Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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In this article, the author discusses diagnosis, complications, and treatment of psychophysiological insomnia. Updates include new information regarding the pathophysiology and unique electroencephalogram characteristic of psychophysiological insomnia. The article also discusses additional data to support cognitive behavioral therapy for insomnia as first-line treatment for psychophysiological insomnia.
• Three types of factors play a role in the development of psychophysiological insomnia: (1) predisposing or constitutional factors, eg, the tendency to worry excessively and the tendency to be hyperaroused; (2) precipitating factors, eg, a transient stressor; and (3) perpetuating factors, eg, the individual's expectation of a poor night's sleep that becomes a self-fulfilling prophecy.
• Psychophysiological insomnia usually begins as a somaticized response to a stressful event and then, depending on genetic and other environmental variables, becomes a more chronic condition because of negative conditioning.
• Many studies have reported hyperarousal in cognitive, somatic, autonomic, hormonal, and EEG domains in patients with primary insomnia. Hyperarousal and its concomitants may be a link to the association of primary insomnia to such complications as hypertension, diabetes, and increased mortality.
• The administration of sedative-hypnotic drugs and cognitive behavioral therapy are 2 effective tools for the management of psychophysiological insomnia.
• This form of insomnia occurs in 1% to 2% of the general population and 12% to 15% of patients presenting to a sleep disorders center (04).
The International Classification of Sleep Disorders, 3rd edition, defines "psychophysiological insomnia" as a clinical and pathophysiological subtype of an insomnia disorder and as "heightened arousal and learned sleep-preventing associations that result in a complaint of insomnia and associated decreased functioning during wakefulness" (04). The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders replaces the term primary insomnia with insomnia disorder to avoid implying directionality when this disorder is co-occurring with other conditions (05).
The essence of psychophysiological insomnia is the focused attention on inability to sleep, which is perceived to be the only source of distress. This concept was analyzed and at least partially confirmed by using tests for attentional bias (the visual dot-probe test [VDP] and an emotional Stroop test [EST]) (62). It was further strengthened in primary insomniacs by their delayed disengagement to the clock when the hours fell within those of the normal sleep period, a finding which fits in with the “attention-intention-effort” model. Other emotional or mental concerns are minimized. Patients typically repress or deny awareness of stress factors, unable to find any reason for the insomnia. Another study found that when tasked with a facial expression recognition task in the early evening, patients with psychophysiological insomnia described expressions displaying sadness and fear as significantly less emotionally intense than good sleepers (42), suggesting there may be a difference in response to emotional stimuli. Another cognitive model of insomnia suggests that individuals with insomnia have a sleep-specific expectancy bias. When study participants with high rates of insomnia were given a reaction time task with different sleep related scenarios, those with insomnia were more likely to solve sleep related scenarios with negative outcomes compared to those with low rates of insomnia (22).
Psychophysiological insomnia is typically acquired during a period when other factors, such as stress, can cause insomnia (precipitating factor). After a few days of sleeping poorly, the patient becomes concerned about his or her inability to sleep, trying harder and harder to get to sleep. That causes arousal and aggravates the insomnia. The stimuli surrounding the bedtime event (such as the bed itself, the bedroom, etc.) may become conditioned triggers to arousal (perpetuating factor). Thus, such patients may have severe problems with sleeping in their own bedroom but often sleep remarkably well in other situations, such as on the living room couch, in a motel, or in a laboratory.
Daytime symptoms include fatigue, negative mood, cognitive impairment, and a decline of quality of life; these symptoms are correlated with perceived poor quality of sleep. Cognitive deficits, such as difficulty with attention and episode memory, have been found to be significantly higher in patients with insomnia. However, it is difficult to tease out whether this is associated with sleep deficits or to dysfunctional belief or attitudes about sleep (30).
According to The International Classification of Sleep Disorders, 3rd edition, psychophysiological insomnia is a subtype of chronic insomnia disorder. The following criteria must be satisfied to characterize psychophysiological insomnia: (1) a complaint of insomnia and a complaint of decreased functioning during wakefulness; (2) indications of learned, sleep preventing associations, such as trying too hard to sleep or showing conditioned arousal to the bedroom; (3) description of increased somatized tension, such as agitation, high muscle tension as manifest in tension headaches, or increased sympathetic tone; (4) the polysomnogram, if used, shows disturbed sleep; (5) no other medical or psychiatric disorder can account for the severity of the sleep disturbance, although most patients with psychophysiological insomnia are somewhat anxious and dysphoric; and (6) other sleep disorders may coexist with the insomnia, eg, poor sleep hygiene and obstructive sleep apnea (04).
If untreated, psychophysiological insomnia can continue for decades. In some cases, it gradually worsens because a vicious cycle of insomnia develops. Overall quality of life, as measured by the Short Form-36 Health Status Survey, is greatly impaired by chronic insomnia (02). When compared to healthy controls and to patients with obstructive sleep apnea and narcolepsy, the subjects suffering from psychophysiological insomnia, similar to ones with sleep apnea and narcolepsy, performed poorer than healthy controls on standardized attention tests but scored as normals on alertness tests.
Other complications are those of any serious insomnia: excessive use of hypnotics, self-treatment with alcohol, treatment of ensuing daytime somnolence by stimulants, and daytime tension with tranquilizers. Psychological complications include a passive and defeatist attitude and other maladaptive behaviors and cognitive and memory impairment. Finally, insomnia (self-defined), when coupled with short sleep duration, is also a predictor of hypertension, diabetes, and overall mortality (64) in men independent of age, obesity, other sleep disorders, and other risk factors. Prospective epidemiological studies have found links between insomnia and suicide risk. Notably, catastrophizing and the sense of defeat have been identified as potential cognitive pathways through which insomnia aggravates suicidality in patients with chronic pain (67). More work is needed on the effects of insomnia on psychiatric and somatic morbidity and mortality.
A 70-year-old female was referred to the Sleep Disorders Center reporting that she had “not slept a full night in 30 years.” Her psychiatric history was significant for depression. Her medical history was significant for fibromyalgia, hypothyroidism, hypertension, and irritable bowel syndrome. The patient identified the death of her husband 30 years ago as the precipitating factor for her insomnia. She was subsequently left to run their successful business and raise the 3 children on her own. The patient reported that over the next 30 years, she developed habits surrounding sleep. Behavioral changes included spending excessive time in bed. She would get into bed at 7:30 p.m. to meditate. She got out of bed at 6:30 a.m. She also drank 3 glasses of wine before bed. The patient reported that she was “careful” about her sleep. She thought about her sleep throughout the day, and her anxiety level increased as bedtime approached. The patient underwent 6 sessions of cognitive behavioral therapy for insomnia, which focused on addressing perpetuating factors such as spending excessive time in bed and alcohol use for sleep. Cognitive therapy focused on her dysfunctional beliefs and increased anxiety about sleep. The patient’s sleep efficiency gradually increased over the 6 sessions, and she became less focused on her sleep.
A few nights of disturbed sleep, as the result of factors such as stress, is a universal human experience. In the majority of cases the trouble is short lived. Three types of factors play a role in the development of psychophysiological insomnia: (1) predisposing or constitutional factors: the tendency to worry excessively about anticipated danger and the tendency to be generally hyperaroused, both metabolically and cognitively; (2) precipitating factors: a transient stressor; and (3) perpetuating factors: the individual's expectation of a poor night's sleep that becomes a self-fulfilling prophecy and the counterproductive trials to sleep.
In some patients with psychophysiological insomnia, no precipitating stress is found. Rather, poor sleep may have gradually developed as an occasionally occurring disturbed night leads to increased concern, causing sleep to deteriorate until it becomes the patient's chief concern. There is clear evidence for the role of familial inheritance in the tendency to develop insomnia.
The interaction of personality traits, affective disorders, and insomnia is also important. Insomnia has been shown to be more frequent in adults with major depressive disorder, generalized anxiety disorder, alcohol dependence, cannabis dependence, and tobacco use (38). It is known that insomnia is a risk factor for future depression (03) and that adverse childhood experiences are a significant risk factor for sleep disturbances in later life (17). Moreover, the number of diagnoses of depression and anxiety early in life has been associated with future insomnia (32).
Growing evidence shows that insomnia has organic components. The pathogenesis and pathophysiology of psychophysiological insomnia is presumed to be moderate hyperarousal or an imbalance of the sleep-wake system towards alertness. Physiological hyperarousal is documented in many types of insomnia. Hyperarousal implies an overactive wake mechanism. The other side of the coin is a possible dysfunctional homeostatic sleep-inducing mechanism. Hyperarousal (13) characterized by difficulty initiating sleep on a nap opportunity also appears to be present during the daytime in patients with psychophysiological insomnia (53). A study that examined the response to questionnaires regarding the cognitive and emotional experience prior to sleep in psychophysiological insomnia revealed that trait hyperarousal was associated with higher levels of both negative and positive emotionality, as well as negative beliefs about sleep in both genders. Among women, high pre-sleep arousal was associated with negative emotionality, whereas in men greater pre-sleep arousal was associated with cognitions about their control oversleep (34).
A large-scale study of twins from the Virginia Adult Twin Studies of Psychiatric and Substance Use Disorders (total n = 7500) examined the genetic overlap of insomnia and other psychopathology. The study found significant overlap between latent additive genetic influences of insomnia with major depressive disorder (56% for females, 74% for males), shared completely with generalized anxiety disorder (100%) but modestly with alcohol abuse or dependence (18%) (48). Presence of anxiety also appears to be involved in objective sleep parameters. Polysomnographic characteristics in 1083 patients undergoing sleep studies showed prolonged sleep onset latency was associated with state anxiety and alterations in REM sleep were associated with trait anxiety (36).
In response to cognitive-behavioral therapy, Krystal and Edinger described a steeper slope of decline in delta power from sleep onset to the end of the sleep period in a group of insomniacs, suggesting a restoration of normal homeostasis as represented by a buildup of delta activity during wakefulness and its dissipation during normal sleep.
Insomniacs display faster heart rates, higher body temperature, and higher electromyogram activity. They are also as or more alert than controls during the day; their Multiple Sleep Latency Tests show increased sleep latency as compared to controls. By electroencephalographic criteria, insomniacs tend to have a higher percentage of faster frequencies both in waking and in NREM sleep (Krystal et al 2002; 21) and lower theta power in the waking EEG (68). Lamarche and Ogilvie compared patients with psychophysiological insomnia to patients with psychiatric insomnia and to normal controls. Electroencephalographic activity showed higher cortical arousal in the psychophysiological insomniacs versus the other 2 groups, which did not differ from each other significantly. Corsi-Cabrera and colleagues found similar results when they compared beta and gamma power in primary insomniacs versus healthy controls (21). They were particularly interested in explaining the nonrestorative quality of sleep reported by many insomniacs. Compared to presleep, the primary insomniacs showed increased beta and gamma power with increased synchronization in anterior and posterior regions of the brain, suggesting that these electrophysiological differences might account for the report of nonrestorative sleep (21).
Buysse and colleagues found that women with primary insomnia had greater EEG spectral activity during NREM sleep, particularly in the earlier hours of sleep, than did normal sleepers. Some studies have shown a positive correlation between objective sleep disturbance and the activity of both limbs of the stress system (the hypothalamic-pituitary-adrenal axis and the sympathetic system) and increased serum levels of ACTH and cortisol in a group of chronic insomniacs.
Adults with insomnia have also shown a significantly greater cortisol awakening response (CAR), and those with worse insomnia (ie, lower subjective sleep efficiency) had higher cortisol levels in the late evening (10:00 pm) in both adults and adolescents (72).
In another study, nocturnal melatonin production was significantly diminished in insomniac patients compared to healthy controls. Single photon emission computed tomography neuroimaging during NREM sleep has shown decreased perfusion in the basal ganglia and other areas of the brain in primary insomniacs compared to normal controls. A study using event related potentials has shown enhanced excitatory and reduced inhibitory processes of auditory stimuli during sleep in patients with primary insomnia, giving further credence to the hyperarousal theory. Another study found no difference between psychophysiologic insomniacs and a good sleeper control group in the number and density of K-complexes during sleep. If K-complexes are indeed protective of sleep, as 1 theory implies, then a lack of this protection is not 1 of the possible factors in the development of psychophysiologic insomnia. Finally, proton magnetic resonance spectroscopy has shown a reduction of the inhibitory neurotransmitter, gamma amino butyric acid (GABA), in patients with primary insomnia.
In 2020, there was a rise in insomnia, anxiety, and depression rates, particularly in first-line health care workers in response to the COVID-19 pandemic. As early as January 2020, a high symptom prevalence of depression, anxiety, and combination of depression and anxiety (48.3%, 22.6%, and 19.4%, respectively) was identified by an online survey of 5000 healthcare workers. Although the prevalence of insomnia was low overall, slightly more front-line workers than second-line workers (10.5% vs. 4.0%, p < 0.001) had moderately severe insomnia on the Insomnia Severity Index (43). Similar results were found in Oman, where as many as 30% of physicians and nurses who treated COVID-19 patients experienced moderate to severe anxiety (08). Studies have shown reduced sleep duration (20), reduced sleep quality, and increased nightmares in both community members (47) and front-line workers (60).
The incidence of psychophysiological insomnia is unknown. Of insomniacs who seek help at sleep centers, about 11.3% to 15% were diagnosed with psychophysiological insomnia in several large studies of sleep disorders centers. In a sample of 881 patients over 60 years of age in Korea, the prevalence of psychophysiological insomnia was 20.5%, and 53.7% of those patients had subsyndromal depression (39). Chronic insomnia was also found to be prevalent in 36.2% of 142 Japanese older adults over 75 years of age, and of those patients, the Geriatric Depression Scale scores were higher (35). Psychophysiological insomnia is often diagnosed as a secondary problem because learned associations often prevent or disrupt sleep in many other forms of chronic insomnia. About 27% of patients in sleep centers are estimated to have psychophysiological insomnia as a secondary problem.
It was first suggested in 1999 that patients who are prone to somatization and who deny emotional stress may be at risk for psychophysiological insomnia (12).
Bruck and colleagues found that both young and older individuals may have unrealistic expectations about sleep, such as sleeping without awakenings (14). Education and reassurance about what “normal healthy” sleep should be may also aid in a prevention program. Although few insomnia sufferers seek professional consultations, many individuals initiate self-help treatments, particularly when daytime impairments such as fatigue become more noticeable.
A useful tool in the identification and possible prevention of worsening psychophysiological insomnia is the Ford Insomnia in Response to Stress Test (FIRST). This test has been used to identify who is at risk for insomnia. In 1 study, responders who had “highly reactive sleep systems” also reported longer sleep onset latencies (FIRST ≥ 16: 65 min; FIRST ≥ 18: 68 min) compared to those with “nonreactive insomnia” (FIRST < 16: 37 min; FIRST < 18: 44 min) (37).
A deterioration of mood and motivation as well as problems with attention, vigilance, and concentration are associated with psychophysiological insomnia. Studies have shown that these symptoms are secondary to central nervous system arousal and not to poor sleep per se.
They are often sensation avoiders, maintaining a rigid, unexciting routine in hopes of attenuating their insomnia.
Key features of psychophysiological insomnia include worry, dysfunctional beliefs, somatic arousal, selective attention, and monitoring of sleep and safety behaviors. These 5 types of cognitive processes are key treatment targets as they may affect remission of insomnia over time (51). These ruminations about sleep are problematic not only at night, but also in the daytime in psychophysiological insomnia (52), suggesting that insomnia is a 24-hour disorder.
Preventative strategies for development of psychophysiological insomnia may include attempts to lessen the patient’s fears of the consequences of insomnia. For example, rumination and beliefs about sleep can play a role in insomnia, particularly in comorbid insomnia. In 1 example, insomnia rumination scores on an insomnia-specific measurement scale predicted insomnia even after controlling for depression (15). Difficulty falling asleep during inpatient detoxification treatment for alcohol dependence predicted relapse 1 month after discharge. Surprisingly, higher dysfunctional beliefs about sleep were associated with lower rates of relapse (61).
Psychophysiological insomnia lies on a continuum with a number of other diagnostic categories.
Idiopathic insomnia is diagnosed if the predisposition towards poor sleep by itself is severe enough to cause insomnia. Psychophysiological insomnia is assumed to start with a somewhat milder predisposition towards poor sleep that usually develops into insomnia only with the occurrence of some other, identifiable stressor acting as the trigger.
A sleep state misperception is when the patient sleeps adequately but does not perceive it as sleep.
Circadian rhythm abnormalities occur when the patient sleeps well but not at socially acceptable times.
Inadequate sleep hygiene is the diagnosis if insomnia is maintained primarily by neglecting sleep hygiene, eg, drinking too much coffee, lacking exercise, napping, staying in bed too long. To the extent that the insomnia is independent of the precipitating causes and also independent of the quality of sleep hygiene, psychophysiological insomnia is the preferred diagnosis.
Generalized anxiety disorder is the preferred diagnosis if anxiety permeates most aspects of a patient's functioning (anxiety in social interactions, about job performance, etc.). This may be difficult to disentangle as insomnia has been found in 40% of patients with symptoms of anxiety and depression symptoms (50). There are also clear associations between characteristics of obsessive compulsive disorder, eg, anxiety sensitivity, and symptoms of insomnia (56). Psychophysiological insomnia is preferred if the anxiety is focused almost exclusively on poor sleep and its consequences on daytime functioning.
Affective disorder is sometimes difficult to separate from psychophysiological insomnia because a dysphoric mood that is ascribed to the effects of poor sleep often accompanies psychophysiological insomnia. It is especially difficult to distinguish dysthymia from psychophysiological insomnia in cases of "masked" depression, ie, when the patient denies overt sadness or hopelessness. Often, the discrimination can be made on other "vegetative signs," such as loss of appetite or libido or the typical diurnal fluctuation of depression (morning being worse). In the final analysis, the diagnostician's sense is important whether depression is still driving the insomnia, or whether the insomnia is driven by maladaptive sleep habits learned during a previous depression. Also, dysthymic patients may typically show depressive traits before the insomnia developed.
Medical causes of insomnia may include, but are not limited to, propriospinal myoclonus, restless legs syndrome, cardiorespiratory disorders, pain, degenerative disorders, prostatic hypertrophy, and obstructive sleep apnea disorder.
Drug-related insomnia may include, but is not limited to, stimulants, theophylline, prednisone, selective serotonin reuptake inhibitors, withdrawal from sedative medication, idiosyncratic reactions to other medications, and toxin related causes such as alcohol or other recreational substance abuse, carbon monoxide, or inorganic mercury.
The diagnosis of psychophysiological insomnia is typically made by interview, paying attention to learned associations preventing sleep and to the patient's display of somatized tension. Typical clinical inquiries might include whether the patient sleeps better away from home, has excessive focus or anxiety about sleep, has difficulty sleeping in their bed but not in other locations, has mind racing, and has somatic tension when trying to sleep.
A psychiatric interview suggested ruling out psychiatric disorders. There can be a close relationship between insomnia and mood disorders. One systematic analysis found a reciprocal relationship between subjective sleep variables (sleep quality, sleep duration, and sleep latency) and daytime affective states over the short term (41).
A general medical evaluation rules out physical problems, such as other medical or neurologic disorders, medication effects, or substance abuse (59). Polysomnography reveals increased sleep latency, increased wakefulness after sleep onset, decreased sleep efficiency, or a combination of these disturbances. There may be increased stage I sleep. However, these features are simply the hallmarks of poor sleep in general; no polysomnographic features are specifically diagnostic of psychophysiological insomnia. Polysomnography in patients with suspected psychophysiological insomnia seems necessary only when other sleep disorders are suspected such as sleep apnea or sleep state misperception, when treatment has failed, or if the cause of insomnia is uncertain (59). Moreover, insomnia (objectively defined via polysomnography) with features of hyperarousal (characterized by a latency to sleep on a multiple sleep latency test of > 14 minutes) resulted in a significant risk of hypertension (46). Actigraphy may be helpful in patients with complaints such as "I don't sleep at all" and should be supplemented with subjective sleep logs. Certain standardized questionnaires like the Insomnia Severity Index are sometimes used to screen for insomnia and determine its severity.
Management for psychophysiological insomnia may include cognitive behavioral treatment for insomnia (CBTI), hypnotic medication, or a combination of the two (Morin et al 2006b; Morin et al 2016). CBTI is an effective non-pharmacological intervention that typically includes sleep restriction therapy, sleep hygiene education, stimulus control therapy, and correcting distorted perceptions of sleep. According to Edinger and colleagues, all components have good scientific evidence to support their use as single-component therapies for chronic insomnia, except sleep hygiene (27).
CBTI is now considered first-line treatment for insomnia according to the American College of Physicians (55). Brain changes before and after CBTI have been found via imaging techniques, specifically in the left middle temporal and left middle occipital gyrus. This was evidenced in a small sample of patients with psychophysiological insomnia who were tested with MRI before and after CBTI (40). Adjunctive approaches to treating psychophysiological insomnia have included using mindfulness and acceptance (Ong et al 2012; 19). A randomized controlled trial of older adults found that mindful awareness practices to improve sleep quality were significantly more helpful for sleep, depression, and fatigue compared to a sleep hygiene intervention alone (11). Mindfulness-based stress reduction and mindfulness-based therapy for insomnia have been found to be well accepted by patients (49) and may also be an effective treatment for insomnia in breast cancer survivors (45). Even just providing relaxation and sleep hygiene can be more helpful for insomnia compared to treatment as usual in postmenopausal women (26).
Specific questionnaires used in CBTI, such as the dysfunctional beliefs and attitudes about sleep scale (DBAS), can be particularly helpful in-patient engagement and adherence to therapy components in patients with psychophysiological insomnia (24). Changes in these dysfunctional beliefs occur in the process of CBTI. Although both components of CBTI (ie, behavioral and cognitive therapy for insomnia, respectively) reduce dysfunctional beliefs, cognitive therapy appears to be more powerful of an intervention to reduce the strength of dysfunctional believes (28).
Carefully calibrated and timed exercise can be an integral component of this approach. These behavioral methods are effective in increasing the total sleep time by 13%, reducing sleep latency by 65%, and reducing the wake time after sleep by 48%. Both behavioral and pharmacological treatments are equally effective in the short-term treatment of insomnia, and the benefits of CBTI can outweigh the benefits of a medication after 2 years; although some have suggested a need for caution in the effectiveness of behavioral medicine interventions in health psychology. The recommended “dose” of cognitive behavior therapy is 4 individual, biweekly sessions, and it can be administered by nurses in a primary care setting, although the efficacy is not as robust as has been reported before with mental health professionals. Therefore, a stepped care approach may be of benefit.
Although CBTI is helpful for improving sleep quality, it may not necessarily result in an increased sleep duration.
In a study that examined insomnia-related worry before and 1 year after completion of CBTI, there were reductions in insomnia-related worry, which was associated with improvements in insomnia severity, sleep continuity, and depression (63). However, clinicians may consider whether CBTI for psychophysiological insomnia is the most beneficial treatment option in patients with significant psychiatric comorbidities. The data has been somewhat mixed on its efficacy in a comorbid population. One study examining 60 patients with logistic regression analyses showed that the presence of psychiatric comorbidity was strongly predictive for negative treatment outcome (65). On the other hand, a meta-analysis of the efficacy of CBTI for psychiatric and medical comorbidities found that CBTI was helpful, with larger effect sizes for comorbid psychiatric conditions. Post-treatment assessments found that 36% of patients who underwent CBTI were in remission from insomnia compared to 16% in the control conditions (69). There is growing evidence to suggest the benefits of targeting insomnia even in the context of other disorders (16).
CBTI is also well adapted to be delivered via telemedicine (07) and Internet-based platforms (58; 70), and several mobile apps have very good data to support their effectiveness for improving sleep and mood (18; 25). Telemedicine has been particularly useful during the COVID-19 pandemic as very few therapists see patients in person. Given the overlap between COVID anxiety and insomnia, one study emphasized addressing “cognitive reappraisal” to better help prepare nurses to alleviate mental health problems and sleep difficulties that are related to COVID-19 (71).
Pharmacotherapy can be used as an adjunct to CBTI or used independently for the treatment of insomnia (09; 57). Although a detailed review of all sleep aids is outside the scope of this review, there are several reviews available on medications for insomnia in adults (31) and in older adults (01).
Hypnotics that have clinically proven efficacy include the nonbenzodiazepine hypnotics: zolpidem, zaleplon, and eszopiclone; ramelteon (a melatonin receptor agonist); the benzodiazepines; and low-dose trazodone only in depressed patients. Antihistamines are rarely indicated because of a poor side effect profile. Over-the-counter hypnotics are of unproved value as hypnotics. A “modest” hypnotic effect was found for the use of 14 nights of valerian-hops and diphenhydramine (25 mg) combination relative to placebo. Melatonin is of proven efficacy in the treatment of insomnia associated with circadian rhythm abnormalities and in schizophrenia, but not in psychophysiological insomnia. There is a paucity of data on the efficacy of antidepressants and over-the-counter sleep aids in the treatment of insomnia. In addition, the risk of serious adverse effects with these medications is well documented. However, several antidepressants that have been shown to be effective for primary insomniacs include trimipramine and doxepin.
According to the National Health and Nutrition Examination Survey, medications commonly used for insomnia between 1999 and 2010 included nonbenzodiazepine receptor agonists (particularly zolpidem) and trazodone (10). Although current Food and Drug Administration guidelines recommend most hypnotic medication only for short-term use, studies have shown that the risk of tolerance, addiction, dependence, and rebound insomnia are minimal (66). One study showed that long-term use of zolpidem is safe, well tolerated, and effective in the treatment of chronic insomnia, and zolpidem CR is approved for long-term use. However, risk for dependence is raised when the recommended dose and timing of zolpidem, or zolpidem-like medications, is exceeded (23). Side effects of zolpidem may include aberrant nocturnal behavior (eg, eating or driving) with amnesia for the behavior after the sleep episode. A review of the concern for abuse potential in zolpidem found that there is risk for driving impairment up to 12 hours after use.
Another nonbenzodiazepine hypnotic, eszopiclone, has also been shown to be consistently effective without adverse effects or tolerance for a period of up to 6 months of nightly usage (66), and the usefulness of eszopiclone has been extended to elderly insomniacs (06). The development of orexin receptor antagonists may lead to an exciting therapeutic option in the future. Suvorexant, a dual orexin receptor antagonist, is FDA-approved and already in the market in the United States (44), and lemborexant received approval in December 2019.
One must keep in mind that the use of medications for insomnia is typically indicated for the short term. A retrospective cohort data review for the last year found that in about 4000 individuals analyzed who were prescribed a hypnotic medication, 59.6% were prescribed hypnotics for only 1 month, 11.3% were prescribed hypnotics for 2 consecutive months, and 10.1% of patients received prescriptions for the entire 12-month observation period (29).
As noted above, the American College of Physicians recommends CBTI as the first-line treatment for insomnia. As a result, some patients are encouraged to add CBTI as an approach to assist with sleep medication taper. CBTI has been shown to be helpful in the process of hypnotic withdrawal with improved sleep over time (09; 33). With only sleep hygiene and psychosocial support, Puustinen and colleagues found that at 3 years after withdrawal from benzodiazepine agonists (BZDA) the number of BZDA-free participants had decreased (54). One-third of the subjects remained BZDA-free, and one-third had reduced their use. Although sleep hygiene and psychosocial support can be helpful, CBTI is preferred for long-term benefit.
Pregnancy may aggravate psychophysiological insomnia, especially in the first and third trimesters.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Deirdre A Conroy PhD
Dr. Conroy of the University of Michigan has no relevant financial relationships to disclose.See Profile
Antonio Culebras MD FAAN FAHA FAASM
Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.See Profile
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