Sleep Disorders

Mr. Z

Mr. Z is a 47-year-old, married man who presented with complaints of insomnia. He has a history of sleep difficulties often associated with life stressors. The typical pattern of his insomnia is to persist for weeks to months before resolution. He has tried several over-the-counter (OTC) sleep aids without success. His primary care physician (PCP) diagnosed him with persistent primary insomnia and prescribed zolpidem (10 mg q.h.s.). Mr. Z had no prior history of psychiatric disorders, obstructive sleep apnea (OSA), seizure disorder, or parasomnias. Because of an incomplete resolution, he was referred for cognitive behavioral therapy (CBT).

TABLE 6-1 Sleep Disorders

Dysomnias (Primary disorders of initiating or maintaining sleep or excessive sleepiness characterized by problems in the amount, quality, or timing of sleep)
▪	Insomnia (Difficulty initiating or maintaining sleep or not feeling rested after an apparent adequate amount of sleep; ≥1 mo)
	▪	Primary
	▪	Secondary
▪	Hypersomnia (Falling asleep easily and unintentionally)
	▪	Primary
	▪	Secondary
▪	Narcolepsy (Reported irresistible attacks of sleep, cataplexy, and recurrent intrusions of rapid eye movement [REM] sleep into the transition period between sleep and wakefulness)
▪	Breathing-related (Sleep disruption due to abnormal ventilation during sleep)
	▪	Sleep apnea
▪	Circadian rhythm (Mismatch between normal rest-activity schedule and circadian sleep-wake pattern)
Parasomnias (Abnormal events during sleep, specific sleep stages, or the threshold between sleep and wakefulness)
▪	Nightmares (Repeated occurrence of frightening dreams that cause awakening)
▪	Sleep terror (Abrupt awakenings usually associated with a panicky scream or cry)
▪	Sleepwalking (Repeated episodes of complex motor behavior initiated during sleep)
(Adapted from American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Text Revision. Washington, DC: American Psychiatric Association; copyright 2000.)

Sleep disorders are prevalent; can be primary or secondary to other psychiatric, psychosocial, substance use, or medical problems; may cause significant physical or psychological symptoms; often go unrecognized; and when diagnosed, may not be adequately managed. The International Classification of Sleep Disorders identifies 88 types, of which insomnia is the most prominent. For example, insomnia is estimated to affect 30% to 40% of the adult population, withmore rigorously defined disorders affecting 10% to 15% of the population. Table 6-1 lists the major categories of sleep disorders and provides a brief description of each.

DIFFERENTIAL DIAGNOSIS

There are numerous conditions that may be considered in the differential diagnosis of the various sleep disorders. Disrupted sleep secondary to a mental disorder, general medical condition, or substance use are common differential diagnostic considerations for all these disorders.

For primary insomnia other considerations may include short sleepers (a normal variant), circadian rhythm sleep disorder, narcolepsy, breathing-related sleep disorder, and parasomnias. For primary hypersomnia other considerations are long sleepers (a normal variant), inadequate amount of nocturnal sleep, and primary insomnia. For narcolepsy, both sleep deprivation and primary hypersomnia may also cause daytime sleepiness. For breathing-related disorders (e.g., OSA) differential considerations are narcolepsy, snoring, and nocturnal panic attacks. For circadian rhythm disorder differential considerations are normal patterns of sleep, normal adjustments following a change in schedule, and volitional patterns of delayed sleep hours.

For nightmare disorder, the differential diagnoses should include sleep terror, panic attacks, and breathing-related disorders. For sleep terror other considerations are nightmares, sleepwalking, seizures, and hypnagogic hallucinations. Finally, for sleepwalking disorder other considerations are sleep terror, breathing-related disorder, and sleep-related epilepsy.

NEUROBIOLOGY OF SLEEP DISORDERS

Because the putative causes for sleep disorders vary depending on the specific type, we briefly describe the major conditions and our understanding of their biological basis.

Insomnia

Although the cause of primary insomnia is poorly understood, one possible factor is an overengaged arousal system. Therefore, these patients are more likely to have increased body temperature, elevated metabolic and heart rates, and increased levels of catecholamines. Further, family aggregation is a risk factor and suggests a genetic basis. Agents working through the γ-aminobutyric acid (GABA)_A-chloride ion complex can improve insomnia. For example, benzodiazepines (BZDs) bind to the GABA_A receptor α₁ subunit to promote sedation.

More recently, non-BDZ agents have become available. They are more selective for the GABA_A α subunit, do not produce active metabolites, and have shorter half-lives compared to the BZDs.

An alternate approach is represented by ramelteon, a melatonin receptor type 1 and type 2 agonist. Its action is thought to facilitate the impact of melatonin on circadian rhythms mediated through the suprachiasmatic nucleus of the hypothalamus.

Hypersomnia

Narcolepsy.

This is the best known primary disorder of excessive daytime sleepiness (EDS). Although its cause is also not
completely understood, various factors may increase the risk of its occurrence including:

Immune system dysfunction
Trauma
Hormonal changes
Stress
Gender (men more than women)
Obesity
Familial history of narcolepsy

The underlying cause appears to be a malfunction in the normal interaction between sleep and arousal centers in the central nervous system (CNS). Further, critical to this process is an impairment in the normal activity of the neurotransmitter, hypocretin, which is produced by cells in the posterior half of the lateral hypothalamus. The evidence to date indicates that damage to this system, perhaps mediated by an autoimmune process, is the major contributor to narcoleptic symptoms.

Sleep-Related Breathing Disorders.

There are three forms of sleep-related breathing disorders (SRBDs), including:

Blockage of the oropharynx (OSA)
Impair diaphragmatic effort (central sleep apnea)
Secondary to excessive weight (central alveolar hypoventilation)

Sleep electroencephalograms (EEGs) often reveal absent or decreased slow-wave sleep or early-onset rapid eye movement (REM) sleep. Long-term adverse effects can include hypertension and vascular events (e.g., myocardial infarction, stroke).

Parasomnias

These disorders are characterized by abnormal events occurring in stage 4 sleep or during transitional periods between sleep and wakefulness.

TREATMENT OF SLEEP DISORDERS

Because most sleep complaints involve the dysomnias and most clinical trials address these specific sleep disorders, we will focus on their treatment.

Pharmacotherapy of Sleep Disorders

Insomnia.

Insomnia is the most common sleep disorder and we will focus on its treatment with more limited discussion of other dysomnias (e.g., narcolepsy, OSA). Medication approaches are dictated by our understanding of the basis for insomnia that can be divided into three groups: primary which represents a small proportion of patients, insomnia as a symptom of other specific sleep disorders (e.g., restless leg syndrome [RLS]), and secondary insomnia that represents most patients and is due to a variety of contributing factors, including:

Medical (e.g., congestive heart failure, musculoskeletal)
Psychiatric (e.g., depression, anxiety)
Pharmacological (e.g., prescribed or OTC medications, substances of abuse, caffeine, nicotine)
Other sleep disorders (e.g., sleep apnea, restless legs syndrome, periodic limb movement disorders)

Although treating the underlying problem may resolve secondary insomnia, often both problems must be addressed to achieve the optimal outcome (e.g., antidepressant plus a sedative-hypnotic [SH] for major depression). This approach is based in part on an increasing recognition of a bidirectional interaction between various comorbid conditions and insomnia. For example, although insomnia is a frequent symptom of depression there is also evidence that insomnia increases the risk for developing depression. Table 6-2 lists the most common agents used for the treatment of insomnia.

Benzodiazepines.

Although most evidence supports the use of SHs for acute, transient insomnia, these agents are also frequently used as chronic treatments despite more limited data. The BZD-SHs all work through the GABA_A receptor-chloride ion complex, inhibiting neuronal firing. The various agents in this class differ primarily in their pharmacokinetics and the presence or absence of active metabolites. These issues often dictate such clinically relevant effects as onset of action, maintenance of effect, and carry-over adverse effects (e.g., EDS).

Nonbenzodiazepines.

More recently, alternate agents that more specifically agonize the GABA_A α subunit (i.e., BZ-1) have become available. These drugs are approved for sleep-onset insomnia
and/or sleep maintenance (depending on which agent or formulation). In general, their greater pharmacodynamic specificity, lack of impact on sleep architecture, pharmacokinetics, and lower risk for drug-drug interactions make them a safer choice over the BZDs-SHs.

TABLE 6-2 Medications for Treatment of Insomnia

*Class/Generic Name*		*Common Trade Name*	*Usual Daily Dose Range (mg/d)*
Benzodiazepines
Long-acting
	Flurazepam	Dalmane	15-45
	Quazepam	Doral	7.5-15
Intermediate acting
	Estazolam	Prosom	0.5-2
	Temazepam	Restoril	15-45
Short acting
	Triazolam	Halcion	0.125-0.25
Nonbenzodiazepines
	Zolpidem	Ambien	5-20
	Zolpidem CR	Ambien CR	6.25-12.5
	Zaleplon	Sonata	5-20
	Eszopiclone	Lunesta	2-3
Melatonin receptor agonists
	Remelteon	Rozerem	8-16
Natural remedies
	Melatonin		0.3-2
	Valerian		400-900
(Adapted from Janicak PG, Davis JM, Preskorn SH, et al. Principles and Practices of Psychopharmacotherapy, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.)