Treating sleep disorders Sue Wilson Centre for Neuropsychopharmacology Imperial College London [email protected] Suggested algorithm for treatment of insomnia 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 drug Offer (patient choice) CBTi Hypnotic drug CBTi Hypnotic drug Z drug Availability? Availability? Z drug PR melatonin 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, parasomnias 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 Benzodiazepine receptor agonists 3 Histamine H1 receptor antagonists 4 Serotonin and noradrenaline reuptake inhibitors with tricyclic structure used in depression (eg amitriptyline) 5 Dopamine and serotonin antagonists used in psychosis (eg quetiapine) Drugs used in insomnia Licensed for insomnia •GABA-A positive allosteric modulators (benzodiazepine receptor agonists and chloral etc) •melatonin (modified release) for older adults •promethazine •diphenhydramine •doxepin (USA) •suvorexant (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 flumazenil) 1.Temazepam 2. Zopiclone 3. Clonazepam 4. Chloral hydrate 5. Zolpidem Some GABA-A positive allosteric modulators Drugs acting at the GABA-A benzodiazepine receptor zopiclone zolpidem zaleplon benzodiazepines eg temazepam, lorazepam (safe in overdose, as long as no other drug involved; effects reversed by flumazenil) Drugs acting at the barbiturate/alcohol receptor chloral hydrate/chloral betaine clomethiazole (dangerous in overdose) Effects of GABA-A positive allosteric modulators •These drugs enhance the effect of GABA, the main inhibitory neurotransmitter in the brain •They all produce sedation, sleep promotion, ataxia, muscle relaxation, effects on memory, anticonvulsant 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 agonist? 1. Temazepam 2. Zolpidem 3. Zopiclone/eszopiclone 4. Clonazepam 5. Nitrazepam 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 neurotransmitters in the arousal system •Histamine neurones in the hypothalamus fire prolifically in active waking, much less in quiet waking, and hardly at all during sleep •Therefore antihistamines 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 antidepressant doses is a noradrenaline and serotonin reuptake inhibitor, 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 hangover 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 placebo onset Self- PSG Self- PSG Self- PSG Self-rated rated rated rated temazepam ? ? lormetazepam 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. Venlafaxine 2. Modafinil 3. Methylphenidate 4. Amphetamine 5. Fluoxetine 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 clomipramine, venlafaxine, fluoxetine or sodium oxybate. Sodium oxybate can also improve daytime sleepiness Treating circadian rhythm disorders • Consider lifestyle eg shift work, student sleep-wake habits • Consider comorbid disorders eg schizophrenia, dementia 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. Restless legs syndrome • Disorder of brain dopamine system, usually