Melatonin Effective Sleep Autism Disorder Document

Sleep Disturbance In
Autism
Eman Alluwaimi
General Paediatric Clinical Fellow
McMaster Children’s Hospital

Objectives
1. General Overview; neurobiological
factors, complications, prognosis
2. Systematic review of Melatonin
3. Overview of other agents

Prevalence of sleep disorders in ASD
• 40% to 80% 1
• Rank as one of the most common
concurrent clinical disorders among
children with ASD 2
• Peak
onset:
second
year
of
life
3
(1) M. Souders, et al. Sleep behaviors and sleep quality in children with autism
spectrum disorders, Sleep,(2009)
(2) X. Ming, et.al. Autism spectrum disorders: concurrent clinical disorders J
Child Neurol (2008)
(3)
Gianno6
F,
et.al.
An
open-‐label
study
of
controlled
release
melatonin
in
treatment
of
sleep
disorders
in
children
with
auBsm.
J
AuBsm
Dev
Disord
(2006)

ASD related Sleep disturbances
Most common:
• late onset sleep: More than an hour
• Frequent waking : Lasts 2-3 Hours
• Reduced sleep duration
Kotagal S, et.al. Sleep in children with autism spectrum disorder.
Pediatr Neurol 2012
Cortesi
F,
et.al.
Sleep
in
children
with
auBsBc
spectrum
disorder.
Sleep
Med
2010

ASD related Sleep disturbances
Others:
• Non-rapid eye movement (REM) arousal
disorders
• REM sleep behaviour disorder
• Rhythmic movement disorder
Kyle P. Johnson,et.al. Assessment and Pharmacologic Treatment of Sleep
Disturbance in AutismChild and Adolescent Psychiatric Clinics of North
America (2008)

Sleep disturbance: Comparison
Sleep
paMerns
in
children
with
and
without
auBsm
spectrum
disorders:
Developmental
comparisons,
Danelle
Hodge,et.al.
Research
in
Developmental
DisabiliBes
(2014)

Neuropathology of Sleep disturbance in
ASD

Normal sleep
When awake
Excitatory
neurons
from
brain
stem
and
hypothalamus
send
signals
to
brain
cortex
along
with
other
areas
of
the
brain
to
keep
us
awake
and
alert

Normal sleep
In sleep
GABA
Melatonin +
• Inhibitory neurons from ventro-lateral preoptic area send their signals to
these areas resulting in sleep
• An example of an inhibitory neurotransmitter is GABA
• This process is controlled by many mechanisms one is through
Melatonin a hormone secreted from the pineal gland

Melatonin Regulation
• Melatonin is made from
the amino acid tryptophan
which is absorbed from
blood into the pineal glad
• Tryptophan is then utilized
through enzymatic
reactions to yield seretonin
• During day light seretonin
is stored inside the
pinealocyte unavailable for
further enzymatic
reactions
5-Hydroxytryptophan
Serotonin

5-Hydroxytryptophan
Serotonin
With
the
onset
of
darkness,
postganglionic
sympatheBc
ouWlow
to
the
pineal
increases
And
the
consequent
release
of
norepinephrine
onto
pinealocytes
Causes
stored
serotonin
to
become
accessible
for
intracellular
metabolism

5-Hydroxytryptophan
Serotonin
N-Acetylserotonin
ASMT
Melatonin
With
the
onset
of
darkness,
postganglionic
sympatheBc
ouWlow
to
the
pineal
increases
And
the
consequent
release
of
norepinephrine
onto
pinealocytes
Causes
stored
serotonin
to
become
accessible
for
intracellular
metabolism

5-Hydroxytryptophan
Serotonin
N-Acetylserotonin
ASMT
Melatonin
• Serotonin
is
converted
to
melatonin
• Consequently
pineal
melatonin
level
rises
many-‐folds

5-Hydroxytryptophan
Serotonin
N-Acetylserotonin
ASMT
Melatonin
In ASD
Many
theories
suggesBng
different
disrupBon
mechanisms
in
melatonin
pathway,
one
is
a
geneBc
defect
leading
to
reduced
funcBon
of
ASMT
enzyme

Neurobiological
abnormaliBes
in
ASD:
Melatonin/seretonin
• AbnormaliBes
in
ASMT
gene
with
low
ASMT
acBvity
leading
to
increased
synthesis
and
asymmetry
in
serotonin
producBon
• In
one
study
(Makkonen
I,2008)
reduced
serotonin
transporter
binding
capacity
was
idenBfied
in
children
with
ASD.
• At
least
four
independent
studies
have
demonstrated
abnormal
melatonin
regulaBon
in
individuals
with
ASD
compared
with
controls,
including
elevated
dayBme
melatonin
and
significantly
lower
nocturnal
melatonin
• loss
of
effect
as
tolerance
Flavia Cortesia,et.al. Sleep in children with autistic spectrum
disorder, Advances in Pediatric Sleep Medicine. (2010)

Neurobiological
abnormaliBes
in
ASD:
GABA
• Hypothesis:
GABAergic
interneurons
migraBon
and
maturaBon
could
be
affected
• A
region
of
geneBc
suscepBbility
has
been
idenBfied
on
chromosome
15q
that
contains
GABA-‐related
genes
Levitt P, et.al. Regulation of neocortical interneuron development and
the implications for neurodevelopmental disorders. Trends Neurosci
2004

Neurobiological
abnormaliBes
in
ASD
• AlteraBon
in
hormone/neurotransmiMer
(melatonin/serotonin)
producBon
• Imbalance
of
excitaBon–inhibiBon
• AbnormaliBes
in
the
hypothalamic–
pituitary–adrenal
axis
regulaBng
circadian
rhythms
Flavia Cortesia,et.al. Sleep in children with autistic spectrum disorder,
Advances in Pediatric Sleep Medicine. (2010)

Risk factors for sleep disturbance
• Biological
• Psychological
• Social/environmental
• Family factors
• Behavioural
Richdale AL, Schreck KA. Sleep problems in autistim spectrum
disorders: prevalence, nature and possible biopsychosocial etiologies.
Sleep Med Rev (2009)
Flavia Cortesia,et.al. Sleep in children with autistic spectrum disorder,
Advances in Pediatric Sleep Medicine. (2010)

• Anxiety
• Autism symptom severity
• Sensory sensitivities
• Gastrointestinal problems
• Intelligence quotient
Grigg-Damberger,et.al. Treatment strategies for complex behavioral insomnia
in children with neurodevelopmental disorders, Current Opinion in Pulmonary
Medicine. (2013)

• Impaired emotional regulation
• Difficulty transitioning
• Impaired communication skills
Hollway JA, et.al. Correlates and risk markers for sleep disturbance in
participants of the Autism Treatment Network. J Autism Dev Disord (2013)

Complications
• May exacerbate disturbed social
interactions, repetitive behaviours, affective
problems, and inattention/hyperactivity1
• Worsen Social skills deficits, stereotypic
behaviour, and increased overall autism
scores 2
(1) Gabriels et al. 2005; Goldman et al. 2012, 2009; Malow et al. 2006; Schreck
et al. 2004
(2) Schreck KA,et.al. Sleep problems as possible predictors of intensified
symptoms of autism. Res Dev Disabil 2004

Complications
• Poor sleep quality and shorter total
sleep time among parents
Meltzer LJ. et.al sleep in parents of children with autism
spectrum disorders. J Pediatr Psychol (2008)

Assessment/Management
• Screening for sleep problems:
• Pediatric
Sleep
QuesBonnaire,
Children's
Sleep
Habits
QuesBonnaire
• History:
• Screen for obstructive apnea and other sleep disorders
• Insomnia: sleep environment/behaviour, Sleep diaries
• Referral to specialist:
• (sleep specialist, neurologist, otolaryngologist)
• Treatment:
• Non-Pharmacological: Behavioral
• Pharmacological
Kyle P. Johnson,et.al, Assessment and Pharmacologic Treatment of Sleep Disturbance in
Autism. Child and Adolescent Psychiatric Clinics of North America (2008)

Pharmacological use
• Melatonin
• Other agents:
• Niaprazine
• Mirtazapine
• Clonidine
• Clonazepam

Melatonin Systematic reviews
1. Rossignol DA,et.al. Melatonin in autism spectrum
disorders: a systematic review and meta-analysis. Dev
Med Child Neurol (2011)
2. Fabian Guénolé a, et.al. Melatonin for disordered sleep
in individuals with autism spectrum disorders:
Systematic review and discussion. Sleep Medicine
Reviews (2011)

Method
• Search engine: PubMed, Google Scholar,
CINAHL,EMBASE, Scopus, and ERIC (untill Oct 2010)
• Two reviewers independently assessed 35 (out of 68)
studies that met the inclusion criteria
• Meta-analysis was performed on five randomized double-blind,
placebo-controlled studies
• Quality assessed using the Downs and Black checklist

Results: Characteristics and trial designs

Result: Sleep duration
73 - 44 minutes longer

Result: Sleep onset Latency
66 and 39 minutes shorter

Genetic bases of sleep deprivement
Five studies
Enzymes involved in Melatonin receptors
melatonin synthesis
alkylamine N- MTNR1A, MTNR1B GPR50
ASMT acetyltransferase
daniel a rossignol, richard e frye, Melatonin in autism spectrum disorders: a systematic review and
meta-analysis. Developmental Medicine & Child Neurology (2011)

Five studies
melatonin synthesis
Four studies
One study reported a partial duplication of ASMT in 6 to 7% of individuals with ASD
compared with 2% of healthy individuals (Cai G 2008)
One study reported that two single-nucleotide polymorphisms in ASMT were
significantly more frequent (Jonsson L 2010)

Five studies
melatonin synthesis
One study
(Jonsson L 2010)
Four studies
No abnormality
Found
abnormality

Five studies
melatonin synthesis
One study
(Jonsson L 2010)
Four studies
No abnormality
two studies
(Chaste P 2010
Jonsson L 2010)
Found Variant genes
abnormality

Five studies
melatonin synthesis
One study
(Jonsson L 2010)
Four studies
No abnormality
two studies
(Chaste P 2010
Jonsson L 2010)
Variant genes
two studies
(Chaste P 2010
Jonsson L 2010)
Found No significance
abnormality

Metabolism of Melatonin
• Four
studies:
night-‐Bme
urinary
excreBon
of
6-‐SM
was
inversely
correlated
with:
• The
severity
of
impairments
in
verbal
communicaBon
and
play
(Tordjman
S,
2005)
• DayBme
sleepiness
(Leu
RM,
2010)
• Abnormal
electroencephalogram
(Nir
I,
1995)
• HyperacBvity
• These
studies
suggest
that
melatonin
metabolism
is
directly
or
indirectly
related
to
certain
auBsBc
behavior

Prevalence of Melatonin usage
• Three
survey
studies
(1071
individuals)
• 2.98
-‐
10.8%70,
mean
of
7.2%
(95%
CI
5.6–
8.7%)
Polimeni
MA
(2005),
Aman
MG
(2003),
Green
VA
(2006)
Rossignol DA,et.al. Melatonin in autism spectrum disorders: a systematic
review and meta-analysis. Dev Med Child Neurol(2011)

Prevalence
of
physician
recommendaBons
Three
survey
studies
(2483
physicians)
(Two
studies
also
included
several
pediatric
condiBons
other
than
ASD)
• 32.4%
(95%
CI
30.6–34.2%)
with
a
range
of
24.982
to
39%.60
recommend
melatonin
usage
• In
one
study,Golnik
AE
(2009)
• 22%
of
physicians
did
not
feel
‘knowledgeable’
enough
about
melatonin
to
recommend
its
use
• 14%
discouraged
melatonin
use
• 39%
were
accepBng
of
its
use
if
the
child
was
already
taking
melatonin.
Owens
JA(2010),
Golnik
AE(2009),
Owens
JA(2003)

Effects
of
melatonin
treatment
on
sleep
18 studies,( one: >18y, another: 3-28y, 16: 2-18y)
• Dose: 0.75mg – 15mg (rare use of 25mg)
• 14days - 4years
• Measurement
of
effect:
subjecBve
(parent
report
quesBonnaires
and
sleep
diaries),
objecBve
(acBgraphy)
• All of these studies reported improvements in sleep
parameters, including improvements in overall sleep,
sleep duration, sleep onset latency, and night-time
awakenings.

Safety
• Side
effects:
difficulty
waking,
dayBme
sleepiness,
and
enuresis
• Seven
studies
:no
side-‐effects
• Remaining
studies:
transient
or
mild
side-‐effects
in
a
small
number
of
individuals.
• Tolerated
when
combined
• Seizure
acBvity:
No
increase
(one
study
reported
an
abnormal
EEG
with
lower
mean
serum
melatonin)

Effect on daytime behavior
• Six
studies
:
improvements
in
dayBme
behavior
in
some
children
with
ASD
• less
behavioural
rigidity,
ease
of
management
for
parents
and
teachers,
beMer
social
interacBon,
fewer
temper
tantrums,
less
irritability,
more
playfulness,
beMer
academic
performance,
and
increased
alertness.
• One
study
(Wright
B,2010)
noted
a
significant
improvement
in
overall
dayBme
behaviour
as
measured
by
the
Developmental
Behaviour
Checklist
when
comparing
melatonin
with
placebo.

Loss of Melatonin effect
Four studies (Andersen IM. 2008, Ishizaki A. 1999, Jan JE.
1996, McArthur AJ. 1998)
• Some attributed the loss of effect to Tolerance: leading to
melatonin dose overtime
• Others attributed it to Slow Melatonin Metabolism:
• Evident by  daytime melatonin level In ASD individuals, even
when melatonin was not recently given, leading to the loss of
normal melatonin circadian rhythm (Nir I. 1995, Ritvo ER. 1993)
• This problem responds to a reduction in melatonin dose rather than
an increase in dose (Braam W. 2010)

Melatonin Systematic review
• 12
citaBons
(4
case
reports,
3
retrospecBve
studies,
2
open-‐
label
clinical
trials,
and
3
placebo-‐controlled
trials)
• literature
supports
the
existence
of
a
beneficial
effect
of
melatonin
on
sleep
in
individuals
with
ASD,
with
only
few
and
minor
side
effects
Fabian Guénolé a, et.al. Melatonin for disordered sleep in
individuals with autism spectrum disorders: Systematic
review and discussion. Sleep Medicine Reviews (2011)

Other agents
• Niaprazine
• Mirtazapine
• Clonidine
• Clonazepam

Niaprazine
Rossi PG1,et.al. Niaprazine in the treatment of autistic disorder. J Child
Neurol.(1999)

Mirtazapine
Posey DJ1,et.al. A naturalistic open-label study of mirtazapine in autistic and other
pervasive developmental disorders, Child Adolesc Psychopharmacol. (2001)

Clonidine
Xue
Ming,
et.al.
Use
of
clonidine
in
children
with
auBsm
spectrum
disorders.
Brain
and
Development
(2008)

Clonazepam
• Severe NREM parasomnias, such as sleep
terrors and sleepwalking
• Rhythmic movement disorder
• REM sleep behaviour disorder
Kyle P. Johnson, et.al. Sleep Patterns in Autism Spectrum Disorders,
Child Adolesc Psychiatric Clin N Am 18 (2009)

PROGNOSIS
• Persist past mid-puberty (Sivertsen B 2012)
• Last for many years, continue into
adulthood (A.M. Robinson 2004)
• In one study, 63% of children with ASD and
sleep problems experienced persistence of
sleep difficulties over time (L. Wiggs,2004)

Conclusion
• Melatonin
proven
to
be
effecBve
• More
data
needed
on:
• Dosing,
Bming,
type
(slow
vs.
fast
release
preparaBons)
• Long-‐term
side
effect
and
follow-‐up

Take Home Message
• Children
and
adolescents
with
an
ASD
are
at
substanBal
risk
for
experiencing
sleep
problems,
parBcularly
insomnia
• The
clinician
assessing
a
child
with
an
ASD
should
screen
carefully
for
sleep
disorders
and
make
referrals
as
indicated
• Consider
slow
melatonin
metabolism
that
needs
to
be
managed
by
lower
melatonin
levels
rather
than
increasing
it
• IdenBfying
and
treaBng
sleep
disorders
may
result
not
only
in
improved
sleep,
but
also
impact
favourably
on
dayBme
behaviour
and
family
funcBoning

Reference
1. Weissman L, Augustyn M. Autism spectrum disorder in children and adolescents: Pharmacologic
interventions. Up to date (2014)
2. Hodge D, et.al. Sleep patterns in children with and without autism spectrum disorders: Developmental
comparisons, Research in Developmental Disabilities (2014)
3. Hollway JA, et.al. Correlates and risk markers for sleep disturbance in participants of the Autism
Treatment Network. J Autism Dev Disord (2013)
4. Kotagal S, et.al. Sleep in children with autism spectrum disorder. Pediatr Neurol (2012)
5. Rossignol DA,et.al. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev
Med Child Neurol (2011)
6. Guénolé a F, et.al. Melatonin for disordered sleep in individuals with autism spectrum disorders:
Systematic review and discussion. Sleep Medicine Reviews (2011)
7. Cortesi F, et.al. Sleep in children with autistic spectrum disorder. Sleep Med (2010)
8. Tricoire H, Locatelli A, Chemineau P, Malpaux B. Melatonin enters the cerebrospinal fluid through the
pineal recess. AU SO Endocrinology. (2002)
9. Reichlin S, Baldessarini RJ, Martin JB. The pineal gland: A model of neuroendocrine regulation. In: The
Hypothalamus, Raven Press, New York (1978)

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