Insomnia

Diagnosis and Management of Common Sleep Disorders An Overview for the Psychiatrist
a report by

E m m a n u e l M i g n o t 1 and R o b s o n C a p a s s o 2
1. Howard Hughes Medical Institute Investigator; 2. Post-doctoral Fellow, Sleep Medicine, Stanford Sleep Disorders Center

Sleep is the golden chain that ties health and our bodies together. Thomas Dekker Untreated sleep disorders such as sleep apnoea, restless legs syndrome (RLS) and narcolepsy are common and often undiagnosed. They have significant effects on quality of life and can even lead to death, for example in the context of an accident caused by tiredness while driving. Furthermore, these disorders can cause symptoms that may be confused with neuropsychiatric conditions such as depression or schizophrenia or that can contribute to treatment resistance. A number of studies have shown associations between sleep and genuine neuropsychiatric disorders. The Basic Neurobiology of Sleep Sleep is not a passive state. The neural substrates underlying sleep states include sleep- and wake-on neuronal networks. Wake-on-promoting systems are typically brainstem and hypothalamic systems that project to the cortex and or the thalamus, which then activates the cortex. These include cholinergic ascending systems (pedunculopontine and laterodorsal tegmental areas and basal forebrain), adrenergic locus coeruleus, serotonergic raphe nuclei, hypocretin-containing lateral hypothalamic systems and histamine-containing tuberomammillary hypothalamic nuclei. General brain activation ensues, with high glutamate release and electroencephalography (EEG) desynchronisation and consciousness. Wakefulness is the co-ordinated expression of many behaviours that are constantly changing in response to variations in the external and internal milieu. Most likely, each arousal system is particularly active under specific circumstances, and there is an intense interaction among them.
1,2

tegmental area (VTA), for example, do not seem to significantly increase overall neuronal activity in wakefulness, but are certainly activated by specific behaviours in wakefulness and are involved in the wakepromoting effects of most stimulants, such as amphetamines, methylphenidate and modafinil. A smaller number of systems are sleep-active in the brain: during nonrapid eye movement (NREM) sleep, most of the brain activity is decreased and the EEG is desynchronised, characterised by the appearance of slow wave activity. Major sleep-promoting centres include a group of anterior gamma-aminobutyric acid (GABA)-ergic hypothalamic and basal forebrain sleep-on networks, including the ventrolateral preoptic (VLPO) and median preoptic (MnPO) nucleus of the hypothalamus.3 These systems strongly inhibit the wake-active systems mentioned above. Of final interest is REM sleep, a paradox as the brain is generally active (most notably the cortex, with a wave-like desynchronised EEG and associated dreaming) while REM and muscle paralysis (atonia) occur. In REM sleep, cholinergic systems and many sleep-on systems are active, but monoaminergic systems are turned off.46 Most antidepressants are strong REM sleep suppressants. Sleep and wake tendencies can be seen as the sum of two processes: homeostatic and circadian. The homeostatic process is a reflection of the sleep debt. It reflects the fact that the longer we are awake, the more sleepy we become. It has been claimed that adenosine (AD), an inhibitory neuro-transmitter, accumulates in the basal forebrain with wakefulness and plays a role in the integration of sleep pressure, inhibiting wake-on systems.2,46 Caffeine is a very popular wakepromoting agent, and its main mechanism of action is through AD receptor antagonism. This homeostatic factor interacts with the circadian process, which has evolved as an adaptation to the solar cycle of light and dark and is present in almost all mammals.

Dopaminergic cell groups of the substantia nigra (SN) and ventral

Emmanuel Mignot is a Howard Hughes Medical Institute Investigator, a Professor of Psychiatry and Behavioral Sciences and Director of the Center for Narcolepsy at Stanford University. He is internationally recognised as having discovered the cause of narcolepsy. Dr Mignot has received numerous grants and honours, including National Sleep Foundation (NSF) awards and the Jacobaeus prize. He is the co-author of over 100 original scientific publications and serves on the Editorial Board of several sleep disorder journals. E: mignot@stanford.edu

Independently of sleep debt, the circadian clock sends a wake-promoting signal that peaks in the afternoon (best tracked by body temperature fluctuations without sleep) so that it opposes the mounting sleep debt that results from having been awake since the morning, maintaining alertness during the day. An opposite interaction occurs during the night so that the tendency to sleep is at its peak in the early hours of the morning, allowing us to sleep longer once the sleep debt has been reduced by the previous sleep cycles. The suprachiasmatic nucleus (SCN) in the hypothalamus functions as the main circadian pacemaker, controlling the timing of the sleepwake cycle, and is mostly influenced by light and, to a lesser extent, by melatonin, a hormone produced in the night by the pineal gland.7 This process may be disrupted in shift workers and when we cross time zones. This is commonly known as jet-lag, and causes a broad constellation of symptoms including fatigue, disorientation, irritability (worse in the early morning of the original time zone) and impaired sleep (worse in the early evening of the original time zone, sometimes called the forbidden zone).

Robson Capasso completed medical school and further surgical training at the Universidade Federal do Parana in Curitiba, Brazil. After completion of psychiatry training at the University of Miami, he is now pursuing a postdoctoral fellowship in Sleep Medicine at the Stanford Sleep Disorders Center.

44

TOUCH BRIEFINGS 2008

Diagnosis and Management of Common Sleep Disorders An Overview for the Psychiatrist

Insomnia Insomnia refers to a complaint of difficulty falling asleep, frequent and/or prolonged awakenings, early-morning awakenings or non-restorative, poor-quality sleep in an individual who has adequate opportunity for sleep. Insomnia is not defined by sleep laboratory measures or any specific sleep duration. Chronic, serious insomnia affects 10% of the population, with a higher predisposition among females.8 As insomnia occurs only when there is adequate opportunity for sleep, it must be distinguished from sleep deprivation, in which the individuals short sleep duration results from inadequate opportunity. The most common daytime impairments associated with insomnia include complaints of fatigue, mood disturbance and impaired cognitive function. Actual daytime sleepiness is not common among individuals with insomnia. Medical conditions, most importantly those associated with pain
9

improve primary insomnia or insomnia associated with medical or psychiatric disorders, both objectively and subjectively. Studies have found that improvements may be achieved more quickly with drug treatment, but are more sustained with cogitive behavioural therapy (CBT).13 One limitation of behavioural therapies is not a lack of efficacy, but the need for repeated

Studies have found that improvements may be achieved more quickly with drug treatment, but are more sustained with cognitive behavioural therapy.

and almost all psychiatric disorders, are also linked to insomnia. A thorough medication history is essential, including prescription drugs (antidepressants or antihypertensives commonly cause insomnia), over-the-counter medications, substances such as caffeine and alcohol and illicit drugs. Insomnia is commonly described as being secondary to other conditions, associated with other sleep disorders (sometimes due to sleep apnoea) or primary (when no other aetiology can be identified). Secondary insomnia refers to the insomnia syndrome when it is thought to be due to a medical or psychiatric disorder, or to the effects of a substance or medication. However, recently a consensus conference has rejected this simple dichotomy due to insufficient evidence, especially in the neuropsychiatric context.9 Why some depression cases are associated with insomnia or excess sleep is unknown, and a causal relationship from depression to insomnia or hypersomnia is not established. Interestingly, several studies have shown that the presence of insomnia predicts the development of depression years later, suggesting that insomnia could participate in the development of depression.10 Poor sleep quality is reported in up to 90% of patients with depression.10 Fava and colleagues demonstrated that patients with co-morbid insomnia and depression experience a faster, more effective antidepressant response when treated with a sleep agent and antidepressant combination than when treated with either a sleep agent or Cognitive Therapy Based on Becks model, this psychotherapeutic approach seeks to modify sleep-related dysfunctional beliefs and thoughts and the maladaptive cognitive processes involved in the exacerbation and perpetuation of insomnia. One example is the belief that one may need eight to nine hours of sleep based on what family and friends report, while in fact there is great individual variability in the required number of hours for a restful night of sleep. Sleep Restriction This involves limiting time in bed to that spent actually sleeping, creating a mild sleep deprivation and increasing homeostatic pressure for sleep; this reduces poor sleep and enhances regularity of sleep/wake. Quality first, than quantity is the motto of sleep restriction therapy. This component may be the most essential. In extreme cases, the fear of not sleeping is so intense that patients may stay in bed for 10 hours trying to sleep more, thereby producing sleep disruption and insomnia. follow-up and coaching of patients for several weeks to ensure compliance and stable behavioural changes, a difficult endeavour in countries where care is rationed. The components of behavioural treatments for insomnia are summarised below.13,14

The most common daytime impairments associated with insomnia include complaints of fatigue, mood disturbance and impaired cognitive function.

Sleep Hygiene Sleep hygiene therapy aims to provide patients with education about how to improve their sleeping habits. One example would be to avoid caffeine or alcohol consumption for four to six hours before bedtime. Another piece of advice is to have a dark bedroom and to avoid bright light exposure when going to the bathroom in the middle of the night, as this may disrupt circadian rhythms (a dimmer switch is recommended).

an antidepressant alone.11 Generalised anxiety disorder patients complain of trouble sleeping in 6070% of cases, and there is an overlap between interventions that target insomnia and those that are used in treating anxiety disorders, including medications and cognitive strategies that target worry, tension and maladaptive cognitions.
12

Stimulus Control Stimulus control therapy is based on the principles of conditioning. It aims to re-establish the bed and bedroom as stimuli for sleep, creating a consistent sleep/wake schedule. Therapists advise: If you are unable to fall asleep in 1520 minutes, get out of bed and engage in a quiet, non-striving activity. Only return to bed when you are sleepy again.

Behavioural Treatments of Insomnia The treatment of insomnia has recently evolved, as insomnia has been shown to often benefit greatly from non-pharmacological interventions. Psychological and behavioural therapies have consistently been shown to Relaxation and Sleep Management Sleep management therapy aims to reduce the cognitive and emotional hyperarousal that is incompatible with sleep.

EUROPEAN PSYCHIATRIC REVIEW

45

Insomnia
with a set of tools to apply in times of stress and insomnia relapses. Evaluation with a sleep log is needed first to determine in which phase of sleep problems occur (e.g. difficulties falling asleep, falling asleep too early
Medication Estazolam Class BZP Duration of Action Intermediate Half-life (hours) 1024 Use Mainly for SMI Side Effects Drowsiness, dizziness, unco-ordination and amnesia Drowsiness, dizziness, unco-ordination and amnesia Drowsiness, dizziness, unco-ordination, amnesia and rebound insomnia upon cessation Drowsiness, dizziness, unco-ordination and amnesia Drowsiness, dizziness, unco-ordination and amnesia Drowsiness

Table 1: US Food and Drug Administration-approved Agents for the Treatment of Insomnia

or too late) and usual daily sleep amounts (generally underestimated by the insomnia patients). In sleep restriction, usual daily sleep amounts are then decreased by 30 minutes to one hour, and the patient is asked to wake at the same time each day. After a few weeks the subject feels more sleepy at bedtime and sleeps more consistently. Feedback and monitoring on a weekly basis are needed to titrate sleep deprivation and timing and to provide cognitive therapy advice. Pharmacological Treatment of Insomnia Insomnia may be treated with CBT and instruction in sleep hygiene, either alone or in association with hypnotic medications.18,19 As taking many of these drugs can become a habit, it is usually best to use pharmaceutical agents for a maximum of three days in a row (this is enough in the context of jet lag), although in some cases pharmacological treatment is more appropriate than behavioural therapies (psychiatric context, failure of behavioural therapy). Almost all US Food and Drug Administration (FDA)-approved options for the treatment of insomnia (see Table 1)1820 are GABAergic modulators acting on the benzodiazepine-binding site of the GABAA receptor, a complex chloride channel composed of a large number of possible subunits. A typical benzodiazepine drug has anticonvulsant, anxiolitic, hypnotic, myorelaxant and amnesic properties, although different compounds can have slightly different effects on the various symptoms depending on the dose. A meta-analysis of benzodiazepine use in the treatment of insomnia showed that sleep latency for patients receiving a benzodiazepine was 4.2 minutes shorter, and that patients slept for an average of 61.8 minutes longer than those in the placebo group.20 The older compounds, of benzodiazepine structure have a broad effect on

Temazepam BZP

Intermediate

3.518.4

Mainly for SMI

Triazolam

BZP

Short

1.55.5

Mainly for SOI

Flurazepam

BZP

Long

2.3100

Quazepam

BZP

Long

3973

Zaleplon

Eszopiclone

N-BZP BZP agonist N-BZP BZP agonist

Short

Mainly for SOI SOI and SMI

Intermediate

Drowsiness, dizziness and unpleasant taste Drowsiness, dizziness Drowsiness, dizziness

Zolpidema

Ramelteon

N-BZP Short BZP agonist Melatonin Short receptor (MT1/MT2) agonist

1.44.5

SOI

many GABAA receptor subtypes, whereas some of the more recent compounds that do not have a benzodiazepine structure (zolpidem, eszopiclone, zaleplon) have a more specialised effect. This last property is likely to increase receptor subtype specificity,21 and these non-benzodiazepine GABAA benzodiazepine receptor-binding compounds may have more hypnotic than myorelaxant, anticonvulsant and antianxiety effects, although this is clearly dose-dependent. At high doses, these compounds are similar to classic benzodiazepines. Less dependence/

25

SOI

SMI = sleep maintenance insomnia; SOI = sleep-onset insomnia; BZP = benzylpiperazine; N-BZP = non-benzylpiperazine; GABA = gamma-aminobutyric acid. # Usually not recommended due to a long half-life and high likelihood of daytime sedation. Alprazolam, lorazepam, clonazepam, siazepam and midazolam are not FDA-approved for treatment of insomnia; however, they are very commonly prescribed as hypnotics. a: Zolpidem has a controlled-release formulation with a dual-layered tablet: one layer releases zolpidem immediately and a second layer provides a slower release of additional zolpidem for maintenance of plasma zolpidem concentrations, and may be used for SOI and SMI.

In some cases, although patients experience difficulty sleeping during the night, maintaining sleep until the late morning is not a problem.

Light Therapy In some cases, although patients experience difficulty sleeping during the night, maintaining sleep until the late morning is not a problem. This is often seen in adolescents, and is known as delayed sleep phase syndrome, a circadian clock disorder. Advanced sleep phase syndrome, another circadian clock disorder, is also sometimes seen in the elderly when living indoors permenantly. In these cases, consistent, daily light therapy can be very helpful in re-training the circadian cycle (morning when delayed, evening when advanced).15 Light therapy may also have antidepressant effects. Regular exercise at scheduled times may also help. Melatonin can
16

tolerance has been suggested for these new compounds at a constant dose, and many patients can take these compounds daily for decades without significant problems. The potential abuse of hypnotic medications remains a concern for some physicians. This may lead them to avoid or limit the use of pharmacological treatment for their insomnia patients; however, abuse of benzodiazepine and benzodiazepine-like hypnotics is rare among insomnia patients. The use of hypnotics should be carefully evaluated in patients with a previous history of substance abuse or dependence, and it is good clinical practice to monitor prescriptions and regularly assess the patients

also be used (particularly in completely blind subjects), and in these cases low physiological doses (0.3mg) should be used.17 However, importantly, melatonin is less effective at re-setting circadian rhythms than bright daylight or light-box exposure at an intensity of 10,000 lux. Behavioural therapies are educational to the patient and can provide insomnia patients

46

EUROPEAN PSYCHIATRIC REVIEW

Diagnosis and Management of Common Sleep Disorders An Overview for the Psychiatrist

medication use.19 The major property to consider for prescription is half-life and duration of action. Zaleplon, for example, acts for only two to three hours, and may be useful for sleep-initiating difficulties or early-morning insomnia in jet-lag. Zolpidem and zolpidem CR or eszopiclone are effective for five to six hours and six to seven hours, respectively.
19,20

dopamine agonists (talipexole, cabergoline, piribidel and alphadihydroergocryptine) and the dopaminergic agents amantadine and selegiline may be effective in the treatment of RLS and PLMD, but the level of effectiveness of these medications is not currently established. Lastly, no specific recommendations can be made regarding dopaminergic treatment of children or pregnant women with RLS or PLMD. The use of dopamine agonists is generally thought to be preferable to that of L-DOPA on a chronic basis. Opioids and benzodiazepines are commonly used for the treatment of these conditions as a second intention; however, the risk of drug dependence must be considered. Importantly, RLS can be secondary to medical disorders, including iron deficiency, neuropathies and renal disease. Ferritin levels should be investigated in these patients: if below 4560mg/ml, iron supplementation should be considered. Hypersomnia/Excessive Daytime Sleepiness Disease and Symptoms The International Classification of Sleep Disorders (ICSD) defines excessive daytime sleepiness (EDS) as the inability to stay awake and alert during the major waking episodes of the day, resulting in unintended lapses into drowsiness or sleep.25 Several factors may cause hypersomnia, including medical and neurological conditions (e.g. rheumatological disorders, congestive heart failure, cancer, hypothyroidism, anaemia,

Ramelteon, a selective melatonin receptor agonist, was recently approved for the treatment of insomnia. This compound has more of an effect on sleep onset than sleep maintenance22 and thus may be less effective in the overall treatment of insomnia, but also has less potential for dependence and thus may be more appropriate for patients with a history of substance abuse. Antihistaminics and sedating antidepressants (mirtazapine, trazodone) lack objective evidence for their use as hypnotics, but are commonly used.8 The mode of action of these drugs is the blocking of the H1 receptors or of the 5-HT2 receptor. A problem with

Insomnia may be treated with cognitive behavioural therapy and instruction in sleep hygiene, either alone or in association with hypnotic medications.

these compounds is that they have not been designed for hypnotic use, and often have a long duration of action, leading to daytime sleepiness and morning grogginess. Restless Legs Syndrome and Periodic Limb Movements of Sleep Despite being different clinical entities, RLS and periodic limb movements of sleep (PLMs) are usually discussed together due to the high chance of co-existence, a similar genetic predisposition and the use of similar treatments. They generally present with insomnia, restless sleep and/or excessive daytime sleepiness, and they may be present in as many as 25% of patients who have sleep disorders. RLS is common and is severe in 34% of the population.
23,24

neurodegenerative disorders such as Parkinsons and Alzheimers disease, head trauma and encephalitis), primary sleep disorders (sleep-disordered breathing [SDB], PLMs, idiopathic hypersomnia, narcolepsy) and medication use or withdrawal (opioids, anticonvulsants, antidepressants, illicit drugs). In a population-based study, hypersomnia was associated with psychiatric disorders in 46.5% of cases.26 It is important to bear in mind that although medical, neurological or psychiatric illness or medication side effects can be a cause of sleepiness, insufficient sleep is the most common cause of EDS in the general population.

Despite being different clinical entities, restless legs syndrome and periodic limb movements of sleep are usually discussed together due to the high chance of co-existence, a similar genetic predisposition and the use of similar treatments.
The atypical features specific to a mood disorder episode include hypersomnia as a diagnostic feature in the diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).27 An association between hypersomnia and a mood episode is reported in 1620% of patients;28 however, there is a paucity of objective findings documented. Nofzinger et al.29 performed a multiple sleep latency test (MSLT) to objectively evaluate daytime sleep latency in depressed patients, and the results did not show abnormalities, suggesting that the hypersomnia in such patients is a subjective complaint. As a result, hypersomnia in a psychiatric context is difficult to evaluate and treat. A misdiagnosis may result in gross mismanagement (e.g. the use of

It is more

common in females (especially during pregnancy), is often familial and is exacerbated by neuroleptics. All patients with a sleep problem should be evaluated for RLS. RLS is a sensorimotor disorder characterised by a nearly irresistible urge to move the legs. It is often accompanied by other dysesthesias or paresthesias occurring primarily at rest and at night, and is alleviated by movement. RLS is frequently associated with PLMs,25 which are repetitive movements that affect one or both legs and usually occur during NREM sleep. PLMs is sometimes associated with awakening. The typical movement found in PLMs is a flexing of the ankle, knee and hip with an extension of the toes. PLMs is found in 80% of RLS patients undergoing polysomnogram.23 According to the Standards of Practice Committee of the American Academy of Sleep Medicine (AASM), The Practice Parameters for the Dopaminergic Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder24 states that: levodopa with decarboxylase inhibitor, and the dopaminergic agonists pergolide, pramipexole and ropinirole are effective in the treatment of RLS and PLMs. Other

EUROPEAN PSYCHIATRIC REVIEW

47

Insomnia
antidepressants in SDB patients complaining of hypersomnolence who are misdiagnosed with depression). In contrast, a number of patients with conversion disorder or depression can be misdiagnosed as having hypersomnia or narcolepsy, with negative consequences. Finally, as will be discussed later, it is not uncommon for patients with a hypersomnia complaint to have a combination of problems that all contribute to the symptoms they are experiencing (typically mood and anxiety disorder, mild sleep apnoea, disturbed sleep at night and poor sleep hygiene). Sleep-related Breathing Disorders The disorders of this subgroup are characterised by disordered breathing during sleep (SDB). Chief among them is obstructive sleep apnoea (OSA), which causes fragmented sleep and sleepiness due to arousals secondary to episodes of complete (apnoeas) or partial (hypopnoeas) upper airway obstruction occurring during sleep with oxygen desaturations. Sleep apnoea is more frequent in males, the obese or those with a small jaw, but should not be excluded in children or even in an underweight female. In addition to EDS, patients may complain of insomnia, fatigue and decreased energy levels (symptoms that are mistakenly attributed to depression), and their partners often report loud snoring or breathing interruptions.30 The estimated prevalence of SDB, defined as an apnoeahypopnoea index (AHI) (an index known to be associated with and to predict an increased risk of high blood pressure and various cardiovascular complications) of 5 or higher, is 9% for women and 24% for men.31 A milder form of SDB, called upper airway resistance syndrome,32 has also been described. In these cases, frank apnoea is not present, but the airway narrows during sleep, forcing the sleeper to increase respiratory effort (fighting to breathe), leading to arousal and disturbing sleep without frank obstruction and oxygen desaturations. These milder events, called respiratory-effort-related arousals (RERAs), are best observed with the use of an oesophageal manometer during the polysomnogram. Problematically, there is only a weak correlation between the presence of sleep apnoea and daytime symptoms such as sleepiness. Consequently, some patients may have severe sleep apnoea, sleep fragmentation and desaturation with a higher risk of cardiovascular complications, but no memory of bad sleep or no complaint of daytime sleepiness. Narcolepsy Narcolepsy is a serious sleep disorder characterised by excessive daytime sleepiness and abnormal REM sleep manifestations, including cataplexy (sudden loss of muscle tone triggered by strong emotions), sleep paralysis, hypnagogic (at sleep onset) and hypnopompic (at wake-up time) hallucinations and sleep-onset REM periods.25 The main finding in these patients is a decrease in hypocretin/orexin concentrations in the cerebrospinal fluid (CSF)37 and in the number of hypocretin neurons in post mortem brain tissue.38 EDS is usually the first symptom to appear, and is exacerbated when the patient is physically inactive. It is often irresistible, despite the individual making desperate efforts to fight the urge to sleep, and is frequently associated with dreaming.39 Despite the EDS, narcoleptic patients generally have disrupted nocturnal sleep, falling asleep as soon as they get into bed but waking up several times during the night. Cataplexy The gold standard diagnostic test is a polysomnogram performed in a sleep laboratory. The AHI is usually determined, as well as lowest and mean oxygen desaturations two important severity factors. An AHI score of >30 and desaturation during sleep of below 80% is severe. Continuous positive airway pressure (CPAP) is still considered to be firstline therapy for treatment of SDB. In CPAP, a nasal or nasaloral mask is provided and continuous positive pressure applied to the upper airway during sleep. By stabilising the airway walls, CPAP alleviates the tendency for the upper airway to collapse, ameliorating breathing disturbances and allowing sleep with less interruption. Studies have shown that CPAP Other symptoms of dissociated REM sleep in patients with narcolepsy include sleep-related hallucinations and sleep paralysis (an inability to move the limbs or the head or to speak or breathe normally, either at is the best diagnostic marker of the disease. It is characterised by a sudden drop of muscle tone triggered by emotional factors, usually by positive emotions such as laughing, or by anger, but almost never by stress, fear or physical effort. It is sometimes limited to facial muscles or to the arms or legs, with dysarthria, jaw tremor, head or jaw dropping, dropping of objects or unlocking of the knees.3941 machine by finding the right pressure device, mask and accessories and coaching them during the first month of prescription. As a result, although some patients find it effective immediately, many patients are discouraged and do not use the device for long enough to see benefits. Alternatives to CPAP for the treatment of OSA include a variety of pharyngeal soft tissue and maxillarymandibular surgical interventions. These procedures address the various points of obstruction in the upper airway or any anatomical variants that predispose an individual to an SBD.35,36 Mandibular advancing dental devices are a treatment option for mild-to-moderate OSA in patients intolerant of CPAP who are not candidates for surgery.36 Surgical therapies for SDB, although liberating when effective (no need for constant use of CPAP), should be carefully considered, as many procedures are ineffective and painful. Similarly, reducing nasal obstruction can ameliorate sleep apnoea by reducing airway resistance and collapse, but is rarely curative. Finally, weight loss can be effective in reducing SDB, although it is difficult to maintain. Any change in body mass index (BMI) of more than 10% should prompt clinicians to reconsider SDB severity. therapy significantly improves subjective and objective measures of daytime sleepiness in patients with OSA.33,34 CPAP is safe, but often not tolerated or used regularly, mainly due to a lack of care by providers, who do not help the patients to tolerate and become accustomed to the

Sleep apnoea is more frequent in males, the obese or those with a small jaw, but should not be excluded in children or even in an underweight female.

Restless legs syndrome can be secondary to medical disorders, including iron deficiency, neuropathies and renal disease.

48

EUROPEAN PSYCHIATRIC REVIEW

Diagnosis and Management of Common Sleep Disorders An Overview for the Psychiatrist

sleep onset or upon awakening, mainly from REM sleep, despite being mentally awake, and usually lasting just a few seconds).41 Sleep paralysis and sleep-related hallucinations are present in only 50% of people with narcolepsy and can be present in another conditions, so cannot be used in diagnosis; however, they should be carefully evaluated as occasionally patients may be misdiagnosed as schizophrenic.42 Onset is usually during adolescence, although cases have been seen in those who are only a few years old and in those above 70 years of age. The negative social impact of narcolepsy has been extensively described. It can impair driving ability, cause car or machine accidents and reduce professional performance (leading to people becoming unemployed, changing jobs frequently or retiring early).
43,44

Current treatments for narcolepsy are aimed at specific symptoms and are not directed against the disease as a whole. Treatment includes stimulants (modafinil, methylphenidate, amphetamines) for daytime sleepiness and sleep attacks,4851 low-dose antidepressants (typically venlafaxine) that are well-known for their REM suppressant capacity for cataplexy and other REM-associated symptoms52,53 and hypnotics for disturbed night-time sleep. Sodium oxybate (-hydroxybutyrate [GHB]) acts as a neurotransmitter via its own receptors and via the stimulation of

A patient with suspected narcolepsy should undergo a polysomnogram followed by a daytime multiple sleep latency test, a test that consists of a series of naps.

Depression has also been

reported in 1837% of cases.45 A patient with suspected narcolepsy should undergo a polysomnogram followed by a daytime MSLT, a test that consists of a series of naps. It is used to see how quickly the patient falls asleep in quiet situations during the day. The MSLT is the standard way of measuring the level of daytime sleepiness. The aim of the polysomnogram is to eliminate other causes of daytime sleepiness (mainly sleep apnoea) and to assess whether the patient has had enough sleep (at least six hours) before the MSLT. Additionally, the polysomnogram might show a shortened REM sleep latency. The MSLT mean daytime sleep latency is eight minutes or shorter, with two or more sleep onsets in REM periods (SOREMPs). The time from sleep onset to REM sleep should be less than 15 minutes in at least two naps. An additional diagnostic tool for the identification of narcolepsy with cataplexy is the association with a specific human leukocyte antigen (HLA) allele, the DQB1*0602, identified in 8595% of patients with narcolepsycataplexy. However, in the US 12% of Asian people, 25% of white people and 38% of African-Americans in the general population have this allele, but obviously only a small fraction of these have narcolepsy. Additionally, HLA is positive in only 4060% of patients with narcolepsy without cataplexy, and in 75% of familial cases of narcolepsy.46,47 However, importantly, sleep paralysis and dream-like hallucinations also occur in isolation in normal people, often in association with sleep deprivation, anxiety and depression. Measuring CSF-hypocretin-1, obtained through lumbar puncture, is often useful in making the diagnosis of narcolepsy. CSF hypocretin 1 concentrations lower than 110ng/l, or 30% of local normal values, are highly indicative of narcolepsy. Low CSF hypocretin

GABAB receptors, and shows efficacy in managing REM-related symptoms including cataplexy, hypnagogic hallucinations and sleep paralysis. It is also effective against sleepiness.5456 Narcolepsy/hypocretin deficiency can be associated with schizophrenia, depression, anxiety, obsessive compulsive disorder and any other psychiatric conditions. In these cases, the clinical picture is often more difficult to recognise, and treatment is more difficult. Hypersomnia In contrast to narcolepsycataplexy, a disorder with a clear pathophysiology (HLA-associated hypocretin deficiency), a number of patients present with sleepiness, some of the narcolepsy symptoms and/or diagnostic results (positive sleep test with short REM latency and/or short sleep latency; HLA positivity) but not low CSF hypocretin. Some of these patients experience severe sleepiness, excessive sleep (more than 10 hours of daytime sleep every day) and documented abnormal MSLT. In these unusual cases, neurological work-up is important. More commonly, patients may present with mildly abnormal nocturnal sleep (mild insomnia, short sleep), excessive napping, a borderline positive MSLT (with or without SOREMPs) and significant subjective complaints of daytime fatigue and sleepiness. In these cases, it is not uncommon to have a combination of problems, such as mild SDB, insufficient nocturnal sleep,

Narcolepsy is a serious sleep disorder characterised by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations, including cataplexy sleep paralysis, hypnagogic and hypnopompic hallucinations and sleep-onset REM periods.
concentrations are highly specific (99%) and sensitive (8789%) for patients with clear-cut cataplexy, and specific (99%) but not sensitive (16%) for those with mild, atypical or absent cataplexy, and for patients with familial or HLA-negative narcolepsy.37,42

depression/anxiety and/or some element of conversion disorder. In these cases, the clinician should treat one condition after the other, using (in order) behavioural and light therapy to consolidate nocturnal sleep, mild non-amphetamine stimulants (atomoxetine, modafinil) to treat a possible central nervous system (CNS) hypersomnia, CPAP to treat mild sleep apnoea and antidepressants and psychotherapy if depression or anxiety disorders are present. Stronger treatments using amphetamine stimulants may be needed, but are best limited, as it is not uncommon for patients to develop a rapid tolerance. The special case of Kleine-Levin Syndrome (KLS), which is probably less rare than commonly thought, should be mentioned, as it is commonly misdiagnosed as a psychiatric condition. The disorder affects adolescents (often males) and is characterised by dramatic and sudden episodes of sleepiness (sleeping for more than 14 hours per day) with a general feeling of fogginess and confusion. Episodes are self-limiting in

EUROPEAN PSYCHIATRIC REVIEW

49

Insomnia
one to three weeks. Aggressiveness when awake, hyperphagia and hypersexuality often occur during the episodes. Most importantly, patients are completely normal between episodes, which re-occur with no pattern for several years to several decades (median 12 years), and finally decrease in intensity and frequency until they stop altogether. Unfortunately, there is no treatment for KLS. The most important recommendation is to leave the patient in a familiar environment (at home) if not in danger during episodes. Stimulants are typically unhelpful if the episodes are intense, as confusion and aggressiveness may result instead of excess sleep. When episodes are frequent, thymoregulators such as lithium or carbamazepine have been suggested to reduce episode frequency.57 Sleepwalking, Night Terrors and Parasomnias Many patients complain of abnormal activity during sleep. REM behaviour disorder affects older males. The patient acts out during dreaming, often hurting himself or the person he shares a bed with. It is typically a precursor of Parkinsons disease or Lewy body dementia.58 Sleepwalking and night terrors occur during slow-wave sleep, which is usually one hour after sleep onset, and are often associated with stress Conclusion A thorough evaluation of sleep disturbances in neuropsychiatric patients is needed. Once identified, problems such as sleep apnea, hypersomnia or insomnia should be aggressively treated, as they may well be causal or participatory to the clinical picture and its impact. Unfortunately, however, expertise in sleep medicine is often not easily available and waiting lists for access to sleep centres are long. Coordinated action by a psychiatrist and a sleep medicine specialist is often needed in these cases, or, even better, psychiatrists should be encouraged to learn the required skills to take advantage of this new discipline and make their patients better. We hope this review will encourage clinicians to enter this new area. and anxiety. Similarly, in adults, some patients may wake up partially and go to eat during the night. A variation of consciousness is often present in these disorders, where the patients is half asleep and half awake. In some cases, these conditions can be difficult to distinguish from nocturnal seizures, although in these cases movements and behaviour are usually more consistent. Behavioural and pharmacotherapy can be helpful in parasomnias.

1. 2. 3. 4. 5. 6.

7. 8. 9.

10. 11.

12. 13.

14. 15.

16. 17.

18. 19. 20. 21. 22. 23.

Espaa RA, Scammell TE, Sleep neurobiology for the clinician, Sleep, 2004;27(4):81120. Saper CB, Chou TC, Scammell TE, The sleep switch: hypothalamic control of sleep and wakefulness, Trends Neurosci, 2001;24:72631. Uschakov A, Gong H, McGinty D, Szymusiak R, Neuroscience, 2007;150(1):10420. Lu J, Greco MA, Sleep circuitry and the hypnotic mechanism of GABAA drugs, J Clin Sleep Medicine, 2006;2(2):S1926. Borbely AA, Achermann P, Concepts and models of sleep regulation: an overview, J Sleep Res, 1992;1:6379. Wurts SW, Edgar DM, Circadian and homeostatic control of REM sleep: promotion of REM tendency by the supra-chiasmatic nucleus, Neuroscience, 2000;20:430010. Moore RY, Suprachiasmatic nucleus in sleepwake regulation, Sleep Med, 2007;8(Suppl. 3):2733. Buysse DJ, Definition, Diagnosis, Classification and Etiology of Chronic Insomnia, J Clin Sleep Medicine, 2005;1(4)4523. NIH State-of-the-Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults, NIH State-of-the-Science Conference Statement, 2005. Tsuno N, Besset A, Ritchie K, Sleep and depression, J Clin Psychiatry, 2005;66(10):125469. Fava M, McCall WV, Krystal A, et al., Eszopiclone co-administered with fluoxetine in patients with insomnia co-existing with major depressive disorder, Biol Psychiatry, 2006;59(11):105260. Papadimitriou GN, Linkowski P, Sleep disturbance in anxiety disorders, Int Rev Psychiatry, 2005;17(4):22936. Morin CM, Combined therapeutics for insomnia: should our first approach be behavioral or pharmacological?, Sleep Med, 2006;7(Suppl. 1):S1519. Morin CM, Cognitive-Behavioral Approaches to the Treatment of Insomnia, J Clin Psychiatry, 2004;65(Suppl. 16):3340. Sack RL, Auckley D, Auger RR, et al., American Academy of Sleep Medicine. Circadian rhythm sleep disorders, Sleep, 2007;30(11): 14841501. Westrin A, Lam RW, Seasonal affective disorder: a clinical update, Ann Clin Psychiatry, 2007;19(4):23946. Lewy AJ, Emens JS, Lefler BJ, et al., Melatonin entrains free-running blind people according to a physiological doseresponse curve, Chronobiol Int, 2005;22(6):10931106. Silber M, Chronic Insomnia, New Eng J Med, 2005;353:80310. Neubauer DN, Pharmacologic approaches for the treatment of chronic insomnia, Clin Cornerstone, 2003;5:1619. Neubauer DN, PDR Clinical Handbook: Insomnia with Clinical Strategies, New York: Thompson, 2004. Holbrook AM, Crowther R, Lotter A, et al., Canadian Medical Association Journal, 2000;162(2):22533. Devi V, Shankar PK, Ramelteon: A melatonin receptor agonist for insomnia, J Postgrad Med, 2008;54(1):458. Karatas M, Restless legs syndrome and periodic limb movements

during sleep, Neurologist, 2007;13(5):294301. 24. Littner MR, Kushida C, Anderson WM, et al., Practice Parameters for the Dopaminergic Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder, An American Academy of Sleep Medicine Report, Sleep, 2004;27(3):5579. 25. International Classification of Sleep Disorders, Diagnostic and coding manual, 2nd edn, American Sleep Disorders Association, Westchester, 2006. 26. Ford DE, Kamerow DB, Epidemiological study of sleep disturbances and psychiatric disorders: An opportunity for prevention?, JAMA, 1989;262:147984. 27. Amercian Psychiatric Association, Diagnostic Criteria from Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), Washington DC, 2000. 28. Tsuno N, Besset A, Ritchie K, Sleep and Depression, J Clin Psychiatry, 2005;66(10):125469. 29. Nofzinger EA, Thase ME, Reynolds CF, et al., Hypersomnia in bipolar depression, Am J Psychiatry, 1991;148(9):117781. 30. Guilleminault C, Tilkian A, Dement WC, The sleep apnea syndromes, Annu Rev Med, 1976;27:46584. 31. Young T, Palta M, Dempsey J, et al., The occurrence of sleep-disordered breathing among middle-aged adults, N Engl J Med, 1993;328:123035. 32. Guilleminault C, Kirisoglu C, Poyares D, et al., Upper airway resistance syndrome: a long-term outcome study, J Psychiatr Res, 2006;40(3):2739. 33. Patel SR, White DP, Malhotra A, et al., Continuous positive airway pressure therapy for treating sleepiness in a diverse population with obstructive sleep apnea: results of a meta-analysis, Arch Intern Med, 2003;163:56571. 34. Morisson F, Decary A, Petit D, et al., Daytime sleepiness and EEG spectral analysis in apneic patients before and after treatment with continuous positive airway pressure, Chest, 2001;119:4552. 35. Riley RW, Powell NB, Guilleminault C, Otolaryngol Head Neck Surg. 1993;108(2):11725. 36. Leibowitz SM, Brooks SN, Black JE, Excessive Daytime Sleepiness: Considerations for the Psychiatrist Psychiatric Clinics of North America, 2006;29:92145. 37. Mignot E, Lammers GJ, Ripley B, et al., The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias, Arch Neurol, 2002;59:155362. 38. Peyron C, Faraco J, Rogers W, A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains, Nat Med, 2000;6:9917. 39. Overeem S, Mignot E, van Dijk JG, et al., clinical features, new pathophysiologic insights and future perspectives, J Clin Neurophysiol, 2001;18:78105. 40. Scammell TE, The neurobiology, diagnosis and treatment of narcolepsy, Ann Neurol, 2003;53:15466. 41. Anic-Labat S, Guilleminault C, Kraemer HC, et al., Validation of a cataplexy questionnaire in 983 sleep-disorder patients, Sleep,

1999;22:7787. 42. Dauvilliers Y, Arnulf I, Mignot E, Narcolepsy with cataplexy Lancet, 2007;369:499511. 43. Broughton R, Ghanem Q, Hishikawa Y, et al., Life effects of narcolepsy in 180 patients from North America, Asia and Europe compared with matched controls, Can J Neurol Sci, 1981;8:299304. 44. Beusterien KM, Rogers AE, Walsleben JA, Health-related quality of life effects of modafinil for treatment of narcolepsy, Sleep, 1999;22:75765. 45. Roth B, Nevsimalova S, Depression in narcolepsy and hypersommia, Arch Neurol Neurochir Psychiatr, 1975;116: 291300. 46. Mignot E, Lin L, Rogers W, et al., Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups, Am J Hum Genet, 2001;68:68699. 47. Siebold, Hansen BE, Wyer JR, et al., Crystal structure of HLADQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy, Proc Natl Acad Sci U S A, 2004;10. 48. Billiard M, Modafinil: pharmacology and therapeutic perspectives, Rev Neurol, 2003;159:1225. 49. Mignot E, Nishino S, Guilleminault C, Dement WC, Modafinil binds to the dopamine uptake carrier site with low affinity, Sleep, 1994;17:4367. 50. Mitler MM, Shafor R, Hajdukovich R, et al., Treatment of narcolepsy: objective studies on methylphenidate, pemoline and protriptyline, Sleep, 1986;9:26064. 51. Auger RR, Goodman SH, Silber MH, et al., Risks of high-dose stimulants in the treatment of disorders of excessive somnolence, Sleep, 2005;28:66772. 52. N Langdon, J Shindler, JD Parkes, Bandak S, Fluoxetine in the treatment of cataplexy, Sleep, 1986;9:3713. 53. M Smith, J Parkes, Dahlitz M, Venlafaxine in the treatment of the narcoleptic syndrome, J Sleep Res, 1996;5:217. 54. TE Scammell, The neurobiology, diagnosis and treatment of narcolepsy, Ann Neurol, 2003;53:15466. 55. J Black, Houghton W, Xyrem International Study Group, Sodium oxybate improves excessive daytime sleepiness in narcolepsy, Sleep, 2006;29:93946. 56. US Xyrem Multicenter Study group, A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy, Sleep, 2002;25:429. 57. Arnulf I, Zeitzer JM, File J, et al., Kleine-Levin syndrome: a systematic review of 186 cases in the literature, Brain, 2005;128:276376. 58. Iranzo A, Molinuevo JL, Santamara J, et al., REM sleep behavior disorder as an early marker for a neurodegenerative disorder: a descriptive study, Lancet Neurol, 2006;5(7):5727.

50

EUROPEAN PSYCHIATRIC REVIEW