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Trastorno del espectro autista en niños y adolescentes:

intervenciones farmacológicas
AUTOR: Laura Weissman, MD
EDITOR DE SECCIÓN: Marilyn Augustyn, MD
EDITOR ADJUNTO: Diane Blake, MD

Todos los temas se actualizan a medida que hay nueva evidencia disponible y nuestro proceso de revisión por pares se
completa.

Revisión de la literatura vigente hasta: octubre de 2023.

Este tema se actualizó por última vez: 27 de octubre de 2021.

INTRODUCCIÓN

El trastorno del espectro autista (TEA) es un trastorno del desarrollo neurológico de base
biológica caracterizado por deficiencias en dos dominios principales: (1) déficits en la
comunicación social y la interacción social y (2) patrones repetitivos restringidos de
comportamiento, intereses y actividades [1 ] . El TEA abarca trastornos previamente conocidos
como trastorno autista (autismo clásico, a veces llamado autismo infantil temprano, autismo
infantil o autismo de Kanner), trastorno desintegrativo infantil, trastorno generalizado del
desarrollo no especificado y trastorno de Asperger (también conocido como síndrome de
Asperger). (Ver "Trastorno del espectro autista en niños y adolescentes: Evaluación y
diagnóstico", apartado de 'Criterios diagnósticos' .)

La discusión que sigue se centrará en las intervenciones farmacológicas para el autismo. Los
temas relacionados se presentan por separado:

● (Ver "Trastorno del espectro autista en niños y adolescentes: características clínicas" .)

● (Ver “Trastorno del espectro autista en niños y adolescentes: Evaluación y diagnóstico” .)
● (Ver "Trastorno del espectro autista en niños y adolescentes: descripción general del
tratamiento" .)
● (Ver "Trastorno del espectro autista en niños y adolescentes: intervenciones conductuales
y educativas" .)
 ● (Ver “Trastorno del espectro autista en niños y adolescentes: Terapias complementarias y
alternativas” .)
● (Ver "Trastorno del espectro autista en niños y adolescentes: terminología, epidemiología
y patogénesis" .)

PRINCIPIOS GENERALES

Overview — The clinical manifestations of ASD vary in intensity, and treatment plans must be
individualized. The primary treatments are developmental and behavioral therapies, typically as
part of Early Intervention or school-based programming. Psychopharmacologic interventions
may be a useful adjunct to behavioral/environmental interventions in children with ASD after
behavioral and educational supports have been maximized including supports to improve the
child's comprehension and ability to communicate. (See "Autism spectrum disorder in children
and adolescents: Behavioral and educational interventions".)

Psychopharmacologic agents do not treat autism itself and should be initiated only after
educational and behavioral interventions are in place, comorbid psychiatric or medical illnesses
ruled out, and psychosocial/environmental stressors considered [2]. In addition to a thorough
medical assessment, formal behavioral analysis conducted by a behavior analyst or behavioral
psychologist may be warranted to clarify the nature of the symptoms under consideration for
treatment. Depending on regional systems and resources, this may be arranged through the
child's educational team at school.

The potential benefits and risks of pharmacologic therapy for children with ASD must be
weighed on a case-by-case basis. Parents and caregivers should be informed if the medication
is being used off-label (only risperidone and aripiprazole are approved by the US Food and Drug
Administration [FDA] specifically for irritability in children with ASD).

The principles for the psychopharmacologic management of individuals with ASD are the same
as for individuals with other psychiatric conditions. Medications should be used to target
specific symptoms that are clearly defined, and the symptoms should be measured over time
(preferably using rating scales) to monitor treatment efficacy. It is also important to periodically
re-evaluate the need for continued treatment.

Children with ASD are more sensitive to psychopharmacotherapy and more likely to have
adverse effects than children without ASD [3,4]. In addition, given their weaknesses
communicating and identifying their emotions, it can be difficult to determine the predominant
target symptom (eg, anxiety, impulsivity, anger) and, therefore, the best psychopharmacologic
agent. For similar reasons, it can be more challenging to monitor certain side effects of
medications (eg, dry mouth, dizziness).

Pretreatment evaluation — Medication may be warranted if the child's behavior interferes

with his or her ability to access therapy and other contributing factors (eg, comorbid illness,
psychosocial/environmental stressors) have been addressed. However, determining which
symptoms to target with medication can be challenging. Few of the various measures for
assessing behavior in children (eg, Vanderbilt scales for attention) are standardized for children
with ASD [5,6]. Behavior scales must be used in conjunction with appropriate clinical and
historical data. Thorough clinical assessment, including information collection from multiple
sources (eg, parents, therapists), may be necessary to identify the most relevant target
behavior.

If available, Functional Behavioral Assessment (FBA) by the child's behavioral therapist can
provide valuable information. FBA is a formal, systematic observation that includes identifying
target behaviors, antecedents, and outcomes in order to better understand the function of the
behavior. Understanding the function of the behavior helps the clinician to identify an
appropriate target for medication. As an example, aggression may result from impulsivity,
anxiety, irritability, or other psychiatric problem (eg, mood or psychotic disorder), which are
treated with different psychopharmacologic agents.

If FBA is not available, the clinician should work to identify and characterize each target
behavior (with input from parents, other caregivers, and school staff, if possible) in terms of [7-
9]:

● How long has it been present? How severe is it?

● What brings it on or makes it worse (eg, time, setting, demands, etc)? Is it amenable to
behavioral interventions?
● Are medical factors contributing (eg, dental or other pain, constipation or gastrointestinal
distress, infection, sleep, seizures, menstrual cycle, etc)?
● What makes it better? How does it respond to behavioral interventions?
● What is the course? Is it getting better or worse?
● Does it interfere with function?
● What supports are available (eg, behavioral services, educational program, respite care,
family support)?

If the symptoms meet criteria for a comorbid psychiatric condition (eg, depression, attention
deficit hyperactivity disorder [ADHD], anxiety), the disorder should be managed accordingly,
with the caveat that the response to medication may differ in children and adolescents for
whom this is a secondary rather than a primary diagnosis. (See "Overview of prevention and
treatment for pediatric depression" and "Attention deficit hyperactivity disorder in children and
adolescents: Overview of treatment and prognosis", section on 'Overview of management' and
"Pharmacotherapy for anxiety disorders in children and adolescents" and "Psychotherapy for
anxiety disorders in children and adolescents".)

Indications — Pharmacologic therapy for children with ASD may be warranted for the
treatment of comorbid psychiatric or neurodevelopmental conditions or for behavioral
symptoms that interfere with learning, socialization, health, safety, quality of life, or overall
functioning [7-10]. When considering the use of medications for target symptoms in children
with ASD, the potential benefits and risks must be weighed on a case-by-case basis.
Pharmacologic therapy generally is initiated after behavioral and environmental interventions
are in place and have been maximized.

Who should prescribe? — Psychopharmacotherapy for children and adolescents with ASD
ideally is prescribed by specialists familiar with ASD (eg, developmental-behavioral
pediatricians, child psychiatrists, child neurologists, etc). However, access to such specialists is
not always available. If primary care clinicians undertake the prescription of psychotropic
agents for children with ASD, consultation with a developmental-behavioral pediatrician, child
psychiatrist, child neurologist, or another mental health professional who is familiar with ASD
may be warranted to ensure that an appropriate medication is chosen and efficacy and adverse
effects are appropriately monitored.

Choice of agent — Factors to consider in choosing pharmacologic therapy for children with
ASD include ( table 1) [7,9]:

● Likelihood of improvement in the target symptom

● Potential adverse effects
● Practical considerations (available formulations, dosing schedule, cost, requirement for
laboratory monitoring)

Risperidone and aripiprazole are the only psychotropic medications approved by the FDA
specifically for treatment of individuals with ASD [11]. However, many other medications are
used off-label. Parents and caregivers should be informed if the medication is being used off-
label.

The study of psychopharmacologic interventions in children with ASD is ongoing [12,13]. Most
of the existing evidence is extrapolated from studies on comorbid conditions (eg, ADHD,
obsessive compulsive disorder, anxiety, etc) in children without ASD. Studies of
pharmacotherapy in children with ASD generally are small, retrospective, and nonblinded; they
are hampered by the lack of diagnostic tools that have been standardized in the ASD
population. Notable exceptions include risperidone and aripiprazole for the treatment of
disruptive behaviors and methylphenidate for the treatment of disruptive behaviors and
hyperactivity/inattention [14,15]. (See 'Risperidone' below and 'Aripiprazole' below and
'Stimulants' below.)

Monitoring — Children with ASD are more sensitive to medication effects and more likely to
have adverse effects than children without ASD [3,4]. Medications should be started at lower
doses, and doses should be increased more slowly than in patients without ASD.

The efficacy and adverse effects of pharmacologic agents should be monitored systematically
during therapy [7,9]. In addition to clinical history, an appropriate tool should be used to
monitor outcome if such a tool is available. Target symptoms of children receiving intensive
behavioral interventions can be monitored using standardized instruments for specific
symptoms (eg, attention rating scales) although these instruments have not been validated for
use in individuals with ASD. In addition, many children with ASD have structured behavioral
programming as a component of their educational and therapeutic program. The data
collection techniques included in their behavioral programming can also be used for monitoring
response to medications. For children who do not have this type of programming, the
prescribing clinician can work with the child's family and school staff to develop of system for
monitoring target symptoms and providing feedback about response to medications. (See
"Autism spectrum disorder in children and adolescents: Behavioral and educational
interventions", section on 'Intensive behavioral interventions'.)

Autism Speaks provides a toolkit to help families and providers ensure safe and careful use
of medications.

The schedule for follow-up should permit an adequate trial of therapy, as well as a timely
modification (different dose, different medication, discontinuation) if the desired effect does not
occur. The specific follow-up interval varies with the medication but generally should be no
longer than three months. After successful control of the target symptom for 6 to 12 months,
withdrawal of the medication for a period of time may be warranted to determine whether it is
still necessary.

The parents and caregivers should be provided with information about the prescribed
medication and its potential adverse effects.

Polypharmacy — It is important to consider additional precautions when prescribing more

than one psychoactive medication for patients with ASD. Many medications used for treating
maladaptive behavior or mood symptoms have sedative effects and taking more than one may
result in excessive daytime sedation. In addition, some medications that share a metabolic
pathway may either enhance or inhibit the metabolism of other drugs, requiring dosing
adjustments. Finally, several medications can prolong QTc and may have additive effects on
heart conduction when used simultaneously (eg, atomoxetine, risperidone, and citalopram). It is
always good practice to complete a medication interaction analysis when treating patients with
more than one medication.

Specific medication interactions may be determined using the Lexicomp drug interactions tool
included with UpToDate.

TARGET SYMPTOMS

Pharmacologic therapy may be warranted for symptom control in children with ASD if
behavioral/environmental interventions are ineffective or insufficient for target symptoms. (See
'Pretreatment evaluation' above.)

Target symptoms that may respond to psychotropic medications include [16]:

● Hyperactivity, impulsivity, and inattention

● Maladaptive behaviors/problem behaviors/irritability (eg, aggression, explosive outbursts,
self-injury)
● Repetitive behaviors and rigidity
● Anxiety
● Mood lability
● Depression

Inattention and hyperactivity — Children with ASD may be inattentive, hyperactive, and
disorganized. These behaviors may be related to comorbid attention deficit hyperactivity
disorder (ADHD) or to other factors that affect function in children with ASD (eg, overarousal,
anxiety). If the behaviors do not improve with environmental or behavioral interventions, they
may respond to pharmacotherapy.

Potential therapies — Potential therapies for symptoms of inattention and hyperactivity in

children with ASD include stimulant medications (eg, methylphenidate, dextroamphetamine),
alpha-2-adrenergic agonists (eg, guanfacine), atomoxetine, atypical antipsychotics (eg,
risperidone), and anticonvulsant mood stabilizers (eg, valproic acid). There is strong evidence
that stimulants and risperidone are beneficial for hyperactivity and marginal evidence for the
benefit of other atypical antipsychotics [17].
Selective serotonin reuptake inhibitors (SSRI) may be helpful if anxiety is contributing to
symptoms. SSRI also may be used for repetitive behaviors and depression. They are discussed
separately. (See 'Anxiety' below and 'SSRI' below and 'Depression' below.)

Stimulants — Randomized controlled trials and meta-analyses indicate that stimulant

medication improves symptoms in approximately 80 percent of children with ADHD without
ASD. (See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with
medications", section on 'Stimulants versus other medications'.)

Methylphenidate also appears to improve symptoms of hyperactivity and inattention in children

with ASD, but the response to methylphenidate is lower in children with ASD than it is in
children with isolated ADHD. A systematic review of four-crossover trials (113 children) [18-21]
found low quality evidence that short-term treatment with methylphenidate may improve
hyperactivity and inattention in children with ASD who can tolerate the medication [22]. In the
largest crossover trial, approximately 50 percent of children with ASD responded to
methylphenidate (as measured on the hyperactivity subscale of the Aberrant Behavior Checklist
[ABC]); the effect size ranged from 0.20 to 0.54, depending upon dose and rater [20], with
greater improvement at higher doses [23].

Studies of amphetamines (dextroamphetamine, dextroamphetamine-amphetamine) in the

treatment of attentional symptoms in children with ASD are lacking. It is not clear that the
results from trials of methylphenidate can be generalized to amphetamines [24]. However,
amphetamines frequently are used in clinical practice.

The side effects of stimulant medications in children with ASD are similar to those in other
patients. However, they occur with greater frequency [3,4]. In a crossover trial of
methylphenidate that included 72 children with ASD and hyperactivity, 18 percent of subjects
withdrew because of adverse effects [20]. In comparison, in a large, randomized trial of
stimulants for attention deficit disorder in children without ASD, the dropout rate was only 3.5
percent [25]. Adverse effects of stimulant medications include, but are not limited to, sleep
disturbance, decreased appetite, irritability, tics, sadness, dullness, and social withdrawal. A
systematic review of four cross-over trials of methylphenidate in children with ASD could not
adequately assess adverse effects because children intolerant to methylphenidate were
excluded [22]. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder
in children and adolescents", section on 'Stimulant adverse effects'.)

Alpha agonists — Alpha-2-adrenergic agonists (eg, guanfacine, clonidine) also are used to
manage symptoms of inattention, hyperactivity, and impulsivity in children with ASD
[4,12,24,26].
Studies of alpha-2-adrenergic agonists are limited, and sample sizes are small. In a multicenter
randomized trial comparing extended-release guanfacine with placebo in 62 children with ASD,
hyperactivity, impulsiveness, and distractibility, guanfacine was effective in reducing behavioral
symptoms [27]. Children receiving guanfacine had greater declines in scores on the ABC-
hyperactivity subscale (43.6 versus 13.2 percent) and higher rates of "much improved" or "very
much improved" on the Clinical Global Impression-Improvement scale (50 versus 9.4 percent).
In an open-label prospective trial of guanfacine in 25 children whose hyperactive symptoms did
not respond to methylphenidate, 47 percent responded to guanfacine (decrease in the mean
parent- and teacher-rated hyperactivity subscale of the ABC from 31.3 to 19.9 and 29.2 to 22.3,
respectively) [28]. Retrospective analysis of guanfacine therapy in 80 children with ASD found
guanfacine to be well tolerated with response rates of 27 and 21 percent for symptoms of
hyperactivity and inattention, respectively [26]. Adverse effects of guanfacine include sedation,
constipation, irritability, and aggression [26,28].

Two small crossover trials using clonidine suggest decreased irritability, stereotypy,
hyperactivity, inappropriate speech, and oppositional behavior [29,30]. However, side effects
included hypotension and sedation. It is uncertain whether some of the reduction in symptoms
could be attributed to the sedative effect.

Children who are treated with alpha-2-adrenergic agonists should have their blood pressure
and heart rate monitored at each visit. Adverse effects of alpha-2-adrenergic agonists include:

● Sedation
● Hypotension
● Rebound hypertension if discontinued abruptly
● Dry mouth
● Dizziness
● Irritability
● Increased aggression and self-injury
● Decreased appetite
● Sleep disturbance
● Headache
● Nocturnal enuresis

Alpha-2-adrenergic agonists can pose significant harm if provided in excess. It is important to

counsel parents about the narrow window of therapeutic safety with these medications and to
keep all medications secured from children in the home. (See "Clonidine, xylazine, and related
imidazoline poisoning".)
 Atomoxetine — Studies of atomoxetine for symptoms of hyperactivity and inattention in
children with ASD are limited [31]. In a randomized trial in 97 children (6 to 17 years) with ASD
and ADHD, atomoxetine resulted in moderate improvement in ADHD symptoms (eg, reduction
in ADHD Rating Scale [ADHD-RS] scores compared with baseline of 8.2 points versus 1.2 point
reduction in the placebo group); among the atomoxetine treated patients, improvement was
greater on the hyperactivity-impulsivity than on the inattention subscore [32]. However, the
difference in the proportion of patients "improved" or "much improved" on the Clinical Global
Impression of ADHD Improvement Scale was not statistically significant [32]. Another small
randomized crossover trial suggested some improvement in hyperactivity symptoms compared
with placebo [33]. However, as with methylphenidate, the overall effect size for atomoxetine in
children with ASD and symptoms of ADHD is smaller than for children with ADHD without ASD
[12,34,35].

Side effects of atomoxetine include, but are not limited to, gastrointestinal symptoms, fatigue,
sleep problems, mood swings, dizziness, and change in appetite. Rare but potentially serious
adverse effects include suicidal ideation and hepatotoxicity. These adverse effects are discussed
separately. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in
children and adolescents", section on 'Atomoxetine adverse effects'.)

Other drugs — Other drugs that may be beneficial for symptoms of hyperactivity and
inattention in children with ASD include risperidone and antiseizure medications [24].

The use of risperidone for symptoms of hyperactivity in children with ASD is supported by open-
label and randomized controlled trials [24,36,37]. In a multicenter, placebo-controlled trial of
101 children with autism, treatment with risperidone (1.8 mg/day) for eight weeks was
associated with decreased mean scores on the hyperactivity subscale of the ABC compared with
baseline (32 to 17 versus 32 to 28 in the placebo group) [36].

Risperidone also may be used for a range of maladaptive behaviors including irritability,
stereotypy, aggression, explosive outbursts, and self-injury and is discussed separately. (See
'Risperidone' below.)

The evidence for antiseizure agents (valproate, topiramate, lamotrigine) is limited to small,
open-label, or observational studies [38-40].

Approach — When, after a discussion of the potential risks and benefits, the clinician and
parents agree that pharmacotherapy is indicated for symptoms of inattention, hyperactivity,
and impulsivity that continue to impair function despite behavioral and environmental
interventions and are not thought to be related to other symptoms (eg, anxiety), a trial of a
stimulant (usually methylphenidate) may be beneficial. An alternative agent may be chosen if
stimulant therapy is not effective or there are other target symptoms that require
pharmacologic intervention (eg, risperidone if disruptive behaviors secondary to irritability also
require treatment). This approach is consistent with that in the Autism Speaks Autism
Treatment Network Psychopharmacology Committee clinical practice pathway for evaluation
and medication choice for ADHD symptoms in children with ASD [41].

If methylphenidate is not tolerated, a trial of another stimulant, atomoxetine, or alpha-agonist

may be warranted [8,41]. (See "Attention deficit hyperactivity disorder in children and
adolescents: Treatment with medications", section on 'Choice of agent' and "Pharmacology of
drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section
on 'Introduction'.)

Maladaptive/problem behaviors — Maladaptive behaviors in children with ASD include

irritability, aggression, explosive outbursts (tantrums), and self-injury. These behaviors may
occur in response to anxiety or frustration, which should be the first targets of management [3].
Maladaptive behaviors also can be due to anxiety, mood disorders, or impulse control
problems; if one of these conditions is identified as a cause for the behavior, medications that
target that symptom should be used. (See 'Anxiety' below and 'Mood lability' below and
'Depression' below and 'Inattention and hyperactivity' above.)

Pharmacotherapy may be indicated if nonpharmacologic therapies are unsuccessful. Combined

pharmacologic and nonpharmacologic interventions may be more beneficial than medication
alone [42,43]. The pharmacologic agent of choice to treat the behavior depends upon the
postulated cause of the disruptive behavior.

Potential agents — The atypical antipsychotic agents, risperidone and aripiprazole [11], are
the only medications approved by the US Food and Drug Administration (FDA) to treat irritability
and self-injurious and aggressive behaviors in children with ASD. Agents that are used off-label
include other atypical antipsychotics (olanzapine, clozapine, quetiapine, ziprasidone),
haloperidol (a typical antipsychotic), antiseizure medications, alpha-2 agonists, mood stabilizers,
SSRI, and beta-blockers. There is strong evidence that risperidone and aripiprazole are
beneficial for disruptive behaviors and marginal evidence for benefit with other atypical
antipsychotics, antiseizure medications, psychostimulants, and naltrexone [17,44].

Risperidone — Risperidone is the most commonly used antipsychotic for the treatment of
maladaptive behaviors in children with ASD [45]. It is approved by the FDA for the treatment of
irritability presenting with aggression, tantrums, and/or deliberate self-injury in children (≥5
years) with ASD.
Randomized controlled trials and systematic reviews indicate a positive response to risperidone
in individuals with autism and disruptive behaviors [36,37,44,46-51]. In a multicenter, placebo-
controlled trial of 101 children with autism and maladaptive behaviors, treatment with
risperidone (1.8 mg/day) for eight weeks was associated with [36,52,53]:

● Higher treatment response; treatment response was defined as 25 percent or greater

decrease in the irritability score and rating of "much improved" or "very much improved"
on the Clinical Global Impression-Improvement (CGI-I) scale (69 versus 12 percent)

● Greater proportion "much improved" or "very much improved" on the CGI-I scale
compared with baseline (75 versus 11 percent)

● Greater decrease in mean irritability score compared with baseline (57 versus 14 percent)

● Improvements in repetitive behaviors and restricted interests, but no effects on social

function or communication (in secondary analysis) [52] (see 'Repetitive behaviors and
rigidity' below)

Dosing of risperidone is discussed separately. See Risperidone drug information.

Adverse effects of risperidone included weight gain, increased appetite, fatigue, drowsiness,
dizziness, drooling, tremor, and constipation. However, they were mild and resolved over a few
weeks [36]. There was no increase in tardive dyskinesia or other extrapyramidal symptoms
compared with the placebo group. No additional adverse effects were noted during the four-
month open-label continuation phase [54]. In postmarketing surveillance, there have been
reports of cases of extrapyramidal symptoms with concomitant use of risperidone and
methylphenidate or dexmethylphenidate with changes to the regimen of one or both
medications (eg, initiation, discontinuation, increased dose, decreased dose) [55,56]. Close
surveillance is warranted with any of these changes. This drug interaction is discussed in the
Lexicomp drug interactions program included with UpToDate.

Adverse effects of atypical antipsychotics and monitoring for adverse effects are discussed in
greater detail below. (See 'Side effects of antipsychotics' below.)

Aripiprazole — Aripiprazole is approved by the FDA for the treatment of irritability in

children (aged 6 to 17 years) with ASD [11].

In multicenter randomized trials, flexible and fixed dosing regimens of aripiprazole for eight
weeks were beneficial in reducing irritability, stereotypy, and hyperactivity in children (aged 6 to
17 years) with autism and irritability (as measured by the ABC and Clinical Global Impressions-
Severity scale) [57-59]. In another multicenter randomized trial, among 85 patients who had a
stable response to 12 weeks of aripiprazole and were randomly assigned to continuation of
aripiprazole or to placebo, the time to relapse did not differ between groups [60]. Given that the
efficacy of aripiprazole for the maintenance treatment of irritability in children with autism has
not been established, it is important to periodically re-evaluate the need for continued
treatment [11].

Adverse effects of aripiprazole included fatigue, vomiting, somnolence, weight gain, tremor,
and extrapyramidal symptoms [15,57,58]. With the fixed-dose regimen, approximately 10
percent of subjects withdrew because of adverse events; serious adverse events occurred in two
subjects (presyncope and aggression) [58].

Development of new impulse-control problems or uncontrollable urges (eg, gambling, binge

eating) also have been reported rarely in adults and children [61]. Indications for aripiprazole in
the reported cases included, but were not limited to, schizophrenia, schizoaffective disorder,
bipolar mood disorder, major depressive disorder, and anxiety disorder; ASD was not
specifically mentioned. Children receiving aripiprazole should be monitored for impulse-control
problems; this may be challenging in those with lower cognitive and language function.

Adverse effects of atypical antipsychotics and monitoring for adverse effects are discussed in
greater detail below. (See 'Side effects of antipsychotics' below.)

Olanzapine — Several small prospective studies (only one of which was blinded)
demonstrated clinical improvement in disruptive behaviors in children with ASD who were
treated with olanzapine (an atypical antipsychotic) [62-65]. However, weight gain and other side
effects, such as sedation, often prohibit continued use of olanzapine. The risk of extrapyramidal
side effects with olanzapine appears to be low.

Other atypical antipsychotics — Other atypical antipsychotics (eg, clozapine, quetiapine,

ziprasidone) are used in clinical practice to treat disruptive behaviors in children with ASD. The
evidence to support the use of these agents consists primarily of open-label studies or case
series [66-69]. Additional research is needed before they can be recommended as the initial
medical therapy for disruptive behavior in children with ASD.

Haloperidol — Randomized controlled trials suggest that haloperidol, a typical

antipsychotic, is effective in the treatment of behavioral symptoms (tantrums, aggression,
hyperactivity, social withdrawal, and stereotypies) in children with ASD [70,71]. However, it is
less effective than risperidone [71]. In addition, the risk of dyskinesia and other extrapyramidal
symptoms (in approximately one-third of patients) limits its use [72].
Children who are treated with haloperidol should be monitored closely. A drug holiday may be
warranted to avoid dyskinesia. Haloperidol should be slowly weaned to prevent withdrawal
dyskinesia. The optimal duration of drug holiday is unclear.

Other agents — Alpha-2 agonists (specifically clonidine) and N-acetylcysteine have

demonstrated some improvement in symptoms with fewer side effects than atypical anti-
psychotics in small, individual studies; however, additional research is needed [44]. Antiseizure
medications, mood stabilizers (eg, lithium), SSRI, stimulants, and beta blockers have been used
to treat disruptive behaviors in children and adolescents with ASD [12,44,73].

Side effects of antipsychotics — The use of antipsychotic agents often is limited by their side
effect profile. Side effects of atypical antipsychotics may include, but are not limited to [8,74-77]:

● Increased appetite
● Weight gain
● Elevated blood sugar secondary to insulin resistance
● Dyslipidemia
● Blood pressure changes
● Electrocardiogram (EKG) changes, such as prolongation of QTc (more common with
ziprasidone [78])
● Fatigue and drowsiness
● Dizziness
● Drooling
● Liver function abnormalities
● Increase in prolactin (of unknown clinical significance)
● Gynecomastia
● Cardiac conduction effects (prolonged QTc)

Less common, but serious, side effects include dystonic reactions, tardive dyskinesia, akathisia
(subjective sense of restlessness, often accompanied by voluntary movements of the limbs or
trunk), neuroleptic malignant syndrome, and agranulocytosis (with clozapine) [36,46,69,79].

Children who are treated with atypical antipsychotic agents should be monitored regularly. At
baseline, the child's weight and height should be measured and body mass index calculated
((calculator 1) [for boys] and (calculator 2) [for girls]) [80]. Given the cardiometabolic side effects,
it is important to take a thorough patient and family history, asking specifically about obesity,
diabetes, dyslipidemia, hypertension, and cardiovascular disease. A baseline EKG should be
obtained; the EKG should be repeated when the patient has reached the steady state
(particularly in patients treated with ziprasidone).
Follow-up visits should include measurement of weight and blood pressure and evaluation for
extrapyramidal findings (the use of a scale, such as the Abnormal Involuntary Movement Scale
[available online from various websites], is helpful). Baseline and follow-up laboratory studies
may include fasting plasma glucose, fasting lipids, complete blood count, liver function tests,
thyroid stimulating hormone (TSH), prolactin, and electrolytes.

The optimal frequency of laboratory monitoring is not clear. We suggest follow-up at three
months after starting medication and every six months thereafter for most of the studies listed
above and when doses are increased. Prolactin and TSH may be monitored less frequently
unless symptoms of abnormalities arise. More frequent testing may be necessary if metabolic
abnormalities are identified.

Treatment approach — As with most psychopharmacologic agents used in children with ASD,
there are few published clinical guidelines regarding medication use for disruptive or
maladaptive behavior such as irritability, aggression, impulsivity, tantrums, and/or deliberate
self-injury in children with ASD [51]. The treatment of disruptive behaviors in children with ASD
involves a tradeoff between benefits and risks [81]. Risperidone and aripiprazole may be
beneficial for aggression and self-injury that are not thought to be related to other symptoms
(eg, anxiety) [37,48]. Other medications (eg, stimulants, SSRI, alpha-adrenergic agonists) may be
more appropriate, depending upon the underlying cause of aggression and self-injury (eg,
hyperactivity, anxiety, impulsivity).

Other atypical antipsychotic agents (eg, clozapine, olanzapine, quetiapine, ziprasidone) and
different classes of drugs (eg, alpha-2 agonists, antiseizure medications, mood stabilizers, SSRI,
and beta blockers) have been used to treat disruptive behaviors in children and adolescents
with ASD [12]. However, there is less evidence to support the use of these agents for this
indication.

Switching to another antipsychotic agent is commonly recommended if there is excessive

weight gain or other adverse effects. However, discontinuation of medication may be warranted
depending upon symptom severity. This is especially true if the individual has been treated for a
long interval (ie, a year or more) and would benefit from a trial off medications to reassess
efficacy and need for treatment. Withdrawal of risperidone and other antipsychotics is often
accompanied by a period of greater behavioral dysregulation. Successful discontinuation of
risperidone and other antipsychotic agents requires a gradual taper over several weeks to
months. (See 'General principles' above.)

Repetitive behaviors and rigidity — Repetitive behaviors, stereotypies, and rigidity in children
with ASD often interfere with function.
 Approach — Repetitive behaviors and rigidity are core symptoms of ASD. They also can be
exacerbated by anxiety or other conditions. Medication may be warranted if the behaviors
interfere with function and have not responded adequately to nonpharmacologic interventions
(eg, behavior therapy). Pharmacologic treatment involves a tradeoff between benefits and risks
[81]. The literature is limited by the lack of tools that specifically measure stereotypies and
rigidity. Many studies measure obsessive-compulsive behaviors, which may not be the best
proxy for stereotypies and rigidity in children with ASD.

When medication is necessary for children with ASD and repetitive behaviors and rigidity that
are thought to be related to anxiety, clinical practice suggests the use of fluoxetine, sertraline,
or another SSRI as the initial medication. Despite the lack of high-quality evidence that SSRIs are
directly beneficial for repetitive behaviors and rigidity in children with ASD [82], they may be
indirectly helpful by reducing anxiety. In addition, SSRIs have fewer serious adverse effects than
other potential treatments. It is unclear whether SSRIs are helpful for stereotypies and rigidity
without comorbid anxiety. (See 'SSRI' below and 'Anxiety' below.)

Potential treatments — Potential treatments for repetitive behaviors in children with ASD
include SSRI, clomipramine, atypical antipsychotics, valproate, and buspirone, although high-
quality evidence to support these therapies is lacking [17]. Naltrexone, secretin, and stimulants
have been shown to be ineffective [17].

SSRI — The use of selective serotonin reuptake inhibitors (SSRI) for repetitive behaviors in
children with ASD is based upon the effectiveness of SSRI in individuals with obsessive-
compulsive disorder (OCD), demonstrated in meta-analysis of randomized controlled trials [83].

● Fluoxetine – Evidence regarding fluoxetine for repetitive behaviors in children with ASD is
mixed. In a multicenter trial in 146 children (age 7.5 to 18 years) with ASD and a score of ≥6
on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), a 20-point scale with
a minimal clinically important difference of two points, who were randomly assigned to 16
weeks of fluoxetine or placebo, a clinically important difference was not detected after
prespecified adjustment for potential confounding factors (eg, sex, verbal ability) [84]. CY-
BOCS scores decreased from baseline in both groups (from 12.8 to 9.02 in the fluoxetine
group and from 13.13 to 10.89 in the placebo group; adjusted mean difference between
groups -1.17, 95% CI -3.01 to 0.67). Another multicenter randomized trial in 158 children
(age 5 to 17 years) with ASD also did not detect a clinically important difference in CY-BOCS
scores between very low dose fluoxetine and placebo groups; similar proportions of
children achieved >25 percent reduction in CY-BOCS from baseline (36 and 41 percent,
respectively) [85]. In an earlier randomized, placebo-controlled crossover study in 44
 children with ASD, fluoxetine was beneficial in reducing repetitive behaviors as measured
on the CY-BOCS [86].

The frequency and severity of adverse effects was similar with fluoxetine and placebo
[84,85].

● Fluvoxamine – In an unpublished randomized trial in children, fluvoxamine had limited

efficacy in reducing repetitive behaviors and was poorly tolerated [87]. However, it may be
beneficial in adults with ASD [88].

● Sertraline – Open-label trials of sertraline in adults with ASD have noted improvements in
repetitive and disruptive behaviors [89,90]. There are no randomized controlled trials in
adults or children.

● Paroxetine – Studies of paroxetine in children with ASD are lacking. Small open-label
studies in individuals with intellectual disability suggest that it may be beneficial in
reducing aggression [91].

● Citalopram – In a multicenter randomized trial in 149 children with ASD, citalopram did not
improve repetitive behaviors and was associated with increased risk of adverse events,
including increased energy level, impulsiveness, decreased concentration, hyperactivity,
stereotypy, diarrhea, insomnia, dry skin, and pruritus [92]. Citalopram also may cause
cardiac conduction effects (prolonged QTc).

● Escitalopram – An open-label trial of escitalopram demonstrated some improvement in

irritability, lethargy, stereotypy, hyperactivity, and inappropriate speech [93]. There was a
wide variability in therapeutic dose that was not related to patient weight.

Children taking SSRI should be monitored for adverse effects, including activation,
sedation, anorexia, agitation, headaches, aggression, anxiety activation, insomnia,
gastrointestinal upset, and drowsiness. Blood pressure and heart rate should be
monitored at follow-up visits.

When used in children and adolescents with depression, SSRI have been associated with
increased suicidal ideation (see "Effect of antidepressants on suicide risk in children and
adolescents"). Increased suicidal ideation has not been demonstrated in studies of SSRI in
individuals with ASD. However, most studies did not assess suicidal ideation and included
too few subjects to detect rare adverse effects, such as suicidal ideation.

Clomipramine — Clomipramine is a serotonin-selective tricyclic antidepressant. The use

of clomipramine for repetitive behaviors in children with ASD is based upon its effectiveness in
individuals with OCD, as demonstrated in controlled trials [94].However, studies of
clomipramine for repetitive behavior in children with ASD have inconsistent findings [95-97].
The use of clomipramine often is limited by its side effects, which may include lethargy, tremors,
tachycardia, insomnia, diaphoresis, nausea, decreased appetite, urinary retention, and severe
constipation.

Risperidone — In secondary analysis of a multicenter placebo-controlled trial of 101

children with autism and disruptive behavior, treatment with risperidone (1.8 mg/day) for eight
weeks was associated with greater decrease in mean CY-BOCS compulsion scale (15.5 to 11.65
versus 15.2 to 14.2) [52]. Adverse effects of risperidone are discussed above. (See 'Side effects of
antipsychotics' above.)

Valproate — Valproate, an antiseizure medication, is also used to treat repetitive

behaviors in children with ASD. It use is supported by a small, blinded randomized controlled
trial that demonstrated improvement in repetitive behaviors as measured by the CY-BOCS [98].

Side effects of valproic acid may include, but are not limited to, irritability, weight gain, anxiety,
and aggression. The pharmacology and use of valproate is discussed separately. (See
"Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on
'Valproate'.)

Buspirone — Buspirone, an anxiolytic, is a serotonin partial agonist. In a randomized trial

comparing two doses of buspirone with placebo in 166 children with ASD, low-dose buspirone
(2.5 mg twice per day) had no effect on core symptoms of ASD (as assessed with the Autism
Diagnostic Observation Schedule [ADOS] Composite Total Score), but improved scores on the
ADOS Restricted and Repetitive Behavior score (a secondary outcome) [99]. Although these
results suggest that buspirone may be a useful adjunct to behavioral interventions for the
treatment of repetitive behaviors, additional study is necessary.

Anxiety — Anxiety is common in individuals with ASD and may contribute to aggressive,
explosive, or self-injurious behaviors. (See 'Maladaptive/problem behaviors' above.)

Anxiety in children with ASD is treated with the same therapies that are used to treat anxiety in
other children. Pharmacotherapy is one arm of a multimodal approach that may include
individual therapy, cognitive behavioral therapy, behavioral interventions/incentives;
accommodations to address sensory sensitivities; and special education services [100-103]. The
components of the multimodal therapy may vary from patient to patient. (See "Psychotherapy
for anxiety disorders in children and adolescents" and "Pharmacotherapy for anxiety disorders
in children and adolescents".)
Symptoms related to anxiety in children with ASD often are treated with SSRI. There are no
randomized trials that specifically assess the efficacy of SSRI in individuals with ASD. However, in
a meta-analysis of randomized controlled trials in children without ASD, SSRI were more
effective than placebo in reducing core symptoms of anxiety in children and adolescents (58
versus 31 percent, relative risk of response 1.9, 95% CI 1.6-2.26) [104]. (See 'SSRI' above.)

The use of SSRI in children with repetitive behaviors is discussed above. (See 'SSRI' above.)

Buspirone (an anxiolytic), and mirtazapine (an alpha-2 antagonist) are other agents that may be
used to treat anxiety in children with ASD [99,105,106].

Mood lability — A number of agents have been used to treat dysregulated mood and
symptoms related to dysregulated mood in children and adolescents with ASD. These include
atypical antipsychotics, SSRI, and mood-stabilizing agents (eg, lithium). None of these agents
has been studied specifically for mood regulation in children with ASD.

Atypical antipsychotics also may be used to treat maladaptive behaviors. Their use is discussed
above. (See 'Treatment approach' above and 'Side effects of antipsychotics' above.)

SSRI also may be used to treat repetitive behaviors and anxiety. Their use is discussed above.
(See 'SSRI' above.)

Depression — Antidepressant therapy may be indicated if depressive symptoms persist despite

counseling and psychosocial interventions. The same medications that are used for depression
in typical children can be used to treat symptoms of depression in children with ASD. (See
"Pediatric unipolar depression and pharmacotherapy: Choosing a medication".)

The efficacy of SSRI and serotonin norepinephrine reuptake inhibitors (SNRI) in the treatment of
children with ASD and depression has not been documented through a sufficient number of
randomized controlled trials to draw any firm conclusions [107]. Nonetheless, SSRI/SNRI may be
warranted for patients who demonstrate clear symptoms of depression (eg, terminal insomnia,
psychomotor disturbance, anorexia, changes in mood from baseline, etc). (See "Pediatric
unipolar depression: Epidemiology, clinical features, assessment, and diagnosis".)

When using antidepressants to treat depressive symptoms in children and adolescents with
ASD, the clinician must be mindful of the increased incidence of behavioral activation
(impulsivity, silliness, agitation, and disinhibition) and other side effects, including a potentially
increased risk of suicidal ideation. (See "Pediatric unipolar depression and pharmacotherapy:
Choosing a medication", section on 'Adverse side effects' and "Effect of antidepressants on
suicide risk in children and adolescents".)
Individuals with ASD may respond to very low doses of SSRI/SNRI, but typical pediatric doses
may be necessary. It is important to "start low and go slow." (See 'Overview' above.)

Other psychiatric conditions — Individuals with ASD may have other coexisting psychiatric
conditions that can be challenging to diagnose. As an example, disorders with disorganized
thought, delusions, or hallucinations may be difficult to diagnose in children with ASD. Referral
to a psychiatrist is suggested for children and adolescents with ASD who are suspected to have
an emerging thought disorder. Treatment of psychosis in children with ASD is similar to that in
children without ASD.

INVESTIGATIVE THERAPIES FOR SOCIAL DEFICITS

Oxytocin — Although small or open-label studies suggested that oxytocin may improve social
interaction or function in children with ASD [108-113], a blinded, randomized trial did not detect
a benefit [114]. Among 290 children with ASD (age 3 to 17 years, stratified for age and verbal
fluency) randomly assigned to a 24-week course of intranasal oxytocin (target dose of 48
international units daily) or placebo, the least-squares mean change from baseline scores on
the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW) were similar
(-3.7 to -3.5, mean difference -0.2, 95% CI -1.5 to 1.0). The ABC-mSW consists of 13 items, scores
range from 0 to 13, and higher scores indicate less social interaction. Secondary measures of
social interaction, including the Social Responsiveness Scale-2 Social Motivation subscale,
Sociability Factor, and Stanford–Binet Intelligence Scale: Fifth Edition Abbreviated IQ, were also
assessed, given the difficulty of capturing changes in social function over time. The least-
squares mean change from baseline scores on the secondary measures were also similar
between groups. In subgroup analysis, no difference was detected among participants with
fluent verbal speech, among participants with minimal verbal fluency, or when analyzed
according to baseline oxytocin levels.

Additional randomized trials are necessary before oxytocin can be recommended to improve
social interaction in children with ASD.

Other investigative therapies — Other pharmacologic agents that demonstrated potential

benefit for social deficits in individuals with ASD in small or open-label studies include D-
cycloserine [115], tetrahydrobiopterin [116], and cognition enhancers used in the treatment of
Alzheimer disease (eg, galantamine, memantine, and rivastigmine) [17,117-122]. Additional
controlled studies are necessary to confirm efficacy and safety before these therapies can be
recommended.
Naltrexone has been shown to be ineffective in the treatment of social deficits [17,122].

ASSOCIATED CONDITIONS

Seizures — Seizures are more common in children with ASD than in the general population (see
"Autism spectrum disorder in children and adolescents: Terminology, epidemiology, and
pathogenesis", section on 'Associated conditions and syndromes'). Pharmacologic management
of seizures in children with ASD is similar to that of seizures in children without ASD. (See
"Seizures and epilepsy in children: Initial treatment and monitoring".)

Gastrointestinal problems — A 2014 meta-analysis found a higher prevalence of

gastrointestinal (GI) symptoms in children with ASD than in the general population [123]. The
American Academy of Pediatrics and Scottish Intercollegiate Guidelines Network recommended
that GI disorders in children with an ASD generally should be managed in the same way as in
children without an ASD [8,124]. However, because children with ASD may not tolerate certain
aspects of the examination or types of diagnostic studies (eg, rectal examination), trials of
pharmacologic therapy for constipation or gastroesophageal reflux may be undertaken based
upon symptoms [124].

Pharmacologic interventions for specific GI problems in children are discussed separately:

● Constipation (see "Chronic functional constipation and fecal incontinence in infants,

children, and adolescents: Treatment")

● Gastroesophageal reflux disease (see "Management of gastroesophageal reflux disease in

children and adolescents")

● Chronic abdominal pain (see "Functional abdominal pain in children and adolescents:
Management in primary care")

● Chronic diarrhea (see "Approach to chronic diarrhea in children >6 months in resource-
abundant settings")

Sleep disturbance — Many children with ASD have associated sleep problems or disorders,
including bedtime resistance, sleep anxiety, sleep-onset disturbances, frequent waking,
restlessness, or abnormal sleep architecture [125-128]. Sleep disturbance may be related to
abnormalities in melatonin, serotonin, or gamma-aminobutyric acid [129,130].

The evaluation of sleep disturbance in children with ASD should include a thorough sleep
history and screen for obstructive apnea and other sleep disorders. Referral to a specialist (eg,
sleep specialist, neurologist, otolaryngologist) may be warranted if a specific sleep disorder is
identified or suspected. (See "Assessment of sleep disorders in children" and "Behavioral sleep
problems in children" and "Evaluation of suspected obstructive sleep apnea in children".)

It is important to ensure appropriate sleep hygiene and use behavioral interventions to

decrease sleep associations before considering pharmacologic interventions [131-135].
Medications are unlikely to be effective in the absence of an appropriate sleep schedule.

There is little evidence for pharmacologic management of sleep disturbance in children. No

medications are approved by the US Food and Drug Administration (FDA) for use for sleep in
ASD. However, several are used in clinical practice.

Melatonin — The benefits of melatonin for sleep onset and maintenance in children with ASD
have been suggested in observational, open-label studies and randomized placebo-controlled
trials [135-147]. In a meta-analysis of five randomized crossover trials (including a total of 57
patients) of melatonin in children with ASD, melatonin increased sleep duration by 73 minutes
and decreased sleep onset latency by 66 minutes compared with placebo but did not affect
nighttime awakenings [142]. Side effects were minimal. In individual studies, the doses ranged
from 0.75 to 10 mg/day, and the duration of treatment ranged from 14 days to 6 months
[139,140,143-145,147,148].

These results suggest that in the short-term (ie, up to six months), 1 to 10 mg of melatonin may
be effective in helping children with ASD to fall asleep and sleep longer when provided 30
minutes before bedtime. However, there are no dosing guidelines for administration and no
information on long-term use or side effects. Side effects of melatonin may include difficulty
waking, daytime sleepiness, and enuresis [137,138].

We suggest melatonin for patients with ASD who have difficulty falling asleep and staying
asleep despite appropriate sleep hygiene and behavioral or environmental interventions. We
usually start with 0.5 to 1 mg, depending upon age, and increase by 1 mg as needed to a
maximum of 10 mg (although in clinical practice, others may use a higher dose).

Melatonin is sold over the counter and does not require a prescription. It is not regulated by the
FDA. When parents/caregivers purchase melatonin, they should seek a formulation that
contains melatonin as the only active ingredient.

Other agents — Some data suggest that low serum ferritin levels in children with ASD may
contribute to symptoms of restless sleep (even in children with normal iron levels) [149]. In an
observational study, oral iron supplementation was beneficial in improving restless sleep in
children with ASD and decreased serum ferritin [149].
Other agents that have been studied in the management of sleep disturbance (increased sleep
latency, night wakings, and decreased total sleep) in children with ASD include niaprazine,
clonidine, and risperidone [17]. In addition, for children who require antiseizure or
antidepressant medications, the timing of administration can be manipulated to take
advantage of the sedative effects.

There are few data to support the use of these medications for sleep in children with ASD. When
used, they should be started at the lowest available dose and titrated as necessary.

● Niaprazine is a histamine H1-receptor antagonist with sedative properties that is available

in Europe [150,151]. In an open study in 25 patients with ASD and sleep disorder,
niaprazine (1 mg/kg per day for 60 days) was associated with improvement in behavior
and sleep disorders; no side effects were observed [151].

● Clonidine (an alpha-2-adrenergic receptor agonist) has sedative effects. In an

observational study, clonidine was effective in reducing sleep latency and nighttime
awakening in children with ASD [152]. Side effects of clonidine include hypotension.

● If a patient who presents with sleep difficulties also is prescribed a medication with a
sedating effect (eg, risperidone, some antiseizure medications, some antidepressants), the
sedating medication could be administered at bedtime; or, if more than one dose is
recommended, the higher dose can be administered at bedtime, if appropriate. However,
given the potential adverse effects, the use of sedating medications for sleep disturbance
alone is not recommended.

Parasomnias — Parasomnias or nonrapid eye movement (NREM) arousal disorders include

sleep walking, sleep terrors, and confusional arousals (see "Parasomnias of childhood, including
sleepwalking", section on 'Disorders of arousal from non-rapid eye movement sleep').
Clonazepam and tricyclic antidepressants have been used to treat NREM arousal disorders in
children with ASD [131]. However, high-quality evidence to support their use is lacking.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Autism spectrum
disorder".)

SUMMARY AND RECOMMENDATIONS

● The target symptom(s) for pharmacotherapy in children with autism spectrum disorder
(ASD) should be clearly defined. Medical causes for the behavior should be excluded, and
behavioral interventions should be maximized before pharmacotherapy is initiated. (See
'Pretreatment evaluation' above.)

● When considering the use of medications for target symptoms, the potential benefits and
risks must be weighed on a case-by-case basis. (See 'Indications' above.)

● Psychopharmacotherapy for children and adolescents with ASD ideally is prescribed by

specialists familiar with ASD (eg, developmental pediatrician, child psychiatrist, child
neurologist). Primary care clinicians who undertake the prescription of psychotropic
agents for children with ASD should consider consultation with a specialist. (See 'Who
should prescribe?' above.)

● Children with ASD who are receiving pharmacologic therapy for target symptoms must be
monitored regularly for efficacy and side effects. Additional precautions may be necessary
for children receiving more than one psychoactive medication. (See 'Monitoring' above
and 'Polypharmacy' above.)

● When, after careful assessment of the patient and a discussion of the potential risks and
benefits, the clinician and parents/patient agree that pharmacotherapy is indicated for
target symptoms in children with ASD:

• For inattention and hyperactivity that are not thought to be related to other symptoms,
such as anxiety, we suggest methylphenidate (Grade 2C). Other stimulants, alpha
agonists, and atomoxetine also have been used. (See 'Approach' above.)

• For maladaptive behaviors including aggression and self-injury that are not thought to
be related to other symptoms, we suggest risperidone or aripiprazole (Grade 2A).
Other medications (eg, stimulants, selective serotonin reuptake inhibitors [SSRI], alpha-
adrenergic agonists) may be more appropriate, depending upon the underlying cause
of aggression (eg, hyperactivity, anxiety, impulsivity). (See 'Treatment approach' above.)

• For isolated repetitive behaviors, evidence is lacking to recommend a specific SSRI;

however, we suggest fluoxetine, sertraline, or another SSRI as the initial medication for
interfering repetitive behavior (Grade 2C), especially if the behaviors are exacerbated
by anxiety. (See 'Repetitive behaviors and rigidity' above.)

• For anxiety, we suggest an SSRI as the initial medication (Grade 2B). (See 'Anxiety'
above.)
 • For dysregulated mood, we suggest an atypical antipsychotic or SSRI as the initial
medication (Grade 2C). (See 'Mood lability' above.)

• For depressive symptoms, we suggest an SSRI or serotonin norepinephrine reuptake

inhibitor as the initial medication (Grade 2B). (See 'Depression' above.)

● Pharmacologic management of seizures in children with ASD is similar to that of seizures

in children without ASD. (See "Seizures and epilepsy in children: Initial treatment and
monitoring".)

● Gastrointestinal disorders in children with ASD generally should be managed in the same
way as in children without ASD. (See 'Gastrointestinal problems' above.)

● Melatonin may be beneficial for sleep disturbance (late onset, frequent waking,
restlessness) that persists despite appropriate sleep hygiene and behavioral interventions.
(See 'Melatonin' above.)

ACKNOWLEDGMENT

We are saddened by the death of Carolyn Bridgemohan, MD, who passed away in August 2019.
UpToDate wishes to acknowledge Dr. Bridgemohan's many contributions to pediatrics, in
particular, her work as our Section Editor for Developmental and Behavioral Pediatrics.

Use of UpToDate is subject to the Terms of Use.

Topic 603 Version 55.0

GRAPHICS

Selected pharmacotherapeutic agents used for symptom management in

children and adolescents with autism spectrum disorders

Potential adverse
Agent Targeted symptom(s)
effects

Atypical antipsychotic agents (eg, Aggression Weight gain

risperidone*, aripiprazole*,
Hyperactivity/inattention Metabolic syndrome
olanzapine)
Repetitive behavior Tremor

Sleep disturbance Extrapyramidal

symptoms

Increased salivation

Sedation

Stimulants (eg, methylphenidate, Hyperactivity/inattention/impulsivity Decreased appetite

dextroamphetamine,
Difficulty falling asleep
dexmethylphenidate)
Irritability

Social withdrawal

Selective serotonin reuptake Aggression Potential increased

inhibitors (eg, fluoxetine, risk of suicidal
Anxiety
fluvoxamine, sertraline, paroxetine, ideation
etc) Depression
Behavioral activation
Repetitive behavior
Irritability

Alpha-2-adrenergic agonists (eg, Aggression Sedation

guanfacine, clonidine)
Hyperactivity/inattention Fatigue

Sleep disturbance Irritability

Constipation

Hypotension

Rebound
hypertension if
discontinued abruptly

Anticonvulsant mood stabilizers Aggression Mood lability

(eg, valproic acid)
Hyperactivity/inattention Fatigue

Repetitive behaviors Insomnia

 Sleep disturbance Diarrhea

Weight gain

Increased appetite

Atomoxetine Hyperactivity/inattention Potential increased

risk of suicidal
ideation

Irritability

Gastrointestinal
symptoms

Fatigue

Melatonin Sleep disturbance Difficulty waking

Daytime sleepiness

Enuresis

Mood stabilizer (eg, lithium) Aggression Weight gain

Nausea

Frequent urination

ASD: autism spectrum disorder.

* Approved by the US Food and Drug Administration for the treatment of aggression and irritability
in children with autism spectrum disorders.

Data from:

1. Hollander E, Phillips AT, Yeh CC. Targeted treatments for symptom domains in child and adolescent autism. Lancet
2003; 362:732.
2. Hyman SL, Levy SE, Myers SM, Council on Children with Disabilities, Section on Developmental and Behavioral
Pediatrics. Identification, evaluation, and management of children with autism spectrum disorder. Pediatrics 2019.
3. Leskovec TJ, Rowles BM, Findling RL. Pharmacological treatment options for autism spectrum disorders in children
and adolescents. Harv Rev Psychiatry 2008; 16:97.

Graphic 80456 Version 6.0

Contributor Disclosures
Laura Weissman, MD No hay relaciones financieras relevantes con empresas no elegibles para revelar.
Marilyn Augustyn, MD Apoyo a subvenciones/investigación/ensayos clínicos: Administración de
recursos y servicios de salud [becas de capacitación]; Red Irving Harris [formación de becas]. Todas las
relaciones financieras relevantes enumeradas han sido mitigadas. Diane Blake, MD No hay relaciones
financieras relevantes con empresas no elegibles para revelar.

El grupo editorial revisa las divulgaciones de los contribuyentes para detectar conflictos de intereses.
Cuando se encuentran, estos se abordan mediante un proceso de revisión de varios niveles y mediante
requisitos de referencias que se deben proporcionar para respaldar el contenido. Se requiere que todos
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evidencia de UpToDate.

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