Comorbid Insomnia: Current Directions and Future Challenges

Insomnia is a leading cause of absenteeism, presenteeism (lost productivity when employees are at work), accidents, and errors in the workplace. Overall direct and indirect costs exceed $30 billion annually. A significant portion of these costs are attributable to patients with comorbid insomnia, making these conditions a significant clinical public health issue. These comorbid conditions include mood and anxiety disorders; chronic pain; respiratory, urinary, and neurologic conditions; diabetes; and cardiovascular diseases. Traditional treatment for insomnia with comorbid conditions has focused on treating the comorbid condition with the expectation that the insomnia will resolve. Recent studies, however, suggest this approach is not the most appropriate. Instead, treating both conditions simultaneously may improve the outcomes for each.

(Am J Manag Care. 2009;15:S6-S13)

Various studies suggest that the vast majority of insomnia patients seen in psychiatric practices, and about 50% of those seen in primary care practices, have comorbid conditions.^1,2 Thus, the issue of insomnia with associated comorbidities, whether the result of, as a contributing factor to, or as a separate entity from the insomnia appears to be a significant patient as well as public health issue,³ although to what extent remains unclear given the lack of consistent diagnosis for insomnia in primary care practices.⁴ There is also little research on the economic and quality-of-life repercussions of comorbid insomnia versus primary insomnia, defined as insomnia with no identifiable cause.

The phrase “comorbid insomnia” emerged from the 2005 National Institutes of Health’s (NIH) State-of-the-Science Conference on Manifestations and Management of Chronic Insomnia in Adults, to describe the presence of insomnia in the context of a medical psychiatric disorder.3 Previously, the condition was known as “secondary insomnia.” The International Classification of Sleep Disorders-2 defines it in 2 ways: “Other Insomnia Due to a Mental Disorder,” for all psychiatric-related comorbidities; “Other Insomnia Due to a Known Physiological Condition,” for all medical comorbidities. The former requires insomnia as well as a mental disorder classified under the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, with the insomnia related in time to the mental disorder. Although the severity of each varies together, that of the insomnia exists beyond what might be typically expected as a symptom of the psychiatric condition. The latter requires the presence of insomnia as well as a medical condition known to affect sleep.⁵ Under DSM-IV, however, the insomnia may be “related” to an Axis I or Axis II disorder, but the temporal continuity is not required between the 2 disorders.⁶ The problem with both definitions is that each assumes that the insomnia is “secondary” to the primary medical or psychiatric condition. However, as articulated in the 2005 NIH conference, the causal relationships appear to be more complex in most disorders.3 This article explores that assumption and highlights its implications for treatment.

Impact of Insomnia

Insomnia has a significant impact on individuals’ health and quality of life, particularly those with comorbid conditions affecting the central nervous system (CNS).^7,8 The impact appears related to theeffect on daytime functioning as well as the status of their comorbid condition. For instance, various studies found that patients with chronic insomnia have significantly higher risks for falls and accidents.^1,9 One study reported that 8% of workers with severe insomnia were involved in industrial accidents compared with 1% of good sleepers (P = .0150).¹⁰ Other studies have shown sleep-onset insomnia to be a statistically significant risk factor in being involved in a traffic accident¹¹; in fact, those suffering from insomnia are more than twice as likely to have an automobile accident.¹²

In addition, adults with severe insomnia miss twice as many workdays as those without insomnia, even when matched for work type and schedule.¹⁰ In fact, insomnia may be the greatest predictor of absenteeism in the workplace.¹³ Employees with severe insomnia have been shown to make significantly more errors at work (15% vs 6%; P <.001), and were more than twice as likely to exhibit presenteeism, or poor efficiency, as those without insomnia (18% vs 8%; P = .0004).¹⁰

People with chronic insomnia also use significantly more medical services than those without insomnia.^4,10,14,15 Leger et al found twice as many individuals with severe insomnia were hospitalized in the year prior to an administered questionnaire (18% vs 9%; P = .0017) than those without insomnia. They also found this cohort used more medications than those without insomnia, particularly cardiovascular, CNS, urogenital, and gastrointestinal drugs.¹⁰

There is also data indicating patients with depressive disorders suffering from insomnia have a greater suicide risk than those without insomnia. This translates into higher costs.^16,17 Even controlling for age, sex, and chronic disease score, average total health services are approximately 60% higher in those with insomnia than in those without insomnia.¹⁸ Ozminkowski et al found that average direct (inpatient, outpatient, pharmacy, and emergency department costs) and indirect costs (absenteeism and the use of short-term disability programs) for adults in the 6 months before a diagnosis for insomnia or beginning prescription treatment for the condition were approximately $1253 greater than for those without insomnia (ages 18-64), whereas average direct costs among adults aged 65 and older were $1143 greater.¹⁹

Although the economic and social costs of comorbid insomnia compared with primary insomnia have yet to be investigated, it is likely that they account for the majority of the annual $30 billion to $35 billion in costs for chronic insomnia simply because comorbid insomnia is so much more prevalent.^17,20

Comorbid Insomnias: Untangling the Complexities

As noted earlier, the prevalence of comorbidities and insomnia is significant. Kuppermann et al examined the records of 369 employees together with a telephone screen to evaluate various aspects of their physical and mental health and sleep quality, and found those reporting a current sleep problem were 4 times more likely to have a possible mental health problem as those reporting no sleep difficulties. They were also significantly more likely to report gastrointestinal problems, frequent headaches, and muscle, back, or neck pain.²¹

Simon and VonKorff evaluated functional impairment and healthcare utilization for patients with and without current insomnia. They found that 24% of patients with insomnia had moderate-to-severe occupational disability compared with 14% of those without insomnia (odds ratio [OR], 1.91). Patients with insomnia were also twice as likely as those without insomnia to have days of restricted activity and days spent in bed due to illness.¹⁸ Overall, 3.5 days of disability per month were associated with insomnia, an amount similar to that seen with anxiety and somatoform disorders.²²

Finally, our work evaluating sleep problems with comorbid mental disorders and role functioning using the National Comorbidity Survey Replication found all sleep problems were significantly and positively related to 1 or more anxiety disorders, mood disorders, impulse-control disorders, or substance abuse disorders.⁸ We also found significant associations between insomnia and self-reported role impairment that cannot be explained only by comorbid mental disorders, all of which supports the NIH conference report’s assertion that insomnia is a significant patient and public health problem.³

Evaluating Comorbid Insomnia

Differentiating between primary and comorbid insomnia can prove challenging for the clinician. Does the accompanying condition play a causal role in the insomnia, is it the consequence of theinsomnia, is it incidental to the insomnia, or is it comorbid? The complexity increases when the influence of sleep-related disorders on sleep quality and insomnia are considered, including sleep apnea and periodic limb movements. Similarly, circadian rhythm disorders, such as shift work disorder (Drake Sleep) or phase delay, are associated with disturbed sleep. These result in insomnia symptoms and represent special cases of comorbid insomnia. Thus, insomnia may be comorbid with medical, psychiatric, circadian, or sleep disorders.

An accurate history from the patient and possibly even the bedpartner is paramount in correctly diagnosing comorbid insomnia. Clinicians should consider comorbid insomnia when the onset of the sleep disturbances coincides with or shortly follows that of the comorbid condition; when the course of the insomnia remits and recurs in conjunction with fluctuations in the comorbid disorder; or can be directly linked to some feature of the comorbid disorder, such as pain from chronic arthritis disrupting sleep. Complicating the diagnosis, however, is the fact that insomnia often precedes a comorbid disorder, in some instances serving as an early warning sign of an occurrence or recurrence.^23,24 Finally, it is important to consider that the treatment of the comorbid condition may lead to the insomnia. Thus, respiratory stimulants, selective serotonin reuptake inhibitors (SSRIs), beta-blockers, and many other drugs are associated with reports of disturbed sleep.

Yet, as noted later in this article and in the article by Neubauer²⁵ in this supplement, the correct diagnosis of comorbid versus primary insomnia is particularly important when determining the appropriate treatment plan.

Medical Comorbid Conditions With Insomnia

Becoming aware of the more common comorbidities, which encompass a wide variety of medical, psychiatric, and sleep disorders, may assist clinicians in managing the condition.

Table 1

Taylor et al found the following prevalence of conditions in those with chronic insomnia compared with those without insomnia: chronic pain (50.4% vs 18.2%), high blood pressure (43.1% vs 18.7%), gastrointestinal problems (33.6% vs 9.2%), breathing problems (24.8% vs 5.7%), heart disease (21.9% vs 9.5%), urinary problems (19.7% vs 9.5%), and neurologic disease (7.3% vs 1.2%) ().²⁰

Table 2

In addition, they found that people with the following medical problems reported significantly more chronic insomnia than those without insomnia: breathing problems (59.6% vs 21.4%), gastrointestinal problems (55.4% vs 20.0%), chronic pain (48.6% vs 17.2%), high blood pressure (44.0% vs 19.3%), and urinary problems (41.5% vs 23.3%) ().²⁰

Leigh et al found insomnia in 31% to 81% of those with osteoarthritis,²⁶ while other studies found high levels in those with other chronic pain conditions, including rheumatoid arthritis and fibromyalgia.²⁷ Those with myocardial infarction have a 1.9 OR of mild insomnia, those with congestive heart failure a 1.6 OR of mild insomnia and 2.5 OR of severe insomnia.²⁸ Over a 2-year period, Katz and McHorney showed that more patients with hip impairment, osteoarthritis, and peptic ulcer disease reported new or worsened insomnia compared with those without these conditions.²⁸

Patients with chronic obstructive pulmonary disease (COPD) have a particularly high prevalence of insomnia, with more than 50% complaining of difficulties initiating or maintaining sleep, and 25% reporting excessive daytime sleepiness.²⁹ Insomnia may also hold significant implications for pulmonary function in those with COPD and other respiratory conditions. Phillips et al showed small but statistically significant falls in forced expiratory volume in 1 second (1.06 ± 0.11 to 1.00 ± 0.09 L; P <.05) and in forced vital capacity (2.56 ± 0.20 to 2.43 ± 0.17 L; P <.05) following a single night of sleep deprivation. Over time, this could have a significant impact on patients’ overall pulmonary status.³⁰

Patients with diabetes also report high rates of insomnia. Skomro et al found that 50% of adults with diabetes had insomnia compared with 31% of controls (P = .04), and 15.5% had high Epworth Sleepiness Scores compared with 6% of controls (P = .02).³¹ Other work finds impaired glucose regulation with shorter sleep times in those with and without diabetes, as well as an increased risk of diabetes.³²

Given that the prevalence, morbidity, and mortality of COPD and diabetes have been increasing in the United States and other countries in recent years,^33,34 and the impact of insomnia on clinical parameters, the comorbidity of insomnia with COPD and diabetes will present a significant challenge to employers and clinicians and will be an increased burden to the healthcare system in coming years.

Psychiatric Comorbidities

Insomnia is frequently (about 40% of the time) comorbid with psychiatric conditions.¹ Ford and Kamerow first reported this link in 1989.² They found that approximately 40% of patients with chronic insomnia met the diagnosis for 1 or more psychiatric disorders compared with 16% of patients without insomnia. Twenty-four percent had anxiety disorders compared with 10% without insomnia (P <.001); 14% were diagnosed with depression (compared with <1% without insomnia [P <.001]), and 8.6% were diagnosed with dysthymia (compared with 2.1% without insomnia [P <.001]).²

In a random sample of 1200 young adults (21- to 30-year-olds) in a 400,000-member health maintenance organization, Breslau et al found a lifetime prevalence of insomnia of 24.6%, with increased prevalence of major depression (31.1% vs 2.7%), any anxiety disorder (35.9% vs 19.1%), alcohol abuse (30% vs 16.7%), and drug abuse (14.4% vs 7.7%) in those with insomnia compared with those without insomnia.³⁵

Crum et al assessed the risk of alcohol-related problems among 1537 individuals at risk for problem drinking. Those who reported sleep disturbances because of worry were twice as likely to develop an alcohol-related problem as those without a sleep disturbance (OR, 2.32; 95% confidence interval [CI], 1.31-4.09). The risk was higher for those with any lifetime history of anxiety disorder or dysphoria (OR, 3.82; 95% CI, 1.56-9.38; and OR, 2.71; 95% CI, 1.25-5.91, respectively).³⁶

The timing of insomnia vis à vis psychiatric disorders may depend on the disorder itself. Most studies find that insomnia tends to precede or appear at the same time as a mood disorder episode (whether initial episode or relapse). In one study, insomnia preceded the onset of depression in 69% of cases evaluated.³⁷ In contrast, insomnia tends to appear at the same time or to follow an anxiety disorder episode (whether initial episode or relapse).³⁸

Insomnia and Major Depression

Figure

Several studies of comorbid insomnia show that depression appears as the condition most likely to exist in conjunction with chronic insomnia ().^35,39-42 Patients with physician-diagnosed major depression have a 2.6 OR of mild insomnia and an 8.2 OR of severe insomnia.²⁸ Meanwhile, Pigeon et al, in evaluating elderly patients with major depressive disorder (MDD) and/or dysthymia, found that those with persistent insomnia were 1.8 to 3.5 times more likely to remain depressed compared with those without insomnia (P = .05).⁴³

In addition to the above-reported link between insomnia and depression persistence and recurrence, concurrent insomnia and depression may contribute to the higher rates of cardiovascular disease associated with MDD and depressive symptoms.²² The Sequenced Treatment Alternatives to Relieve Depression (STAR *D) study of 4041 outpatients with MDD found cardiac disease associated with symptoms of sympathetic arousal and early-morning insomnia.⁴⁴

This is particularly interesting given that patients with chronic insomnia do show physiologic signs of hyperarousal, including increased levels of catecholamines, increased basal metabolic rate⁴⁵ and elevated core body temperature, altered heart rate, increased level of CNS as well as systemic metabolic rate, and elevated fast frequency electroencephalograph activity.⁴⁶ Many of these variables are also implicated in the development and progression of cardiovascular disease.⁴⁷

Treating Comorbid Insomnia

The treatment paradigm for comorbid insomnia has traditionally focused on treating the medical or psychiatric disorder with the expectation that the insomnia will also resolve.⁴⁸

This paradigm has affected treatment modalities for insomnia, with cognitive behavioral therapy (CBT) and hypnotics as monotherapy typically used only in those with primary insomnia, and psychiatric interventions reserved for those with comorbid insomnia.⁴⁹ It has also affected research on the appropriate treatment for comorbid insomnia.⁴⁸

Yet while treatment may resolve most symptoms of the comorbid disorder, it often does not improve the insomnia. Nierenberg et al reported that 45% of patients treated for 8 weeks with fluoxetine to MDD remission still exhibited disturbed sleep. Given that 91% of patients with posttreatment insomnia also had pretreatment insomnia, the authors concluded that the symptom was a residual one not related to medication side effects.50 Katz and McHorney showed that the majority of patients with comorbid conditions still had insomnia 2 years later.²⁸ This compares to 6% in those with primary insomnia at 1 year.² They also showed that 23% developed new-onset insomnia at the 2-year follow-up.²⁸

Conversely, treating the insomnia as a separate entity may prove more effective.^51-55 A report of several patients receiving CBT for posttraumatic stress disorder (PTSD) showed the therapy successfully resolved the patients’ PTSD, but patients still complained of insomnia. After CBT for insomnia, however, their insomnia resolved.⁵⁶

Other research finds that treating the insomnia and other medical or psychiatric condition concurrently improves insomnia in conditions as diverse as alcohol discontinuation,⁵⁷ rheumatoid arthritis,⁵⁵ menopausal-associated insomnia,⁵³ and generalized anxiety disorder.⁵⁸ Eaton et al hypothesized that

47% of the incidence of depression at the 1-year follow-up could have been prevented by addressing existing insomnia at baseline.⁵⁹

In addition, treating both the insomnia and the comorbid condition simultaneously may improve the comorbid condition more than treating it alone. Krystal et al randomized 545 patients with insomnia and comorbid MDD to either fluoxetine with nightly eszopiclone (3 mg) or placebo for 8 weeks followed by 2 weeks of continued fluoxetine plus single-blind placebo (n = 387).⁶⁰ The cotherapy group showed greater improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) scores at week 8 (P = .0004) than the monotherapy group, an improvement that was maintained at week 10 (P <.0001). The cotherapy group also exhibited significantly higher depression response and remission rates at week 10 (P <.02), specifically, with regard to HAMD-17 ratings of feelings of guilt; early, middle, and late insomnia; work and activities; retardation; agitation; anxiety psychic; somatic symptoms general; and hypochondriasis compared with the monotherapy group. Importantly, the augmentation of the antidepressant was significant even when the sleep items were excluded from the analysis. The cotherapy group maintained the improvements obtained in the double-blind period during the single-blind run-out period. In addition, after patients stopped taking eszopiclone, they continued to maintain improvements in sleep latency, wake after sleep onset, and total sleep time in the 2-week period after discontinuation (P <.05).

The percentage of patients exhibiting clinically significant insomnia was greater in the monotherapy group than in the cotherapy group at weeks 8 and 10 (54.4 vs 36.8 and 58.7 vs 40.0, respectively; P <.009). In addition, the percentage of patients with moderate-to-severe insomnia declined from 88% to 15.2% at week 8 in the cotherapy group, but only from 89% to 27% in the monotherapy group, an improvement that continued through week 10 (P <.009).

This improvement in the comorbid condition by improving sleep has also been shown by using CBT for insomnia in conjunction with an SSRI versus an SSRI only, with those patients undergoing CBT showing a more robust antidepressant response.⁶¹

Conclusion

The prevalence of chronic insomnia coexisting with 1 or more psychiatric or medical conditions is significant, with particularly high rates seen in patients with depression, chronic pain, respiratory conditions, and diabetes. Although the specific economic and quality-of-life repercussions of comorbid insomnia have not been differentiated from those with primary insomnia, they are likely quite significant. It is clear that insomnia and comorbid conditions have a bidirectional effect, with the status of each impacting the other, potentially affecting the treatment course and outcome. Treating insomnia and the comorbid condition simultaneously as separate conditions may result in greater improvements in each than treating either individually. Additional research is required on the outcomes of such a treatment approach.

Acknowledgment

Thank you to Debra Gordon, medical writer, who assisted in the writing of this article.

Author Affiliations: From the Henry Ford Hospital Sleep Disorders and Research Center, Detroit, and Department of Psychiatry, University of Michigan, Ann Arbor.

Funding Source: Financial support for this work was provided by Sepracor.

Author Disclosure: Consultant to Abbott, Actelion, Arena, BTG, Cephalon, Evotec, Intec, Intra-Cellular, Jazz, Merck, Neurim, Neurocrine, Neurogen, Organon, Pfizer, Procter & Gamble, Sanofi, Schering-Plough, Sepracor, Shire, Somaxon, Takeda, TransOral, Vanda.

Authorship Information: Acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; provision of study materials or patients; administrative, technical, or logistic support.

Address correspondence to: Thomas Roth, PhD, Director, Henry Ford Hospital Sleep Disorders and Research Center, 2799 W Grand Blvd, Detroit, MI 48202. E-mail: troth1@hfhs.org.

1. Roth T, Roehrs T. Insomnia: epidemiology, characteristics, and consequences. Clin Cornerstone. 2003;5(3):5-15.

2. Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA. 1989;262(11):1479-1484.

3. NIH State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in adults. NIH Consens State Sci Statements. 2005;22(2):1-30.

4. Fullerton DS. The economic impact of insomnia in managed care: a clearer picture emerges. Am J ManagCare. 2006;12(8 suppl):S246-S252.

5. American Academy of Sleep Medicine. The International Classification of Sleep Disorders-2. Westchester, IL:

American Academy of Sleep Medicine; 2005.

6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

7. Roth T. Insomnia: definition, prevalence, etiology, and consequences. J Clin Sleep Med. 2007;3(5 suppl):S7-S10.

8. Roth T, Jaeger S, Jin R, Kalsekar A, Stang PE, Kessler RC. Sleep problems, comorbid mental disorders, and

role functioning in the National Comorbidity Survey Replication. Biol Psychiatry. 2006;60(12):1364-1371.

9. Roth T. Prevalence, associated risks, and treatment patterns of insomnia. J Clin Psychiatry. 2005;66(suppl

9):10-13.

10. Leger D, Guilleminault C, Bader G, Levy E, Paillard M. Medical and socio-professional impact of insomnia.

Sleep. 2002;25(6):625-629.

11. Sagberg F. Driver health and crash involvement: a case-control study. Accid Anal Prev. 2006;38(1):28-34.

12. Passaro EA. Insomnia. Last updated: October 27, 2008; http://www.emedicine.com/neuro/topic418.htm.

Accessed November 18, 2008.

13. Leigh JP. Employee and job attributes as predictors of absenteeism in a national sample of workers: the importance of health and dangerous working conditions. Soc Sci Med. 1991;33(2):127-137.

14. Hatoum HT, Kong SX, Kania CM, Wong JM, Mendelson WB. Insomnia, health-related quality of life and healthcare resource consumption. A study of managed care organisation enrollees. Pharmacoeconomics. 1998;14(6):629-637.

15. Novak M, Mucsi I, Shapiro CM, Rethelyi J, Kopp MS. Increased utilization of health services by insomniacs—an epidemiological perspective. J Psychosom Res. 2004;56(5):527-536.

16. Stoller MK. Economic effects of insomnia. Clin Ther. 1994;16(5):873-897.

17. Walsh JK, Engelhardt CL. The direct economic costs of insomnia in the United States for 1995. Sleep. 1999;22(suppl 2):S386-S393.

18. Simon GE, VonKorff M. Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatry. 1997;154(10):1417-1423.

19. Ozminkowski RJ, Wang S, Walsh JK. The direct and indirect costs of untreated insomnia in adults in the United States. Sleep. 2007;30(3):263-273.

20. Taylor DJ, Mallory LJ, Lichstein KL, Durrence HH, Riedel BW, Bush AJ. Comorbidity of chronic insomnia with medical problems. Sleep. 2007;30(2):213-218.

21. Kuppermann M, Lubeck D, Mazonson P, et al. Sleep problems and their correlates in a working population. J Gen Intern Med. 1995;10(1):25-32.

22. Spitzer RL, Kroenke K, Linzer M, et al. Health-related quality of life in primary care patients with mental disorders. Results from the PRIME-MD 1000 study. JAMA. 1995;274(19):1511-1517.

23. Ford DE, Mead LA, Chang PP, Cooper-Patrick L, Wang NY, Klag MJ. Depression is a risk factor for coronary

artery disease in men: the precursors study. Arch Intern Med. 1998;158(13):1422-1426.

24. Perlis ML, Giles DE, Buysse DJ, Tu X, Kupfer DJ. Self-reported sleep disturbance as a prodromal symptom in recurrent depression. J Affect Disord. 1997;42(2-3):209-212.

25. Neubauer DN. Current and new thinking in the management of comorbid insomnia. Am J Manag Care. 2009;19:S24-S32.

26. Leigh TJ, Hindmarch I, Bird HA, Wright V. Comparison of sleep in osteoarthritic patients and age and sex matched healthy controls. Ann Rheum Dis. 1988;47(1):40-42.

27. Ancoli-Israel S. The impact and prevalence of chronic insomnia and other sleep disturbances associated with chronic illness. Am J Manag Care. 2006;12(8 suppl):S221-S229.

28. Katz DA, McHorney CA. Clinical correlates of insomnia in patients with chronic illness. Arch Intern Med. 1998;158(10):1099-1107.

29. George CFP, Bayliff CD. Management of insomnia in patients with chronic obstructive pulmonary disease. Drugs. 2003;63(4):379-387.

30. Phillips BA, Cooper KR, Burke TV. The effect of sleep loss on breathing in chronic obstructive pulmonary disease. Chest. 1987;91(1):29-32.

31. Skomro RP, Ludwig S, Salamon E, Kryger MH. Sleep complaints and restless legs syndrome in adult type 2 diabetics. Sleep Med. 2001;2(5):417-422.

32. Gottlieb DJ, Punjabi NM, Newman AB, et al. Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med. 2005;165(8):863-867.

33. Mannino DM. COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity. Chest. 2002;121(5 suppl):121S-126S.

34. Cowie CC, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health and Nutrition Examination Survey 1999-2002. Diabetes Care. 2006;29(6):1263-1268.

35. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry. 1996;39(6):411-418.

36. Crum RM, Storr CL, Chan Y-F, Ford DE. Sleep disturbance and risk for alcohol-related problems. Am JPsychiatry. 2004;161(7):1197-1203.

37. Johnson EO, Roth T, Breslau N. The association of insomnia with anxiety disorders and depression: exploration of the direction of risk. J Psychiatr Res. 2006;40(8):700-708.

38. Ohayon MM, Roth T. Place of chronic insomnia in the course of depressive and anxiety disorders. J Psychiatr Res. 2003;37(1):9-15.

39. Chang PP, Ford DE, Mead LA, Cooper-Patrick L, Klag MJ. Insomnia in young men and subsequent depression. The Johns Hopkins Precursors Study. Am J Epidemiol. 1997;146(2):105-114.

40. Dryman A, Eaton WW. Affective symptoms associated with the onset of major depression in the community: findings from the US National Institute of Mental Health Epidemiologic Catchment Area Program. Acta Psychiatr Scand. 1991;84(1):1-5.

41. Livingston G, Blizard B, Mann A. Does sleep disturbance predict depression in elderly people? A study in inner London. Br J Gen Pract. 1993;43(376):445-448.

42. Roberts RE, Shema SJ, Kaplan GA, Strawbridge WJ. Sleep complaints and depression in an aging cohort: a prospective perspective. Am J Psychiatry. 2000;157(1):81-88.

43. Pigeon WR, Hegel M, Unützer J, et al. Is insomnia a perpetuating factor for late-life depression in the IMPACT cohort? Sleep. 2008;31(4):481-488.

44. Fraguas R Jr, Iosifescu DV, Alpert J, et al. Major depressive disorder and comorbid cardiac disease: is there a depressive subtype with greater cardiovascular morbidity? Results from the STAR*D study. Psychosomatics. 2007;48(5):418-425.

45. Bonnet MH, Arand DL. 24-Hour metabolic rate in insomniacs and matched normal sleepers. Sleep. 1995;18(7):581-588.

46. Roth T. A physiologic basis for the evolution of pharmacotherapy for insomnia. J Clin Psychiatry. 2007;68(suppl 5):13-18.

47. Kamarck TW, Everson SA, Kaplan GA, et al. Exaggerated blood pressure responses during mental stress are associated with enhanced carotid atherosclerosis in middle-aged Finnish men: findings from the Kuopio Ischemic Heart Disease Study. Circulation. 1997;96(11):3842-3848.

48. Stepanski EJ, Rybarczyk B. Emerging research on the treatment and etiology of secondary or comorbid insomnia. Sleep Med Rev. 2006;10(1):7-18.

49. Buysse DJ, Reynolds CF 3rd, Kupfer DJ, et al. Effects of diagnosis on treatment recommendations in chronic insomnia—a report from the APA/NIMH DSM-IV field trial. Sleep. 1997;20(7):542-552.

50. Nierenberg AA, Keefe BR, Leslie VC, et al. Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry. 1999;60(4):221-225.

51. Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry. 1999;60(10):668-676.

52. Nolen WA, Haffmans PM, Bouvy PF, Duivenvoorden HJ. Hypnotics as concurrent medication in depression. A placebo-controlled, double-blind comparison of flunitrazepam and lormetazepam in patients with major depression, treated with a (tri)cyclic antidepressant. J Affect Disord. 1993;28(3):179-188.

53. Dorsey CM, Lee KA, Scharf MB. Effect of zolpidem on sleep in women with perimenopausal and postmenopausal insomnia: a 4-week, randomized, multicenter, double-blind, placebo-controlled study. Clin Ther. 2004;26(10):1578-1586.

54. Fava M, McCall WV, Krystal A, et al. Eszopiclone coadministered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry. 2006;59(11):1052-1060.

55. Walsh JK, Muehlbach MJ, Lauter SA, Hilliker NA, Schweitzer PK. Effects of triazolam on sleep, daytime sleepiness, and morning stiffness in patients with rheumatoid arthritis. J Rheumatol. 1996;23(2):245-252.

56. DeViva JC, Zayfert C, Pigeon WR, Mellman TA. Treatment of residual insomnia after CBT for PTSD: case studies. J Trauma Stress. 2005;18(2):155-159.

57. Le Bon O, Murphy JR, Staner L, et al. Double-blind, placebo-controlled study of the efficacy of trazodone in alcohol post-withdrawal syndrome: polysomnographic and clinical evaluations. J Clin Psychopharmacol. 2003;23(4):377-383.

58. Pollack M, Kinrys G, Krystal A, et al. Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder. Arch Gen Psych. 2008;65(5):551-562.

59. Eaton WW, Badawi M, Melton B. Prodromes and precursors: epidemiologic data for primary prevention of disorders with slow onset. Am J Psychiatry. 1995;152(7):967-972.

60. Krystal A, Fava M, Rubens R, et al. Evaluation of eszopiclone discontinuation after cotherapy with fluoxetine for insomnia with coexisting depression. J Clin Sleep Med. 2007;3(1):48-55.

61. Manber R, Edinger JD, Gress JL, et al. Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia. Sleep. 2008;31:489-495.

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