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Melatonin for Insomnia in Children with Autism Spectrum Disorders Beth A. Malow, M.D., M.S. Professor of Neurology Director, Vanderbilt Sleep Disorders Center and Vanderbilt Sleep Research Core Studies supported by Vanderbilt Institute for Clinical and Translational Research, Autism Speaks, and NIH/NICHD Presentation Outline Provide an overview of the causes of insomnia in autism spectrum disorders (ASD) Introduce melatonin and its role in sleep and other biological functions Present the evidence for melatonin as a promising therapeutic agent for sleep in ASD Discuss completed and ongoing clinical trials of melatonin in ASD Autism: Comorbidities Core symptoms: Impaired social interaction Impaired communication Restricted interests/ repetitive behaviors Comorbidities: Epilepsy GI disturbances Anxiety, OCD, ADHD Sleep disturbance Is the sleep disturbance intrinsic to autism or secondary to comorbidities? Can we affect comorbidities and core symptoms by improving sleep? Sleep Concerns in Autism Studies using parentally-completed measures, actigraphy and polysomnography report insomnia Prolonged time to fall asleep Later bedtime Decreased sleep duration and continuity Increased arousals and awakenings Early morning wake time Insomnia occurs even in children with normal intelligence (50%) Non 24-hour sleep-wake pattern also described Allik, 2006; Hering, 1999; Honomichl, 2002; Hoshino, 1984; Malow, 2006; Patzold, 1998; Richdale, 1995 and 1999; Stores, 1998; Krakowiak, 2008; Takese, 1998; Wiggs, 2004; Williams, 2004 “Poor sleeper” with ASD: up for hours Causes of Insomnia in ASD are multifactorial Medical (GI) and Neurological (epilepsy) Psychiatric (anxiety, bipolar phenotype, depression, obsessive compulsive or ADHD symptomatology) Medications (antidepressants, stimulants, some antiepileptics) Sleep Disorders: obstructive sleep apnea, parasomnias, restless legs syndrome/periodic limb movement disorder Sensory sensitivities; repetitive behavior Behavioral: lack of a bedtime routine, need to have a parent present when falling asleep. Children may have difficulty understanding parental expectations regarding sleep. Parents may have difficulty effectively conveying these expectations given other priorities and stressors. Biological: neurotransmitter abnormalities, including melatonin, possibly GABA and serotonin How was melatonin’s role in sleep discovered? Accidental discovery of sleep inducing properties of melatonin – Aaron Learner (1959) High IV doses (up to 2g) in patients with vitiligo: no change in skin pigment, however patients reported increased daytime sleepiness What is melatonin? Endogenous Hormone – Ubiquitous: bacteria, algae, fungi, plants, insects and vertebrates – In most vertebrates, including humans, synthesized primarily in the pineal gland and regulated by the SCN via the light/dark cycle – “Hormone of darkness” primarily secreted at night beginning 2 hours before habitual bedtime – Crosses blood brain barrier – Also synthesized in retina, GI tract, skin, bone marrow, and lymphocytes Hypnotic – Inhibits the drive for wakefulness Circadian Clock Hormone (Chronobiotic) – Endogenous synchronizer: stabilizes circadian rhythm Vitamin: anti-oxidant/free radical scavenger Reproductive hormone: declining melatonin may signal onset of puberty Receptors are widespread; mostly in SCN. G-protein receptors » MT1 : suppresses neuronal firing activity in SCN; “opens the sleep gate” » MT2: induces phase shifts in SCN » MT3?? Inflammation in rat, intraocular pressure in rabbit S R Pandi-Perumal, FEBS Journal, 2006 Most common treatments for autism |-------------------------------------------------------------------------------| 1 Speech and Language Therapy 58.5 2 Occupational Therapy 47.3 3 Applied behavior analysis (ABA) 26.3 4 Social Skills Group 14.9 5 Picture Exchange Communication System (PECS) 14.0 |-------------------------------------------------------------------------------| 6 Sensory Integration Therapy 12.9 7 Visual Schedules 12.9 Interactive Autism 8 Physical Therapy 12.4 Network Database, 9 Social Stories 11.5 2008 10 Casein-free diet 9.1 |-------------------------------------------------------------------------------| 11 Melatonin 8.6 12 Gluten-free diet 8.4 13 Risperdal 8.4 14 Weighted Blanket or Vest 8.1 +------------------------------------------------------------------------------IAN, 2008 Supplemental melatonin trials in ASD Appealing to parents --“dietary supplement” with few adverse effects. Open-label trial of 15 children with Asperger disorder (by DSM-IV diagnosis), ages 6-17 years, and severe sleep problems every night or almost every night per parent report. Those on psychotropic medication or with major psychiatric comorbidity were excluded. Children were treated with 3 mg melatonin 30 minutes before bedtime for 2 weeks. Showed a 50% reduction in sleep latency, as measured by actigraphy, over baseline. Child Behavior Checklist scores also improved (depression, anxiety, withdrawal). Minimal adverse effects. Three weeks after withdrawal of melatonin, sleep and behavioral measures were not significantly different. Paavolen J, Child Adoles Psychopharm, 2003 Supplemental Melatonin Trials in ASD Open-label trial of 25 children with ASD, ages 2-9 years, diagnosed by DSM-IV criteria. Excluded children with epilepsy and syndromic autism and those taking concurrent medications or who had prior use of melatonin. Children were treated with melatonin (combination of slow and fast release) 30-40 minutes before bedtime, beginning at 3 mg and titrated up to 4-6 mg as needed. Behavioral tx also done. Improvement in Children’s Sleep Habits Questionnaire and sleep diaries at 1-3-6 months. No adverse effects. After melatonin was discontinued, 16 children worsened, but readministration of melatonin was effective with treatment gains maintained at 12 and 24-month follow-ups. Giannotti F, J Autism Dev Disord, 2006 Retrospective Melatonin Study Large retrospective study of 107 children, age 2-18 years, with ASD treated with 0.75- 6 mg melatonin 30 minutes before bedtime 90% were on psychotropic drugs All parents of children received sleep hygiene counseling 25%: sleep no longer a concern at follow-up appointments 60%: improved sleep but continued parental concerns No increase in seizures or new-onset seizures Only 3 children has mild side effects: morning sleepiness, “fogginess,” increased enuresis Andersen, Kaczmarska, McGrew, Malow J Child Neurol, 2008 Melatonin in children with multiple disabilities Supplemental melatonin has been successfully used in children with other neurodevelopmental disorders, such as Angelman’s syndrome and Smith-Magenis syndrome Those with multiple disabilities may also benefit from supplemental melatonin treatment May have underlying circadian disorder with delayed sleep phase Other factors: pain, seizures, head injuries, tumors-- also affect sleep and should be taken into account Jan and Freeman, Dev Med Child Neurology, 2008 Remember Sleep Hygiene “Although interventions for sleep problems in these children often involve a combination of behavioral and pharmacologic strategies, the first line of treatment is the promotion of improved sleep habits or ‘hygiene.’” hJan et al, Pediatrics, 2008 Causes of Insomnia in ASD are multifactorial Medical (GI) and Neurological (epilepsy) Psychiatric (anxiety, bipolar phenotype, depression, obsessive compulsive or ADHD symptomatology) Medications (antidepressants, stimulants, some antiepileptics) Sleep Disorders: obstructive sleep apnea, parasomnias, restless legs syndrome/periodic limb movement disorder Sensory sensitivities; repetitive behavior Behavioral: lack of a bedtime routine, need to have a parent present when falling asleep. Children may have difficulty understanding parental expectations regarding sleep. Parents may have difficulty effectively conveying these expectations given other priorities and stressors. Biological: neurotransmitter abnormalities, including melatonin, possibly GABA and serotonin Components of Successful Sleep (for any child) “Sleep Hygiene” Daytime habits: • • • • • Exercise Abundant light Avoid caffeine Limit naps Selective bedroom use Evening habits • Calming Activities • Less light • Limit electronic video games, etc Sleep environment • • • • Temperature Texture Sound Minimal light Bedtime • • • • Routine Regular Bedtime/Waketime Timing Amount Family Inventory of Sleep Habits (FISH) DIRECTIONS: For each item below, please indicate how often it was true within the last month: Never Occasionally Sometimes Usually Always 1. My child gets exercise during the day. 2. My child wakes up at about the same time each morning. 3. In the hour before bedtime, my child engages in relaxing activities. 4. My child has drinks or foods containing caffeine after 5 pm (examples: chocolate, Coca Cola). (R) 5. In the hour before bedtime, my child engages in exciting or stimulating activities (examples: rough play, video games, sports). (R) 6. My child’s room is dark or dimly lit at bedtime. 7. My child’s room is quiet at bedtime. 8. My child goes to bed at the same time each night. 9. My child follows a regular bedtime routine that lasts between 15 and 30 minutes. 10. I stay in my child’s room until he/she falls asleep. (R) 11. After my child is tucked in, I check on him/her before he/she falls asleep. (R) 12. My child watches TV, videos, or DVDs to help him/her fall asleep. (R) 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 Malow, J Child Neurol, 2009 Visual schedules clarify bedtime routines Time for bed Put on pajamas Use the bathroom Wash hands Brush teeth Get a drink Read a book Get in bed and go to sleep Strategies for Sleep Resistance and Night Wakings Traditional: “Crying it Out” may not be best approach “Checking-In” – Let your child try to fall asleep on his/her own and leave room – Go back into your child’s room if he/she is upset – Comfort but keep interactions “brief and boring” – Extend the length of time between visits The Rocking Chair Method – Let your child fall asleep on his/her own but stay in room in rocking chair with your back to your child – Move the chair closer to the door each night until you are out of the door Rewards: Morning stickers or basket of presents. The Bedtime Pass (Friman) Bedtime pass Vanderbilt Melatonin Pilot Study Pilot study to determine dose-response, tolerability, and adverse effects of melatonin in children with ASD and sleeponset delay, ages 4-10 years. Receive ADOS and ADI-R, sleep and behavior scales, and 17 weeks of actigraphy. Results will help us plan a multicenter placebo-controlled double-blind randomized trial of melatonin for sleep in ASD. Objective Sleep Outcome Measure: Actigraphy Actigraphy is a promising technique for measuring sleep patterns and responses to treatment in children, especially those with neurodevelopmental disorders (Am. Acad. of Sleep Med, 2007) Does require parents to keep accurate sleep diaries as actigraph needs to be interpreted in context of when child went to bed Melatonin Study Results to Date- Sleep All 12 completers tolerated melatonin without adverse effects. Nine of 10 children tolerated actigraphy and achieved a satisfactory response at relatively low doses— 3 children at 1 mg 6 children at 3 mg Only 2 children required 6 mg None required 9 mg Sleep latency, as measured by actigraphy, decreased from 38.7 ± 14.3 minutes to 22.6 ± 7.9 minutes (p = 0.005) with treatment. Improvements with treatment were also noted in CSHQ domains of sleep onset delay (p = 0.002), bedtime resistance (p = 0.039), and sleep duration (p = 0.001). Non-responder who did not tolerate actigraphy was diagnosed with bipolar disorder after study completed. She responded well to risperidone, with improved sleep. Melatonin Study Results– Daytime Behavior and Other Measures Improvements were also noted by parent report in the Repetitive Behavior Scale domains of compulsive (p = 0.006) and ritualistic (p = 0.012) behavior, and the Parenting Interview for Autism domain of affective responses (p = 0.04). Vanderbilt Melatonin Pilot Study NICHD-supported trial extends our work to performing concurrent pharmacokinetic studies and polysomnography. Measure nocturnal blood melatonin at baseline and at each dose and relate to polysomnography and actigraphy findings. Also measure 6-sulfoxymelatonin levels in urine in all children Questions?