Associated Disorders and Conditions

Introduction

Patients with insomnia most commonly have comorbid conditions. Psychiatric disorders, medical disorders, circadian rhythm disorders, or substances or medications coexist in nearly 85% of chronic insomnia sufferers (Table 6-1).

A polysomnographic study determined that insomnia was 2.2 times as likely to occur in patients with prior medical disorders than in those without. These disorders included heart disease, hypertension, diabetes, stomach ulcers, arthritis, migraine, asthma, chronic obstructive pulmonary disease (COPD), neurological problems and menstrual problems. The prevalence of insomnia increased with the increasing number of medical disorders (Figure 6-1).

Conversely, people with prior insomnia are more likely to report medical problems. In a community sample study, individuals with insomnia were found to be significantly more likely than those without insomnia to report various medical problems (Figure 6-2). These included heart disease (21.9% vs 9.5%), high blood pressure (43.1% vs 18.7%), neurologic disease (7.3% vs 1.2%), breathing problems (24.8% vs 5.7%), urinary problems (19.7% vs 9.5%), chronic pain (50.4% vs 18.2%) and gastrointestinal problems (33.6% vs 9.2%).

These associations may be multifactorial and multidirectional, and may be related to many risk factors for disease. The complex nature of these correlations and the direction of causality have yet to be fully elucidated, and may vary in each individual case. Nonetheless, insomnia appears to be a risk factor for developing medical and/or psychiatric conditions.

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Psychiatric Comorbidities

Insomnia confers a heightened risk for the presence of a current psychiatric disorder, and many (about 40%) of the comorbidities associated with insomnia are psychiatric in nature. Anxiety disorders are the most frequent psychiatric diagnoses in patients with insomnia. One study found that the odds of having at least one psychiatric diagnosis were 5.04 times greater in patients with severe insomnia compared with those without insomnia. Increasing insomnia severity was associated with increased occurrence of chronic medical and psychiatric illnesses. In one study in psychiatric inpatients, insomnia was present in 79.3% of patients, while clinically moderate to severe insomnia had a prevalence of 57.7%.

As discussed in the prior chapter, the relationship between insomnia and psychiatric comorbidities may be bidirectional. It is more common for insomnia to emerge prior to rather than during or following major depression, and insomnia may be predictive of an increased risk for the future emergence of a psychiatric disorder. Moreover, in those with treated depression and in remission, persistence of insomnia leads to greater risk of recurrence of insomnia. Therefore, the presence of insomnia should alert clinicians to the possibility of an impending psychiatric condition.

Clinical experience suggests that patients who have insomnia in the context of a psychiatric disorder may not appreciate the connection between insomnia and their emotional impairment. They may also not be aware of the psychiatric disorder itself and focus, instead, on insomnia. Therefore, when evaluating patients with insomnia, the stigmata of specific psychiatric conditions should be carefully elicited. In the clinical management of insomnia, it is not atypical for patients to fit diagnostic criteria for a depressive or anxiety disorder, even though they do not “feel” depressed or anxious.

Anxiety Disorders

Insomnia and anxiety disorders often coexist. Those that are commonly associated with insomnia include generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD) and panic disorder. Chronic insomnia sufferers are about 17 times more likely to have clinically significant anxiety (i.e., anxiety needing clinical attention). Similarly, it is estimated that 70% to 90% of patients with GAD have insomnia as a complaint. Even in individuals with insomnia who do not have a current psychiatric disorder, the persistence of insomnia confers an increased risk for the development of future anxiety disorders.

Two anxiety disorders, GAD and PTSD, include sleep disturbance as part of the diagnostic criteria. Fifty percent to 70% of GAD sufferers and 70% to 90% of PTSD patients report sleep disturbances. The sleep of GAD patients is characterized by an increased time required to fall asleep and increased awakenings and arousals after falling asleep, as well as a decrease in the percentage of time slept in deeper stages (3 and 4) of sleep. Patients with PTSD frequently awaken with startle symptoms and physiologic arousal following trauma-related nightmares, typically during REM sleep.

When a patient presents with the main symptoms of insomnia in the context of an anxiety disorder, it is clinically helpful to attempt to understand the relationship between these two entities and the relative contribution of each entity to the clinical picture. Clearly, treatment of the anxiety disorder with agents specifically intended for each disorder is paramount. Studies reveal that this practice can diminish insomnia severity as well, although this area has not been well explored. In addition, appropriate management of the comorbid insomnia directly may be relevant, especially if it is a significant cause of distress and impairment.

If left untreated, insomnia may develop into an independent and self-perpetuating disorder. For example, persistently disturbed sleep caused by an anxiety disorder may lead to the development of anticipatory anxiety prior to bedtime and increased mental and physical activation, which, in turn, further disturbs sleep. In this scenario, concurrent management of the insomnia with CBT-I and/or pharmacologic agents may be of greater value than treatment of the anxiety disorder alone.

Mood Disorders

There is a strong association between insomnia and mood disorders; insomnia is reported by most patients with major depression (up to 80-100% during a depressive episode). Sleep patterns include difficulty falling asleep, frequent nocturnal awakenings, early morning awakening, nonrestorative sleep, decreased total sleep and disturbing dreams. Daytime fatigue/tiredness is also common. Note that in the Patient Health Questionnaire 9 (PHQ-9), one question concerns sleep, and a different question concerns daytime energy levels. Insomnia is a common complaint in bipolar patients in the depressed phase. In the latter, hypersomnia is also a frequent complaint, with lengthy nocturnal sleep periods extending into the day, difficulty awakening and excessive daytime sleepiness. Hypersomnia is also common in seasonal affective disorder, during episodes of winter depression. During manic periods, however, patients usually report significantly reduced amounts of total sleep, often with a subjective sense of a decreased need for sleep. Conversely, 14% to 20% of individuals with significant complaints of insomnia show evidence of major depression, whereas rates of depression are <1% in those without sleep complaints.

Longitudinal studies indicate that insomnia is more likely to emerge prior to, rather than following, the onset of the acute phase of a mood disorder. The complaint of insomnia also confers an increased risk for the development of new psychiatric disorders over the course of the ensuing year, a risk that diminishes if the insomnia resolves. Other studies have noted an enhanced risk for mood disorders for a median of 34 years following the complaint of insomnia. From a clinical standpoint, these data suggest that the presence of chronic insomnia should alert the clinician to the possibility of the future emergence of a mood, anxiety, or substance use disorder. And though little evidence exists that its treatment reduces the incidence of a mood disorder, appropriate intervention for resolution of the insomnia should be considered.

Insomnia, depression and anxiety often form a clinical triad. The Nord-Trondelag Health Study (HUNT)-2 study examined the association of insomnia symptoms and physical and mental conditions in 47,700 individuals, aged 20 to 89 years, in Norway. Individuals who reported insomnia symptoms were significantly more likely (adjusted odds ratio [OR] 2.42) to also have anxiety (Hospital Anxiety and Depression Scale–Anxiety [HADS-A] ≥8). Similarly, the likelihood of depression (Hospital Anxiety and Depression Scale–Depression [HADS-D] ≥8) was significantly higher in individual with insomnia symptoms (adjusted OR 1.99).

Insomnia that occurs during a depressive episode should, at least in theory, be mitigated following management of the underlying depression. However, insomnia persists in many of the individuals whose depression has been successfully managed, in which case it may represent either a side effect of the antidepressant or a symptom of a persistent, subsyndromal depression. It may also indicate an independent insomnia disorder.

The presence of insomnia in the depressed patient is also associated with greater levels of suicidal ideation. Sleep disturbances in these patients, particularly nightmares, have been shown to be associated with recurrent suicidal behavior, gestures, or threats, or self-mutilating behavior. Therefore, the observation of chronic insomnia should alert the clinician to the possibility of the future emergence of a mood, anxiety, or substance use disorder, especially in those who have had prior such problems. Additionally, the lack of sufficient response to the treatment of presumed insomnia should be an indication of an underlying disguised mood, substance use, or anxiety disorder that may warrant independent management.

Bipolar Disorder

An estimated 45-55% of patients with bipolar disorder experience insomnia in inter-episode periods. The depressed phase of bipolar disorder is characterized by extended period of sleep and hypersomnia, although sleep quality is often impaired. On the other hand, diminished need for sleep is one of the hallmark symptoms of mania. Polysomnographic studies of unmedicated manic patients have demonstrated shortened total sleep time, increased time awake in bed and shortened REM latency—similar to patterns seen in depressed patients. It is unclear whether polysomnographic abnormalities seen in mania are caused by the neurophysiological underpinnings of the processes that result in mania or secondary to other features of mania, such as increased levels of physical or mental activity, or changes in metabolism.

Impaired sleep can also predict the onset of manic episodes in patients with bipolar disorder. Many triggers of mania, including biological causes (drugs, hormones, withdrawal, etc.), psychic effects (separation, bereavement, etc.), and direct disturbances of sleep schedules (from newborn infants, shift work, travel, etc.), could be related to the genesis of mania through sleep reduction. Thus, sleep deprivation may be both a cause and a consequence of mania. Therefore, in mania, regarding sleep:

• Fundamental marker is decreased need for sleep
• Sleep deprivation is a common precipitator of mania and may in fact be a fundamental etiological agent in mania
• Decreased total sleep time is a predictor of future manic episodes
• Total sleep time may be a marker of response as well as a target of treatment in mania.

Schizophrenia

Insomnia is present in approximately 40% of patients with schizophrenia, although it is seldom the predominant complaint. It occurs regardless of either medication status (never medicated or presently on medications) or the phase of the clinical course (acute or chronic). Patients typically have both sleep-onset and sleep-maintenance insomnia. Patients often complain of daytime sleepiness, but it is unclear whether this is due to the distorted sleep architecture, the medication(s) used, to the disease itself, or a combination of these. A meta-analysis of polysomnographic findings from studies in individuals with mental disorders found that schizophrenia was associated with sleep continuity and sleep architecture alterations and longer REM latency (8 studies).

Attention-Deficit Hyperactivity Disorder (ADHD)

Sleep difficulties are present in 25% to 50% of children with ADHD although the etiology is poorly understood. In adults, it may be secondary to other comorbid psychiatric disorders, such as MDD, anxiety disorders, personality disorders, substance abuse disorders, or bipolar disorder. However, in one study of adults with ADHD and no identifiable psychiatric comorbidity, sleep was still impaired. Polysomnography showed increased nocturnal motor activity, and the degree of objective sleep disturbance was disproportionately higher than that reported on subjective measures. Data from a Dutch population-based study showed an insomnia prevalence of 43% among adults with clinically significant ADHD.

The increased nocturnal motor activity of adult patients with ADHD may be also related to restless legs syndrome (RLS), a neurologic disorder of uncertain etiology characterized by unpleasant sensations deep inside the legs (discussed below). One study demonstrated that patients diagnosed with RLS had symptoms compatible with ADHD. The authors speculated that RLS could manifest as hyperactivity and, by producing poor sleep quality, could lead to cognitive impairment, including lack of concentration. An alternative hypothesis is that RLS and ADHD may be part of a single symptom complex related to dopaminergic dysfunction. However, even though this and other data show an association between ADHD and RLS, further clinical trials and epidemiologic studies are needed to quantify the relationship and the degree of association. Nonetheless, the clinician who sees either condition should address the possibility of coexistence of the two.

Substance Abuse

Most addictive substances can induce sleep disturbances that persist despite abstinence and may increase the risk for relapse. Insomnia is extremely common in active and recovering alcoholics. Studies consistently show that use of illicit drugs can lead to insomnia and also that those with insomnia have a greater likelihood of abusing drugs. Across seven studies of 1577 alcohol-dependent patients undergoing treatment, more than one half reported insomnia symptoms (mean 58%), a rate that is substantially higher than the rate of the general population (33%). Nicotine, marijuana, cocaine, stimulants and opioids also can disrupt sleep (Table 6-2). The clinician should keenly be aware of this bidirectional relationship and address each condition accordingly.

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Neurological Comorbidities

As insomnia is a disorder of the nervous system, it is associated with many types of neurological abnormalities, such as stroke, sleep-disordered breathing and movement disorders.

Neurodegenerative Diseases and Insomnia

Alzheimer’s Disease

Twenty-five percent of Alzheimer’s patients experience insomnia at some point during their illness. Moreover, disrupted nocturnal sleep, as well as increased levels of daytime sleepiness, appears to intensify with worsening disease. This has been demonstrated by polysomnography and actigraphy, as well as by behavioral observations. Aberrancies of sleep have been speculated to evolve from gliosis and neuronal loss in the suprachiasmatic nucleus, which have been demonstrated histologically.

Many caregivers of patients with Alzheimer’s disease complain of disturbed sleep. Additionally, the physical and emotional stress of caregiving may be related to the development of inflammatory and coagulation responses. In a study, caregivers showed higher levels of proinflammatory cytokine interleukin-6 and the procoagulant marker D-dimer. The reduced total sleep time (TST) and poorer sleep efficiency here were thus associated with more inflammation and more coagulability, giving rise to higher rates of CV disease.

Parkinson’s Disease

A particular type of sleep disturbance has been described in certain patients with Parkinson’s disease: dream-enactment behaviors, which represent the absence of normal REM atonia. If occurring in isolation, this is referred to as REM sleep behavior disorder. Patients experience aggressive and frightening dreams and concomitantly flail their arms and vocalize aggressively, at times injuring the bed partner. They are at times known to get out of bed and walk while asleep as they are literally acting out their dreams. However, unlike sleepwalking, these movements are typically purposeful and coordinated, arising out of REM sleep and associated with dream recall. Interestingly, there is suggestion that these sleep symptoms may predate the development of the neurologic manifestations of the disease by more than a decade.

Stroke

Data are emerging on the relationships between sleep and stroke. In patients with stroke the most common sleep disorder is sleep apnea. Stroke patients have also been reported to experience sleep disturbances (78%) and daytime sleepiness (49%). Although the nature of the association between stroke and obstructive apnea is unknown, OSA is a risk factor for hypertension, atrial fibrillation, coronary artery disease and diabetes, which in turn are risk factors for stroke.

Stroke victims have been shown to experience sleep-related complaints both immediately before and after stroke. Factors that may cause the insomnia after stroke include disability, dementia, anxiety and use of a psychotropic drug. Sleep disorders are slightly more common in hemorrhagic stroke patients as opposed to ischemic stroke and occur more commonly in the right cerebral hemisphere of the brain compared to the left.

Huntington Disease

Sleep disturbances are present in nearly 90% of patients with Huntington disease (HD). As HD progresses, sleep stages N1 and N2 are increased and sleep stage N3 and REM are decreased. Patients with HD have significantly more movements and increased activity during sleep, and display more periodic limb movements. With increasing HD severity, sleep latency increases, sleep maintenance becomes more difficult, sleep efficiency reduces, wakefulness after sleep onset increases, circadian rhythmicity becomes compromised and sleepiness ensues. HD is associated with brainstem atrophy, particularly in the dorsolateral hypothalamus (site of hypocretin/orexin production) and anterior ventral hypothalamus (site of the suprachiasmatic nucleus). This may explain the sleep disruption that is associated with HD.

Movement Disorders and Insomnia

Restless Legs Syndrome

RLS is a sensorimotor disorder whose core symptom is a nearly irresistible urge to move the limbs, which is often but not always accompanied by other uncomfortable sensations felt deep inside the limbs or by a feeling that is simply difficult or impossible to describe. Terms used include “creepy, crawly, pulling, crampy, tingling, weird pain, electric, stinging, tension, itching, nervousness, growing pains and burning.” They can be felt anywhere in the legs but most commonly in the calves. RLS can be either idiopathic (primary) or secondary to other conditions.

Epidemiologic studies indicate that RLS is present in about 5% to 15% of the general population. However, many patients with RLS often go undiagnosed or misdiagnosed. Criteria for diagnosis are listed in Table 6-3.

Sleep and movement disorders overlap in a number of important ways. Because RLS typically occurs in the evening and while one is sleeping, it causes difficulty falling asleep and even staying asleep. Symptoms typically peak between midnight and 4 am; however, the circadian rhythm nature of the symptoms persists even in unconventional sleep/wake cycles (e.g., in shift workers). RLS patients are twice as likely to have significant insomnia as patients without RLS (35% vs 16%; P <0.05). Despite the discomfort of RLS, most patients consider sleep-related RLS symptoms to be most troublesome (Figure 6-3).

Even though the cause is unknown, RLS is believed be related to dopaminergic dysfunction. Pharmacologic evidence that RLS is highly responsive to dopaminergic agents suggests this. Furthermore, the symptoms of RLS and PLMD are worse during the night, a time when the circadian levels of dopamine are at their lowest. The finding of a reduced ferritin and elevated transferrin levels in the cerebrospinal fluid (CSF) in some patients suggest that patients with RLS may possess low brain iron levels.

One study showed an association between the increased levels of thalamic glutamate/glutamine levels in patients with RLS and the nocturnal arousals. Understanding this dichotomy and the interaction of these two differing systems may be important for understanding RLS neurobiology and developing better treatments for RLS.

RLS is a common sleep disorder, diagnosis of which is made on clinical grounds and does not necessitate any sleep testing. However, testing for underlying conditions that cause or worsen RLS, such as iron deficiency, renal insufficiency and pregnancy, is warranted.

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Periodic Limb Movement Disorder

Periodic limb movement disorder (PLMD) is a neurologic motor condition characterized by periodic episodes of repetitive, highly stereotyped limb movements that occur during sleep (PLMS), in conjunction with clinical sleep disturbance or fatigue that cannot be accounted for by another primary sleep disorder or other etiology. Unlike RLS, where the diagnosis is made clinically, PLMD diagnosis is established by polysomnography. On the PSG, the frequency of limb movements is seen to be >5/hour in children and >15/hour in adults.

Unlike RLS, PLMD is rarely diagnosed in patients under the age of 30 but is found in 44% of patients aged 65 and older. Frequently unnoticed by patients, these involuntary movements occur periodically throughout the night and are sometimes accompanied by awakenings, leading to the complaint of insomnia or daytime sleepiness. They tend to cluster in episodes that last anywhere from a few minutes to several hours and can fluctuate in severity from one night to the next. These movements are very different from nocturnal leg cramps, which are painful spasms of the calf or foot that are often experienced initially while falling asleep. These occur with greater frequency during pregnancy, in women, in the elderly, after intense exercise, as a result of diabetes, with fluid and electrolyte imbalances and with musculoskeletal disorders. There is some relationship between PLMD and RLS, and some investigators consider the two to be the same condition. PLMs are so common in RLS patients that they are considered to be supportive of an RLS diagnosis when other RLS symptoms are present; conversely, up to 80% of those with RLS also experience PLMS.

The causes of PLMD are unknown. However, research has shown that people with a variety of medical problems, including Parkinson’s disease and narcolepsy, may have frequent PLMs in sleep. PLMD may be induced by medications, most notably, antidepressants. In fact, given that many normal physiologic changes occur with aging, including reduced muscle mass and diminished skin elasticity, perhaps the higher prevalence of PLMS in elderly individuals actually represents a normal function of aging as opposed to a true sleep disorder. PLMD should be suspected in patients who complain of insomnia and/or daytime sleepiness where no obvious cause/solution is found, and referred for PSG.

Sleep Disorders and Blindness

Blind individuals are not only handicapped by their loss of vision but are also affected because the loss of sight, and therefore exposure to day/night light changes, can have a secondary impact on their circadian rhythm. Most completely blind people have circadian rhythm that is “free running” (i.e., that is not synchronized to environmental time cues and that oscillates on a cycle slightly longer than 24 hours), referred to as non–24-hour sleep-wake disorder. This condition causes recurrent insomnia and daytime sleepiness when the rhythm drifts out of phase with the normal 24-hour cycle. It has been estimated that non-24 occurs in more than half of all people who are totally blind.

The influence of light on circadian rhythms, and hence on the timing of sleep, is assumed to be mediated by melatonin, a hormone of the pineal gland, whose secretion is inhibited by light and enhanced during darkness. Therapy with melatonin, in addition to ensuring the regular timing of daily activities, may help entrain the circadian rhythm. Tasimelteon, a melatonin receptor agonist, received FDA approval in 2014 for the treatment of non–24-hour sleep-wake disorder in blind individuals.

Sleep Disorders and Pain

Induced disturbances to slow-wave (deep) sleep in normal, healthy subjects has been shown to produce not only non-refreshing sleep but also nonspecific generalized muscle aching and fatigue. Sleep problems associated with chronic pain may also be a feature of psychiatric disturbances that occur as a result of physical, psychosocial, vocational and economic concerns. Studies have indicated that the pain-sleep relationship is bidirectional: pain while awake can cause sleeplessness and, in turn, poor-quality sleep can exacerbate or worsen pain. This can then cause a vicious circle of increasing pain and sleeplessness, one amplifying the other. Diminished sleep increases pain sensitivity and restoring sleep reverses this effect. Pain also impairs mood, energy and cognitive function, all of which can also secondarily impair sleep. The extent of sleep disturbance is related to the severity of pain.

In one chronic pain disorder, fibromyalgia, sleep disturbance is especially common. Poor sleep worsens and perpetuates symptoms, so intensive treatment is indicated. There are a paucity of studies that give guidance on whether and which sleep treatment may improve the insomnia and/or fibromyalgia symptoms. One study has suggested that zolpidem may help with the insomnia but not with the pain of fibromyalgia. Guidelines suggest using behavioral modification methods first, and also treating the fibromyalgia optimally. If these are effective, medications indicated for insomnia may be appropriate.

Sleep-Related Breathing Disorders

Sleep has several effects on breathing, including changes in respiratory control and upper airway resistance. These sleep-related modifications in the respiratory system do not induce adverse effects in healthy subjects, but they may cause problems in patients with various respiratory conditions, including COPD and OHS.

Chronic Obstructive Pulmonary Disease

COPD patients experience a delayed onset of sleep, increased nighttime arousals and awakenings and poorer sleep efficiency compared with individuals without COPD. Symptoms related to sleep disturbances occur in approximately 10% of patients with moderate to severe COPD above the age of 65 years. The degree of disturbance corresponded roughly with the severity of pulmonary disease.

Several risk factors may contribute to poor sleep quality. Shortness of breath, coughing and excess mucus production may be exacerbated in the supine position, causing delayed sleep onset and arousals. Hypoventilation causes the most important gas-exchange alteration during sleep in COPD patients, leading to hypercapnia and hypoxemia, especially during REM sleep when marked respiratory muscle atonia occurs. Patients with COPD who are hypoxemic during wakefulness experience an exaggeration of this abnormality during sleep, as increased respiratory efforts may lead to arousals and awakenings.

Drugs used to treat COPD, such as systemic corticosteroids and β₂-agonists, may further disrupt sleep. Likewise, drugs that improve COPD, such as ramelteon, have been shown to improve polysomnographic parameters, such as total sleep time, sleep efficiency and number of awakenings. This indicates that treatment of COPD symptoms may lead to improvements in sleep quality.

Obstructive Sleep Apnea Syndrome

The main pathologic entity in obstructive sleep apnea syndrome (OSAS) is the repetitive cessation of breathing during sleep. Despite the occurrence of apneas up to hundreds of times during the night, patients with OSAS are typically oblivious to this intermittent suffocation. Apneas are believed to be caused by one or more of the following factors: anatomic narrowing of airways, increased collapsibility of airway tissues, disturbance in the reflexes that affect the caliber of the upper airway, or abnormalities of pharyngeal muscle function. The many effects of OSAS are illustrated in Figure 6-4.

The main presenting symptoms of OSAS are excessive daytime sleepiness, snoring and weight gain. However, insomnia is a presenting symptom in a minority of these patients as well. Patients with OSAS also experience more insomnia than those without the disease. Krell and Kapur assessed the prevalence of insomnia complaints in patients undergoing sleep laboratory evaluation for OSAS. Of 255 consecutive patients with OSAS who underwent polysomnography, 54.9% reported a complaint of insomnia. Of these, 33.4% reported difficulty initiating sleep, 38.8% difficulty maintaining sleep, and 31.4% early morning awakenings.

COPD and OSAS can coexist. Even though the prevalence of OSAS is not greater in COPD patients compared with the general population, the effect of COPD is to produce more profound oxyhemoglobin saturation decrements if it complicates OSAS.

OSAS contributes to morbidity and mortality, as well as decrements in quality of life. Patients with sleep-disordered breathing have a significantly higher rate of stroke or death from any cause, and the increase is independent of other risk factors, including age, sex, race, body mass index (BMI), hypertension, smoking and cholesterol levels. All-cause mortality is increased by 47% in patients with comorbid OSAS and insomnia, compared to individuals with neither condition. A retrospective chart review analysis by Shepertycky and coworkers found that at the time of OSAS diagnosis, women with OSAS were more likely to be treated for depression, to have insomnia, and to have hypothyroidism than were men with the same degree of OSAS.

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Circadian Rhythm Sleep Disorders

A variety of sleep disorders are characterized by a persistent or recurrent pattern of sleep disruption that is due to a mismatching between the sleep/wake schedule required or desired by a person’s environment or lifestyle and their circadian sleep/wake pattern. To be diagnosed with this disorder, this mismatch must lead to excessive insomnia or daytime sleepiness, or cause clinically important distress or impair work or social life. Also, the insomnia cannot occur solely during a psychiatric disorder or another sleep disorder and it is not directly caused by a general medical condition or substance use, including prescription medications and drugs of abuse. The exacerbating effect of disrupted circadian rhythms on sleep may contribute to a worsening of insomnia.

Delayed Sleep-Phase Disorder

In this disorder, the onset of the major sleep episode is delayed, usually by ≥2 hours, in relation to the desired clock time. An example may be a patient complaining of insomnia, characterized by consistently being unable to fall asleep until 1 or 2 am, then finding it difficult to wake up until 10 am to noon. The disorder occurs most common in adolescence. Specific treatment options include morning bright-light therapy, chronotherapy (gradual delay of the sleep/wake period to a later time by an increment of an hour or two per day until it is in line with the desired light/dark schedule), or supplementing with evening melatonin.

Advanced Sleep-Phase Disorder

In this disorder, the major sleep episode is advanced, usually by ≥2 hours, with respect to the desired clock time, which results in the inability to stay awake until the desired bedtime or the inability to remain asleep until the desired arising time. Unlike other sleep-maintenance disorders, the early morning awakening occurs after a normal amount of undisturbed sleep. Typical sleep-onset times are between 6 and 9 pm, and awakening times are between 3 and 5 am. In contrast to DSPD, therefore, the insomnia complaint is one of early morning awakening. This disorder is more likely to appear in the elderly. Treatment options include evening bright light therapy and gradual phase delays of the sleep/wake cycle.

Time Zone Change Syndrome

More commonly called “jet lag disorder,” this circadian rhythm disorder is characterized by varying degrees of difficulty in initiating or maintaining sleep, excessive sleepiness, decrements in subjective daytime performance and somatic complaints (e.g., headaches, altered appetite, and GI function) following rapid travel across multiple time zones.

Shift-Work Disorder

This sleep disorder affects people who frequently rotate shifts or work at night, who have difficulty adjusting to schedules that contradict the body’s natural circadian rhythm. SWSD consists of a constant or recurrent pattern of sleep interruption that results in insomnia or excessive sleepiness. Other symptoms of SWSD include difficulty concentrating, headaches, and lack of energy. Resulting consequences of these impairments include higher incidences of car accidents, work-related errors and sick leave.

Free-Running Disorder

Free-running disorder (FRD), also known as non–24-hour sleep–wake syndrome, is a cyclic debilitating circadian rhythm sleep disorder characterized by an inability to sleep on a 24-hour schedule. The condition is very rare in normally sighted people and can be developed from environments with continuous low light levels and atypical schedules (e.g., submarine duty). However, FRD occurs often in persons who are totally blind and who have no access to the entraining effects of the light/dark cycle. Totally blind people, living in normal society, often have a free-running circadian period of about 24.5 hours, similar to research subjects living in time-free environments who are isolated from a normal 24-hour light/dark cycle. Thus, blind patients with FRD are thought to reflect a failure of entrainment.

In sighted people, FRD typically begins in the teenage years and rarely after age 30. In blind persons, FRD can occur at any age, depending on when light perception is lost. Sighted males are at significantly greater risk for FRD.

In blind individuals, reduced total sleep time and other sleep abnormalities have been documented. The occurrence of free running rhythms in persons with total blindness indicates that some light/dark signal is critical for normal entrainment of humans. However, the light intensity threshold for entrainment is very low.

Both appropriately timed bright light exposure and melatonin administration have been shown to entrain patients with FRD. Treatment must be sustained or relapse will occur. Entrainment may not occur for weeks or months after initiating treatment, depending on the phase of the patient’s rhythm at the start of treatment and the period of the free-running rhythm.

Cardiovascular Comorbid Disorders

Insomnia is associated with an increased risk for cardiovascular disease (CVD), independently of classic coronary risk factors, such as age, smoking and obesity. This may be due to hyperarousal, in which chronic sympathetic activation leads to an elevated resting heart rate and elevated levels of inflammatory cytokines lead to hypertension, all known to result in CVD. Metabolic changes, increased cortisol levels and endothelial dysfunction, are also common in patients with insomnia and are associated with CVD.

A meta-analysis of prospective studies suggested that insomnia was associated with an increased risk of developing and/or dying from CVD during follow-up. Patients who reported suffering from insomnia had a 45% increased risk of morbidity and/or mortality from CVD compared with those who did not have sleep complaints (relative risk 1.45, 95% CI 1.29-1.62; P <0.00001).

Sleep complaints may also be associated with an increased risk of acute myocardial infarction (MI). Difficulties initiating and maintaining sleep and nonrestorative sleep were found in studies to be associated with a moderate increase in MI risk. Both short and long sleep durations have been found to be associated with an increased risk of developing CV disease.

Gastrointestinal Disorders

Gastroesophageal reflux disease (GERD) occurs when stomach acid, or content, flows backwards into the esophagus. At least 20% of adults in the United States report having heartburn once a week or more. Among patients with frequent heartburn, the majority reported difficulties initiating sleep or maintaining sleep through the night. Additionally, approximately 74% of GERD subjects have experienced sleep-related GER. Sleep-related GER is associated with long reflux episodes (>5 minutes), higher esophagitis grades, Barrett’s esophagitis and esophageal adenocarcinoma.

The severity of GERD symptoms is related to the severity of the sleep disturbance. Disturbed sleep in the form of arousals and awakenings is, in turn, thought to serve a protective function for the esophagus, as it facilitates esophageal acid clearance. However, it is also associated with insomnia and daytime fatigue. Diminished esophageal acid clearance during sleep, which occurs under normal conditions, is also thought to be responsible for the high rate of sleep-related reflux symptoms in GERD sufferers, which, in turn, is due to a variety of factors, including the loss of gravitational drainage, diminished swallowing and slower gastric emptying.

The relationship between GI disturbances and sleep seems to be bidirectional: so that the sleep disturbance might influence reflux and reflux might influence sleep disturbance. There is a higher prevalence of GI problems in those with chronic insomnia compared with those without (33.6% vs 9.2%; OR 3.33, 95% CI, 1.83-6.05). In a population-based, cross-sectional study based on two health surveys during 2 years in the 1980s and during 2 years in the 1990s in Norway, persons with insomnia were found to have a 3-fold greater risk of reflux compared with persons without insomnia, even when adjusted for age, sex, smoking, body mass index and socioeconomic status.

Acid reflux events are able to disrupt sleep architecture. Disorders of initiating and maintaining sleep were associated with reflux symptoms. In addition, according to a 2006 US National Health and Wellness Survey of 11,685 respondents with reflux symptoms, 68% experienced sleep difficulties, with 49% reporting sleep onset insomnia and 58% reporting sleep maintenance insomnia. Respondents with reflux symptoms during sleep time were more likely to have sleep onset insomnia (OR 1.43) and sleep maintenance insomnia (OR 1.56) compared with respondents with reflux symptoms only during wakefulness.

Sleep disturbances can also have a significant impact on an individual’s health and quality of life, resulting from decreased daytime functioning. In the 2006 National Health and Wellness Survey, respondents with reflux with sleep difficulty had more HCP visits, loss of work productivity and reductions in their health-related quality of life. Similarly, a systematic review of 5 population-based studies showed that sleep-related GER is associated with poor sleep quality, arousals from sleep, fatigue and impaired work productivity. Thus, reflux during sleep time seems to affect wake time functioning and quality of life.

Summary

Insomnia is associated with a plethora of comorbid medical and psychiatric conditions and while the exact reciprocal nature of these relationships has not yet been elucidated, it is clear that insomnia plays a role in exacerbating and worsening symptoms for people with chronic illnesses, significantly decreasing their health-related quality of life and potentially interfering with treatment.