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Home , Chloral betaine, Clomethiazole, Clonazepam, Nitrazepam

Treating sleep disorders

Sue Wilson

Centre for Neuropsychopharmacology Imperial College London [email protected] Suggested algorithm for treatment of

Diagnosis of insomnia

Associated with another disorder yes no Ensure other disorder is adequately treated Significant distress and daytime symptoms in spite of good sleep habits Insomnia persists

Likely to resolve soon (eg bereavement, short term stressor etc) yes - no Consider 3-7 days of Z Offer (patient choice) CBTi drug CBTi Hypnotic drug Z drug Availability? Availability? Z drug PR if over 55 ReviewReview After CBTiAfter CBTi InIn 4 weeksweeks

Improved Not improved British Association for Psychopharmacology consensus ? Open appointment Reassess statement on evidence-based treatment of insomnia, and circadian rhythm disorders Refer J Psychopharm (2010) 24(11) 1577–1600 Consider alternative medication https://www.bap.org.uk/pdfs/BAP_Guidelines-Sleep.pdf Which elements of cognitive behavioural therapy for insomnia (CBTi) have a good evidence base

1 Sleep hygiene

2 Psychodynamic psychotherapy

3 Sleep restriction and stimulus control

4 Mindfulness

5 Relaxation Cognitive behavioural therapy for insomnia (CBTi) Very good evidence base for multicomponent CBTi May last longer than pharmacological treatment Can be individual or group-based, also online Multicomponent, usual elements are *Sleep scheduling and bedtime restriction Stimulus control *Addressing dysfunctional attitudes and beliefs about sleep Relaxation/exercise Sometimes mindfulness-based stress reduction (* current evidence for these components very good)

HOWEVER many patients do not choose this option Which of these pharmacological treatments often used for chronic insomnia have a good evidence base?

1 Melatonin

2

3 Histamine H1 receptor antagonists

4 and noradrenaline reuptake inhibitors with tricyclic structure used in depression (eg )

5 Dopamine and serotonin antagonists used in (eg ) used in insomnia

Licensed for insomnia •GABA-A positive allosteric modulators (benzodiazepine receptor agonists and etc) •melatonin (modified release) for older adults • • • (USA) • (USA)

Unlicensed prescribed frequently •Histamine H1 antagonists (and OTC) •Older drugs for depression

Sometimes prescribed Drugs for psychosis Which of these drugs are benzodiazepine receptor agonists? (ie effects reversed by the antagonist )

1.

2.

3.

4.

5. Some GABA-A positive allosteric modulators

Drugs acting at the GABA-A benzodiazepine receptor zopiclone zolpidem eg temazepam,

(safe in overdose, as long as no other drug involved; effects reversed by flumazenil)

Drugs acting at the / receptor chloral hydrate/ (dangerous in overdose) Effects of GABA-A positive allosteric modulators

•These drugs enhance the effect of GABA, the main inhibitory in the brain

•They all produce , sleep promotion, , muscle relaxation, effects on memory, effects

•For insomnia, these effects are unwanted during the day, therefore the duration of action of the drug is important Which is the shortest-acting benzodiazepine receptor ?

1. Temazepam

2. Zolpidem

3. Zopiclone/

4. Clonazepam

5. Time profiles of plasma levels of some GABA-A PAMs taken at 23:00

Zaleplon**

Zolpidem

Zopiclone

Temazepam liquid Temazepam tablet

Nitrazepam

Clonazepam

23:00 01:00 03:00 05:00 07:00 09:00 11:00 Time of day Darker blue represents higher plasma concentration Longer-term studies with benzodiazepine receptor agonists

Good evidence for maintained efficacy and safety in controlled studies of:-

• zolpidem (3-7 nights per week for 6 months) (Krystal et al 2008) • eszopiclone nightly for 12 months (Roth et al 2005) • zaleplon for 12 months in elderly (Ancoli-Israel et al 2005)

These suggest dependence (tolerance/withdrawal) is not inevitable with hypnotic therapy up to 1 year, and is not characteristic of the several agents studied

Stopping these drugs is more successful when patients have CBTi before and during the taper (Belleville et al 2007) Histamine and sleep •Histamine is one of the key wakefulness-maintaining in the arousal system

•Histamine neurones in the fire prolifically in active waking, much less in quiet waking, and hardly at all during sleep

•Therefore are unlikely exert their effect in sleep itself, but require activation of the histamine system to have their effect.

•They may promote quiet waking at the time of desired sleep and may also have effects to decrease short awakenings during sleep Doxepin

•Doxepin is a drug with a tricyclic structure, used in depression.

•At doses is a noradrenaline and serotonin , and an antagonist at various brain receptors

•Its most potent action is as a histamine H1 antagonist

•Therefore at very low doses it will affect histamine receptors but have little effect at transporters or other brain receptors

•Low dose (3-6mg as opposed to antidepressant dose of ~100mg) licensed for insomnia in USA

•4 good studies showing improvement in subjective amount of waking during the night Melatonin •Endogenous hormone secreted nightly in the pineal gland •The ‘hormone of darkness’ • Exogenous melatonin brings sleep forward, ie when given in late evening reduces sleep latency •Does not prolong sleep or reduce night-time awakenings •Has no motor, memory or known effects •Very few side effects

• Prolonged release formulation marketed as a POM for the indication insomnia in adults aged >55, in whom it improves subjective sleep quality. (Clinical trials in adults conducted only in this age group)

• Also used in children with learning disability to aid settling at night Individual drugs (efficacy in insomnia) Level 1b

Significantly Wake time Sleep onset Total sleep Sleep different from after sleep latency time quality onset Self- PSG Self- PSG Self- PSG Self-rated rated rated rated temazepam ? ?             zopiclone        zolpidem       zaleplon     eszopiclone        PR melatonin   Hypersomnia (excessive daytime sleepiness, EDS)

Apart from insufficient sleep and sleepiness at wrong time due to circadian rhythm disorder, 3 main disorders to treat 1) Obstructive sleep apnoea – treated with physical means usually CPAP 2) Narcolepsy – EDS and cataplexy symptoms treated with drugs 3) Idiopathic hypersomnia – behavioural interventions and sometimes drugs Which of these treatments used in narcolepsy does NOT improve cataplexy

1.

2. Modafinil

3. Methylphenidate

4. Amphetamine

5. Hypersomnia (excessive daytime sleepiness, EDS) • Usually treated at specialist sleep centres • For EDS in narcolepsy, drugs used are: • Modafinil, a dopamine uptake inhibitor • Amphetamines* (dexamfetamine or lisdexamfetamine), dopamine and noradrenaline uptake inhibitors, dopamine and noradrenaline releasers • Methylphenidate*, dopamine and noradrenaline uptake inhibitor, dopamine and noradrenaline releaser

• No drug is licensed for idiopathic hypersomnia, but the above are sometimes used as part of package including behavioral interventions

• Cataplexy in narcolepsy is often ameliorated by the starred stimulants above; it also can be treated with , venlafaxine, fluoxetine or . Sodium oxybate can also improve daytime sleepiness Treating circadian rhythm disorders

• Consider lifestyle eg shift work, student sleep-wake habits • Consider comorbid disorders eg ,

If these are ruled out, delayed sleep phase syndrome is usually treated at a specialist sleep centre.

Melatonin is effective in jet lag disorder, delayed sleep phase syndrome and free-running disorder, and light therapy is effective in delayed sleep-phase syndrome Precise timing of both of these is essential More challenging circadian rhythm disorders

• Delayed sleep phase syndrome, non-24 sleep wake rhythm and irregular sleep wake rhythm are all common in psychosis. • Behavioural treatment is recommended but not always possible

• In dementia, irregular sleep pattern and in particular troublesome behavior in the evening or night is a problem. Which treatment should NOT be used in elderly patients with dementia to treat irregular sleep wake scheduling disorder?

1. Behavioural measures to increase daytime activity

2. Increased light levels in daytime

3. Decreased light at night

4. Sleep-promoting medication eg benzodiazepine receptor agonist or melatonin Elderly people with dementia and sleep-wake rhythm disorder (ISWRD) Recommendations • that clinicians treat ISWRD in elderly patients with dementia with light therapy (versus no treatment). [WEAK FOR] • that clinicians avoid the use of sleep-promoting medications to treat demented elderly patients with ISWRD (versus no treatment). [STRONG AGAINST] • that clinicians avoid the use of melatonin as a treatment for ISWRD in older people with dementia (versus no treatment). [WEAK AGAINST] • that clinicians avoid the use of combined treatments consisting of light therapy in combination with melatonin in demented, elderly patients with ISWRD (versus no treatment). [WEAK AGAINST]

AASM Task Force on circadian rhythm disorders. J Clin Sleep Med. 2015 11(10): 1199–1236. • Disorder of brain dopamine system, usually treated by a neurologist • Strong evidence for involvement of Fe in brain, symptoms often ameliorated by treating low ferritin • Unknown cause , but responds to dopaminergic drugs as in Parkinson’s disease (rotigotine often used) • RLS can be caused or made worse by many psychotropic drugs • • • sometimes serotonin reuptake inhibitors • older histamine H1 antagonists • older drugs used in depression eg amitriptyline, doxepin, probably because of H1 antagonism Parasomnias Parasomnias most often treated are • the non-REM parasomnias - night terrors and sleepwalking • REM sleep behavior disorder Which of these treatments has a good evidence base to treat non-REM parasomnias such as night terrors and sleepwalking? 1.

2. Clonazepam

3.

4. Zopiclone

5. None of these Parasomnias Non- REM parasomnias – no controlled studies in adults Small studies and case series for Clonazepam Paroxetine (RCT in children shows efficacy for 5HTP) Do drugs cause sleepwalking?

Case report evidence points to drugs provoking sleepwalking in a few people who have no previous history; sleepwalking resolves on stopping the drug1

Most of these drugs are very sedating and with rapid effects • zolpidem • • temazepam • But also • sodium oxybate • olanzapine paroxetine •

Often reports of taking night-time medication and not going to bed

1Pressman 2007 Which of these drugs might you try in order to ameliorate REM behaviour disorder?

1. Mirtazapine

2. Venlafaxine

3. Melatonin

4. Parasomnias First focus of treatment should be safety of patient and bed partner

Non- REM parasomnias Small studies and case series for Clonazepam Paroxetine Imipramine (RCT in children shows efficacy for 5HTP) REM sleep behavior disorder Melatonin Clonazepam Drugs which probably provoke symptoms of REM behaviour disorder or make them worse mirtazapine all serotonin reuptake inhibitors Not bupropion venlafaxine duloxetine possibly imipramine, clomipramine (doubtful, no violent behaviours reported but high doses reduce REM atonia even in normals) bisoprolol tramadol

Typically occurs within a few days of starting treatment or increasing dose (teeth-grinding)

• Can appear or be made worse during treatment with serotonin reuptake inhibitors / venlafaxine

• SRI-induced bruxism ameliorated by adding