Zammit G, Sainati S, Zhang J
Sleep Med. 2006;7:17-24
The study authors report the results of a double-blind, randomized,
placebo-controlled study of ramelteon, a novel agent for chronic primary
insomnia.
One hundred seven patients (64% women, 36% men; mean age, 37.7) with chronic
insomnia for at least 3 months enrolled in this double-blind, randomized,
placebo-controlled, crossover study of 4 doses of ramelteon (4 mg, 8 mg, 16 mg,
and 32 mg). Each patient participated in each of the 5 study arms, which lasted
2 days, and were separated by a 5- to 12-day washout period. Polysomnography
was performed after each dose of medication (or placebo).
One hundred three patients completed the study. Latency to persistent sleep
(LPS) as measured by polysomnography was 37.7 minutes with placebo. Compared
with placebo, all doses of ramelteon resulted in statistically significant
reductions in LPS: LPS was 24 minutes with ramelteon 4 mg, 24.3 minutes with
ramelteon 8 mg, 24 minutes with ramelteon 16 mg, and 22.9 minutes with
ramelteon 32 mg (P < .001 for all doses). In addition, subjective
sleep latency was 57 minutes with placebo compared with 43.9 minutes with
ramelteon 16 mg (P = .040). Total sleep time as measured by
polysomnography was 400.2 minutes with placebo. Total sleep time was longer
with all ramelteon doses compared with placebo: 411 minutes with ramelteon 4 mg
(P ≤ .050), 412.9 minutes with ramelteon 8 mg (P ≤
.010), 411.2 minutes with ramelteon 16 mg (P ≤ .050), and 418.2
minutes with ramelteon 32 mg (P ≤ .001). Ramelteon did not improve
wake after sleep onset or subjective sleep quality. Next-day performance was
not adversely affected by ramelteon, as measured by word list memory and digit
symbol substitution tests. The most common adverse events were headache,
somnolence, and sore throat.
Ramelteon significantly reduces LPS and increases total sleep time as
measured by polysomnography without adverse next-day effects.
A variety of drugs are used for the treatment of insomnia, including GABAA
benzodiazepine receptor sedative hypnotics (eszopiclone, zaleplon, and
zolpidem), benzodiazepines, sedating antidepressants, antipsychotics, and
over-the-counter antihistamines. Ramelteon is a novel pharmacologic agent that
acts as a highly selective agonist on MT1/MT2 receptors in the suprachiasmatic
nucleus. MT1 receptors may
mediate the suppressive effect of melatonin and MT2 receptors affect phase shifting. Thus, it appears that
the primary target of ramelteon is the body's chronoregulation of sleep rather
than providing sedation as a fortuitous side effect of other actions. Results
from this study show that ramelteon significantly improved objectively measured
sleep latency and total sleep time without residual next-day effects, thereby
suggesting that ramelteon will be an important pharmacologic agent for many
patients with sleep-onset insomnia.
From
Epilepsia
January 2006 (Volume 47, Number 1)
Effect of Levetiracetam on Nocturnal Sleep and Daytime Vigilance in
Healthy Volunteers
Cicolin A, Magliola U, Giordano
A, Terreni A, Bucca C, Mutani R
Epilepsia. 2006;47:82-85
In this article, statistically significant increases in total sleep time,
sleep efficiency, and stages II and IV of nonrapid eye movement (NREM) sleep
were observed with levetiracetam compared with placebo in 14 healthy volunteers
after 3 weeks of treatment.
Fourteen healthy adult volunteers (7 men, 7 women; mean age, 28.9 years)
participated in a double-blind, placebo-controlled, crossover study of
levetiracetam (≤ 2000 mg/day) or placebo for 3 weeks separated by a
4-week washout period. The Epworth Sleepiness Scale was performed at baseline.
Polysomnography was performed 1 week after a steady-state dose of levetiracetam
(2000 mg/day) was reached. Subsequently, subjects completed the Epworth
Sleepiness Scale and Multiple Sleep Latency Test.
Statistically significant reductions were observed after treatment with
levetiracetam in total sleep time (P = .01), REM (P = .004), wake
after sleep onset (P = .004), and the number of stage shifts (P =
.001). Sleep efficiency (P = .004) and time spent in NREM stages II (P
= .001) and IV (P = .001) significantly increased. There were no
significant differences in Epworth Sleepiness Scale scores, the mean sleep time
per night based on sleep logs, REM latency, or Multiple Sleep Latency Test
scores. Mean levetiracetam serum concentrations were 14.9 ±
4.7 mcg/mL.
Levetiracetam has beneficial effects on sleep without resulting in excessive
daytime somnolence in healthy volunteers.
Sleep disruption and excessive daytime sleepiness commonly occur in people
with epilepsy. Nocturnal seizures may disrupt sleep and may not be remembered
by the patient. Antiepileptic drugs often have a sedating effect and may
contribute to daytime somnolence. Less commonly, antiepileptic drugs may have
alerting properties and result in insomnia, as may be seen with felbamate (Felbatol,
MedPointe,
From
Sleep and Biological Rhythms
June 2005 (Volume 3, Number 2)
Dreaming and Schizophrenia: A Common Neurobiological Background?
Gottesmann C
Sleep Biol Rhythms. 2005;3:64-74
This article probes the physiologic similarities between the rapid eye
movement (REM) dream state and schizophrenia.
In a wide-ranging discussion, the study author compares the physiology of
the REM dream state with the pathophysiology of schizophrenia.
The study author observes that 40-Hz electroencephalographic (EEG) activity,
which occurs during REM sleep, is uncoupled over the cortical areas. This
uncoupling may parallel a "problem of connectivity" that occurs with
schizophrenia. Decreased blood flow occurs in the dorsolateral prefrontal
cortex during REM sleep and in schizophrenia. Hallucinations that occur in
schizophrenia may be due to a decrease in sensory constraints, which also occur
during REM sleep. The study author speculates that the failure of inhibitory
cortical neurotransmitters could allow the individual to remember "useless
memories" created during REM dreams, perhaps leading to schizophrenia.
Dopamine levels are decreased during REM sleep compared with waking, which
could correlate with the negative symptoms of schizophrenia, which may also be
due to reduced levels of dopamine.
Dreams, with their disjointed, at times illogical, and time-distorted
imagery, harbor similarities with the psychotic mentation of schizophrenia. In
addition, a decrease in the neurotransmitter dopamine appears to play an
important role in REM sleep as well as in the negative symptoms of
schizophrenic psychosis. The study author postulates that REM sleep could
become an experimental model for schizophrenia.
Although dreams have fascinated humankind for millennia, the study of dreams
is fraught with technically challenging methodologic
problems. Dreams that occur during REM sleep represent a normal physiologic
phenomenon, but at least superficial similarities exist with the abnormal state
of schizophrenia. The study author articulates some commonalities underlying
the physiology of dreams and the pathology of schizophrenia. However, it is
premature to establish REM sleep as a neurobiological model for schizophrenia.
Continued research may lead to an increased understanding of the creation of
dreams and perhaps provide insights leading to novel treatments for schizophrenia.
From
Journal of Neurology, Neurosurgery & Psychiatry
January 2006 (Volume 77, Number 1)
Effects of Sleep Deprivation on Cortical Excitability in Patients
Affected by Juvenile Myoclonic Epilepsy: A Combined Transcranial Magnetic
Stimulation and EEG Study
Manganotti P, Bongiovanni LG, Fuggetta G, Zanette G, Fiaschi A
J Neurol Neurosurg Psychiatry. 2006;77:56-60
The study authors measured the effects of sleep deprivation with magnetic
stimulation and electroencephalography (EEG) in 10 patients with juvenile
myoclonic epilepsy (JME) and in 10 controls.
Ten patients with JME (8 women, 2 men; ages 16-33) were compared with 10
controls (5 women, 5 men; ages 18-30). Eight of the patients were treated with
phenobarbital and valproate, whereas the other two did not receive treatment.
Subjects were studied with EEG and magnetic stimulation presleep and postsleep deprivation. Patients were sleep-deprived in the
hospital from midnight until morning. Stimulation was over the presumed hand
area of the motor cortex and recorded from the contralateral thenar eminence.
Epileptic activity was quantified on the basis of 30 minutes of EEG recording
before and after sleep deprivation.
At baseline, JME patients had significantly decreased short-latency
intracortical inhibition (SICI) values compared with controls (P <
.001). This effect was larger in the 2 untreated patients than those on
antiepileptic drugs. Sleep deprivation further decreased SICI values in
patients with JME, but not in controls (P < .001). At baseline,
short-latency intracortical facilitation (SICF) did not differ between patients
and controls. However, sleep deprivation significantly increased SICF in
patients with JME, but not in controls (P < .005). Motor threshold
(MT) was significantly reduced by sleep deprivation in patients with JME, but
not in controls (P < .001).
Several variables measured by magnetic stimulation were significantly
affected by sleep deprivation in patients with JME: SICI decreased; SICF
increased; and MT decreased.
Every textbook on epilepsy mentions sleep deprivation as a
"trigger" for seizures, yet little is known
about the pathophysiology of this phenomenon. This study reveals that sleep
deprivation can significantly modify the results of several variables (SICI,
SICF, and MT) elicited by magnetic stimulation that represent primary motor
cortex excitability. Of interest, patients treated with antiepileptic drugs had
less prominent changes in SICI. If these results are routinely reproducible,
this paradigm could prove extremely valuable in pursuing our understanding of
the pathophysiology of epileptic activity and in providing a platform for the
evaluation of new antiepileptic drugs. (Drugs that have the greatest effects on
magnetic excitability parameters would merit further study.)
This study suffers from several basic technical limitations. The small
population includes adults and children who may well differ in cortical
excitability. The subjects were not sex-matched and were poorly age-matched. In
addition, 8 patients were treated with antiepileptic drugs, whereas 2 were not.
In such a small study, these variables should be eliminated. Future studies
should endeavor to provide age- and sex-matched controls, control for
treatment, and focus on adults or children. Further, although the text clearly
states that SICI decreased, the table and figure reveal an apparent increase
and are difficult to interpret. The EEG results were also not clearly reported
relative to sleep deprivation.
Supported by an independent educational grant from
Takeda.
Medscape 2006