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Are Hypnotic Medications A Risk Factor for Parasomnias?

Andrew Krystal, MD
Duke University
North Carolina

A number of reports link hypnotic medications to parasomnias such as somnambulism, confusional arousals, and sleep eating. However, little systematic research has been carried out to determine if the risks of these events are increased as a result of taking hypnotic medications. In this presentation, we report a review of the available data from placebo-controlled trials of hypnotic medications in order to determine if hypnotic medications increase the risks of these events. This was accomplished by comparing the rate that a parasomnia or parasomnia-like event was reported as an adverse event in these studies in placebo and drug groups. We conclude that the risk of these events in insomnia patients as well as insomnia patients treated with hypnotics is exceedingly low and we discuss:

1. possible reasons why we found a rate lower than that of the general population; and

Pharmacogenomic and Pharmaco-Epidemiology issues in hypnotic drugs

Julia Stingl/Kirchheiner, MD, PhD and Maurice Ohayon, MD, DSc, PhD
University of Ulm
Stanford University

Hypnotics are widely used to treat and self-treat any kinds of sleep disorders. Substances specifically developed to treat insomnia as well as drugs with sedative properties or herbals are commonly used in the population.

Individual genetic underpinnings may modulate the side effects associated with these drugs. Polymorphic drug metabolism leads to considerable differences in drug exposure affecting the duration of the hypnotic effects as well as undesired adverse effects. Beside its role in drug metabolism, polymorphic drug metabolizing enzymes play a role in endogenous substrate metabolism affecting physiological processes. CYP2D6, a polymorphic liver enzyme, is involved in the metabolism of many psychotropic drugs, beneath them a lot of substances that possess sedative side effects. Beside its hepatic role, CYP2D6 is found to be widely expressed in the brain. It is involved in dopamine and serotonin biotransformation and may affect basic neural processes involved in alertness and sustained attention. Thus, in addition to metabolism of drugs affecting sleepiness and sedation, the constitutional role of this genetic polymorphism may impact on the outcome of insomnia and sleep disturbances.

On the epidemiological side, the number of individuals using psychotropic drugs allows to describe the therapeutic and adverse effects of these drugs. Categorization of the population by age, sex, job employment, socio-professional and familial environment may help to identify the risk factors inherent to some subcategories of the population. The wide range of prescription of some of these molecules and notably hypnotics, benzodiazepines and antidepressants is unveiling the various effects of these drugs.

The combination of epidemiology and genetics is raising at a higher level the possibility to trace the categories of individuals or families at greater risk to present a good therapeutic answer or unexpected adverse events. The major interest of this approach is that the frequency of the effects, their incidence and their risk factors are not estimations as in a clinical setting: they are prevalence rates inside of the general population. Determining the population susceptible to have positive or negative effects is then more conveniently assessed.

The role of genetic polymorphisms in the metabolism and effects of commonly used hypnotics such as benzodiazepine-like substances, antidepressants and antipsychotic drugs will be highlighted, and recent findings to the role of drug metabolizing enzymes in the brain will be presented. The epidemiological data collected in North America by the Sleep-Eval system will serve as an example of what could be reached to precise the prevalence and risk factors of Parasomnias and their associations with medical conditions and hypnotics in the general population.

Circadian Rhythms: Role in Parasomnias?

Phyllis C. Zee, MD, PhD
Northwestern University, Chicago

In humans, the most apparent function of the circadian system is the regulation of the sleep-wake cycle, and this system promotes both sleep and wakefulness at discrete points of the 24 hour period. Circadian rhythms are endogenously generated, and are entrained to the 24 hour light/dark and social/behavioral cycles. Interaction between the circadian and sleep homeostatic processes determines the timing, duration and quality of sleep. Alterations in the function of the central circadian clock or its entraining pathways result in disturbances in the timing, as well as the quality of sleep. Despite the importance of the circadian system for the regulation of sleep and wake, little is known of how circadian timing influences the development or presentation of rapid eye movement (REM) and non-REM parasomnias. In addition to the propensity for sleep, the timing, distribution and stability of REM sleep across the night are circadian regulated, perhaps through the action of melatonin. Exogenous administration of melatonin not only increases non-REM sleep propensity, but can also increase the amount and stability of REM sleep. Although the precise action of melatonin in the treatment of REM Behavior Disorder (RBD) is unclear, it has been shown that those patients with RBD with low melatonin secretion and a tendency to more REM disruption benefited most from treatment. This observation raises the possibility that an intrinsic abnormality of the circadian regulation of melatonin secretion could play a role in the pathophysiology of RBD. Chronic circadian misalignment and irregular sleep/wake schedules, such as seen circadian rhythm disorders, including delayed sleep phase disorder (DSPD) and shift work disorder (SWD) can lead to sleep loss and sleepiness, which in turn can potentially increase the frequency of parasomnia events. However, there is lack of data on the prevalence of parasomnias in CRSD's and the effect of circadian regularity in the management of non-REM and REM sleep parasomnias in children and adults.

Posttraumatic Parasomnia

Thomas C. Neylan, MD
University of California San Francisco

The National Comorbidity Survey estimates that approximately 50% of the population in the United States are exposed to traumatic events and that the lifetime prevalence of posttraumatic stress disorder (PTSD) is approximately 7.8%.

Multiple studies have demonstrated that patients with PTSD complain of recurrent nightmares and sleep continuity disturbances, which are listed separately in the re-experiencing and hyperarousal clusters in DSM-IV.

Much less is known about the prevalence of parasomnias associated with trauma exposure despite frequent observations in clinical settings of patients and bedpartners who complain of confusional arousals and nocturnal violent behavior.

We will review the current evidence showing an association between exposure to traumatic stress with confusional arousals and nocturnal violence.

We will also focus on functional neuroanatomy implicated in Posttraumatic Stress Disorder and will discuss implications for understanding the link between trauma exposure and parasomnias.

We will end with a discussion of a possible research agenda focused on understanding:

1. the role of sleep as a predictor of risk and resilience following trauma exposure;
2. the implications of parasomnias as a severity marker of for post-trauma psychological distress;
3. the concept of regional hyperarousal as a model for understanding the functional neuroanatomy of parasomnias and PTSD.