1. 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

2. 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

3. 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?

4. 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
New slide

5. “Poor sleeper” with ASD: up for hours

6. 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

8. 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

9. What is melatonin? Endogenous Hormone Hypnotic
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

10. Most common treatments for autism
       | |             1                    Speech and Language Therapy   58.5              2                           Occupational Therapy   47.3  
                          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                                          Physical Therapy   12.4                                            Social Stories   11.5           10                               Casein-free diet   9.1
   | |                                            Melatonin   8.6
                                     Gluten-free diet   8.4
         13                                      Risperdal   8.4          14                    Weighted Blanket or Vest   8.1
      
Interactive Autism Network Database, 2008
IAN, 2008

11. 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

12. 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) 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 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

13. Retrospective Melatonin Study
Large retrospective study of 107 children, age 2-18 years, with ASD treated with 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

14. 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

15. 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

16. 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

17. 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

18. Family Inventory of Sleep Habits (FISH)
Malow, J Child Neurol, 2009

19. 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

20. 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.

21. The Bedtime Pass (Friman)

22. Vanderbilt Melatonin Pilot Study
Pilot study to determine dose-response, tolerability, and adverse effects of melatonin in children with ASD and sleep-onset 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.

23. 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
-8 autistic children selected from 22 randomly chosen subjects with autism. 12 of the 22 had abnormal sleep patterns and 10 did not. 8 of the 12 were able to wear actigraphy. The 10 children with no reported sleep problems did not wear the actiwatches.
-Questionnaire and 72 hours of actigraphy
-Did not discuss whether subjects had ID or not.
-Wiggs and Stores: -All children had been dx’d by psychiatrists, pediatricians, & clinical psychologists according to ICD-10 criteria in Great Britain.
-40 children with autism, 18 on the autistic spectrum, and 11 with Asperger’s
-Used the Simonds and Parraga Sleep Questionnaire
-Sleeplessness defined as parents reporting the frequent occurrence (ie happening 3 or more times/week) of any of the items concerned with these sleep problems, namely: reluctance to go to bed; fear of going to bed; problems settling child; child takes longer than 1 hour to settle to sleep; waking in the night; insisting on sleeping with someone else; waking before 5 am (early waking); and excessive daytime sleeping.
-Sleep diary x 1 week
-Subjects were taking meds but no soporifics, specifically no MLT or chloral hydrate
-Able to compare objective sleep data with normal values for the 46 children aged b/w 6 and 12 (ages for which norms were available).
-Results: the most common sleep disorders underlying the symptoms of sleeplessness were behavioral in origin and these behavioral sleep d/o’s were more common in those < 8 y/o. Actigraphically determined sleep patterns of children w/ sleeplessness did not differ from those w/o reported sleeplessness, although both groups of children with ASDs had disturbed sleep compared w/ normal values.
-Authors theorize that those with reported “problems” of sleeplessness can be distinguished only by the fact that they make their parents aware of the fact that they are awake, ie they signal when awake vs. self soothe.

24. 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.

25. 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).

26. 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

27. Questions?