Sleep Initiation and Maintenance Disorders: Richardson GS

Richardson GS. · Sleep Research Laboratory, Henry Ford Hospital, Detroit, MI, USA. · Sleep Med. · Pubmed #18346677 No free full text.

Abstract: Despite the wide prevalence and important consequences of insomnia, remarkably little is known about its pathophysiology. Available models exist primarily in the psychological domain and derive from the demonstrated efficacy of behavioral treatment approaches to insomnia management. However, these models offer little specific prediction about the anatomic or physiological foundation of chronic primary insomnia. On the other hand, a growing body of data on the physiology of sleep supports a reasonably circumscribed overview of possible pathophysiological mechanisms, as well as the development of physiological models of insomnia to guide future research. As a pragmatic step, these models focus on primary insomnia, as opposed to comorbid insomnias, because the latter is by its nature a much more heterogeneous presentation, reflecting the effects of the distinct comorbid condition. Current understanding of the regulation of sleep and wakefulness in mammalian brain supports four broad candidate areas: 1) disruption of the sleep homeostat; 2) disruption of the circadian clock; 3) disruption of intrinsic systems responsible for the expression of sleep states; or 4) disruption (hyperactivity) of extrinsic systems capable of over-riding normal sleep-wake regulation. This review examines each of the four candidate pathophysiological mechanisms and the available data in support of each. While studies that directly test the viability of each model are not yet available, descriptive data on primary insomnia favor the involvement of dysfunctional extrinsic stress-response systems in the pathology of primary chronic insomnia.

Richardson GS. · Division of Sleep Medicine, Henry Ford Hospital, Detroit, MI 48202, USA. · J Clin Psychiatry. · Pubmed #16336035 No free full text.

Abstract: The human circadian system regulates rhythmicity in the human body and establishes normal sleep and wake phases. The suprachiasmatic nuclei (SCN), located in the hypothalamus above the optic chiasm, make up the human pacemaker known as the circadian or biological clock, but other essential parts of the circadian system include the pineal gland, retina, and retinohypothalamic tract. The importance of light in resetting the intrinsic human circadian cycle, the intrinsic period of which is slightly longer than 24 hours, ensures that the human cycle will stay entrained to the earth's 24-hour daily cycle. Within the SCN neurons, circadian rhythmicity is generated by the regular transcription of proteins. Since the circadian system is the foundation of the sleep-wake cycle, disorders and abnormalities in sleep are often connected with disorders or abnormalities in the circadian system. Circadian rhythm sleep disorders, such as jet lag syndrome and shift work sleep disorder, are those specifically attributed to dysfunctions or insufficiencies in the circadian system. Taking into consideration the preeminence of the circadian clock in timing sleep, it is likely that other sleep disorders, such as insomnia, are also linked to circadian system abnormalities.

Richardson GS, Roth T, Kramer JA. · Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, MI, USA. · MedGenMed. · Pubmed #11965211 links to  free full text

Abstract: CONTEXT: Insomnia is the most frequently reported sleep symptom, severely affecting up to 15% of the US population. The need to effectively treat this disorder is underscored by the significant adverse consequences on the productivity, safety, overall health, and quality of life of the affected individual. Pharmacologic intervention has traditionally involved the use of benzodiazepine receptor agonists (BzRAs), for which efficacy and general safety have been established. OBJECTIVE: The purpose of this paper is to examine the potentially unique role of zaleplon in the treatment of insomnia. DATA SOURCE: The clinical experience of the authors was critically applied to peer-reviewed published papers or abstracts regarding zaleplon, which were identified via MEDLINE (1995-September 2000). RESULTS: Adverse effects, usually related to residual sedation, impose limits on the use of older BzRAs and have prompted the development of new sleep medications with advantageous adverse event profiles. Zaleplon demonstrates a very rapid onset and offset of effect that permits symptomatic rather than prophylactic administration, resulting in comparable efficacy and reduced risk of the adverse effects associated with longer half-life agents. CONCLUSIONS: The characteristics of zaleplon may translate into distinct and significant clinical advances in the treatment of insomnia.

Richardson GS, Roth T. · Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Mich 48202, USA. · J Clin Psychiatry. · Pubmed #11388590 No free full text.

Abstract: Research on insomnia has provided a number of important new insights, but fundamental deficits in our understanding remain. In considering priorities for future research, 3 areas warrant immediate attention. First, a causal relationship between insomnia and the adverse outcomes seen in insomnia patients needs to be established. Second, currently available symptomatic therapies need to be optimized. Recent data suggest that some benzodiazepine receptor agonists produce their hypnotic effect without side effects that were presumed to be inherent to sedation. Understanding the neuropharmacology underlying this differential effect would allow substantial improvements in the risk-benefit ratio for these drugs. Finally, the mechanisms of insomnia need to be better understood. Several lines of evidence suggest that physiologic arousal is important to the clinical presentation of primary insomnia. It remains unclear, however, whether this activation is primary or secondary to the insomnia itself. If physiologic hyperarousal causes primary insomnia, it would provide new approaches to the management of this disorder.

Ancoli-Israel S, Richardson GS, Mangano RM, Jenkins L, Hall P, Jones WS. · Department of Psychiatry 116A, University of California San Diego and Veterans Affairs, San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA 92161, USA. · Sleep Med. · Pubmed #15716214 No free full text.

Abstract: BACKGROUND AND PURPOSE: Insomnia is a common problem that increases with age and can last months to years. While substantial data establish the efficacy and safety of short-acting hypnotic therapy for the management of short-term insomnia using benzodiazepines receptor agonists (BzRAs), there are few studies on the continued efficacy and safety of these drugs when used for sustained periods. This paper reports the results of a 1-year open-label extension phases of two randomized, double-blind trials of zaleplon. PATIENTS AND METHODS: In the open-label phase, older patients self-administered zaleplon nightly from 6 to 12 months and were then followed through a 7-day single-blind placebo-controlled run-out period. RESULTS: The safety profile in this population of older adults was similar to that observed in a short-term trial of an equivalent population. The data also suggested that long-term therapy produced and maintained statistically significant improvement in time to persistent sleep onset, duration of sleep and number of nocturnal awakenings (P<0.001 for each variable) for treatment durations of up to 12 months. Discontinuation was not associated with rebound insomnia. CONCLUSION: The open-label trial of long-term hypnotic therapy with zaleplon 5 and 10 mg suggests that they are safe and effective for the treatment of insomnia in older patients. Placebo-controlled, double-blind trials are needed in zaleplon and other BzRAs to confirm these results.

Richardson GS, Zammit G, Wang-Weigand S, Zhang J. · Henry Ford Hospital, Sleep Disorders Center, Detroit, MI 48202, USA. · J Clin Psychiatry. · Pubmed #19284927 No free full text.

Abstract: OBJECTIVE: To evaluate the long-term safety and subjective sleep effects of ramelteon in adults with chronic insomnia. METHOD: Subjects with primary insomnia (DSM-IV-TR criteria) for >or= 3 months received ramelteon nightly for 1 year; a 3-day placebo run out followed. Subjects aged >or=65 years received open-label ramelteon 8 mg (N = 248); those aged 18 to 64 years received ramelteon 16 mg (N = 965). Subjects completed sleep diaries and returned to the clinic at week 1 and at months 1, 2, 3, 4, 6, 8, 10, and 12 for safety assessments and investigator-performed Clinical Global Impressions. The study was conducted from February 2003 through September 2004. RESULTS: There were no noteworthy changes in vital signs, physical examinations, clinical chemistry, hematology, or urinalysis values and no electrocardiogram changes to suggest adverse cardiac effects. Endocrine values remained within normal range throughout treatment. Consistent statistically significant (p <or= .05) decreases in free thyroxine (in adults) and free testosterone (in older men) were detected. Duration of menses increased by approximately 1 day. A total of 40.8% of subjects reported at least 1 adverse event possibly associated with ramelteon use. The adverse events reported varied considerably, the incidence of individual adverse events was low, and the frequencies of adverse events were similar at months 6 and 12. In both groups, subjective sleep latency and total sleep time improved by month 1 and was sustained during the 1-year period. At 6 months and 1 year, Clinical Global Impressions indices were improved. During placebo run out, subjective sleep latency did increase but did not return to baseline. CONCLUSION: Year-long administration of ramelteon was well tolerated. Ramelteon was associated with sustained improvements in subjective sleep latency, subjective total sleep time, and Clinical Global Impressions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00671086.

Richardson GS. · Henry Ford Hospital, Detroit, MI 48202, USA. · Sleep. · Pubmed #10755803 No free full text.

Abstract: The optimal management of insomnia in the primary care setting should be viewed as a public health problem that will require specific attention. Important recent strides in the understanding of insomnia, its consequences, and its treatment do not always provide a basis for management strategies in a setting with distinct practical limitations. A somewhat different research focus will be needed if the scientific advances are to be translated into practical improvements in therapy. In primary care today, multiple agendas compete for the physician's time. Therefore, it is necessary to view diagnosis and management in terms of both what is efficient and what is optimally effective. Much can be learned from experience with medical risk factors of broad prevalence, such as hypercholesterolemia and hypertension. Large outcome trials demonstrating the benefits of drug therapy were required before pharmacologic management became standard care in the primary care setting. For insomnia, specific issues that must be addressed include the components of diagnosis that will guide therapy and affect prognosis. How can the 10% of adults with insomnia in the primary care practice be subdivided to identify those most in need of therapy? Stated another way, what are the features of insomnia that predict risk? Is duration important? Severity? Frequency? Which treatments are most effective? Which are most efficient in terms of the time required of patient and practitioner? Do treatments for insomnia produce patient satisfaction? Do they prevent adverse outcomes, such as depression and automobile accidents? Studies are now addressing many of these questions. In selecting research priorities, however, the practical application of this information in the clinical setting is important if the ultimate goal is to reduce the number of patients suffering from insomnia and its consequences.