Sleep and sleep disorders

Andy Montgomery

Talk Outline

• 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

• Rapid onset

• EEG “awake”

• Jerky eye movements

• Muscle paralysis

• Autonomic arousal

• Usually several short wakenings

Stage EEG Eye movt EMG

Wake Low-amp, mixed some alpha

Many varied, usually fast

High

1 Low amp, mainly irregular theta

Slow rolling lateral movt

Slightly lowered

2 Sleep spindles, K complexes low amp theta

None Lowered

3 High amp delta,K complexes

None Low

4 As 3 None Low

REM Low amp irregular, saw-toothed

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

• 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– 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

Sleep wake cycle•jet lag•Shift work•Irregular routine

Psychological stress•Bereavement•Increased arousal•Worry about alarm•Noise•children

Psychiatric disorder•Depression •anxiety

Pharmacological-blocker•AD•Caffeine•Alcohol•Stimulants•Withdrawal

Physical•Pain•Pregnancy•Illness (cardio/resp)•Urinary

Short term insomnia

Insomnia- perpetuation

Short term insomnia

Long term insomnia

Anxiety about sleep

Good sleep

Poor sleep habitsGood sleep habits

Insomnia- treatment

• Establish primary diagnosis

• Acknowledge distress

• Treat precipitating factors/primary cause

• Educate about trigger factors and reassure

• Establish good sleep habits

Insomnia- treatmentHypnotics

• 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

• 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

• 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

• 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

• 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

• 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

• 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