Why is sleep such a big deal?

1. Why is sleep such a big deal? By Deborah bilder, m.D. Triple Board Associate Professor, Department of Psychiatry, Division of Child & Adolescent Psychiatry Adjunct associate professor, Departments of Pediatrics and Educational Psychology University of Utah

2. Disclosures • Consultant, Advisory Board and Steering Committee member for BioMarin Pharmaceuticals • Scientific and Clinical Advisors Board member for Audentes Therapeutics

3. Overview What happens during sleep? Why does sleeplessness stress us out? Autism + Sleep disturbance = Agitation

4. What does a sleep-deprived child look like? • Tired • Irritable • Hyperactive • Hungry

5. The physiology of Falling asleep • When the night falls, and the light dims, our circadian clock takes action • The circadian clock signals the pineal gland produces and releases melatonin, and we fall asleep

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7. Light • Major regulator of the circadian clock • The summer equinox is a bipolar stress test* • Even if the rest of the room is dark, if you are looking at light, light is influencing your circadian rhythm • “Blue light has a dark side”1 *the world according to me 1. https://www.health.harvard.edu/staying-healthy/blue-light-has-a-dark-side

8. Once asleep

9. Dornbush MP, Pruitt SK. Teaching the Tiger. Page 18

10. Cortisol and our stress response • Connected to emotional and physiologic regulators in our brain and throughout our body Johnson et al. Pediatrics 2013; 131(2):319-327

11. Diurnal Cortisol curve

12. Cortisol curve during depression Wong et al. PNAS 2000; 97(1): 325-330

13. Sleep dictates our stress response system • Cortisol release follows a daily rhythm that synchronizes with our sleep cycle

14. Sleep cycle and cortisol rhythm • When you mess with one, you mess with both Balbo et al. Int J Endocrinol2010; 2010: 759234

15. Sleep cycle and cortisol rhythm • When both are already messed up, it is far easier to fix sleep than it is the cortisol rhythm • That’s why: • I always start with sleep • I will not move beyond the topic of sleep until restorative sleep has been achieved

16. Oster et al. Endocr Rev 2017; 38(1):3-45

17. Purpose of sleep • Restores our brain’s ability to think • Consolidates memory • Maintains mood stability and emotional regulation • Maintains our cardiovascular system • Influences our immune response

18. Autism and sleep • 60% to 86% of children with ASD have insomnia • Insomnia: delayed sleep onset, intermittent awakening, premature awakening • Insomnia in children with ASD significantly affects parent’s sleep and increase parental stress Souders MC et al. Curr Psychiatry Rep 2017; 19:34

19. Causes of insomnia in asd • Behavioral insomnia • Sleep apnea, nocturnal seizures, restless leg syndrome, discomfort (reflux, constipation) • Circadian rhythm gene variants • Abnormal melatonin release • Arousal and sensory dysregulation • Psychosocial stress Souders MC et al. Curr Psychiatry Rep 2017; 19:34

20. Melatonin • Melatonin is made from serotonin • The most consistent biomarker in autism is elevated serotonin – we don’t know why • Multiple (10+) treatment studies support the use of melatonin (3 to 5 mg) about 30 minutes before bedtime for insomnia in children with ASD Gabriele S et al Neuropsychopharmacology 2014 24(6), 919–929; Souders MC et al. Curr Psychiatry Rep 2017; 19:34

21. Autism and cortisol rhythm: ASD vs. Neurotypical • With normal IQ • the same awakening response and total amount of cortisol released throughout the day • Flattened daytime decline in cortisol with higher cortisol nadir in evening • Elevated evening cortisol associated with daily stress and sensory sensitivity • Subgroup (about 25%) had a particularly flattened cortisol rhythm • Greater within child variation of cortisol over days • With co-occurring ID: • Elevated cortisol through the day with flattened daytime and nighttime slopes • Relationship between cortisol levels and impairments in social interaction and language • Elevated cortisol response to stressor Corbett BA et al. J Psychiatric Neurosci. 2008; 33(3),227-234; Corbett BA et al. Autism Res 2009; 2:32-39; Tomarken AJ et al. Psychoneuroendocrinology2015; 217-226; Corbett BA et al. Psychoneuroendocrinology 2006; 31(1):59-68

22. Autism and stress response • Stressor was mock MRI scanner • When mean IQ = 77 of ASD group, significantly increase cortisol response to stressor • However, when repeated in ASD group with normal IQ, no difference initial or subsequent stress responses between ASD and NT groups • ASD group with normal IQ showed significant within child variable in cortisol rhythm compared to NT group Corbett BA et al. Psychoneuroendocrinology 2006; 31(1):59-68; Corbett BA et al. J Psychiatric Neurosci. 2008; 33(3),227-234 ;

23. In both children and adults: At least 70% have or have had at least one additional psychiatric diagnosis Anxiety and ADHD are particularly prevalent Also, Major Depressive Disorder, Bipolar Disorder, and Psychosis > 1 is common Psychiatric Comorbidity Leyfer OT et al. J Autism Dev Disord2006;36:849-861 Buck TR, et al. J Autism Dev Disord2014

24. Treatment Hierarchy Sleep Disturbance Mania/Bipolar Depression/Anxiety ADHD

25. Correcting sleep disturbance • Autism Treatment Network’s Sleep Tool Kit • Sleep hygiene: setting your child up for success • Comfortable bedroom (right temperature, quiet, and dark) • All nighttime caregivers follow the same, set routine • “Choose a Bedtime…and Keep It” https://www.autismspeaks.org/tool-kit/atnair-p-strategies-improve-sleep-children-autism

26. More on sleep hygiene • Exercise is good, but not before bedtime • Avoid caffeine (soda) after 12 PM • Comfortable bedroom (right temperature, quiet, and dark) • Teach your child to fall asleep alone https://www.autismspeaks.org/tool-kit/atnair-p-strategies-improve-sleep-children-autism

27. Short of general anesthesia, no medication will get your teenager to sleep if he/she has something better to do

28. Medication (+ Sleep hygiene) • Medication selection depends on what physiologic/psychiatric phenomenon is interfering with sleep • Medication intervention may involve discontinuing rather than starting a medication • If sleep disturbance is primary: • melatonin (without other active ingredients) • other medications: clonidine, trazodone, mirtazapine

29. Sleep and stress response are intrinsically linked Most pathologic emotional experiences are related to an abnormal stress response Fixing sleep disturbance is an ideal place to start Good sleep hygiene is the cornerstone of any effective sleep treatment plan Melatonin (without any other active ingredients) Big Picture

30. acknowledgments • The clients and families we serve