Psychiatry SC071: I Can’t Fall Asleep: Sleep Physiology And Sleep Disorders

Question 1

Major sleep disorders

Answer 1

1. Insomnia disorder
   - Primary / Comorbid
   - Acute (<1 month) / Subacute (1-3 month) / Chronic (>3 months)
2. Hypersomnolence disorder
   - Narcolepsy
3. Parasomnia (abnormal behaviour during sleep)
   - Sleep-wake transition
   - NREM
   —> Sleepwalking
   —> Sleep-related eating disorder
   - REM
   —> REM sleep behavioural disorder
   —> Sleep paralysis
4. Breathing-related sleep disorder
   - OSAS
5. Movement-related sleep disorder
   - Restless leg syndrome (RLS) / Periodic limb movement disorder (PLMD)
6. Circadian rhythm sleep-wake disorder (CRSWD) (irregular sleeping pattern)

Question 2

Clinical approach to patients with sleep disorder

Answer 2

1. History taking
2. P/E + MSE
3. Blood test + Imaging
4. Sleep investigation
   - **Subjective scales (e.g. Insomnia Severity Index, Epworth Sleepiness scale)
   - **Sleep diary (esp. important in Circadian rhythm sleep-wake disorder)
   - ***Actigraphy (a watch) / other sleep-tracking devices: wearable device to assess movement / rest activity / sleep-wakefulness
   - Laboratory / Home-based sleep studies
   —> Full-night polysomnography (PSG) (measure EEG (brain), EOG (eyes), EMG (muscle))
   —> Daytime sleep studies (e.g. Multiple Sleep Latency Test MSLT —> assess daytime sleepiness)

Question 3

Sleep physiology

Answer 3

• Normal physiological drive
• All animals have rest-activity cycle
• Differ dramatically in Timing + Amount + Type across species
• Sleep-wake cycle will remain ***regular even in free running state (no alarm clock)
• But cycle will **shift (since circadian rhythm is actually **25 hours (i.e. shift 1 hour per day) —> easier to sleep later, more difficult to sleep earlier)

Other circadian rhythms (with 24-hour cycle):
- Core body temp
- Urine volume
- Cerebral blood flow
- Systolic BP
- Melatonin
- Cortisol
- Thyrotrophin
- Growth hormone

Question 4

Neuro-pathway regulating circadian rhythm

Answer 4

Light
—> Retino-chiasmatic tract
—> Suprachiasmatic nucleus (SCN) (in Hypothalamus) (Internal clock)
—> Synchronise with night-darkness cycle by ***Pineal gland
—> Pineal gland secrete melatonin
—> Signals to other organs

When SCN lesioned —> Sleep occur throughout 24 hours

Disorder with SCN lesion:
- Neurodegenerative disorders
—> Dementia
—> Parkinson’s
Result: Irregular sleep-wake cycle

Question 5

Definition of Sleep

Answer 5

• Reversible behavioural state of perceptual disengagement from + unresponsiveness to environment
• Sleep is associated with a typical pattern of physiological + behavioural processes

Sleep-wake regulation:
- 2 process model
1. Circadian rhythm (**Process C)
- Governed by **SCN + controlled by a set of clock genes
- 2 **peaks of sleepiness at 3am + 3pm
- **Melatonin: key neurotransmitter

2. Sleep-wake homeostasis (**Process S)
   - Product of complex network of brain regions + neurotransmitter pathways
   - Control sleep **onset + **maintenance
   - Accumulation of **sleepiness (longer the wakefulness —> greater the sleepiness)
   - ***Adenosine: key neurotransmitter

Sleepiness:
- Normal physiological drive
- Propensity to fall asleep
- Differ from feelings of tiredness, fatigue, lack of energy

Question 6

EEG, EOG, EMG

Answer 6

All necessary for sleep staging

Deep sleep:
- Reduced wakefulness

REM sleep:
- A lot of brain activity

Question 7

***Sleep cycle

Answer 7

• NREM + REM sleep
• NREM: Stage 1-4
• Cycles every 90 mins
• REM latency: 90 mins
• ***Shortened REM latency in depression + other sleep disorders (Sleep phase delay hypothesis)
• More NREM stage 3 + 4 (deep sleep) in first half of sleep
• More REM (dreaming sleep) in 2nd half of sleep, associated with longest period of apnea in OSA (SpC Psychi PP)

Stages:
- Stage 1 (2-5%)
- Stage 2 (45-55%)
- Stage 3 + 4 (13-28%) (i.e. Slow wave sleep (SpC Psychi PP))
- REM (20-25%)
- Wake (<5%)

Wake
—> NREM stage 1 to 4
—> REM
(1 NREM-REM cycle)
—> NREM stage 1 to 4

N2: Longest in healthy adults (SpC Psychi PP)
N3: Sleepwalking associated (SpC Psychi PP)

Children:
- More deep sleep (for body repair, regeneration)

Elderly:
- More broken sleep (more awake time)

NB:
- Sleep need (amount) is the same regardless of age!

Question 8

Sleep deprivation studies

Answer 8

3 major research areas:
1. Experimental studies with animals
2. Experimental studies with human
3. Epidemiological studies on effects of insufficient sleep in human

Animal:
- Animal become weak + uncoordinated + lost ability to regulate body temp —> begin eating much more —> but metabolic rates become so high that they continue to lose weight

Human:
- Partial sleep deprivation + Short sleep deprivation (<7 hours) —> associated with mental + physical health risks e.g. cardiometabolic diseases
- Long sleep duration (>9 hours) also has health risks
- NB: may have confounding factors

Question 9

Individual sleep need

Answer 9

• Determined by sleep + waking in a free-running manner for >=1 week (i.e. no alarm clock)
• Sleep as long as you need
• Wake up naturally
• If feel tired / sleepy in daytime —> haven’t sleep enough
• No compensation (i.e. 補眠) (∵ Sleep has to be continuous)
• Consensus: ***7 hours

Question 10

1. Insomnia disorder

Answer 10

DSM-5:
- A predominant complaint of dissatisfaction with sleep quantity / quality in addition to **DIS (difficulty initiating slepe), **DMS (difficulty maintaining sleep) + **EMA (early morning awakening)
- **3 nights / week
- **>=3 months (i.e. has to be chronic vs acute/subacute insomnia)
- **Distress + Impairment in functioning
- ***Exclusion criteria

Prevalence:
- DSM-5: HK: 10.8%
- DSM-IV: HK: 22.1% (∵ only require 1 month)

Insomnia Severity Index:
- 0-7: normal
- 8-14: mild
- 15-21: moderate
- 22-28: severe

Etiology / Classification:
1. Diagnosis
- Primary
- Comorbid

2. Duration
   - Acute (<1 month)
   - Subacute (1-3 month)
   - Chronic (>3 months)
3. Cause
   - Psychological insomnia
   - Sleep state misperception
   - Poor sleep hygiene (refer to ICSD-3)
4. 3”P” model:
   - Prediposing
   - Precipitating (contribute more to Acute insomnia)
   - Perpetuating (contribute more to Chronic insomnia) (can be physiological / cognitive / behavioural / emotional)
   —> Insomnia becomes chronic due to perpetuating factors
5. Physiological / Cognitive / Behavioural models

Question 11

Primary vs Comorbid insomnia

Answer 11

Primary insomnia:
No medical / psychiatric / specific sleep disorders are found

Comorbid insomnia:
Used “Comorbid” instead of “Secondary” (∵ don’t know which one more important)
1. Medical disorder
- Pain
- Night sweat
- Hot flushes
- Cancer
- COAD
- Parkinsonism
- etc.

2. Psychiatric disorder
   - MDD
   - Anxiety disorders
   - Schizophrenia
   - etc.
3. Sleep disorder
   - Circadian sleep-wake disorder
   - OSA
   - Periodicity limb movement disorder
   - etc.

Treat ***both symptoms at the same time rather than only treat one symptom (e.g. do not treat pain only)

Question 12

Management of Insomnia disorder

Answer 12

Goal:
1. Improve sleep quality + quantity
2. Improve insomnia related daytime impairments

2 key treatment:
1. Psychological + Behavioural treatment
- ***CBT
- Mindfulness-based therapies
- Hypnosis

2. Pharmacological
   - BDZ receptor agonist (Zopiclone, **Zolpidem)
   - Melatonin receptor agonist (*Ramelteon) (N/A in HK)
   - Low dose Doxepin

Other drugs:
- Off-label drugs
—> Sedative antidepressant (e.g. Remeron, **Trazodone, Paroxetine)
—> Sedative antipsychotics (e.g. **Quetiapine)
- Drugs with health risks —> BDZ (e.g. Lorazepam, Clonazepam)
- OTC drugs (e.g. Promethazine, Melatonin, Valerian)
- TCM (e.g. Chinese herbal formula, Acupuncture, Auricular therapy, Acupressure)
- Other complimentary / alternative medicine therapies (e.g. Exercise, TaiChi, Qigong, Yoga, Western herbs, Aromatherapy)

Question 13

***Zolpidem, Zopiclone

Answer 13

Mechanism:
- **Bind to BDZ receptor —> Cl influx —> **Hyperpolarisation —> relaxation effect
- ***Selective binding to BDZ1 (α1 / α5 subunit) —> absence of myorelaxant + anticonvulsant effect
- BDZ: non-selective bind to all BDZ receptor subtypes

SE (vary with individual):
1. Hangover (higher than recommended dose)
2. Daytime sleepiness (higher than recommended dose)
3. Falls
4. Motor Incoordination
5. Amnesia
6. Poor memory
7. Automatism
8. ***Sleepwalking (FDA warning on sleep related complex behaviour: sleepwalking, sleep driving)
(9. Tolerance, Abuse, Dependence)

FDA:
- Zolpidem 5mg (half of normal dose)
- Zopiclone 3.75mg (half of normal dose)
—> for women to avoid daytime sedation + impairment in activities that require alertness

Zolpidem:
- ***Shorter t1/2
- Extensive hepatic metabolism by CYP3A4 (60%), 2C9 (20%), 1A2 (15%) and others
- Inactive metabolites
- 48-67% of metabolites excreted in urine, the rest into the bile
- <1% of active drug excreted in urine
- Interaction with CYP3A4 inhibitors (e.g., erythromycin) + CYP3A4 inducers (e.g., phenytoin, St. John’s wort)
- Cmax = 1.6 hrs, elimination half-life = 2.5 hrs

Zopiclone:
- ***Longer t1/2
- Undergo hepatic metabolism by (CYP)3A4 (major) + 2C8
- One metabolite is active and accounts for 11% of metabolism + excreted in urine
- Interaction with CYP3A4 inhibitors (e.g., erythromycin) + CYP3A4 inducers (e.g., phenytoin, St. John’s wort)
- Cmax and T1/2 longer than Zolpidem

Question 14

CBT for Insomnia (CBT-I)

Answer 14

1. Sleep education
2. Stimulus control
3. Sleep restriction
4. Relaxation training
5. Cognitive therapy

• Self-help / Individual / Group / Face-to-face / Telephone-administered
• Nurse / Therapist-administered
• No. of sessions: 1-8

Stepped care model:
- Least restrictive + costly treatment first —> “Self-correcting” movement between steps
- Higher expertise for more severe disease

Question 15

2. Hypersomnolence disorder

Answer 15

Causes of sleepiness:
1. **Insufficient sleep
2. **OSAS
3. **Narcolepsy
4. Idiopathic Hypersomnolence
5. **Periodic limb movement disorder
6. ***Sleep-wake circadian disorder
7. Medical, Psychiatric, Substance-use disorders

Adverse effects of sleepiness:
- Motor vehicle accidents
- Work-related accidents
- Impaired neuropsychological function
- Impaired motor performance
- Reduced QoL

Epworth Sleepiness Scale:
- Subjective measure of sleepiness
- High correlation with Multiple Sleep Latency Test (MSLT)
- Chances of dozing in 8 activities (0-3 marks: chance of dozing)
- ESS total score >=10 indicates excessive sleepiness
1. Sitting + reading
2. Watching TV
3. Sitting inactive in a public place
4. As a passenger in a car for 1 hour without a break
5. Lying down in the afternoon when circumstances permit
6. Sitting + talking to someone
7. Sitting quietly after lunch without alcohol
8. In a car, while stopped for a few mins in traffic

Multiple Sleep Latency Test:
- Objective measured of sleepiness
- Ask patient to sleep for 20 mins at 2 hour interval (9am, 11am, 1pm, 3pm)
- Measure mean sleep + REM latencies
- Pathological sleepiness: mean sleep latency <5 mins
- REM latency: for diagnosis of Narcolepsy (嗜睡症) (>=1 sleep onset REM on 4 naps)

Question 16

Narcolepsy

Answer 16

• Rare disorder

4 characteristic symptoms:
1. ***Excessive sleepiness / Sleep attacks

2. ***Cataplexy (vs Catalepsy)
   - sudden loss of bilateral muscle tone (head drop, facial sagging, jaw drop, slurred speech, buckling of knees, few seconds - mins)
   - provoked by strong emotion
   - consciousness remain clear
   - varies in severity
3. ***Sleep paralysis
   - transient, generalised inability to move / speak during transition between REM sleep to wakefulness (1- several mins) (被鬼砸)
4. ***Hypnagogic hallucination
   - vivid perceptual experiences occurring at sleep onset, visual, tactile, kinetic, affect often fear / dread, being about to be attacked, caught in fire, flying through air

Type 1: Orexin / Hypocretin-1 deficiency + Cataplexy
Type 2: Normal Orexin / Hypocretin-1 level + No cataplexy

Investigations:
- Diagnosis: **Overnight PSG + **MSLT (Short sleep latency **<5 mins + Sleep onset REM **<20 mins)
- HLA DQB1*0602 allele
- CSF Hypocretin-1 level

Treatment:
1. **Stimulant drug (Modafinil, Armodafinil, Methylphenidate) to suppress daytime sleepiness
2. **Antidepressant for Cataplexy
3. ***Gamma hydroxybutyrate for both symptoms

Question 17

4. Breathing-related sleep disorder

Answer 17

Symptoms:
1. Loud + habitual snoring
2. Intermittent pattern of snoring (loud snoring followed by apnea (completely no sound) —> air forced to open up airway again —> loud snoring)
3. Choking, waking up with SOB
4. Insomnia (arousal due to need to open up airway)
5. Excessive sleep movement
6. Daytime sleepiness (cannot be reversed by sleeping longer)
7. Dry mouth
8. Nocturia (changes in abdominal pressure stimulating bladder)
9. Morning headache (tension type, first hour after waking up due to vasoconstriction in response to desaturation)
10. Poor concentration + memory
11. Irritable

Diagnosis:
- Overnight PSG —> ***Apnea-Hyponea index (AHI): 5-15 times / hour (mild), 15-30 (moderate), >30 (severe)

Treatment:
1. CPAP
2. Dental appliance
3. Surgery
4. Positional device (for supine isolated OSA)

Question 18

General management for reversing sleepiness

Answer 18

1. Regular + adequate sleep
2. Caffeine (200mg / 2-3 cups) not later than 4pm
3. Short naps (15 mins)
4. Bright light therapy (10000 lux for 30 mins) (for shift work, jet lag, seasonal affective disorder)
5. Nature of shift work (forward shift is better: easier to delay sleep, regular night shift, 12-hour 2-shift)
6. Nasal CPAP, surgery, dental appliance (for OSAS)
7. Modafinil, CNS stimulant (for Narcolepsy)

Question 19

3. Parasomnia

Answer 19

• Any abnormal behaviour during sleep

Classify according to the ***sleep phase when Parasomnia occurs
1. Sleep-wake transition
2. NREM
- Sleepwalking
- Sleep-related eating disorder
3. REM
- REM sleep behavioural disorder
- Sleep paralysis

History suggestive of NREM Parasomnia:
- 1st half of night
- unable to recall behaviour
- unrelated to dreams

History suggestive of REM Parasomnia:
- later half of night
- acting out dream content
- partial recall of behaviour / dream content

Question 20

NREM Parasomnia: Sleepwalking, Sleep-related eating disorder

Answer 20

Sleepwalking:
- **Incomplete transition from **Deep sleep to **Wake (Mentally asleep, Motor awake)
- Talking, hand movement, standing, walking, urinating, eating
- **Neurodevelopmental disorder (vs Neurodegenerative): peak age of onset 7 yo (usually disappear ~9-10 yo, but can reappear in adult due to precipitating factors)
- Precipitating factors: physical exertion, heavy exercise, fever, drugs, OSAS, PLMD

Treatment:
1. Accident prevention
2. Treat precipitating factors e.g. OSAS
3. Drug treatment: ***Clonazepam (make sleep more continuous)

Sleep-related eating disorder:
- Eating food with resultant increased weight
- Treatment:
1. **SSRI
2. **Topiramate
3. ***Clonazepam

Major differences:
1. Age of onset
- Sleepwalking: Childhood
- SRED: Middle age

2. Identified trigger factors (e.g. trauma, stress)
   - Sleepwalking: Uncommon
   - SRED: Common
3. Nocturnal episodes nightly / almost nightly
   - Sleepwalking: Uncommon
   - SRED: Common
4. Total loss of awareness during episode
   - Sleepwalking: Common
   - SRED: Rare
5. Presence of dream-like mentation
   - Sleepwalking: Common
   - SRED: Rare
6. Injuries
   - Sleepwalking: Common
   - SRED: Rare
7. History of eating disorder
   - Sleepwalking: Uncommon
   - SRED: Common
8. Current insomnia
   - Sleepwalking: Rare
   - SRED: Common
9. Psychiatric disorder
   - Sleepwalking: Uncommon
   - SRED: Common

Question 21

REM Parasomnia: REM sleep behavioural disorder (RBD)

Answer 21

Clinical features:
- Frequent vivid, action-packed violent dream
- Loss of muscle atonia —> enactment of dream content

• ***Elderly mostly
• Problem with ***REM sleep regulation
• 50% associated with neurological condition: **Organic lesion at brainstem area, other **neurodegenerative disorders which affect REM sleep control
• High future risk of neurodegenerative disorders (e.g. Parkinson’s)
• OSA can precipitate RBD

Treatment:
- ***Clonazepam (very effective)

Question 22

REM Parasomnia: Sleep paralysis

Answer 22

• Awakening from ***REM with muscle atonia “Ghost oppression”
• Incomplete transition between **REM and **Wake (Mentally awake, Motor paralysed)
• Clear sensorium, difficulty in breathing, acute anxiety, hypnagogic imagery
• Mostly isolated
• Precipitating factor: Sleep deprivation, Irregular sleep habits, Over tiredness, Stress
• More frequent sleep paralysis is either familial / associated with Narcolepsy

Treatment (To suppress REM sleep):
1. **TCA
2. **SSRI

Question 23

Dreaming

Answer 23

• Mental activity during sleep
• Most occur in REM
• Sensory modality of dreams: Visual, Auditory, Vestibular (motion), Temp, Tactile, Olfactory, Gustatory
• Function: Organisation of memory
• Can recall dream —> indicate that sleep is not continuous (i.e. poor sleep)
• Occipital lobe responsible for dreaming (SpC Psychi PP)

Drugs that increase dreaming:
1. Beta-blockers (Atenolol, Propranolol)
2. Antidepressant (SSRI, SNRI)
3. Antipsychotic (Risperidone)
4. GABA agonist (Gabapentin, Zopiclone, BDZ)
5. AChE inhibitor (Donepezil, Rivastigmine)
6. Dopamine agonist (Levodopa)

Treatment:
1. Image rehearsal therapy (for PTSD-associated nightmares, Nightmare disorder)
2. Atypical antipsychotic, Clonidine, Gabapentin, Prazosin (2nd line for PTSD-associated nightmares)
3. Prazosin, Nitrazepam, Triazolam (2nd line for Nightmare disorder)

Question 24

5. Movement-related sleep disorder: Restless leg syndrome (RLS) / Periodic limb movement disorder (PLMD)

Answer 24

Restless leg syndrome (RLS): **Daytime syndrome
Periodic limb movement disorder (PLMD): **Nighttime syndrome
- commonly occur together (80-90% RLS will have PLMD)

RLS:
- Urge to move one’s legs which is often accompanied by an unpleasant sensation
- 80-90% will have PLMD which is a common cause of insomnia + excessive daytime sleepiness first diagnosed during sleep study
- Sequence of >=4 LMs separated by >=5 sec + <90 sec
- RLS worsens during rest and at night

PLMD:
- Characterised by periodic episodes of **repetitive + highly **stereotyped limb movements during sleep, causes ***repeated arousal.

2 phenotypes of RLS:
1. Early-onset, Familial / Idiopathic RLS (more common)
2. Late-onset, Sporadic / Secondary RLS (Fe deficiency anaemia, renal failure, neuropathy etc.)

Investigations:
1. Ferritin level

Diagnosis:
- RLS: History
- PLMD: Overnight PSG

Treatment:
1. Treat underlying cause
- **Fe supplement (Fe sulphate 325mg bd on an empty stomach) indicated when ferritin < 75 µg/L
- **B12 supplement (for neuropathy)

2. Drugs
   - Alpha-2-delta ligands (Gabapentin, Pregabalin)
   - Dopamine agonists (Levodopa, Pramipexole, Ropinirole)
   - Opioids (Oxycodone)
   - ***Clonazepam

Question 25

6. Circadian rhythm sleep-wake disorder (CRSWD)

Answer 25

Types:
1. Delayed Sleep-Wake Phase Disorder (DSWPD) (most common: 80% of all CRSWD cases)
2. Advanced SWPD
3. Non-24 hr SWPD
4. Irregular SWPD

DSWPD:
- more common in adolescents and young adults
- Diagnosis: Sleep diary, Actigraphy, Chronotype questionnaire, Salivary dim light melatonin onset (DLMO)

Treatment:
1. Low dose **melatonin (0.5 mg) 5 hr before habitual sleep onset / 2-4 hr before DLMO
2. Evening light restriction + 2 hr of **bright light therapy (10000 lux) on awakening