Insomnia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adnan Ezici, M.D[2]

Insomnia is a sleep disorder characterized by an inability to sleep and/or inability to remain asleep for a reasonable period. Insomniacs typically complain of being unable to close their eyes or “rest their mind” for more than a few minutes at a time. Both organic and nonorganic insomnia constitute a sleep disorder.^[1][2].Insomnia is a medical term for a sleep disorder, in which a person have difficulty with falling asleep, staying asleep or feeling unfresh in the morning because of poor sleep^[3]. In 1970, Sleep Disorders Clinic was founded at the Stanford University with the availability of performing nocturnal polysomnography and multiple sleep latency tests. In the same year, with the use of flurazepam, benzodiazepines were first promoted for insomnia treatment. The Association of Sleep Disorders Centers (ASDC) was launched and led by Dr. Dement in 1975. In 1984, the Clinical Sleep Society (CSS) was declared by the Association of Sleep Disorders Centers (ASDC). In 1999, the Association of Sleep Disorders Centers (ASDC) renamed the American Academy of Sleep Medicine. The association between sleep deprivation and poor outcomes (e.g., death, skin lesions, weight loss, etc.) was made by Rechtschaffen et al. in 1989. Nonbenzodiazepine hypnotics (i.e. zolpidem, zaleplon, eszopiclone) were available for the treatment of insomnia in 1990s. Ramelteon (a selective melatonin receptor agonist), which has a completely different mechanism of action from the medications that were found a couple of decades ago (e.g., benzodiazepines, nonbenzodiazepine hypnotics, etc.), was approved by the FDA in 2005. In 2017, human circadian clock gene CRY1 mutations were first implicated in the pathogenesis of delayed sleep phase disorder (DSPD). It is thought that insomnia is caused by either molecular mechanism, hyperarousal model, sleep switch Model, cognitive and behavioural Model(3P model), and genetic factors. Genes involved in the pathogenesis of insomnia include apoE4, PER3, 5HTTLPR SNP (Single Nucleotide Polymorphism), CLOCK gene, HLA-DQB1*0602, CRY1. Insomnia may be classified according to the duration of difficulty sleeping into 3 groups: short-term insomnia disorder (< 3 months), chronic insomnia disorder (sleep disturbances that occur at least three times per week for > 3 months), and other insomnia disorder. Common causes of insomnia include alcoholism, anxiety, caffeine, depression, medication, sleep disorders(e.g., circadian rhythm sleep disorder, obstructive sleep apnea, movement disorders, narcolepsy, etc.), and stress. Causes that have a bidirectional relationship with insomnia or sleep disturbances include gastroesophageal reflux disease, fibromyalgia, epilepsy, migraine and other type of headaches. There is insufficient evidence to recommend routine screening for insomnia. However, physicians should ask about the presence of difficulty sleeping. If the patient reports severe and frequent problems with sleeping, further evaluation of insomnia might be required. Insomnia disorder (difficulty sleeping despite optimum conditions with daytime impairment, which cannot be explained by another sleep disorder) must be differentiated from other diseases that cause difficulty sleeping such as normal variants (short sleeper, excessive time in bed), circadian rhythm sleep disorders, obstructive sleep apnea, movement disorders, narcolepsy, and substance/medication-induced sleep disturbances. The prevalence of insomnia disorder is 10,000-20,000 per 100,000 (10%-20%) in the primary care setting. There is no significant association between increased risk of death and insomnia. Insomnia is found to be higher in incidence among the population of age <35 years. There is no racial predilection to insomnia disorder. However, sleep disturbances more likely affect individuals of the black race. Common risk factors in the development of insomnia include advancing age, poor health conditions, lack of social connection, and female gender. Common complications of insomnia include anxiety, major depressive disorder, and substance abuse. The presence of chronic insomnia is associated with a particularly poor prognosis among patients with insomnia. Chronic insomnia might cause depression, hypertension, and mortality in older adults. The diagnostic study of choice for insomnia is sleep history. Polysomnography must be performed when there is either a suspicion of an underlying sleep disorder, unusual nocturnal activity, or severe difficulty sleeping without an explanation. Multiple sleep latency test must be performed when there is a suspicion of narcolepsy. Actigraphy must be performed when there is a suspicion of circadian rhythm sleep disorder and the patient cannot provide the history of sleep pattern, or for the patients with insomnia that is unresponsive to treatment. The hallmark of insomnia is difficulty sleeping. History is the most important diagnostic study of choice while evaluating insomnia. Possible underlying or coexisting psychiatric or medical disorders should be evaluated along with a detailed sleep history. Patients with insomnia may have a positive history of underlying sleep disorders. Symptoms of underlying or coexisting medical disorders should be evaluated while taking the history. DSM-5 diagnostic criteria for insomnia disorder (which is a diagnosis of exclusion) are symptoms occur ≥ 3 days/week for ≥ 3 months, symptoms cause functional impairment or distress, problems initiating or maintaining sleep, and awakening early in the morning, and being unable to return to sleep, symptoms occur despite having enough time to sleep, symptoms are not caused by an underlying substance or medication use, and no underlying or coexisting psychiatric or medical disorder that explains symptoms. Physical examination of patients with insomnia is usually normal. However, physical examination findings of the underlying or coexisting medical conditions might be found. There are no diagnostic laboratory findings associated with insomnia. However, laboratory tests should be done if there is a suspicion of an underlying or coexisting medical condition. There are no ECG findings associated with insomnia. There are no x-ray findings associated with insomnia. There are no echocardiography/ultrasound findings associated with insomnia. However, echocardiography may be helpful in the diagnosis of associated conditions with insomnia, which includes heart disease, heart failure, and previous myocardial infarction. There are no CT scan findings associated with insomnia. However, a CT scan may be helpful in the diagnosis of conditions associated with insomnia such as cerebrovascular accident. There are no MRI findings associated with insomnia. There are no other imaging findings associated with insomnia. Other diagnostic studies for insomnia include polysomnography, which demonstrates findings of underlying sleep disorders such as obstructive sleep apnea, and periodic limb movement disorder; multiple sleep latency test, which demonstrates mean sleep latency ≤8 min with at least 2 sleep-onset REM periods in patients with narcolepsy; and actigraphy, which demonstrates increased sleep onset latency, increased wake after sleep onset, increased total sleep time, increased number of wakings during night, and decreased sleep efficiency. Clinical practice guideline by the American Academy of Sleep Medicine (AASM) noted about non-pharmacological therapy for insomnia as “initial approaches to treatment should include at least one behavioral intervention such as stimulus control therapy or relaxation therapy, or the combination of cognitive therapy, stimulus control therapy, sleep restriction therapy with or without relaxation therapy—otherwise known as cognitive behavioral therapy for insomnia (CBT-I).”^[4]. Pharmacologic medical therapies for insomnia include (either) benzodiazepines (e.g., triazolam, temazepam, etc.), nonbenzodiazepine receptor agonists (e.g., zaleplon, zolpidem, eszopiclone), antidepressants (doxepin), melatonin, melatonin agonists (ramelteon), orexin receptor antagonists (i.e., lemborexant, suvorexant), and/or antihistamines. Surgical intervention is not recommended for the management of insomnia. There are no established measures, both for the primary and the secondary prevention of insomnia.

In 1970, Sleep Disorders Clinic was founded at the Stanford University with the availability of performing nocturnal polysomnography and multiple sleep latency tests. In the same year, with the use of flurazepam, benzodiazepines were first promoted for insomnia treatment. The Association of Sleep Disorders Centers (ASDC) was launched and led by Dr. Dement in 1975. In 1984, the Clinical Sleep Society (CSS) was declared by the Association of Sleep Disorders Centers (ASDC). In 1999, the Association of Sleep Disorders Centers (ASDC) renamed the American Academy of Sleep Medicine. The association between sleep deprivation and poor outcomes (e.g., death, skin lesions, weight loss, etc.) was made by Rechtschaffen et al. in 1989. Nonbenzodiazepine hypnotics (i.e. zolpidem, zaleplon, eszopiclone) were available for the treatment of insomnia in 1990s. Ramelteon (a selective melatonin receptor agonist), which has a completely different mechanism of action from the medications that were found a couple of decades ago (e.g., benzodiazepines, nonbenzodiazepine hypnotics, etc.), was approved by the FDA in 2005. In 2017, human circadian clock gene CRY1 mutations were first implicated in the pathogenesis of delayed sleep phase disorder (DSPD).

It is thought that insomnia is caused by either molecular mechanism, hyperarousal model, sleep switch Model, cognitive and behavioural Model(3P model), and genetic factors. Genes involved in the pathogenesis of insomnia include apoE4, PER3, 5HTTLPR SNP (Single Nucleotide Polymorphism), CLOCK gene, HLA-DQB1*0602, CRY1.

Insomnia may be classified according to the duration of difficulty sleeping into 3 groups: short-term insomnia disorder (< 3 months), chronic insomnia disorder (sleep disturbances that occur at least three times per week for > 3 months), and other insomnia disorder.

Common causes of insomnia include alcoholism, anxiety, caffeine, depression, medication, sleep disorders(e.g., circadian rhythm sleep disorder, obstructive sleep apnea, movement disorders, narcolepsy, etc.), and stress. Causes that have a bidirectional relationship with insomnia or sleep disturbances include gastroesophageal reflux disease, fibromyalgia, epilepsy, migraine and other type of headaches.

There is insufficient evidence to recommend routine screening for insomnia. However, physicians should ask about the presence of difficulty sleeping. If the patient reports severe and frequent problems with sleeping, further evaluation of insomnia might be required.

Insomnia disorder (difficulty sleeping despite optimum conditions with daytime impairment, which cannot be explained by another sleep disorder) must be differentiated from other diseases that cause difficulty sleeping such as normal variants (short sleeper, excessive time in bed), circadian rhythm sleep disorders, obstructive sleep apnea, movement disorders, narcolepsy, and substance/medication-induced sleep disturbances.

The prevalence of insomnia disorder is 10,000-20,000 per 100,000 (10%-20%) in the primary care setting. There is no significant association between increased risk of death and insomnia. Insomnia is found to be higher in incidence among the population of age <35 years. There is no racial predilection to insomnia disorder. However, sleep disturbances more likely affect individuals of the black race.

Common risk factors in the development of insomnia include advancing age, poor health conditions, lack of social connection, and female gender.

Common complications of insomnia include anxiety, major depressive disorder, and substance abuse. The presence of chronic insomnia is associated with a particularly poor prognosis among patients with insomnia. Chronic insomnia might cause depression, hypertension, and mortality in older adults.

The diagnostic study of choice for insomnia is sleep history. Polysomnography must be performed when there is either a suspicion of an underlying sleep disorder, unusual nocturnal activity, or severe difficulty sleeping without an explanation. Multiple sleep latency test must be performed when there is a suspicion of narcolepsy. Actigraphy must be performed when there is a suspicion of circadian rhythm sleep disorder and the patient cannot provide the history of sleep pattern, or for the patients with insomnia that is unresponsive to treatment.

The hallmark of insomnia is difficulty sleeping. History is the most important diagnostic study of choice while evaluating insomnia. Possible underlying or coexisting psychiatric or medical disorders should be evaluated along with a detailed sleep history. Patients with insomnia may have a positive history of underlying sleep disorders. Symptoms of underlying or coexisting medical disorders should be evaluated while taking the history. DSM-5 diagnostic criteria for insomnia disorder (which is a diagnosis of exclusion) are symptoms occur ≥ 3 days/week for ≥ 3 months, symptoms cause functional impairment or distress, problems initiating or maintaining sleep, and awakening early in the morning, and being unable to return to sleep, symptoms occur despite having enough time to sleep, symptoms are not caused by an underlying substance or medication use, and no underlying or coexisting psychiatric or medical disorder that explains symptoms.

Physical examination of patients with insomnia is usually normal. However, physical examination findings of the underlying or coexisting medical conditions might be found.

There are no diagnostic laboratory findings associated with insomnia. However, laboratory tests should be done if there is a suspicion of an underlying or coexisting medical condition.

There are no ECG findings associated with insomnia.

There are no x-ray findings associated with insomnia.

There are no echocardiography/ultrasound findings associated with insomnia. However, echocardiography may be helpful in the diagnosis of associated conditions with insomnia, which includes heart disease, heart failure, and previous myocardial infarction.

There are no CT scan findings associated with insomnia. However, a CT scan may be helpful in the diagnosis of conditions associated with insomnia such as cerebrovascular accident.

There are no MRI findings associated with insomnia.

There are no other imaging findings associated with insomnia.

Other diagnostic studies for insomnia include polysomnography, which demonstrates findings of underlying sleep disorders such as obstructive sleep apnea, and periodic limb movement disorder; multiple sleep latency test, which demonstrates mean sleep latency ≤8 min with at least 2 sleep-onset REM periods in patients with narcolepsy; and actigraphy, which demonstrates increased sleep onset latency, increased wake after sleep onset, increased total sleep time, increased number of wakings during night, and decreased sleep efficiency.

Clinical practice guideline by the American Academy of Sleep Medicine (AASM) noted about non-pharmacological therapy for insomnia:

• “Initial approaches to treatment should include at least one behavioral intervention such as stimulus control therapy or relaxation therapy, or the combination of cognitive therapy, stimulus control therapy, sleep restriction therapy with or without relaxation therapy—otherwise known as cognitive behavioral therapy for insomnia (CBT-I).”^[4]

Pharmacologic medical therapies for insomnia include (either) benzodiazepines (e.g., triazolam, temazepam, etc.), nonbenzodiazepine receptor agonists (e.g., zaleplon, zolpidem, eszopiclone), antidepressants (doxepin), melatonin, melatonin agonists (ramelteon), orexin receptor antagonists (i.e., lemborexant, suvorexant), and/or antihistamines.

Surgical intervention is not recommended for the management of insomnia.

There are no established measures for the primary prevention of insomnia.

There are no established measures for the secondary prevention of insomnia.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Adnan Ezici, M.D[2]

It is thought that insomnia is caused by either molecular mechanism, hyperarousal model, sleep switch Model, cognitive and behavioural Model(3P model), and genetic factors. Genes involved in the pathogenesis of insomnia include apoE4, PER3, 5HTTLPR SNP (Single Nucleotide Polymorphism), CLOCK gene, HLA-DQB1*0602, CRY1.

The normal physiology of sleep can be understood as follows: The sleep-wake cycle is mediated by circadian rhythm and sleep-wake homeostasis, which is essential for sleeping at night and wakefulness during the day.^[1] Although sleep is influenced by a myriad of conditions, both physical and environmental, most sleep patterns follow a circadian rhythm which is in turn regulated by a number of compounds in the body.^[2]

• These compounds are broadly divided into either sleep-promoting or wake-promoting.^[3]
• Examples of sleep-promoting compounds are melatonin, adenosine, serotonin, etc.
• Wake-promoting compounds include catecholamines, histamine, etc.
• Although all cases of insomnia cannot be explained by an imbalance between sleep-promoting and wake-promoting compounds, an imbalance or an excess of either points to a sleep-wake disorder of some kind.
• Comorbid conditions like GERD, restless leg syndrome, anxiety disorder can result in chronic insomnia.
• Local sleep theory proposed by Krueger et al, defines sleep as a “fundamental emergent property of highly interconnected neurons”^[4]. This theory states that in insomnia, compounds which regulate sleep act locally at the site of neurons and influence sleep-wake regulation.

It is thought that insomnia is mediated by^[5]:

• Molecular Mechanism
  • Hormones causing wakefulness: Catecholamine, Histamine, Orexin
  • Hormones promoting sleep: Adenosine, serotonin, GABA, melatonin, Prostaglandin D2
• Hyperarousal model
  • Cognitive
  • Physiologic
  • Cortical
• Sleep switch Model (Orexin mediated)
  • Inhibition of sleep-promoting areas:Ventrolateral preoptic nucleus and median preoptic nucleus
  • Stimulation of wake-promoting areas:Tuberomammillary nucleus, dorsal raphe nucleus, locus coeruleus
• Cognitive and Behavioural Model(3P model): This model of insomnia helps to explain how acute insomnia becomes chronic and aids in assessing insomnia in individual patients
  • Precipitating factors
  • Predisposing factors
  • Perpetuating factors

Genes involved in the pathogenesis of insomnia include:^[5]

• ApoE4
• PER3
• 5HTTLPR SNP (Single Nucleotide Polymorphism)
• CLOCK gene
• HLA-DQB1*0602
• CRY1.^[6]