INSOMNIA Pathophysiology Insomnia usually results from an interaction of biological, physical, psychological, and environmental factors.

Although transient insomnia can occur in any person, chronic insomnia appears to develop only in a subset of persons who may have an underlying predisposition to insomnia. The evidence supporting this theory is that compared with persons who have normal sleep, persons with insomnia have the following:

Higher rates of depression and anxiety Higher scores on scales of arousal Longer daytime sleep latency Increased 24-hour metabolic rates Greater night-to-night variability in their sleep More electroencephalographic (EEG) beta activity (a pattern observed during memory processing/performing tasks) at sleep onset Increased global glucose consumption during the transition from waking to sleep onset, on positron emission tomography of the brain

Hyperarousal In experimental models of insomnia, healthy subjects deprived of sleep do not demonstrate the same abnormalities in metabolism, daytime sleepiness, and personality as subjects with insomnia. However, in an experimental model in which healthy individuals were given caffeine, causing a state of hyperarousal, the healthy subjects had changes in metabolism, daytime sleepiness, and personality similar to the subjects with insomnia. Clinical research has also shown that patients with chronic insomnia show evidence of increased brain arousal. For example, studies have indicated that patients with chronic primary insomnia demonstrate increased fast-frequency activity during non rapid eye movement (NREM) sleep, which is an EEG sign of hyperarousal, and evidence of reduced deactivation in key sleep/wake regions during NREM sleep compared with controls. Furthermore, patients with insomnia have higher day and night body temperatures, urinary cortisol and adrenaline secretion, and adrenocorticotropic hormone (ACTH) levels than patients with normal sleep. These results support a theory that insomnia is a manifestation of hyperarousal. In other words, the poor sleep itself may not be the cause of the daytime dysfunction, but merely the nocturnal manifestation of a general disorder of hyperarousability. Spielman model The Spielman model of chronic insomnia posits 3 components: predisposing factors, precipitating factors, and perpetuating factors. According to this model, predisposing factors may cause the occasional night of poor sleep, but in general, the person sleeps well until a precipitating event (eg, death of a loved one) occurs, which triggers acute

insomnia. If bad sleep habits develop or other perpetuating factors set in, the insomnia becomes chronic and will persist even with removal of the precipitating factor. Theoretical model of the factors causing chronic insomnia. Chronic insomnia is believed to primarily occur in patients with predisposing or constitutional factors. These factors may cause the occasional night of poor sleep but not chronic insomnia. A precipitating factor, such as a major life event, causes the patient to have acute insomnia. If poor sleep habits or other perpetuating factors occur in the following weeks to months, chronic insomnia develops despite the removal of the precipitating factor. Adapted from Spielman AJ, Caruso LS, Glovinsky PB: A behavioral perspective on insomnia treatment. Psychiatr Clin North Am. 1987 Dec;10(4):541-53. Genetics A number of individual genes that are involved in sleep and wakefulness have been isolated. However, current evidence suggests that a network of genes, rather than a single gene or a subset of genes, is responsible for sleep. The neurotransmitters and signaling pathways that serve wakefulness also serve other functions. Studies indicate differential genetic susceptibility to exogenous influences such as caffeine, light, and stress. For example, one study found that differences in the adenosine 2A receptor gene (ADORA2) determine differential sensitivity to caffeines effect on sleep. The ADORA2A 1083T>C genotype determined how closely the caffeine-induced changes in brain electrical activity (ie, increased beta activity) during sleep resembled the alterations observed in patients with insomnia. In addition, circadian clock genes have been identified that regulate the circadian rhythm. Such genes include CLOCK and Per2. A mutation or functional polymorphism in Per2 can lead to circadian rhythm disorders, such as advanced sleep phase syndrome (sleep and morning awakening occur earlier than normal) and delayed sleep phase syndrome (sleep and morning awakening are delayed). A missense mutation has been found in the gene encoding the GABAA beta 3 subunit in a patient with chronic insomnia. Polymorphisms in the serotonin receptor transporter gene may modulate the ability of an individual to handle stress or may confer susceptibility to depression. In depression, serotonin is an important neurotransmitter for arousal mechanisms. Furthermore, antagonism of the serotonin 5HT2 receptor promotes slow-wave sleep. Fatal familial insomnia A rare condition, fatal familial insomnia (FFI, previously known as thalamic dementia) is an autosomal dominant human prion disease caused by changes in the PRNP (prion protein) gene. FFI involves a severe disruption of the physiologic sleep pattern that progresses to hallucinations, a rise in catecholamine levels, autonomic disturbances (tachycardia, hypertension, hyperthermia, and diaphoresis), and significant cognitive and motor deficits. Mean age of onset is 50 years, and average survival is 18 months.

FFI and a subtype of familial Creutzfeldt-Jakob disease (CJD) share the same mutation at codon 178 (Asn178) in the PRNP gene. They differ in that a methioninevaline polymorphism is present at codon 129 in PRNP in this subtype of familial CJD. Sporadic fatal insomnia (SFI) shares a similar clinic course with FFI but does not appear to be inherited. A mutation at codon 178 of the PRNP gene is not found in these patients, but patients have been found to be homozygous for methionine at codon 129 in PRNP. Precipitating factors In retrospective studies, a large proportion of patients with insomnia (78%) can identify a precipitating trigger for their insomnia. Morin and colleagues showed that these patients demonstrate an increased response to stress as compared with controls. A number of factors can trigger insomnia in vulnerable individuals, including depression, anxiety, sleep-wake schedule changes, medications, other sleep disorders, and medical conditions. In addition, positive or negative family events, work-related events, and health events are common insomnia precipitants. Perpetuating factors Regardless of how insomnia was triggered, cognitive and behavioral mechanisms are generally accepted to be the factors that perpetuate it. Cognitive mechanisms include misconceptions about normal sleep requirements and excessive worry about the ramifications of the daytime effects of inadequate sleep. Conditioned environmental cues causing insomnia develop from the continued association of sleeplessness with situations and behaviors that are typically related to sleep. As a result, patients often become obsessive about their sleep or try too hard to fall asleep. These dysfunctional beliefs often produce sleep disruptive behaviors, such as trying to catch up on lost sleep with daytime naps or sleeping in, which in turn reduces the patients natural homeostatic drive to sleep at their habitual bedtime. Learned sleep-preventing associations are characterized by overconcern about inability to fall asleep. Consequently, these patients develop conditioned arousal to stimuli that would normally be associated with sleep (ie, heightened anxiety and ruminations about going to sleep in their bedroom). A cycle then develops in which the more these patients strive to sleep, the more agitated they become, and the less they are able to fall asleep. They also have ruminative thoughts or clock watching as they are trying to fall asleep in their bedroom.

ETIOLOGY Many clinicians assume that insomnia is often secondary to a psychiatric disorder, However, a large epidemiologic survey showed that half of insomnia diagnoses were not related to a primary psychiatric disorder. A diagnosis of insomnia does, however, increase the future risk for depression or anxiety. Insomnia may also be secondary to other disorders or conditions, or it may be a primary condition (see the image below). The International Classification of Sleep Disorders, 2nd Edition (ICSD-2) classifies insomnia into 11 categories, as follows:

Adjustment insomnia (acute insomnia) Psychophysiologic insomnia (primary insomnia) Paradoxical insomnia Insomnia due to medical condition Insomnia due to mental disorder Insomnia due to drug or substance abuse Insomnia not due to substance or known physiologic condition, unspecified Inadequate sleep hygiene Idiopathic insomnia Behavioral insomnia of childhood Primary sleep disorders causing insomnia

Adjustment insomnia (acute insomnia) Adjustment insomnia is also known as transient, short-term, or acute insomnia. Causes can be divided into 2 broad categories: environmental and stress-related. Environmental etiologies include unfamiliarity, excessive noise or light, extremes of temperature, or an uncomfortable bed or mattress. Stress-related etiologies primarily involve life events, such as a new job or school, deadlines or examinations, or deaths of relatives and close friends. Adjustment insomnia typically lasts 3 months or less. The insomnia resolves when the stressor is no longer present or the individual adapts to the stressor . Psychophysiologic insomnia (primary insomnia) Primary insomnia begins with a prolonged period of stress in a person with previously adequate sleep. The patient responds to stress with somatized tension and agitation. In a person experiencing normal sleep, as the initial stress abates, the bad sleep habits are gradually extinguished because they are not reinforced nightly. However, in a patient with a tendency toward occasional poor nights of sleep, the bad habits are reinforced, the patient "learns" to worry about his or her sleep, and chronic insomnia follows. The patient will have evidence of conditioned sleep difficulty and or/heightened arousal in bed, as indicated by one or more of the following:

Excessive focus on and heightened anxiety about sleep

Difficulty falling asleep at the desired bedtime or during planned naps, but no difficulty falling asleep during other monotonous activities when not intending to sleep Ability to sleep better away from home than at home Mental arousal in bed characterized by either intrusive thoughts or a perceived inability to volitionally cease sleep-preventing mental activity Heightened somatic tension in bed reflected by a perceived inability to relax the body sufficiently to allow the onset of sleep

The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance abuse disorder. Paradoxical insomnia In paradoxical insomnia, one or more of the following criteria apply:

The patient reports a chronic pattern of little or no sleep most nights, with rare nights during which relatively normal amounts of sleep are obtained Sleep log data from one or more weeks of monitoring often show no sleep at all for several nights each week; typically, daytime naps are absent following such nights There is typically a mismatch between objective findings from polysomnography or actigraphy and subjective sleep estimates from a selfreported sleep diary

At least one of the following is observed:

The patient reports constant or near-constant awareness of environmental stimuli throughout most nights The patient reports a pattern of conscious thoughts or rumination throughout most nights while maintaining a recumbent posture

The daytime impairment reported is consistent with that reported by other insomnia subtypes but is much less severe than expected given the extreme level of sleep deprivation reported. The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance-abuse disorder. Insomnia due to medical condition In patients with insomnia associated with a medical condition, medical disorders may include the following:

Chronic pain syndromes from any cause (eg, arthritis, cancer) Advanced chronic obstructive lung disease Benign prostatic hypertrophy (because of nocturia) Chronic renal disease (especially if on hemodialysis) Chronic fatigue syndrome Fibromyalgia Neurologic disorders

Neurologic disorders may include Parkinson disease, other movement disorders, and headache syndromes, particularly cluster headaches, which may be triggered by sleep. In a retrospective community-based study, more people with chronic insomnia reported having the following medical conditions than did people without insomnia[43] :

Heart disease (21.9% with chronic insomnia vs 9.5% without insomnia) 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%) Gastrointestinal problems (33.6% vs 9.2%)

In addition, people with the following medical problems more often reported chronic insomnia than did patients without such medical problems.

Heart disease (44.1% vs 22.8%) Cancer (41.4% vs 24.6%) High blood pressure (44% vs 19.3%) Neurologic disease (66.7% vs 24.3%) Breathing problems (59.6% vs 21.4%) Urinary problems (41.5% vs 23.3%) Chronic pain (48.6% vs 17.2%) Gastrointestinal problems (55.4% vs 20.0%)

The sleep disturbance cannot be better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance abuse disorder. Insomnia due to mental disorders Most chronic psychiatric disorders are associated with sleep disturbances. Depression is most commonly associated with early morning awakenings and an inability to fall back asleep. Conversely, studies have also demonstrated that insomnia can lead to depression: insomnia of more than 1-year duration is associated with an increased risk of depression. Schizophrenia and the manic phase of bipolar illness are frequently associated with sleep-onset insomnia. Anxiety disorders (including nocturnal panic disorder and posttraumatic stress disorder) are associated with both sleep-onset and sleepmaintenance complaints. To meet the formal definition of this form of insomnia, a mental disorder must be diagnosed according to the criteria of the Diagnostic and Statistical Manual 4th Edition, Text Revision (DSM-IV-TR). The insomnia must be temporally associated with the mental disorder; however, in some cases, insomnia may appear a few days or weeks before the emergence of the underlying mental disorder.

The insomnia is more prominent than that typically associated with the mental disorders, as indicated by causing marked distress or constituting an independent focus of treatment. The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance-abuse disorder. Insomnia due to drug/substance abuse Sleep disruption is common with the excessive use of stimulants, alcohol, or sedativehypnotics. One of the following applies:

The patient has current, ongoing dependence on or abuse of a drug or substance known to have sleep-disruptive properties either during periods of use or intoxication or during periods of withdrawal The patient has current ongoing use of or exposure to a medication, food, or toxin known to have sleep-disruptive properties in susceptible individuals

The insomnia is temporally associated with the substance exposure, use, or abuse, or acute withdrawal. The sleep disturbance cannot be better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance abuse disorder. Insomnia not due to substance or known physiologic condition, unspecified This diagnosis is used for forms of insomnia that cannot be classified elsewhere in ICSD-2 but are suspected to be the result of an underlying mental disorder, psychological factors, or sleep disruptive processes. This diagnosis can be used on a temporary basis until further information is obtained to determine the specific mental condition or psychological or behavioral factors responsible for the sleep difficulty. Inadequate sleep hygiene Inadequate sleep hygiene practices are evident by the presence of at least 1 of the following:

Improper sleep scheduling consisting of frequent daytime napping, selecting highly variable bed or rising times, or spending excessive amounts of time in bed Routine use of products containing alcohol, nicotine, or caffeine, especially in the period preceding bedtime Engagement in mentally stimulating, physically activating, or emotionally upsetting activities too close to bedtime Frequent use of the bed for activities other than sleep (eg, television watching, reading, studying, snacking, thinking, planning) Failure to maintain a comfortable sleeping environment

The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, medication use, or substance abuse disorder.

Idiopathic insomnia This sleep disturbance is a long-standing complaint of insomnia, with insidious onset in infancy or childhood. No precipitant or cause is identifiable. The course is persistent, with no sustained periods of remission. This condition is present in 0.7% of adolescents and 1% of very young adults.[44] Behavioral insomnia of childhood A child's symptoms meet the criteria for insomnia based on parents or other adult caregivers observations. Two types of this sleep disturbance are recognized: sleeponset association and limit-setting. The sleep-onset association type is characterized by the following:

Falling asleep is an extended process that requires special conditions Sleep-onset associations are highly problematic or demanding In the absence of associated conditions, sleep onset is significantly delayed or sleep is otherwise disrupted Nighttime awakenings require caregiver intervention for the child to return to sleep

The limit-setting type is characterized by the following:

The child has difficulty initiating or maintaining sleep The child stalls or refuses to go to bed at an appropriate time or refuses to return to bed following a nighttime awakening The caregiver demonstrates insufficient or inappropriate limit-setting to establish appropriate sleeping behavior in the child

Primary sleep disorders causing insomnia Included in this category are the following:

Restless legs syndrome(RLS) Obstructive sleep apnea/hypopnea syndrome Circadian rhythm disorders

Restless legs syndrome RLS is a sleep disorder characterized by the following:

An urge to move the legs, usually accompanied by uncomfortable and unpleasant physical sensations in the legs Symptoms begin or worsen during periods of rest or inactivity such as lying or sitting Symptoms are partially or totally relieved by moving, such as walking or stretching, at least as long as the activity continues Symptoms are worse or occur only in the evening or at night

RLS may be associated with periodic limb movement disorder (PLMD), which is characterized by repetitive periodic leg movements that occur during sleep. If RLS is predominant, sleep-onset insomnia is generally present; if PLMD is predominant, sleep-maintenance insomnia is more likely. Obstructive sleep apnea/hypopnea syndrome A minority of patients with obstructive sleep apnea/hypopnea syndrome complain of insomnia rather than hypersomnolence. Often, these patients complain of multiple awakenings or sleep-maintenance difficulties. They may also have frequent nocturnal awakenings because of nocturia. Circadian rhythm disorders Circadian rhythm disorders include the following:

Advanced sleep phase syndrome Delayed sleep phase syndrome Shift-work sleep disorder Irregular sleep-wake rhythm

In advanced sleep phase syndrome, patients feel sleepy earlier than their desired bedtime (eg, 8 pm) and they wake up earlier than they would like (eg, 4-5 am). This condition is more common in the elderly (see Geriatric Sleep Disorder). These patients typically complain of sleep-maintenance insomnia. In delayed sleep phase syndrome, patients do not feel sleepy until much later than the desired bedtime, and they wake up later than desired or socially acceptable. On sleep diaries or actigraphy, these patients show a consistent sleep time with earlier wake times that correspond to school or work days and delayed wake times on weekends, time off, and vacations. Delayed sleep phase syndrome often begins in adolescence and may be associated with a family history in up to 40% of patients. These patients report difficulty falling asleep at usually socially desired bedtimes and complain of excessive daytime sleepiness during school or work. Shift-work sleep disorder is a complaint of insomnia or excessive sleepiness that typically is temporally related to a recurring work schedule that overlaps with the usual sleep time. This can occur with early morning shifts (eg, starting at 4-6 am), where patients are anxious about waking up in time for their early shift, particularly when they have a rotating-shift schedule. Evening shifts that end at 11 pm can result in insomnia because the patient may need some time to wind down from work before retiring to bed. Night shift work can be associated with both sleep-onset and sleep-maintenance insomnia. Triggers may include exposure to sunlight on the drive home from work, daylight exposure in the bedroom, and social and environmental cues (eg, picking up children at school, paying bills, household chores).

Irregular sleep-wake rhythm is typically seen in persons with poor sleep hygiene, particularly those who live or work alone with minimal exposure to light, activity, and social cues. It may also be seen in persons with dementia or some other neurodegenerative disorder. These patients randomly nap throughout the day, making it difficult, if not impossible, to fall asleep at a habitual bedtime with a consolidated sleep period.