Sleep Medicine Reviews (2007) 11, 71–79 THEORETICAL REVIEW Insomnia: Pathophysiology and implications for treatment Thomas Roth à , Timothy Roehrs, Ron Pies Sleep Disorders and Research Center, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA KEYWORDS Insomnia; HPA axis; Hyperarousal 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. & 2006 Elsevier Ltd. All rights reserved. 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. 2–4 In addition, insomnia has been found to precede the onset of major depression. 5–7 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 im- portant areas of functioning (American Psychiatric Association, 2000). DSM-IV-TR specifies that pri- mary insomnia cannot occur exclusively during the course of narcolepsy, breathing-related sleep dis- order, circadian rhythm disorder, or a parasomnia, ARTICLE IN PRESS www.elsevier.com/locate/smrv 1087-0792/$ - see front matter & 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2006.06.002 à Corresponding author. Tel.: +1313 9165171; fax: +1 313 916 5167. E-mail address: troth1@hfhs.org (T. Roth).