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Evidence-Based Treatments for Autism Spectrum Disorder

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Current Treatment Options in Psychiatry (2015) 2:38–56
DOI 10.1007/s40501-015-0031-z

Child and Adolescent Psychiatry (M DelBello, Section Editor)

Evidence-Based Treatments
for Autism Spectrum Disorder
Laura C. Politte, M.D.1,*
Yamini Howe, M.D.2
Lisa Nowinski, Ph.D.2
Michelle Palumbo, M.D.2
Christopher J. McDougle, M.D.2
Address
*,1
Carolina Institute for Developmental Disabilities, University of North Carolina
School of Medicine, 101 Renee Lynne Court, Carrboro, NC 27510, USA
Email: laura.politte@cidd.unc.edu
2
Massachusetts General Hospital, Lurie Center for Autism, Harvard Medical School,
1 Maguire Road, Lexington, MA 02421, USA

Published online: 30 January 2015

* Springer International Publishing AG 2015

This article is part of the Topical Collection on Child and Adolescent Psychiatry

Keywords Autism spectrum disorders I Pervasive developmental disorders I Intellectual disability I

Psychopharmacology I Complementary and alternative medicine I Cognitive behavioral therapy I Dietary
interventions

Opinion statement
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental
disorders that manifest in early childhood and persist throughout the lifespan; treatment
should reflect the unique challenges for that individual at each developmental stage. In
early childhood, treatment should focus on the acquisition of language, play skills, joint
attention, and effective communication strategies through intensive behavioral and
educational interventions, particularly Applied Behavioral Analysis (ABA). Middle child-
hood and adolescence presents a time for continued skills acquisition, including devel-
opment of social skills, peer relationships, and maximizing supports for academic weak-
nesses. In older adolescence and young adulthood, developing vocational and adaptive
living skills to maximize opportunities for independence becomes important. ASD are
lifelong disorders, and treatment in adulthood includes ensuring opportunities for social,
leisure, and vocational activities, maintaining physical health through diet and exercise,
and support for transitions in caregiving as parents age. Throughout the lifespan, clini-
cians should remain mindful of medical complications that can affect behavior and may
not be readily apparent in individuals with limited verbal abilities, including gastrointes-
tinal problems such as reflux and constipation, seizures, and allergies. Current pharma-
cological interventions are primarily aimed at ameliorating the challenging emotional and
behavioral symptoms that accompany ASD rather than the core symptoms of ASD them-
selves. However, substantial evidence-based research into most medications for ASD is
 Evidence-Based Treatments for Autism Spectrum Disorders L. Politte, et al. 39

lacking. Two atypical antipsychotics, risperidone and aripiprazole, have indication for the
treatment of severe irritability in youths with ASD, though all other medication use in ASD
is considered off-label. Behaviorally based therapies, including ABA and cognitive-
behavioral therapy (CBT), may be helpful for symptoms of depression, anxiety, and
impaired self-regulation. Clinicians should remain mindful that many families will seek
out complementary and alternative medicine (CAM) approaches for their child, and
appropriate guidance about the safety and efficacy of these interventions should be
offered. Drug therapies that directly target the varied neurobiological underpinnings of
ASD are an area of great interest for future research and treatment.

Introduction
Autism spectrum disorders (ASD) are a group of resistance to change and difficulty with transitions, is also
neurodevelopmental disorders defined by impairments a hallmark of ASD.
in social communication and patterns of restricted, repet- The estimated prevalence of ASD has increased dra-
itive behaviors or interests [1]. ASD traits are often appar- matically in the past several years, rising from 1 in 150
ent in infancy and typically persist across the lifespan, children in 2002 to 1 in 68 in 2012 [3••, 4]. The precise
ranging from mild to severe in terms of functional im- cause of this sharp rise is unknown, but may include
pact. Early deficits in social communication can include increased awareness and detection of ASD, broader clin-
diminished eye contact, lack of social smile, decreased ical interpretation of the diagnostic criteria, and a true
responsiveness to name (in the setting of normal hear- increase due to undetermined environmental factors.
ing), and reduced attempts to establish joint attention Males are 4.5 times more likely to be diagnosed with
(e.g., pointing to objects of interest, referencing a care- ASD than females [3••]. Genetic variations are detected
giver’s response). Children and adults with ASD typically in as many as 30 % of individuals with autism, including
exhibit a reduced range of facial expressions and have 5–7 % with single-gene disorders (such as tuberous
difficulty integrating verbal and non-verbal forms of sclerosis and fragile X syndrome), 5 % with disorders
communication. Identifying and interpreting others’ of metabolism, and 7–20 % with copy number variants
emotional states and communicative intent (e.g., joking, (CNVs) [5]. Approximately 31 % of individuals with
sarcasm) can also be challenging. While some individuals ASD meet criteria for Intellectual Disability (ID; full-
with ASD desire to connect with others but lack the social scale IQ ≤70), and an additional 23 % have cognitive
pragmatic skills to do so successfully, others have mini- functioning in the borderline range (full-scale IQ 71–
mal interest in relationships and prefer solitary activities, 84) [3••]. Medical co-morbidities in ASD are also com-
making little effort to share their interests. Though no mon, including seizure disorders in 30 % (with bimodal
longer considered a core diagnostic feature, many with peak of onset in infancy and adolescence), gastrointes-
ASD have language delays, and a minority of individuals tinal problems, and sleep disturbance [6–9].
never develop functional speech. Characteristic atypical Treatment across the lifespan requires a multi-
uses of language include echolalia, pronoun reversal, disciplinary approach that may integrate Early Intensive
unusual tone of voice, use of scripted phrases, and ab- Behavioral Intervention (EIBI), special education, psy-
normal prosody. Young children often demonstrate a chopharmacology, medical interventions, physical ther-
lack of imaginative play and may prefer repetitive play apy, occupational therapy, speech therapy, vocational
activities, such as stacking blocks or arranging toys in a therapy, social skills training, and instruction in adaptive
particular order. Repetitive behaviors in ASD can include living skills. Development of language before school age
Blower-order^ movements, such as stereotypy (e.g., hand and early joint attention skills are predictive of positive
flapping, spinning, body rocking) and self-injury, as well outcomes, and thus a great deal of attention has been
as Bhigher-order^ behaviors, such as unusual attachment focused on early intervention [10–14]. However, the
to objects, insistence on sameness, and restricted interests capacity for growth does not end with childhood, and
[2]. Abnormal responses to sensory input, including hy- integrated treatment approaches should continue into
persensitivity and hyposensitivity, are now recognized as adulthood. The specific goals of treatment will change
characteristic features. BCognitive rigidity,^ including depending on the cognitive level and functional abilities
40 Child and Adolescent Psychiatry (M DelBello, Section Editor)

of the individual with ASD, though interventions should present an overview of current treatment options for
always aim to enhance quality of life, relationships, and the management of both core ASD symptoms and asso-
degree of independence. In the sections below, we ciated clinical features.

Treatment
Diet and lifestyle

& Goals for care for individuals with ASD should include consideration of
daily life (adaptive) functioning and development of meaningful and
functional skills across school, work, home, and community settings.
Clinicians should coordinate multidisciplinary evaluations for indi-
viduals with ASD, including consultation with developmental and
educational specialists, speech/language pathologists, occupational
therapists, and physical therapists, in addition to psychiatrists, psy-
chologists, and behavioral therapists [15••]. Goals of care should also
be tailored to consider key times of transition between service models
(i.e., Early Intervention, local school department, or state Department
of Developmental Services), as well as transition from adolescent to
adult services. Families should be counseled regarding disability laws
and rights as well as plans for long-term care and guardianship.
& Gastrointestinal (GI) symptoms are common among individuals with
ASD, but with a wide range of reported prevalence in studies ranging
from 9 to 91 % [16•]. Gluten-free and casein-free (GC/CF) diets are
commonly sought by patients based on anecdotal evidence. However,
there is an insufficient evidence basis in the medical literature to
support the use of a GF/CF diet [17]. GI symptoms should be evaluated
by the individual’s primary care physician with consideration of referral
to a gastroenterologist for further evaluation [7].
& Patients with ASD are often restrictive in the range of foods that they
will eat and are therefore at risk for nutritional deficiencies or excess.
Consultation with primary care physicians, a nutritionist, or feeding
therapists may be needed to expand the range of foods a patient will
accept. Calcium intake is of particular concern, but there is limited
evidence to support daily vitamin supplementation [18].
& Obesity is common among individuals with ASD, particularly given
common use of atypical antipsychotics, and can affect health and
quality of life [19].

Pharmacologic treatment
To date, no medications are approved for the treatment of core symptoms of
ASD, including social communication deficits and restricted, repetitive behav-
iors and interests. Pharmacologic interventions in ASD are primarily aimed at
reducing commonly associated symptoms, including inattention, impulsivity,
hyperactivity, compulsions, anxiety, sleep disturbance, and irritability—namely
severe tantrums, self-injury, and aggression.
 Evidence-Based Treatments for Autism Spectrum Disorders L. Politte, et al. 41

Antidepressant and anxiolytic medications [tricyclic antidepressants (TCAs), selective serotonin

reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs),
and buspirone]
Antidepressants have been studied for the treatment of irritability, re-
petitive behaviors, and compulsions in ASD with mixed results. While
some small, open-label trials and randomized trials have suggested a
benefit for the agents fluoxetine [20, 21] and clomipramine [22–25] in
reducing repetitive behaviors, a relatively large randomized controlled
trial (RCT) of citalopram in children failed to show any benefit [26]. A
meta-analysis of RCTs of SSRIs for repetitive behaviors in ASD, including
unpublished data, suggested a publication bias and no cumulative ben-
efit [27•]. While SSRIs and other antidepressants are rarely helpful in
alleviating repetitive behaviors, they may be helpful for treatment of
depression and anxiety, which are particularly common in higher-
functioning individuals with ASD. Evidence regarding the treatment of
depression and anxiety in ASD is lacking.

Standard dosage

If SSRIs and SNRIs (e.g., duloxetine, venlafaxine) are used in children with
ASD, start with one fourth to one half of the lowest available dose and
titrate slowly (e.g., increase by one fourth to one half tablet every 1–
2 weeks), monitoring for tolerability.

Contraindications

Avoid concurrent use with agents that increase risk for serotonin
syndrome.

Main drug interactions

Avoid concurrent use with monoamine oxidase inhibitors (MAOIs)

and other agents that increase risk for serotonin syndrome (e.g.,
linezolid).

Main side effects

Behavioral side effects with antidepressant use in ASD are common, par-
ticularly in pre-pubertal children, and may include irritability, hyperactiv-
ity, insomnia, and agitation—symptoms commonly referred to as
Bbehavioral activation^ [26]. Other side effects can include nausea, diar-
rhea, and somnolence. SSRIs are preferred to TCAs due to their greater
safety and tolerability profiles.

Special points

Buspirone tends to have a milder side effect profile than SSRIs and
can be effective for the management of anxiety and irritability in
ASD [28], though evidence from well-designed RCTs is lacking.
Mirtazapine may also cause less behavioral activation than SSRIs and
42 Child and Adolescent Psychiatry (M DelBello, Section Editor)

can help to regulate sleep disturbances [29]. Mirtazapine can be

helpful in the management of problematic sexual behaviors in ASD
[30–33]. Increased appetite and weight gain are notable side effects
of mirtazapine.

Cost-effectiveness

Generic formulations exist for fluoxetine, sertraline, citalopram,

escitalopram, paroxetine, fluvoxamine, mirtazapine, buspirone,
duloxetine, and venlafaxine.

Stimulants
Symptoms of Attention Deficit-Hyperactivity Disorder (ADHD), including hy-
peractivity, impulsivity, and inattention, are present in as many as 50 % of
individuals with ASD [34]. Methylphenidate (MPH) and mixed amphetamine
salt (MAS) formulations may be used in the treatment of ADHD symptoms,
though children with ASD are more prone to side effects and show a less robust
response rate compared to children with ADHD (49 % vs. 77 %) [35, 36].
Standard dosage

Target MPH dose is 1–2 mg/kg/day; target MAS dose is 0.5–1 mg/kg/day.
Maximum dose reached may be limited by side effects. An ideal dose is reached
when therapeutic effects are maximized with a minimum of side effects.

Contraindications

Structural heart disease, arrhythmia, severe or uncontrolled asthma. For

individuals with a family history of hypertrophic obstructive cardiomyop-
athy (HOCM) or sudden death in young people, obtain an electrocardio-
gram (ECG) before starting.

Main drug interactions

Concurrent use with MAOIs increases the risk for hypertensive crisis.

Main side effects

Lowered appetite, weight loss, headache, stomachache, insomnia, anxiety, irri-

tability, emergence or exacerbation of tics, elevated heart rate and blood pressure.

Special points

If a partial response is obtained but increasing the stimulant dose

leads to side effects, consider using in combination with an alpha-2
agonist. Consider short-acting preparations for younger children,
who are more prone to side effects, and extended-release prepara-
tions for older children and adolescents, to minimize disruptions to
the school day. Many capsules can be opened and sprinkled for
non-pill swallowers; a MPH transdermal patch and long-acting liq-
uid MPH formulation are also available.
 Evidence-Based Treatments for Autism Spectrum Disorders L. Politte, et al. 43

Cost-effectiveness

Both MPH and MAS are available in generic short-acting and extended-
release preparations.

Alpha-2 agonists
Alpha-2 agonists, including guanfacine and clonidine, are often used in
the treatment of ADHD symptoms—particularly hyperactivity and
impulsivity—and are often better tolerated than stimulants in ASD
[37, 38]. Clonidine is more sedating than guanfacine and can also be
used as a sleep aid, though it has a short duration of action (approx-
imately 6 h) and is more effective for sleep initiation than for main-
tenance of sleep.
Standard dose

For guanfacine, start with 0.25–0.5 mg each morning and increase by

0.5 mg weekly in two divided doses up to 4 mg/day, as tolerated. Maximum
dosing is 6 mg/day; use three divided doses (TID) for doses 94 mg/day. For
clonidine, start with 0.025 mg TID (or 0.025 mg at bedtime, if used for
sleep onset) and increase by 0.025 mg/dose weekly up to 0.2 mg TID, as
tolerated. Max dose is 0.6 mg/ day. Extended-release preparations of
guanfacine and clonidine are also available, though these must be
swallowed whole.

Contraindications

Hypotension. Use with caution in those with structural heart disease or

arrhythmia.

Main drug interactions

Avoid concurrent use of agents that lower blood pressure.

Main side effects

Lowered blood pressure, lowered heart rate, sedation, sleep disturbance,

constipation, irritability.

Special points

May be used in combination with either stimulants or atomoxetine for

partial responders. Initial drowsiness is common, though typically subsides
within days. Alpha-2 agonists must be gradually tapered when
discontinuing due to risk of rebound hypertension with abrupt cessation.

Cost-effectiveness

Guanfacine and clonidine are available in generic forms, though extended-

release preparations are currently more expensive.
44 Child and Adolescent Psychiatry (M DelBello, Section Editor)

Atomoxetine
Atomoxetine is a non-stimulant that may be used for associated symp-
toms of ADHD in ASD. Improvements in hyperactivity are generally
more robust than improvements in inattention, and response rates are
similar to those reported in studies of stimulants in ASD, though effect
sizes are more modest [39, 40].

Standard dosage

Recommended dosing is approximately 1.2 mg/kg/day, up to a maximum

of 100 mg/day. A cautious titration schedule is recommended for most,
starting with 10 mg every morning and increasing by 10 mg weekly to
maximum tolerated dose. May be dosed twice daily to minimize side effects
or if a Bwearing off^ effect occurs later in the day with once daily dosing.

Contraindications

Use with caution in individuals with structural heart disease or arrhythmias.

Main drug interactions

Concurrent use with MAOIs increases risk for serotonin syndrome.

Main side effects

Somnolence, nausea/gastrointestinal upset, headache, sleep disturbance,

lowered appetite, increased heart rate, increased blood pressure, and
irritability.

Special points

As with stimulants, children with ASD appear to have a more modest

therapeutic response to atomoxetine than children with ADHD without
ASD [40]. Higher-functioning children with ASD show higher response
rates compared with their peers with more severe autistic symptoms or ID
[41, 42].

Cost-effectiveness

Atomoxetine is not yet available in generic form and is more expensive than
generic stimulant, guanfacine, and clonidine preparations.

Atypical antipsychotics
Atypical antipsychotics are primarily used for the treatment of severe
irritability in ASD, including mood lability, severe tantrums, aggression,
and self-injury. Based on the results of relatively large RCTs, risperidone
and aripiprazole are the only two medications specifically approved by
the Food and Drug Administration (FDA) for treatment of severe irrita-
bility in children with ASD (for ages 5–16 years old for risperidone and
6–17 years old for aripiprazole) [43–46]. The potential benefits of these
 Evidence-Based Treatments for Autism Spectrum Disorders L. Politte, et al. 45

medications must be weighed against their side effect profile, which can
include weight gain and metabolic derangement. Atypical antipsychotics
are preferred over first-generation antipsychotics for their lower risk of
extrapyramidal symptoms (EPS) and tardive dyskinesia (TD).

Standard dosage

Varies by agent. For risperidone, start with 0.25–0.5 mg at bedtime

and increase by 0.25–0.5 mg daily each week up to a maximum of
4 mg/day; many patients will have a therapeutic response at a lower
dose. May be given once daily or in two to three divided doses. For
aripiprazole, start with 2.5 mg in the morning or at bedtime and
increase to 2.5 mg each week up to a maximum of 20 mg/day; most
patients will have a therapeutic response at a lower dose. May be
given once daily or in two divided doses.

Contraindications

No absolute contraindications, though should be used with caution in

elderly patients due to increased risk of death associated with antipsychotic
use in this population.

Main drug interactions

Concurrent use with metoclopramide increases the risk of extrapyramidal

symptoms and neuroleptic malignant syndrome (NMS). Avoid concurrent
use with medications that also cause prolongation of the QT interval (e.g.,
pimozide, cisapride, select antibiotics).

Main side effects

Increased appetite, weight gain, somnolence, fatigue, muscle stiffness, EPS,

drooling, QT interval prolongation, elevated cholesterol, elevated fasting
blood glucose, nausea and vomiting. All atypical antipsychotics, aside from
aripiprazole, are associated with elevated prolactin levels, which can lead to
menstrual irregularities and galactorrhea in females as well as gynecomastia
and galactorrhea in males. Ziprasidone tends to be weight-neutral, though
is associated with a greater degree of QT prolongation, and EKGs should be
obtained at baseline, with dosage changes, and every 6–12 months during
maintenance treatment. For all agents, fasting glucose and lipid panels
should be obtained at baseline and then every 6–12 months thereafter.

Special points

Before beginning an antipsychotic for irritability, a careful medical evalua-

tion should be done to rule out physical discomfort as a source of agitation.
Similarly, environmental factors that may be contributing to or maintain-
ing maladaptive behavior patterns should first be identified and modified
through behavioral interventions. Some parents find that when their chil-
dren gain weight while taking antipsychotics, they become more difficult to
manage physically when agitated.
46 Child and Adolescent Psychiatry (M DelBello, Section Editor)

Cost-effectiveness

Generic preparations are available for risperidone, olanzapine, quetiapine,

and ziprasidone.
Complementary and alternative medicine (CAM)

& Up to 50 % of families with children with ASD use CAM treatments at

some point, with higher rates among those with GI symptoms, seizures,
and behavioral problems [47, 48]. Despite their frequent use, clinical
trials are lacking to support or refute most CAM interventions, both
ingestible and non-ingestible [49•].
& Clinicians should assist families in weighing the safety profile, ease of
use, degree of evidence, and expense associated with CAM treatments
under consideration.
& Despite initial enthusiasm for secretin based on positive case reports,
intravenous secretin therapy for treatment of ASD symptoms has not
been found effective in more than 16 RCTs and is not recommended
[50].
& Melatonin has been shown to improve sleep onset in numerous con-
trolled trials and is currently recommended as a first-line medication
for initial insomnia in ASD [51]. Melatonin is available over-the-
counter in a number of different preparations. A typical starting dose is
3 mg given 1 h before bedtime, increasing by 3 mg every week up to
9 mg/day as needed. Younger children may start with 1–2 mg with
smaller dosing increments.
& Multivitamin supplementation can be considered for individuals with
limited or poor diets [49•].

Interventional procedures
Hyperbaric oxygen therapy

& Hyperbaric oxygen therapy (HBOT) is proposed to improve ox-

ygen levels in the body, which leads to decreased inflammation
and less oxidative stress. There has been some evidence to sug-
gest increased levels of inflammation, oxidative stress, and ab-
normalities in inflammatory markers, such as cytokines, in indi-
viduals with ASD, thus, leading to the hypothesis that HBOT
may improve these abnormalities with resultant improvement of
ASD symptoms [52].
& The evidence for the efficacy of HBOT is limited to multiple case series,
an open-label study, and a few controlled trials, three of which were
double-blind and placebo-controlled. Only one of the randomized
placebo-controlled trials had a positive significant finding [53]. The
findings of the other RCTs did not support the earlier finding [54, 55].
In a different study, changes in cytokine levels were not associated with
 Evidence-Based Treatments for Autism Spectrum Disorders L. Politte, et al. 47

a positive response to HBOT [52].

& In the studies with ASD populations, HBOT was well tolerated;
however, known complications from HBOT in other disorders
include CNS oxygen toxicity, which can cause seizures, and
barotrauma, which can lead to tympanic membrane rupture. At
this time, the use of HBOT for the treatment of ASD is not
recommended.
Chelation therapy

& Heavy metal exposure, namely mercury, has been proposed as a cause
for the increased prevalence of ASD. Chelation therapy is approved for
detoxification of heavy metals from the body in documented cases,
such as in lead poisoning.
& Strong evidence of chelation’s benefit for the treatment of ASD is
lacking. In 2007, the NIMH halted a clinical trial after animal models
demonstrated Blasting cognitive impairment^ [56]. Furthermore, there
have been deaths reported secondary to hypocalcemia from intrave-
nous chelation using the agent EDTA [57, 58]. As such, chelation
therapy is not recommended.
Electroconvulsive therapy for catatonia

& ECT is a highly effective treatment in disorders such as major depres-

sion and catatonia in typical developing individuals. The majority of
the evidence for ECT in catatonia in ASD is limited to case reports and
small case series. Published results so far have been positive. Larger
controlled trials are warranted [59].

Assistive devices/technology

& Individuals with ASD often have language impairments and may
not develop the ability to communicate using speech. Frustration
with communication can cause or exacerbate behavioral prob-
lems, such as aggression, self-injurious behaviors, or chronic
irritability. Alternative and Augmentative Communication (AAC)
systems and protocols have been developed to aid in language
acquisition and can serve as a means of communication in
individuals with limited or no verbal language abilities. Careful
evaluation by a speech-language pathologist experienced in the
use of AAC methods for individuals with ASD is recommended.
& In children, the Picture Exchange Communication System (PECS) is
widely used and has been shown to be effective in some controlled
trials and observational studies, particularly when used in early child-
hood [60].
& Technological breakthroughs with touch screen handheld devices have
led to rapid development of software and speech-generating devices
48 Child and Adolescent Psychiatry (M DelBello, Section Editor)

[61]. Evidence for efficacy of AAC devices for minimally verbal children
is emerging [62]
Physical, speech, and other therapies
Although many of the primary interventions for ASD involve behavioral treat-
ment, several adjunctive therapies can be instrumental in treating the related
language, motor, and sensory challenges inherent in ASD.

& Speech Therapy: Individuals with ASD present with a variety of lan-
guage and communication challenges across the lifespan. Speech ther-
apy is often an integral intervention aimed to address the myriad of
speech and language concerns experienced by individuals with ASD,
including delayed language development, impaired articulation, and
limited social pragmatics and social communication skills. Speech
therapy has been found effective in increasing the use of spontaneous
speech in individuals with ASD [63]. In addition, speech therapy has
been found to improve overall conversational competence, parent-
rated pragmatic functioning and social communication, and teacher-
rated classroom learning skills for school-age children with ASD [64].
& Occupational Therapy: Many individuals with ASD also experience
delays and ongoing deficits in gross motor coordination and fine
motor skill [65, 66]. Occupational therapy can be effective in
remediating the gross and fine motor challenges in individuals with
ASD and has even been found to result in gains in early cognitive
development [67].
& Sensory Integration Therapy: Separate, but related to an individual’s
need for OT, some individuals with ASD present with sensory pro-
cessing differences that require specific intervention. In fact, atypical
sensory processing is now included as a diagnostic subcriterion in the
DSM-5. Although the empirical support for sensory integration therapy
is limited [68], sensory integration approaches are often utilized in
occupational therapy for individuals with ASD [69].

Other treatments (behavioral, educational, and psychosocial

interventions)
Behavioral interventions

& Applied Behavior Analysis (ABA) and Discrete Trial Training

(DTT): There is a substantial body of literature that supports the
use of early, intensive behavioral interventions for children with
ASD [70–72]. ABA, or DTT, is one of the most common forms
of behavior therapy and is based on the behavior analysis.
Complex behaviors are broken down into smaller, Bdiscrete^
skills and taught in a systematic fashion over time using sub-
stantial repetition and reinforcement [73].
 Evidence-Based Treatments for Autism Spectrum Disorders L. Politte, et al. 49

& Pivotal Response Training (PRT): Building on basic models of

ABA, PRT focuses explicitly on Bpivotal^ areas of learning and
development, including an individual’s motivation and response
to cues, in order to build new skills and behaviors. A focus on
natural reinforcers replaces the use of the tangible and edible
reinforcers in DTT [74, 75].
& Floortime: Based in the Developmental Individual Difference
Relationship-based (DIR) model, Floortime is a framework for early
intervention that focuses on a child’s broad social-emotional develop-
ment, rather than isolated or discrete skills. Intervention is primarily
play-based and focuses on activities that are appropriate to a child’s
developmental level and interests [76, 77].
& Early Start Denver Model (ESDM): Combining elements of structured
ABA with more informal Brelationship-based^ approaches to interven-
tion, the ESDM pulls from the therapeutic methods described above
and has been found to reduce ASD symptom severity over time [78,
79••].
Educational interventions

& Special Education Services: Many children with ASD require substantial
support in their educational programming. An Individualized Educa-
tion Program (IEP) is often an essential part of planning and moni-
toring a student’s appropriate academic progress. Students can be
placed on an IEP as early as 3 years old and many remain in formal
school programming through their 22nd birthday.
& Treatment and Education of Autistic and Related Communication
(TEACCH): The TEACCH model is a set of teaching and intervention
strategies that is based on the specific learning needs of an individual
with ASD, including strength in visual processing, reduced executive
functioning skills, and difficulties with social communication. Emerg-
ing research suggests some positive effects on perceptual, motor, verbal,
and cognitive skill development, as well as improved social skills and
behavior [80].

Psychosocial interventions

& Parent Management Training: Parent management training has been

found effective in reducing parental stress and improving management
of problematic behaviors such as aggression, non-compliance, and self-
injury in children with ASD [81–85]. In addition, the combination of
parent training and medication has been found to reduce serious
maladaptive behaviors more than medication alone, and in some cases
even allows for a lower medication dose [86].
& Cognitive Behavioral Therapy (CBT): Research suggests that CBT is
effective in reducing concurrent psychiatric symptoms, such as anxiety,
in individuals with ASD [87•].
50 Child and Adolescent Psychiatry (M DelBello, Section Editor)

& Family Therapy: Parents of children with ASD often experience in-
creased psychological distress, marital problems, and family conflict
[88•, 89, 90]. Family therapy, including couples counseling, may be
helpful in supporting the overall well-being of a family system.
Emerging therapies
Oxytocin

& Oxytocin is a peptide hormone that is responsible for labor contractions,

lactation, and more recently has been associated with the development
of social behaviors. Oxytocin and its effects have been studied in mul-
tiple disorders, including depression, anxiety, personality disorders,
schizophrenia, and ASD. Low oxytocin levels have been identified in
some individuals with ASD, and social impairment in ASD may be due
to dysfunction within the oxytocin system in a subset of individuals.
& Multiple studies have demonstrated oxytocin’s effects on social moti-
vation, social initiation, social cognition, and repetitive behaviors in
ASD [91]. Small clinical trials and other small studies have been
completed at this time with overall mixed results; larger clinical studies
are currently in progress [91–93].
& The use of oxytocin for the treatment of ASD is not recommended at
this time.
Arbaclofen

& Arbaclofen is a GABA-B agonist that is related to the muscle-relaxing

agent, baclofen. In animal models, arbaclofen has been demonstrated
to decrease anti-social and repetitive behaviors. Studies in patients with
fragile X syndrome have shown similar findings.
& A small, open-label trial in idiopathic ASD demonstrated improve-
ments in irritability and social withdrawal scales, obsessive-compulsive
symptoms, and social responsiveness [93]. Side effects of the medica-
tion included agitation, irritability, fatigue, increased motor activity,
insomnia, and diarrhea.
& Due to lack of substantive evidence from RCTs, the use of arbaclofen for
the treatment of ASD is not recommended at this time [94].

Memantine

& Memantine is an FDA-approved medication for the treatment of

Alzheimer’s disease. Memantine is an NMDA antagonist that modu-
lates glutamate release. Glutamate toxicity has been cited as a proposed
mechanism for ASD [95].
& Multiple case reports, open-label studies, and one randomized con-
trolled trial of memantine suggest a positive effect for social commu-
nication deficits. Side effects reported included abdominal pain, appe-
tite changes, dizziness, insomnia, nausea, sedation, worsening of
 Evidence-Based Treatments for Autism Spectrum Disorders L. Politte, et al. 51

behaviors, irritability, and rash [96]. Dosages in the studies ranged from
2.5 to 30 mg per day.
& Further studies are required at this time. Currently, the use of
memantine is not recommended.

N-Acetylcysteine

& N-Acetylcysteine (NAC) has antioxidant properties and modulates

glutamate. The results of two small RCTs are promising in terms
of reducing autism-related irritability. In both trials, NAC was
well tolerated with mild side effects of gastrointestinal symp-
toms, increased appetite, nervousness, fatigue, and daytime se-
dation [97, 98].
& The use of NAC for the treatment of ASD is not recommended at this
time due to lack of substantive evidence.
Pediatric considerations

& Early intensive behavioral treatment programs are well established as

the treatment of choice for children with ASD and have been shown to
improve outcomes significantly [99]. Given that intervention services
before diagnosis are limited, early identification and referral to treat-
ment services is key to improving outcomes. The American Academy of
Pediatrics (AAP) has recommended routine surveillance for ASD at
every well-child visit, standardized developmental screenings at ages 9,
18, and 30 months, and ASD-specific screenings at ages 18 and
24 months [100].
& Routine health care is important for individuals with ASD, as with all
individuals. However, those with ASD may be more likely to have
medical conditions relating to etiology, such as fragile X syndrome or
tuberous sclerosis, that affect health care needs. Specific repetitive
behaviors can affect health, and clinicians should be alert to these
symptoms. For example, repeated skin picking or rubbing can lead to
skin infection, and pica or mouthing behaviors increase the risk of lead
exposure. Furthermore, routine health visits can be difficult due to
behavioral, sensory, and communication challenges. Clinicians should
be alert to these needs and help individuals access routine dental and
medical care. Accommodations, such as slowing the pace of the visit
and using visual supports and stories, may be used [101]. Specific
behavioral goals for treatment planning might include learning to
tolerate blood pressure checks and blood draws, and learning to swal-
low pills.
52 Child and Adolescent Psychiatry (M DelBello, Section Editor)

& Use of psychotropic medications is common among children and

adolescents with ASD [102•]. However, given the limited evidence
basis, variable efficacy, and high rate of side effects for psychotropic
medications, the common adage Bstart low and go slow^ should be
followed when prescribing psychotropic medications for children and
adolescents with ASD.
Conclusion
ASD are complex neurodevelopmental disorders that require a multi-
disciplinary treatment approach across the lifespan. The greatest strength
of evidence for treatment of core social communication impairments in
ASD exists for behavioral interventions, particularly when implemented
early in development. Pharmacological interventions may be helpful in
alleviating associated emotional and behavioral symptoms, though a
careful medical evaluation must first be conducted to rule out physical
sources of discomfort or other etiologies for maladaptive behaviors
(such as seizures). Novel treatments that target specific neurobiological
processes in ASD and are effective for core deficits of the disorder are an
important area of focus for future research.

Acknowledgment

This manuscript was funded, in part, by the Nancy Lurie Marks Family Foundation.

Compliance with Ethics Guidelines

Conflict of Interest
Laura C. Politte declares that she has no conflict of interest.
Yamini Howe declares that she has no conflict of interest.
Lisa Nowinski declares that she has no conflict of interest.
Michelle Palumbo declares that she has no conflict of interest.
Christopher McDougle declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors. Among
cited articles where one of the authors of the current report were authors, local Institutional Review Board approval
was obtained and maintained for studies where human (or animal) subjects research was performed.
 Evidence-Based Treatments for Autism Spectrum Disorders L. Politte, et al. 53

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