Elsevier

Sleep Medicine Reviews

Volume 11, Issue 1, February 2007, Pages 71-79
Sleep Medicine Reviews

THEORETICAL REVIEW
Insomnia: Pathophysiology and implications for treatment

https://doi.org/10.1016/j.smrv.2006.06.002Get rights and content

Summary

Interest in developing a greater understanding of the pathophysiogical mechanisms underlying primary insomnia has increased. Recent evidence indicates that there may be some neuroendocrine and clinical similarities between primary insomnia and major depressive disorder, that abnormal corticotropin releasing factor (CRF) activity occurs in major depression, and that CRF hyperactivity appears to mediate the hyperarousal seen in primary insomnia. These findings all point to the possibility of hypothalamic–pituitary–adrenal (HPA) axis and CRF overactivity in both disorders. More recent findings have strengthened the evidence that primary insomnia may be linked with mood disorders and is associated with HPA axis overactivity and excess secretion of CRF, adrenocorticotropin releasing hormone, and cortisol. These insights have implications for managing chronic primary insomnia, such as use of antiglucocorticoid agents.

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.

References (70)

  • D. Riemann et al.

    Primary insomnia: a risk factor to develop depression?

    J Affect Disord

    (2003)
  • A.J. Rothschild

    Challenges in the treatment of depression with psychotic features

    Biol Psychiat

    (2003)
  • Z. Rihmer et al.

    Dexamethasone suppression test in masked depression

    J Affect Disord

    (1983)
  • R. Yehuda

    Psychoneuroendocrinology of post-traumatic stress disorder

    Psychiat Clin North Am

    (1998)
  • O.M. Wolkowitz et al.

    Antiglucocorticoid treatment of depression: double-blind ketoconazole

    Biol Psychiat

    (1999)
  • C.L. Ravaris et al.

    Clinical use of ketoconazole in hypocorticoluric depressives

    Biol Psychiat

    (1994)
  • G.S. Richardson et al.

    Future directions in the management of insomnia

    J Clin Psychiat

    (2001)
  • G. Goldsmith et al.

    Effect of sleep quality on symptoms of irritable bowel syndrome

    Dig Dis Sci

    (1993)
  • L.M. McCracken et al.

    Disrupted sleep patterns and daily functioning in patients with chronic pain

    Pain Res Manage

    (2002)
  • P.P. Chang et al.

    Insomnia in young men and subsequent depression. The Johns Hopkins Precursors Study

    Am J Epidemiol

    (1997)
  • T. Roth

    The relationship between psychiatric diseases and insomnia

    Int J Clin Pract Suppl

    (2001)
  • C.L. Drake et al.

    Insomnia causes, consequences, and therapeutics: an overview

    Depress Anxiety

    (2003)
  • S.E. Katz

    Possible paroxetine–zolpidem interaction

    Am J Psychiat

    (1998)
  • G.K. Zammit et al.

    Quality of life in people with insomnia

    Sleep

    (1999)
  • G. Hajak

    Epidemiology of severe insomnia and its consequences in Germany

    Eur Arch Psychiat Clin Neurosci

    (2001)
  • D. Leger et al.

    SF-36: evaluation of quality of life in severe and mild insomniacs compared with good sleepers

    Psychosom Med

    (2001)
  • T. Roth et al.

    Daytime consequences and correlates of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. II

    Sleep

    (1999)
  • W.F. Seidel et al.

    Daytime alertness in relation to mood, performance, and nocturnal sleep in chronic insomniacs and noncomplaining sleepers

    Sleep

    (1984)
  • E. Stepanski et al.

    Daytime alertness in patients with chronic insomnia compared with asymptomatic control subjects

    Sleep

    (1988)
  • M.H. Bonnet et al.

    Activity, arousal, and the MSLT in patients with insomnia

    Sleep

    (2000)
  • B.W. Riedel et al.

    Objective sleep measures and subjective sleep satisfaction: how do older adults with insomnia define a good night's sleep?

    Psychol Aging

    (1998)
  • T. Shochat et al.

    Sleep disorders in the elderly

    Curr Treat Options Neurol

    (2001)
  • M.E. Thase et al.

    Abnormal electroencephalographic sleep profiles in major depression: association with response to cognitive behavior therapy

    Arch Gen Psychiat

    (1996)
  • N. Brunello et al.

    Depression and sleep disorders: clinical relevance, economic burden and pharmacological treatment

    Neuropsychobiology

    (2000)
  • J. Fawcett et al.

    Time-related predictors of suicide in major affective disorder

    Am J Psychiat

    (1990)
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