Psych Grand Rounds- Primary Sleep Disorders

7/28/2019 Psych Grand Rounds- Primary Sleep Disorders

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PRIMARY SLEEP DISORDERS

Grand RoundsPsychiatry DepartmentSan Fernando General Hospital

Dr. Shivan A.C. Mahabir

March 01, 2013


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Introduction

Sleep is defined behaviorally by four criteria: (1) reduced motoractivity, (2) decreased response to stimulation, (3) stereotypicpostures (in humans, for example, lying down with eyes closed),and (4) relatively easy reversibility (distinguishing it from coma,hibernation, and estivation).

- Universal Behaviour

- Exact functions unknown

- Prolonged sleep deprivation leads to severe physical and cognitive

impairment and finally death

- Sleep disturbances occur in virtually all psychiatric illnesses andare frequently part of the diagnostic criteria for specific disorders.


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Theories of Sleep

- originally thought fatigue causes decrease of sensory stimulationleading to decrease in brain activity which led to sleep.

- transection of ascending sensory pathways in brain stem (therebydecreasing stimulation) did not affect wakefulness or sleep.

- lesions of reticular formation in the brainstem showed that: therostral portion of the reticular formation above the ponscontributes to wakefulness. The caudal part of the reticularportion below the pons normally inhibits the rostral area to causesleep. (Moruzzi, 1950s)

-sleep is actively induced and highly organised brain state withdifferent phases


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Regulation of Sleep

- endogenous circadian rhythm

- entrained by light via the retinohypothalamic tract to thesuprachiasmatic nucleus of the hypothalamus

-Total sleep time remains fairly stable from day to day even underwidely varying conditions, and is only modestly affected byvariations in activity and sensory stimulation.

-The only behavioral factor that reliably and substantially increasessleep is prior sleep loss


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Phases of Sleep

- 2 distinct cyclical phases in a highly structured pattern (Kleitman,Aserinksky, Dement in 1950s)

- non rapid eye movement (NREM)

- rapid eye movement (REM)

- Humans usually fall asleep by entering non-REM sleep, a phaseaccompanied by characteristic changes in theelectroencephalogram (EEG). The sleeper next moves into REMsleep, which is characterized not only by rapid eye movementsbut also by a surprisingly complete inhibition of skeletal muscle

tone. It is during this phase of sleep that most dreams are thoughtto occur.


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NON-REM Sleep

-Neuronal activity is low, and metabolic rate and brain temperatureare at their lowest. Sympathetic outflow decreases and heart rateand blood pressure decline. Parasympathetic activity increasesand then dominates during the non-REM phase. Muscle tone and

reflexes are intact.

Non-REM sleep is divided into four characteristic stages.

Stage 1 represents the transition from wakefulness to the onset ofsleep and lasts several minutes. The EEG shows a low-voltage,mixed-frequency pattern. In stage 1 and throughout the non-REM

phase there is some activity of skeletal muscle but no rapid eyemovements. Rather, the sleeper shows slow, rolling eyemovements..


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NON-REM Sleep

Stage 2 is characterized by bursts of sinusoidal waves called sleepspindles (12- 14 Hz) and high-voltage biphasic waves calledK complexes, which occur episodically against a background ofcontinuing low-voltage EEG activity.

The EEG in stage 3 shows high-amplitude, slow (0.5-2 Hz) deltawaves.

In stage 4 the slow-wave activity increases and dominates the EEGrecord.

Stages 3 and 4 in humans are sometimes called slow-wave sleep. Insome animals all of non-REM sleep is called slow-wave sleep.


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EEG patterns in human sleep

Figure 47-1 Electroencephalogram (EEG) patterns in the stages ofhuman sleep. Non-REM sleep has four stages. Stage 1 ischaracterized by a slight slowing of the EEG, stage 2 by high-

amplitude K complexes and spindles (low-amplitude clusters).Slow, high-amplitude delta waves characterize stages 3 and 4.

REM sleep is characterized by eye movements and loss of muscletone, in conjunction with a stage 1 EEG. The higher-voltageactivity in the EOG tracings during stages 3 and 4 reflects high-amplitude EEG activity in prefrontal areas rather than eyemovements. EOG = electro-oculogram; EMG = electromyogram.


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REM Sleep

In humans the EEG during REM sleep reverts to a low-voltage,mixed-frequency pattern similar to stage 1 of non-REM sleep

intense bursts of firing generate high-voltage spike potentials in theEEG called ponto-geniculo-occipital spikes (PGO spikes), after thebrain structures in which the spikes appear most prominently. PGOspikes of REM sleep may be generated by internal activation ofthe neural circuit for the startle response. PGO spikes arecorrelated with the bursts of eye movements in REM sleep.


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REM Sleep

Consistent with the overall increase in neural activity during REMsleep, brain temperature and metabolic rate rise.

In contrast to the waking state, however, almost all skeletal muscletone is lost (atonia); the skeletal muscles that remain active arethose controlling the movements of the eyes, middle ear ossicles,and diaphragm. In addition, some small, phasic twitches occur.

During REM sleep penile erections occur regularly in men, andwomen show clitoral engorgement.


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REM Sleep

In both sexes the pupils become highly constricted (miosis),reflecting the high ratio of parasympathetic to sympathetic outputto the pupil.

Homeostatic mechanisms are attenuated: respiration is relativelyunresponsive to changes in blood CO2, and responses to heat andcold are greatly reduced or even absent. As a result, bodytemperature drifts toward ambient temperatures.


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REM/NREM Cycling

The non-REM and REM phases alternate cyclically during sleep.Human adults usually begin sleep by progressing from stage 1through stage 4 of non-REM sleep.

This progression is intermittently interrupted by body movements

and partial arousals. After about 70-80 minutes the sleeperusually returns briefly to stage 3 or stage 2 and then enters thefirst REM phase of the night, which lasts about 5-10 minutes.

In humans the length of the cycle from the start of non-REM sleep tothe end of the first REM phase is about 90-110 minutes. This cycle

of non-REM and REM sleep is typically repeated four to six times anight. In successive cycles the duration of non-REM stages 3 and 4decreases while the length of REM phases increases.


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REM/NREM Cycling

The cycling of human sleep stagesat different times of life.Childhood is broadly defined toinclude early adolescence, and

old age spans the period fromthe mid 50s to the early 70s.(From Zepelin 1983, bypermission.)


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Classification of SleepDisorders

DSM - IV -TR divides sleep disorders into 1. Primary Sleep Disorders,2. Sleep disorders related to another mental disorder and 3. Othersleep disorders (due to a medical disorder or substance induced)

Primary sleep disorders are divided into

1. Dyssomnias:a. Primary Insomniab. Primary Hypersomniac. Narcolepsyd. Breathing-related sleep disorder

e. Circadian rhythm sleep disorder (sleep-wake schedule disorder)f. Dyssomnia not otherwise specified.


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Classification of SleepDisorders

2. Parasomnias:

a. nightmare disorder (dream anxiety disorder)

b. sleep terror disorder

c. sleepwalking disorderd. parasomnia not otherwise specified.


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Assessment

It is important to determine if another sleep disorder (seepreliminary questions above), or a physical (such as pain, heart orlung disease), neurological (such as Parkinsons disease orcerebrovascular disease) or psychiatric disorder (such asdepressive illness, anxiety disorder, or substance misuse) is the

primary diagnosis.

In depression, however, in many cases insomnia should be regardedas a co-morbid condition, rather than as a secondary one.

The majority of epidemiological evidence suggests that insomniatypically predates other psychiatric symptoms and may represent

an independent risk factor for the development of depression inparticular


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Investigations

Laboratory studies appropriate for those with sleep disorders includethe following:

Hemoglobin and hematocrit

Arterial blood gases

Thyroid function tests

Drug and alcohol toxicology screening

Oximetry may be performed during sleep to examine blood oxygenlevels for clinically important desaturations suggestive of sleepapnea or other forms of sleep-disordered breathing.

Although no imaging studies are directly indicated for the workup ofinsomnia, underlying medical conditions call for appropriateinvestigation using suitable studies.


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Indices and Scoring Systems

A Beck Depression Index or similar clinical screening tool may beused to detect an underlying depressive illness as a contributingfactor in insomnia.

An Epworth Sleepiness Score or another objective measure ofdaytime sleepiness may lead to clues to the presence of anotherunderlying sleep disorder. For example, approximately 20% ofpatients with sleep apnea present with a history of nighttimeinsomnia; however, patients are excessively sleepy by day andhave an abnormal score on the Epworth Sleepiness Scale.

Sleep Journal

Subjective measures of sleep are obtained by means of a sleepjournal. A sleep journal kept for approximately 2 weeks may helpdetermine the extent of the sleep disturbance. Patients shouldrecord the total hours slept per night, the frequency of nighttimeawakenings, and the level of restfulness provided after sleep.Additional, more objective measures of sleep may be available if apatient has a sleep partner who keeps a 2-week journal orprovides a relevant history.


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Electroencephalography andPolysomnography

Objective measures of sleep may be obtained by means ofelectroencephalography (EEG) or polysomnography (PSG). Thesestudies may be helpful in determining sleep and wakefulness inthe intensive care unit (ICU) or in the sleep laboratory.

Monitored PSG is the standard for evaluating measures of sleep. This

study includes measures of multiple channels of EEG,electrooculography (EOG), chin and leg electromyography (EMG),nasal and oral airflow, oximetry, abdominal and chestmovements, and electrocardiography (ECG). Monitored PSG canhelp the physician discriminate between rapid eye movement(REM) sleep and non-REM (NREM) sleep, as well as determining

causes of sleep disturbance.Patients with chronic medical conditions, such as fibromyalgia or

anxiety disorders, often have characteristic alpha brain-waveactivity that intrudes into the deeper stages of sleep. This activitycan readily be seen on the EEG during PSG. Patients with insomniaoften have some degree of sleep-state misperception, wherein

they perceive and believe that they achieve significantly lessslee than the actuall do. This can be documented b


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Questionnaire to screen forsleep disorders other than

insomnia


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Diagnosis Algorithm


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Circadian Rhythm Disorders

Circadian rhythm disorders are sleep disorders where there is amismatch between circadian rhythms and required sleepwakecycle.

Thus there can be sleeplessness when trying to sleep at a time notsignalled by the internal clock, and excessive sleepiness when

needing to be awake.

Some circadian disorders (jetlag and shift-work disorder) are due toan individual lifestyle, including work and travel schedules, thatconflicts with the internal clock.

Others are:

delayed sleep-phase syndrome (DSPS), where there is difficultyfalling asleep before 23 a.m. (sometimes later), and on dayswithout work/school/college the preferred wake time is after 10a.m., resulting in sleep-onset insomnia and difficulty waking up inthe morning on days when an early bedtime for an early starttime is necessary.

free-running sleep disorder, where there is a daily increment of


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DSM-IV-TR Diagnostic Criteria forCircadian Rhythm Sleep Disorder

A. A persistent or recurrent pattern of sleep disruption leading toexcessive sleepiness or insomnia that is due to a mismatchbetween the sleep-wake schedule required by a person'senvironment and his or her circadian sleep-wake pattern.

B. The sleep disturbance causes clinically significant distress or

impairment in social, occupational, or other important areas offunctioning.

C. The disturbance does not occur exclusively during the course ofanother sleep disorder or other mental disorder.

D. The disturbance is not due to the direct physiological effects of a

substance (e.g., a drug of abuse, a medication) or a generalmedical condition.

Specify type:Delayed sleep phase type: a persistent pattern of late sleep onset and late awakeningtimes, with an inability to fall asleep and awaken at a desired earlier timeJet lag type: sleepiness and alertness that occur at an inappropriate time of day relativeto local time, occurring after repeated travel across more than one time zone

Shift work type: insomnia during the major sleep period or excessive sleepiness duringthe major awake period associated with night shift work or frequently changing shift


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Treatment of CircadianRhythm Sleep Disorder

What is known

Melatonin is effective in jet lag disorder (1a), delayed sleep phasesyndrome (Ib) and free-running disorder (IIa)

Light therapy is effective in delayed sleep-phase syndrome (III)

What is not known

What are the best efficacy measures subjective versus objective?

Is there a need to distinguish between adults and adolescents indelayed sleep-phase disorder, since sleep times are somewhatdelayed in normal adolescence?

Is there a need to distinguish between sighted and blindindividuals?

Is melatonin or light therapy more effective for delayed sleep-phase disorder?


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Treatment of CircadianRhythm Sleep Disorder

Recommendations

. Clinical assessment is essential in DSPS and free-running disorder(A/B).

. Melatonin may be useful in DSPS, free-running disorder and jet lag(A).

. Other approaches such as behavioural regimes and scheduled lightexposure (in sighted individuals) can also be used (B/C).


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Parasomnias

Parasomnias are unusual episodes or behaviours occurring duringsleep which disturb the patient or others.

Assessment of parasomnia may be possible with a detailed historyfrom the patient or a witness but, in general, for an adequate

diagnosis referral to a specialist sleep centre for polysomnography(PSG) and video recordingmay be necessary.

Violent or unusual night-time attacks may arise from deep non-REMsleep (night terrors and sleepwalking) or from REM sleep (severerecurrent nightmares, REM behaviour disorder),

Treatments depend on which disorder is present.


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Night Terrors

Night terrors (also called sleep terrors) are recurrent episodes ofabrupt awakening from deep non-REM sleep, usually in first thirdof the night, usually with a scream and signs of intense fear andautonomic arousal. The patient is unresponsive to comforting;they may sit up in bed and sometimes engage in automatic

behaviour associated with fear and escape. There is usually nodetailed recall, and if the patient wakes from a terror (notcommon), there is confusion and disorientation and only a vaguememory of fear.

Night terrors are common in children, with about 3040% having atleast one episode, and repeated episodes in about 5%. The peakage for these is at about 27 years, with a gradual diminution upto early adolescence (DiMario and Emery, 1987).

In some cases night terrors persist into adult life; the prevalence inadults is unknown. Almost all adult patients have had night terrorsor sleepwalking as a child (Crisp, 1996).

There is a strong genetic component (Nguyen et al., 2008), and night


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DSM-IV-TR Diagnostic Criteriafor Sleep Terror Disorder

A. Recurrent episodes of abrupt awakening from sleep, usuallyoccurring during the first third of the major sleep episode andbeginning with a panicky scream.

B. Intense fear and signs of autonomic arousal, such as tachycardia,rapid breathing, and sweating, during each episode.

C. Relative unresponsiveness to efforts of others to comfort theperson during the episode.

D. No detailed dream is recalled and there is amnesia for theepisode.

E. The episodes cause clinically significant distress or impairment in

social, occupational, or other important areas of functioning.

F. The disturbance is not due to the direct physiological effects of asubstance (e.g., a drug of abuse, a medication) or a generalmedical condition.

(From American Psychiatric Association. Diagnostic and Statistical

Manual of Mental Disorders. 4th ed. Text rev. Washington, DC:


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Sonambulism (Sleepwalking)

Sleepwalking alone probably has 1520% lifetime prevalence.

The main symptom is of automatic behaviour at night with thesufferer unresponsive to surroundings and other people. Thebehaviour is most commonly walking around, but can include

other behaviours which are highly familiar to the subject such asdressing, washing, making tea, arranging objects in the house,etc.

Some cases of sleepwalking seem related to use of certain drugs, forexample alcohol and hypnotics, especially zolpidem and triazolam(Pressman, 2007).

It is rare for affected individuals to present for treatment, except ifthey have injured themselves or a partner, have put themselvesinto potential danger, or have excessive daytime fatigue becauseof nighttime disturbance.

Another reason for presentation is anxiety and disruption of sleep of

partner, family or housemates.

DSM IV TR Di ti C it i f


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DSM-IV-TR Diagnostic Criteria forSleepwalking Disorder

A. Repeated episodes of rising from bed during sleep and walkingabout, usually occurring during the first third of the major sleepepisode.

B. While sleepwalking, the person has a blank, staring face, isrelatively unresponsive to the efforts of others to communicate

with him or her, and can be awakened only with great difficulty.C. On awakening (either from the sleepwalking episode or the next

morning), the person has amnesia for the episode.

D. Within several minutes after awakening from the sleepwalkingepisode, there is no impairment of mental activity or behavior

(although there may initially be a short period of confusion ordisorientation).

E. The sleepwalking causes clinically significant distress orimpairment in social, occupational, or other important areas offunctioning.

F. The disturbance is not due to the direct physiological effects of asubstance (e.g., a drug of abuse, a medication) or a general

T t t f NREM Sl


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Treatment of NREM SleepDisordersThere is little high-level evidence for treatments in these disorders.

There are no controlled trials of treatment of non- REM parasomniasin adults (see Harris and Grunstein, 2009).

Priorities are to minimize possible trigger factors such as frighteningfilms, caffeine, alcohol or meals late a night, and to make surethere is a stable and adequate sleepwake schedule. It isimportant to safeguard against harm to the patient, such as bylocking windows, bolting doors, or sleeping on the ground floor,and safety of the bed partner or nearby children also requiresattention.

Drug treatment decisions should be based on the frequency and

severity of events.Clonazepam in doses up to 3mg per night has been reported to be

effective (case series, n69) (Schenck and Mahowald, 1996).

Smaller case serieshave reported good effects of paroxetine (Wilsonet al.,1997) and imipramine (Cooper, 1987) (both effective

immediately), and there is a small case series of hypnotherapy in

Ni ht /REM Sl


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Nightmares/REM SleepBehaviour Disorder

Nightmares and REM sleep behaviour disorder (RBD) are disordersarising from REM sleep, and the main difference in presentationfrom the non-REM episodes is that they are normally recalled bythe patient, who wakes from them and is aware of the episodeand can describe it.

RBD is a disorder, first described in the late 1980s, with violentcomplex behaviour at night, which is mostly recalled by thepatient. There are two sleep abnormalities;lack of atonia during REM sleep andincreased vividness and/or unpleasant content of dreams.

The violent behaviour is described as acting out of dreams, made

possible by the lack of the normal muscle paralysis in REM sleep.Its incidence is unknown (probably


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DSM-IV-TR Diagnostic Criteria forNightmare Disorder

A. Repeated awakenings from the major sleep period or naps withdetailed recall of extended and extremely frightening dreams,usually involving threats to survival, security, or self-esteem. Theawakenings generally occur during the second half of the sleepperiod.

B. On awakening from the frightening dreams, the person rapidlybecomes oriented and alert (in contrast to the confusion anddisorientation seen in sleep terror disorder and some forms ofepilepsy).

C. The dream experience, or the sleep disturbance resulting from theawakening, causes clinically significant distress or impairment in

social, occupational, or other important areas of functioning.D. The nightmares do not occur exclusively during the course of

another mental disorder (e.g., a delirium, posttraumatic stressdisorder) and are not due to the direct physiological effects of asubstance (e.g., a drug of abuse, a medication) or a generalmedical condition.

(From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th

Treatment of REM Sleep


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Treatment of REM SleepDisorders

For nightmares, psychological treatments are effective and thesefocus on exposure writing down dreams or guided imagery,pleasant images, and changing the ending (Burgess et al., 1998;Krakow et al., 1995).

There have been a few case series showing beneficial effects of thealpha-1 adrenergic blocker prazosin in reducing nightmaresrelated to post-traumatic stress disorder in both military andcivilian settings (Raskind et al., 2007).

Nightmares have been reported to be triggered or worsened bymany drug treatments, including cholinesterase inhibitors, beta-blockers, SSRIs (especially paroxetine levodopa, and following

withdrawal from antidepressants.

Treatment of REM Sleep


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Treatment of REM SleepDisorders

There are no prospective or controlled studies of drug treatment ofREM behaviour disorder, but case series suggest a good effect forclonazepam 14mg (Aurora et al., 2010; Boeve et al., 2004) inreducing the number of episodes and injuries during them,although it should be used with cautionin patients with dementia,disorders of gait or balance, or concomitant OSAS.

Smaller beneficial effects have been reported for melatonin 312 mg(Gagnon et al., 2006).

Single case studies and small series have reported beneficial effectsof clonidine (Nash et al., 2003), donepezil (Massironi et al., 2003)and sodium oxybate (Kosky et al., 2008).

Drugs which can worsen RBD or provoke its symptoms include SSRIs,venlafaxine, mirtazapine, bisoprolol, and tramadol (Gagnon et al.,2006).


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Primary Insomnia

Primary insomnia is diagnosed when the chief complaint isnonrestorative sleep or difficulty in initiating or maintaining sleep,and the complaint continues for at least a month

The term primary indicates that the insomnia is independent ofany known physical or mental condition.

Primary insomnia is often characterized both by difficulty fallingasleep and by repeated awakening.

Increased nighttime physiological or psychological arousal andnegative conditioning for sleep are frequently evident.

Patients with primary insomnia are generally preoccupied with

getting enough sleep. The more they try to sleep, the greater thesense of frustration and distress and the more elusive sleepbecomes.

DSM IV TR Diagnostic Criteria


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DSM-IV-TR Diagnostic Criteriafor Primary Insomnia

A. The predominant complaint is difficulty initiating or maintainingsleep, or nonrestorative sleep, for at least 1 month.

B. The sleep disturbance (or associated daytime fatigue) causesclinically significant distress or impairment in social, occupational,or other important areas of functioning.

C. The sleep disturbance does not occur exclusively during thecourse of narcolepsy, breathing-related sleep disorder, circadianrhythm sleep disorder, or a parasomnia.

D. The disturbance does not exclusively occur during the course ofanother mental disorder (e.g., major depressive disorder,

generalized anxiety disorder, a delirium).E. The disturbance is not due to the direct physiological effects of a

substance (e.g., a drug of abuse, a medication) or a generalmedical condition.

(From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th

ed. Text rev. Washington, DC: American Psychiatric Association; copyright 2000, with

Neurotransmitters GABA /


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Neurotransmitters GABA /ADENOSINE

The inhibitory effects of GABA are mediated through the GABAAreceptor, which is a complex of proteins with binding sites for anumber of sleep-promoting drugs, in particular benzodiazepines,so-called Z-drugs and barbiturates, all of which enhance theeffects of GABAs actions at the GABAA receptor

The other main sleep-promoting neurotransmitter is adenosine.Brain levels of this rise during the day and are thought to lead tosleepiness, which increases the longer the time since the lastsleep. The arousing and sleep-impairing effects of caffeine

(Landolt et al., 2004) are thought to be due to blockade ofadenosine-A2 receptors, so attenuating this natural process(Porkka-Heiskanen et al., 2002).

Neurotransmitters


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Neurotransmitters -MELATONIN

Melatonin is a natural hormone that is produced in the pineal glandand which has an important role in regulating circadian rhythms(Cajochen et al., 2003; Dijk and von Schantz, 2005).

The circadian pacemaker in the suprachiasmatic nucleus (SCN) ofthe hypothalamus drives melatonin synthesis and secretion fromthe pineal gland. Once melatonin appears in the plasma it enters

the brain and binds to melatonin receptors in the hypothalamus,forming a feedback loop.

The SCN contains melatonin 1 and melatonin 2 receptors, and muchresearch is ongoing about their role in sleep/wake regulation andcircadian rhythms. Melatonin has both phase-shifting effects

(changing the timing of the biological clock), and direct sleep-facilitating effects.

Neurotransmitters -


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Neurotransmitters -MELATONIN

Administering exogenous melatonin or analogues such as ramelteon(licensed in the USA) can promote sleep onset.

A slow-release formulation of melatonin has been licensed on thebasis of improved sleep continuity and daytime well-being inpeople aged over 55 years with insomnia.

Melatonin production is reported to decline with age and to be lowerin middle-aged and elderly patients with insomnia than in goodsleepers (Attenburrow et al., 1996; Dowling et al., 2008; Haimov,2001; Leger et al., 2004).


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Treatment Algorithm

l i


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Sleep Hygiene

Educating patients in good sleep hygiene is the keystone oftreatment. The following advice should be given to patients:

Use the bed for sleep and sex only (no television watching or readingin bed)

Avoid caffeine, especially late in the day; avoid activities that will getyou stimulated and upset late in the day; practice relaxationtechniques before bedtime

Exercise each day

Maintain a regular schedule for bedtime and wakening; avoid naps

Do not watch the clock while in bed; avoid struggling to fall asleep inbedinstead, get up and spend quiet time out of bed until sleepcomes

Ph h


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Pharmacotherapy

What is known about drug treatments for insomnia

Z-drugs and short-acting benzodiazepines are efficacious forinsomnia (Ia)

Safety (adverse events and carryover effects) are fewer and less

serious with decreasing half-lives (Ib)

Prolonged release melatonin improves sleep onset latency andquality in patients over 55 (Ib)

What is not known Does improvement in insomnia last after treatment is stopped?

Does treatment reduce risk of subsequent depression?

Ph th


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Pharmacotherapy

Recommendation

. It is important to treat insomnia because the condition causesdecreased quality of life, is associated with impaired functioning inmany areas, and leads to increased risk of depression, anxietyand possibly cardiovascular disorders (A).

. Goal of treatment to less suffering and improve daytime function

. Type of treatment:. Patient-guided. By particular pattern of problem, i.e. sleep onsetinsomnia,maintenance. By choice of treatments with an evidence base

. Factors which clinicians need to take into account when prescribingare efficacy, safety, and duration of action (A).

. Other factors are previous efficacy of the drug or adverse effects,history of substance abuse or dependence (D).

A tihi t i


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Antihistamines

Antihistamines are sedating and are sold as over-the-counter (OTC)sleeping medications. There is limited evidence that OTCantihistamines work, although recently some modest benefitshave been reported after 2 weeks dosing with diphenhydraminein mild insomnia (Morin et al., 2005b).

Antihistamines are commonly used in alleviation of insomnia in drugand alcohol withdrawal where traditional hypnotics are lesssuitable due to the risk of cross-dependence, although there areno controlled trials in this setting.

Recommendations

. Antihistamines have a limited role in psychiatric and primary carepractice for the management of insomnia (D).

H ti


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Hypnotics

What is known about long-term hypnotic treatment

Insomnia is often long-lasting and is often treated with hypnoticsfor long periods in clinical practice (Ib)

These studies suggest that dependence (tolerance/withdrawal) is

not inevitable with hypnotic therapy up to 1year with eszopiclone,zolpidem, ramelteon (Ib)

There is also evidence that dependence may be more likely withsome agents or with polysomnography outcome measures ascompared with self-report measures of outcome

Intermittent dosing may further reduce the risk of tolerance anddependence (Ib)

H pnotics


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Hypnotics

What is not known

How can we predict the needed treatment duration?

How and when should treatment be discontinued?

Should dosing for longer periods be nightly orintermittent? How do we detect the abuse-prone individual in the clinic?

Does hypnotic therapy affect the course of insomnia or

associated conditions?

Hypnotics


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Hypnotics

Recommendations

. Use as clinically indicated (A).

. To stop medication, try intermittent use at first if it makes sense,then try to stop at regular intervals, say every 36 months

depending on ongoing life circumstances and with patientsconsent (D).

. CBT during taper improves outcome (A).

Nonbenzodiazepine Hypnotics


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Class Summary: These agents are used for the treatment of acuteand short-term insomnia.

Zolpidem (Ambien)

Zolpidem binds at a benzodiazepine receptor subtype (omega I).This receptor is found more in the central nervous system (CNS)

than in the peripheral nervous system, which helps to account forthe drug's hypnotic effect without significant muscle-relaxantproperties. Unlike benzodiazepines, zolpidem does not suppressnormal sleep architecture.

Zolpidem is rapidly absorbed, with a fast onset of action (20-30 min),and thus is a good drug for sleep induction. It decreases sleeplatency and increases sleep duration.



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Zaleplon (Sonata)

Zaleplon is not structurally related to benzodiazepines, barbiturates,or other drugs with known hypnotic properties. It interacts withthe GABA-benzodiazepine receptor complex, causing sedation. Itshould be taken immediately before bedtime.

Zaleplon decreases the time to sleep onset. Its shorter onset ofaction means that peak serum concentrations are achieved within1 hour of administration. This may account for the lower incidenceof daytime grogginess and the reduced withdrawal reboundinsomnia.



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Eszopiclone (Lunesta)

Eszopiclone is a nonbenzodiazepine hypnotic pyrrolopyrazinederivative of the cyclopyrrolone class. Its precise mechanism ofaction is unknown, but it is believed to interact with GABAreceptors at binding domains close to or allosterically coupled tobenzodiazepine receptors.

Eszopiclone is indicated for treatment of insomnia by decreasingsleep latency and improving sleep maintenance. It has a shorthalf-life (6 h). Higher doses (ie, 2 mg for elderly adults and 3 mgfor nonelderly adults) are more effective for sleep maintenance,whereas lower doses (ie, 1 mg for elderly adults and 2 mg fornonelderly adults) are suitable for treating difficulty in falling

asleep.

Ramelteon (Rozerem)

Ramelteon is a melatonin receptor agonist with high selectivity forhuman melatonin MT1 and MT2 receptors. MT1 and MT2 arethou ht to romote slee and to be involved in maintenance of

Antidepressants


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Antidepressants

What is known

There is limited evidence for efficacy of doxepin, trimipramine,trazodone, paroxetine in insomnia (Ib)

Antidepressants may affect a wide range of brain receptors andhave longer-lasting carry-over effects than traditional hypnotic

drugs antidepressants are associated with increased risks ofroad accidents especially early in treatment in depression (Ib)

What is not known

Is the effect of antidepressants on insomnia lasting (particularly asthey are often prescribed for long periods)?

Are they more efficacious than traditional hypnotics?

Do they improve mood or reduce the risk of emergent depressionin patients?

Antidepressants


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Antidepressants

Recommendations

. Use drugs according to a knowledge of pharmacology (A).

. Consider antidepressants when there is coexistent mood disorderbut then use at therapeutic doses (A).

. Beware toxicity of tricyclic antidepressants in overdose even when

low unit doses prescribed (A).There are no controlled studies of hypnotic efficacy of low-dose

amitriptyline in insomnia, and tricyclics are more likely to be lethalthan licensed hypnotics in overdose (Nutt, 2005a).

The seemingly paradoxical action of paroxetine to improve sleep is

probably related to its good efficacy in many anxiety disorders,where it seems to reduce recurrent thinking and ruminations.

Taking SSRIs, venlafaxine, mianserin or mirtazapine increases therisk of restless legs syndrome (RLS) and periodic limb movementsin sleep (PMLS) (Hoque and Chesson, 2010), and SSRIs are knownto induce or exacerbate sleep bruxism (Wilson and Argyropoulos,

2005)

Antipsychotics


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Antipsychotics

AntipsychoticsWhat is known about use of antipsychotics for treatment of insomnia

Olanzapine and quetiapine improve sleep in healthy volunteers (Ib)

Quetiapine improves sleep in primary insomnia (IIb)

Side effects are common because of the pharmacological actionsof these drugs (I)

What is not known

How do they compare with traditional hypnotic drugs?

RecommendationSide effects are common because of the pharmacological actions of

these drugs and there are a few reports of abuse.

Together these indicate no indication for use as first-line treatment(D).

Cognitive Behavioural


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Therapy

Psychological treatment of insomnia should be consideredappropriate for two reasons. First, insomnia is apsychophysiological disorder, in which mental and behaviouralfactors play predisposing, precipitating and perpetuating roles.

Essential features of insomnia are heightened arousal and learnedsleep-preventing associations. Arousal can reflect a generalcognitive hypervigilance and many patients describe racingthoughts as a problem when they are trying to sleep.

A cycle develops in which the more one strives to sleep, the moreagitated one becomes, and the less able one is to fall asleep. CBTfor insomnia (CBTi) employs a package of interventions designed

to encourage poor sleepers to think and behave like goodsleepers

National Institutes of Health Consensus and State of the ScienceStatement (NIH, 2005) concluded that a CBT package containingcognitive and behavioural methods is as effective as prescriptionmedications are for short-term treatment of chronic insomnia.

Moreover, there are indications that the beneficial effects of CBT,

Cognitive Behaviouralh


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Therapy

What is known about CBT for insomnia - CBT

CBT is an effective treatment for insomnia delivered eitherindividually or in small group format (Ia)

CBT has been found to be as effective as prescription medications

for short-term treatment of chronic insomnia.Moreover, there areindications that the beneficial effects of CBT may last well beyondthe termination of active treatment (Ia)

What is not known

Are long-term effects of a short-term course of hypnotics better or

worse than after CBT?

Long-term effects of CBT versus optimized (e.g. intermittent) useof hypnotics in the long term

Special Population:M l W


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Menopausal Women

Recommendations

. Clinicians should appreciate that there is a rise in incidence ofsleep-disordered breathing after the menopause and that clinicalpresentation, often including insomnia, in women is different thanin men.

. The use of hormone therapy should involve informed individualizedtreatment of symptoms, looking at risks and benefits in light ofrecent studies.

. Follow recommendations for insomnia in other sections.

Special Populations: PregnantW


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Women

Recommendations

. Good sleep hygiene and lifestyle (D).

. Manage general pregnancy-associated complaints, e.g. decreasefluid intake, pillow support (D).

. The benefits of CBT in pregnancy have not been published butapproach would appear sensible (B).

. Recognize RLS by careful history and investigations if necessary.

. Dopamine agonists are contraindicated (FDA category C or greater)

Special Populations: PregnantW


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Women

Recommendations

. Iron and folic acid supplementation have been shown to beeffective in RLS. Supplementation is suggested even if levels arenot low (D)

. Keep caffeine low as it can exacerbate RLS (D)

. Mild to moderate exercise in the early evening, stretching, massage(D)

. If patient suffers from intractable insomnia and a pharmacologicalagent is required, zolpidem is preferable as it is short acting and

does not have anticholinergic side effects.Short-term use is recommended after discussion on potential risks

and benefits (D).

Special Populations: Elderly


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Special Populations: Elderly

Recommendations

. CBT is effective and should be offered as a first line where available(A).

. When a hypnotic is indicated in patients over 55, prolonged-release

melatonin should be tried first (B).. If a GABA hypnotic is used then a shorter half-life will minimize

unwanted hangover (A).

Special Populations: Children


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p p

Recommendations

. Behavioural strategies should be tried in children with disturbedsleep (A).

. Melatonin administration can be used to advance sleep onset to

normal values in children with ADHD who are not on stimulantmedication (A).

References


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Kaplan & Sadock's Synopsis of Psychiatry, 10th Edition

American Psychiatric Association. Diagnostic and Statistical Manualof Mental Disorders, 4th ed, Text Revision (DSM IV-TR).Washington, DC: American Psychiatric Association; 2000.

Normal sleep and sleep disorders. In: Kaplan and Sadock's Synopsis

of Psychiatry. 10th ed. Baltimore, Md: Williams & Wilkins;1997:749-772.

Sleep DisordersAuthor: Roy H Lubit, MD, PhD; Chief Editor: Iqbal Ahmed, MBBS,FRCPsych (UK)

http://emedicine.medscape.com/article/287104-overviewSleep and Dreaming, Disorders of Sleep and Wakefulness. In:

Principles of Neural Science. 4th Edition. Kandel ER

Wilson SJ, Nutt DJ et al. British Association for Psychopharmacologyconsensus statement on evidence-basedtreatment of insomnia,

parasomnias and circadian rhythm disorders; Journal of

Thank You...
http://emedicine.medscape.com/article/287104-overviewhttp://emedicine.medscape.com/article/287104-overview


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Documents

Psych Grand Rounds- Primary Sleep Disorders