Исследование антагониста орексинных рецепторов в терапии инсомнии

Study Objectives:

To assess the acute effects of SB-649868 in male subjects with Primary Insomnia with regard to (1) objective and subjective sleep parameters, (2) safety and tolerability, (3) next-day residual effects.

Design:

Multicenter, randomized, double-blind, placebo-controlled crossover study using a complete set of Williams orthogonal Latin Squares

Setting:

9 sleep centers in Germany

Patients:

52 male subjects with a diagnosis of primary insomnia (difficulty in sleep initiation and maintenance) confirmed by polysomnography

Interventions:

SB-649868 (10, 30, 60 mg) and placebo administered after dinner 90 minutes before bedtime

Measurements and Results:

Sleep effects assessed by polysomnography during 2 consecutive nights and by sleep questionnaires completed by subjects after each night at the sleep laboratory. Safety and tolerability were assessed by adverse events collection, electrocardiogram (ECG), vital signs, laboratory tests. Next-day residual effects were assessed by Digit Symbol Substitution Test, and modified Verbal Learning Memory Test administered at “lights on” after night 2. SB-649868 significantly reduced latency to persistent sleep, wake after sleep onset (WASO), and increased total sleep time (TST) compared to placebo. A dose-dependent effect was observed. A dose-dependent increase in absolute and percent REM sleep and reduction in REM sleep latency was observed mainly at the 60-mg dose. SB-649868 was well tolerated with inconsistent next day residual effects. SB-649868 sleep effects were correlated with SB-649868 circulating levels.

Conclusion:

The data demonstrate the sleep-promoting properties of the orexin antagonist SB-649868 in male patients with insomnia.

The Orexin Antagonist SB-649868 Promotes and Maintains Sleep in Men with Primary Insomnia 

Нарушения дыхания во сне и психиатрические расстройства

The mechanism(s) underlying the connection between SDB and psychiatric symptoms is a matter of debate. From a psychiatric perspective, one can conceptualize the relationship as stemming from a direct physiological consequence of the general medical condition (in this case, sleep deprivation and nocturnal hypoxia/hypercapnia). Therefore, the increased prevalence of depression with SDB would not be surprising given that such a relationship is seen in other diseases that produce hypoxia and impair quality of life (eg, chronic obstructive pulmonary disease). On the other hand, excessive sleepiness and fatigue as a result of sleep apnea produce significant social and personal problems and result in depression. Ishman and colleagues showed that the daytime sleepiness is a strong predictor of depressive symptoms in patients with SDB.

Sleep apnea and depression can be bridged conceptually by vital exhaustion. Vital exhaustion refers to a state characterized by elevated somatic and cognitive symptoms of depression without affective symptoms. Our group as well as others demonstrated that vital exhaustion profiles were affected in patients with SDB. Therefore, depressive manifestations in patients with sleep apnea may reflect the patients’ vital exhaustion, which differs dramatically from melancholic affective mood changes observed in more typical forms of depression and dysthymia. As such, depressive phenomena in patients who have sleep apnea should be more akin to depression secondary to chronic medical illness.

The Correlation Between Sleep-Disordered Breathing and Psychiatry 

Празозин как препарат выбора при ночных кошмарах в структуре ПТСР

Prazosin is an α1-adrenergic receptor antagonist with good CNS penetrability. The rationale for reducing adrenergic activity to address intrusive PTSD symptoms has been well documented. In open-label trials, a chart review, and placebo-controlled trials,prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo. In these studies, prazosin doses ranged from 1 to 20 mg/d, with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only agent recommended in the AASM’s Best Practice Guide for treating PTSD-related nightmares.

 PTSD nightmares: Prazosin and atypical antipsychotics

Влияние различных антидепрессантов на фазы сна

A clinical consequence of REM suppression can be a change in frequency and intensity of dreaming, as well as a pronounced exacerbation of intense, disturbing dreams related to “REM rebound” on discontinuation. Pulmonary specialists sometimes advocate use of an activating TCA such as protriptyline because it may help suppress REM sleep—when sleep apnea episodes may be accentuated—and also provide benefit for the daytime somnolence that many patients with sleep apnea experience.

The Effects of Antidepressants on Sleep

Нарушение циркадных ритмов у больных шизофренией

In order to take a systematic look at the circadian rhythms of people with schizophrenia, Foster and his colleagues recruited 20 people with the disease and instructed them to wear movement-detecting wristwatches for six weeks. The amount of motion detected can be analyzed to determine whether the person is asleep or awake, given the vastly different movement patterns between the two states.
The patients also filled out questionnaires and kept daily diaries of their sleep and activities. All of the patients were taking medication to control their symptoms, and they had all been stable on that medication for at least three months. Finally, the patients gave 48 hours work of urine samples to be tested for melatonin, a hormone that regulates sleep (melatonin makes a person sleepy).
For comparison, the researchers asked another 21 mentally healthy but unemployed adults to wear the same watches and keep the same records as the people with schizophrenia. Unemployed people were chosen because the patients with schizophrenia were all unemployed, and employment can alter sleep patterns by forcing people to get up with an alarm clock.

A comparison between the two groups revealed that while unemployed people keep fairly regular sleep hours, every person with schizophrenia in the sample had a sleep problem.
"What became very clear is that they are massively and completely disrupted," Foster said.
This disruption did not follow a common pattern. Some people with schizophrenia went to bed late and got up late, with their melatonin release patterns delayed by several hours compared with healthy counterparts. Others would get up later and later every day, their circadian rhythms "drifting" through time. The most severely affected showed no normal 24-hour sleep-wake pattern at all. They'd alternate sleep and activity throughout the day and night.

The results weren't the result of unemployment, because the unemployed-but-healthy group did not show them. Nor could they be linked to any specific medication or dosage level, Foster said.

Better Sleep May Help Improve Schizophrenia 

Празозин как средство от ночных кошмаров

Mayo Clinic investigators have completed a systematic literature review of prazosin in the treatment of nightmares. Researchers investigated 12 prazosin studies, four of which were randomized controlled trials.
“The studies showed the drug was well-tolerated and can take effect rapidly, within days to weeks, and some patients reported a return of nightmares when the course of prazosin was stopped,” said Simon Kung, M.D., principal investigator of the study.

 Blood Pressure Drug Relieves PTSD Nightmares

Нелекарственные методы лечения инсомнии

Stimulus control therapy. Bootzin et al5 first evaluated stimulus control therapy for conditioned insomnia (subsequently identified as primary insomnia). This therapy’s goal is to interrupt the conditioned activation that occurs at bedtime. Patients are instructed to:

*

go to bed when sleepy
*

remain in bed for no more than 10 minutes (20 minutes if elderly) without sleeping
*

if unable to sleep, get up, do something boring, and return to bed only when sleepy
*

repeat getting up and returning as frequently as necessary until sleep onset.

For the first 2 weeks of stimulus control therapy, patients are required to self-monitor their sleep behaviors using a sleep diary. Stimulus control therapy is beneficial for primary insomnia and insomnia related to anxious preoccupation. About 70% of patients with conditioned insomnia will improve using stimulus control therapy,4 but it is not clear whether the primary effective intervention is:

*

patients dissociating conditioned responses at bedtime, or
*

the inevitable sleep restriction caused by getting out of bed.

Relaxation training. Progressive muscle relaxation is a common behavioral treatment of insomnia. Patients learn to tense and then relax individual muscles, beginning at the feet or head and working their way up or down the body. Patients are taught the difference between tension and relaxation to facilitate a relaxation response at bedtime. Another method is the body scanning technique, in which the patient “talks” to each body part, telling it to “relax… relax… relax.”

Relaxation training is predicated on the belief that insomnia is caused by somatized tension and psychophysiologic arousal. The greatest challenge to effective relaxation training is that patients need extensive daytime practice before they can bring the method to the bedroom.

Remind patients that “practice makes perfect.” Therapists often instruct patients to start practicing their relaxation method during the day while self-monitoring by sleep diary and restricting time in bed at night.2

CBTi is the most extensively investigated nonpharmacologic therapy for insomnia.6 It has been used to effectively manage comorbid insomnia in patients with psychiatric disorders,7,8 such as depression,9 generalized anxiety,10 and alcohol dependence,11 as well as those with breast cancer,12 traumatic brain injury,13 and fibromyalgia.14 Age does not appear to be a limitation; research trials show the technique is effective in elderly patients.15

CBTi incorporates cognitive strategies and behavioral interventions to improve sleep quality. Patient self-monitoring with sleep diaries and worksheets is essential.

CBTi commonly is provided in 5 to 8 sessions over 8 to 12 weeks, although studies have described abbreviated practices that used 2 sessions16 and CBTi delivered over the Internet.17 Highly trained clinical psychologists are at the forefront of therapy, but counselors and nurses in primary care settings have administered CBTi.18 For primary insomnia, CBTi is superior in efficacy to pharmacotherapy:

*

as initial treatment19
*

for long-term management4
*

in assisting discontinuation of hypnotic medication.20

Put your patients to sleep: Useful nondrug strategies for chronic insomnia

Рекомендации по лечению инсомнии и других расстройств сна

Recommendations for Diagnosis and Treatment

Specific evidence-based recommendations for diagnosis and treatment of insomnia and other sleep disorders, and their accompanying level of evidence rating, are as follows:

* The diagnosis of insomnia is primarily based on complaints provided in the clinical interview by the patient, family, and/or caregiver, ideally corroborated by a patient diary (level of evidence, A).
* Referral to a specialist sleep center may be indicated for other tests in some cases, such as actigraphy for differential diagnosis of circadian rhythm disorder (level of evidence, A), polysomnography for suspected parasomnia or other primary sleep disorder (level of evidence, A), or in the case of treatment failure (level of evidence, D).
* Insomnia should be treated because it impairs quality of life and many areas of functioning and is associated with an increased risk for depression, anxiety, and possibly cardiovascular disorders (level of evidence, A). Treatment goals are to reduce distress and to improve daytime function. Choice of treatment modality is based on the particular pattern of problem, such as sleep-onset insomnia or sleep maintenance, as well as on the evidence supporting use of specific treatments.
* For chronic insomnia, cognitive behavioral therapy (CBT)-based treatment packages are effective and should be offered to patients as a first-line treatment (level of evidence, A). CBT, which may include sleep restriction and stimulus control, should be made available in more settings.
* When prescribing hypnotic drug treatment, clinicians need to consider efficacy, safety, and duration of action (level of evidence, A). Other issues to consider may include previous efficacy or adverse effects of the drug and history of substance abuse or dependence (level of evidence, D).
* Recommendations for long-term hypnotic drug treatment are to use it as clinically indicated (level of evidence, A). To discontinue long-term hypnotic drug therapy, intermittent use should first be attempted if feasible. Depending on ongoing life circumstances and patient consent, discontinuation should be attempted every 3 to 6 months or at regular intervals (level of evidence, D). During taper of long-term hypnotic drug treatment, CBT improves outcome (level of evidence, A).
* When using antidepressants, clinicians should apply their knowledge of pharmacology (level of evidence, A). When there is a comorbid mood disorder, antidepressants should be used at therapeutic doses (level of evidence, A). However, clinicians should beware that overdose of tricyclic antidepressants can be toxic even when low-unit doses are prescribed (level of evidence, A).
* Because of frequent adverse effects of antipsychotic drugs, as well as a few reports of abuse, there is no indication for use as first-line treatment of insomnia or other sleep disorders (level of evidence, D).
* Antihistamines have a limited role in psychiatric and primary care practice for the management of insomnia (level of evidence, D).

New Guidelines Issued for Insomnia and Other Sleep Disorders