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Milton K. Erman, MD
 

Primary Psychiatry. 2007;14(6):31-35

Dr. Erman is clinical professor in the Department of Psychiatry at the University of California, San Diego School of Medicine, is a staff scientist for the Scripps Research Institute Department of Neuropharmacology, and is the president of Pacific Sleep Medicine Services.

Disclosure: Dr. Erman is a consultant to Cephalon, Mallinckrodt, Neurocrine, sanofi-aventis, and Takeda; is on the speaker’s bureaus of Forest, sanofi-aventis, and Takeda; is on the advisory boards of Cephalon, Neurocrine, sanofi-aventis, and Takeda; has received grant/research support from Arena, Cephalon, Eli Lilly, GlaxoSmithKline, Mallinckrodt, Merck, Organon, Pfizer, Pharmacia, ResMed, sanofi-aventis, Schwarz Pharma, and Takeda; and owns stock in Cephalon, Forest, Merck, Neurocrine, Pfizer, sanofi-aventis, and Sepracor.

 


“There is only one thing people like that is good for them; a good night’s sleep.”

Edgar Watson Howe (American Editor, Novelist and Essayist, 1853-1937)

In most areas of medical practice, an understanding of the etiology of a clinical condition is helpful in making appropriate choices about the need to treat, about which treatments should be given, and when treatment is appropriate. In the assessment and treatment of insomnia such information is critical and contributes strongly to the physician’s capacity to develop a treatment plan that is likely to be effective for the treatment of the insomniac patient.

Comorbid medical and psychiatric conditions contribute to the development of insomnia and these comorbid conditions are made worse by the presence and persistence of insomnia. When conditions such as depression, chronic pain, and even sleep apnea are present, they must be recognized and addressed as a component of the overall treatment plan. These conditions are associated with documented changes in sleep architecture, as well as subjective complaints of disturbed, poor quality sleep.

When insomnia is persistent, it may have significant impact on social and work functioning, health outcomes, and comorbid conditions. Insomniacs demonstrate higher rates of absenteeism from work, poorer quality of life, greater risk of falls, higher rates of mortality, etc.

How can recognition of these conditions affect treatment choices and patient outcomes? When sleep is disrupted in association with conditions such as nocturnal pain, restless legs, or depression, the comorbid disorder must be treated to maximize the probability of a successful treatment response. For all patients, consideration of sleep habits and education about sleep hygiene should be incorporated into treatment regimens, whether or not hypnotic medication is used as well.

Assessing Insomnia

At all ages, healthy individuals should be able to sleep well. Since sleep needs vary among individuals and across the lifecycle, it is not possible to specify a specific amount of sleep that is “needed” or “ideal” for any individual. Individuals with healthy, normal sleep should be free of symptomatic complaints about their sleep (ie, insomnia complaints), and should be able to remain alert throughout the daytime, avoiding unwanted naps or bouts of sleep suggestive of a hypersomnia (excessive sleepiness) disorder. Normal sleep occurring at inappropriate or undesirable hours may be a component of sleep disorders such as delayed sleep phase syndrome and advanced sleep phase syndrome.

Two general categories of insomnia exist, primary insomnia and comorbid insomnia. Primary insomnia is defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)1 by insomnia symptoms lasting at least 1 month, causing fatigue or impairment, and not caused by a mental or physical disorder, a primary sleep disorder, or the effects of a medication. Patients with primary insomnia are typically the subject population identified as a group to be tested to determine whether medications are effective as hypnotics. The State of the Science Conference2 emphasized the role that comorbid conditions can have in generating and perpetuating insomnia complaints. The report noted that insomnia usually appears in the presence of at least one other disorder. Particularly common core beauties are major depression, generalized anxiety, substance abuse, attention deficit/hyperactivity in children, dementia, and a variety of physical problems.”

Comorbidities

Depression

Clinicians have long recognized and have been taught in clinical training that sleep and mood are closely related. The DSM-IV1 includes symptoms of disturbed sleep as one of the primary diagnostic criteria for major depression and for mania. A large portion of research performed over the past 40 years has validated this relationship, and has also demonstrated that specific abnormalities of sleep are seen in association with depressive disorders.

Sleep is altered in depression, whether assessed subjectively or objectively. Depressed patients complain of difficulty initiating sleep at the start of night, of problems with sleep maintenance and non-restorative sleep, as well as of the “classic” complaint of early morning awakening (Figure).2-4 Severity of sleep complaints has been used as a tool to assess treatment response, with data demonstrating that the more severe the sleep complaint, the more treatment resistant the depression is likely to be.4

Depressed patients demonstrate objective changes in sleep continuity and architecture. Critical work demonstrating these relationships was performed at the University of Pittsburgh by Kupfer and colleagues5 and by Gillin and colleagues6 at the National Institute of Mental Health (NIMH). It was first demonstrated in the 1970s that sleep electroencephalogram (EEG) data could be used to predict treatment outcomes with antidepressants5 or to differentiate depressed patients from insomniacs and healthy controls.6 Sleep abnormalities associated with depression included reduced rapid eye movement (REM) latency and alterations in REM density and activity.7,8 Sleep abnormalities characteristic of depression can also persist for prolonged periods of time in otherwise asymptomatic individuals.9

Research has also demonstrated that changes in sleep architecture are predictive in the diagnosis of depression, of probable response to treatment, and of risk of relapse in the future. For example, Nofzinger and colleagues10 have shown that features of sleep which are disturbed in depression, such as REM density, may be ”normalized” with cognitive therapy, while others, such as REM latency or slow wave sleep, are not affected. Thase and colleagues11 have shown that severely depressed patients with more disturbed polysomnographic sleep profiles were less likely to benefit from cognitive-behavioral therapy.

It is reasonable to question whether the presence of insomnia prior to the onset of depression increases the likelihood that depression will develop. A large body of epidemiologic data suggests that this is the case. In 1989, Ford and Kamerow12 presented data gathered as part of the NIMH Epidemiologic Catchment Area study. There were 7,954 respondents questioned at baseline and again 1 year later about sleep complaints and psychiatric symptoms. Far higher rates of psychiatric disorder were seen in those with insomnia (40%) compared with of those with no sleep complaints (16.4%). Although this could be interpreted as a sign of the concurrent comorbidity of these disorders, this hypothesis was refuted by data reflecting the presence of depression at the 1-year follow-up interview. Those who had insomnia at both interviews had almost 40 times the risk of developing new major depression compared with subjects who never reported insomnia (odds ratio=39.8). For subjects whose initial insomnia had resolved by the time of the second interview, there was only a slight increased risk of depression compared to those who had never experienced insomnia (OR=1.6).

Dryman and Eaton13 used data from the Epidemiologic Catchment Area Program to examine relationships between insomnia symptoms and the onset of major depression. Overall, the results indicated a strong positive association between initial insomnia symptoms and the development of depressive symptoms over the following year. Perlis and colleagues14 have also shown that new episodes of major depression are often preceded by periods of insomnia.

Chang and colleages15 reviewed data from The Johns Hopkins Precursors Study, a long-term prospective study of 1,053 male medical students at Johns Hopkins University. Data gathered on sleep habits during medical school assessed the risk for subsequent clinical depression. Over a median follow-up period of 34 years, the relative risk of developing clinical depression was doubled among those who experienced insomnia in medical school compared with those who did not have insomnia.15

Breslau and colleagues16 performed a longitudinal prospective study of 1,200 individuals between 21 and 30 years of age, drawn from members of a large health maintenance organization (HMO) in Michigan. Lifetime prevalence of insomnia alone was 16.6%. The relative risk for new onset of major depression during the 3.5 year follow-up period in those with insomnia at baseline was 4. Long-term insomnia remains a significant risk factor for subsequent major depression.

Sleep Apnea

Sleep apnea patients frequently present with complaints of fatigue which they may attribute to insomnia. Obstructive sleep apnea (OSA) is the most common form of sleep apnea and is a state-dependant disorder of breathing. OSA occurs because of obstruction in the upper airway, developing due to the reduced muscle tone during sleep and the negative upper airway pressure associated with inspiratory effort. Apnea is usually worse in REM sleep, due to reductions in muscle tone and activity associated with the REM state and changes in breathing dynamics associated with REM. The most common clinical signs of OSA are loud snoring, interrupted or absent breathing in sleep, breathing pauses observed by a bed-partner or family member, and excessive daytime sleepiness. Some patients report awareness of awakening from sleep with a sensation of choking, at times associated with dreams of drowning or suffocating. Other common symptoms include a history of restless sleep, morning headache, morning sore throat, and daytime fatigue.17

How may a patient with apnea present with an insomnia complaint? These patients will typically report no problems with sleep initiation, but will report awakening several times over the course of the night. They report that they are usually able to to return to sleep without great difficulty, and report obtaining a relatively “normal” amount of sleep, often 7–8 overall hours. They complain of fatigue in the morning and throughout the rest of the day, relating this to their insomnia. Their focus is, “Help me to sleep through the night so I can be rested when I wake in the morning.” These patients are not aware of their multiple apnea events occurring over the night; they often report awakening 4–5 times over the night, likely associated with more severe apneas and tendencies to larger drops in oxygen saturation seen in REM sleep.

These patients, with complaints of several awakenings during the night and of nonrestorative sleep or fatigue, should be evaluated with polysomnography (laboratory sleep studies). Although portable monitoring devices to evaluate suspected OSA are available, these devices as effective diagnostic instruments provide limited data of uncertain validity and reliability.18 Since they provide no formal EEG data, sleep cannot be differentiated from wake, and REM sleep from non-REM sleep. These limited studies are usually performed in an unattended fashion in the patient’s home, a poorly controlled, and often chaotic, environment. Since these studies usually are performed without a sleep technician present, no observations can be made about body position, movement, or the sleep environment. The diagnosis of sleep apnea may often be strongly suggested based on history and physical examination, but the Practice Parameters of the American Academy of Sleep Medicine (AASM) still define polysomnography as the “reference or ‘gold standard’“ in the evaluation of sleep disordered breathing. The issue of the use of portable monitoring devices in the investigation of suspected OSA has been reviewed by the AASM,19 with the general finding that none of these devices were felt to be suitable for use in an unattended setting.

OSA is associated with an increased risk of cognitive abnormalities and of affective disorders such as depression.20 Cognitive impairment associated with apnea may be misdiagnosed as dementia, with capacity for substantial improvement in cognition associated with effective treatment. Similarly, untreated apnea may exacerbate depression severity or limit response to therapy, with substantial improvement in mood seen after treatment is initiated.21 OSA is associated with a wide variety of health-related consequences, quality of life is demonstrably impaired in patients with OSA, including complaints of fatigue, memory impairment, reduced concentration, depressed mood, and irritability. Some patients may experience decreased libido or erectile dysfunction.  

Nasal continuous positive airway pressure (CPAP) administered via a nasal mask or interface is the treatment of choice for moderate to severe obstructive sleep apnea. Although patients may be skeptical about their capacity to use CPAP, continuing technical improvements in the design of masks and CPAP units has lead to dramatically increased acceptance of CPAP therapy. Other medical treatment options include efforts at weight loss, avoidance of alcohol, avoiding all sedating medications at night (unless CPAP is used), and avoiding the supine position in sleep.

Restless Leg Syndrome

Restless legs syndrome (RLS) is another disorder that may be associated with poor sleep. RLS is diagnosed on the basis of symptomatic complaints. Patients use a broad range of terms to describe the sensation of discomfort they experience in their limbs, including creeping, crawling, tingling, pulling, twitching, tearing, aching, throbbing, prickling or grabbing sensation in the calves, and crawling/tingling/electrical sensations in the legs or arms. Symptoms typically are more severe during periods of inactivity or rest or while sitting or lying down. There is also a strong circadian component, with symptoms typically worse in the evening and nighttime hours. As many as 5% to 10% of the adult population suffers from RLS, with initial symptoms often appearing in early adulthood. The disorder may appear in childhood, but, in general, older patients are more likely to experience RLS complaints than younger ones. Due to lack of physician awareness of this disorder, it is not uncommon for patients to experience symptoms for as long as 25 years without receiving appropriate diagnosis or treatment.

Dopamine agonists have been demonstrated to be effective in treating RLS complaints. The only medications formally approved by the United States Food and Drug Administration at this time for RLS are ropinirole and pramipexole, although other dopamine agonists are often used in an “off label” fashion. Sedating benzodiazepines such as clonazepam have often been used in treatment of this disorder. Although such agents do not alter the frequency of leg movement activity and may lead to residual sedation, patients may experience a sense of relief, presumably on the basis of sleep consolidation.

Consequences of Insomnia

In a large number of research studies, insomnia has been demonstrated to impact daytime function and quality-of-life. Katz and McHormey22 examined the association between insomnia and Health-Related Quality of Life (HRQOL) in patients with chronic illness, attempting to exclude effects of depression, anxiety, and medical comorbidities.There were 3,445 patients recruited from practitioners of family medicine, internal medicine, endocrinology, cardiology, and psychiatry. Patients completed a self-administered questionnaire and were given a diagnosis of 1 or more of 5 chronic medical and psychiatric conditions.

Outcomes included sleep items, HRQOL, chronic medical comorbidity, depression, and anxiety. Insomnia was defined as the complaint of difficulty initiating or maintaining sleep. Insomnia was severe in 16% and mild in 34% of study patients. Patients with insomnia demonstrated significant reductions in HRQOL; insomnia was independently associated with worsened HRQOL to almost the same extent as chronic conditions such as congestive heart failure and clinical depression.

The impact of insomnia varies significantly between individuals. In a telephone survey study, Zammit and colleagues23 questioned individuals with insomnia complaints about their absenteeism from work. Insomnia subjects reported a highly significant (P<.0001) difference from age and sex matched normal controls, with a rates of absenteeism almost 10 times that of controls (15.8% vs 1.6%).23 Use of sleep-promoting medication, either prescription or over the counter, was not a basis for exclusion from the study.

It is reasonable to assume that insomniacs, who report sleeping less at night, should feel sleepy in the daytime on the basis of sleep deprivation. Indeed, formal sleep deprivation (sleep restriction) is used in several behavioral therapies utilized to treat insomnia. However, when daytime testing is performed on insomnia patients, excessive daytime sleepiness, is typically not seen.24,25 This absence of daytime sleepiness, despite reduced amounts of sleep at night, is presumed to be a consequence of increased levels of physiologic, cognitive, and cortical arousal experienced by insomniacs. This increased level of arousal prevents sleepiness during the daytime, but interferes with the capacity to fall asleep and stay sleep during the night.26

Some data suggests that insomnia patients may experience impairments in daytime function similar to those experienced by patients with hypersomnia conditions. For example, in one survey exploring problems experienced by individuals with or without sleep complaints, 9% of individuals reporting chronic insomnia problems reported having had a serious accident in the past year, compared to only 2% among individuals without insomnia complaints.27,28

Dew and colleagues29 reviewed polysomnographic data collected from 184 community-dwelling individuals between 55 and 80 years of age who had participated in polysomnographic sleep research studies at the University of Pittsburgh. None had impaired cognition, complaints of insomnia or hypersomnias, or any significant health problems. They were not taking any medications known to affect sleep. Data were collected on survivors at intervals of up to 19.5 years following the initial evaluation, with a mean interval of 12.8 years. Among the analyses performed were calculation of sleep latency (the duration of wakefulness after “lights out” until entry into consolidated sleep) and of sleep efficiency (percent of time spent asleep per night, defined as total sleep time/time in bed). Controlling for age, gender, and baseline medical burden, individuals with baseline sleep latencies >30 minutes were at 2.14 times greater risk of death (P=.005,) Those with sleep efficiency <80% were at 1.93 times greater risk (P=.014). Similar results were seen in another study, performed in community-dwelling older individuals. Pollak and colleagues30 found that “severe” insomnia among males (but not females) was related to increased risk for mortality during a 3.5 year follow-up period.

Concern is often expressed about the role that medications may play in provoking falls in elderly patients who awaken during the night. Various factors could play a role in the risk of falls associated with medication, including ataxia, that may be seen as a dose-related side effect of benzodiazepine agonist medications. Another group of agents used off label to treat insomnia, heterocyclic and tricyclic antidepressants (TCAs; ie, trazodone and amitriptyline) may also increase risk of falls secondary to orthostatic hypotension, a side effect seen in association with treatment with these agents.

A recent study by Avidan and colleagues31 examined the rate of falls in a nursing home population in Michigan. Among study conclusions was that, in elderly nursing home residents, insomnia, but not hypnotic use, was associated with a greater risk of falls. Although this may seem counterintuitive, if hypnotic medications reduce episodes of awakening during the night and prevent elderly residents from falling due to orthostasis or tripping over objects in their bedrooms, appropriate hypnotic medications could be of benefit in reducing falls. The authors observed: “These data are among the first to suggest that current hypnotics may not make a major contribution to falls or hip fractures among institutionalized older people.”31 To explain this finding, they also observed: “These data could support the speculation that reduction of insomnia using short-acting, non-benzodiazepine hypnotics may actually reduce the risk for subsequent falls.”31 PP

References

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2. National Institutes of Health. National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep. 2005;28(9):1049-1057.

3. International Classification of Sleep Disorders. Diagnostic and Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.

4. Sleep Disorders. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision. Washington, D.C.; American Psychiatric Association. 2000:551-607.

5. Kupfer DJ, Foster FG, Reich L, Thompson SK, Weiss B. EEG sleep changes as predictors in depression. Am J Psychiatry. 1976;133(6):622-626.

6. Gillin JC, Duncan W, Pettigrew KD, Frank BL, Snyder F. Successful separation of depressed, normal, and insomniac subjects by EEG sleep data. Arch Gen Psychiatry. 1979;36(1):85-90.

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9. Rush AJ, Erman MK, Giles DE, et al. Polysomnographic findings in recently drug-free and clinically remitted depressed patients. Arch Gen Psychiatry. 1986;43(9):878-884.

10. Nofzinger EA, Schwartz RM, Reynolds CF 3rd, et al. Affect intensity and phasic REM sleep in depressed men before and after treatment with cognitive-behavioral therapy .J Consult Clin Psychol. 1994;62(1):83-91.

11. Thase ME, Simons AD, Reynolds CF III. Abnormal electroencephalographic sleep profiles in major depression: association with response to cognitive behavior therapy. Arch Gen Psychiatry. 1996;53(2):99-108.

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13. 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.

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

15. Chang PP, Ford DE, Mead LA, et al. Insomnia in young men and subsequent depression. The Johns Hopkins Precursors Study. Am J Epidemiol. 1997;146(2):105-114.

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

17. Guilleminault CG, Bassiri A. Clinical features and evaluation of obstructive sleep apnea-hypopneas syndrome and upper airway resistance syndrome. In: Kryger M, Roth T, Dement W, eds. Principles and Practice of Sleep Medicine. 4th ed. Philadelphia, Pa: Elsevier Saunders; 2005;87:1043-1052,

18. Liesching TN, Carlisle C, Marte A, Bonitati A, Millman RP. Evaluation of the accuracy of SNAP technology sleep sonography in detecting obstructive sleep apnea in adults compared to standard polysomnography. Chest. 2004;125(3):886-891.

19. Chesson AL Jr, Berry RB, Pack A; American Academy of Sleep Medicine; American Thoracic Society; American College of Chest Physicians. Practice parameters for the use of portable monitoring devices in the investigation of suspected obstructive sleep apnea in adults. Sleep. 2003;26(7):907-913.

20. El-Ad B, Lavie P. Effect of sleep apnea on cognition and mood. Int Rev Psychiatry. 2005;17(4):277-282.

21. Suhner AG, Darko DD, Erman MK, Riel KF, Mitler MM. Depressive symptoms in patients with OSA and the impact of nasal CPAP treatment. Sleep. 2003;25:A225.

22. Katz DA, McHormey CA. The relationship between insomnia and health-related quality of life in patients with chronic illness. J Fam Pract. 2002;51(3):229-235.

23. Zammit GK, Weiner J, Damato N, et al. Quality of life in people with insomnia. Sleep. 1999;22(suppl 2):S379-S385.

24. Stepanski E, Zorick F, Roehrs T, Young D, Roth T. Daytime alertness in patients with chronic insomnia compared with asymptomatic control subjects. Sleep. 1988;11(1):54-60.

25. Bonnet MH, Arand DL. The consequences of a week of insomnia. II: Patients with insomnia. Sleep. 1998;21(4):359-368.

26. Bonnet MH, Arand DL. Hyperarousal and insomnia. Sleep Med Rev. 1997;1(2):97-108.

27. National Sleep Foundation. 2003 Sleep in America Poll. Available at: http://www.sleepfoundation.org/_content/hottopics/2003SleepPollExecSumm.pdf. Accessed August 23, 2006.

28. Balter MB, Uhlenhuth EH. New epidemiologic findings about insomnia and its treatment. J Clin Psychiatry. 1992;53(Suppl):34-39.

29. Dew MA, Hoch CC, Buysse DJ, et al. Healthy older adults’ sleep predicts all-cause mortality at 4 to 19 years of follow-up. Psychosom Med. 2003;65(1):63-73.

30. Pollak CP, Perlick D, Linsner JP, Wenston J, Hsieh F. Sleep problems in the community elderly as predictorsof death and nursing home placement. J Community Health. 1990;15:123-135.

31. Avidan AY, Fries BE, James ML, et al. Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc. 2005;53(6):955-962.