Sleep Problems and Remedies from Ambien to Zolpidem

The diagnosis of sleep problems is based on now standardized criteria summarized both in Diagnostic and statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and the more detailed classification of the ICSD (International Classification of Sleep Disorders) (Pressman and Orr, 1997). Unlike psychiatric diagnoses, which are typically obtained from a conversation with a psychiatrist through structured interview, sleep disorders have more "objective" criteria, consisting of electroencephalogram (EEG) measures of (i) sleep latency, (ii) REM latency (including "REM latency minus awake"), (iii) amount of SWS, (iv) amount of REM sleep, (v) eye movement density in REM sleep, and (vi) sleep efficiency (i.e., total number of minutes of sleep divided by the total time in bed). There is abundant data using these measures not only in standard nonpsychiatric sleep disorders, such as apnea, but also in many psychiatric disorders (Douglass, 1996).

Objectively measured sleep problems allow clinicians to provide pharmacological assistance that has been standardized in clinical populations (Kryger et al., 2000). The enormous amount of drug development in this area attests to the prevalence of sleep problems in our society. Although there is no space to detail this massive literature, the list of effective sleep aids now on the market is lengthy, and far exceeds the list of those agents approved by the Food and Drug Administration (FDA) (Table 4.1). This is because all the benzodiazepine (BZ) receptor agonists can serve as sleeping aids, but the approved ones are typically the shorter-acting agents such as triazolam (Halcion) for individuals simply having difficulty falling asleep. The longer-acting agents can sustain sleep, but are more likely to have sedative carryover effects into the morning (Mitler, 2000).

The problems with BZs, with regard to cognitive impairment, memory loss, and addictive potential (Chapter 19), are sufficiently large that a vigorous search was mounted for other effective agents that have no such problems. A new class of non-BZs that are stimulants for the BZ receptor, and hence GABA facilitators of SWS processes, has revolutionized the medication of sleep problems. The fast-acting, short-duration agent that has taken away a substantial market-share from triazolam (Halcion) is zolpidem (Ambien), which can be taken in the middle of the night to counteract early-morning wakenings. Of course there are also highly effective longer-acting agents, such as flurazepam, as well as a large number of BZs as well as sedating antidepressants that are still commonly used for sleep problems (Table 4.1). Also, there is vigorous research activity to develop slow-release forms of the fast-acting agents, as well as natural ingredients such as melatonin, to help sustain sleep through the night. Of course, chronic use of BZs is not advised because of strong withdrawal reactions when tolerance has developed to these agents (see Chapter 16). The one highly effective over-the-counter agent is the natural hormone melatonin, whose efficacy has long been known (Arendt, 1995) but which has not been promoted by the pharmaceutical or medical community since it has not been approved by government regulatory boards. Obviously, there is little incentive for conduct of necessary efficacy trials for agents that cannot be patented. Accordingly, the search continues to identify melatonin congeners that can be patented. Even though there is now a large number of such agents, there is yet no clear evidence that any of them will have a substantially better efficacy profile than the natural ingredient, except perhaps when they begin to market using slow-release forms that might better sustain somnolence.

Although there are no sleeping aids that are specific to the problems of any given psychiatric disorders, such as depression or schizophrenia, it is noteworthy that practically all the selective serotonin facilitating antidepressants can promote sleep and ameliorate sleep problems (Kryger et al., 2000). Among the earlier generation of drugs, Amitriptyline was especially sedating, but most of the modern SSRIs can improve sleep, especially as their antidepressant effects kick in, although none is approved for the treatment of insomnia.

Considering the antistress effects of a good night's sleep for all forms of mental distress, the search for more specific interventions will continue. Since CRH arousal in the brain provokes generalized stress and anxiety effects in the mammalian brain, antagonists for those receptors should be effective in promoting better sleep patterns. Preclinical data already suggest that such a beneficial profile is present in some of the available CRH receptor antagonists (Lancel et al., 2002).

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