National Sleep Disorders Research Plan
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Section 5 Content:
Immunomodulation, Neuroendocrinology and Sleep    
Sleep-Disordered Breathing
Narcolepsy and Other Hypersomnias  
Restless Legs Syndrome/Periodic Limb Movement Disorders
Sleep in Other Neurological Disorders


Sleep in Psychiatric, Alcohol, and Substance Use Disorders


Virtually all psychiatric and substance use disorders are associated with sleep disruption. Epidemiological and clinical studies indicate that psychiatric disorders are the most common cause of chronic insomnia. Alcohol dependence leads to complaints of insomnia and sleep disruption that can persist for months into abstinence and recovery. Psychiatric disorders can also be associated with daytime sleepiness, fatigue, abnormal circadian sleep patterns, disturbing dreams and nightmares. Conversely, increasing evidence suggests that primary insomnia (without concurrent psychiatric disorder) is a risk factor for later developing psychiatric disorders, particularly depression, anxiety, and substance use disorders

Preliminary studies suggest that sleep disorders such as Sleep-Disordered Breathing (SDB), Restless Legs Syndrome (RLS), and sleep-related movement disorders may be unrecognized or under-recognized in children and adults presenting with psychiatric symptoms and psychiatric disorders, and occur with increased prevalence in alcohol dependent persons. The relationship between sleep and psychiatric disorders is further supported by the observation that sleep deprivation can ameliorate depressive symptoms and exacerbate manic symptoms, and that alcohol dependent persons show an impairment in the homeostatic recovery of sleep following sleep deprivation. Moreover, insomnia and certain types of EEG sleep patterns, such as reduced REM latency or increased REM sleep, have been associated with poor treatment outcomes in psychiatric disorders, including relapse or recurrence of depression and alcoholism.

Increasing attention has been paid to sleep abnormalities in post-traumatic stress disorder (PTSD) and nightmares, both in terms of descriptive studies (e.g., findings regarding REM and NREM dream disturbances, movement disorders) and therapeutic studies (e.g., dream rehearsal therapies). Polysomnographic markers for adult depression such as decreased latency to REM sleep onset have not been consistently found in depressed children and adolescents, but other EEG measures (such as inter- and intrahemispheric coherence) have been identified as potential correlates of mood disorders in children. African Americans are particularly vulnerable to the effects of alcohol dependence, and polysomnographic and spectral analytic studies show a striking loss of delta sleep and delta power in this population. Furthermore, studies using structural and functional neuroimaging paradigms have begun to elucidate possible mechanisms linking sleep disturbance and psychiatric illness.

Psychoactive substances have acute and chronic effects on sleep architecture. Several aspects of sleep are compromised in individuals taking these drugs, depending on the drug. Difficulty in initiating and maintaining sleep as well as poor sleep quality are common in patients on opiates. In fact, heroin addicts seeking treatment often report sleep disturbances, notably insomnia, as precipitating causes of relapse. A similar dysregulation in the normal cycles of sleep may contribute to severe dependence observed with GHB (gamma-hydroxybutyrate) where regular users report constant waking and must take more to reinstate sleep. Even patients stabilized on methadone may have SDB, daytime sleepiness and poorer sleep efficiency. Infants born to substance-abusing mothers have a several times greater risk of Sudden Infant Death Syndrome (SIDS). Chronic cocaine users also have lower sleep efficiency and significant sleep onset delay. By contrast, abstinence from cocaine as well as amphetamines produces hypersomnia. Since some investigators have observed sleep disruption despite long abstinence in chronic cocaine users, the mechanisms underlying sleep architecture and homeostasis and the mechanisms underlying effects of psychoactive drugs may have much in common. Further understanding of these relationships will advance both fields.

Most of the recent research progress has been related to improved understandings of the associations between psychiatric disorders and various sleep symptoms (e.g., insomnia and nightmares), sleep EEG patterns (e.g., delta EEG activity), and sleep disorders (e.g., SDB and movement disorders). Less progress has been made in identifying fundamental pathophysiological mechanisms linking psychiatric disorders and sleep. Despite some promising early leads, for example, sensitive and specific sleep biomarkers of psychiatric disorders have not been validated. Similarly, endogenous circadian rhythm disturbances have not been identified in most patients with depression or other psychiatric disorders.

Given the basic observations that cytokines regulate sleep in animals, increasing attention has focused on the role of cytokines in the regulation of sleep in humans and the contribution of abnormal regulation of the complex cytokine network to sleep disturbance in alcohol dependent persons. Despite initial progress in the study of sleep disturbances among children with depression, little is known about the characteristics or consequences of sleep disturbances in most childhood psychiatric disorders. After focusing almost exclusively on the relationships between sleep and depression, psychiatric sleep research has only recently begun to focus attention on other disorders, such as PTSD. The application of sleep and circadian rhythm therapies to psychiatric disorders has also been limited, and their efficacy not consistently demonstrated. Clinical neuroscience studies are only beginning to move beyond the examination of EEG sleep correlates of psychiatric disorders to the investigation of common mechanisms and the consequences of disordered sleep in psychiatric and substance dependent populations. Abnormalities of immune system functioning are coupled, for example, with disordered sleep in alcohol dependent populations. Finally, insomnia and sleep disturbances are known to be risk factors for psychiatric disorders including alcohol dependence, but long-term follow-up studies have not yet been done to determine whether intervention can reduce these risks and the progression of these disorders.

Progress In The Last Five Years

- Insomnia has been identified as a risk factor for the subsequent development of psychiatric disorders, including mood, anxiety, and substance use disorders.

- Insomnia and EEG sleep have been identified as correlates of poor outcome in depression, schizophrenia, and alcohol dependence.

- Structural and functional neuroimaging studies have begun to identify neuroanatomic correlates of sleep disturbance in depression and schizophrenia, and of therapeutic sleep deprivation in depression. For instance, slow wave sleep deficits in schizophrenia are associated with negative symptoms and frontal cortical volume loss. Patients with depression have higher absolute cerebral glucose metabolic rate than healthy subjects, and blunted activation of limbic structures (amygdala, anterior cingulate) during REM sleep compared to wakefulness. Improvement of depression following one night of sleep deprivation is associated with decreased relative metabolism in the anterior cingulate cortex

- Reduced latency to REM sleep has been identified as a familial sleep biomarker for increased risk of developing depression.

- Differences in sleep responses to cholinergic and serotonergic drugs have been identified in patients with depression compared to healthy controls.

- Individuals with PTSD have a high incidence of SDB, motor dyscontrol, and dream disturbances during both NREM and REM sleep.

- The efficacy of dream imagery rehearsal for traumatic nightmares has been demonstrated in early clinical trials.

- Abnormalities of sleep quantity and sleep depth persist for months into recovery from alcohol dependence, and are more profound in African American alcoholics compared to Euro-American alcoholics. The decay of delta sleep in alcoholics is coupled with impairment in the regulation or plasticity of slow wave sleep.

- Dysregulation of cytokine expression is a biomarker of abnormal sleep in recovering alcohol dependent persons.

- Sleep disturbances are apparent in individuals taking psychoactive drugs and have been found to persist long after withdrawing from these drugs. For some, sleep disturbance can be so severe as to reverse treatment success and precipitate a relapse to addiction or dependence.

- Drugs can damage brain areas and neural systems involved in sleep maintenance. For example, studies primarily in animals have shown that MDMA ("ecstasy") causes reduction in serotonin in axons and axon terminals. Cocaine causes severe depletion of dopaminergic neural systems.

Research Recommendations

- Evaluate whether insomnia and hypersomnia are modifiable risk factors for poor outcomes in mood, anxiety, and psychotic disorders, alcoholism, and substance abuse disorders. Three types of studies are needed. First, studies should investigate whether insomnia and hypersomnia are modifiable risk factors for the development of new-onset psychiatric disorders. Second, studies should investigate whether insomnia or specific EEG sleep characteristics are modifiable risk factors for poor outcomes among individuals with existing psychiatric disorders. Third, prospective, long-term longitudinal studies are needed to follow the concurrent course of sleep and psychiatric disorders from childhood into adulthood, and to elucidate possible mechanisms for the relationship between sleep disturbance and psychiatric disorders. These studies will be aided by the identification of sensitive, specific, and objective markers of insomnia and hypersomnia.

- Further evaluate the relationships between stress and sleep in clinical disorders such as PTSD and other forms of acute and chronic stress. Studies are specifically needed to (1) further characterize the nature of stress-related sleep disturbances (e.g., insomnia, nightmares and other dream disturbances, movement disorders during sleep), (2) examine causal relationships between stress and sleep disturbances, and (3) investigate the efficacy of behavioral and pharmacological interventions for treating stress-related sleep disturbances.

- Evaluate the neurobiological characteristics and mechanisms of sleep disturbances in primary insomnia, depressive disorders, and anxiety disorders, to better define the inter-relationships. Such studies should include approaches such as functional neuroimaging studies and neurochemical studies in living human subjects and in brain tissue.

- Identify relationships between neurobiological mechanisms involved in the development of regulatory aspects of arousal, affect, and sleep in childhood and adolescence, including the role of various neurotransmitter systems. Examine the relationship between critical periods of brain development and sleep-wake cycle regulation, and the impact of sleep disturbances and insufficient sleep in early childhood in modifying the normal evolution of these various regulatory systems. These studies should also assess (1) potential links between entrainment of circadian rhythms in the first year of life and circadian irregularity during childhood and subsequent vulnerability to psychiatric illness, (2) potential effects of stressful or traumatic events on hyper- and hypo-arousal mechanisms in children, and (3) development of sleep patterns and maladaptive coping mechanisms.

- Determine the role of cytokines in the homeostatic regulation of sleep in humans and whether abnormalities in the cytokine network lead to disturbances of sleep in psychiatric populations also at risk for infectious or inflammatory disorders. Studies are also needed to determine whether pro-inflammatory cytokine antagonists can ameliorate sleep disturbance in alcohol populations who show evidence of immune activation.

- Evaluate the efficacy and safety of behavioral and pharmacologic treatments for sleep disturbances in both adults and children with psychiatric disorders. The influence of such treatments on outcome of the co-existing psychiatric disorder should also be examined. Examples include the concurrent treatment of insomnia in individuals with major depression, and the use of dream imagery rehearsal in individuals with PTSD.

- Assess the efficacy of behavioral and pharmacological interventions targeting sleep in improving the clinical course of alcoholism and risk of relapse.

- Further investigate the neurobiological basis for the beneficial effects of sleep deprivation in mood disorders. Such studies should also be useful generally to address fundamental questions regarding the mechanism of antidepressant treatments. Functional imaging methodologies, including receptor ligand studies, may be particularly relevant.

- Investigate the prevalence and impact of primary sleep disorders on psychiatric disorders. Examples include SDB and sleep-related movement disorders.

- Investigate sleep effects of medications commonly used to treat psychiatric disturbances in adults, children, and adolescents. Studies should include short and longer-term investigations examining beneficial and adverse effects of these medications on subjective measures, sleep architecture, respiration during sleep, and motor control during sleep.

- Investigate the brain mechanisms underlying sleep architecture that are also affected by psychoactive drugs, including temporary acute effects and long-term effects related to chronic drug taking. Knowledge of the neural changes brought on by drug effects should help to better understand which of these neural mechanisms are associated with sleep cycles. Conversely, an improved knowledge base of neural systems involved in sleep can aid in the understanding of the process of drug reward, addiction, and dependence.

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