THEORETICAL REVIEWInsomnia: Pathophysiology and implications for treatment
Introduction
Despite more than 30 years of research into the nature of insomnia, our understanding of its basic pathophysiology has lagged behind that of other sleep disorders, such as narcolepsy and sleep apnea.1 In part, this discrepancy stems from the heterogeneous nature of insomnia, which is both a primary condition with a pathophysiology, and a condition co-existing with numerous medical and psychiatric disorders. The course of the co-existing medical or psychiatric disease may be modulated by the course of the sleep disturbance.2, 3, 4 In addition, insomnia has been found to precede the onset of major depression.5, 6, 7
The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) defines the term primary insomnia as difficulty initiating or maintaining sleep, or non-restorative sleep, that results in clinically significant distress or impairment in social, occupational, or other important areas of functioning (American Psychiatric Association, 2000). DSM-IV-TR specifies that primary insomnia cannot occur exclusively during the course of narcolepsy, breathing-related sleep disorder, circadian rhythm disorder, or a parasomnia, or during the course of another mental disorder (e.g., major depression), and it cannot be due to a general medical condition or substance use disorder (Table 1). Primary insomnia has been conceptualized as sleep disturbance not arising from a medical, psychiatric, circadian, behavioral, or pharmacologic cause, or from a primary sleep disorder.8
The DSM-IV-TR criteria inform clinicians what primary insomnia is not, but do not define what it is, beyond a complaint of difficulty initiating or sustaining restful sleep lasting more than a month. It is unclear what pathophysiologic mechanisms drive primary insomnia and what implications these have for insomnia morbidity and treatment. This paper provides a brief overview of the epidemiology, morbidity, and risk factors associated with insomnia, and will also briefly highlight the specific research still needed in each of these areas. Next the paper discusses the question of primary insomnia etiology, focusing on the critical role of hyperarousal and abnormal corticosteroid regulation—a pathophysiology that may be the unifying link between primary insomnia, depression, and perhaps other disorders. Finally, the implications of this new research will be explored as it relates to insomnia pharmacotherapy.
Section snippets
Epidemiology
Prevalence estimates for insomnia range from 10% to 50% of the adult population. Summaries of the epidemiologic evidence conclude that 10–13% of the adult population suffers from chronic insomnia, and an additional 25–35% has transient or occasional insomnia.9, 10 It is estimated that 75% of population-based chronic insomnia is associated with psychiatric and medical diseases, or with primary sleep disorders and primary insomnia accounts for approximately 25% of all chronic insomnia.11 Thus,
Hyperarousal in insomnia
Chronic primary insomnia has been characterized as a state of hyperarousal. The hyperarousal can be seen in various signs of peripheral and central activation (see Table 2) and with various symptom and behavioral manifestations such as excessive worry and reactivity.10 An underlying pathophysiology for the hyperarousal, as described below, has been hypothesized. The hyperaroused state of insomnia differs from the daytime sleepiness and impaired performance that results from sleep restriction,
Pathophysiology of the HPA axis: findings in primary insomnia
Two findings in healthy, normals suggest a linkage between primary insomnia and mood disorders. The first finding demonstrated that in normal male subjects infusions of either cortisol or adrenocorticotropic hormone (ACTH) reduced rapid eye movement (REM) sleep compared with placebo infusions.43 The second result suggested that intravenous CRF may lead to blunted growth-hormone secretion and reduced slow-wave sleep in normal men.44 Importantly, these effects resembled effects seen among
Insomnia, hyperarousal, and mood disorders
The most common comorbidity associated with chronic insomnia is psychiatric disorder, specifically depression.8 Recent epidemiological studies provided strong evidence that insomnia is an independent predictor of incident depression.5, 6 The occurrence of insomnia symptoms for a period of more than 2 weeks is predictive of increased risk for depression over the subsequent 1–3 years.49
The question remains, however, whether insomnia causes depression or depression causes insomnia, or if either
HPA hyperfunction: treatment implications for depression and insomnia
As HPA overactivity is a common factor in primary insomnia and some subtypes of depression, it seems reasonable to ask whether both disorders might respond to the same therapeutic intervention. Two important questions related to these issues come to mind. First, would strategies that reduce HPA activity and/or glucocorticoid effects ameliorate both major depression and primary insomnia? Second, as HPA overactivity is an integral feature of insomnia, how effective are the currently available
Conclusion
Chronic insomnia is a highly prevalent, yet incompletely understood condition. People with insomnia report significantly impaired daytime function across a number of emotional, social, and physical domains. These deficits reported by insomnia sufferers are additionally associated with enormous personal and societal costs. Several studies show that insomnia is an important predictor of poor physical and emotional health and that insomnia may independently alter the course of affective disorders.
Acknowledgements
The authors would like to acknowledge that they received compensation from Sepracor for the services they provided in support of the development of this manuscript. The authors wish to acknowledge H. Heith Durrence for his assistance in preparing this manuscript.
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