Clinical manifestations

Prognosis and complications

Insomnia is often a chronic condition, with retrospective reports indicating that about 80% of severely affected individuals have had the problem for longer than 1 year, and approximately 40% report a duration of longer than 5 years. Longitudinal studies suggest that 30% to 80% of those identified with moderate to severe insomnia show no significant remission over time.

Prolonged insomnia is associated with an increased risk of unipolar major depression, bipolar depression, anxiety, and substance use disorder and may be an independent risk factor for heart disease, hypertension, and diabetes, particularly when sleep time is less than 6 hours per night (06; 08).

Complications of insomnia include impaired responses to infections, increase in inflammation, higher levels of the stress hormone cortisol, and other biomarkers related to fatigue and poor health. Pain is recognized as a cause of sleep disturbances.

Clinical vignette

A 43-year-old woman presented to her primary care physician for a routine appointment. A screening history revealed complaints of poor nighttime sleep resulting in excessive fatigue, increased irritability, and difficulty concentrating.

A sleep questionnaire and detailed history revealed 8 years of difficulty initiating and maintaining sleep, progressively worsening. The onset of her sleep problems coincided with the birth of her first child. The patient had needed to rise several times during the night to feed her baby; however, her sleep problems did not remit when the child began sleeping through the night. The patient had attempted to treat her insomnia with sleep medication but was unable to find a drug that had tolerable side effects; many of the medications she tried left her feeling groggy and “hungover” the following day.

It typically took the patient about 60 to 90 minutes to fall asleep. She reported waking up spontaneously two to three times per night and, subsequently, had difficulty falling asleep; she reported spending up to 3 hours awake during the night. She had difficulty functioning at work as a schoolteacher due to increased fatigue and poor concentration.

The patient reported a history of hypothyroidism but stated that this was adequately controlled with medication. She denied any other medical conditions that could potentially interfere with sleep. Her husband described occasional soft snoring but denied any other notable nighttime behaviors.

Her sleep logs revealed a pattern consistent with an insomnia disorder, with extended time to fall asleep and extended awakenings throughout the night. She would attempt to nap two to three times per week but would be unable to fall asleep after lying down. Her sleep schedule was regular, but she tended to go to bed earlier on nights following a particularly bad night of sleep and attempted to sleep in on the weekends.

Her self-report and her husband’s report of nighttime symptoms were not consistent with obstructive sleep apnea or any other occult sleep disorder; therefore, referral for an overnight sleep study was unwarranted.

The patient was followed for five biweekly sessions of cognitive behavioral therapy for insomnia. This treatment consisted of stimulus control therapy, sleep restriction therapy, sleep hygiene education, and cognitive therapy in addition to a final session reviewing techniques to maintain treatment gains and prevent relapse. Within the first 2 weeks of treatment, the patient began sleeping more solidly and noticed improvements in daytime fatigue and alertness. Her sleep continued to improve as sleep opportunity was gradually expanded. Treatment was discontinued when the patient reported that she was getting an adequate amount of sleep and was no longer experiencing daytime symptoms. At a later follow-up appointment, the patient reported that despite occasional nights of poor sleep related to transient stressors, she could maintain the gains she made in treatment. She reported that she was falling asleep more quickly and no longer waking up during the night.

Biological basis

Current evidence for the pathophysiology of insomnia converges on the hypothesis that it is a stress-related disorder according to the diathesis-stress model, with hyperarousal as a key factor (18; 17). In fact, evidence for increased CNS brain metabolism, sympathetic activity, high-frequency EEG activation and REM density, and activation of arousal-promoting neurotransmission consistent with the central and peripheral hyperactivation of stress and inflammatory systems, have been shown in insomnia (18; 17). Therefore, insomnia is considered a stressor that impairs neuroplasticity, leading to a state of allostatic overload, favoring medical and psychiatric disorders (11).

In this framework, the hyperactivity of the HPA axis has consistently been demonstrated to be related to a functional reduction of the cortical GABAergic system and with deficient GABAergic synapses associated with CNS hyperarousal in insomnia. Increased GABA levels in subjects suffering from insomnia have been found and may reflect a potential compensatory allostatic response to chronic hyperarousal.

Maladaptive changes in neuroplasticity are hypothesized in insomnia, reflecting GABAergic alterations (13). In particular, insomnia is associated with a reduction in slow-wave sleep and diminished sleep-related consolidation of declarative and procedural memories. As impaired neuroplasticity favors the accumulation of neurotoxic proteins, neuroinflammation, and stress system alterations, insomnia is considered to be a causal factor in neurodegenerative (21) and neuropsychiatric disorders (16).

In addition, few data in animals and humans have reported that disrupted sleep and insomnia may be related to the overactivation of the orexinergic system. Some more consistent data in humans and animals reported the overactivation of orexins in response to acute stress and in stress-related disorders. Taken together, these findings may lead to the hypothesis that an orexin overactivation may be associated with stress-related hyperarousal and the hyperactivation of arousal-promoting systems in insomnia (15).

Other hypotheses are related to melatonin production. The production of melatonin generally decreases with age, and it is related to an increase in insomnia prevalence in the elderly. This relationship between increasing age, declining melatonin production, and increasing insomnia prevalence has led to the “melatonin-replacement” hypothesis. In this framework, treatments with melatonin may replenish the deficiency in the endogenous hormone involved in sleep promotion and may improve overall sleep quality (28). In summary, current models of insomnia hypothesize that wake-promoting transmitters like orexin, catecholamine, and histamine may be hyperactivated, whereas sleep-promoting neurotransmitters like GABA, adenosine, and melatonin may be deficient.

A downward spiral of insufficient overnight adaptation to distress resulting in accumulating hyperarousal, which, in turn, impedes restful REM sleep has been hypothesized in insomnia. REM sleep dysregulation and its negative consequences on emotion and cognition have been related to a dysfunctional stress response in insomnia (24).

Persistent hyperactivity in the ventral emotional system that includes the amygdala has been described in insomnia-related hyperarousal with dysfunctional top-down regulation of emotions (18; 17).

Etiology and pathogenesis

Current models recognize insomnia in the framework of the diathesis-stress model with predisposing, precipitating, and perpetuating factors for insomnia (Table 1). Predisposing factors interact with precipitating factors for developing acute insomnia. Perpetuating factors contribute to insomnia chronicity. A downward spiral of insufficient overnight adaptation to distress maintains the cycle of insomnia.

Table 1. Insomnia Disorder

Neurologic/psychiatric disorders with comorbid insomnia. The following are some examples of such disorders:

Alzheimer disease. Sleep disorders occur in 20% to 50% of patients, and the most common problem is difficulty in falling and staying asleep. There is increased duration and frequency of awakening during night.

Parkinson disease. Sleep disorders occur in 1% to 5% of patients, and incidence increases with age. Insomnia is due to tremors, painful dystonia, nocturia, depression, and medications.

Epilepsy. Approximately 25% of patients with epilepsy have seizures during sleep. Epileptic episodes may cause recurrent dreams, nightmares, and frequent arousals that may result in awakenings and a complaint of insomnia.

Ischemic stroke. Insomnia or excessive sleepiness and sleep disordered breathing are frequently seen in patients who have an ischemic stroke.

Mood disorders. Insomnia is a comorbid condition in mood disorders and a clinically significant feature that is highly prevalent across patients’ entire course. As many as 80% to 100% of people during the depressive episode period, and 45% to 55% during the bipolar inter-episode period, experience insomnia. Insomnia can be related to illness severity, cognitive dysfunctions, levels of hopelessness, low levels of resilience, increased risk of substance abuse, aggressive and impulsive behaviors, emotional dysregulation, and increased suicidal risk. In addition, it plays an important role in relapses and recurrences; it is considered an independent risk factor as well as an early sign occurring prior to both depressive and manic episodes. Insomnia as a comorbidity in patients with psychiatric disorders is associated with a more adverse course and lower response rates to treatment (16).

Anxiety disorders. Insomnia is a major predictor for the onset of anxiety (06). Insomnia is highly prevalent in individuals experiencing anxiety and affects more than 80% of patients with general anxiety disorder and 70% with panic disorder. It is an indicator of increased morbidity and low responsiveness to treatment, and it is related to the severity of worry, fear, and hypervigilance.

Genetics and epigenetics of insomnia. A genetic and epigenetic model of insomnia has been revised (15). Insomnia is emerging as a complex stress-related sleep disorder with polygenic etiology (25). Twin and family studies have shown that insomnia may run in a family. It is moderately heritable, with a heritability of 40%, and is stable across time. Heritability is stronger in females than in males.

Studies have suggested that genes may play a role in the development of insomnia symptoms, especially for women, but also underline the potential role of environmental influences in insomnia. In this framework, the sleep reactivity, such as the extent of insomnia development after a stressor, has emerged as an important heritable trait in insomnia influencing the degree of “arousability” after a stressor. Data on candidate genes and genome-wide association studies may confirm that insomnia has a polygenic etiology, and it is currently listed as one of the most polygenic traits, following major depressive disorder (25). Several variants have been observed in genes regulating neural function, brain regions, immune responses, nervous system development, processes of neurodegeneration, and epigenetic modifications in insomnia. Importantly, variants have been observed in circadian regulating genes, such as CLOCK 3111 T/C, PER1, PER2, and PER3; in genes involved in serotonin regulation; in genes regulating orexin receptors; and in genes regulating BDNF. Indeed, it is estimated that current genome-wide association study SNPs explain 17.3% of the total heritability, suggesting a strong role of genes and environmental interactions in insomnia. The importance of the role of the interaction between stressors and genes involved in insomnia is emerging, such as circadian genes or genes involved in serotonin functioning. In this framework, an epigenetic model of insomnia would be useful. It may explain the complexity of this stress-related disorder’s “arousability” after a stressor. Epigenetic data on insomnia are lacking, but results of a distinct pattern of DNA methylation in disturbed sleep after psychosocial stressors has been shown in humans. Also, data on distinct patterns of DNA methylation in fragmented sleep and insufficient sleep may be helpful for understanding insomnia. Additionally, epigenetic data on the effect of acute sleep loss and on sleep deprivation may suggest that when insomnia is established, it may favor a change in DNA expression, as well as possibly contribute to insomnia chronicity.

Importantly, insomnia symptoms may share some genetic influence with factors contributing to some psychiatric disorders. They may be a part of the same genetic cluster correlated with insomnia. Like other mental and stress-related disorders, the polygenic risk of insomnia may be a causal factor in some psychiatric and medical disorders, as well as long-term consequences on the brain of genes and environmental interactions in insomnia.

Epidemiology

Insomnia is a highly prevalent disorder in the United States. According to the polls by the National Sleep Foundation, approximately 35% of the adult population reports that they have experienced insomnia every night or almost every night within the past year. Rates of chronic insomnia are higher for women, increase with age, and are around 6% to 10% in the adult population.

Prevention

Differential diagnosis

Confusing conditions

Insomnia may be confused with circadian rhythm disorders, especially with a delayed phase, and with restless legs syndrome.

Associated or underlying disorders

Associated neuropsychiatric disorders are listed below. Some of these have been discussed in subtopics of etiology and pathogenesis.

In addition, insomnia is a symptom of several medical disorders. Other important details to inquire about include environmental noise, nightmares, partial arousal disorders, REM sleep behavior disorder, nocturnal seizures, nocturia, enuresis, sleep paralysis, and hypnagogic hallucinations.

Diagnostic workup

Insomnia is primarily diagnosed by clinical evaluation through a sleep history and detailed medical, substance, and psychiatric history. The sleep history should cover specific self-administered questionnaires, at-home sleep logs, symptom checklists, psychological screening tests, bed partner interviews, insomnia complaints, pre-sleep conditions, sleep-wake patterns, other sleep-related symptoms, and daytime consequences.

The history helps to establish the type and evolution of insomnia, perpetuating factors, and identification of comorbid medical, substance, or psychiatric conditions. Instruments that are helpful in the evaluation and differential diagnosis of insomnia include polysomnography and daytime multiple sleep latency test (MSLT) and are not indicated in the routine evaluation of chronic insomnia, including insomnia due to psychiatric or neuropsychiatric disorders.

Actigraphy is indicated as a method to characterize circadian rhythm patterns or sleep disturbances in individuals with insomnia.

Management

According to previous international guidelines, primary treatment goals in subjects with insomnia should be to improve sleep quality and quantity and to improve insomnia-related daytime impairments. Other sleep-specific outcomes should include the improvement of wake time after sleep onset (WASO), sleep onset latency (SOL), number of awakenings, total sleep time (TST), or sleep efficiency.

A correct diagnosis fostered by thorough and competent evaluation is one of the most important considerations regarding treatment. Secondary causes that need specific treatment (apnea, restless legs syndrome, etc.) must be identified and addressed directly.

Cognitive behavioral therapy for insomnia. Cognitive behavioral therapy for insomnia (CBT-I) has received support from several studies as an effective treatment for insomnia, and it is currently the first-line treatment. CBT-I is a multicomponent intervention that addresses behavioral and psychological factors that contribute to the development and maintenance of insomnia. Two core components of CBT-I are stimulus control therapy and sleep restriction therapy. Stimulus control therapy is a behavioral strategy that aims to “reconnect” the sleeping quarters with the act of sleeping. Patients are advised to use the bed only for sleeping or for sexual relations. If unable to sleep, the patient should get out of the bed and engage in a low-level, low-light activity (04). Sleep restriction therapy makes therapeutic use of the increased sleep pressure associated with a restricted opportunity for sleep, typically approximately 6 hours per 24-hour period. Patients should be advised that this technique is designed to enhance sleepiness and are warned to use appropriate caution to avoid accidents when undertaking this treatment plan. Education about sleep hygiene is often included as a component of CBT-I. Examples of sleep hygiene instructions include limiting the variability of bedtime and risetime with a regular sleep-wake schedule, avoiding daytime naps, and avoiding caffeine and bright light exposure toward the end of the day. The cognitive component of CBT-I serves to identify and modify any maladaptive beliefs or thoughts the patient has about sleep, including setting realistic expectations regarding sleep patterns and next-day consequences of sleep loss. CBT-I may also include adjunctive treatments such as relaxation training or light therapy as needed.

CBT-I can be integrated with alternative/complementary therapies such as mindfulness meditation, and yoga (27).

A meta-analysis suggests that it is an effective treatment for insomnia sufferers with comorbid psychiatric conditions (07). CBT-I has also been shown to be effective in treating patients with insomnia that is comorbid with medical illness (05). Research suggests that CBT-I may be useful in treating insomnia associated with breast cancer (23), chronic pain (09), and fibromyalgia (12). Indeed, CBT-I is not widespread across countries, and it is not often available. Pharmacotherapy remains the first option in the majority of countries.

Pharmacotherapy. The pharmacological principles related to the treatment of insomnia are highly complex, and voluminous literature exists on this topic. The choice of pharmacologic agents should be directed by symptom pattern, treatment goals, past treatment responses, patient preference, cost, availability of other treatments, comorbid conditions, contraindications, and side effects. Drugs approved for insomnia treatment according to international guidelines are gamma-aminobutyric acid (GABAa) receptor agonists, melatonin receptor agonists, and orexin receptor antagonists. Other compounds, such as antidepressants, antihistamines, antipsychotics, or antiepileptics, should not be considered first-line treatment options for insomnia. Indeed, low doses (subtherapeutic for depression) of sedating tricyclics, particularly amitriptyline, dosulepin, and doxepin, have been used to treat insomnia for decades. Only doxepin has received the recommendation for insomnia treatment, but it is not available in all countries. Trazodone is an antagonist at 5HT1a, 5HT2, and a1 adrenergic receptors as well as a weak 5HT reuptake inhibitor; it is the second most prescribed medication for insomnia in the U.S., but data for its use are limited.

Gamma-aminobutyric acid (GABAa) receptor agonists include short/intermediate benzodiazepines (brotizolam, lormetazepam, temazepam, triazolam) and nonbenzodiazepine compounds, the so-called Z-drugs, including zolpidem, zaleplon, zopiclone, and eszopiclone. They were found to be effective for short-term use and to be equally effective in improving SOL, WASO, TST, and sleep efficiency. In particular, an extended-release formulation of zolpidem has shown good results in improving WASO. A variety of side effects have been reported with respect to these classes of drugs, including hangover, nocturnal confusion, falls, negative effects on next‐day cognitive performances, rebound insomnia, tolerance, and dependency. Z-drugs have been reported with the risk of severe parasomnia. Indeed, insomnia is often long lasting and is often treated with these hypnotic compounds for long periods in clinical practice. Still, the longer-term safety and efficacy of these hypnotics remain uncertain. Trying intermittent use or using CBT-I or prolonged release melatonin 2 mg during tapering has been suggested.

Among melatonin receptors, M1 and M2 agonists prolonged-release melatonin 2 mg and ramelteon have been approved for insomnia treatment. Melatonin receptor agonist prolonged-release melatonin 2 mg has been shown to mimic the physiological release of melatonin by releasing melatonin gradually and acting on melatonin receptors. Prolonged-release melatonin 2 mg has been shown to be effective in improving SOL, WASO, TST, and sleep efficiency and to reduce night awakenings without altering the physiological sleep structure. Prolonged-release melatonin 2 mg has been shown to be well tolerated and is not associated with impairment of psychomotor functions, memory recall, and driving skills. It has not shown side effects, such as hangover, nocturnal confusion and falls, negative effects on next‐day cognitive performance, rebound insomnia, tolerance, and dependency. In some countries, prolonged-release melatonin 2 mg has been approved for the treatment of chronic insomnia in people aged 55 or older.

Ramelteon has been shown to be effective on SOL, WASO, and TST. Indeed, it is not available in most countries.

The newest molecules for the treatment of insomnia are dual orexin receptor antagonists (DORA) OX1R and OX2R, which are G protein–coupled receptors. OX1R and OX2R mRNAs are widely expressed in the brain in a pattern similar to that of orexin nerve terminals. There are few studies showing that OX1R antagonists are involved in regulating the stress system and that anxiety-like behaviors are involved in hyperarousal. Inhibition of OX1R attenuated cage-exchange stress-induced hyperarousal and anxiety-like behaviors, whereas selective inhibition of OX2R prevented ACTH release elicited by psychological stress in mice, suggesting that both OX1R and OX2R are specific targets in preventing the overactivation of the arousal system and HPA axis, respectively, under stress (15).

It has been hypothesized that antagonizing both orexin receptors would elicit the most powerful sleep-promoting effects; therefore, many of the studies around orexin antagonists have focused on DORAs. Inhibition of both OX1R and OX2R DORAs regulates REM and NREM sleep processes and contributes to restoring alterations in sleep-related insomnia and, in turn, promoting physiological sleep. This may be vital to reactivate sleep and its functions, which could be useful for stress and emotion regulation as well. By acting on the transition between wake and sleep, it is possible that DORAs may reset the flip-flop switch mechanism in insomnia, which has been hypothesized to be impaired. All these functions may prove pivotal for regulating sleep processes, sleep-dependent brain plasticity, and stress/emotional reactivity in insomnia and, in turn, contributing to “switching off” hyperarousal in insomnia (15). Approved DORAs for insomnia treatment are suvorexant, lemborexant, and daridorexant.

Drugs used in the past for the treatment of insomnia, as well as those currently used, are listed in Table 2.

Table 2. Drugs Used for the Treatment of Insomnia

Sedating medications should be used with caution in the elderly due to evidence suggesting an increased risk for falls in this population. The aforementioned are recommended for use according to the AASM clinical practice guidelines based on level of evidence for the pharmacologic treatment of chronic insomnia in adults, which is weak as compared to no treatment (20).

Combination of CBT-I with other therapies. CBT-I can be integrated with alternative/complementary therapies such as mindfulness meditation, yoga, acupuncture, and tai chi (27). A retrospective observational study has shown that efficacy of cognitive behavioral therapy combined with eszopiclone for the treatment of sleep disorders patients transferred out of the intensive care unit was better than use of eszopiclone alone (26).

Special considerations

Pregnancy

Insomnia disorder may affect almost 30% of pregnant and postpartum women. Insomnia symptoms are frequent sleep disorders during pregnancy and postpartum and may be risk factors for perinatal psychopathology. Assessing and treating insomnia during the peripartum period is essential and should be included in the routine evaluation of pregnant women as it may prevent peripartum psychopathology. Cognitive behavioral therapy for insomnia (CBT-I) should be the preferred treatment choice peripartum, as for insomnia patients. It may also be useful to improve mood, anxiety symptoms, and fatigue. Pharmacological treatment may be considered when women who present with severe forms of insomnia symptoms do not respond to nonpharmacologic therapy.

Among the pharmacological options available for insomnia, limited data are available for pregnancy and lactation. Lorazepam has been the most studied compound in pregnancy, and trazodone is promising (14).