Treatment of Sleep Disorders

Treatment of Sleep Disorders

Oxford Clinical Psychology

A Guide to Treatments That Work (4 ed.) Edited by Peter E. Nathan and Jack M. Gorman Publisher: Oxford University Press Print ISBN-13: 9780199342211 DOI: 10.1093/med:psych/9780199342211.001.0001

Print Publication Date: Jul 2015 Published online: Aug 2015

Treatment of Sleep Disorders Chapter: (p. 659) Treatment of Sleep Disorders Author(s): Deepa Burman, Daniel J. Buysse, and Charles F. Reynolds DOI: 10.1093/med:psych/9780199342211.003.0021 This chapter provides an evidence-based review of the seven categories of DSM-5 sleep-wake disorders. Specific sleep-wake disorders vary widely in their clinical manifestations, etiologies, treatment, and the level of evidence supporting those treatments. Sleep-wake disorders are prevalent, increase the risk of many common mental and substance use disorders, and exacerbate these disorders, with which they typically co-occur. Unless properly treated in their own right, sleep-wake disorders can impair treatment response and worsen the long-term course of mental disorders. Thus, it is important for psychiatrists and other mental health practitioners to understand the diagnosis and treatment of sleep-wake disorders and when to refer the patient for consultation with a sleep medicine specialist.

Introduction Traditionally, psychiatrists have considered sleep disorders/problems to be symptoms of psychiatric disorders. Chronic sleep problems affect 50% to 80% of patients in a typical psychiatric practice, compared with 10% to 18% of adults in the general U.S. population. Similarly psychiatric morbidity is high in patients seen in the sleep disorders clinic. In reality, the relationship between sleep and psychiatric disorders is found to be bidirectional, such that each can amplify the disability and suffering of the other. Moreover, sleep disturbances such as insomnia disorder are potent risk factors for the onset of common mental disorders. For example, Baglioni and colleagues (2011) found that nondepressed people with insomnia have a twofold risk of developing depression (Roth et al., 2006). Understanding sleep disorders is thus critical for the management of psychiatric patients. According to the DSM-5 classification of sleep-wake disorders there are 10 disorder groups: insomnia disorder, hypersomnolence disorder, narcolepsy, breathing-related sleep disorders, circadian rhythm sleep-wake disorders, non–-rapid-eye-movement (NREM) sleep arousal disorders, nightmare disorder, rapid eye movement sleep behavior disorder, restless legs syndrome, and substance/medication-induced sleep disorder. Impairment of daytime function is a critical feature of all these disorders. The goal of this chapter is to review evidence-based treatment for DSM-5-defined sleep-wake disorders and to provide guidance to the nonspecialist about when to consider referral to a sleep specialist for further assessment and management of patients. In each section below, we provide citations to clinically useful reviews of treatment. Further details on the features and pathophysiology of individual sleep disorders can be found in other sources such as “Clinical Pharmacology of Other Drugs Used as Hypnotics” by Buysse and colleagues (2010), in Principles and Practice of Sleep Medicine, edited by Kryger and colleagues. (p. 660) Insomnia Disorder Overview and Diagnosis Insomnia is a significant health problem because of its high prevalence, treatment challenges, and high socioeconomic burden. It is characterized by difficulty in falling or staying asleep or returning to sleep after a middle-of-the-night awakening. An essential feature of insomnia disorder is dissatisfaction with sleep quality or quantity. It is the most prevalent of all sleep disorders, with a higher female preponderance compared to males. DSM-5 consolidated various insomnia disorders from DSM-IV into a single diagnosis because of the difficulty in discriminating “primary” and “secondary” forms and the reality of high comorbidity. To warrant an insomnia disorder diagnosis, the sleep difficulty should occur at least 3 nights a week for at least 3 months despite adequate opportunity for sleep. This distinguishes it from sleep deprivation. Nonrestorative sleep is no longer a feature of insomnia in DSM-5. A detailed and careful 24-hour sleep-wake history is crucial for the diagnosis and management of insomnia disorder. Evaluation using a 1- or 2-week sleep-wake diary should be considered whenever possible. An example of a sleep-wake diary can be seen in Figure 21.1. Polysomnography is not usually indicated for insomnia disorder unless there is concern about other coexisting sleep disorders based on history.

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Figure 21.1 Sleep diary. A sleep diary (log) is a visual record designed to gather information about a patient’s sleep patterns. It should be completed within an hour of getting out of bed, and the best estimate of sleep wake timing should be recorded. (Adapted from the American Academy of Sleep Medicine.)

Patients should be reassessed every few weeks or monthly until symptoms are stable or have resolved. Because of the high relapse rate, regular follow-ups every 6 months or annually should be considered. “Sleep hygiene” measures should be combined with other forms of insomnia treatment, but sleep hygiene alone has not been found to be effective for treatment of chronic insomnia. Management Insomnia treatments aim to improve the amount and quality of sleep and also to enhance daytime function. Ideally, short-term pharmacological treatment should be supplemented with behavioral and cognitive strategies. Whenever medications are prescribed, treatment goals and expectations should be discussed along with safety, side effects, potential for dose escalation, and rebound insomnia. Long-term medication treatment should be accompanied by consistent follow-up and ongoing monitoring for efficacy, side effects, and newly developed comorbid conditions. Psychological and Behavioral Treatments Psychological and behavioral treatments for insomnia have been evaluated in many randomized controlled trials (RCTs) and meta-analyses. In general, these treatments aim to reduce sleep latency and improve sleep consolidation by changing behaviors, habits, and cognitions that interfere with sleep. The best evidence for efficacy among the various approaches is for multicomponent cognitive-behavioral treatment of insomnia (CBT-I), stimulus control therapy, and sleep restriction therapy. Behavioral approaches are comparable to medications in efficacy and are found to be more durable. Currently there is insufficient evidence to recommend sleep hygiene education, imagery training, or cognitive therapy as monotherapies. Table 21.1 summarizes the major components of behavioral and psychological treatments for insomnia that can be administered individually or in a group. Table 21.1 Psychosocial Treatments of Insomnia Type of Treatment

Description

CBT-I

Multimodal treatment that combines cognitive therapy with behavioral interventions.

Stimulus control

Based on operant and classical conditioning principles:

Key Elements

Evidence for Efficacy

Evidence Grade

Sleep education Stimulus control techniques Sleep restriction techniques Cognitive therapy techniques May include relaxation training.

Based on various meta-analyses, systematic review, and clinical trials. The findings indicate that nonpharmacological therapies produce reliable and durable changes in several sleep parameters of chronic insomnia patients. The data indicate that between 70% and 80% of patients treated with nonpharmacological interventions benefit from treatment.

Type 1 & 2 studies

Hofmann, Asnaani, Vonk, Sawyer, & Fang, 2012 C. M. Morin, Culbert, & Schwartz, 1994 Montgomery & Dennis, 2003 Morin et al., 2006 Okajima, Komada, & Inoue, 2011

Go to bed only when sleepy. Use the bed and bedroom for sleep only. Do not read, watch

Based on at least 2 between- group design studies demonstrating efficacy in more than one way. Stimulus control was as effective as sleep education plus relaxation and more effective than

Type 1–3 studies

Riedel, Lichstein, & Peterson, 1998 Lacks,


Key References

Treatment of Sleep Disorders principles: nonsleep activities and the bedroom environment can serve as stimuli that interfere with sleep. Treatment prescribes behaviors that strengthen associations between the environment and sleep.

Relaxation techniques

Biofeedback

Sleep restriction

Sleep hygiene

Do not read, watch television, talk on the phone, worry, or plan activities in the bedroom. If unable to fall asleep within 10–20 min, leave the bed and the bedroom. Return only when feeling sleepy again. Set the alarm and wake up at a regular time every day. Do not use the snooze button on the alarm. Do not nap during the day.

plus relaxation and more effective than a waitlist control. Stimulus control treatment produced significant improvements on most sleep parameters relative to no additional treatment.

Lacks, Bertelson, Sugerman, & Kunkel, 1983 Morin et al., 1994 Smith, Perlis, Park, & Smith, 2002 Baillargeon & Demers, 1998

Muscular tension and cognitive arousal are incompatible with sleep. Relaxation decreases waking arousal and facilitates sleep at night.

Specific techniques may include progressive muscle relaxation, guided imagery, paced breathing.

Clinical trials. Studies contrasting relaxation-based interventions to a control condition found relaxation more effective than waitlist, placebo, or no treatment. Relaxation was more effective for sleep onset.

Type 2 & 3 studies

Friedman, Bliwise, & Yesavage, 1991 Means, Lichstein, & Epperson, 2000 Lichstein, Riedel, & Wilson, 2001

Three types of biofeedback have been specifically tested for the treatment of insomnia: EMG, theta EEG, and sensorimotor rhythm EEG.

Visual or auditory feedback to patients helps them control physiological parameters and reduce somatic arousal.

Very few studies with effects of biofeedback for treating insomnia. All studies available show that it is an effective modality for treatment of insomnia, but it takes longer than other forms of relaxation therapy with little appreciable advantage.

Type 3 & 6 studies

Nicassio & Boylan, 1982 Freedman & Papsdorf, 1976 VanderPlate & Eno, 1983 Cortoos, de Valck, Arns, & Breteler, 2010

Restrict time awake in bed by setting strict bedtime and rising schedules limited to the average number of hours of actual sleep reported in 1 night. Keep a fixed wake-up time, regardless of actual sleep duration. If after 10 d sleep efficiency is lower than 85%, further restrict bedtime by 15–30 min. Increase time in bed by advancing bedtime by 15–30 min when the time spent asleep is at least 85% of time in bed.

Based on clinical trials and metaanalysis. Reduction in wake time after sleep onset, increased sleep efficiency and total sleep time. Also noted to have improvement in subjective assessment.

Type 2–4 studies

Vincent, Lewycky, & Finnegan, 2008 Wohlgemuth & Edinger, 2000 Morin, Hauri, Espie, & Spielman, 1999 Spielman, Saskin, & Thorpy, 1987 Morin et al., 1994

Specific recommendations vary across studies. Typical recommendations include: Do not try to sleep if not sleepy. Avoid stimulants (caffeine, nicotine). Limit alcohol intake. Maintain a regular sleep

Insufficient evidence to be an option as a single therapy. Whether this therapy is effective when added to other specific approaches could not be determined from available data.

Type 2–5 studies

Jefferson, Drake, Scofield, & Myers, 2005 Stepanski & Wyatt, 2003 Schoicket, Bertelson, & Lacks, 1988 Hauri,

Based on experimental evidence that sleep is regulated by circadian and homeostatic processes. Treatment increases homeostatic sleep drive by reducing time in bed and maintaining a consistent wake time in the morning to reinforce circadian rhythms. Recommendations promoting behaviors that help sleep, discouraging behaviors that interfere with sleep


Treatment of Sleep Disorders Maintain a regular sleep schedule 7 nights per wk. Avoid naps. Get regular exercise at least 6 h prior to sleep. Keep the bedroom dark and quiet. Cognitive therapy

Identify, challenge, and replace dysfunctional beliefs and attitudes regarding sleep and sleep loss. These beliefs increase arousal and tension, which impede sleep and further reinforce the dysfunctional beliefs.

Challenge unhelpful beliefs and fears about sleep (e.g., overestimation of numbers of hours of sleep necessary to be rested; apprehensive expectation that sleep cannot be controlled; fear of missing opportunities for sleep). Thought journaling to reduce rumination. Design behavioral “experiments” to test beliefs about sleep.

Hauri, 1991a

Ongoing research to be an option as a single therapy. Extensive evidence for effectiveness when used with other therapies.

Type 3 studies

Belanger, Savard, & Morin, 2006 Harvey, 2002 Harvey et al., 2007 Okajima et al., 2011 Yook, Lee, Ryu, Kim, & Choi, 2008

CBT-I combines cognitive therapy with behavioral techniques and is typically delivered over six to eight individual treatments. It relies on the patient being an active participant in his or her own treatment. The behavioral component may include stimulus control therapy and/or sleep restriction therapy with or without use of relaxation therapy. Cognitive therapy aims at changing the patient’s beliefs and attitudes about insomnia. It uses a psychotherapeutic method to reconstruct cognitive pathways with positive and appropriate concepts about sleep and its effects (Hauri, 1991b; Jacobs, Pace-Schott, Stickgold, & Otto, 2004; Spielman, Saskin, & Thorpy, 1987). Cognitive-behavioral approaches use sleep diaries for assessment and monitoring of treatment outcomes. They require patients to work on bedtimes and wake times, thereby using voluntary waking behaviors to influence sleep. The generic applicability of the behavioral/psychological approaches rests with their basis in the two-process model of sleep regulation along with an understanding that stimulus-linked conditions or sleep-related beliefs that foster wakefulness are often good targets for modification. Substantial data support the process of sleep propensity being normally governed by the length of time a person is (p. 661) (p. 662) (p. 663) (p. 664) (p. 665) (p. 666) continuously (i.e., not napping) awake (“Process S”) and by the biological time of day as set by the suprachiasmatic nuclei of the hypothalamus governing the body’s circadian rhythms (“Process C”). It is Process C that makes it more difficult to remain awake between 3 and 5 a.m. (Fig. 21.2).

Figure 21.2 The two-process model. Alertness level is determined by the interaction between two regulatory processes. The sleep homeostatic drive (Process S) promotes sleep and builds up during extended wakefulness, reaching a maximum in the late evening (near the usual sleep time). The circadian rhythm system (Process C) promotes wakefulness during the day. It is biphasic and tends to dip in the midafternoon. Process C also reaches its peak in the evening to counterbalance the accumulation of homeostatic drive that has built up throughout the day, and it begins to fall just before the usual bedtime. This system promotes wakefulness during the day and consolidates sleep at night (Borbely, 1982).

Based on these principles, CBT-I includes restricting time in bed to match actual sleep time, setting a regular sleep-wake time regardless of the duration of sleep the night before. New treatment modalities are being investigated to disseminate these treatments and reduce patient burden and costs; they include home-based treatment (Espie, Inglis, Tessier, & Harvey, 2001), telephone interventions, Internet-based interventions (Morin, Stone, Trinkle, Mercer, & Remsberg, 1993), and self-help material (Mimeault & Morin, 1999). Pharmacological Treatments Hypnotic therapy should be considered for insomnia when the patient is significantly distressed by disturbed sleep, when the sleep disturbance is deleterious to the patient’s overall safety or health, when cognitive-behavioral approaches are unavailable or unsuccessful, or when the patient is unwilling or unable to engage in CBT. Benzodiazepine receptor agonists are the mainstay of pharmacological treatment for insomnia, although many agents other than benzodiazepine receptor agonists are also used in the treatment of insomnia; these include agents classified as antidepressants,


Treatment of Sleep Disorders antipsychotics, antihistamines, anticonvulsants, melatonin agonists, and herbals as well as chloral hydrate and sodium oxybate (Bertisch, Herzig, Winkelman, & Buettner, 2014). Among the many medications used to treat insomnia, a much smaller number are approved by the U.S. Food and Drug Administration (FDA) for this indication. Currently approved drugs include benzodiazepine receptor agonists, one tricyclic drug, one melatonin receptor agonist, antihistamines, barbiturates (Krystal, 2009; Walsh 2004) and an orexin receptor antagonist. Table 21.2 summarizes various pharmacological treatment methods for insomnia and Table 21.3 summarizes herbal and over-the-counter treatments. Table 21.2 Pharmacological Treatments Medications

Key Clinical Points

Main Side Effects

Relative Contraindications

Benzodiazepine receptor agonists (nonbenzodiazepines)

First-line hypnotics. Margin of safety or therapeutic index is wide.

Sedation, anterograde amnesia, ataxia, sleep walking, sleep violence or sleep related eating disorders, respiratory depression. Rebound insomnia, tolerance and abuse may occur.

Concomitant illnesses such as obstructive sleep apnea, substance use disorder, or advanced liver disease.

RCTs of benzodiazepine receptor agonist hypnotics Adults younger than 65 years N = 1894 Moderate effect sizes (d = 0.56– 0.71) for selfreported outcomes of sleep latency, total sleep time, number of awakenings, sleep quality Z scores for effect sizes range from 0.71 to 0.76

Type 1 studies

Buysse, 2013 Roehrs & Roth, 2012 SchutteRodin, Broch, & Buysse, 2008 Riemann & Perlis, 2009 Walsh & Roth, 2011

Benzodiazepines

Agonists at benzodiazepine receptor GABAA site. Different medications have different durations of action.

Sedation, ataxia, anterograde amnesia, ataxia, sleep walking, sleep violence or sleep related eating disorders, respiratory depression. Rebound insomnia, tolerance and abuse may occur.

Concomitant illnesses such as obstructive sleep apnea, substance use disorder, or advanced liver disease.

RCTs of benzodiazepine hypnotics compared to placebo or other active treatments N = 2,672 Self-report outcomes: Significant difference favoring benzodiazepines vs. placebo for sleep latency, total sleep time Polysomnography outcomes: Significant difference favoring benzodiazepines vs. placebo for total sleep time Side effects (drowsiness, dizziness, lightheadedness): Significantly more likely in patients taking benzodiazepines vs. placebo. Reduce time to sleep onset, prolonged stage 2, prolonged total sleep time and some reduction in REM sleep.

Type 1 & 2 studies

Holbrook et al., 2001 Holbrook, Crowther, & Lotter, 2000 Nowell, Mazumdar, Buysse, & Dew, 1997



Evidence Grade

Key References


Sedative antidepressants (e.g., doxepin, trazodone)

Sedative nature due to central anticholinergic or antihistaminergic activity. There is also possible effect of serotonin 5HT2 receptor antagonism and alpha 1 antagonism. Helpful in patients with concomitant depression. Doxepin is FDA approved for sleep maintenance insomnia.

Somnolence, headache, dizziness and nausea. Priapism is a relatively uncommon side effect of trazodone.

Hypersensitivity and use of MAO inhibitors within 14 days. Dry mouth, constipation, narrow- angle glaucoma, and urinary retention with doxepin. Trazodone to be used with caution in those at risk of falls because of orthostatic hypotension.

Ramelteon

First melatonin receptor agonist for treatment of insomnia

Headache, dizziness, somnolence, fatigue, nausea

Mirtazapine

Sedating effects diminish in doses greater than 30 mg due to adrenergic effects. Antagonizes adrenergic, serotonergic and histaminergic receptors. Used in doses lower than typically used in their FDAapproved indications. Antagonize dopamine, histamine, serotonin, muscarinic,

Sedative antipsychotics: quetiapine, olanzapine

RCTs of benzodiazepine receptor agonists and antidepressant drugs in chronic insomnia Antidepressants: Significant effects on polysomnographic wake after sleep onset, sleep efficiency, total sleep time; and on sleep diary rating of sleep quality Adverse events significantly greater for benzodiazepine receptor agonists and antidepressants vs. placebo

Type 1–3 studies

Krystal, Lankford, Durrence, & Ludington, 2011 Richey & Krystal, 2011 Wiegand, 2008 Buscemi, Vandermeer, Friesen, & Bialy, 2007 Glass, Sproule, Herrmann, & Busto, 2008 Mendelson, 2005

History of angioedema with ramelteon and concurrent use of fluvoxamine. Use in severe liver failure.

8 placebo-controlled RCTs of ramelteon in chronic insomnia. Sleep latency reduced in patients 18–64 years old. No difference in percentage of REM on polysomnography between ramelteon and placebo. Well tolerated without major side effects. No dose– response relationship observed. No nextday residual daytime sedation.

Type 1 & 2 studies

Mayer, WangWeigand, & RothSchechter, 2009 Reynoldson & Elliott, 2008 Sateia, Kirby-Long, & Taylor, 2008 Miyamoto, 2009 Ferguson, Rajaratnam, & Dawson, 2010 Kuriyama, Honda, & Hayashino, 2014

Increased appetite and weight gain. Dry mouth and constipation.

Used with in caution in patients with bipolar disorder, obesity, liver disease and kidney disease

Clinical trials and open- label studies. Improves sleep continuity in depressed patients with poor sleep quality. Decreased sleep latency, increased total sleep time and sleep efficiency. No effect on REM sleep.

Type 3–6 studies

Winokur et al., 2000 Wichniak, Wierzbicka, & Jernajczyk, 2012

Orthostatic hypotension, dizziness, dry mouth, constipation, blurred vision, urinary retention, weight gain and sedation. Can lead to extrapyramidal

Used with caution in patients with myocardial infarction, ischemia or conduction abnormalities, closed-angle glaucoma, decreased gastrointestinal motility, urinary retention, or

Clinical studies demonstrate decrease in sleep latency, increased sleep efficiency and improved subjective sleep quality.

Type 3, 5, & 6 studies

Monti & Monti, 2004 Anderson & Griend, 2014 Wiegand et al., 2008 Wine, Sanda, & Caballero, 2009 Cohrs et al., 2004


Treatment of Sleep Disorders muscarinic, cholinergic, and adrenergic receptors. Improves sleep primarily in patients with mood disorders.

extrapyramidal side effects, which are less common in newer agents. Olanzapine associated with cognitive impairment, glucose intolerance, elevated risk of mortality among patients with dementia.

retention, or hypotension.

2004

Table 21.3 Over-the-Counter Medications for Insomnia Medications

Key Clinical Points

Main Side Effects


Evidence Grade

Melatonin

Used both as a hypnotic and as a chronobiotic to phase shift circadian rhythms. Studied in adults and children.

Daytime somnolence

Crossover studies and clinical trials, Associated with reduced sleep latency and improved quality of sleep. Less consistent effects on sleep maintenance. Dose–response effect has not been established.

Type 2, 3, 4, 5 studies

Smits, Nagtegaal, van der Heijden, Coenen, & Kerkhof, 2001 FerracioliOda, Qawasmi, & Bloch, 2013

Valerian root

One of the 10 most popular herbal products sold in the United States

Hepatotoxic

Meta-analysis of 18 studies found that valerian decreased objective sleep latency by less than 1 minute compared to placebo.

Type 2, 3, 4, 5 studies

Nunes & Sousa, 2011 Sarris & Byrne, 2011 Balderer & Borbély, 1985 FernándezSan-Martín et al., 2010

Antihistamines (e.g., diphenhydramine and doxylamine)

Antagonizes H1 histamine receptors

Closed-angle glaucoma, decreased gastrointestinal motility, urinary retention, asthma, chronic obstructive pulmonary disease, and severe liver disease. There have been reports of coma and rhabdomyolysis occasionally occurring with doxylamine.

Type 2, 3, 5 studies

Glass et al., 2008 Griend & Anderson, 2012 Smith & Smith, 1985

Sleep-enhancing effects of diphenhydramine noted in placebo- controlled trials of sleep disturbance in a mixed group of psychiatric patients. Effects on sleep maintenance more consistent than sleep onset. No studies with doxylamine.

Key References

There is considerable evidence indicating that the benzodiazepine receptor agonists are efficacious in the treatment of insomnia, whether primary or comorbid, chronic or transient. They have a wide margin of safety as commonly used in clinical practice. Meta-analyses have demonstrated the they are efficacious in the treatment of chronic insomnia (Holbrook, Crowther, Lotter, & Endeshaw, 2001; Soldatos, Dikeos, & Whitehead, 1999) on selfreported outcomes of sleep latency, sleep duration, number of awakenings, and sleep quality. Effects are comparable in magnitude to those of CBT (Smith, Fogg, & Eastman, 2009). The 2005 National Institutes of Health state-of-the-science report on the management of chronic insomnia concluded that the benzodiazepine receptor agonists are the only medications with an established (p. 667) (p. 668) (p. 669) (p. 670) (p. 671) (p. 672) scientific basis (i.e., clearly defined risk and benefit by dose) for use for insomnia. Thus, for most patients with chronic insomnia, pharmacotherapy should be initiated with a benzodiazepine receptor agonist at the lowest effective dose for the shortest clinically necessary period of time. Benzodiazepine receptor agonists act at a specific recognition site on the GABA-A receptor that is distinct from the actual GABA binding site. They increase the affinity for GABA binding, thereby promoting the inhibitory actions of this neurotransmitter. Significant differences in pharmacokinetic profiles exist among the benzodiazepine receptor agonists, thereby providing physicians with therapeutic options that have differing durations of action, with half-lives varying from 1 hour to greater than 100 hours. Half-life and duration of action can help to guide the clinician on the choice of a particular drug. For instance, a patient with primarily sleep-onset difficulties may benefit from a short-acting hypnotic, whereas a patient who has trouble staying asleep may benefit from a longer-acting agent (Kryger, Roth, & Dement, 2010; Mendelson, 2011).


Treatment of Sleep Disorders The primary contraindications to the use of benzodiazepine receptor agonists are concomitant illnesses, such as obstructive sleep apnea, substance abuse disorder, or advanced liver disease. However, these cases represent relative rather than absolute contraindications. Although they are generally well tolerated, benzodiazepine receptor agonists can cause adverse effects, including sedation, memory impairment, impaired balance, impaired driving performance the day after dosing, and complex sleep-related behaviors. The latter may include eating, walking, and sexual activity while ostensibly asleep. Abrupt discontinuation of benzodiazepine receptor agonists can be associated with rebound insomnia and withdrawal symptoms. Doxepin is a tricyclic antidepressant approved as a hypnotic agent. At low doses (3 to 6 mg) it has been approved as a hypnotic. It reduces wakefulness across the night and improves sleep efficiency (Krystal et al., 2011). At hypnotic doses, doxepin has antihistamine (H1) effects and very few effects on serotonin, norepinephrine, or dopamine neurotransmission. This accounts for sedation and without some of the toxicity and side effects associated with anticholinergic properties at high doses. Although not formally approved, low-dose trazodone and mirtazapine are commonly used to treat insomnia. Melatonin and a melatonin receptor agonist, ramelteon, have been used as hypnotics, and ramelteon is FDA approved for this purpose. Both have been shown to decrease subjective sleep latency. They have fewer side effects compared to benzodiazepine receptor agonists (Buysse, Bate, & Kirkpatrick, 2005; Erman, Seiden, Zammit, Sainati, & Zhang, 2006). Antihistamines are another class of commonly used over-the-counter agents to treat insomnia. Their efficacy and side effects have not been rigorously evaluated. Most promising use has been shown in insomnia associated with allergy symptoms. Other drugs used in the treatment of insomnia include valerian, gabapentin and pregabalin, and sedating antipsychotic drugs. Very limited evidence supports the efficacy and safety of these drugs for treating insomnia. In 2014 the FDA approved the orexin receptor antagonist suvorexant for the treatment of insomnia, the first drug its class.

Hypersomnolence Disorder and Narcolepsy Overview and Diagnosis The essential feature of hypersomnolence disorder and narcolepsy is excessive daytime sleepiness that is not due to disturbed nocturnal sleep, occurring at least three times a week for at least 3 months. In narcolepsy, irresistible sleep occurs intermittently during waking hours. In addition, the patient must have at least one of the following: cataplexy episodes, defined by brief episodes of sudden bilateral loss of muscle tone precipitated by strong emotions but preserved consciousness; hypocretin deficiency in cerebrospinal fluid; or nocturnal polysomnography findings of REM latency less than 15 minutes or mean sleep latency of less than 8 minutes with two episodes of REM sleep during a mean sleep latency test. The mean sleep latency test is the key test for diagnosis of narcolepsy, in which the patient is required to take five naps during the day. The mean time to sleep onset and the presence of REM sleep are measured. For improved validity of the mean sleep latency test, it should be interpreted in the context of the patient’s clinical findings. In hypersomnolence disorder, excessive sleepiness occurs despite a main sleep period of at least 7 hours. Nighttime sleep is of long duration with good sleep continuity but is nonrestorative. (p. 673) A careful history must be obtained in all cases. Because of its importance in the diagnosis of narcolepsy, cataplexy should be assessed in detail. Possible substance abuse must be elicited as well. The Epworth Sleepiness Scale, an eight-item self-report instrument that assesses the tendency to doze in various scenarios, is commonly used to assess sleepiness in hypersomnolence disorder, narcolepsy, and other sleep disorders. The total score ranges from 0 to 24, with a score of 10 or more suggesting pathological sleepiness. Sleep logs and/or actigraphy can be helpful to rule out sleep deprivation/restriction. Narcolepsy is associated with deficiency of the peptide neurotransmitter hypocretin (orexin) and loss of orexincontaining cells in the lateral hypothalamus. Projections from the lateral hypothalamus innervate arousal centers of the brain stem and posterior hypothalamus, and loss of orexinergic cells is associated with instability of sleep-wake states. Levels of hypocretin-1 in cerebrospinal fluid can be measured; low levels are found in most cases of narcolepsy. Because of difficulty in performing lumbar punctures and the absence of routine clinical laboratories for assays, its use is reserved for complex cases. Although driving and working can be impaired in untreated cases, once hypersomnolence disorder or narcolepsy is controlled, patients can consider driving with caution. In addition to medical and behavioral management, referral to support groups is often helpful for social support. Management Since no cure of hypersomnolence or narcolepsy currently exists, treatment is aimed at symptom control to allow patients to live a full personal and professional life. Treatment of hypersomnolence is very similar to that of narcolepsy. The mainstay of treatment is pharmacological, although adjunctive behavioral therapy plays a role in adapting to the situation. Treatment aims at reducing excessive daytime sleepiness, improving nighttime sleep, and managing cataplexy symptoms if present. Since the medications are used on a long-term basis and have considerable adverse effects, treatment must balance maintaining an active life with avoiding adverse effects and developing tolerance to medications. Table 21.4 summarizes various pharmacological treatment options based on symptoms of narcolepsy, and Table 21.5 gives an overview of medications used for narcolepsy.



Table 21.4 Hypersomnolence Disorders: Narcolepsy Treatment Based on Symptoms Symptoms Addressed

Key Clinical Points

Medications Used

Excessive daytime sleepiness

Continuous daytime sleepiness with sleep attacks, usually the first symptom and present in 100% of the patients. Treatment includes conservative measures and medications.

Modafinil (standard) Sodium oxybate (standard)

Key References

Littner et al., 2001 Wise, Arand, Auger, Brooks, & Watson, 2007

Amphetamine (guideline) Methamphetamine (guideline) Dextroamphetamine (guideline) Methylphenidate (guideline) Selegiline (option) Cataplexy

Sudden usually bilateral, partial or complete loss of muscle tone provoked by emotional stimuli. Most accurate marker of the disease.

Sodium oxybate (option) Tricyclic antidepressants (option) Selective serotonin reuptake inhibitors (option)

Sleep paralysis

Inability to move limbs or head or to speak or breathe normally either at sleep onset or awakening despite being mentally awake. May be associated with hypnagogic hallucinations.

Sodium oxybate (standard) Tricyclic antidepressants (guideline)

Houghton, Scammell, & Thorpy, 2004 Dauvilliers, Arnulf, & Mignot, 2007 Lopez & Dauvilliers, 2013 Dauvilliers, Billiard, & Montplaisir, 2003 Dauvilliers et al., 2003 La Herrán-Arita & GarcíaGarcía, 2013

Selective serotonin reuptake inhibitors (guideline) Venlafaxine (guideline) Selegiline (option) Table 21.5 Medications for Narcolepsy Medication/Medication Class

Key Clinical Points

Main Side Effects


Evidence Grade

Nonamphetamine stimulants; for example modafinil (100–400 mg once daily or in divided doses) and armodafinil

For treatment of excessive daytime sleepiness. Mechanism of action is unknown but hypothesized to selectively activate wake-generating sites in the hypothalamus.

Headache, nausea, dizziness, insomnia

Results from many multicenter studies indicate significant impact of modafinil on sleepiness.

Type 1 and 2 studies

La Herrán-Arita & GarcíaGarcía, 2013 Golicki, Bala, Niewada, & Wierzbicka, 2010 Wisor & Eriksson, 2005, 2010

Helpful in excessive daytime

Nervousness,

Currently

Type 2

Mignot, 2012

Amphetamine-like


Key References

Treatment of Sleep Disorders Amphetamine-like stimulants: Amphetamines 5–60 mg divided doses Methylphenidate 5–60 mg divided doses

Helpful in excessive daytime sleepiness. Increase dopamine transmission. Tolerance may develop requiring escalating doses. Effectiveness may be restored by “drug holiday.”

Nervousness, headache, loss of appetite, palpitations, irritability, tremors

Currently available stimulants have not been tested parallel to placebo control or with each other in narcolepsy patients.


Mignot, 2012 Wisor et al., 2001 Heal et al., 2013 Mitler, Erman, & Hajdukovic,1993

Sodium oxybate 6–9 g of liquid solution divided nightly

Useful for cataplexy and excessive sleepiness in narcolepsy. Can cause rapid sedation and amnesia. Available only from a single central pharmacy.

Sedation, enuresis, respiratory suppression

Based on RCTs and case series

Type 1 & 3 studies

Anon., 2003 Mayer, 2012 Black & Houghton, 2006 Black, Pardi, Hornfeldt, & Inhaber, 2010

Selective serotonin reuptake inhibitors

Used for treatment of cataplexy. Less efficacious but better side effect profile compared to tricyclics.

CNS excitation, nausea, sexual difficulties

Based on case series and case reports

Type 4–6 studies

Lopez & Dauvilliers, 2013 Vignatelli, D’Alessandro, & Candelise, 2008 Frey & Darbonne, 1994 Langdon, Shindler, Parkes, & Bandak, 1986

Tricyclic antidepressants

Were the first medications to treat cataplexy; currently used as the last resort.

Dry mouth, urinary retention, constipation

-

Type 3 studies

CamposRodriguez et al., 2012 La Herrán-Arita & GarcíaGarcía, 2013 Schmidt, Clark, & Hyman, 1977 Roth, 2007

Norepinephrine and serotonin uptake inhibitors

Effective for cataplexy, sleep paralysis and hypnagogic hallucinations. Venlafaxine has been used in both adults and children. Atomoxetine is a highly specific noradrenergic reuptake inhibitor and tried in cases of resistant cataplexy after failure of fluoxetine, venlafaxine, and other serotonin reuptake inhibitors.

Nausea, dry mouth, elevated blood pressure, insomnia, withdrawal syndrome

Based on case series

Type 3 & 6 studies

Lopez & Dauvilliers, 2013 Møller & Østergaard, 2009 Ratkiewicz & Splaingard, 2013 Houghton et al., 2004

Stimulants Stimulants are indicated in the treatment of excessive daytime sleepiness. They produce substantial improvement in daytime alertness in a dosedependent manner. Amphetamines and related drugs, which include methylphenidate, dextroamphetamine, and mixed amphetamine salts, are most commonly used. They increase dopaminergic and noradrenergic neurotransmission by blocking reuptake of these neurotransmitters via the dopamine reuptake transporter and by increasing presynaptic dopamine release (Riddle, Fleckenstein, & Hanson, 2005). Stimulants are available in immediate-release and sustained-release forms. The usual duration of effect of immediate-release preparations is 3 to 6 hours. A combination of the two forms often provides the best balance between acute effects and sustained alertness. The optimal combination, timing, and dose to provide maximal efficacy vary on an individual basis. Patients may report “peaks” and “crashes” associated with the onset and offset of drug effects with short-acting preparations alone. Side effects may include increased heart rate and blood pressure and symptoms of anxiety, nervousness, and tremor. There have also been reports of methylphenidate causing an increased risk of sudden cardiac death, but Schelleman and colleagues found a lack of dose–response relationship, suggesting there may not be a causal association. Nocturnal sleep disruption can result from doses taken in the late afternoon and early evening. In some cases patients may experience psychotic symptoms such as hallucinations and paranoid delusions. Tolerance, dependence, and abuse can also occur. If tolerance develops, medication class can be switched or the patient can take periodic “drug holidays;” the latter may help to preserve the efficacy of stimulant medications. Modafinil and armodafinil are wake-promoting agents comparable in efficacy to traditional stimulants in promoting alertness. Their exact mechanism of action is unknown but appears to involve local effects in the hypothalamus or effects on the dopamine transporter (U.S. Modafinil in Narcolepsy Multicenter Study Group, 2000). The effect of modafinil lasts relatively long due to its half-life of 12 to 15 hours. (p. 674) The efficacy of modafinil has been evaluated extensively in excessive daytime sleepiness due to narcolepsy, idiopathic hypersomnia, and sleep apnea (La Herrán-Arita & GarcíaGarcía, 2013). Side effects include headache, nervousness, and small increases in blood pressure. Modafinil inhibits hepatic enzymes and can reduce the effectiveness of oral contraceptives (La Herrán-Arita & García-García, 2013; Littner et al., 2001).


Treatment of Sleep Disorders Lisdexamfetamine is a pro-drug of d-amphetamine that has been used in children with attention-deficit/hyperactivity disorder. It provides a more gradual increase in brain drug concentrations, reducing pleasurable effects of the d-amphetamine. Increasing its dose enhances its efficacy but also delays its time of peak effect. This makes it less favorable for abuse and diversion purposes (Heal, Smith, Gosden, & Nutt, 2013). There have not been studies evaluating lisdexamfetamine specifically for narcolepsy, and it is not FDA approved for this indication but has been used as an “off-label” drug for treatment of narcolepsy. Sodium oxybate can also enhance alertness in narcolepsy (Mamelak, Black, Montplaisir, & Ristanovic, 2004), but it is primarily used for the treatment of cataplexy. Atomoxetine and bupropion are other agents (p. 675) (p. 676) used in patients with hypersomnolence, but their efficacy has not been formally evaluated. Anticataplectic Drugs First-line treatment for cataplexy consists of antidepressants, mainly venlafaxine, desmethylvenlafaxine, duloxetine, or fluoxetine (Morgenthaler et al., 2007a). Sodium oxybate (gamma hydroxybutyrate) is also a very effective treatment for cataplexy, with additional positive effects on daytime sleepiness (Anonymous, 2002, 2003). Sodium oxybate is administered in gram doses so it is given as a liquid at the beginning of the night and in the middle of the night. Two doses through the night are required because of its very short elimination half-life, ranging from 20 to 70 minutes. Although the half-life is very short, it exerts longer-lasting physiological effects through unknown mechanisms (Pardi & Black, 2006). It increases slow-wave sleep and REM sleep. Sodium oxybate is strictly controlled by the U.S. Drug Enforcement Agency because of its abuse potential and the possibility of diversion to other individuals. Side effects include profound sleepiness, sleepwalking, amnestic behaviors, and respiratory suppression in large doses.

Breathing-Related Sleep Disorders Overview and Diagnosis Breathing-related sleep disorders include three distinct disorders: obstructive sleep apnea hypopnea, central sleep apnea, and sleep-related hypoventilation. All of these are associated with impaired ventilation during sleep, resulting in sleep disruption and daytime fatigue or sleepiness. Effective treatment can have a positive impact on quality of life and morbidity of psychiatric patients. These disorders are also important to recognize in patients with psychiatric conditions because of symptom overlap, such as disrupted sleep, sleepiness, irritability, and depression (Harris, Glozier, Ratnavadivel, & Grunstein, 2009). A careful history of symptoms followed by in-lab or at-home diagnostic polysomnography is warranted. A sleep study (polysomnogram) records breathing patterns in addition to other parameters. Two types of breathing events are typically identified: hypopneas, characterized by reduction in airflow by 30% with oxygen desaturation of at least 3%, and apneas, characterized by cessation of airflow for at least 10 seconds. The number of apneas and hypopneas per hour of sleep is known as the apnea-hypopnea index, which is a measure of severity of obstructive sleep apnea hypopnea and central sleep apnea. More than five events in one hour are considered abnormal in adults. Sleep-related hypoventilation may or may not be associated with an increased apnea-hypopnea index but is characterized by low oxygen saturation (hypoxemia) or carbon dioxide retention (hypercapnia). Management The goals of treatment for patients with obstructive sleep apnea syndrome are correcting the breathing disturbance, controlling symptoms, and reducing comorbidities associated with sleep apnea to improve quality of life. Table 21.6 summarizes treatments for obstructive sleep apnea. Table 21.6 Breathing-Related Sleep Disorders: Obstructive Sleep Apnea Treatment Modality

Key Elements


Evidence Grade

AASM Grade

Positive pressure therapy

First-line treatment. Main limitation is willingness to accept therapy and remain adherent. Many variants available, such as continuous, bilevel, or autoadjusting positive pressure therapy. Splints open airway while sleeping.

Based on various RCTs with strong evidence. Many studies have intention-to-treat designs. Studies to assess and validate a mechanical device such as continuous positive airway pressure are difficult to design.

Type 1–3 and 3 studies

Gold standard in moderate to severe cases and option in mild cases

McDaid et al., 2009 Epstein et al., 2009 Pagel, 2007 CamposRodriguez et al., 2012

Oral appliance

Device inserted in the mouth. Tongue retaining and mandibular repositioning. Minimum of 6–10 teeth in each arch is needed. Not recommended as first line in patients with severe obstructive sleep apnea, but may be considered if unable to tolerate positive airway pressure therapy or failed surgery.

Various RCTs have demonstrated efficacy of oral appliance in mild to severe cases. Better tolerated than positive pressure in some cases. Need to establish uniform definition of treatment success and patient characteristics associated with treatment success need to be determined.


Standard for primary snoring. Guideline for patients with mild to moderate obstructive sleep apnea who prefer or are not candidates for continuous positive airway pressure or cannot tolerate continuous positive airway pressure.

Ferguson et al., 2006 Hoffstein, 2007 Ngiam et al., 2013 Pliska & Almeida, 2012 Doff et al., 2013


Key References


Surgery

Tracheostomy was the first treatment option available. Evaluation of patients includes fiberoptic evaluation of upper airway. Various options available like maxillary mandibular advancement, uvulopalatopharyngoplasty, palatal implants or multilevel or stepwise approach.

Few systematic reviews and a very small number of RCTs. There is lack of high-level controlled studies and absence of standardized criteria to describe “surgical success.”

Type 3–6 studies

Option as an adjunct to treatment of obstructive sleep apnea in obese patients. It can be used as first line in mild to moderate cases.

Aurora et al., 2010a Caples et al., 2010 Sommer, Maurer, Hörmann, & Stuck, 2012

Medical management

Weight loss, modafinil for residual sleepiness, topical nasal corticosteroids for rhinitis, positional therapy

Few RCTs have evaluated adjunct treatments for obstructive sleep apnea. Weight loss has been well documented to have a positive impact on obstructive sleep apnea. Several studies documenting sleep position influencing severity of sleep apnea. Modafinil has been shown to improve residual sleepiness after treatment of sleep apnea in patients who do not have an identifiable cause of hypersomnolence based on few studies with variable level of evidence.

Type 1–6 studies

Option as an adjunct to primary treatment

Dixon et al., 2012 Sarkhosh et al., 2013 Neill, Angus, Sajkov, & McEvoy, 1997 Chapman et al., 2014 Darwish et al., 2010 Keating & Raffin, 2005 Schwartz, Hirshkowitz, Erman, & SchmidtNowara, 2003

Oxygen therapy

Oxygen therapy has not been proved to improve outcomes in obstructive sleep apnea. May be useful in treatment of severe hypoxemia untreated by positive pressure therapy.

Level 2 and level 3 studies, few of which were based on specialpopulation patients. The evidence suggests that providing supplemental oxygen during sleep is not sufficiently effective in reducing apnea frequency and increasing daytime alertness to stand alone as therapy for most patients.

Type 2 and 5

Not recommended as primary treatment

Mehta, Vasu, Phillips, & Chung, 2013 Owens, 2013

Somatic Treatments Positive Airway Pressure Therapy Positive airway pressure therapy helps to passively open the upper airway during sleep and acts as a pneumatic splint. In addition, it may also increase upper airway size and stiffen the upper airway walls, likely due to “tracheal tug”—the downward pull on upper airway structures during lung expansion (Alex, Aronson, Onal, & Lopata, 1987). RCTs have also shown positive airway pressure to improve sleepiness, quality of life, and blood pressure. Observational studies have shown reduction in cardiovascular mortality. Optimal adherence to therapy is a major limiting factor in reducing effectiveness (Campos-Rodriguez et al., 2012). Various modes of positive pressure therapy delivery include continuous positive airway pressure, bilevel positive airway pressure, autotitrating positive pressure devices, and devices with a backup rate. Table 21.7 lists these devices and gives brief descriptions. Table 21.7 Positive Airway Pressure Delivery Mode

Mechanism of Pressure Delivery

Continuous positive airway pressure (CPAP)

Continuous pressure during exhalation and inhalation

Bilevel positive airway pressure (BPAP)

Separate pressures during exhalation (lower) and inhalation (higher). Can be with or without a backup rate. Backup rate is helpful in patients who cannot generate effective breathing effort.

Autotitrating positive airway pressure

Minimum and maximum pressure fluctuates between set limits. Can be AutoCPAP or AutoBPAP.

Oral Appliance Therapy Oral appliances are devices that are inserted into the mouth for treatment of snoring and sleep apnea. (p. 677) (p. 678) (p. 679) Two main types


Treatment of Sleep Disorders are the tongue retaining device and mandibular repositioning appliances, also known as mandibular advancement devices. They are typically used in mild to moderate sleep apnea when patients cannot tolerate positive pressure therapy. RCTs have demonstrated improvement in the apnea-hypopnea index, sleepiness, quality of life, and 24-hour blood pressure. Higher adherence to mandibular advancement devices is likely the cause of improved effectiveness compared to continuous positive airway pressure, despite lower efficacy. The most common minor and temporary side effects of therapy include temporomandibular joint pain, myofascial pain, tooth pain, salivation, dry mouth, gum irritation, and morning-after occlusion (Ferguson, Cartwright, Rogers, & Schmidt-Nowara, 2006; Pliska & Almeida, 2012). Surgery Various surgical procedures are available for management of upper airway obstruction. One of the most common is uvulopalatopharyngoplasty, but recent low-level evidence has shown that this procedure alone does not reliably normalize the apnea-hyponea index when treating moderate to severe sleep apnea. Low-level evidence has also shown another technique, maxillomandibular advancement, to be effective in the treatment of severe obstructive sleep apnea. Prior evidence has shown tracheostomy to be an effective single intervention to treat obstructive sleep apnea; however, concerns about patient safety, autonomy, and quality of life preclude its routine use, and it is considered only when deemed necessary by clinical urgency in cases of life-threatening obstructive sleep apnea and recurrent severe hypercapnic respiratory failure (Aurora et al., 2010a; Camacho et al., 2014; Caples et al., 2010). Medical Management Clinical trials have shown long-term improvements in sleep-disordered breathing and sleep quality from lifestyle interventions aimed at weight loss that include dietary modification and aerobic exercise, especially when combined with a primary treatment for obstructive sleep apnea (Dixon et al., 2012). In addition to dietary weight loss, bariatric surgery can be considered as an adjunctive treatment, especially in cases of morbid obesity. Positional therapy (avoiding the supine position) and reduction in alcohol use should be also considered as helpful measures in some patients. The use of topical nasal steroids is recommended in patients with obstructive sleep apnea and concurrent rhinitis. Modafinil is recommended for treatment of residual excessive daytime sleepiness in patients with obstructive sleep apnea after effective positive airway pressure treatment has been provided and when no other identifiable causes of sleepiness have been identified (Morgenthaler et al., 2006).

Circadian Rhythm Sleep-Wake Disorders Overview and Diagnosis In humans, many physiological and behavioral processes occur roughly on a 24-hour or circadian cycle. The suprachiasmatic nucleus in the anterior hypothalamus is the master circadian pacemaker in mammals. External stimuli called zeitgebers entrain the nucleus to the light-dark cycle. Misalignment (p. 680) between endogenous circadian rhythm and exogenous factors results in a variety of disorders, classified in DSM-5 as circadian rhythm sleep-wake disorders. An essential feature for diagnosis is a persistent or recurrent pattern of sleep-wake disturbance resulting in a mismatch between endogenous rhythm and personal or societal demands. DSM-5 distinguishes the following types of disorders. Delayed sleep phase type is characterized by delayed sleep onset and awakening. Sleep duration and quality are normal when patients are allowed to sleep during their own “biological night.” Advanced sleep phase type is characterized by a sleep cycle that is advanced compared to conventional societal norms. Irregular sleep-wake type occurs when the sleep-wake pattern is disorganized and variable throughout the 24-hour period; this type is commonly seen in neurodegenerative disorders and institutionalized elderly persons (Sack et al., 2007; Zee & Vitiello, 2009). Non-24-hour sleep-wake type is defined by a sleep pattern that is entrained to an endogenous circadian rhythm that is usually slightly more than 24 hours, accompanied by a daily drift usually to later times. It occurs commonly in blind individuals. Shift work type is associated with an unconventional shift work schedule, with insomnia during the time allotted for rest and/or excessive sleepiness while at work. Diagnosis of these disorders is based on clinical presentation and thorough history. Sleep-wake logs are a useful tool to assess the sleep-wake pattern. Actigraphy can provide objective verification of activity and resting patterns. Polysomnography may be useful to rule out other sleep disorders, like obstructive sleep disorder or periodic limb movement disorder. Management Improved daytime function, nighttime sleep, and quality of life are the major treatment goals for circadian rhythm sleep wake disorders. The main approach in treatment is to realign the timing of the endogenous circadian rhythm with the required sleep-wake schedule. Bright light and melatonin can reset the circadian clock in a time-of-day–dependent manner when given at specific times. Bright light in the morning advances rhythms and in the evening delays them. Melatonin in the evening advances rhythm and in the morning (theoretically) delays rhythm. The “switch point” between advances and delays for both bright light and melatonin occurs at the time of core body temperature minimum, about 2 to 3 hours before habitual wake time. Consequently, bright light or melatonin close to the time of core body temperature minimum can have large and unpredictable effects on circadian rhythm timing. Table 21.8 gives an overview of common treatments used in circadian rhythm sleep disorders. A treatment outline for specific disorders is given below.



Table 21.8 Circadian Rhythm Disorders Treatment Modality

Key Elements

Type of Disorder Addressed


Evidence Grade

Key References

Light therapy

Timed light exposure can shift circadian phase and increase objectively determined alertness. Exposure to bright light at the wrong circadian time can perpetuate or exacerbate changes in sleepwake period.

Best evidence in delayed sleep phase syndrome but may be considered as an option in other circadian rhythm disorders

Cohort, case control studies, and case series


Morgenthaler et al., 2007b WilhelmsenLangeland et al., 2013

Melatonin

Important modulator of circadian rhythms. In addition to phase-resetting properties, evidence supports role in sleep modulation by increasing evening sleep propensity and reducing core body temperature.

Shift work, jet lag. Effective for entraining circadian rhythms in blind people with freerunning sleep-wake cycles.

RCTs, cohort and case control studies

Type 2 & 3 studies

Morgenthaler et al., 2007b WilhelmsenLangeland et al., 2013 Weingarten & Collop, 2013 Cajochen, Kräuchi, & Wirz-Justice, 2003 Herxheimer & Petrie, 2001

Hypnotics

Can increase duration of daytime sleep but have not shown to improve alertness in early morning hours during shift work

Jet lag, shift work

RCTs, cohort and case control studies

Type 2 & 3 studies

Morgenthaler et al., 2007b Buxton, Copinschi, van Onderbergen, Karrison, & van Cauter, 2000 Walsh, Sugerman, Muehlbach, & Schweitzer, 1988

Chronotherapy

Successful delay of sleep times by 3 hours daily over a 5- to 6-day period until the desired sleep time is achieved. Followed by rigid adherence to a set sleep-wake schedule and good sleep hygiene practices. Light exposure at wrong time may limit effectiveness and practicality.

Delayed, advanced sleep phase disorders

Based on case reports and committee consensus


Morgenthaler et al., 2007b Singh, Sharma, & Malviya, 2012d

Stimulants

Modafinil and caffeine counter sleepiness and improve performance during night shift compared to placebo.

Shift Work Disorder (SWD), jet lag

Based on RCTs


Sack et al., 2007 Darwish, Bond, & Ezzet, 2012 Czeisler et al., 2005 Ker, Edwards, Felix, Blackhall, & Roberts, 2010

Delayed Sleep Phase Syndrome Treatment includes slowly advancing the circadian rhythm and avoiding bright light in the evening. Melatonin (0.5 to 5 mg) can be used to advance the sleep cycle when given 6 to 9 hours before the dim-light melatonin onset (~1 to 3 hours before sleep onset) (Mundey, Benloucif, Harsanyi, Dubocovich, & Zee, 2005). Bright light in the morning hours, near the time of usual awakening, also helps to advance circadian rhythms. Combination therapy with morning bright light and evening melatonin can improve subjective sleepiness, fatigue, and cognitive function (Wilhelmsen-Langeland et al., 2013). Good sleep hygiene is an essential component of treatment (see Table 21.3). Advanced Sleep Phase Syndrome Similar to delayed sleep phase syndrome, appropriately timed bright light and melatonin are used to treat advanced sleep phase. Bright light between


Treatment of Sleep Disorders 7 and 9 p.m. is used to delay the natural sleep-wake window and other circadian rhythms. Bright light should be avoided in the early morning to minimize phase-advancing effects. No published studies currently validate the effectiveness of morning melatonin in this disorder (Lack & Wright, 1993; Lack, Wright, Kemp, & Gibbon, 2005), and concerns about a direct sedating effect with morning administration weigh against this treatment. Irregular Sleep-Wake Disorder and Non-24-Hour Sleep-Wake Disorder Treatment of irregular sleep-wake cycle and non-24-hour sleep-wake cycle depends on whether a person has light perception. It mainly entails consolidating (p. 681) (p. 682) the sleep period. Melatonin, increased social cues, and bright light immediately after awakening are options for sighted individuals or blind people with intact retino-hypothalamic pathways. In blind individuals without light perception, lack of entrainment from environmental light cues is the main problem. Exogenous melatonin at a fixed time every day (dose range 0.3 to 10 mg approximately 1 hour before the desired bedtime) can help entrainment (Hack, Lockley, Arendt, & Skene, 2003). Tasimelteon, a melatonin receptor agonist, has recently been approved by the FDA, based on two trials, for the treatment of non-24-hour sleep-wake disorder in blind individuals. Shift Work Disorder The treatment of shift work disorder—specifically overnight shift work—includes interventions to (1) decrease sleep pressure at night (scheduled naps or hypnotics before daytime sleep), (2) increase alertness using caffeine or stimulants at the beginning of the work shift, and/or (3) minimize bright light exposure at the end of the work shift by wearing dark glasses while traveling home from work and using blackout curtains to make the bedroom as permissive for sleep as possible (Morgenthaler et al., 2007b). Bright light during the first half of the night shift may also help to delay circadian rhythms and improve shift work adaptation. Modafinil and armodafinil are both FDA approved for use in shift workers with excessive sleepiness during work hours (Czeisler et al., 2005). On days off, night-shift workers may have regular daytime social or family responsibilities and often revert to nocturnal sleep hours. An experimental paradigm of “compromise phase position” has been promising wherein the individual goes to bed slightly earlier and does not completely invert his or her schedule on days off (Smith et al., 2009). Jet Lag Disorder The basic strategy for treatment includes symptom management and realigning circadian clock to the new time zone as soon as possible. American Academy of Sleep Medicine practice parameters consider timed melatonin administration as a “standard” and timed and dosed bright light as a treatment “option” for jet lag disorder. While traveling east, treatment should be started before travel. This involves gradually moving the sleep period before travel by 1 hour earlier each day and having the patient exposed to at least 1 hour of bright light in the morning. After arrival at the destination, light should be avoided in the morning, followed by exposure to high levels of light in the afternoon. Exogenous melatonin should be taken 5 hours before habitual bedtime. Hypnotics can be used at bedtime if needed at the destination. While traveling west, treatment should be started at the destination. Morning bright light should be avoided and light exposure in the evening should be maximized. Hypnotics can be taken at bedtime if needed. Good sleep hygiene and a 30-minute nap during the day are a helpful adjuncts in cases of both east and west travel. Combination therapy with somatic and behavioral interventions, including a regular sleep schedule and good sleep hygiene, is usually beneficial for all circadian rhythm sleep-wake disorders.

Parasomnias According to DSM-5, the parasomnias include sleep disorders with undesirable physical events or experiences that occur at entry into sleep, during sleep, or during arousals from sleep. They include NREM sleep arousal disorders, nightmare disorders, and REM sleep behavior disorder. Many of them are benign, especially during childhood, but they can cause physical harm and poor health due to sleep disruption. NREM Sleep Arousal Disorders Overview and Diagnosis NREM sleep arousal disorders include parasomnias that occur from arousals during NREM sleep, most often sleep stage N3 or slow-wave sleep. They include confusional arousals, sleep terrors, and sleepwalking. Other specific behaviors may include sleep-related eating disorder and sleep-related sexual activity. DSM-5 defines three specific ones—NREM parasomnias, sleepwalking, and sleep terrors. Recurrent episodes of partial arousals from sleep occur usually during the first third of the night, when NREM sleep is deepest. There is typically minimal or no recall of the event, with minimal or no dream imagery. (p. 683) (p. 684) Sleepwalking is characterized by repeated episodes of rising from bed and walking about during sleep. During the episodes, the individual has reduced alertness and responsiveness, blank stare, and absent communication with others. There is relative unresponsiveness to efforts by others to awaken the individual, and if awakened he or she has limited recall of the episode. Sleep terrors include repeated sudden awakenings from sleep, usually with a scream or cry. Excessive autonomic arousal and behavioral manifestations of intense fear occur. The individual is difficult to awaken or difficult to comfort during the episode. Sleep terrors are also called “night terrors” or “pavor nocturnus.” Confusional arousals are not specifically included in a part of DSM-5 but are considered to be related to other NREM parasomnias. Confusional arousals are brief, incomplete arousals that start in N3 sleep. During episodes, the individual usually does not leave the bed. Primary sleep disorders such as sleep apnea or periodic limb movement disorders can aggravate these conditions. Sleep-related eating disorder is classified as a subtype of sleepwalking in DSM-5. It involves partial arousals from sleep in which the patient involuntarily eats and drinks. It can occur in isolation or comorbidly with restless legs syndrome, periodic limb movements, and sleep-related breathing disorders (Howell, Schenck, & Crow, 2009). Sleep-related sexual behavior (“sexsomnia”) is also classified as a subtype of sleepwalking in DSM-5. It consists of inappropriate sexual behaviors during sleep without conscious awareness and may have medicolegal implications. This may result in feelings of shame or guilt leading to depression (Schenck, Arnulf, & Mahowald, 2007). Management Treatment of NREM parasomnias is directed at reducing symptoms of self-harm or harm to others based on the frequency of events (Mahowald &


Treatment of Sleep Disorders Cramer Bornemann, 2005). Somatic Treatment Clonazepam (0.5 to 1 mg) has been successful in the long-term management of parasomnias. If the disorder is limited to the first half of the sleep period, short-acting benzodiazepine receptor agonists such as triazolam or zolpidem have been used. Dopaminergic agents, opiates, and topiramate have been used and found to be effective in sleep-related eating disorder. If nonpharmacological treatment is not enough to manage symptoms, use of pharmacotherapy may be helpful in the treatment of sleepwalking (Schenck & Mahowald, 2000, 2002). Psychosocial and Behavioral Treatments Reassurance about the benign nature of childhood NREM parasomnias, especially in episodic cases, is usually sufficient. For more severe episodes, nonpharmacological treatments have been found to be helpful in children. These include maintaining a regular sleep-wake schedule and reducing sleep pressure by avoiding sleep deprivation. For sleepwalking, ensuring a safe sleeping environment is crucial to management, which would include safety locks on doors. NREM parasomnia episodes may be triggered by sleep disruption due to obstructive sleep apnea or periodic limb movement disorder. These cases may benefit from treatment of the primary sleep disorder (Schenck & Mahowald, 2010). Nightmare Disorder and REM Sleep Behavior Disorder Overview and Diagnosis REM sleep is characterized by increased physiological activation, atonia of muscles, and dreams or active mentation. The most common parasomnias occurring during REM sleep are REM sleep behavior disorder and nightmare disorder. REM sleep behavior disorder is characterized by loss of normal muscle tone along with dream enactment (often violent). According to DSM-5, the presence of atonia during REM sleep on a polysomnogram or a history suggestive of REM sleep behavior disorder, along with a diagnosis of alpha synucleinopathy (e.g., Parkinson’s disease), can be used to diagnose REM sleep behavior disorder. Nightmare disorder is characterized by recurrent disturbing dreams during REM sleep, often resulting in awakening, distress, and impairment of daytime function. Management Treatment of REM parasomnias is directed at reducing symptoms of self-harm or harm to others based on the frequency and bothersome nature of events. Table 21.10 lists treatment options for REM behavior disorder. (p. 685)



Table 21.10 REM Parasomnia—REM Sleep Behavior Disorder Treatment Modality

Key Elements


Evidence Grade

Key References

Clonazepam

Long-acting benzodiazepine. May preferentially control phasic locomotor activity at the brain stem level without restoring atonia via a serotonergic effect. May also modify dream content in REM sleep behavior disorder.

Based on case series and case reports


Aurora et al., 2010c Fantini & FeriniStrambi, 2012

Melatonin

Studies show success in patients with synucleonopathies, memory problems and sleepdisordered breathing. Decreased episodes of REM sleep without atonia and movement time in REM, as opposed to studies with clonazepam.

Evidence less strong than for clonazepam. Based on clinical consensus. Case series with very few subjects.


Aurora et al., 2010c Kunz & Mahlberg, 2010 Anderson & Shneerson, 2009 Boeve, Silber, & Ferman, 2003

Nonpharmacological

Injury-prevention techniques. Modifying sleep environment has best evidence for treatment of REM sleep behavior disorder.

Consensus-based recommendation by American Academy of Sleep Medicine

Type 6 studies

Aurora et al., 2010c Schenck, Lee, Bornemann, & Mahowald, 2009

Dopamine agonist— pramipexole

PET and SPECT scans have suggested dysfunction of dopaminergic nigrostriatal system, due to which dopamine agonists have been considered.

Efficacy studies have shown contradictory results.


Aurora et al., 2010c Sasai, Inoue, & Matsuura, 2012 Schmidt, Koshal, & Schmidt, 2006

(p. 686) REM Sleep Behavior Disorder Benzodiazepine receptor agonists are the first-line treatment of REM sleep behavior disorder. Clonazepam (0.5 to 1 mg) is the most commonly used medication. Not only does it reduce the frequency of events, but it may also modify dream content in REM sleep behavior disorder. Melatonin and pramipexole have also been used with some success (Aurora et al., 2010c). Ensuring the safety of the sleep environment for the patient and his or her bed partner is an essential adjunct to treatment. Medication-induced cases usually resolve after discontinuing the offending agent (Mahowald & Schenck, 2005). Nightmare Disorder Prazosin has been shown to be effective in RCTs for treatment of nightmare disorder associated with posttraumatic stress disorder (Cukor, Spitalnick, Difede, Rizzo, & Rothbaum, 2009). Medications, including benzodiazepines and sedating antidepressants such as trazodone, are used to treat nightmares, but little empirical evidence supports their efficacy. Dream rehearsal therapy is useful for recurrent nightmares. This treatment involves scripting and rehearsing a new dream scenario to replace the common, distressing dreams (Augedal, Hansen, Kronhaug, Harvey, & Pallesen, 2013). Table 21.9 summarizes some treatment modalities for nightmare disorder.



Table 21.9 Nightmare Disorder Treatment Modality

Key Elements


Evidence Grade

Key References

Nonpharmacological

Trauma-focused cognitive-behavioral therapy, including imagery rehearsal technique; lucid dreaming therapy; sleep dynamic therapy; relaxation; and rescripting therapy and self-exposure therapy

Based on case series and case studies. Some case control studies.


Bisson, Roberts, Andrew, Cooper, & Lewis, 2013 Bisson & Andrew, 2007 Germain, Buysse, & Nofzinger, 2008 Augedal et al., 2013

Prazosin

For nightmares associated with posttraumatic stress disorder. Postural hypotension.

Based on 3 RCT/placebocontrolled studies and some case series. Found to be moderate to strongly beneficial.


Augedal et al., 2013 Hudson, Whiteside, Lorenz, & Wargo, 2012 Aurora et al., 2010b Taylor, Freeman, & Cates, 2008

Clonidine

Nightmares associated with posttraumatic stress disorder

No RCTs. Paucity of hard data.

Type 3 studies

Alao, Selvarajah, & Razi, 2012 Aurora et al., 2010b

Restless Legs Syndrome Overview and Diagnosis Restless legs syndrome is a sensorimotor neurological disorder causing uncomfortable sensations in the leg that are described by patients as aching, burning, tingling, creeping, crawling, or “pins and needles” (Kerr, McKinon, & Bentley, 2012). DSM-5 describes restless legs syndrome as an urge to move the legs that worsens during rest and in the evenings and is relieved by moving around. There may be associated repetitive leg jerks at night during sleep, which are called periodic limb movements (Rye & Trotti, 2012). These limb movements are characterized by rhythmic, repetitive stereotypic dorsiflexion/extension of the big toe, dorsiflexion at the ankle, and sometimes flexion at the knee and hip joints. For the leg movements to be counted as periodic limb movements, they must be 0.5 to 10 seconds in duration and have an amplitude greater than 8 µV above the resting baseline anterior tibial electromyogram level on a polysomnogram. The periodic limb movement index is defined as the number of these movements per hour of sleep. An index above 15 in adults and above 5 in children is considered diagnostic for periodic limb movement disorder in the ICSD-2 (International Classification of Sleep Disorders-2) diagnostic and coding manual. Improvements in restless legs syndrome and periodic limb movement disorder seen with L-dopa and dopamine agonists support the hypothesis that dopamine may be involved in the pathophysiology of these disorders (Cervenka et al., 2006). Restless legs syndrome may be idiopathic (primary) or secondary. Those with an affected first-degree relative commonly have primary restless legs syndrome. Secondary causes include renal failure, pregnancy, iron deficiency, and medications. Iron is an important co-factor in the dopamine synthesis pathway. It is also necessary for intracellular mitochondrial function in dopamine-producing neurons (Yeh, Walters, & Tsuang, 2012). Management The goals of treatment of restless legs are to improve symptoms that result in disturbances in sleep onset or sleep maintenance, causing sleep disruption and daytime sleepiness. Treatment options are outlined in Table 21.11. Table 21.11 Restless Legs Syndrome Treatment Modality

Key Elements

Side Effects


Evidence Grade

Dopamine agonist— pramipexole,

First line

Nausea, orthostatic hypotension, daytime

Based on double-blind

Type 1 & 2 studies


Key References Aurora et al., 2012

Treatment of Sleep Disorders pramipexole, ropinirole

hypotension, daytime fatigue and somnolence, compulsive or impulsive behavior, tolerance and augmentation

double-blind placebocontrolled studies with long- term follow-up studies showing sustained efficacy

2 studies

2012 Manconi et al., 2011 Scholz, Trenkwalder, Kohnen, Riemann, Kriston, & Hornyak, 2011a Varga et al., 2009 Zintzaras et al., 2010 Bassetti et al., 2011 Scholz, Trenkwalder, Kohnen, Riemann, Kriston, & Hornyak, 2011b Trenkwalder et al., 2008

Dopamine precursors (e.g., Ldopa/carbidopa)

Quick onset and short duration of action due to higher rebound

Morning rebound or augmentation in early evening, daytime somnolence

Open-label placebocontrolled studies


Opiates

Useful in severe cases, when patients are unresponsive to other agents. Useful during withdrawal from dopamine agonist after severe augmentation.

Constipation, dependence, respiratory depression at high doses. Use with caution in patients who snore and have sleep apnea.

Several open-label and controlled clinical trial


Benzodiazepine rector agonists

Used to improve quality of sleep and reduce periodic leg movements associated with arousals. Improves sleep continuity.

Sedation, ataxia, anterograde amnesia, sleepwalking, sleep violence or sleeprelated eating disorders, respiratory depression. Rebound insomnia, tolerance, and abuse may occur.

Based on placebocontrolled crossover studies and case series

Type 2 and 6

Shinno et al., 2010 Facheris, Hicks, Pramstaller, & Pichler, 2010 Saletu et al., 2001

Anticonvulsants— Neurontin

More potent and fewer side effects than dopaminergic agonists. Useful in neuropathic restless leg syndrome.

Daytime fatigue and somnolence

Open-label and one placebocontrolled study


Burke & Faulkner, 2012 Yaltho & Ondo, 2010 Hayes, Lemon, & Farver, 2012 Lee et al., 2011

Iron supplementation

Iron deficiency and conditions involving iron deficiency such as end-stage renal disease, pregnancy, gastric surgery have been associated with secondary restless legs syndrome. Iron deficiency in substantia nigra may be associated with abnormal regulation of transferrin receptor. Most clinicians recommend achieving a ferritin level of >45 to 50 mcg/mL.

Constipation, nausea, gastrointestinal upset, dark stools

Based on RCTs

Type 1–3 studies

Hornyak et al., 2014 Mohri et al., 2012 Trotti, Bhadriraju, & Becker, 2012 .

Nonpharmacological

Good sleep hygiene; avoid alcohol use; stretching exercises and leg massages

NA

NA


Hornyak et al., 2014 Aurora et al., 2012 Romenets & Postuma, 2013


Walters, 2013

Treatment of Sleep Disorders Somatic Treatment Evaluation and treatment of reversible causes should be first attempted. A serum ferritin level less than 50 mcg/dL should be treated with iron replacement therapy. Vitamin B12 , folate, vitamin D, and magnesium deficiency should also be treated (Cuellar, Hanlon, & Ratcliffe, 2011). Dopamine agonists, including pramipexole and ropinirole, are considered as first-line therapy and have been tested in controlled trials for treatment of restless legs syndrome. The most common side effects are sleepiness, nausea, and hypotension. They may be associated infrequently with compulsive gambling, spending, or sexual behavior. Rotigotine is a non-ergot dopamine receptor agonist available in a transdermal patch form (Bogan, 2014). (p. 687) (p. 688) (p. 689) Levodopa/carbidopa is a dopaminergic medication that can also decrease restless legs syndrome symptoms and periodic limb movements. Augmentation and rebound effects are common with these medications. Augmentation is the tendency for symptoms to develop earlier in the day or to become more severe than prior to treatment and is usually treated by switching to a dopamine agonist (Cuellar et al., 2011; Romenets & Postuma, 2013; Silber, Becker, Earley, Garcia-Borreguero, & Ondo, 2013; Wilt et al., 2013). Other medications include benzodiazepines, which can decrease arousals but do not decrease the number of movements, and opioids, which are also used for some treatment-resistant cases. Anticonvulsants such as gabapentin and carbamazepine can also be considered. Gabapentin may be useful in cases of restless legs associated with painful sensations (Silber et al., 2013). Psychosocial and Behavioral Treatments Nonpharmacological treatments that have been helpful include stretching exercises, massage, and hot baths. Avoiding tobacco, alcohol, caffeine, and antihistamines can also help decrease symptoms. If restless legs syndrome occurs during treatment with a selective serotonin reuptake inhibitor, switching to a different class of medication may be helpful (Hening, Buchfuhrer, & Lee, 2007).

Summary Treatment of sleep disorders can be initiated in most cases by non-sleep specialists. A significant number of patients seen in psychiatry clinics experience sleep disturbances. Most patients with insomnia can be treated by psychiatrists, especially given the coexistence of psychiatric disorders and insomnia. The close relationship that psychiatrists have with their patients provides an understanding of the biopsychosocial context in which their patients live, something that is undoubtedly important in successful treatment of sleep disorders. Referral to sleep specialists should be considered when there is evidence of coexisting multiple sleep disorders or when insomnia is complicated by evidence of other sleep disorders, such as sleep apnea or narcolepsy. Patients who do not respond to brief behavioral interventions or who fail to respond to conventional management options may also be good candidates for referral.

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