Textbook of Psychiatry/Sleep Disorders
- 1 Introduction
- 2 Epidemiology
- 3 The Physiology of Sleep
- 3.1 The Ascending Reticular Activating System (ARAS) and Hypothalamic Structures Involved in Sleep Control
- 3.2 The Pineal Gland and Melatonin
- 3.3 The Sleep-wake Rhythm
- 3.4 The Sleep Drive vs. The Circadian Rhythm
- 3.5 Sleep Duration
- 3.6 The Electroencephalographic Measurement of Sleep and its Division into Stages
- 3.7 Sleep Architecture and the Hypnogram
- 3.8 Theories of Functions of sleep
- 4 Instruments for the Evaluation of Sleep Disorders
- 5 Sleep Disorder Classification Systems: Differences and Similarities
- 6 Descriptions of Specific Sleep Disorders
- 6.1 Primary (Non-organic) Insomnia
- 6.2 The Non-Psychopharmacological Treatment of Primary Insomnia
- 6.3 Psychopharmacological Treatment of Insomnia
- 6.4 Primary (Non organic) Hypersomnia
- 6.5 Narcolepsy
- 6.6 Breathing Related Sleep Disorders
- 6.7 Disorders of the Sleep Wake Schedule (Circadian Rhythm Sleep Disorders)
- 6.8 Sleepwalking [somnambulism]
- 6.9 Sleep terrors [Night Terrors]
- 6.10 Nightmares
- 6.11 REM Sleep Behaviour Disorder
- 6.12 Sleep Paralysis
- 6.13 Bruxism (Tooth Grinding) During Sleep
- 6.14 Sleeptalking [Somniloquy]
- 6.15 Head Banging During Sleep
- 6.16 Restless Leg Syndrome
- 6.17 Periodic Limb Movement Disorder
- 7 Other Rarer Sleep Disorders
- 8 Sleep Disorders Directly Associated with Another Psychiatric Illness
- 9 Sleep Disorders Resulting From General Medical Conditions
- 10 Sleep Disorders Related to the Use of A Substance
- 11 Suggested Reading
- 12 References
Sleep is behavior manifested in all mammals, and within various other classes of the animal kingdom, including even some more primitive organisms such as the fruit fly(Huber et al. 2004). Human beings spend up to a third of their lives asleep. Yet sleep is an enigma from an evolutionary viewpoint in that an organism is at its most vulnerable to predators while in the state of sleep. However, that it is crucial to the wellbeing and survival of organisms is evident from experiments, in which rats inevitably die after prolonged sleep deprivation(Rechtschaffen et al. 1983).
The normal pattern of sleep in humans is highly vulnerable to aberrations due to both internal and external factors. When sleep disturbances occur, they can profoundly influence cognition, mood, psychomotor function, immune function, endocrine function and many other aspects of physiology. Thus sleep disorders cut a large swathe through medicine in general, with disturbances in sleep cropping up in diverse specialties including among others neurology, respiratory medicine and psychiatry.
In psychiatric practice, disturbances of sleep are often the primary presenting complaint of the patient or are often in someway related to it. The[DS1] psychiatrist, therefore, often stands at the forefront of sleep disorders and as suggested by Stahl, sleep should be considered as one of the vital signs in psychiatry (Stahl & Stahl 2008).
Sleep disorders have a serious impact on society. Firstly[DS2], sleep disorders can contribute very deleteriously to the physical health of an individual. Take for example obstructive sleep apnoea and its association to hypertension and heart failure (Phillips & Somers 2003; McEvoy 2003). These individuals will have a high morbidity and mortality rate and contribute to the cost of health services within a country. As another important example, excessive daytime sleepiness, the hallmark of many sleeps disorders, can have massive impact on the frequency of motor vehicle accidents and dangerous mistakes at work. Consider those in careers where mistakes can potentially be fatal like pilots, doctors and those who operate heavy machinery. There is no doubt that the accurate diagnosis and early appropriate treatment of sleep disorders can save lives and reduce health care costs around the world.
Sleep disorders are a heterogeneous group of disorders and it is often difficult to obtain precise values for their incidence and prevalence as many cases never present to health care workers and estimates often rely on self-report surveys.
According to Ohayon[DS3] et al, the epidemiology of insomnia has progressed well in contrast to excessive daytime sleepiness (EDS). This is because EDS is a core symptom of multiple, diverse, sleep disorders like narcolepsy, primary hypersomnia, obstructive sleep apnoea and others, rather than a stand alone diagnosis(Ohayon et al. 2010)[DS4].
According to a study done in Canada in 2006 by Morin et al on 2001 randomly selected adults, 29.9% reported insomnia symptoms, and 9.5% met DSM-IV or ICD-10 criteria for insomnia(Morin et al. 2006). Other papers report estimates of annual incidence of insomnia and EDS to be between 35-40% for the U.S population(Hossain & Shapiro 2002).
Obstructive sleep apnoea has an estimated prevalence of 2% in woman and 4% in men with some studies suggesting even higher numbers than these(Young et al. 1993). Narcolepsy seems to be a far rarer disorder with two Scandinavian studies finding a prevalence of .026% in Finland and .022% in Norway(Hublin et al. 1994; Heier et al. 2009). Shift worker sleep disorder has been estimated to have a prevalence of 10% among shift workers according to study done in Detroit (Drake et al. 2004).
The Physiology of Sleep
The Ascending Reticular Activating System (ARAS) and Hypothalamic Structures Involved in Sleep Control
The control of sleep and wakefulness is also influenced by the ascending reticular activating system (RAS) in the brainstem. This consists of specific nuclei within the brainstem whose cell bodies send ascending projections diffusely throughout the entire brain including cortical and subcortical structures. It includes serotonin produced in the raphe nuclei; noradrenalin produced in the locus coeruleus; dopamine produced in the ventral tegmental area of the midbrain and acetylcholine produced in cell bodies located at the pons midbrain junction.
Residing in the hypothalamus is the ventral lateral preoptic nucleus (VLPO), which produces gamma-amino-butyric acid (GABA), the tuberomammiallry nucleus (TMN), which produces histamine, and a small set of neurons in the lateral hypothalamus which produce orexin (also known as hypocretin). The latter plays a critical role in the pathogenesis of narcolepsy.
As a general rule the cell bodies of the RAS fire while awake and via their ascending projections stimulate wide areas of the cortex and the hypothalamus. Acetylcholine in particular projects to the thalamus. When asleep, the firing of the serotonergic, noradrenergic, dopaminergic and acetylcholinergic cell bodies are suppressed by the VLPO. Histamine production from the TMN is also suppressed during sleep by the VLPO. This is true for non-REM (NREM) sleep only. During REM sleep, the acetylcholinergic cell bodies continue to fire just as they would during wakefulness. This is one of the striking similarities between REM sleep and wakefulness.[DS5]
A rapid transition occurs between sleep and wakefulness and vice versa. This can be explained by the VLPO, which acts as a sleep switch, and can rapidly suppress the ascending RAS. The VLPO, on the other hand, can be rapidly inhibited by histamine released by the TMN or by stimulation of the RAS by external stimuli such as pain or noise. Overall, the control of the VLPO regarding when to turn on and off, is achieved via input from SCN.
Orexin, a peptide neurotransmitter, produced by the lateral hypothalamus, is presumed to act as a stabiliser on the system and allow wakefulness to continue in an uninterrupted fashion during the day. Loss of the orexin neurons destabilises the system, which allows the frequent unwanted lapses into sleep that occur in narcolepsy (and the loss of muscle tone that occurs in cataplexy).
Histamine produced by the TMN promotes wakefulness and the TMN has projections into the cortex. Histamine 1 (H1) receptors occur on the neurons in the cortex and facilitate this arousal. Histamine 2 receptors (H2) are found outside the CNS, in the stomach, and are involved in acid secretion. Blockade H1 receptors produces drowsiness and many pharmacological agents readily cross the blood brain barrier and are H1 antagonists. Such substances can be used as treatments for insomnia or as sedation in various situations. Unfortunately the H1 antagonism of certain psychotropics and subsequent drowsiness is an unwanted side effect in many cases. In addition some novel agents, such as modafinil, are thought to increase histamine release by the TMN and thereby promote wakefulness. This can then act as treatment for sleep disorders where excessive daytime sleepiness is the main feature for instance in narcolepsy.
The Pineal Gland and Melatonin
Another important structure involved is the pineal gland, which forms part of the epithalmus and is situated just behind the third ventricle. It is involved on the production of melatonin. Melatonin is an indolamine neurohormone synthesised from serotonin. It is secreted into the plasma as the pineal gland falls outside the blood blain barrier. There are melatonin receptors MT1, MT2 and MT3 in the human body. The suprachiasmatic nucleus (SCN) has melatonin receptors on its surface, specifically MT1 and MT2 receptors, and via this mechanism, melatonin is thought to alter sleep wake cycles. Exposure to light, specifically light in the blue spectrum, suppresses the secretion of melatonin, whereas darkness increases secretion. Melatonin lowers body temperature, produces drowsiness and reduces the time needed to fall asleep, which is known as sleep latency.
Exogenous melatonin has been used as an over the counter sleep aid for many years. Some studies have shown that exogenous melatonin can be used successfully to improve insomnia, particularly sleep onset insomnia via reducing sleep latency[DS6]. More often, melatonin is used, often in combination with bright light therapy, to treat circadian rhythm sleep disorders by phase delaying or phase advancing a patient’s rhythm to the desired position. Jet lag is a common example where this is useful.
Synthetic substances have been created which act as agonists on melatonin receptors. Examples included ramelteon and the novel antidepressant agomelatine, which will be discussed below.
The Sleep-wake Rhythm
The human body follows a circadian rhythm guiding its sleeping and waking. This is controlled by an internal biological clock. This exists as an independent endogenous process and need not be reliant on external cues. External cues can influence circadian rhythms, however, and these are known as zeitgebers. The circadian rhythm approximates 25 hours in humans who have no to exposure to any zeitgebers. This can be established in a process known as free running where human beings are placed in an environment such as cave for a prolonged period of time and are allowed to sleep and wake when they want. Zeitgebers such as light, noise and demands of work can entrain an individual to a different circadian rhythm. Humans exposed to the natural daylight will generally enter a rhythm of 24 hours. Many other physiological functions besides sleep follow this internal rhythm including importantly body temperature as well secretion of hormones like cortisol.
The suprachiasamatic nucleus (SCN) in the anterior hypothalamus plays the commanding role in controlling the circadian rhythm. The SCN can receive neural inputs directly from light entering the eye. Light falls on specific retinal ganglion cells containing the pigment melanopsin, which then converts the light into action potentials that travel along the retinal-hypothalamic tract to the SCN.
It has become clear from more recent work that there are molecular mechanism at play within the neurons of the SCN that help generate the sleep wake cycle(Pace-Schott & Hobson 2002). Two proteins, within the cells of the SCN, called CLOCK and BMAL1 stimulate the transcription of proteins PER and CRY. PER and CRY then inhibit CLOCK and BMAL1 transcription forming a negative feedback loop. The proteins are built up and broken down generating a rhythm within the cell taking 24 hours. Mutations in the genes controlling these proteins could in theory lead to sleep disorders and present an interesting area of investigation.
The Sleep Drive vs. The Circadian Rhythm
There is also thought to be a homeostatic drive to sleep. The sleep drive increases the longer one stays awake and acts to decrease arousal. It diminishes during sleep. If kept awake continuously, the drive to sleep becomes so overwhelming that a human would choose sleep over food or water. Adenosine accumulation within the brain is thought to be the mechanism generating sleep drive. Caffeine, a methylxanthene, is thought to act by blocking the actions of adenosine and thereby reducing the sleep drive and promoting wakefulness.
There is also an opposing drive regulated by the circadian rhythm, which increases during the day promoting wakefulness and decreases at night allowing a person to sleep. The circadian rhythm is biphasic and has a small dip in the afternoon, which accounts for the decreased wakefulness and urge to sleep often experienced in the afternoon.
The duration that a person sleeps which allows them to feel refreshed seems to be genetically determined and can vary widely from person to person. The duration of sleep follows a normal distribution with 7.5 hours as the mean(Higgins & George 2007).
There seems to be, however, risks to sleeping to for too long or too short. In particular large population based studies going back 40 years consistently show that both short sleepers (less then 7 hours a night) and long sleepers (more than 8 hours a night) have an increased risk of mortality(Christer Hublin 2007).
There are profound changes in sleep that occur across the lifespan(Ohayon et al. 2004) as mentioned briefly above. There are variations in the total amount of time asleep as well changes to the architecture of sleep. Neonates spend up to 16 hours in a 24-hour cycle asleep with approximately 50% of that time in REM sleep. As a child ages so their total sleep duration decreases towards the adult mean with a similar change to the percentages of REM and slow wave sleep. This pattern continues into adulthood and beyond, so that as we age, the amount of REM sleep we obtain decreases as well as the amount of slow wave sleep. Correspondingly the percentage of stage 1 and stage 2 sleep increases. Total sleep time shows a gradual decrease with age. The amount of nocturnal awakenings increases with age. Sleep latency also increases with age. Therefore, it is a frequent complaint of geriatric patients that they struggle to fall asleep, wake up frequently during the night and do not sleep as much as they used to.
It has long been known that prolonged sleep deprivation is detrimental. Chronic sleep restriction causes measurable progressive declines in cognitive and psychomotor function. This includes decreases in sustained attention, alertness, memory, psychomotor speed and reaction time(Van Dongen HP et al. 2003). It’s also thought that chronic sleep restriction causes negative consequences for the immune and endocrine system. Of note, however, is that acute sleep restriction is known to be a potent antidepressant. However, the antidepressant effect is not sustained and so is not useful as a long-term antidepressant strategy. But understanding how or why acute sleep restriction exhibits this effect could generate insight into the neurobiology of depression.
The Electroencephalographic Measurement of Sleep and its Division into Stages
Sleep is not a passive process as was thought for many centuries. In the early 1950’s Kleitman and Aserinsky discovered that by monitoring sleeping subjects via electroencephalography (EEG) they could delineate various distinct stages during a given nights sleep. Importantly the discovery of rapid eye movement sleep (REM) allowed sleep to be broadly divided into non rapid eye movement (NREM) and REM stage.
REM sleep was uniquely identified not only by its EEG pattern but also by rapid conjugate eye movements and its association with vivid, recallable dreams. Within NREM another 4 distinct stages were delineated based on their characteristic EEG. They became known as a stage 1, 2, 3 and 4. Sometimes stages 3 and 4 are known as deep wave sleep or ? sleep. , it became apparent that normal sleep showed a characteristic pattern of progression through the stages interspersed with periods of REM sleep. The duration of various stages varied though the night with gradual lengthening of REM sleep periods and shortening of slow wave sleep periods. This can be graphically represented on a hypnogram as discussed later.
In addition to the EEG patterns of each sleep state it was discovered that various other physiological measures changed during the different stages. These included muscle tone, ocular movements, temperature, heart rate, respiration, oxygen saturation (important in studying sleep apnoea), overall metabolic rate and tumescence (penile and clitoral erections, important in studies of impotence).
Hence to truly perform an accurate assessment of sleep study one needs to combine various measurements, at the very least EEG, electroculogram (EOG) to track eye movements and electromyelogram (EMG) to detect muscle activity. Modern sleep laboratories now use polysomnography (PSG) to study sleep and this consists of EEG, electroculogram (EOG) with channels for right and left eyes, electromyelogram (EMG) of chin and right anterior tibialis muscles, electrocardiogram (ECG), pulse oximetry, body temperature and video recording of the patient. In some studies additional channels can be used like microphone to detect a snore, and monitoring of nasal airways and diaphragmatic movements (Kaufman 2007).
EEG patterns can be broadly classified into 4 categories for the purposes of sleep investigation. Awake patterns include ? (>12Hz) and ? (8-12Hz) rhythms. These 2 rhythms are characterised by low amplitude, rapid frequency patterns. ? is associated with an alert, vigilant, problem solving state of consciousness. ? rhythm is a slightly slower frequency and larger amplitude and is present when the eyes are closed and an individual is in a relaxed state. Stage 1 NREM sleep is characterised by a drowsy state and an EEG frequency (4-8 Hz) called ?. This is lightest state of sleep and subjects can be aroused by external stimuli more easily then the deeper stages. Once entering stage 1 sleep the fast conjugate eyes movement of wakefulness are replaced by slow rolling eye movements.
Stage 2 sleep also consists of ? activity but it is distinguished by the presence of K complexes and sleep spindles. K complexes are isolated large amplitude slow EEG waves and sleep spindles are episodic bursts of fast EEG activity lasting approximately 0.5 seconds(Hales 2008). Stage 3 is the beginning of slow wave sleep with further slowing of frequency and widening of amplitude. Stage 4 is deep sleep characterised by a very slow frequency (1-3Hz) and extremely large amplitude rhythm called ?.
REM sleep, surprisingly, consists of an EEG rhythm almost identical to the ? and ? rhythm of wakefulness with a fast frequency and low amplitude pattern.
Sleep Architecture and the Hypnogram
The progression through the night of sleep stages and the relative lengths of each stage can be depicted in a figure known as a hypnogram, with time on the horizontal axis and depth of sleep on the vertical. REM sleep is usually indicated by a thick horizontal line or as a line intermediate between stage 1 and wakefulness.
In a healthy young adult, stage 1 sleep lasts 30 seconds to 7 minutes(David et al. 2012). NREM stage 2 then follows and slow wave sleep should commence by approximately 30 to 45 minutes after sleep onset(David et al. 2012). Stage 3 and 4 sleep can last for few minutes to an hour. It’s then followed by brief episodes of stage 3 and 2 sleep followed by the commencement of REM sleep.
REM sleep will the usually have commenced by 75 to 90 minutes of after sleep onset. This period of time is called the REM sleep latency period and is an important biological measure in many psychiatric disorders. One of the most robust findings in psychiatry is that patients with major depression have reduced REM latency and that after treatment with antidepressants the REM latency period lengthens and normalises. Reduced REM latency also occurs in narcolepsy, sleep apnoea and the sleep-deprived individual.
As a general rule the length and intensity of REM periods increase during the night and the periods of slow wave sleep decrease with ? sleep periods sometimes absent by the latter stages of the night. The first REM period is approximately 10 minutes and the 5th REM period lasting up to an hour(David et al. 2012).
In a typical 8-hour sleep a person will go though 5 cycles of NREM and REM sleep. A consistent finding is that sleep architecture changes with age. At the beginning of life a neonate spends almost 16 hours a day sleeping with 8 of those hours in REM sleep. As one gets older the proportion of stage 4 sleep decreases slowly to the extent that in the very elderly ? sleep is completely absent.
As an individual progresses through stage 1 sleep to 4 the degree of arousability decreases with increasingly larger stimuli required to wake an individual. In general, slow wave sleep is thought to be physically regenerative, allowing the body to restore itself after the day’s physical exertion. During NREM sleep the respiration, heart rate, body temperature and overall metabolic rate gradually decreases. In fact the more physical activity an individual performs during the day the greater proportion of slow wave sleep during the following nights sleep.
People with decreased slow wave sleep proportion report sleep that is non-restorative. This is a common symptom among the elderly, the depressed and those with fibromyalgia. Certain psychotropics, for example the anticonvulsant pregabalin, can increase the proportion of slow wave sleep and thereby increase the individual’s sense of restorative sleep.
Dreaming does occur during NREM sleep however the dreams are less vivid and complex compared to REM sleep and people are less likely to remember them. The dreams so characteristic of REM sleep are vivid, nonsensical, bizarre and often immediately recallable when an individual is awaked during the REM period.
In terms of bodily movement, in NREM sleep there is persistent face and limb tone with repositioning every 15 to 20 minutes.
It is in REM sleep that there is flaccid, areflexic paresis affecting skeletal muscle except the eyes and respiratory muscles. The activity in the EMG goes from continual activity in stage 1 sleep to complete silence during REM sleep. It is thought the peri-locus ceruleus is responsible for abolishing muscle tone during sleep(Kaufman 2007). Without this paresis during REM sleep people would act out their dreams and potentially harm themselves or others. Unfortunately this seems to be the problem in REM sleep behaviour disorder where patients thrash about violently during periods of REM sleep. Besides been dangerous in its own right it may be a harbinger of the development of Parkinson’s disease.
Also during REM sleep the activity of the autonomic nervous system increases and hence pulse, respiration and blood pressure all increase and is often accompanied by penile erections. Cholinergic activity seems to drive REM sleep where as there is a decrease in the activity of all the other neurotransmitters during REM including serotonin, dopamine and noradrenalin. Anticholinergic medications therefore have the capacity to disrupt or suppress REM sleep.
Theories of Functions of sleep
There are many theories regarding the functions of sleep (ref). That sleep is essential to well-being is beyond dispute. In humans complete sleep deprivation results in increasing cognitive impairment in multiple domains eventually leading to severe neuropsychiatric effects including hallucinations. After a certain point a person will begin to have periods of microsleeps where brief millisecond intrusions of ? or slow wave sleep intrude into consciousness involuntarily. As mentioned above, in the rat, death is the result of complete sleep deprivation(Rechtschaffen et al. 1983).
One theory is that sleep allows physical restoration of the body. This is supported by the fact that humans who are sleep deprived can develop impaired glucose tolerance and insulin sensitivity as well as endocrine abnormalities similar to the changes observed in normal ageing(Spiegel et al. 1999).
Animals with smaller body surface areas and therefore higher metabolic rates have longer average sleep durations. This could suggest that sleep plays some role in reversing the oxidative stress placed on the brain by the toxic by-products of metabolism(Higgins & George 2007).
Sleep also seems to play a role in learning and memory consolidation. Sleep seems to improve the retention of procedural memory however declarative memory does not seem to improve with sleep(Higgins & George 2007).
There could also be a role for sleep in the processing of emotionally laden experiences as there is clear activation of the limbic system during REM sleep(Nofzinger et al. 1997)[DS7].
Instruments for the Evaluation of Sleep Disorders
Definition of Measurements and Terms Used in Sleep Medicine
The time that an individual takes to fall asleep is known as the sleep latency. Normal sleep latency varies between 10 and 20 minutes. Sleep latency varies inversely with the degree of sleepiness. Many conditions can result in changes in sleep latency. Shortened sleep latency can result from sleep restriction, certain medications like benzodiazepines and the many conditions that result in excessive daytime somnolence (EDS) like narcolepsy and obstructive sleep apnoea. Prolonged sleep latency is the defining feature of primary sleep onset insomnia. It can also occur secondary to stimulant drugs, anxiety disorders, depression, mania, acute psychosis and restless leg syndrome(Kaufman 2007).
As explained above the, the time of onset of the first REM period is known as REM latency. Sleep efficiency refers to the amount of time spent asleep as shown by EEG over the amount of time spent in bed.
The proportion of REM sleep and NREM sleep in a night can be affected by certain conditions. In a phenomenon known as REM rebound an individual deprived of REM sleep previously will have shortened REM latency, longer then normal REM periods and REM occupying a greater percentage of total sleep time. REM rebound can occur after long-term administration of REM suppressing psychotropics such as tricyclic antidepressants and alcohol[DS8].
Epworth Sleepiness Scale
This is a questionnaire developed by Dr. Murray Johns of Epworth hospital designed to assess the level of an individual’s daytime sleepiness. It consists of eight situations in which a respondent gives an answer between 0 and 3 rating their likelihood of falling asleep in that situation. The higher the answer the higher the chance of falling asleep in the given circumstance. A total score of 10 or more is considered abnormal and a person is advised to obtain further investigation from a doctor or sleep medicine specialist. In narcolepsy, this test has a 93.5% sensitivity and 100% specificity using a cut of 10 points(Johns 2000).
Multiple Sleep Latency Test
This is the test used to make a definitive diagnosis of narcolepsy. The patient must have a normal nights sleep the night before that has been confirmed on PSG to rule out other causes of EDS like sleep apnoea. On the day of the test, the patient, 2 hours after awakening, is presented with five 20 minute nap opportunities the day. During the nap opportunities PSG’s are performed specifically looking at the sleep latency and the REM latency. To confirm a diagnosis of narcolepsy an individual should have 2 or more sleep latency periods of less than five minutes each. In addition the patient should 2 or more have REM latency periods beginning within 10 minutes. Some severe patients may have Sleep Onset REM Periods (SOREMPs)(Kaufman 2007).
Maintenance of Wakefulness Test
This test is designed to check the ability of a person to stay awake in a controlled situation with very little stimulation. Typically a person will be in a dimly lit room, sitting upwards in a comfortable position in a bed, without any outside sound, and at room temperature. They are connected to polysomnography equipment. They should undergo four sleep trials, which last forty minutes. The objective is to try and stay awake for as long as possible during the forty minutes. They are not allowed to perform any actions like pinching themselves or singing to try and stay awake during the trial. If they fall asleep they are woken up after 90 seconds. There are two-hour breaks scheduled between each trial. During the breaks the patient must get out of bed and stay awake. Lunch is provided. The patient also must have had a normal breakfast.
Importantly the patient must have had a normal nights sleep the night before. Sleep onset in a trial is defined as entering a stage 2, 3, 4, REM or 3 consecutive periods of stage 1 sleep(B. J. Sadock et al. 2009). Falling asleep in under 8 minutes is considered abnormal(B. J. Sadock et al. 2009). An individual falling asleep between 8 and 40 minutes carries unknown clinical significance. It is known that 59% of healthy volunteers remain awake during all forty minute trials(B. J. Sadock et al. 2009). This test can be used to test if an individual is able to function during the day, especially from an occupational point of view, given they have a sleep disorder. It can be helpful to track progress for individuals on treatment for a sleep disorder like narcolepsy and monitor there response to treatment.
Sleep Disorder Classification Systems: Differences and Similarities
By far the most comprehensive classification system for sleep disorders is the Second Edition of the International Classification Of Sleep Disorders (ICSD-2) published by the American Academy of Sleep Medicine(AASM 2005). However most psychiatrists, will refer to and use the ICD-10 Classification of Mental and Behavioural Disorders (WHO 1992) for nonorganic sleep disorders and The International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) (WHO 2005) for organic sleep disorders. Perhaps more frequently however The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) Fourth Edition Text Revision (APA 2000) is used.
Both the ICD-10 and the DSM IV-TR contain sections on sleep disorders. The ICD-10 contains a section on sleep disorders which they entitle nonorganic sleep disorders. Sleep disorders considered to be organic in origin are included in various other sections outside of the mental and behavioral section.
The nonorganic sleep conditions listed are insomnia, hypersomnia, disorder of the sleep wake schedule, sleepwalking (somnambulism), sleep terrors (night terrors), nightmares in which they include dream anxiety disorder, other nonorganic sleep disorders and nonorganic sleep disorder unspecified under which they include emotional sleep disorders not other wise specified.
Other important sleep disorders that are considered to be organic in origin are classified in disorders of the nervous system. Here there are separate categories for multiple different disorders. They include disorders of initiating and maintaining sleep (insomnia), disorders of excessive somnolence (hypersomnia), disorders of the sleep wake schedule under which is listed delayed sleep wake syndrome and irregular sleep-wake pattern, sleep apnoea under which is listed a central and obstructive type and excludes Pickwickian syndrome and sleep apnoea of the newborn, narcolepsy and cataplexy, other sleep disorders under which Klein-Levin syndrome is listed and finally a sleep disorder unspecified category.
Restless leg syndrome is listed under a subcategory of disorders of the nervous system called other extrapyramidal and movement disorders. Periodic limb movement disorder is not listed in the ICD-10 as of version 2010 accessible online (WHO 2010).
Enuresis is considered by some to form part of the sleep disorder spectrum as it often can occur only nocturnally. However, the diagnosis of enuresis includes either diurnal or nocturnal voiding of urine into bed or clothes inappropriate for an individuals mental age. In ICD-10 it is listed under behavioural and emotional disorders with onset usually occurring in childhood and adolescence.
Although the DSM-IV-TR and ICD-10 overlap somewhat with regards to their classification of sleep disorders, there are some important differences. DSM-IV-TR divides its sleep disorder section into primary sleep disorders, sleep disorders related to another mental disorder and other sleep disorders. Primary sleep disorders can be considered to overlap to some extent with the ICD-10 term nonorganic sleep disorder. However the DSM-IV-TR splits primary sleep disorders into dysomnias and parasomnias. A dysomnia refers to a disorder that disrupts the ability to initiate or maintain sleep or that causes excessive daytime sleepiness. A parasomnia refers to an abnormal event or behaviour that intrudes on NREM or REM sleep. These words are mentioned in the ICD-10 but the classification is not organised specifically around these terms.
In dysomnias, the DSM-IV-TR includes narcolepsy and breathing related sleep disorders, which are not listed as nonorganic sleep disorders in ICD-10. The DSM-IV-TR uses the term circadian rhythm sleep disorder, which could be considered interchangeable with ICD-10 term sleep-wake schedule disorder. However, in DSM-IV-TR, it includes subtypes not mentioned in ICD-10 including delayed sleep phase type; jet lag type; shift work type and an unspecified type which includes advanced sleep phase; non-24-hour sleep-wake pattern; irregular sleep wake pattern and other unspecified type.
The dysomnia not otherwise specified category contains a wide range of disorders including insomnia or hypersomnia due to environmental factors (this is not found in ICD-10); sleep deprivation (not found in ICD-10); restless leg syndrome (not classified as a nonorganic sleep disorder in ICD-10) and periodic limb movement disorder (not found in ICD-10).
Under parasomnias the DSM-IV-TR lists nightmare disorder; sleep terror disorder and sleepwalking disorder, all of which overlap, with their counterparts in ICD-10. Under parasomnias not otherwise specified is listed REM sleep behaviour disorder (which doesn’t appear in ICD-10) and sleep paralysis (which doesn’t appear as a stand alone diagnosis in ICD-10).
DSM IV-TR has a category for sleep disorders related to another major Axis I or Axis II disorder that causes either insomnia or hypersomnia. Generally speaking, the most important psychiatric illnesses known to affect sleep profoundly are major depressive disorder, bipolar mood disorder, the anxiety spectrum disorders and schizophrenia. Although sleep disturbances are often among criteria for defining these individual disorders (for example in depression and mania), this category requires the sleep disturbance to be severe enough to warrant specific clinical attention in its own right.
DSM IV-TR has a separate category for sleep disorders arising as a result of a general medical condition. A wide range of medical conditions can influence sleep and vice versa. Some specific examples include seizures related to sleep; cluster headaches during sleep; paradoxical hemicrania during sleep; asthma influenced by sleep; cardiovascular symptoms related to sleep; gastro- oesophageal reflux during sleep; and paroxysmal nocturnal haemoglobinuria.
Another important example in clinical practice is chronic pain, which has a very close bidirectional relationship with sleep and, indeed, with mood. This could include patients with malignancies, chronic painful sensory neuropathies and fibromyalgia. Many such patients can present with a sleep disorder. At present fibromyalgia is not a listed condition within DSM IV TR, however, it has diagnostic criteria set out by the American College of Rheumatology.
In DSM-V-TR, a sleep disorder can be put in a substance induced sleep disorder category if it is thought to arise directly from the use or withdrawal of a specific substance. ICD-10 lacks such a category.
Descriptions of Specific Sleep Disorders
Primary (Non-organic) Insomnia
According to the ICD-10 insomnia is characterised by a difficulty falling asleep, maintaining sleep or a complaints of non-refreshing sleep. The fact that it is primary indicates that it is not secondary to a known causative organic factor, the direct effect of a substance or another psychiatric illness. The duration of the symptoms to establish the diagnosis is a month and in the case of the ICD-10 a patient must have sleep disturbances at least 3 times a week. In addition to this the disturbance in sleep must result in a disturbance in socio-occupational functioning or marked personal distress.
Primary insomnia can be transient in nature and can often be precipitated by a concurrent or upcoming stressor. However it can also be chronic and some individuals have idiopathic insomnia, which plagues them their whole lives. Insomnia can also be divided into initial (sleep onset) insomnia or maintenance insomnia where a person has difficulty staying asleep with frequent nocturnal awakenings.
Primary sleep onset insomnia is often associated with a phenomenon known as psychophysiological or conditioned insomnia. In this situation an individual develops a vicious circle of anxiety about not been able to fall asleep which itself results in greater difficulty falling asleep. The reason it is sometimes called conditioned is that the insomnia is associated with the bedroom or environment the patient usually sleep in. Therefore such patients often fall asleep when away from home in another house or on the couch in front of the television. Whereas at home in their own bedroom they ruminate over their inability to fall asleep and as a result induce a state of hyperarousal preventing sleep onset.
The Non-Psychopharmacological Treatment of Primary Insomnia
The non-psychopharmacological treatment of primary insomnia especially for those with psychophysiological insomnia is to institute a program of sleep hygiene. The premise behind this strategy is that many people with primary insomnia have fundamental bad habits in their daily life leading to their difficulty sleeping. Generally sleep hygiene involves some of the following: going to bed at the same time and arising at the same time every night regardless of how much sleep a patient thinks they got; once going to bed allowing a maximum time of twenty minutes to elapse to fall asleep – if not asleep by this time then the patient is instructed to get up and go and do another activity until they feel sleepy again; the bedroom is to be used only for two activities: either sleeping or sex; patients are to try to eliminate stimulants such as caffeine or at least have their last caffeinated beverages before 4 P.M; try to avoid alcohol in the evenings before bed; establish and exercise program but avoid heavy exercise within 2 to 3 hours before bedtime; have a cool, dark and quiet bedroom. There are also a group of people who have so called sleep state misperception(B. J. Sadock & V. A. Sadock 2007). Such individuals will have the subjective belief that they are not sleeping enough during the night due to too frequent awakening or taking too long to fall asleep. However when such people are studied in a sleep lab all their sleep parameters are found to be within normal limits
Psychopharmacological Treatment of Insomnia
Introductory sentence on the range of different drugs Transient primary insomnia is often treated with hypnotics particularly benzodiazepines or Z-drugs like zolpidem and zopiclone. As a general rule such drugs should only be used for the briefest time possible to avoid tolerance and withdrawal symptoms after stopping. Two weeks of use is the general rule especially for benzodiazepines.. Z-drugs are used preferentially for this as it was thought these drugs were less likely to cause issues of tolerance and rebound insomnia on withdrawal as compared with benzodiazepines. According to (Stahl & Stahl 2008), the best long term studies in this regard have been done with eszopilcone although zoplidem, zopiclone, zaleplon and zolpidem CR are also widely used. Z—drugs are positive allosteric modulators of the GABA-A receptor[DS9]. This means they facilitate the action of GABA at these receptors by inducing a conformational change in the receptor complex In particular zolpidem and zaleplon bind specifically to the ? 1 subtype of the GABA-A receptor. The ? 1 subtype mediates the hypnotic and amnestic effects seen with these drugs. They lack the muscle relaxing and anxiolytic actions of benzodiazepines, which bind non selectively to all GABA-A subtypes including ? 2 and ? 3(Stahl & Stahl 2008).
Melatonin is sold as an over the counter medication and is an agonist at melatonin 1, 2 and 3 receptors. It seems to be effective for sleep onset. Newer treatments becoming available for the treatment of insomnia include the melatonergic agent ramelteon which is a full agonist at melatonin 1 (MT1) and melatonin (MT2) receptors. The novel antidepressant agomelatine is also an agonist at MT1 and MT2 receptors as well been an antagonist at 5HT2C receptors. It is thought it may potentially act as an effective hypnotic in addition to its antidepressant effects[DS10].
Many other agents are used off label for the treatment of chronic insomnia.[DS11] These include the sedating antidepressant trazadone. The sedating and sleep inducing effects arise primarily from its potent antihistamine 1 (H1) receptor blockade and ?1 receptor antagonism. However trazadone can also cause enhance slow wave sleep through 5HT2A and 5HT2C antagonism.
Low doses of the sedating antidepressant mirtazapine and the atypical antipsychotic quetiapine can also be used as hypnotics primarily through their H1 receptor and 5HT2A blockade.
The tricyclic antidepressant doxepin acts as an extremely potent H1 receptor blocker at low dosages of between 1 to 6mg has been reformulated for use as a chronic insomnia treatment with seemingly little or no risk of tolerance or abuse potential.
An important factor to consider in use of a hypnotic is its half-life. Drugs with especially long half lives may have unwanted carry over effects into the next day like sedation, memory problems and falls in the elderly. Benzodiazepines in particular vary widely in their half-life, and therefore selection may be guided by whether one is treating initial insomnia or targeting sleep maintenance. Five benzodiazepines are approved for use in insomnia by the FDA. Flurazepam and quazepam have very long half-lives and can cause problems especially in the elderly with carry over effects. Estazolam and temazepam have intermediate half-lives and can be used for sleep maintenance. Triazolam has an extremely short half-life and can be used for sleep onset insomnia(Stahl & Stahl 2008). Out of the Z-drugs eszopiclone and zolpidem controlled release can be used for sleep maintenance and zolpidem and zaleplon can be used for sleep onset.
Primary (Non organic) Hypersomnia
This disorder is characterised by excessive daytime somnolence (EDS). However, the patient in question must have no other symptoms or signs of narcolepsy (cataplexy, sleep paralysis, hypnagogic hallucinations) and no breathing related sleep disorder like sleep apnoea. In addition their EDS is not a result of insufficient sleep or due to the effects of a substance or another general medical condition. In other words, this is a diagnosis of exclusion once all other cause of EDS have been ruled out. According to ICD-10 the EDS should occur nearly every day for a month or recurrently for shorter periods of time.
There are people who are long sleepers and such individuals although having a long sleep time have normal sleep architecture. Such people often have a family history of long sleepers. There are also individuals who complain of EDS and therefore take frequent daytime naps, however, display normal findings in a MLTS therefore ruling out narcolepsy. For such individuals such daytime somnolence can be extremely disabling and still warrant treatment. Similarly to narcolepsy primary hypersomnia can be treated with stimulants such as methylphenidate, amphetamines or modafinal[DS12].
Narcolepsy is characterised by the clinical tetrad of excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations. Not all narcoleptic have all four symptoms, however EDS needs to be present and cataplexy is very strong indicator that true narcolepsy is present.
EDS is experienced as irresistible sleep attacks during the day. Cataplexy is the sudden loss of muscle tone usually in response to a strong emotional reaction like laughing. Laughter is often the most common precipitant, however other strong emotions like anger can also precipitate it. The loss of muscle tone can be complete and the individual can collapse on the floor or it can be subtler involving only the muscles of the face, often with the jaw muscles losing tone and the patient’s mouth hanging open.
Sleep paralysis is a phenomenon experienced while falling asleep or waking up whereby an individual feels as though they are awake and fully aware of their surroundings however they are unable to move or speak. This is often accompanied by feelings of fear or terror. It is almost as though the muscle paralysis characteristic of REM sleep is still in effect even though the individual is conscious of their surroundings.
Hypnagogic hallucinations are hallucinations experienced in the period just before sleep onset. These occur in a large percentage of the population and are not considered pathological in isolation. In narcolepsy they could reflect direct intrusion of the contents of REM sleep into consciousness as the REM latency of narcoleptics can be greatly reduced.
It is now known that narcolepsy is the direct result of the loss of specialised neurons in the hypothalamus that secrete the neuropeptide hypocretin also know as orexin. The reason it has two names is that two different groups of researchers discovered this peptide independently before its role in narcolepsy was fully elucidated. Hypocretin seems to work by influencing the monoamines of the reticular activating system as well as histamine to allow wakefulness to be stabilised. It is possible to produce, via genetic alteration, animals lacking hypocretin activity in some way. This has been done, most notably in dogs, which then display all the characteristic signs of narcolepsy(Siegel n.d.).
Narcolepsy in humans, however, does not have a strong degree of heritability with identical twins having about a 13% concordance rate for narcolepsy(Siegel n.d.). There is a strong correlation, however, with a HLA subtype known as HLADQB1*0602. 95% of Caucasian’s with narcolepsy possess this HLA variant(Siegel n.d.). In these individuals hypocretin levels in the cerebrospinal fluid are undetectable. However, this genetic variant alone is not sufficient to produce the disease as shown by the twin data. But it does suggest an autoimmune basis for the development of narcolepsy. This has been further strengthened by the fact that post mortem examinations of the brains of narcoleptic patients show gliosis in the region of the hypocretin cells (and not in the surrounding cells), which suggest some sort of inflammatory process was at work(Siegel n.d.).
Most narcolepsy patients develop symptoms in their second decade of life. The disease can be disabling with many patients completely unable to function socially and occupationally. Cataplexy can be particularly troublesome with many narcoleptics developing personal strategies to avoid strong emotions like laughing. Patients often will take multiple short naps (twenty minutes) during the day. They experience the naps as extremely refreshing. Narcolepsy patients also demonstrate fragmented nightime sleep but do not on average sleep longer than non-narcoleptics. Narcoleptics have a shortened REM latency period with many narcoleptics dropping straight into REM sleep after falling asleep.
Narcolepsy can be confirmed in the sleep laboratory by performing a multiple sleep latency test (MLST) as explained above. Briefly, in this test a patient should have a polysomnogram to rule out sleep apnoea and other causes of EDS before the test and should have a normal night’s sleep before the night of the test. On the day of the test the patient will have an opportunity to have 4 or 5 naps separated by 2-hour periods. The sleep latency and REM latency are then measured. In narcolepsy sleep latencies are reduced below the normal, often below five minutes. REM latencies are often drastically reduced below the normal 90 minutes to 10 minutes or less. Sometimes they are completely absent with patients having so called sleep onset REM periods(Kaufman 2007).
The treatment of narcolepsy is primarily psychopharmacological. To target EDS patients can be treated with stimulants like methylphenidate and amphetamines. Modafinal is often preferred as a first line agent as it has a lower potential for abuse (although true narcoleptics very rarely abuse their stimulants(Siegel n.d.)).
To target cataplexy and other symptoms tricyclic antidepressants were traditionally prescribed for example imipramine. They seemed to work by virtue of their REM suppressing abilities via their anticholinergic effects. More recently selective serotonin reuptake inhibitors have also been used for this purpose, as they also seem to suppress REM sleep.
Gamma hydroxybutarate (GHB) also known as sodium oxybate seems to be highly effective for the treatment of both EDS and cataplexy. Its trade name is Xyrem. It is FDA approved for this purpose. Large doses have to be used and the effect on cataplexy can take a few weeks of treatment to become apparent(Siegel n.d.). Its exact mode of action in narcolepsy is unknown however GHB is well known to powerfully increase slow wave sleep, which allows an individual to feel more rested and increase daytime alertness. GHB is a controlled substance due to its potential for abuse and reputation as a “date-rape” drug.
Breathing Related Sleep Disorders
Breathing related sleep disorders is actually a category in DSM-IV TR that acts as an umbrella term to cover both obstructive or central sleep apnoea and central alveolar hypoventilation syndromes. In ICD-10 sleep apnoea is listed under disorders of the nervous system. This category excludes congenital breathing disorders like congenital central alveolar hypoventilation syndrome which are listed elsewhere and Pickwickian syndrome which is listed under disorders of obesity. Pickwickian syndrome is considered to be alveolar hypoventilation related to morbid obesity. Breathing related sleep disorders usually present with excessive daytime somnolence although insomnia can also infrequently be a complaint.
Obstructive sleep apnoea (OSA) occurs when then there is collapse of the upper airway during sleep as a result of the negative air pressure during inspiration and the floppy nature of the tissue in the oropharynx which looses tone during sleep. Thus there is a functional obstruction of the upper airway, which can either be complete or partial. Airflow though the nasal and oral airway then ceases or is reduced despite continued respiratory effort of the diaphragm and accessory respiratory muscles. Because of the reduced airflow, at the alveolar level is there is a decrease in the oxygenation of arterial blood. As the arterial blood desaturates to a certain critical point, a reflex occurs at the brainstem level which causes a brief arousal from sleep which allows airway patency to return and airflow to resume. This arousal disrupts sleep and can occur during either NREM or REM sleep.
A period of apnoea lasting at least ten seconds is taken during sleep studies to constitute an apnoea. If airflow obstruction is partial it is referred to as a hypopnoea. Patients with OSA can have hundreds of apnoeas with brief arousals from sleep during the night which produces extremely disrupted sleep architecture. The result is excessive daytime somnolence that is sometimes extremely severe. Risk factors for OSA include snoring, been male, obesity, small jaw (micrognathia), middle age, hypothyroidism and acromegaly.
There are multiple severe medical consequences that go hand in hand with OSA. Patients can develop cardiac arrhythmias during apnoeas. There is a clear association of systemic hypertension and OSA although whether OSA is causative in systemic hypertension is debatable as these patients are often overweight and have multiple other symptoms of the metabolic syndrome. OSA results in pulmonary hypertension and in the long term can result in cor pulmonale. Patients with OSA come to the attention of psychiatrists as they have complaints of EDS as well a host of other neurocognitive difficulties. They can have memory problems, difficulty concentrating and often decreased sex drive(B. J. Sadock & V. A. Sadock 2007). It is not clear at this point whether the risk of major depressive disorder is increased in OSA patients or not(B. J. Sadock & V. A. Sadock 2007).
OSA can be successfully treated with the use of nasal continuous positive airway pressure (CPAP) machines. If used properly nasal CPAP can virtually eliminate apnoeas by splinting the airway continuously throughout sleep. The results can be astounding as patients experience a normal nights sleep without any arousals, often for the first time in years. The biggest problem with CPAP is patient adherence as the machines can be uncomfortable to tolerate during sleep and cause nasal dryness. Some patients do not apply the mask correctly.
If CPAP fails, a secondary, more invasive option is surgical intervention, which involves manipulation of the oropharynx. A simple measure to decrease OSA is to loose weight although this is difficult to achieve and maintain for patients. Other simple measure includes avoiding alcohol and other sedatives before bed and not sleeping in the supine position. SSRI’s can be used to reduce the amount of REM sleep for patients as most apnoeas do occur during REM(B. J. Sadock & V. A. Sadock 2007). Theophylline at one point was considered to be a useful agent for reducing apnoeas however it interferes with sleep architecture and has fallen out of use. Patients with OSA can be given modafinal as an adjunct to reduce EDS however this simply provides symptomatic relief without addressing the root problem.
Central sleep apnoea occurs as a result of failure of the respiratory centers in the brainstem to breathing. During the polysomnogram there is no movement of the diaphragm or respiratory muscles during apnoeas. This problem tends to occurs in the elderly(B. J. Sadock & V. A. Sadock 2007).
Disorders of the Sleep Wake Schedule (Circadian Rhythm Sleep Disorders)
For this category, ICD-10 uses the term sleep-wake schedule whereas DSM-IV TR uses the term circadian rhythm. These are a group of disorders where there is a mismatch between the endogenous circadian rhythm of an individual and the sleep-wake schedule imposed by society. The result is that a person is either excessively sleepy during the period he should be awake or has insomnia or increased arousal during the period he should be sleeping.
The disorders can be divided up into phase advance and a phase delayed categories. A person with a phase delayed sleep-wake cycle will find difficulty falling asleep at night until much later (sometimes into the early morning hours) and then have difficulty waking up at the prescribed time for school or work. If allowed to awaken naturally, the person would sleep a normal amount of time, with normal sleep architecture. Such patients with phase delay are naturally far more alert and productive in the evening and are know as “night owls”(B. J. Sadock et al. 2009). Phase delay seems to occur commonly in teenagers. They often outgrow this tendency by the time they reach adulthood. People with a phase delayed sleep-wake cycle can often be significantly impaired at school or work due to insufficient sleep.
An individual with a phase advanced sleep-wake schedule will naturally fall asleep earlier in the evening then others, however, will wake up earlier in the morning than expected. This tendency is common in the elderly. These individuals are often known as “larks”(B. J. Sadock et al. 2009). Phase advanced individuals experience far less occupational difficulties as they are generally well rested during the conventional working day.
Simply trying to enforce a conventional sleep wake schedule on people with circadian rhythm disorders is unsuccessful. Specific treatments are required. Before the advent of light therapy, chronotherapy was used to treat phase-delayed individuals. In this laborious process, a person would have to go to sleep later and sleep for the same amount of time each 24-hour cycle until they had reached a sleep period that coincided with what was required. This could often take a full week or more, which could obviously interfere with work and school.
Now, bright light therapy can be used in the morning. During this process a person is exposed to light from a 10000-lux full spectrum light in the morning. This has the effect of shifting circadian rhythm so that the person feels sleepy earlier in the evening. Now bright light therapy can be done with lights that produce light in a narrow spectrum, involving blue light of a certain wavelength, as it was found that this was the wavelength of light, which seems to act upon the neural circuitry controlling the sleep-wake cycle. People with phase advance can use bright light therapy in the early evening to shift their cycle so that they can go to sleep later and wake up later.
In the DSM IV TR certain specific subtypes of sleep-wake schedule disorders are mentioned. In Jet Lag type a person can induce a sleep-wake schedule disorder by rapidly crossing time zones during long haul flights. Usually crossing one to two time zones presents very minor difficulties. However more time zones than this, especially in an east to west flight, can produce marked difficulties in re-synchronising the circadian pacemaker. The process can take between 2 to 7 days(B. J. Sadock & V. A. Sadock 2007). This can result in businessman, and often sportsmen, been cognitively impaired due to sleep deprivation at crucial times in business meetings or major sporting events. Ingesting melatonin at the new, desired time of sleep onset could be used to treat jet lag. Another option is to use the melatonin agonist ramelteon.
Shift worker sleep disorder is a disruption to sleep-wake schedule due to unusual and often frequently changing work times. Usually a person who works a night shift may experience difficulty sleeping during the day. Often they may sleep a few hours but far less then the optimal seven a person requires. The result is that they experience sleepiness during their nightshift. The fact that the timing of shifts can often change frequently also results in a chaotic disruption to the sleep wake schedule without sufficient time for an individual to adjust. Sleepiness on the job results in increased mistakes. Doctors are often exposed to unpredictable and unusually long working hours where mistakes due to sleepiness can be potentially disastrous. The only approved pharmacological treatment for shift worker disorder currently is the wake promoting agent modafinal. Other measures can include manipulating light exposure. A night shift worker can expose himself to bright light during the night and then, during the day, try to prevent or minimise exposure to light outside.
Sleepwalking is one of the parasomnias. The DSM IV–TR criteria are almost identical to those of ICD-10 except that DSM-IV–TR specifies that the sleepwalking must cause significant distress or somehow interfere with social and occupational functioning.
Sleepwalking is a condition characterized by a person performing motor activities such as sitting up in bed and often walking around during sleep. The episode tends to occur during the 1st third of the night’s sleep and is phenomenon that takes place during stage 3 and 4 NREM sleep.
While a person is sleepwalking they have a blank look on their face and are relatively unresponsive to others trying to speak to them. They frequently return to bed or lie down somewhere else and go back to sleep. They can be woken up during an event with great difficulty however this it not advised as they can wake up extremely confused and agitated. It is better to slowly lead the person back to their bed. Significantly, a person will have no memory of the event at all. There have been isolated reports of people performing more complex motor activities during sleep like driving a car(B. J. Sadock & V. A. Sadock 2007). Primary sleepwalking patients do not have any abnormalities on EEG or imaging nor do they have any other obvious medical or psychiatric associations. It has been observed that the tendency to sleep walk runs in families suggesting a genetic component. There most likely is an underlying neurophysiological abnormality that has not yet been detected.
The epidemiology of the disorder is such that about 15% of children have at least one episode.(B. J. Sadock & V. A. Sadock 2007). It effects males more then females, starts between ages 4 and 8 and has a peak prevalence at the age of 12 years(B. J. Sadock & V. A. Sadock 2007). Sleepwalking seems to be made worse my sleep deprivation(B. J. Sadock & V. A. Sadock 2007).
The majority of children with sleepwalking outgrow it by adulthood. Therefore treatment is most often supportive including giving reassurance to patients and families. Affected individuals in whom treatment may be necessary would be more severe cases where individuals place themselves at risk of physical harm during sleepwalking.
Benzodiazepines can be tried off label to try treat the condition(B. J. Sadock & V. A. Sadock 2007) or the tricyclic antidepressant imipramine(Kaufman 2007). It has been noted that the Z-drug zolpidem can actually induce sleepwalking(B. J. Sadock & V. A. Sadock 2007). An important intervention may simply be making the surrounding environment safer or locking doors leading into certain rooms.
Sleep terrors [Night Terrors]
Sleep Terrors are another form of parasomnia that occurs exclusively during NREM sleep and during the 1st third of sleep during the night. During these events, a person (usually a child) sits ups suddenly in bed and begins screaming and thrashing about and appears in marked psychological distress. During the episode the person has increased heart rate and breathing rate with sympathetic activation.
The patient is usually not responsive to verbal commands or attempts to calm them down. The event usually last a few minutes and the patient lies down and returns to sleep. In the morning there is no recall for the event. This is in contrast to a nightmare, which occurs during REM sleep, but which is usually recalled vividly by the patient. If a patient is woken or roused to consciousness during a sleep terror they will usually be disorientated or appear to have sleep drunkenness for a few minutes.
Like sleepwalking, sleep terrors are a disorder of childhood and usually abate during adulthood. The patient will also frequently have a family history of sleep terrors. They occur more commonly in boys than in girls and approximately between 2 and 6 percent of children have the disorder(B. J. Sadock & V. A. Sadock 2007). Treatment involves counseling and reassuring the parent’s of children of sleep terrors. During a sleep terror, they can try to gently calm the patient, make sure they do not harm themselves in anyway physically and allowed them to settle and return to sleep. Pharmacological intervention can be tried in severe persisting cases. Benzodiazepines or tricyclic antidepressants have been tried off label. As with sleep walking, sleep terrors may reflect an underlying neurological abnormality. In people who develop the disorder in the teenage years or older, it may the harbinger for development of temporal lobe epilepsy(B. J. Sadock & V. A. Sadock 2007).
In contrast to Sleep Terrors, nightmares occur during the second half of the period of sleep and occur during REM sleep. As such, patients who have nightmares usually remember them in vivid detail. The dreams usually encompass frightening themes involving threats to one’s life or wellbeing. Again, in contrast to sleep terrors, a person can be awakened from a nightmare and be fully orientated with no period of confusion or sleep drunkenness. Nightmares typically affect people more during periods of increased stress in their life. However the DSM-IV-TR makes the point clear that the person should not qualify for a diagnosis of posttraumatic sleep disorder, as nightmares can be a common symptom in this disorder. On their own, nightmares are usually a self-limiting phenomenon and improve or abate with time. Again medications can be used off label for treatment including tricyclic antidepressants or SSRI’s, both of which are REM suppressing agents.
REM Sleep Behaviour Disorder
This is a disorder characterised by loss of the normal descending inhibitory control of the voluntary musculature during REM sleep. The flaccidity, immobility and arelfexia that are characteristic of REM sleep are lost. This descending inhibition is thought to arise from the area surrounding the locus coeruleus in the brain stem. Once this REM paralysis is lost, an individual can physically act out during their dreams. This can result in violent thrashing about that can often injure the sleeping partner.
On a polysomnogram it is clear that the disturbance is occurring during REM sleep. In addition the patient will often report a vivid dream upon been awakened during an episode. This disorder commonly occurs in men over the age of 65. It is now known to have a strong association to the development of Parkinson’s Disease (and Dementia with Lewy bodies) and can precede its onset by about 5 to 10 years. The treatment of choice for REM sleep behaviour disorder is the benzodiazepine clonazepam usually in a dose ranging between .05mg to 2mg at night. It is usually highly effective at controlling the disorder. Carbamazepine has also been used successfully. The disorder can also occur in patients who have had infarcts in and around the locus cerelous.
Sleep paralysis can occur as an isolated phenomenon even though it is classically associated with narcolepsy. In this distressing parasomnia an individual, either on falling asleep or just waking up, is aware their surroundings however cannot move or speak. It can be accompanied by hypnogogic or hypnopompic hallucinations classically of a creature that is coming to do an individual harm. This phenomenon has been called various things in various cultures like an “incubus”(B. J. Sadock et al. 2009).
Sleep paralysis is not always pathological and occurs in an estimated 7 to 8% of adults(B. J. Sadock et al. 2009). The event will usually resolve by itself when the sleeper attempts to moves the eyes or body or is touched by another person(B. J. Sadock et al. 2009).
Bruxism (Tooth Grinding) During Sleep
It has been estimated that 5 to 10% of the population have nocturnal tooth grinding sufficient to produce dental damage(B. J. Sadock & V. A. Sadock 2007). It can also produce damage to the temperomandibular joint(Kaufman 2007) This phenomenon usually occurs during stage 2 sleep. The bed partners of individuals with this problem will often be the one to report it, as is it can be a disturbing noise and the patient is unaware of it. Treatment consists of a dental bite plate worn at night or sometimes orthodontic surgical procedures(B. J. Sadock & V. A. Sadock 2007).
Sleeptalking is a relatively common phenomenon and occurs in both children and adults in all stages of sleep. The talking is often just a few words and is difficult to make out or make sense of. It can also occur as part of the other parasomnias. No specific treatment is needed(B. J. Sadock et al. 2009).
Head Banging During Sleep
This disorder has been known by many names including jactatio capitas nocturna. It consists of a to and fro movement of the body, usually during the transition between wakefulness and sleep(B. J. Sadock et al. 2009). It very rarely progresses in to slow wave sleep(B. J. Sadock & V. A. Sadock 2007). It is known as a sleep related rhythmic movement disorder in the International Classification of Sleep Disorders. The only treatment is to provide a safe environment so that the patient does not injury himself during the rocking movement.
Restless Leg Syndrome
Restless leg syndrome (RLS) syndrome consists of an irresistible urge to move the legs due to an unpleasant sensation in that area. This sensation is removed by moving the legs. It usually occurs in initial stages of sleep or at other times when a patient is attempting to rest(Kaufman 2007). It can also occur during wakefulness.
The movement of the legs appears involuntary however it is a voluntary movement but the patient finds the move to urge irresistible. Patients often get up walk around, scratch their legs or make bicycle movements with their legs(Kaufman 2007). This can interfere with sleep by prolonging sleep latency and interrupting sleep of the patient’s partner. It can therefore result in excessive daytime somnolence.
It is not to be confused with periodic limb movement disorder, however 80% of people with RLS also have periodic leg movement disorder. In periodic limb movement disorder the movements occur only during sleep, they occur at regular intervals and they are not associated with this irresistible, uncomfortable urge to move the legs(Kaufman 2007).
RLS has a well-known association with iron deficiency and pregnancy (in which an iron deficient state often develops). There is often a positive family history of RLS with 3 to 5 fold increase in risk in first degree relatives[DS13] Simply replacing iron stores with supplements may cure the RLS. It can also occur in folate or vitamin B12 deficiency.
RLS is also not to be confused with akathisia, which is an inner feeling of restlessness that patients can develop on neuroleptics. As such, it is classified as an extra pyramidal side affect of antipsychotics. Such patients often cannot sit still and often pace up and down. Akathisia can even occur with SSRI’s. The atypical antipsychotic aripiprazole has a high rate of inducing akathisia in patients, especially upon initiation. Akathisia can be extremely troubling and some patients even commit suicide. Finally a restless pacing patient may have movements driven by their psychosis, a severe agitated depression or agitated catatonia. Removing the offending drug in akathisia cures the problem and allows it to be differentiated from RLS.
It has been suggested that RLS results from a decreased affinity of dopamine for D2 receptors in the basal ganglia(Kaufman 2007). Therefore treatment of this disorder involves dopaminergic medications including those used to treat Parkinson’s disease. Ropinorole and pramipexole which are primarily D2 receptor agonists can be used and work very well. The FDA[DS14] approved treatment for RLS is gabapentin enecarbil, which is the prodrug of gabapentin.
Periodic Limb Movement Disorder
In this disorder there is involuntary contraction of the muscles of the lower legs, always involving at least the feet and it occur primarily in NREM sleep stages 1 and 2(Kaufman 2007). The movements are periodic in nature and occur every 20 to 40 seconds and last for between 0.5 and 5 seconds(B. J. Sadock et al. 2009). The consistent feature is dorsiflexion of the ankle. This can lead to arousal in patients but not always excessive daytime somnolence. However it can cause EDS in the sleep partner. This disorder typically occurs in males older than 55(Kaufman 2007). Treatment often consists of dopaminergic agonists like pramipexol and ropinorole as well.
Other Rarer Sleep Disorders
This is a rare condition that typically occurs in young males and consists of long periods hypersomnia and then upon awakening hyperphagia, irritability and confusion. These periods usually last about two weeks(Kaufman 2007). Patients can have up to 6 episodes or more. There is no physiological marker or specific change on PSG that can confirm this diagnosis. The syndrome seems to be self- limiting and often disappears in the forties or fifties(B. J. Sadock et al. 2009).
Fatal Familial Insomnia
This is a rare disease, which is an inherited prion disease similar to Creutzfeld-Jacob disease. In typically begins in the early fifties beginning with insomnia that just continues to get worse and is refractory to treatment. The patient then develops a whole host of other autonomic and endocrine abnormalities and inevitably dies within 6 to 36 months(Kaufman 2007).
Sleep Disorders Directly Associated with Another Psychiatric Illness
A variety of psychiatric disorders can cause alteration in sleep. Major depressive disorder is classically characterised by repeated night time awakenings, early morning awakening and far worse mood in the mood, which improves during the day known as diurnal variation. Also these patients have a reduced REM latency and a long first period REM period and reduced stage 3 and 4 sleep(B. J. Sadock & V. A. Sadock 2007). This may explain why sleep deprivation can cause an increase in mood. The characteristic feature of tricyclic and SSRI antidepressants are their suppression of REM sleep, which accompanies the clinical response of increase in mood.
In contrast, in true mania, an individual may have a decreased need for sleep (not insomnia) or feel completely refreshed after only 2 to 3 hours.
Anxiety disorders in general cause sleep onset insomnia and treatment of the underlying anxiety disorder resolves the sleep disorder. Panic disorder can manifest during stage 3 and 4 sleep and cause a patient to awaken in terror(B. J. Sadock & V. A. Sadock 2007). This can lead to misdiagnosis of sleep terrors or sleep apnoea.
In schizophrenia stage 3 and 4 sleep as well as total sleep time are reduced(B. J. Sadock & V. A. Sadock 2007).
Other relevant conditions in differential diagnosis of sleep problems include post traumatic stress disorder where nightmares are a frequent component of the re-experiencing of the traumatic event(B. J. Sadock & V. A. Sadock 2007).
Dementia deserves mention because sufferers often suffer sleep reversal with frequent naps (a polyphasic sleep pattern) during the day and insomnia and behavioural disturbance at night(Kaufman 2007). The simple intervention of preventing such patients from napping during the day can often help dramatically with nocturnal behavioural disturbance. As evening approaches, and light intensity falls dementia patients can tend towards confusion, disorientation and behavioural disturbance in a phenomenon known as sundowning.
Sleep Disorders Resulting From General Medical Conditions
Almost any general medical condition can lead do a disruption in sleep including dysomnias and parasomnias. Neoplastic, endocrine, degenerative and cardiovascular conditions can all result in sleep disturbances even when pain is not present. When pain is not managed adequately in end of life conditions like malignancies disruptions in sleep can be profound.
Certain medical conditions are directly linked in some way to sleep. Epilepsy in particular is linked to sleep in that up to 45% of patients with primary generalised epilepsy have seizures most often during sleep(Kaufman 2007). The seizures seem to occur in stage 1 and 2 NREM sleep and towards the period of awakening, and spare the period of REM sleep(Kaufman 2007). Focal seizures seem to be less restricted to the NREM period. A focal seizure involving the frontal lobe may resemble a parasomnia such as sleepwalking or sleeptalking and must be distinguished on EEG(Kaufman 2007). Another important fact is that sleep deprivation is a tool used to provoke seizures as it as has been known for many years that this technique can elicit abnormalities on EEG that might not have been present on previous testing(Kaufman 2007).
Sleep can also precipitate cluster headaches, which are severe unilateral headaches, as well as chronic paroxysmal hemicrainia, which is similar in that it has a vascular basis. Both disorders seem to occur in REM sleep with paroxysmal hemicrania occurring almost exclusively in REM sleep.
With regards to cardiovascular disorders, angina pectoris and myocardial infarction are more likely to occur during REM sleep as there is fluctuation in blood pressure, pulse and cardiac output(Kaufman 2007). Thrombotic stroke seems to occur more during NREM sleep when blood pressure and pulse fall(Kaufman 2007).
Gastroesphageal reflux disease can be worsened during sleep and this is most likely related to been in the recumbent position. There is a possibility of asthma attacks occurring or been exacerbated by sleep.
Sleep Disorders Related to the Use of A Substance
The different substances, illicit, legal, over the counter and prescribed, that can cause sleep disorders are legion. Important examples include the stimulants (ranging from coffee to cocaine) and the sedative-hypnotic drugs (ranging from alcohol to benzodiazepines). Prescription medications used to treat sleep disorders including stimulants and hypnotics can be abused by certain patient populations and result in a sleep disorder. However, there are also many medications that are often prescribed by physicians for other medical indications, for example beta-blockers or certain antibiotics that can also affect sleep. The affect of a substance can be to cause insomnia, hypersomnia or a parasomnia of some sort. Also many substances have a direct effect on sleep architecture. The DSM IV TR allows specification for whether a sleep disturbance is caused within intoxication or withdrawal.
The effect of alcohol on sleep is complex having effects during both intoxication and withdrawal. With acute use, initially alcohol will decrease sleep latency and once asleep REM sleep will be reduced. There will be a consequent increase in slow wave sleep. Later on in the sleep period the person will have increased periods of REM and frequent awakenings almost in a delirious state(Kaufman 2007). Overall they will have decreased total sleep time as well decreased slow wave sleep in total. In alcoholics withdrawing, insomnia is experienced at night but excessive daytime somnolence during the day(Kaufman 2007). At night they will experience REM rebound.
Many stimulants when abused can cause marked disturbances in sleep. Such drugs include amphetamines, cocaine, methylphenidate and caffeine. During a binge phase of a powerful stimulant like cocaine an individual may go many consecutive days without the need to sleep. During the following “crash” an individual will develop hypersomnolence, excessive daytime somnolence and, often, a very low mood. This pattern is classically seen with cocaine and amphetamines.
Some patients who complain of insomnia, are often ingesting large amounts of caffeine during the day without been aware of the effect it is having on their sleep. Simply reducing or eliminating caffeine intake, or preventing its ingestion after 3 pm in the afternoon can have a drastic effect in improving the insomnia. Other common offenders include ephedrine and pseudoephedrine which are included in cold preparations as nasal decongestents but are often abused for the their appetite suppressing effects. They can cause marked insomnia. Also “fat burners” are over the counter preparations that commonly contain caffeine and pseudoephedrine and patients may develop severe insomnia on these supplements.
Often patients using benzodiazepines as hypnotic agents over a longer period may develop tolerance and begin to increase the dose to achieve the same effect. Eventually such individuals can become dependent on huge doses of benzodiazepines and it becomes an especially challenging problem to wean such patients off the drug. Long term users of benzodiazepines or z-drugs who stop abruptly can then experience severe rebound insomnia. There have also been reports of somnambulism and other parasomnias with the use if z-drugs like zolpidem.
Gamma Hydroxybutyrate is licenced by the FDA for the treatment of narcolepsy. However it is also frequently used illicitly. Originally it was abused by the bodybuilding community as it produced a large spike in growth hormone nocturnally. Additionally, it also dramatically increased slow wave sleep and therefore powerfully increased sense of restorative sleep. However it gained a reputation as a “date rape” drug and this has probably limited investigations into its uses in legitimate sleep disorders.
Patients with thyroid disorders and sometimes other medical disorders will be on synthetic thyroid preparations of T3 and T4. Hyperthyroidism tmay be accompanied by insomnia. Conversely poor adherence and lapsing into hypothyroidism can result in excessive daytime somnolence. T3 is often used in psychiatry as an augmenting agent in major depression as well as in bipolar disorder in patients who are on lithium. Therefore careful monitoring of thyroid function is critical especially when patients complain of sleep disturbances. Also thryroid hormones can be abused as weight loss drugs among the bodybuilding and weight-loss community and can lead to hyperthyroidism and insomnia.
SSRI’s can often result in insomnia especially in the initiation phase. Fluoxetine in particular can be quite activating. It can be prudent in these situations to provide patients with a short course of benzodiazepines.
Bupropion is a noradrenergic and dopaminergic reuptake inhibitor that is used for depression and for smoking cessation. It can be a stimulating substance and insomnia is a potential side effect.
Other antidepressants can be particularly sedating including most notably trazodone, mirtazapine and the tricyclics like amitriptyline. Tricyclics provide sedation via their blockade of alpha-receptors, histamine 1 receptors and anti muscarinic effects. As mentioned above, this can used to therapeutic advantage in patients suffering with insomnia but can also prove a nuisance to depressed patients who then develop excessive daytime somnolence. Anticonvulsants like valproate frequently lead to daytime somnolence for patients with epilepsy or bipolar disorder, which can lead to non-compliance.
Corticosteroids have the well-known association of inducing mania and sometime psychosis in patients and therefore are a frequent cause of sleep disturbance. Vasopressin and adrenocorticohormone type drugs also seem to be psychoactive and can also lead to sleep disturbances.
Among the antibiotics, the flouroquniolones like ciprofloxacin have a well-known side effect of causing insomnia and sometimes bad or vivid dreams. Beta blockers are another class of commonly prescribed drug that can cross the blood brain barrier and lead to insomnia or bad dreams. The anti-retroviral agent efavirinz is associated with neuropsychiatric side effects including insomnia and bad or vivid dreams.
Dopamine agonists used to treat Parkinson’s disease, including drugs like pramipexole and ropinirole can lead to insomnia and parasomnias that have to be separated out from the well-known sleep disorders that already occur in Parkinson’s disease itself. Statin drugs can also lead to insomnia as well oral contraceptives and the anti hypertensive agent used in pregnancy alpha-methyldopa(B. J. Sadock & V. A. Sadock 2007).
Opioid intoxication can lead to marked sedation whereas withdrawal produces marked insomnia along with all the other characteristic signs of opioid withdrawal. This can be seen amongst heroin abusers but also among hospital patients on long-term morphine that is abruptly withdrawn for some reason.
Nicotine is one the most widely abused substances in the world. Technically nicotine is classified as a stimulant. Through a complex interaction with cholinergic receptors it results in a release of dopamine in the reward system of the brain, which is pleasurable and stimulating. However, people who have been dependent on it for a long time usually find smoking a cigarette relieves their nicotine withdrawal and thereby facilitates subsequent relaxation and sleep.
Sadock, B.J. & Sadock, V.A., 2007. Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry Tenth, North American Edition, Lippincott Williams & Wilkins.
Sadock, B.J. et al., 2009. Kaplan and Sadock's comprehensive textbook of psychiatry, Lippincott Williams & Wilkins.
Kaufman, D.M., 2007. Clinical Neurology for Psychiatrists, W B Saunders Company.
Stahl, S.M. & Stahl, S.M., 2008. Stahl's Essential Psychopharmacology, Cambridge Univ Pr.
Hales, R.E., 2008. The American Psychiatric Publishing Textbook of Psychiatry, American Psychiatric Pub.
AASM, 2005. The International Classification of Sleep Disorders -Second Edition, Amer Academy of Sleep Medicine.
APA, 2000. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR Fourth Edition (Text Revision) 4th ed, Amer Psychiatric Pub.
Christer Hublin, M.P.M.K.J.K., 2007. Sleep and Mortality: A Population-Based 22-Year Follow-Up Study. Sleep, 30(10), p.1245.
David, A. et al., 2012. Lishman's Organic Psychiatry: A Textbook of Neuropsychiatry 4th ed, Wiley-Blackwell.
Drake, C.L. et al., 2004. Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep, 27(8), pp.1453–1462.
Hales, R.E., 2008. The American Psychiatric Publishing Textbook of Psychiatry, American Psychiatric Pub.
Heier, M.S. et al., 2009. Prevalence of narcolepsy with cataplexy in Norway. Acta neurologica Scandinavica, 120(4), pp.276–280.
Higgins, E.S. & George, M.S., 2007. The neuroscience of clinical psychiatry, Lippincott Williams & Wilkins.
Hossain, J.L.J. & Shapiro, C.M.C., 2002. The prevalence, cost implications, and management of sleep disorders: an overview. Sleep and Breathing, 6(2), pp.85–102.
Huber, R.R. et al., 2004. Sleep homeostasis in Drosophila melanogaster. Sleep, 27(4), pp.628–639.
Hublin, C.C. et al., 1994. The prevalence of narcolepsy: an epidemiological study of the Finnish Twin Cohort. Annals of Neurology, 35(6), pp.709–716.
Johns, M.W.M., 2000. Sensitivity and specificity of the multiple sleep latency test (MSLT), the maintenance of wakefulness test and the epworth sleepiness scale: failure of the MSLT as a gold standard. Journal of Sleep Research, 9(1), pp.5–11.
Kaufman, D.M., 2007. Clinical Neurology for Psychiatrists, W B Saunders Company.
McEvoy, R.D., 2003. Obstructive Sleep Apnea and Heart Failure: Two Unhappy Bedfellows. American Journal of Respiratory and Critical Care Medicine, 169(3), pp.329–331.
Morin, C.M. et al., 2006. Epidemiology of insomnia: prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors. Sleep Medicine, 7(2), pp.123–130.
Nofzinger, E.A. et al., 1997. Forebrain activation in REM sleep: an FDG PET study1. Brain Research.
Ohayon, M.M. et al., 2004. Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan. Sleep, 27(7), pp.1255–1273.
Ohayon, M.M., Guilleminault, C. & Chokroverty, S., 2010. Sleep epidemiology 30 years later: Where are we? Sleep Medicine, 11(10), pp.961–962.
Pace-Schott, E.F. & Hobson, J.A., 2002. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nature reviews. Neuroscience, 3(8), pp.591–605.
Phillips, B.G. & Somers, V.K., 2003. Hypertension and obstructive sleep apnea. Current hypertension reports, 5(5), pp.380–385.
Rechtschaffen, A. et al., 1983. Physiological correlates of prolonged sleep deprivation in rats. Science (New York, N.Y.), 221(4606), pp.182–184.
Sadock, B.J. & Sadock, V.A., 2007. Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry Tenth, North American Edition, Lippincott Williams & Wilkins.
Sadock, B.J. et al., 2009. Kaplan and Sadock's comprehensive textbook of psychiatry, Lippincott Williams & Wilkins.
Siegel, J.M., In Session with J.M. Siegel, PhD (28:44 Minutes)?. Available at: http://psychcast.mblcommunications.com.
Spiegel, K., Leproult, R. & Van Cauter, E., 1999. Impact of sleep debt on metabolic and endocrine function. The Lancet, 354(9188), pp.1435–1439.
Stahl, S.M. & Stahl, S.M., 2008. Stahl's Essential Psychopharmacology, Cambridge Univ Pr.
Van Dongen HP et al., 2003. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep, 26(2), pp.117–126.
WHO, 2010. ICD-10 Version:2010. apps.who.int. Available at: http://apps.who.int/classifications/icd10/browse/2010/en [Accessed May 15, 2012].
WHO, 2005. ICD-10, WHO, 1992. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines [ICD-10 CLASSIFICATION OF MENTA], World Health Organization.
Young, T.T. et al., 1993. The occurrence of sleep-disordered breathing among middle-aged adults. New England Journal of Medicine, 328(17), pp.1230–1235.
This entire Document is under © Anthony Koller 2012