New Research on Insomnia

June 1, 2008

A number of studies have found decreased scores on quality-of-life scales in persons with insomnia, which is associated with a wide assortment of daytime impairments, some intuitive and some startling.

[[{"type":"media","view_mode":"media_crop","fid":"23130","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_8740964767071","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1768","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right; margin: 10px;","title":" ","typeof":"foaf:Image"}}]]Anyone who has spent a sleepless night needs no convincing about the subjective discomfort associated with lying in bed awake and unable to sleep. In addition to nighttime discomfort, insomnia is associated with a wide assortment of daytime impairments, some intuitive and some startling. A number of studies have found decreased scores on quality-of-life scales in persons with insomnia. On the Short Form (SF-36) Health Survey, persons with insomnia score lower than good sleepers on measures such as emotional role, mental health, and vitality. They also have lower scores on the Medical Outcomes Study Cognitive Scale and higher rates of absenteeism from work and lower productivity.1,2 Some years ago I examined the possibility that sleep disturbance might be a predictor of employment longevity. A questionnaire about sleep was given to newly hired employees at a large international bank in New York. Two years later, we examined how many of the responders were still employed by the bank. Among officers, those no longer working at the bank were more than twice as likely to have reported difficulty in sleeping as were those still employed there.3

These findings are similar to those of an earlier study of military personnel. Navy recruits who reported sleep disturbance at the time of induction had higher attrition rates and were less likely to be promoted or to be asked to reenlist.4 They also had more sick days, which is of some significance because later studies showed that persons with insomnia use the health care system substantially more often than those who do not have insomnia.

In a study of 1100 primary care patients, those who described sleep disturbance on initial intake were more likely to make phone calls to the doctor, visit the doctor's office or emergency department, undergo blood tests, or receive prescriptions in the next 8 weeks.5 The reasons for this higher rate of health care use are unclear. There is also a higher rate of falls in community-dwelling older adults with sleep disturbances, particularly women.6 Although most of us are familiar with the caution about the dangers of falls for nursing home patients who take hypnotics, one study of more than 34,000 nursing home residents found that having insomnia raised the risk of falls (odds ratio, 1.52; 95% confidence interval [CI], 1.38 to 1.66), while the use of hypnotics did not.7 Although this does not rule out the possibility that certain therapies may be associated with falls, it indicates that insomnia itself is an independent risk factor.8 Insomnia also appears to be a complicating factor in patients with depression. The coexistence of insomnia and depression is of course very common, but when severe, it is associated with higher rates of suicide as well as poorer response to cognitive-behavioral therapy.9,10 Given the many difficulties associated with insomnia, a review of new ways of thinking may be timely. This article looks at new data on the underlying physiology of insomnia, evidence that suggests that insomnia is a risk factor for other disorders, and the interaction between insomnia and coexisting conditions.

Pathophysiology

Not surprisingly, most research has been oriented to examining possible physiological counterparts to the clinical impression that persons with insomnia have excessive arousal. Early work focused on elevated heart rate and core temperature at the time of sleep onset.11 Later studies have suggested that those persons who have insomnia with sleep disruption documented on the polysomnogram have elevated nighttime circulating concentrations of cortisol and adrenocorticotropic hormone.12-14 This does not appear to be a result of sleep deprivation per se, since most studies of sleep deprivation do not report increased hypothalamic-pituitary-adrenal axis (HPA) activity. Persons with insomnia have an elevated whole-body metabolic rate, which is not seen in study participants who do not have insomnia but whose sleep has been experimentally disrupted.15,16 Perhaps most intriguing are positron emission tomography (PET) scan studies that indicate that persons with insomnia have increased overall cerebral glucose metabolic rates both when asleep and awake. In the study by Nofzinger and colleagues,17 findings indicate that although overall cerebral metabolism was elevated by day, there was a relatively lower metabolic rate in the prefrontal areas, which has been speculated to be associated with complaints of fatigue.

Persons with insomnia appear to be excessively physiologically aroused, although a number of questions remain. Most of these changes have been observed primarily in patients who have objective sleep disturbance seen on the polysomnogram, as opposed to the very interesting group who complain of sleep disturbance but who manifest minimal objective sleep changes. Whether this is a difference of degree (as has been suggested by the whole-body metabolic rate studies) or represents some fundamental difference in kind is not yet known. Similarly, whether these physiological changes have health consequences (and hence might be related to the higher rate of health care use) is uncertain. Perhaps the strongest case for the latter comes from the HPA studies, insofar as elevated cortisol has been reported to be a risk factor for coronary artery atherosclerosis.18 Finally, there remain questions of causality-are elevated circulating cortisol or cerebral glucose metabolism causes or correlates of insomnia?

Insomnia as a risk factor

Insomnia has been shown to be a risk factor for depression and anxiety disorders. In terms of temporal sequence, the most common presen- tation for sleep disturbance and depression is for insomnia to appear first, rather than at the same time or after depressive symptoms.19 As an example of studies showing increased later risk of depression, Breslau and colleagues20 monitored 1200 young adults for 3 years and found that those with insomnia at baseline had about a 4-fold increased likelihood of a new major depression developing (95% CI, 2.2 to 7.0). A recent formal analysis suggests that insomnia is a state marker of depression and anxiety, and a trait marker of anxiety disorders.21

A study of more than 2000 persons found that those who had a sleep complaint "on most nights" were substantially more likely to complain of anxiety, depression, or widespread pain (in 4 or more areas) a year later.22 There are also studies that link insomnia to hypertension even when possible confounding variables such as age and weight are held constant, as well as with increased risk of death from atherosclerotic heart disease.23 Often, sleep disturbance persists in the presence of the various illnesses.

Interaction with coexisting illness

Findings from several recent studies indicate that treatment of insomnia can ameliorate the symptoms of some coexisting illnesses. These studies are not fully consistent and can be difficult to interpret because of variations in methodology, duration of treatment, and choice of drug. (The interested reader may wish to look at more detailed reviews.24,25) In a study of 545 patients with depression, Fava and colleagues26 compared fluoxetine and eszopiclone 3 mg daily with fluoxetine and placebo. Significant improvement was seen at weeks 4 (P = .01) and 8 (P = .002) in the group treated with fluoxetine and eszopiclone on the Hamilton Rating Scale for Depression (HAM-D), and in weeks 2 through 8 on the Clinical Global Impression Severity scale, compared with those who received only fluoxetine and placebo. There were significantly (P = .009) more responders in the combination therapy group than in the monotherapy group (59% vs 48%). This suggests that adjunctive treatment of the accompanying sleep disturbance may result in more effective antidepressant response.

On the other hand, a smaller (N = 190), shorter duration (4-week) study with a different hypnotic (zolpidem 10 mg) and antidepressant (any of 3 SSRIs) found improvements in sleep, alertness, and the SF-36 Vitality subscale but not in the HAM-D.27

It is also possible that benefits for depression that result from adjunctive treatment of coexisting insomnia might not be confined to pharmacological approaches. Manber and colleagues28 recently reported that cognitive-behavioral therapy for insomnia, when given as adjunctive therapy to depressed patients receiving escitalopram, resulted in a higher rate of remission of depression at the end of the 12-week study period.

Pollack and colleagues29 randomly selected 595 patients with generalized anxiety disorder who had a sleep disturbance into groups that received escitalopram 10 mg/d plus eszopiclone 3 mg/d and those who received escitalopram plus placebo for 8 weeks. Scores on the Hamilton Rating Scale for Anxiety were reduced by half or more at week 8 significantly (P < .01) more often in the eszopiclone than in the placebo group (62% vs 49%). Remission of both insomnia and anxiety symptoms occurred significantly (P < .05) more often in the eszopiclone group as well.

Similar types of findings (again, with some inconsistencies) have been found in the adjunctive treatment of sleep disturbance in patients with rheumatoid arthritis.24 There are also data that indicate that in the first 6 months of pharmacological treatment of insomnia, there is a relative decline in general health care costs compared with untreated patients with insomnia.30 A recent review of nonpharmacological and pharmacological treatment for insomnia found that 14 of 20 studies showed improvement in health, function, or quality of life.25

New ways of thinking about insomnia

The studies outlined in this article have led to a number of changes in the way sleep researchers approach insomnia. The growing recognition that insomnia is associated with changes in quality of life and a wide range of daytime impairments has led to interest in including these types of variables, as well as traditional measures of sleep, in treatment efficacy studies. In other words, we need to examine not only how treatments affect sleep but how they affect waking life as well.

The growing evidence that insomnia is a risk factor for a variety of other illnesses, and the finding that the treatment of insomnia may improve the therapy of some coexisting illnesses have also contributed to a change in thinking. This found expression in the 2005 NIH state-of- the-science statement on chronic insomnia.31

One result has been that most sleep researchers now refer to insomnia in the context of another illness as "comorbid insomnia," rather than "secondary insomnia." This is much more than a change in phraseology, because it emphasizes that insomnia is a process that can interact with a coexisting illness and is not merely a consequence of the other disorder. Of course, there are a number of ways in which a risk factor might be associated with a second illness: insomnia, for instance, might be an early manifestation of another condition; alternatively, sleep disturbance might make a person more susceptible to another illness, or both might be consequences of a more fundamental disorder. In a recent article, I outlined these various possibilities, using the interrelationship of insomnia and depression as a model.24

Conclusion

If these studies continue to support the comorbid model, this would suggest a very specific change in the way many of us treat insomnia. For sev- eral decades, most sleep researchers emphasized that when insomnia is found accompanying another illness, the best strategy was to treat the underlying illness (for instance, major depression or arthritis), and the insomnia would then "take care of itself." The new data raise the possibility that adjunctive nonpharmacolog-ical or pharmacological management of the sleep disturbance may make it easier to treat the accompanying illness.

Disclosures:

This is not an industry-supported project. The author serves as a consultant or member of the speakers' bureau for the following companies: Neurocrine Biosciences, Neurogen, Sanofi-Aventis, Sepracor, and Takeda. He is also a consultant to the nonphar-maceutical companies Abiant, VivoMetrics, and ScienceFirst.

References:

References


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