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Sleep and sleep disorders
Andy Montgomery
Talk Outline
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Normal Sleep
Diagnosing sleep disorders
Insomnia
Hypersomnia
Parasomnias
Circadian sleep rhythm disorders
Psychiatric disorders and sleep
Pharmacology and sleep
Normal sleep
• 1/3 of adult lives asleep
• Role poorly understood
• Sleep deprivation consequences
– Cognitive impairment
– Hormonal rhythm disturbance
– Rebound after deprivation
Normal sleep
• Quantity
– 7-8 hours
– <6 increased reports dissatisfaction
• Control by 2 processes
– Circadian process
– Homeostatic process
The Circadian process
• 24 hour cycle
– Many cells and organs
• Principle time-keeper:
– Supra-chiasmatic nucleus
• Influenced by light and temperature
• Some sleep disorders associated with genetic
variant
• Determines owl/lark
The homeostatic process
• Aka recovery drive to sleep
• Increases in proportion to time awake
• 2 processes interact
– Generates
• Post-lunch dip
• mid-evening activity
• Other influences
– Arousal, relaxation, anxiety
Physiology of sleep control
• Orexin (hypocretin)
– Peptide hormone
– Promotes wakefulness
• Wakefulness
– Ascending arousal system dominant
• Sleep
– Inhibition of arousal systems
Sleep structure
• Polysomnography
– Simultaneous record
• EEG
• Muscle activity
• Eye movements
• 4-5 cycles
– Quiet sleep alternating with REM
• Increased duration through night
Hypnogram
Sleep structure:
quiet sleep
• 4 stages
• 1: dozing “just resting eyes”
• 2: deeper, occasional jerks, reduced HR &RR
• 3&4: slow HR & RR
• EEG
• Progressive slow synchronous activity
– Reduced cortical arousal
– Increased thalamo-cortical synchrony
Sleep structure:
REM
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Rapid onset
EEG “awake”
Jerky eye movements
Muscle paralysis
Autonomic arousal
• Usually several short wakenings
Stage
EEG
Eye movt
Many varied,
usually fast
EMG
Wake
Low-amp, mixed
some alpha
High
1
Low amp, mainly Slow rolling
irregular theta
lateral movt
Slightly lowered
2
Sleep spindles,
None
K complexes low
amp theta
Lowered
3
High amp delta,
K complexes
None
Low
4
As 3
None
Low
REM
Low amp
irregular, sawtoothed
Rapid jerky,
lateral
absent
Age variants
• 24 hour rhythm
– Develops at 3/12
• High levels REM in childhood
• Aging
– Time awake increases
– Slow wave reduces
– GH release reduces
Dreaming
• Only remembered if REM followed by
wakefulness
• Occurs in
– REM
• Bizarre, storyline
– Slow wave
Sleep and cognition
• Sleep enhances memory consolidation
• Transfer from short-term to long-term
memory
– Dependent on hippocampal activity
– Sleep deprivation associated with reduced
hippocampal neurogenesis
Sleep disorders
• Diagnosis
– Take sleep history
– Questionnaires and diaries can be helpful
– Sleep centres: polysomnography, actigraphy, video
recording
• Classified in ICD 10 and DSM IV
– 3 categories
• Insomnia
• Hypersomnia
• Parasomnia
Questions to ask
• Time:
– Bed, getting up, ?regular pattern
– Falling asleep
• Waking episodes
• Quality (Pittsburgh Sleep Quality Index)
• How many bad nights/week?
Questions to ask
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Naps during day
Mood
Motor activity during sleep
Behaviour during sleep
Day-time somnolence (Epworth sleepiness
scale)
• Snoring
• Use of drugs
Investigations
• Actigraphy
– Monitors movement via wrist band
– Can be used over days- weeks
– Sleep- less movement
• Overnight video recording
Actigraphy
Polysomnography
• Terms
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Time in bed
Sleep onset (to stage 1 or 2)
Sleep onset latency
Sleep period: onset to wake
Total sleep time
Number of wakenings
Sleep efficiency (total sleep/time in bed)
Wake after sleep onset
REM onset latency
Time in each sleep stage
Insomnia
• Major public health problem
• 10-15% adults persistent insomnia
– Low quality of life
– Increased absenteeism
– Physical illness
– Mental illness
Insomnia
• Symptoms
– Too little
– Too long to go to sleep
– Poor quality
– Unrefreshing
– Impaired daytime function
• Daytime sleepiness uncommon (circadian
rhythm disorder)
Insomnia
• Two main types:
– Sleep onset insomnia
– Sleep maintenance insomnia
Insomnia - precipitating factors
Psychological stress
•Bereavement
•Increased arousal
•Worry about alarm
•Noise
•children
Psychiatric disorder
•Depression
•anxiety
Pharmacological
-blocker
•AD
•Caffeine
•Alcohol
•Stimulants
•Withdrawal
Short term
insomnia
Sleep wake cycle
•jet lag
•Shift work
•Irregular routine
Physical
•Pain
•Pregnancy
•Illness (cardio/resp)
•Urinary
Insomnia- perpetuation
Short term insomnia
Poor sleep habits
Good sleep habits
Anxiety about sleep
Good sleep
Long term insomnia
Insomnia- treatment
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Establish primary diagnosis
Acknowledge distress
Treat precipitating factors/primary cause
Educate about trigger factors and reassure
Establish good sleep habits
Insomnia- treatment
Hypnotics
• Act at GABA-A benzodiazepine receptor
– Generally safe and effective in short
term
– SE
• Muscle relaxation
• Memory impairment
• Ataxia
– Potentiated by EtOH
– Avoid long term px
Insomnia- other drugs
• Sedative AD
– Mirtazapine
– Agomelatine
• Melatonin
• Anti-histamines
Psychological treatments
• Sleep hygiene
– Regular hours
– Daytime exercise
– Morning daylight exposure
– Reduced daytime napping
– Avoid stimulants
– Bed-time routine
Psychological treatments
• Behavioural techniques
– Stimulus control
• Avoid clock watching
• Don’t watch TV
• Don’t stay in bed if awake
– Sleep restriction
– Relaxation training
Psychological treatments
• Cognitive techniques
– CBT
• Avoid negative thoughts associated with not
sleeping
– Rehearsal and planning session
– Paradoxical intent
Sleep restriction
Hypersomnia
• Feeling sleepy during day
– Distinct from tired
• 37% adults a few days a month
• 16% a few days / week
• Main causes
– Fragmentation of sleep
• Obstructive sleep apnoea
– Intrusion of sleep phenomena into wake
• narcolepsy
– Disturbed circadian rhythm.
Obstructive sleep apnoea:
symptoms
• Excessive daytime sleepiness
• Loud snoring
• Interruptions of breathing
– Resumes with loud gasp, violent movement
• Marital problems
• Dry mouth, sore throat, headache
• Depression
• Present in 0.5% men BMI >25
Obstructive sleep apnoea:
treatment
• Weight loss
• Continuous positive pressure ventilation
• Consider modafinil if remain sleepy during
day
Narcolepsy
• 3-4/10,000
• HLA DQB1*0602 (18-35% in controls)
• Symptoms
– Sudden onset sleep
– Sleepiness
– Cataplexy
– Hypnogogic/pompic hallucinations
– Poor nocturnal sleep
Narcolepsy
• Cause
– Lack of orexin neurones/release in
hypothalamus
– Possible cross-reaction autoimmune disorder
after infection in adolescence
• Diagnosis
– Clinical picture
– Reduced REM latency
Narcolepsy
• Treatment
– Education
– Day-time naps
– Drugs
• Daytime sleepiness
– Modafinil/dexamphetamine
• Cataplexy
– 5HT enhancing drug: SSRI, clomipramine
• Night-time sleep disruption
– Sodium oxybate
Other causes of daytime
sleepiness
• Idiopathic hypersomnia
• Kleine-Levine syndrome
– Rare, reversible disorder
– Hypersomnia +/- excessive eating &
hypersexuality
– Onset adolescence
– Typical duration 4-8 years
– ? autoimmune
Parasomnias
• Unusual behaviours occurring during sleep
• Exacerbated by anxiety
• Variable drug treatments
Night terrors
• Recurrent episodes of abrupt waking
usually first 1/3 of night
• Intense fear and autonomic arousal
• Unresponsive to comforting
• No detailed recall
• Significant distress
Night terrors
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Occur in 30-40% children
Generally resolve with aging
Can recur at times of stress
Comorbidity with anxiety common
Often run in families
Night terrors
• Cause
– Genetic component
– Incomplete arousals from SW sleep
• Treatment
– Clonazepam
– Paroxetine (immediate effect)
Night terrors hypnogram
Parasomnias -SWS
• Sleep walking
– Automatic behaviour
– No recall
– 15-20% lifetime prevalence
• Confusional arousals
– Semi-purposeful movements
• Sleep bruxism
• Sleep talking
Parasomnias -REM
• Nightmares
– Wake oriented (vs night terrors)
– Association with depression and PTSD
– Psychological treatment
• Guided imagery- rehearse happy endings
• Sleep paralysis
– Waking with fear, foreboding, unable to move
– Common-25% experience
– Treatment- good sleep hygiene
Parasomnias -REM behaviour
disorder
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Violent, short duration
Several episodes/night
Can wake
Remembers dream
– Violent unpleasant content
• Strong association with subsequent IPD OR
LBD (45-85%)
• Made worse by AD
• Treat by making sleep environment safe
Circadian rhythm sleep
disorders
• Jet lag
– Worse for travel east (natural clock 24.5hr)
– Melatonin may help
• Delayed sleep phase syndrome
– Unable to sleep before 2-3AM
– Preferred wake time after 10 AM
– Causes insomnia and sleepiness on work days
• Advanced sleep phase disorder
– rare
Circadian rhythm sleep
disorders
• Non 24hr circadian sleep disorder
– Sleep pattern advances daily
– Most common in congenitally blind
• Irregular sleep wake rhythm
– Seen in dementia- ? Loss of melatonin
neurons in SCN
• Shift work sleep disorder
Sleep and depression
• Sleep disturbance common in depression
– Almost 100% some disturbance
• Depression common in insomnia*
– 14-21% c/o insomnia depressed
– 9% c/o hypersomnia depressed
– 1% no sleep problem depressed
– Depression most common diagnosis
associated with insomnia
*Epidemiologic study of sleep disturbances and psychiatric disorders.
An opportunity for prevention?
JAMA. 1989 Sep 15;262(11):1479-84.
Sleep complaints in mood
disorders
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Initial insomnia
Frequent/extended wakening
EMW
Vivid dreams, -ve emotional content
Lack of adequate rest
• Hypersomnia (BPAD depressed, SAD)
• Reduced sleep (mania)
(MDD)
Subjective effects of AD on sleep
• Few good studies
– Mismatch between subjective sleep and
objective measure
– AD may affect subjective sleep
Polysomnography findings: MDD
• Initiation and maintenance
– ↑sleep latency
– Frequent awakenings
– EMW
• Reduced SWS
– Absolute and relative
– Fewer delta waves
• REM
– Reduced REM latency
– ↑REM in first half night
– More eye movements
Polysomnography in at-risk
population
• Two 1st degree relatives with MDD
– Reduced SWS in first NREM sleep cycle
– Increased REM density first REM period
J Affect Dis 2001 62:33-
Functional imaging: depression
• REM
– Increased activation wake vs sleep
• Midbrain reticular formation
• L hemisphere cortical regions: (DLPFC, FEF)
• Limbic/paralimbic regions: (hipp, basal forebrain,
ACC, MPFC)
• NREM
– Increased whole brain metabolism
BPAD & dysthymia
• BPAD
– Similar findings to MDD (depressed & manic)
• Dysthymia
– Minimal changes
Treatment effects
• Pharmacological tx most effective in pt
with sleep architecture disturbance
Which depressed patients will respond to interpersonal psychotherapy?
The role of abnormal EEG sleep profiles.
Am J Psychiatry. 1997 Apr;154(4):502-9.
SSRI effects on REM
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Reduced REM
Increased REM latency
Effects within 2-3 days
effects mediated ↑ synaptic 5HT
?5HT1A
– 1A knockout mice no effect of citalopram on
REM latency
– 5HT1a agonists reduce REM
– Tryptophan depletion removes SSRI REM
effect
SSRI effects SWS
• Increased time Stage1
• Increased awakenings
• Increased time awake
• Effects diminish over ~5/7 (except fluoxetine)
• ?5HT2 mediated
– Agonists disturb sleep
– Antagonists promote sleep
TCA effects
• REM: similar to SSRI
• SWS:
– imipramine, clomipramine, desipramine:
increased sleep fragmentation
– Amitriptyline: improve sleep healthy
volunteers, not in MDD
• ? 5HT2 antagonism effect
MAOI
• REM
– Phenelzine complete REM suppression
• 5HT mechanism- reversed by tryp. depl.
• ?MAOB effect
– Moclobemide: minimal effect
• SWS
– Increased sleep fragmentation
Other AD
• Mianserin
– Suppressed REM
– Reduced SWS fragmentation (?H1 blockade)
• Mirtazepine, trazadone, nefazadone
– Increased REM onset latency
– Reduced fragmentation (5HT2 antagonism)
• Reboxetine
– Minimal effect on REM or SWS
• Venlafaxine
– SSRI like effects
Other AD
• Agomelatine
– 5HT2c antagonist
– MT1/ MT2 agonist
– Effective AD
(antidepressant efficacy of agomelatine: meta-analysis of published and
unpublished studies BMJ 2014;348:g1888)
– Increased SWS, reduced sleep latency
– No effects on REM latency, total REM or REM densityThe
International Journal of Neuropsychopharmacology (Impact Factor: 5.64). 11/2007;
10(5):691-6.
Effects of AD on HAM-D sleep
items
Drugs. 2005;65(7):927-47.
Change in perception of sleep
quality with nefazadone
Psychiatry Res. 2003 Sep 30;120(2):179-90.
AD adverse effects on sleep
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Restless legs
Eye-movements in SWS
Bruxism
Nightmares
Withdrawal nightmares
Sleep deprivation effects
• One study
– [123I]IBZM SPET
– Increased DA release after sleep deprivation
Sleep and schizophrenia
• Rarely predominant complaint
• Disturbance may precede relapse
• Insomnia occasionally very severe
• Studies contradictory
– Variety of definitions of schizophrenia
– Older patients included
– Medicated patients
Unmedicated patients
• Stage 2 latency increased
• Increased nocturnal wakenings
• Reduced sleep efficiency
• ? REM latency reduced
Medicated patients- typical
antipsychotics
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Stage 2 latency increased
Reduced stage 2 & 4
Total sleep time reduced
Reduced sleep efficiency
• Reduced REM latency
• Reduced total REM sleep
Medicated patients- atypical
antipsychotics I
• Olanzapine
– Increased total sleep
– Increased sleep efficiency
– Reduced stage 2 latency
– Reduced total REM
• Risperidone
– Minimal data
– Increased SWS
Medicated patients- atypical
antipsychotics II
• Clozapine
– Increased total sleep
– Increased sleep efficiency
– No effect on REM
– ? Rebound insomnia after abrupt stop