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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 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 • • • • • 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 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 • • • • • 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 • • • • • 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