Transcript grant writing - Child Development

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
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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
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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
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Insomnia occurs even in children with normal intelligence (50%)
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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
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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?
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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
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Speech and Language Therapy 58.5
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Occupational Therapy 47.3
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Applied behavior analysis (ABA) 26.3
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Social Skills Group 14.9
5 Picture Exchange Communication System (PECS) 14.0
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Sensory Integration Therapy 12.9
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Visual Schedules 12.9
Interactive Autism
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Physical Therapy 12.4
Network Database,
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Social Stories 11.5
2008
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Casein-free diet 9.1
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Melatonin 8.6
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Gluten-free diet 8.4
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Risperdal 8.4
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Weighted Blanket or Vest 8.1
+------------------------------------------------------------------------------IAN, 2008
Supplemental melatonin trials in ASD
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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
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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
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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
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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
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“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






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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:
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Exercise
Abundant light
Avoid caffeine
Limit naps
Selective bedroom use
Evening habits
• Calming Activities
• Less light
• Limit electronic video
games, etc
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Sleep environment
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Temperature
Texture
Sound
Minimal light
Bedtime
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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)
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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
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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
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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?