Department
www.jpedhc.org
Pharmacology Continuing Education
Section Editors
Pharmacologic
Teri Woo, PhD, RN, CPNP
University of Portland School of
Nursing, Kaiser Permanente,
Treatment for the
Portland, Oregon
Elizabeth Farrington, PharmD,
Core Deficits and
FCCP, BCPS, FCCM
University of North Carolina School
of Pharmacy and North Carolina
Children’s Hospital, Chapel Hill,
Associated
North Carolina
Symptoms of Autism
in Children CE
Lis West, MS, CPNP, Julee Waldrop, MS, FNP, PNP,
& Susan Brunssen, PhD, RN
OBJECTIVES
Based on the content of the article, you will be able to:
1. Identify five core deficits and associated behaviors of autism.
2. Examine the evidence for specific pharmacologic treatments for the core deficits
and associated symptoms of autism in children.
3. Discuss the importance of caregiver education with regard to side effects of phar-
macologic therapies.
4. Identify pharmacologic therapies that provide researchers with an abundance of
possible future research avenues.
Lis West, Pediatric Nurse Practitioner,
Carolina Pediatric Group, Fayetteville, NC.
ABSTRACT
The results support moderate success
Autism is a neurodevelopmental condi-
in treating the associated behaviors of
Julee Waldrop, Clinical Associate
Professor, University of North Carolina,
tion affecting 1 out of 160 children in
autism and minimal success in treating
Chapel Hill, NC.
the United States today. Only risperi-
core deficits across all drug classes. Pre-
done has Food and Drug Administra-
liminary evidence demonstrates possi-
Susan Brunssen, Assistant Professor,
tion approval for the pharmacologic
ble uses for atypical antipsychotic
University of North Carolina, Chapel Hill,
management of autism in children.
agents, selective-serotonin reuptake
NC.
However, health care providers may
inhibitors, stimulants, and N-methyl-
Correspondence: Julee Waldrop, MS,
prescribe other drugs used off-label to
D-aspirate receptor antagonists in de-
FNP, PNP, The University of North
assist autistic children and their families
creasing the core behaviors and associ-
Carolina, CB#7225, Chapel Hill, NC 27599
with the core deficits and associated be-
ated symptoms of autism. More studies
e-mail: jwaldrop@med.unc.edu.
haviors of this condition. Evidence for
and longer periods of follow-up are
J Pediatr Health Care. (2009). 23, 75-89.
the use of these medications will be
needed before definitive guidelines
discussed in this continuing education
can be suggested. J Pediatr Health
0891-5245/$36.00
offering. Meta analyses, randomized
Care. (2009) 23, 75-89.
Copyright Q 2009 by the National Asso-
clinical trials, and other prospective ex-
ciation of Pediatric Nurse Practitioners.
perimental studies of pharmacotherapy
Key words: Autism, autism symp-
Published by Elsevier Inc. All rights
conducted in the United States in the
toms, autism management, side effects,
reserved.
past 10 years in children between the
core deficits, parent education, phar-
doi:10.1016/j.pedhc.2008.12.001
ages of 5 and 15 years were reviewed.
macologic.
Journal of Pediatric Health Care
March/April 2009
75

---

Autism is a lifelong, biologically
TABLE 1. Core deficits and associated behaviors of autism
based, neurobehavioral disorder
that affects verbal and nonverbal
Core deficits
Associated behaviors
communication,
social
interac-
Impaired social interaction:
Hyperactivity/inattention:
tions, and daily activities. The
 Prefers to play alone
 Hyperactivity
prevalence of autism is increasing,
 Lack of or poor peer relationships
 Inattention
with reported rates of 1:150 in 2007
 Rare initiation of interaction with others
 Impulsiveness
(Centers for Disease Control and
 Missed social cues
 Restlessness
 Difficulty with social engagement—
Prevention
[CDC],
2007)
and
social withdrawal
a male to female ratio of 4.3:1. In
 Lack of interest in sharing pleasure or
the United States, as many as
gratification with others
483,000 persons younger than 20
 Lack of nonverbal communication to
years are affected by autism, and
monitor/control social interactions
 Difficulty with empathy
114,000 of those are children youn-
 Lethargy with no drive for social
ger than 5 years. By the year 2056,
interaction
the prevalence of autism is pro-
Impaired communication and
Aggression:
jected to increase by 43%, affecting
imaginative play:
 Tantrums
as many as 163,000 children youn-
 Difficulty with communication
 Self-injury
engagement
 Anxiety
ger than 5 years (Fombonne,
 Difficulty reading body language
 Irritability
2003). The alarming increase in
 Speaking with fixation on a topic
 Maladaptive behavior
children diagnosed with autism
 Echolalia
 Emotional lability
highlights the pressing need for
 Delayed or deviant language
practitioners to have not only an
 Muteness
 Reversal of pronouns
understanding of autism but also
 Difficulty with creative thinking
an understanding of how to treat
 Difficulty with reflective thinking
the core and associated behaviors
Restrictive, repetitive activities and
Repetitive:
of autism.
interests:
 Obsessive-compulsive-like behaviors
Autism is a multidimensional
 Bound by routines
 Motor stereotypies: hand-flapping,
 Intense focus on favored objects
rocking, lip licking
disorder, often referred to as Au-
Sleep disorders:
tism Spectrum Disorder or Perva-
 Difficulty falling asleep
sive Developmental Disorder. The
 Difficulty remaining asleep
term ‘‘spectrum’’ exemplifies the
Tics
wide variance in type and intensity
Data from APA, 1994; Findling et al., 1997; McDougle et al., 1997; Perry et al., 1997;
of autism symptoms and behaviors
RUPPAN, 2002; Gringras, 2000.
and includes the overlapping sub-
diagnoses of Autism Disorder, As-
perger Syndrome, and Pervasive
needs, strengths, and deficits. The
confirm their efficacy and safety in
Developmental Disorder Not Oth-
behaviors of autism fall into two cat-
autistic children.
erwise Specified, as well as the un-
egories: core deficit behaviors and
More importantly, many phar-
common
Rhett
Syndrome
and
associated symptoms (Table 1). Al-
macologic treatments are being
Childhood Disintegrative Disorder
though autism has no cure and no
prescribed off-label to autistic chil-
(American Psychiatric Association
single drug or therapy has proven
dren with little research to support
[APA], 1994). For this article, the
effective for treating all the behav-
such use and, when studied, most
term autism will refer to Autism
iors of autism, behavioral and edu-
of the research includes only a small
Spectrum Disorder/Pervasive De-
cational interventions help improve
number of subjects. For example, in
velopmental Disorder.
overall functioning. Pharmacologic
a 2001 survey in North Carolina
The Diagnostic and Statistical
therapy can augment responses to,
(Langworthy-Lam, Aman, & Van
Manual of Mental Disorders, 4th
and benefits from, behavioral and
Bourgondien, 2002), 26% of respon-
edition (DSM-IV; APA, 1994) defines
educational interventions as well
dents reported using buspirone
the core criteria of autism as: (a)
as improve overall functioning.
despite a lack of supportive pla-
poor shared social interaction, (b)
Thus, in an attempt to control asso-
cebo-controlled studies. In some
impaired communication and imag-
ciated symptoms and improve core
facilities, guanfacine is considered
inative play, and (c) very limited
deficits, medical providers may pre-
a first-line drug treatment for Atten-
and narrowed interests and activi-
scribe pharmacologic treatments
tion Deficit/Hyperactivity Disorder
ties. Autism, however, also is a het-
not approved by the U.S. Food and
(ADHD) symptoms in autistic chil-
erogeneous disorder, with each per-
Drug Administration (FDA) without
dren
(McDougle,
2004),
even
son
having
specific
individual
adequate published research to
though only one placebo-controlled
76
Volume 23  Number 2
Journal of Pediatric Health Care

---

study exists. In addition, drugs such
years
conducted
in
the
U.S.
very much improved or much
as clomipramine have failed to
Searches returned 12 randomized
improved.
show efficacy in the autistic popu-
clinical trials and nine other pro-
lation yet have been prescribed
spective studies. Study authors, re-
Antipsychotic Agents
to autistic children (Aman, Van
search design, sample size, dosing
Typical and atypical antipsy-
Bourgondien, Wolford, & Sarphare,
schedules, and adverse effects are
chotic agents have shown some
1995).
summarized in Table 2.
efficacy in the treatment of autism.
Conventional neuroleptic agents
such as haloperidol have been
used to treat the more aggressive
With the exception of risperidone, the FDA has not
and violent behaviors associated
with autism, but their neurologic
approved any pharmacologic drug for the
adverse effects are often unaccept-
treatment of autism in children.
able. Some success in treating the
more
disruptive
behaviors
of
autism is attributed to haloperidol,
but it has been used sparingly be-
With the exception of risperi-
RESULTS
cause of the high risks of extra py-
done, the FDA has not approved
Results are presented by class of
ramidal symptoms (EPS), tardive
any pharmacologic drug for the
compounds,
according
to
the
dyskinesia, and withdrawal dyski-
treatment of autism in children.
strength of overall evidence for
nesia (Campbell et al., 1997; Ma-
However, caretakers may seek
the efficacy of that class. The re-
lone, Maislin, Choudhury, Gifford
help in identifying pharmacother-
search reviewed shows moderate
& Delaney, 2002; Research Units
apy as an adjunct to current behav-
success in treating the associated
on Pediatric Psychopharmacology
ioral and educational management
behaviors of autism and minimal
Autism Network [RUPPAN], 2002).
even if it is prescribed off-label. Un-
success in treating core deficits.
Long term-use of haloperidol in-
fortunately, without knowing phar-
Criteria for judging efficacy of
creases the risk of withdrawal dys-
macotherapy options and possible
therapy varied according to study
kinesia and, without medication
behavioral effects, the search for
design, sample size, and measure-
holidays, may result in irreversible
appropriate pharmacotherapy may
ment instruments; the investigators’
tardive
dyskinesia
(Campbell
prove long, arduous, and frustrating
interpretations were accepted for
et al.). As a result, only one study
for the practitioner, caretaker, and
this review. Assessment instru-
comparing haloperidol with olan-
patient. The purpose of this article
ments used to quantify behavioral
zapine has been conducted during
is to examine the evidence for spe-
responses to treatment included
the past 10 years, and the results
cific pharmacological treatments
the Aberrant Behavior Checklist-
support the findings of earlier stud-
for the core deficits and associated
Community
Version
(ABC-CV),
ies (Malone, Cater, Sheikh, Choud-
symptoms of autism in children.
Clinical Global Impressions Scale
hury & Delaney, 2001).
(CGI), Vineland Adaptive Behavior
Several atypical antipsychotic
METHODS
Scale (VABS), Ritvo-Freeman Real
agents may be helpful in the treat-
Pub-Med and Cumulative Index
Life Rating Scale, Self Injurious Be-
ment of disruptive and maladap-
to Nursing and Allied Health Liter-
havior Questionnaire (SIBQ), Child
tive
behaviors
associated
with
ature (CINAHL) were searched for
Autism Rating Scale (CARS), Chil-
autism. Currently, the atypical anti-
peer-reviewed,
English-language
dren’s Yale-Brown Obsessive Com-
psychotic agents risperidone and
studies using the key terms autism,
pulsive Scale (CY-BOCS), Screen
olanzapine
have
demonstrated
pervasive developmental disorder,
for Child Anxiety Related Emotional
more favorable results than have
pharmacotherapy, antipsychotics,
Disorders (SCARED), Swanson, No-
other
similar
atypical
antipsy-
antidepressants, stimulants, anti-
lan and Pelham Questionnaire-IV
chotics.
convulsants, opiate antagonists,
(SNAP-IV) for the DSM-IV criteria
Risperidone. Risperidone
is
alpha-2-noradrenergic
agonists,
for ADHD, and the Child Psychiatric
the most widely researched drug
N-methyl-D-aspirate (NMDA) re-
Rating Scale. Treatment effect was
for behavior modification in chil-
ceptor antagonists, acetylcholines-
most often measured by assessing
dren with autism. In October
terase
inhibitors,
and
specific
behavioral changes using the ABC
2006, the FDA approved risperi-
drug names. Studies were selected
and the CGI subscales of illness se-
done for the treatment of irritable,
with emphasis given to meta-anal-
verity (CGI-S) and global improve-
aggressive, and self-injurious be-
yses, and prospective experimen-
ment (CGI-I). Unless otherwise
haviors in children with autism,
tal and quasi-experimental studies
specified, ‘‘responder’ is defined
and currently it is the only drug
in autistic children ages 5 to 18
as an improvement on the CGI of
approved for the treatment of
Journal of Pediatric Health Care
March/April 2009
77

---

TABLE 2. Research meeting review criteria for pharmacotherapy for core deficits and
associated symptoms of asthma
Drug, author
Research design
Sample size
Dosing schedules
Adverse effects
Risperidone,
8-wk, open-label,
6 male subjects,
Initial: 0.25 mg hs
Weight gain, sedation
Findling et al.
uncontrolled pilot
ages 5-9 y
 Increased in 0.25 mg
(1997)
study
weekly increments,
bid, until therapeutic
 Doses could be
divided unevenly for
increased therapeutic
response
 End dose 0.75-1.5
mg/day (0.03-0.06
mg/kg/day), mean
daily dose 1.1 mg/day
(0.04 mg/kg/day)
Risperidone,
12-wk, prospective,
18 subjects (15 males),
Initial: 0.5 mg hs
Weight gain, sedation
McDougle et al.
systematic,
ages 5-18 y
 Weekly increments of
(1997)
open-label trial
0.5 mg
 Doses divided (bid)
after first increase until
maximum response
 Optimal dose range:
1-4 mg/day, average
1.8 Æ 1.0 mg/day
Risperidone,
Open label pilot trial
6 subjects (5 male),
Initial: 0.5 mg/day qd or
Sedation, salivation,
Perry et al.
ages 7-14 y
bid
stereotypies
(1997)
 Increased in incre-
ments of 0.5 mg
‘‘every few days’’
 Increases based on
response, adverse ef-
fects, and proportion
to adult doses
 Optimal dose: 1-6 mg/
day, average 2.7 Æ
2.2 mg/day
Risperidone,
Multi-site, multi-phased
101 (82 males),
Initial:
Weight gain,
RUPPAN
study:
ages 5-17 y
\ 20 kg - 0.25 mg hs
drowsiness, increased
(2002)
Phase 1: 8-wk double-
$ 20 kg - 0.5 mg hs,
appetite, fatigue,
blind, randomized,
 #45 kg: increased in
drooling, dizziness
placebo-controlled
0.5 mg increments to
trial;
bid by day 4 and then
Phase 2: 8-wk, open-
increased to maxi-
labeled control study
mum by day 29 of
for non-responders in
2.5 mg/day, 1 mg am,
Phase 1 placebo
1.5 hs
group
 >45 kg: 3.5 mg/day,
1.5 mg am and 2.0 mg
hs by day 29
 Change in dosing
based on adverse
effects or therapeutic
results allowed before
day 29
 No increases in doses
after day 29
 Dose range: 1.0-3.5
mg/day, average 1.8
Æ 0.7 mg/day
4-month continuation
63 subjects, ages 5-17 y
 Continuation of
No additional adverse
phase (phase 3) of
RUPPAN (2002)
effects reported
RUPPAN (2002) study
continued on page 79
78
Volume 23  Number 2
Journal of Pediatric Health Care

---

TABLE 2. Continued.
Drug, author
Research design
Sample size
Dosing schedules
Adverse effects
Risperidone,
8-wk, randomized,
38 children ages 5-17 y
 Mean entry dose into
Increased appetite
RUPPAN
double-blind, placebo
discontinuation
(2005a)
substitution study of
phase: about 2 mg/
withdrawal (Phase 4 of
kg/day
RUPPAN 2002)
 During 4-month
phase, doses could
be adjusted based on
therapeutic response
and adverse effects
with a maximum of 3.5
mg/day for subjects
weight 15-45 kg and
4.5 mg/day for sub-
jects weighing >45 kg
Olanzapine,
7-wk, open-labeled,
12 subjects (8 males),
Olanzapine:
Sedation, weight gain
Malone et al.
randomized, parallel
ages 5-12 y
 Initial: # 40 kg 2.5 mg
(2001)
comparison control
qod and >40 kg 2.5
group, pilot study
mg qd
 Increments of 2.5 mg/
day
 Maximum of 5 mg/wk
increment until thera-
peutic
 Maximum dose 20
mg/wk
 Range 5-10 mg/day,
mean 7.9 Æ 2.5 mg/
day
Haloperidol:
 Initial: #40 kg
0.25 mg/day, >40 kg
0.5 mg/day
 Increments of 0.5 mg/
day to maximum of
1 mg/wk increment
 Maximum dose 5 mg/
day
 Range 0.5-2.5 mg/
day, mean 1.4 Æ 0.7
mg/day
Olanzapine,
8-wk, double-blind,
11 subjects (9 male),
Subjects \40 kg:
Weight gain, increased
Hollander et al.
randomized, placebo-
ages 6-14 y
 Initial: 2.5 mg qod
appetite, sedation,
(2006)
controlled, parallel
 Increased to 2.5 mg/
constipation
treatment pilot study
day after day 3
 Then increased 5 mg/
day weekly to maxi-
mum of 20 mg/day
Subjects >40 kg:
 Initial: 2.5 mg qd
 Increased 5 mg/day
after day 3
 Then increased
5 mg/day weekly to
maximum of 20 mg/
day
 Dose range:
7.5 mg/day-12.5 mg/
day, mean 10 Æ 2.04
mg/day
continued on page 80
Journal of Pediatric Health Care
March/April 2009
79

---

TABLE 2. Continued.
Drug, author
Research design
Sample size
Dosing schedules
Adverse effects
Quetiapine,
16-wk, open-label,
6 males ages 6-15 y
Initial: 25 mg hs
Sedation
Martin et al.
flexible-dose, trial
 Increased no more
(1999)
than 100 mg/week bid
until therapeutic
 Dose range: 100-350
mg/day (1.6-5.2 mg/
kg/day), bid
 Average dose: 225
mg/day Æ 108.4 mg/
day
Quetiapine,
12-wk, open-labeled,
9 subjects (8 males) ages
Initial: 25 mg bid for 3
Weight gain, sedation
Findling et al.
flexible-dose pilot
10-17 y
days
(2004)
study
 50 mg bid for next 11
days, increased in in-
crements of 50 mg bid
every other wk until
150 mg bid reached
 Then increased in in-
crements of 25-75 mg
bid every other week
until therapeutic or no
longer tolerable
 Maximum of 750 mg/
day
 Doses could be de-
creased, divided un-
equally, or tid due to
adverse effects, range
100-450 mg/day
Fluvoxamine,
10-wk prospective,
28 subjects (14 male),
Initial: 12.5 mg if\40 kg,
Akathisia, agitation,
Martin et al.
open-label study
ages 7-18 y
25 mg if >40 kg divided
behavioral activation,
(2003)
twice a day
sleep difficulties
 Wks 0-4: increased in
weekly increments of
12.5 mg or 25 mg until
maximum of 1.5 mg/
kg/day reached
 Wks 4-10: dose
maintained and only
decreased for adverse
effects
Fluoxetine,
3-phase study:
39 subjects (30 male),
Wk 1: 2.5 mg/day
Agitation, behavioral
Hollander et al.
1) 8-wk, randomized,
ages 5 to 16 y
Wks 2 and 3: titrated per
activation
(2005)
double-blind placebo
subject’s weight, symp-
study followed by
toms and adverse
2) 4-wk washout phase,
effects, maximum of 0.8
followed by
mg/kg/day
3) 8-wk, double-blind,
Wks 4-8: maintain dose
placebo crossover
at day 28, only lowered
trial
for adverse effects
Escitalopram,
10-wk, prospective
28 subjects (25 male),
Dose per day:
Irritability, hyperactivity
Owley et al.
open-label trial
ages 6-17 y
Wk 1: 2.5 mg; Wk 2: 5
(2005)
mg; Wk 3: 10 mg; Wk 4:
15 mg; Wk 5: 20 mg
 Average dose 11.1 mg
Æ 6.5 mg
 Downward titration for
adverse effects of
sleep problems, irrita-
bility, or hyperactivity
continued on page 81
80
Volume 23  Number 2
Journal of Pediatric Health Care

---

TABLE 2. Continued.
Drug, author
Research design
Sample size
Dosing schedules
Adverse effects
MPH,
3-wk, double-blind,
13 autistic children (10
 0.3 and 0.6 mg/kg/
Drowsy, dull, sad,
Handen et al.
placebo-controlled
males), ages 5-11 y
dose given 2-3 times
unhappy
(2000)
crossover study
daily
 Lower dose always
preceded higher dose
MPH,
2-wk double-blind,
72 children ages 5-14 y
 Dose dependant on
Decreased appetite,
RUPPAN
randomized, placebo-
with MPH, in last 2
weight
difficulty falling asleep
(2005b)
controlled crossover
years, no known
 Phase 1: Placebo x1
designed study
adverse reaction to
day, low dose (0.125
followed by an 8-wk
MPH
mg/kg/dose), medium
open-label phase
dose (0.25 mg/kg/
dose), and high dose
(0.5 mg/kg/dose) in
ascending order for 2
days each
 Phase 2: 3 random
ordered groups of low,
medium, and high
MPH doses, tid
 Phase 3: 8-wk open
label for responders
at ‘‘best’’ personal
dosage
Atomoxetine,
8-wk, prospective,
16 children ages 6-14 y
Wk 1: 0.5 mg/kg/day
Irritability
Posey et al.
open-label study
Wk 2: 0.8 mg/kg/day
(2006)
Wk 3: 1.2 mg/kg/day
 If no improvement per
the CGI at end of wk 4,
dose increased to 1.4
mg/kg/day
 Dose to be decreased
for adverse effects
Atomoxetine,
Double-blind, placebo-
13 subjects, ages 5-15 y
 Atomoxetine and
Gastrointestinal
Arnold et al.
controlled,
placebo matched
symptoms, fatigue,
(2006)
randomized, stratified,
 Initial: 0.25 mg/kg/day
increased pulse
crossover pilot
 Increments of 0.3-0.4
mg/kg/day every 4-5
days
 Based on adverse
effects or until
therapeutic
 Maximum dose 1.4
mg/kg/day, no more
than 100 mg/day
 Range 20-100 mg/
day
 Wks 1-3: titration
 Wks 4-6: mainte-
nance
 Wk 7: drug washout
 Wks 8-10: titration of
crossover
 Wks 11-13: mainte-
nance of crossover
 Dose adjusted for
those taking CYP2D6
inhibitors
continued on page 82
Journal of Pediatric Health Care
March/April 2009
81

---

TABLE 2. Continued.
Drug, author
Research design
Sample size
Dosing schedules
Adverse effects
Divalproex sodium,
8-wk, 2:1 randomized,
13 children ages 5-17 y
Initial: 125 mg/day
No significant difference
Hollander et al.
double-blind,
 Increments of 125 mg/
between treatment
(2005)
placebo-controlled
day every 4 days for
and placebo
trial
the first 2 weeks, per
therapeutic response
and tolerability
 Maximum of 30 mg/
kg/day and trough
serum level of 50-100
mg/mL
 End-point mean dose
822.92 Æ 326.21 mg/
day, range 500-1500
mg/day with serum
trough levels 58.23 Æ
21.63 mg/mL
Levetiracetam,
10-wk, double-blind,
20 patients, ages 5-17 y
Days 1-4: 125 mg/day
Agitation, aggression
Wasserman et al.
placebo-controlled
Days 5-8: 250 mg/day
(2006)
study
 After day 8: increased
by 250 mg/day every 4
days until therapeutic
or intolerable
 Average dose 862.5
Æ 279.19 mg/day,
range 500-1250 mg/
day
Guanfacine,
8-wk, prospective, multi-
23 subjects (21 male),
 1.0 to 3.0 mg/day di-
Sedation, irritability,
Scahill et al.
site, open-label trial
ages 5-14 y
vided bid or tid for 8
sleep disturbance
(2006)
wk
 Decrease in medica-
tion allowed at any
time for adverse ef-
fects
Amantadine,
Randomized, double-
39 subjects (34 male),
 Wk 1: placebo, 0.25
Insomnia
King et al.
blind, placebo-
ages 5-15 y
mL/kg/day
(2001)
controlled, parallel-
 Wks 2-5: placebo or
group study
amantadine group
once a day for week 2,
2.5 mg/kg/day (0.25
mL/kg/day), twice
a day for weeks 3-5
 Average dose 168.3
mg/dose, range of 90-
200 mg/dose
bid, Twice a day; CGI, Clinical Global Impressions Scale; hs, bedtime; MPH, methylphenidate; qd, every day; qod, every other day; tid, three
times a day.
autism (FDA, 2006). Risperidone
& Waldrop, 2006, for a review).
found for compulsive behavior
is a dopamine and serotonin re-
Overall improvement from base-
(CY-BOCS) (P \ .0001, McDougle
ceptor antagonist that has a high
line on the CGI-I scale (P \ 00.1,
et al., 1997; P = .005, McDougle
affinity for serotonin receptors
Perry et al., 1997; Findling, Max-
et al., 2005). Using the irritability
(Taketomo, Hodding, & Kraus,
well
&
Wiznitzer,
1997)
and
and stereotypy (P = .02) subscale
2003).
compared with placebo (P \ .001,
of the VABS, significant improve-
Several studies of risperidone in
RUPPAN, 2002) and with
the
ment was noted from baseline
autistic children use similar doses
CARS (P \.005, Findling, Maxwell,
(RUPPAN, 2005b). Irritability also
and schedules and show similar re-
& Wiznitzer, 1997). Responder
was improved compared with pla-
sults (Table 2). All of the studies
rates of 66% to 82.5% (CGI) also
cebo (P \ .001) (RUPPAN, 2002).
find risperidone to be safe and ef-
were noted (McDougle et al.,
The Ritvo Freeman Real Life Rating
fective for a variety of symptoms
1997; RUPPAN, 2005b). Significant
Scale showed overall improve-
associated with autism (See West
decreases
from
baseline
were
ment from baseline (P \ .009,
82
Volume 23  Number 2
Journal of Pediatric Health Care

---

McDougle et al., 1997; P \ .001,
normal movements, EPS, or dyski-
replicated
placebo-controlled,
McDougle et al., 2005). Subscales
nesias are described, but weight
double-blind studies supporting
on affectual reactions (P \ .008,
gain and sedation were again
their use in the pediatric autistic
P \ .008), sensory response (P \
notable adverse effects (Malone et
population.
.005, P = .004) (McDougle et al.,
al., 2001; Hollander et al., 2006)
Fluvoxamine. An open-label
1997;
McDougle
et
al.,
2005,
(Table 3).
study of fluvoxamine in autistic
respectively) and sensory motor
Quetiapine. Quetiapine is a
children ages 7 to 18 years showed
behaviors (P = .002, McDougle
dopamine and serotonin receptor
no significant improvement in
et al., 2005) improved as well. Im-
antagonist as well as a histamine
global functioning (GCI), repeti-
provement from baseline also was
and adrenergic receptor antagonist
tive behaviors (CY-BOCS) or anxi-
significant
in
the
maladaptive
(Lacy, Armstrong, Goldman, &
ety symptoms (SCARED) from
baseline. Responder rate (as mea-
sured by either a 25% decrease in
either
CY-BOCS,
SCARED,
or
improvement on the GCI) was
SSRIs are helpful in treating the core deficits of
100% for female subjects (four of
communication and socialization as well as
four) compared with 29 for male
subjects (four of 14) (Table 2).
repetitive, irritable, and anxiety symptoms of
Unfortunately, adverse effects of
autism.
agitation, behavior activation, and
insomnia in 50% of the subjects
were
noted
(Martin,
Koenig,
behavior component of the VABS
Lance,
2006).
Because
similar
Anderson, & Scahill, 2003) (Table
(P \ .001) (McDougle et al.,
antipsychotic agents have demon-
2).
2005) and in the aggression com-
strated efficacy in the treatment of
Fluoxetine. In the only pla-
ponent (SIBQ) (P \.0001, McDou-
disruptive behaviors of autism,
cebo-controlled crossover trial, flu-
gle et al., 1997). In addition, 68% of
quetiapine was anticipated to yield
oxetine was superior to placebo
the responders maintained a posi-
similar results. However, studies
(P = .004, effect size 0.76) in reduc-
tive response during a 4-month
(Table 2) showed no significant
ing
repetitive
behaviors
(CY-
drug maintenance phase (RUP-
improvements, and adverse effects
BOCS). Although there was a 56%
PAN, 2005a; McDougle et al.,
caused many subjects to drop out
improvement (GCI), it was not sta-
2005); however, no further im-
of the studies (Martin, Koenig,
tistically significant compared with
provements were seen in any of
Scahill, & Bregman, 1999; Findling
placebo (Hollander, Phillips, et al.,
the measurements. Adverse effects
et al., 2004). Although no medica-
2005) (Table 2). No significant ad-
included weight gain in 67% to
tion-related EPS were reported by
verse effects, including suicidal
83% of subjects, sedation in 33%
either
study,
researchers
con-
ideation, were noted when com-
to 66% of subjects, and increased
cluded that quetiapine is not effec-
pared with placebo. The few ad-
serum prolactin levels by as much
tive or well tolerated for the treat-
verse effects noted, even though
as 57% (Table 2).
ment of autism symptoms.
not significant, were sedation, agi-
Olanzapine. Like risperidone,
tation, and anorexia.
olanzapine is a dopamine and se-
Antidepressants
Escitalopram. Use of escitalo-
rotonin receptor antagonist with
The similarity of autism symp-
pram showed significant overall
high affinity binding for dopamine
toms to serotonin-related disorders
improvement compared with pla-
receptors as well as muscarinic,
such
as
obsessive
compulsive
cebo (CGI, P \ .001). Significant
histamine, and adrenergic recep-
disorder has led researchers to in-
improvement from baseline also
tors (Eli Lilly, 2006). Two small
vestigate the efficacy of serotonin
was demonstrated by the ABC in ir-
studies (Table 2) demonstrated sig-
reuptake inhibitors and selective
ritability, lethargy, stereotypy, hy-
nificant improvement over time
serotonin
reuptake
inhibitors
peractivity,
and
inappropriate
(P \.05) for all items in the autism
(SSRIs) in the treatment of autism.
speech (P \ .001). Unfortunately,
factor of the Child Psychiatric Rat-
SSRIs inhibit serotonin reuptake
escitalopram showed adverse ef-
ing Scale except underproductive
(Posey, Erickson, Stigler, & McDou-
fects of irritability and hyperactiv-
speech (Malone et al., 2001) and
gle, 2006) but have little effect on
ity with increasing dose. A variable
a 50% to 83% responder rate
the reuptake of other neurotrans-
dose range for tolerability also was
(GCI) (Hollander et al., 2006; Ma-
mitters such as dopamine and nor-
reported (Tables 2 and 3) (Owley
lone et al., 2001). However, no sta-
adrenalin, which limits the adverse
et al., 2005).
tistically significant changes in GCI
affects of SSRIs. Unfortunately,
SSRIs are helpful in treating the
were observed. No reports of ab-
there
are
few
prospective
or
core deficits of communication
Journal of Pediatric Health Care
March/April 2009
83

---

TABLE 3. Possible pharmacological approach for core deficit and associated behaviors of
autism
Core deficits and associated behaviors*
Impaired
Restrictive,
Impaired social
communication and
repetitive activities
interaction
imaginative play
and interests
Inappropriate
speech/
Inappropriate
Social
repetitive
Repetitive
Odd
Drugs
speech
withdrawal Lethargy Maladaptive
speech
behaviors behaviors Compulsions Stereotype
Risperidone
x
x
x
x
x
x
Olanzapine
Quetiapine
Fluvoxamine
x
Fluoxetine
x
Escitalopram
x
x
x
Methylphenidate
x
x
x
Atomoxetine
x
x
x
x
x
Divalproex
x
x
Levetiracetam
Guanfacine
x
x
Amantadine
x
x
x
*No drugs have been associated with improvements for the core deficits and associated behaviors of sleep disorder and tics.
and socialization as well as repeti-
children have moderate to severe
typy (P = .05) and inappropriate
tive, irritable, and anxiety symp-
difficulties
with
distractibility,
speech (P = .02) subscales (RUP-
toms of autism. Autistic children
concentration, finishing tasks, hy-
PAN, 2005b). In a study by Handen
show moderate responses to the
peractivity,
excitability,
fidgeti-
et al. (2000), almost 62% of chil-
SSRIs fluvoxamine and fluoxetine,
ness,
and
decreased
attention
dren demonstrated a response as
while escitalopram decreases hy-
span (Lecavalier, 2006). Unfortu-
defined by a 50% decrease in the
peractivity,
irritability,
anxiety,
nately, stimulants are not as ef-
Teacher Connors Hyperactivity In-
and repetitive behaviors in autistic
fective in the autistic population
dex (P \ .0086). The hyperactivity
children. Of particular interest is
and have increased adverse ef-
(P \ .003), stereotypy (P \ .008)
fluvoxamine, because female au-
fects when compared with their
and inappropriate speech (P \
tistic subjects show a selective re-
effects on typically developing
.001) subscales of the ABC were
sponse to this drug. Although
peers. For example, methylpheni-
also significantly better than pla-
only one study asked about sui-
date has a success rate of 70%
cebo. However, a different global
cidal ideation (Hollander, Phillips,
(Greenhill et al., 2001) to 90%
assessment tool (CARS) found no
et al., 2005), the sample was small
(Elia, Borcherding, Rapoport, &
change in global autism symptoms
and the probability still exists and
Keysor,
1991)
in
controlling
or improvement in core deficit
should be monitored for all chil-
ADHD symptoms in typically de-
behaviors (Table 2).
dren taking SSRIs. Unfortunately,
veloping children, with adverse
Adverse effects of irritability,
many drugs in the antidepressant
effects as low as 1.4% (Greenhill
lethargy, sadness, dullness, and so-
class are often plagued by intolera-
et al., 2001).
cial
withdrawal
increase
with
ble adverse effects.
Methylphenidate. Methylphe-
higher
methylphenidate
doses
nidate stimulates the brain stem
(Handen et al., 2000; RUPPAN,
Medications Used for
and cerebral cortex by blocking
2005b). Because a high rate of ad-
Attention Deficit Hyperactivity
the reuptake of norepinephrine
verse effects was also noted in the
Disorder Symptoms
and dopamine to increase the
placebo group (Handen et al.), it
Symptoms of ADHD are not un-
availability of these neurotransmit-
is difficult to identify and attribute
usual in the course of autism and
ters (Taketomo, Hodding, & Kraus,
significant adverse effects to meth-
frequently are targeted by pharma-
2006). Methylphenidate demon-
ylphenidate (Table 2).
cologic
interventions
(Handen,
strated a significant effect on the
Atomoxetine. Atomoxetine is
Johnson,
&
Lubetsky,
2000).
hyperactivity
subscale
of
the
a selective norepinephrine reup-
ADHD symptoms are the most
ABC (P \ .009 teacher; P \ .001
take inhibitor with a 43% response
common associated symptoms of
parent) and a significant improve-
rate, defined as 25% improvement
autism; more than 50% of autistic
ment over placebo in the stereo-
on the ABC-Hyperactivity Subscale
84
Volume 23  Number 2
Journal of Pediatric Health Care

---

Document Outline

• Pharmacologic Treatment for the Core Deficits and Associated Symptoms of Autism in Children
  • Methods
  • Results
    • Antipsychotic Agents
    • Risperidone
    • Olanzapine
    • Quetiapine
    • Antidepressants
    • Fluvoxamine
    • Fluoxetine
    • Escitalopram
    • Medications Used for Attention Deficit Hyperactivity Disorder Symptoms
    • Methylphenidate
    • Atomoxetine
    • Anticonvulsant Agents
    • Divalproex sodium
    • Levetiracetam
    • Alpha-2 Adrenergic Agonists
    • Guanfacine
    • N-methyl-D-aspirate Receptor Antagonists
    • Amantadine
  • Discussion
  • Summary
  • References

---