ASD is defined by the DSM-V as the presence of persistent impairment in
reciprocal social communication and social interaction, and restricted, repetitive
patterns of behavior, interests, or activities, present from early childhood, and
impairing everyday functioning (Table 88-1).
1 The diagnosis is made clinically,
though standardized behavioral diagnostic instruments, including caregiver
interviews, questionnaires, and clinician observation measures (e.g., Autism
Diagnostic Interview and Autism Diagnostic Observation Schedule), are available to
potentially assist in diagnosis.
by all of the following, currently or by history (examples below):
initiate or respond to social interactions.
poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body
language or deficits in understanding and use of gestures; to a total lack of facial expressions and
friends; to absence of interest in peers.
following, currently or by history (examples below):
lining up toys or flipping objects, echolalia, idiosyncratic phrases).
Insistence on sameness, inflexible adherence to routines, or ritualized patterns or verbal nonverbal
greeting rituals, need to take same route or eat food every day).
preoccupation with unusual objects, excessively circumscribed or perseverative interest).
smelling or touching of objects, visual fascination with lights or movement).
Severity is based on social communication impairments and restricted, repetitive patterns of
Symptoms must be present in the early developmental period (but may not become fully manifest until
social demands exceed limited capacities, or may be masked by learned strategies in later life).
should be below that expected for general developmental level.
After a child is identified to have a developmental disorder, further diagnostic
workup is warranted to identify an etiologic cause, because some causes may be
treatable (e.g., metabolic disorder), some may inform of other potential comorbid
medical problems (e.g., cardiac conditions in Down syndrome and fragile X
syndrome), and some may help inform parents of risks for future children. This
further etiologic workup should include a thorough medical history (including
prenatal and birth history), a family history going back three or more generations, and
a physical and neurologic examination focused on findings consistent with
If children with ID or GDD still do not have a known etiologic cause after this
workup, they should be referred for chromosomal microarray and possibly screening
for inborn errors of metabolism given the treatable nature of some metabolic
4 The American College of Medical Genetics and Genomics proposes that
in the event of a diagnosis of ASD without a known cause despite the above workup,
all children should undergo chromosomal microarray, those children with clinical
indicators should undergo metabolic or mitochondrial testing, fragile X testing should
be performed for all boys, MECP2 (Rett syndrome) testing should be performed in
all girls, PTEN testing in children with macrocephaly, and neuroimaging only if
specific clinical indicators (e.g., seizures, regression, history of stupor/coma,
behavior analysis (ABA) services.
What signs and symptoms of autism spectrum disorder does L.B. demonstrate?
Based on the DSM-5 criteria for ASD, L.B. is showing persistent deficits in social
communication and social interaction in multiple settings, as demonstrated by his
deficits in nonverbal communication (poor facial expressions), lack of relationship
building with children, and poor social–emotional reciprocity (lack of shared
enjoyment). L.B. also demonstrates restricted, repetitive patterns of behavior with his
stereotyped “woop”-ing noises and his inflexible insistence on sameness, with
aggression associated with transitions.
Therapy and Psychosocial Interventions
Individuals with ID or ASD can benefit from many different services to help with
issues of communication, social skills, sensory integration, behavior modification,
gross and fine motor, executive functioning, and adaptive functioning. Most of these
services are provided to children through the public education system, at no cost to
the families, as ensured by the Individuals with Disabilities Education Act (IDEA).
The IDEA provides all states with grants to provide early intervention services for
children with developmental delays under the age of 3. Services vary between states,
though each child and family are evaluated and given an Individualized Family
Service Plan (IFSP), which spells out the services to be provided, which may
include, but are not limited to, physical therapy, occupational therapy, speech and
language therapy, and behavioral therapy. For children reaching the age of 3 years,
and still eligible for specialized education, an Individualized Education Plan (IEP) is
drafted, which outlines the services to be provided in the school setting, starting in
preschool. IEP services could include all of the same types of services as above, as
well academic support, social skills groups, social pragmatics counseling,
vocational training, and emotional counseling. IEPs are required to be reevaluated
every 3 years, with updated testing and evaluation. Families must consent to both
IFSPs and IEPs, and if they disagree with the supports proposed, there is a process
by which they can appeal to have changes made.
Despite the services assured by the IDEA, children and families with
developmental disabilities also often receive psychosocial services in their
communities. In fact, in the 2011 Survey of Pathways to Diagnosis and Services,
almost two-thirds of children with ASD and/or ID were receiving a communitybased service.
28 The odds of using any school- or community-based service were
almost 8 times more likely for children with ASD, and over 9 times more likely for
children with ID, compared to children without those respective diagnoses.
To address the core symptoms of ASD, which include social communication
deficits and repetitive, restricted behaviors and interest, the most prevalent treatment
modality has been applied behavior analysis (ABA). ABA is a behavioral therapy
rooted in the concepts of operant conditioning, in which an antecedent leads to a
behavior, which results in a consequence. In ABA, preferred behavior, such as an
appropriate social response, is reinforced with an incentive. Classic ABA employs
the use of discrete trial training (DTT), in which specific skills are broken down into
discrete components and systematically taught in highly structured settings, often
using incentives like food and stickers. Critics of this form of ABA worry that
children with ASD are unlikely to apply the learned skills outside of the trial setting.
As a result, multiple different therapy approaches have been created, such as Pivotal
Response Therapy and the Early Start Denver Model, both derivations of ABA, and
the Developmental, Individual-differences, Relationship-based (DIR) Floortime
approach, which all operate in more naturalistic settings, focus more on building
child initiation and motivation, and employ natural incentives like positive affect and
affection. The research evidence to support such interventions for children and young
adults with ASD varies widely, as is explored in Wong et al.’s
recent review. Operant conditioning though, and the principles of manipulating
antecedents, behavior, and reinforcements, remains the mainstay for the treatment of
aggressive behaviors in individuals with developmental disabilities.
Individuals with ID often require the same types of interventions as individuals
with ASD, though perhaps with a stronger emphasis on adaptive functioning training,
and building skills of independent living. Likewise, for individuals with ID, the
evidence base for psychological interventions is varied. One recent review and
meta-analysis of psychological therapies for individuals with ID showed that in the
literature, individual therapy seems to be superior to group interventions, and
sizes exist for therapy for depression and anger, though there is no evidence that
therapy has an effect on interpersonal functioning.
The evidence supporting psychopharmacologic interventions in individuals with
ID/ASD is relatively limited. There are only a few large double-blind, randomized,
placebo-controlled trials (RCTs), many of which were funded by, or affiliated with,
the manufacturers of the particular study medications. Most of the existing RCTs are
for individuals with ASD and are of children and adolescents, likely, in part, because
of the complications involved in consenting adults with ID/ASD to participate in
research. Additionally, the targets for medication intervention with the strongest
research evidence are behaviors, which relay little about any possible underlying
emotional etiology for the individual.
Despite the limitations of the evidence, clinicians working with individuals with
ID/ASD know that medications can often serve a very important role as part of a
comprehensive treatment plan. Although much of the literature is of studies of
children with ASD, it should be noted that a large percentage of these studies
contained many individuals with comorbid ID (76%,
). However, the literature confirms that individuals with ID/ASD are more
sensitive to adverse events from medications compared to their neurotypical peers,
and therefore, pharmacologic interventions should be performed with caution.
At the time of this writing, there are no medications approved by the U.S. Food
and Drug Administration (FDA) to treat any of the core diagnostic elements of
ID/ASD. The target symptom behaviors with the most research evidence include
hyperactivity, irritability, repetitive behaviors, and self-injurious behavior. As
anxiety disorders are the most common comorbid psychiatric conditions in
individuals with ID/ASD, anxiety/depression is another frequent target for
psychopharmacologic intervention, though with considerably less research support.
Sleep disturbances are also remarkably common in individuals with developmental
disabilities and often are a target for medication intervention.
Individuals with ID/ASD have high rates of comorbid ADHD, with literature in
children with ASD showing prevalence rates of about 30% for children derived from
community, nonclinical, populations (28%37 and 31%38
children evaluated in the clinical setting.
39 The mainstay of treatment for symptoms of
ADHD in individuals with ID/ASD, like their neurotypical peers, includes
stimulants, α2 agonists, and atomoxetine.
Stimulants are a group of medications derived either from methylphenidate or
amphetamine that act by increasing the amount of dopamine and norepinephrine in the
neuronal synaptic cleft. This increase in dopamine and norepinephrine is the result of
blocking the reuptake of dopamine and norepinephrine (methylphenidate and
amphetamine) and increasing the release of dopamine and norepinephrine
in their recent meta-analysis of pharmacologic treatments of
symptoms of ADHD in children with PDD, found four RCTs of stimulant
medications. All four RCTs studied methylphenidate and found it to be superior to
placebo for the treatment of global ADHD symptomatology and specifically
hyperactivity. In the largest of the four RCTs (n = 66),
41 effect sizes for hyperactivity
and impulsivity symptoms were greater than for inattention symptoms (0.77 vs. 0.60
for parent rating; 0.48 vs. 0.35 for teacher rating).
The effect size for the treatment of ADHD symptoms in children with PDD (0.67
40 however, was lower than estimates in a meta-analysis of
stimulant treatment of typically developing children with ADHD (0.77 for
methylphenidate and 1.03 for amphetamine).
In the study conducted by the Research
Unit on Pediatric Psychopharmacology (RUPP) group,
41 49% of children experienced
a therapeutic response, compared to 69% in the Multimodal Treatment Study of
Children with ADHD (MTA), which studied mostly neurotypical children (ID was an
exclusion criteria, and ASD was not mentioned as a comorbid diagnosis in any
Adverse events were more common in children with PDD treated with
methylphenidate versus placebo, with increased rates of decreased appetite,
insomnia, depressive symptoms, irritability, and social withdrawal.
adverse events with methylphenidate were also larger in children with PDD
compared to typically developing children, as evidenced by 18% of RUPP study
41 discontinuing the medication due to adverse events (primarily
irritability), compared to 1.4% in the MTA study.
Mean dosage in the four RCTs ranged from 0.29 to 0.45 mg/kg/dose.
analysis of the RUPP study data showed that methylphenidate doses of 0.25 and 0.5
mg/kg/dose were more consistently effective for treating ADHD symptoms than the
35 The highest dose used in the RUPP study was 0.625
mg/kg/dose, compared to the MTA study, in which the highest dose used was 0.8
Daily methylphenidate doses may be titrated weekly, until an optimal dose is
obtained. Improvement in symptoms should be noted within the first week.
Overall, the research literature shows that methylphenidate can be used to improve
ADHD symptoms, especially hyperactivity, in children with PDD, though with lower
effect sizes, lower tolerated doses, and more risk of adverse effects than children
without developmental disabilities.
guidelines suggest that amphetamine salts can be an option for children demonstrating
insufficient benefit or dose-limiting adverse events from methylphenidate.
Although the exact mechanism in ADHD is unknown, α2 agonists are thought to work
by stimulating the α2 adrenoceptors on norepinephrine-containing neuron cell bodies
in the locus coeruleus which modulates the tonic and phasic firing to the prefrontal
cortex. This allows the person to have increased attention on the desired task.
α2 Agonists include clonidine, a nonselective α2 adrenergic receptor agonist, and
guanfacine, a selective α2A adrenergic receptor agonist. α2 Agonists were initially
marketed for the treatment of hypertension, though have been shown to also improve
For clonidine, one small study (n = 8)
47 was identified by Reichow et al.
at clonidine versus placebo for the treatment of ADHD in children with PDD.
Although the original study found no statistically significant results, the effect size
for improvement in ADHD symptoms and irritability
was in the medium range (γ = 0.51 and 0.64, respectively) and smaller for
improvements in hyperactivity (γ = 0.30) and stereotypic behavior (0.24). The
report increased rates of hypotension and drowsiness
in some children who took clonidine. Mean dosage ranged from 0.15 to 0.20 mg/day.
One small pilot RCT (n = 11) looking at guanfacine treatment in children with
developmental disabilities showed statistically
significant reductions in hyperactivity subscales and global rating of improvement,
with 5 of the 11 participants deemed to be responders.
included drowsiness, irritability, and enuresis, as well as diarrhea, constipation, and
social withdrawal; additional adverse events from an open-label study of guanfacine
in children with PDD include sleep disturbance (insomnia or midsleep awakening).
Doses in both studies ranged from 1 to 3 mg/day.
Overall, a small collection of literature suggests that clonidine and guanfacine may
be beneficial for the treatment of ADHD symptoms in children with ASD/ID, with
similar adverse events as reported in neurotypical children, though more evidence is
needed to draw any more extensive conclusions about the use of these medications in
Atomoxetine is a medication for ADHD that acts by inhibiting the reuptake of
norepinephrine, therefore increasing the amount of norepinephrine in the synaptic
cleft. Dosing is generally once daily, with adjustments after a minimum of 3 days to a
target daily dose. Clinical benefit has been noted within the first 1 to 2 weeks.
40 meta-analysis found two RCTs comparing atomoxetine to
placebo in children with PDD, though only the larger of the two (n = 97)
statistically significant benefits for the treatment of global ADHD symptoms and
hyperactivity (effect sizes calculated by Reichow et al.
respectively). In this study by Harfterkamp et al.,
51 changes in the subscales of
inattention and oppositional behavior did not reach statistical significance for
children on atomoxetine compared to placebo.
Children with PDD in the Harfterkamp et al.
51 study demonstrated increased rates
of nausea, decreased appetite, and early morning awakening compared to study
participants taking placebo. Mean dosage in the two studies was 1.2 mg/kg/day
52 This dosing is perhaps only slightly lower than other large studies of
atomoxetine in children with ADHD without developmental disorders (mean final
atomoxetine dose was 1.45 mg/kg/day, 53.0 mg/day
the drug manufacturer’s studies, of presumably mostly neurotypical children with
ADHD, indicates no additional benefits for doses above 1.2 mg/kg/day.
Similar to the α2 agonists, it seems that atomoxetine shows benefits in the literature
for addressing ADHD symptoms in children with PDD, particularly for hyperactive
symptoms, with similar dosing and adverse events to children with ADHD without
Tricyclic antidepressants (TCA), which primarily act as serotonin–norepinephrine
reuptake inhibitors (SNRIs), had been a part of older treatment algorithms for the
treatment of ADHD in typically developing children
54 and, as a result, have also been
studied in children with ASD. In Gordon et al.’s crossover RCT of clomipramine and
(5 weeks each intervention), both drugs were
significantly superior to placebo for reducing the hyperactivity domain of the
Children’s Psychiatric Rating Scale (CPRS) Autism Relevant Subscale, though no
different from each other. TCAs are known for adverse effects, primarily
antimuscarinic in nature, which includes dry mouth, blurred vision, decreased
gastrointestinal motility, and urinary retention. TCAs can also cause irregular heart
rhythms, tachycardia and hypotension, and should be used in caution in patients with
preexisting cardiac conditions and can be fatal with just small excesses in dose.
TCAs are also highly metabolized by the cytochrome P450 hepatic enzymes,
including 3A4 and 2D6. Therefore, inhibitors of these enzymes can lead to increased
concentrations and higher risk of side effects including cardiac abnormalities.
Although antipsychotic medications are not typically part of the treatment
algorithm for ADHD in children with typical development,
and aripiprazole for the treatment of children with ASD and irritability/aggression
symptoms did show statistically significant improvement in hyperactivity subscales
). As a result, atypical antipsychotics are part of a
treatment algorithm developed by the Autism Speaks Autism Treatment Network
Psychopharmacology Committee Medication Choice Subcommittee for symptoms of
ADHD in individuals with ASD, if they have not shown adequate improvement from
stimulants, atomoxetine, and α2 agonists.
Other medications, which have not yet been included in standard practice, though
have shown some promising evidence for improvement in hyperactivity symptoms in
RCTs of children with ASD, include omega-3 fatty acids,
62 when each added to risperidone.
CASE 88-1, QUESTION 2: L.B., now 5 years of age, has been receiving ABA services for nearly 2 years
What pharmacotherapy and formulation would be most appropriate for L.B.’s target symptoms?
Clinical trials have shown that stimulants can be a very effective treatment option
for children with attention-deficit/hyperactivity disorder (ADHD). The American
Academy of Child and Adolescent Psychiatry (AACAP) and the American Academy
of Pediatrics (AAP) recommend the use of methylphenidate, over that of
amphetamines or nonstimulant medication, in preschool children where behavioral
modification therapy has not been adequate. The metabolism of methylphenidate in
preschool children is slower than that of older children, and therefore the starting
dose is lower, and the optimal dose is likely lower than in older children.
Based on this information, you recommend starting L.B. on methylphenidate IR
solution 1.25 mg twice daily, with an increase to 2.5 mg twice daily on day 3, with
subsequent dose increases every 3 days to reduce target symptoms, up to a maximum
of 7.5 mg 3 times daily. You recommend that the parents keep a journal of the
responses and possible experienced adverse effects during this period with a report
back to the pediatrician at the end of the week.
Irritability/aggression is the pharmacologic target behavior with the most robust RCT
evidence in children with ASD. Most of this evidence comes from four large RCTs
of either risperidone or aripiprazole.
In this context, risperidone and
aripiprazole are the only two medications with FDA approval for the
children and adolescents (risperidone—age 5–17 years; aripiprazole—age 6–17
33 studies of risperidone were 8 weeks in
duration, in a population of children and adolescents with either solely autistic
32 or mostly autistic disorder
(70% of study population had autistic
disorder; rest were diagnosed with either PDD NOS, Asperger disorder, or
childhood disintegrative disorder), and with mostly comorbid ID (64% of study
). Both showed risperidone to have
statistically significant improvements, compared to placebo, in the Irritability
subscale of the Aberrant Behavior Checklist (ABC-I) (ABC-I is a 15-item subscale
that includes items such as “injures self,” “physical violence to self,” “aggressive to
other children and adults,” “irritable,” “temper outbursts,” “depressed mood,”
“mood changes,” and “yells” or “screams” inappropriately; individual items are
rated on a scale ranging from 0—not at all a problem, to 3—severe),
ABC subscales for hyperactivity and stereotypy. The subscales for social withdrawal
and inappropriate speech only showed statistically significant improvements for
risperidone compared to placebo in Shea et al.’s study.
“response” was different in each study. In McCracken et al.,
defined as at least a 25% decrease in the ABC-I score and a rating of much improved
or very much improved on the Clinical Global Impression rating scale (CGI),
improvement subscale (CGI-I). With this definition, 69% were responders in the
risperidone group and 12% in the placebo group. In Shea et al.,
defined as having a 50% or greater decrease from baseline in at least two of the five
ABC subscales with none of the other subscales presenting a 10% or larger increase.
With this definition, 69% of subjects in the risperidone group were responders,
compared to 40% in the placebo group.
32 study participants in the risperidone group, compared to
placebo, experienced significantly higher rates of increased appetite, fatigue,
drowsiness, dizziness, and drooling, with trends of increased rates of tremor,
tachycardia, and constipation (P = 0.06). In a 16-week open-label extension of
32 study, the most common adverse events were excessive
appetite, enuresis, tired during day, dry mouth, excess saliva, rhinitis, coughing, and
63 Risperidone-treated participants in Shea et al.’s study
significantly greater increases in weight, pulse rate, and systolic blood pressure and
had a significantly higher rate of reported somnolence (73% risperidone vs. 8%
placebo). Extrapyramidal symptoms (EPS) were endorsed by 28% of the
risperidone-treated participants in Shea et al.,
33 compared to 13% in the placebo
group. Mean weight gain in both 8-week studies for those taking risperidone was 2.7
kg. Mean final daily risperidone dose was 1.8
the mean final daily risperidone dose of 2.8 mg in a large RCT of the antipsychotic
treatment of early-onset schizophrenia and schizoaffective disorder in children and
adolescents (ID was an exclusion criteria).
Although prolactin was not mentioned in either 8-week study of risperidone, a
long-term follow-up of the McCracken et al.
32 study confirmed that risperidone
treatment was associated with a 2- to 4-fold increase in serum prolactin levels.
66 study of risperidone in adults with ASD showed similarly
beneficial findings for the reduction in aggressive behavior, compared to placebo,
and common adverse events also included sedation and weight gain. The mean final
daily dose of risperidone was 2.9 mg, which is in contrast to the mean daily dose of
risperidone of 3.9 mg in a large RCT of adults with schizophrenia.
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