Autistic Spectrum Disorders

Last Updated: April 25, 2006

Synonyms and related keywords: PDD, pervasive development disorder, Rett
disorder, Rett's disorder, childhood disintegrative disorder, Asperger disorder,
Asperger syndrome, Asperger's syndrome, autism, autistic spectrum disorder, autism
spectrum disorder, autistic disorder, PDD not otherwise specified, PDD-NOS

Background: The autistic spectrum disorders are a neurobiologically diverse

group of conditions whose precise relationship to each other is unclear, yet
they present with a consistent, diffuse pattern of abnormality across several
areas of behavior. Individuals with these disorders do not present merely with
slow or limited development, but rather with development that is atypical in the
pervasive but diffuse areas of functions affected.

Three main clusters of behaviors define autism, as follows: (1) social

abnormalities, especially a lack of social reciprocity; (2) language
abnormalities, with deviant communication features and limited development
of language; and (3) rigid, stereotyped, repetitive patterns of unusual
behavior.

Case reports consistent with autism exist from the 1890s, but Kanner first
defined the syndrome in 1943, as did Asperger a year later.

The Diagnostic and Statistical Manual of Mental Disorders, Third Edition

(DSM-III), published in 1980, offered the first official definition and description
of autism in the United States.

The prevailing public face of autism comes from the movie Rain Man in which
actor Dustin Hoffman played an adult with autism with not only the behavioral
rigidity, peculiar language, and social abnormality characteristic of the
syndrome but also the savant abilities present in a quarter of individuals with
autism who also have an intelligence quotient (IQ) of at least 35. Autistic
spectrum disorders include autistic disorder, Asperger disorder, PDD not
otherwise specified (PDD-NOS), Rett disorder, and childhood disintegrative
disorder.

Pathophysiology: Despite extensive investigation, no consistent pattern of

the cause of autism has emerged. In fact, more than 60 different disease
entities have been shown to be likely causes of autism, including genetic,
infectious, endocrine, toxic, and space-occupying etiologies. This suggests
that autism is a final common clinical presentation of a variety of underlying
neurobiological and genetic processes.
The rest of this section presents some of the many proposed mechanisms
behind the development of autism.

Although abnormalities have been reported on every chromosome as

associated with autism, some of the more common genes of interest are on
the X chromosome. This makes intuitive sense, as the incidence of the
disorder is much higher in males, and they have only one X chromosome.
Genes of interest on the X chromosome include FMR1 (fragile X) and FMR2
(FRAXE syndrome), MECP2 (Rett syndrome), ARX, NGLN3, and NGLN4.
The 22nd chromosome is also of particular interest, with sites at band 22q11
and 22q13 responsible for velocardiofacial syndrome, DiGeorge syndrome,
and adenylosuccinate lyase deficiency. Interest in mitochondrial DNA is
growing, as a recent unreplicated Portuguese study had estimated that more
than 7% of children with autism have mitochondrial disease.

The first biochemical abnormality discovered in autism was found in 1961 in a

group of 23 patients, one third of whom were reported to have high levels of
whole blood serotonin. Subsequent studies have confirmed this observation,
as well as noting that about 5% of autistic children instead have low levels of
serotonin. The significance of this is still unclear, but one explanation is that
these abnormalities may be secondary to still another etiology. When certain
disorders associated with autism are treated, the associated serotonin
abnormality disappears; this happens when treating hypothyroidism with
thyroid hormone and when treating phenylketonuria (PKU) with a low
phenylalanine diet.

Endogenous brain opioids are suggested to be increased in autism, but

studies have shown both increased and decreased levels of opioids in
different case series. Some open clinical trials suggest that naltrexone, an
opioid antagonist, can affect the core symptoms, but these findings have not
been replicated. A subsequent controlled trial of naltrexone showed no impact
on core symptoms.

Vasopressin and oxytocin have been shown to play a role in social

attachment, but no evidence exists as yet of such problems in autism. Studies
of the dopaminergic, noradrenergic, and neuropeptide systems do not reveal
evidence of consistent abnormalities.

Searches for structural abnormalities produce similar inconsistent results.

Abnormalities of the ventricular system are reported, but these abnormalities
are neither consistent nor specific. The frontal lobes, the insula, the limbic
system, the corpus callosum, the thalamus, the brainstem, and the cerebellum
have all had reported structural and/or functional abnormalities noted in
autism, but again, no location has a consistent pattern of dysfunction. A
current belief is that autism may more likely reflect abnormalities within a
particular neural system or multiple neural systems, which are the connected
networks of a variety brain regions.

Several immune dysfunctions were detected, including anomalies in cell-

mediated immunity, with some measures inversely correlated with severity of
autistic symptoms. Abnormally elevated interferon-alpha levels, antibodies
against myelin basic protein, and antibodies in both subjects and first-degree
relatives to neuron-axon filament proteins also have been found. Allergic
reactions may play a role, as autistic children have increased eosinophil and
basophil response to immunoglobulin E (IgE)mediated reactions. Finally,
enhanced immune response to viral infections, with autoimmune activation, is
postulated. All together, these and other findings suggest depressed immune
function, autoimmune mechanisms, or faulty immune regulation may be
associated with the etiology of autism, but the causal connection between
immune changes and autistic symptoms has yet to be made.

Abnormal electroencephalogram (EEG) results can be found in as many as

43% of individuals with autism, particularly in those with lower IQs. Seizures
are estimated to occur in as many as 30% of children with autistic disorder. A
few epileptic syndromes are clearly linked to the diagnosis of autism, including
tuberous sclerosis, Lennox-Gastaut, West syndrome, Landau-Kleffner
syndrome, and pyridoxine-dependent seizures. However, the authors'
experience with seizures in autism has not generally led to better
understanding of the origin of autistic symptoms.

The pathophysiology of childhood disintegrative disorder and Asperger

disorder is unknown, although Asperger disorder appears to follow a familial
transmission pattern. Associated disorders like seizures are less common in
Asperger disorder than in autism.

Rett disorder is transmitted as a dominant X-linked illness with full or nearly

full penetrance, with early death of most male fetuses through spontaneous
abortion. Diffuse generalized atrophy of the cerebrum and cerebellum is
present, with nonspecific, generalized EEG abnormalities present by age 2
years. Mutations in MECP2 gene (methyl-CPG-binding protein 2) are present
in 80% of classic Rett disorder patients, with recent reports of CDKL5 gene
mutations present in some of the MECP2 negative cases. Phenotypic
variability in Rett syndrome is now thought to be related to X chromosome
inactivation patterns and variations in the location of the mutation. Autism
cases without Rett features have been shown to not have mutations in
MECP2, further confirmation that Rett syndrome and autism are separate
entities.
Frequency:

In the US: Current estimates are that slightly more than 0.1% of the
general population has classic autism by DSM-IV criteria. When the full
autism spectrum is viewed, the prevalence is higher, with 0.3-0.7%
having the disorder: Asperger disorder is estimated to occur in 0.2-
0.5% of school-aged children, Rett disorder occurs in 5-15 girls per
100,000, and childhood disintegrative disorder occurs with a frequency
of 1-4 cases in 100,000. Prevalence rates of autistic disorder in more
recent studies have been noted to be as much as 40 times higher than
past studies, but this does not necessarily mean that the true
prevalence of the disorder is increasing. This is because more recent
studies are performed in an environment of higher awareness of the
disorder and use more inclusive diagnostic criteria. Remember that as
recent as the 1970s, autistic children were more commonly labeled as
psychotic, thus making comparisons with this era of data highly
suspect.

Internationally: Depending upon diagnostic criteria used, rates are

similar to those in the United States.

Mortality/Morbidity: Increased mortality is seen in autism, with a risk that

increases with age, and it is observed to be an even greater problem with
females with the disorder. The increased mortality may be due to associations
with severe mental retardation and other medical conditions, such as epilepsy.
Mental retardation is present in 75% of affected individuals. Depending on the
population studied, epilepsy develops in 4-42% of affected individuals, with
some of the increased rates due to associated mental retardation. The course
of illness is often unpredictable. A gradual clearing of some of the symptoms
can occur in adulthood but with the persistence of residual deficits. An
intellectual decline can occur during adolescence. Depending on severity, 2-
17% of patients may achieve a nonretarded level of cognitive and adaptive
functioning. Marriage is rare, but as they mature, adult patients may have
greater success in achieving employment and developing the capacity for
independent residence.

Studies have shown 3 consistent factors that relate to improved outcome: (1)
higher IQ, (2) presence of speech, and (3) overall severity of disorder.
Mentally retarded autistic individuals who have not gained useful verbal
communication by age 5 years are unlikely to live independently as adults.
Intensive early preschool intervention of 25 or more hours per week with
either applied behavior analysis (ABA) or other therapies focused on
improving functioning (language and social interactions) have been shown by
a few well controlled and many more retrospective studies to improve
outcomes.

Sex:

Male-to-female ratio for autism is 3:4. Female prevalence increases as

disease severity increases.

Asperger disorder and childhood disintegrative disorder show a similar

male-to-female ratio of about 4:1.

Rett disorder was previously believed to never occur in males, but case
reports and improved genetic studies have now shown this is possible.

Age: In most cases, these disorders can be detected and distinguished from
other forms of developmental delay before age 3 years. Parent interviews and
videotapes have demonstrated manifestations as early as age 12 months.
Parental concern develops at the mean child age of 19 months, and they first
seek professional advice at a mean child age of 24 months.

Childhood disintegrative disorder typically develops in children aged 3-

4 years, while Rett disorder becomes apparent in children aged 18
months to 4 years. Individuals with Asperger disorder may have
delayed detection because of the greater subtlety of presentation.

According to some parents and investigators, a subset of children have

social and verbal regression between age 2 and 5 years that heralds
the onset of more typical autistic symptoms. These children, due to
their atypical presentation, are among those labeled as PDD-NOS.

History: Diagnosis of autism

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,

Text Revision (DSM-IV-TR), from which the symptom list below is taken
directly, requires the presence of at least 6 of the below symptoms and at
least 1 item from each of the 3 symptom groupings. In addition, at least 2
symptoms must come from the social impairment group of symptoms. Delays
or abnormal functioning as depicted in any one of the symptom groups must
be present by age 3 years. This means that patients with autism have
impairments in social interactions, in communication, and in patterns of
behavior.
 (Group 1) Qualitative impairment in social interaction, as manifested by
at least 2 of the following:
o Marked impairment in the use of multiple nonverbal behaviors
such as eye-to-eye gaze, facial expression, body postures, and
gestures to regulate social interaction
o Failure to develop peer relationships appropriate to
developmental level
o A lack of spontaneous seeking to share enjoyment, interests, or
achievements with other people (eg, by a lack of showing,
bringing, or pointing out objects of interests)
o Lack of social or emotional reciprocity

(Group 2) Qualitative impairments in communication as manifested by

at least 1 of the following:
o Delay in, or total lack of, development of spoken language (not
accompanied by an attempt to compensate through alternative
modes of communication such as gestures or mime)
o In individuals with adequate speech, marked impairment in the
ability to initiate or sustain conversation with others
o Stereotyped and repetitive use of language or idiosyncratic
language
o Lack of varied, spontaneous make-believe play or social
imitative play appropriate to developmental level

(Group 3) Restricted repetitive and stereotyped patterns of behavior,

interests, and activities, as manifested by at least 1 of the following:
o Encompassing preoccupation with one or more stereotyped and
restricted patterns of interest that is abnormal either in intensity
or in focus
o Apparently inflexible adherence to specific, nonfunctional
routines or rituals
o Stereotyped and repetitive motor mannerisms (eg, hand or
finger flapping or twisting, or complex whole body movements)
o Persistent preoccupation with parts of objects

Characteristic deviant communication features in autism include a lack

of social chat, pragmatic deficits, pronoun reversal, delayed echolalia,
neologisms, lack of emotion in speech, phrase repetitions, and
idiosyncratic use of language. Behavioral manifestations frequently
involve repetitive, self-stimulatory behavior, especially in more severely
affected individuals. This behavior can be self-injurious in some, as
with arm biting, head slapping, and skin picking.
 Childhood disintegrative disorder is characterized, in contrast, by
normal development for at least 2 years, followed by loss of previously
acquired skills in language, social skills, bowel or bladder control, play,
and motor skills, while presenting with the autistic triad of abnormal
communication and social interaction and repetitive, stereotyped
behavior.

Rett disorder is characterized by normal development for 7-18 months,

followed by rapid deterioration of behavior and mental status,
deceleration of previously normal head growth, loss of hand skills and
social engagement (both of which were developing normally), the
appearance of poorly coordinated gait or trunk movements, and the
development of severe impairment of language and psychomotor
retardation. Abnormal sleep patterns have been noted to develop as
early as age 4 months, heralding the change in developmental
trajectory.

Individuals with Asperger disorder are often seen as having a milder

version of autism. Similar to autism, patients with Asperger disorder
have restricted and stereotyped behavior patterns and interests, plus
significant social impairments. However, unlike autism, patients with
Asperger disorder have much less impairment in cognitive
development and have no significant general delay in language
development.

PDD-NOS is diagnosed when no other specific autistic spectrum

disorder can be diagnosed, but a severe and pervasive impairment in
relating to others still is present. In addition, to receive a PDD-NOS
diagnosis, either (1) verbal or nonverbal communication difficulties or
(2) stereotyped behaviors or interests should be present.

Some controversy exists of the difference between PDD-NOS and

Asperger disorder. DSM-IV-TR actually gives both diagnoses the same
diagnostic code (299.80), though it states that the PDD-NOS label
cannot be used if any of the more specific autistic disorders can be
diagnosed. PDD-NOS has the broadest definition in the category:
impairment in 2 of 3 autistic symptom clusters (difficulty relating to
others, communication problems, and repetitive behaviors) makes the
diagnosis.

In addition to the specific disorders included in DSM-IV-TR, evidence

from genetic studies (see Causes) suggests that many family members
of autistic persons have a broader autistic phenotype with milder
features and characterized by (1) less severe stereotyped repetitive
 behaviors, (2) more subtle social deficits, (3) normal intelligence, (4)
the lack of abnormal language features (including pronoun reversal and
echolalia), and (5) lack of association with epilepsy.

Reading the DSM-IV-TR criteria carefully is advisable when making an

autistic spectrum diagnosis.

Physical: Overall, relatively little is found on physical examination other than

the characteristics of comorbid conditions, where present, such as fragile X
syndrome or tuberous sclerosis.

A neurological examination can screen for possible inborn metabolic

and degenerative diseases.

Head circumference is greater than the 97th percentile in 25% of

individuals with autistic disorder; arrest of head circumference growth
in Rett disorder can occur in children older than 5 months.

Motor clumsiness may occur, especially with Asperger disorder.

A slight increased risk of nonspecific minor congenital abnormalities

exists.

Mental status examination findings include poor eye-to-eye gaze, lack

of social interaction, stereotypic and repetitive use of language, inability
to carry a conversation, preoccupation with a few stereotyped patterns
of interest, and stereotyped and repetitive motor mannerisms.

Causes:

Genetics: An estimated 3-9% of those with autistic traits have

chromosome aberrations, and the location of these abnormalities have
been reported on every chromosome. The most frequently observed
associated chromosomal anomaly is fragile X, which is reported to be
present in 2-4% of individuals with autism. Tuberous sclerosis seems to
be the next most common chromosomal anomaly in autism, with
estimates from 1-4% of cases.

The rate of autism in siblings of autistic individuals is 2-6%. This means

that the risk or occurrence among siblings is 6 times the risk in the
general population, which, though suggesting a genetic cause, is a rate
much lower than that found in single gene diseases. The concordance
rate for monozygotic twins is 60-90%; for dizygotic twins, it is less than
5%. The rate for dizygotic twins rises to 10% when broad-spectrum
 diagnostic criteria are used. Possible increased risk for anxiety and
depressive disorders is seen in family members, which may present
even before the patient with autism shows signs of illness. Six to
twenty-four percent of siblings have some form of cognitive disorder,
including learning disabilities.

Most studies indicate that relatives of individuals who are autistic have
an increased rate of social deficits that are qualitatively similar to those
found in autism. Two studies show that the pattern and the severity of
autism in one family member or between monozygotic twins is of little
or no predictive value in determining the severity or pattern of illness in
the other affected family member. This indicates that even when the
genetic liability is identical, the variations in clinical manifestation are
wide.

Autoimmune mechanisms have been postulated, but thus far, little

consistent evidence exists beyond that outlined in Pathophysiology to
support these hypotheses. Major epidemiologic studies have failed to
find evidence that measles, mumps, and rubella (MMR) vaccine use or
thimerosal (mercury vaccine preservative) exposure is associated with
autism. Birth season of March or August was once proposed to be a
risk for autism, with the implication that seasonal viral exposures trigger
autoimmune responses, but this has not been a consistent finding.

No specific cause has been detected for childhood disintegrative

disorder.

Genetic abnormalities are the likely cause of Rett disorder, as a small

group of monozygotic twins showed 100% concordance, while
dizygotic twins showed no concordance. A dominant X-linked
inheritance with full or nearly full penetrance and with early death of
affected males through spontaneous abortion is probable. Genetics
have determined that 80% of classic Rett syndrome cases have
mutations in one gene, methyl-CPG-binding protein 2 (MECP2). Two
studies looking for this mutation in autism cases without Rett features
were negative, further arguing that autism and Rett syndrome are
distinct entities.

Early data in Asperger disorder are strongly suggestive of a genetic

component. Although specific genetic mutations have been found in a
few patients (Xp22.13, Xp22.3, Xq13, Xp22.1), the vast majority of
Asperger disorder cases have no specific explanation yet.
 Research had suggested that environment and season of birth
predicted the development of an autistic disorder, but subsequent
investigators have not confirmed these associations. In particular, the
observation of an increased incidence of autistic disorder among
children of immigrant parents now appears to point to genetics rather
than environment as the culprit.

Other Problems to be Considered:

Fragile X
Phenylketonuria
Other mental retardation
Schizotypal personality disorder
Schizoid personality disorder
Selective mutism
Expressive language disorder
Mixed receptive-expressive language disorder
Stereotypic movement disorder
Congenital deafness
Congenital blindness
Attachment disturbance/psychosocial deprivation
Epilepsy
Landau-Kleffner syndrome
Obsessive compulsive disorder
Tuberous sclerosis
Tourette disorder

Lab Studies:

Screen for phenylketonuria.

Chromosomal analysis can be used to look for fragile X (present in 2-

4% of cases) and other chromosomal abnormalities. This is indicated
for males with autism spectrum disorder due to the fragile X
association.

Imaging Studies:

MRI may be helpful as part of a neurological investigation in the

presence of focal neurological findings or severe developmental delay,
but it cannot be used for diagnosis of autism.

Other Tests:
 EEG is useful in the presence of symptoms consistent with seizures
because of the high prevalence of seizure disorder in individuals with
autism. Importantly, Landau-Kleffner syndrome (a rare acquired
epileptic aphasia) may make someone appear autistic, but treatment is
uniquely centered on seizure control.

An audiological examination is appropriate for possible hearing

impairment if a lack of response to auditory stimulation is a concern.

Psychological and neuropsychological testing for mental retardation

and other language disorders can be difficult in the face of severe
language difficulties, but specific tests are available. Cognitive and
linguistic assessments are crucial so that individualized treatment can
be developed, with programs aimed at the appropriate level. Some
amount of prognostic prediction can be made based on the degree of
cognitive disabilities.

Neuropsychological testing can be helpful in autistic spectrum

disorders, especially Asperger disorder, to determine the specific areas
of deficit and strength. Savant skills (cognitive skills that are both 1
standard deviation above the general population mean and 2 standard
deviations above the patient's own cognitive level) are present in 25%
of individuals with autism whose IQ is over 35.

Psychiatric assessment is necessary and can help rule out comorbid

attention deficit disorder (ADD), mood disorder, obsessive-compulsive
disorder, anxiety disorders, and tic disorders. However, the reliable
diagnosis of other psychiatric disorders is increasingly difficult with
increasing severity of autistic symptoms.

Home environment and emotional supportiveness of family should be

evaluated.

Medical Care: Treatments should be individualized and should focus on

behaviors, communication, and social deficits.

Behavioral interventions

o Traditional applied behavior analysis (often called ABA)

evaluates the ABC's of behavior (antecedents, behaviors,
consequences) and aims to mold a patient's behavior into more
socially and functionally useful patterns. Although helpful, the
treatment may be insufficient, in that, the meaning of the
behavior to the child must be understood as much as possible.
 The difficult behaviors of individuals with autism frequently serve
a communicative purpose as the means by which these
individuals attempt to influence their environment. In many
school districts, this is considered the standard of care for young
autistic children.
o Aggressive, self-injurious, or stereotyped behaviors can indicate
a need for help, or they can be used to escape from stressful
situations, obtain desired objects or stimulation, or protest
against unwanted events and activities.
o Useful principles for dealing with troublesome behaviors include
(1) the establishment of clear and consistent rules, (2)
introduction of changes one step at a time, (3) exploration of
underlying factors, (4) consideration of environmental
modifications, and, possibly, (5) the use of obsessions as
reinforcers for positive behaviors.
o Individuals who are autistic find it difficult to attend to more than
one stimulus at a time, so cues must be kept simple.
Reinforcement of desired behaviors, with punishment of
behavioral excesses (eg, through time outs), can be effective.

Increasing communication skills

o Children aged 6-7 years who do not develop useful speech

remain highly impaired in the use of verbal communication and
require an alternative system, such as signs or pictorially based
systems.
o Facilitated communication, where a therapist guides the
patient's hand to utilize nonverbal language systems, is not
effective.
o For those with some speech, programs may help improve
comprehension, enhance speech complexity, or correct
problems of intonation and articulation. However, to be effective,
they must be more than isolated 1-hour speech therapy
sessions, as they need to involve the active participation of all
those working with the patient.
o Echolalia or stereotyped speech needs to be understood in
terms of its role in communication, particularly of feelings and for
stress relief, with efforts made to deal with the underlying cause,
as well as consistent behavioral interventions to extinguish the
troublesome aspects of the behavior.

Modifying social difficulties

 o In severely disturbed individuals, highly inappropriate behaviors,
such as screaming or masturbating in public, should be the
focus of treatment using behavioral techniques.
o Social skills training in every situation to which a person is
exposed is useful. Education of peers about the effects of
autism can improve interaction and enhance integration. The
inability of people with autism to understand the thoughts, ideas,
or feelings of others (the "theory of mind" deficit of autism) can
be targeted and improved through appropriate educational
programs.
o Combined, structured education programs have been designed
that are effective for improving functioning and increasing the
capacity for children with autism to be integrated into normal
schools. Programs in general are most effective when begun
early (age 2-4 y) and involve intensive full spectrum
interventions.
o Adults with autism continue to need treatment and, depending
on severity, are likely to continue to require high levels of
supervision and structure, with specialized daycare, group
settings, and, at times, residential care. Individuals with
Asperger syndrome require similar intervention. The relative
preservation of function may create unrealistic expectations and
an underestimation of needs. Specific testing of a complexity to
sufficiently document the subtle abnormalities is essential in
treatment planning.
o A large array of alternative treatments exist for autism, most with
only anecdotal evidence of their utility. Before committing to an
alternative treatment, families and professionals need to look
carefully at the supporting evidence for it, the cost, and ensure
its administration will be safe for their child.
o Hospitalization is rarely indicated and only when self-injurious or
aggressive behavior is so severe it can no longer be managed
at home. Hospitalization, when required, is often difficult to
obtain as most communities do not have an acute care
psychiatric hospital equipped for the type of behavior
management treatment required for these patients. Residential
treatment or long-term hospitalization is occasionally necessary.

Consultations:

Neurologist if seizure disorders are present

Speech and language therapist

 Behavioral psychologist with experience with autistic spectrum
disorders in devising behavioral plans

Neuropsychologist may be helpful, especially with developing

educational plans

Medications do not treat the disorder itself, although core symptoms in some
individuals may be affected by medications. Most research to date has been
conducted on children, contrary to the usual methodology in medicine. In
general, medications are used to target symptoms, symptom complexes, or
comorbid disorders, such as ADD, obsessive-compulsive disorder,
depression, dysthymia, and tic disorders. Use of medications has become
more common, with the prevalence of autistic children taking medications
(psychotropics, antiseizure medications, megavitamins) rising from 42% in
1995 to 65% in 2003 (Coleman, 2005). Less evidence of efficacy exists in the
other PDDs, so treatment decisions in those cases are often based on the
evidence that exists in autism. As a general rule, autistic children seem to be
more sensitive to psychoactive medications, so the adage of start low and go
slow with every drug trial is particularly applicable to this population.

The newer generation antipsychotics have developed a frontline position in

the treatment of autism. This is due to several well-designed studies with one
of these agents, risperidone (Risperdal), showing broad effects on several of
the core symptoms of autism. Dosages in these studies were low, usually in
the 1-2 mg/d range, although doses as high as 4.5 mg were used in larger
children. Other second-generation antipsychotics have not received as much
study with autism, but many practitioners try them out with individual patients
when risperidone is not effective or not tolerated. The relative lack of long-
term adverse effects of the second-generation antipsychotics when compared
with traditional antipsychotics makes them a more attractive option.

Antidepressants play several roles in the treatment of individuals with autism

and PDDs. They are used to treat comorbid depressive disorders, obsessive-
compulsive disorder, or other comorbid anxiety disorders, but they also may
play a role in symptom management because of the effect they have on
serotonin dysfunction, which is an issue for at least some individuals with
autism. Any of the antidepressants may play a role in the treatment of
depressive disorders, but the only evidence for efficacy in either anxiety
symptoms or obsessive-compulsive symptoms is for the selective serotonin
reuptake inhibitors (SSRIs), including clomipramine. These drugs may
decrease obsessive stereotyped behaviors and also may enhance overall
communication and improve social reciprocity, to minor degrees.
Stimulants have been shown to be helpful in treating ADD symptoms in the
autistic spectrum disorders, but with lower efficacy (~50% vs 80-90% in
nonautistic patients) and have a notably higher rate of side effects. Beta-
blockers play a more limited role in the treatment of autism, and the PDDs
and are used solely for the treatment of aggression and self-injurious
behavior, where they can reduce the intensity and frequency of the behavior.
Patients whose symptoms are characterized by overactivity, overarousal, poor
frustration tolerance, and self-injurious behavior may be the most likely to
benefit.

With regard to opioid antagonists, at one point, it was felt that increased
opiate activity might cause the social and behavioral abnormalities in autism.
Some evidence of abnormalities in this system has been found, but control of
symptoms shows no effect on core symptoms of autism. Studies have shown
a decrease in hyperactivity. No effect on self-injurious behavior has been
shown. One study of Rett disorder showed a more rapid deterioration in the
illness of those receiving naltrexone. Much hope was recently placed on the
use of secretin injections; however, careful evaluation of treatment with this
hormone in autism failed to find significant treatment benefits. Some small-
scale studies showed positive responses to use of stimulants in autism;
however, the use of stimulants is uncommon in this condition. This is because
side effects are particularly frequent, with worsened irritability, aggression, and
insomnia. Stimulant use is best reserved for higher functioning patients with
comorbid symptomsconsistent with ADHD.

No evidence exists as to whether it is better to use SSRIs, antipsychotics,

alpha agonists, or stimulants as the first line of treatment for autism, so the
decision must be left to the clinician's judgment and the primary behavioral
target. Multiple medications may be necessary for optimal medication
management. If drugs from one category are not effective, it would suggest
that a trial of drugs from another category should be considered. As with any
medication used in the treatment of autism, dosages used generally should be
lower than those used for comparably aged healthy individuals, with more
gradual dosage adjustments.

Drug Category: Antidepressants -- Have central and peripheral anticholinergic

effects, as well as sedative effects, and block the active reuptake of norepinephrine
and serotonin. Fluvoxamine and fluoxetine have the most research support for use in
autism, though the body of literature is far from extensive.

Drug Name Fluvoxamine (Luvox) -- Has been

shown to reduce repetitive thoughts,
maladaptive behaviors, and
aggression, and to increase social
 relatedness and language use. Potent
selective inhibitor of neuronal
serotonin reuptake. Does not
significantly bind to alpha-adrenergic,
histamine, or cholinergic receptors and
thus has fewer side effects than
tricyclic antidepressants.
25-200 mg PO qd, with dosage titrated
Adult Dose
in 25-mg increments
<8 years: Not established
Pediatric Dose 8-19 years: 25-200 mg PO qd or
divided bid, increase by 25 mg q4-7d
Documented hypersensitivity; MAOI
Contraindications use within previous 2 wk, use of
ergotamine, pimozide, thioridazine
May prolong the elimination of drugs
oxidized in the liver; inhibits the
cytochrome P450 2D6 isoenzyme,
which may lead to elevation in plasma
levels of tricyclic antidepressants,
phenothiazine neuroleptics, and type
1C antiarrhythmics
Lithium, tryptophan, and other
serotonergic medications may
Interactions
enhance the effects of fluvoxamine;
risk of a hypertensive crisis increases
in coadministration with MAOIs;
fluvoxamine potentiates effect of
triazolam, alprazolam (reduce dose at
least 50%); increases plasma level of
theophylline; increased toxicity
combined with alcohol, cimetidine,
sertraline, phenothiazines, warfarin
C - Safety for use during pregnancy
Pregnancy
has not been established.
Caution in liver dysfunction or
cardiovascular disease, history of
seizures, history of mania, or suicidal
Precautions tendencies; monitor for
suicidality/agitation qwk x4, then q2wk
x2, followed by q4wk x1, then as
indicated
 Fluoxetine (Prozac) -- Best studied of
the SSRIs, consider as a first-line
agent, like fluvoxamine. In 2002,
Delong et al studied 129 autistic
children aged 2-8 years and found
positive benefits in 52%. Studies have
shown improvement in irritability,
lethargy, stereotypies, and
inappropriate speech, although some
Drug Name
may develop worsening of
hyperactivity, irritability, and agitation.
Long half-life of this drug can cause
problems if such adverse reactions are
noted, so some consider it a second-
line drug. Selectively inhibits
presynaptic serotonin reuptake with
minimal or no effect in the reuptake of
norepinephrine or dopamine.
Adult Dose 10-60 mg PO qd
2-7 years: 0.15-0.5 mg/kg/d (Delong,
2002)
Pediatric Dose 7-17 years: 10-60 mg PO qd, may
increase by 10 mg q14d; consider limit
of 30 mg/d in lower weight patients
Documented hypersensitivity;
concurrently taking MAOIs or took
Contraindications
them in last 2 wk; coadministration
with ergotamines and phenothiazines
Interactions Lithium, tryptophan may increase the
risk of adverse effects, including
serotonin syndrome; inhibits the
metabolism of cytochrome P450 2D6
isoenzyme increasing plasma
concentrations of tricyclic
antidepressants, phenothiazine
neuroleptics, and type 1C
antiarrhythmics; cimetidine may
decrease clearance of drug; causes
increase in phenytoin plasma levels;
increases toxicity of diazepam,
trazodone by decreasing clearance;
also increases toxicity of MAOIs,
 highly protein-bound drugs
C - Safety for use during pregnancy
Pregnancy
has not been established.
Caution in hepatic impairment and
history of seizures; MAOIs should be
discontinued at least 14 d before
Precautions
initiating fluoxetine therapy; monitor for
suicidality/agitation qwk x4, then q2wk
x2, then q4wk x1, then as indicated
Clomipramine (Anafranil) -- Second-
line treatment after the SSRIs due to
higher incidence of adverse effects.
More effective than placebo and
desipramine, and benefits obsessive-
Drug Name compulsive symptoms, social
interactions, stereotypies, and self-
injury. Affects serotonin uptake while it
affects norepinephrine uptake when
converted into its metabolite,
desmethylclomipramine.
25 mg PO qd, increase by 10-25 mg
Adult Dose
q7-14d to 200 mg
>10 years: 25 mg PO qd, increase by
of 10-25 mg q7-14d to 200 mg; not to
Pediatric Dose exceed 3 mg/kg/d or 200 mg/d,
whichever is smaller; consider using
divided doses during initial titration
Documented hypersensitivity; recent
myocardial infarction; MAOI use within
Contraindications previous 2 wk; concurrent use with
pimozide, linezolid, flumazenil,
cisapride, class 1a antiarrhythmics
Interactions Barbiturates, phenytoin, and
carbamazepine decrease effects of
clomipramine; clomipramine increases
effects of anticholinergics,
sympathomimetics, alcohol, and CNS
depressants; toxicity of MAOIs
increases with clomipramine; avoid
use with cimetidine or erythromycin or
other drugs that effect QT interval;
 caution in presence of 2D6 inhibitors
(increase levels)
C - Safety for use during pregnancy
Pregnancy
has not been established.
Abrupt withdrawal may cause
discontinuation syndrome with
agitation, gastrointestinal upset,
headache, dizziness, lethargy, and
irritability
May be fatal in overdose, so caution
Precautions should be used in individuals at risk for
overdose or suicide attempts
Caution in severe cardiopulmonary or
renal impairment and those unable to
metabolize sorbitol; monitor for
suicidality/agitation qwk x4, then q2wk
x2, then q4wk x1, then as indicated

Drug Category: Antipsychotics -- Have shown benefit in behavior

modification.

Risperidone (Risperdal) -- A double-

blind placebo-controlled study in
children aged 5-17 years with autism
showed positive effects on irritability,
stereotypic behavior, and hyperactivity
(Rupp, 2002). A double-blind placebo
control study in adults demonstrated
significant benefit in decreasing
repetitive behaviors, aggression,
anxiety, depression, irritability, and in
Drug Name improvement in the overall behavioral
symptoms of autism. Along with
fluvoxamine/fluoxetine, this is a DOC.
Binds to dopamine D2-receptor with 20
times lower affinity than for 5-HT2-
receptor affinity. Improves negative
symptoms of psychoses and has
reduced incidence of extrapyramidal
side effects than typical antipsychotics.
At higher doses, its effects are more
like a typical antipsychotic.
 0.25-6 mg PO qd in single or divided
Adult Dose
doses
3.5-6.5 years: 0.25-0.75 mg/d (Masai,
2001)
Pediatric Dose >20 kg: Start with 0.5 mg qhs,
gradually increase to max of 1 mg in
am and 1.5 mg hs (Rupp, 2002)
Contraindications Documented hypersensitivity
Coadministration with carbamazepine
may decrease effects; risperidone may
inhibit effects of levodopa; clozapine
Interactions
may increase risperidone levels; avoid
combining with haloperidol,
ziprasidone
C - Safety for use during pregnancy
Pregnancy
has not been established.
May cause extrapyramidal reactions,
hypotension, tachycardia, and
arrhythmias; may cause prolactin
elevation to point of inducing
galactorrhea; risk of neuroleptic
Precautions
malignant syndrome, tardive
dyskinesia, diabetes mellitus; monitor
for involuntary movements at baseline
and q6mo at minimum; screen lipids
and fasting blood sugar levels yearly
Olanzapine (Zyprexa) -- A small open
study of children and adults with
autism has demonstrated improvement
in overall symptoms of autism, as well
as in hyperactivity, social relatedness,
affective responses, sensory
responses, language, self-injurious
Drug Name
behavior, aggression, irritability,
anxiety, and depression. Of similar
value as risperidone. May inhibit
serotonin, muscarinic, and dopamine
effects. Use is limited by frequent
weight gain side effect, and it can
cause sedation.
Adult Dose 2.5-20 mg PO qd
 Not established for autistic children,
Pediatric Dose
most administer similar to adults
Contraindications Documented hypersensitivity
Fluvoxamine may increase effects of
olanzapine; antihypertensives may
increase risk of hypotension and
orthostatic hypotension; levodopa,
Interactions
pergolide, bromocriptine, charcoal,
carbamazepine, omeprazole, rifampin,
and cigarette smoking may decrease
the effects of olanzapine
C - Safety for use during pregnancy
Pregnancy
has not been established.
Caution in narrow-angle glaucoma,
cardiovascular disease,
cerebrovascular disease, prostatic
hypertrophy, seizure disorders,
Precautions hypovolemia, and dehydration; risk of
neuroleptic malignant syndrome,
tardive dyskinesia, diabetes mellitus;
monitor for involuntary movements at
baseline and q6mo at minimum
Haloperidol (Haldol) -- Hyperactive or
normoactive children with autism have
been found to experience decreased
hyperactivity, aggressiveness, temper
tantrums, withdrawal, and
Drug Name stereotypies. Hypoactive children have
not experienced any benefit. Because
of adverse effects, it is recommended
that olanzapine and risperidone be
used preferentially if this class of drug
is required.
Adult Dose 0.5-5 mg PO bid/tid
Pediatric Dose 0.5-4 mg PO qd
Documented hypersensitivity; narrow-
angle glaucoma; bone marrow
Contraindications suppression; severe cardiac or liver
disease; severe hypotension;
subcortical brain damage
Interactions May increase tricyclic antidepressant
 serum concentrations and hypotensive
action of antihypertensive agents;
phenobarbital or carbamazepine may
decrease effects of haloperidol;
haloperidol coadministration with
anticholinergics may increase
intraocular pressure;
encephalopathylike syndrome
associated with concurrent
administration of lithium and
haloperidol
C - Safety for use during pregnancy
Pregnancy
has not been established.
Severe neurotoxicity manifesting as
rigidity or inability to walk or talk may
occur in patients with thyrotoxicosis
also receiving antipsychotics; if IV/IM,
watch for hypotension; caution in CNS
depression or cardiac disease; if
history of seizures, benefits must
Precautions outweigh risks; significant increase in
body temperature may indicate
intolerance to antipsychotics
(discontinue if occurs); significant risk
of tardive dyskinesia, rare risk of
neuroleptic malignant syndrome;
monitor for involuntary movements at
baseline and q6mo at minimum

Drug Category: Stimulants -- Increase release of dopamine and norepinephrine,

and block their reuptake.

Drug Name Methylphenidate (Ritalin) -- Also

available in long-acting forms of
Concerta, Ritalin LA, Metadate CD,
and Methylin ER. Early studies in
autism found an increase in irritability
and stereotypies, but studies
performed since the late 1980s have
shown benefits in small double-blind
placebo controlled trials of autism
patients with comorbid ADD.
 Symptoms responding to treatment
include hyperactivity, irritability, and
inattention. Core symptoms of autism
do not improve with methylphenidate.
Response rate is lower than in the
nonautistic population, and side effects
are more common. Doses higher than
0.6 mg/kg led to social withdrawal and
irritability in some children.
Adult Dose 5-15 mg PO bid/tid
Pediatric Dose 0.3-0.6 mg/kg PO bid/tid
Documented hypersensitivity; narrow-
angle glaucoma; severe anxiety
Contraindications
history; MAO inhibitor use within 14 d;
history of arrhythmias; drug abuse
May increase warfarin or phenytoin
levels, rare reports of sudden cardiac
death when combined with alpha2-
agonists; do not combine with MAO
Interactions inhibitors; may increase SSRI levels;
may increase tricyclic antidepressant
levels; may lower seizure threshold
with carbamazepine or bupropion; may
have additive effects with caffeine
C - Safety for use during pregnancy
Pregnancy
has not been established.
Controlled substance with abuse
potential; higher rate of side effects of
all types in autistic patients; important
Precautions
to start with low dosage, and increase
slowly with monitoring; may increase
tics
Drug Name Dextroamphetamine and amphetamine
mixtures (Adderall, Adderall XR) --
Drug not studied in autism, but most
consider this the next alternative to
methylphenidate when that is not
tolerated. Use like methylphenidate for
symptom-specific treatment of
hyperactivity, irritability, and inattention
when ADD is a comorbidity. Core
 symptoms of autism are not expected
to improve with this medication.
Anticipate a higher rate of side effects
and need for lower dosages than in the
nonautistic ADD patient.
Adult Dose 5-40 mg PO every am bid
2.5 mg PO every am bid to start,
increase by 2.5-5 mg/d/wk
Pediatric Dose
Many consider 1 mg/kg/d to be
maximum dosage
Documented hypersensitivity;
symptomatic cardiac disease;
structural cardiac anomalies;
Contraindications
hypertension; hyperthyroidism;
glaucoma; drug abuse; MAO inhibitor
use within 14 d
May reduce effect of phenothiazines;
frequent antacid use may increase
levels; increases effect of meperidine;
caution in combining with alpha2-
agonists; do not combine with MAO
Interactions inhibitors; may increase SSRI and
tricyclic antidepressant levels; may
lower seizure threshold with
bupropion; additive effects with
caffeine, modafinil; lithium may lessen
effects
C - Safety for use during pregnancy
Pregnancy
has not been established.
Controlled substance with abuse
potential; higher rate of side effects of
all types in autistic patients; important
Precautions
to start with low dosage, and only
increase slowly with monitoring; may
increase tics, if present

Drug Category: Alpha2-agonist -- Stimulate central (brain) alpha2-adrenergic

receptors.

Drug Name Clonidine -- Blood pressure

medication, useful in autistic children
 with ADD and hyperarousal: 2
controlled studies have shown efficacy
in autism. One retrospective study in
use with fragile X (for which
approximately 30% had autism)
showed improved ADHD symptoms,
tantrums, and aggression. Lowers
blood pressure, and abrupt withdrawal
of high doses of medicine can
precipitate a hypertensive crisis.
Adult Dose 0.1-0.3 mg PO bid
0.05 mg PO qd, then increase by 0.05
Pediatric Dose
mg/d q7d to 0.3 mg/d
Documented hypersensitivity; caution
if hypotensive, coronary artery
Contraindications
disease, or cardiovascular disease; not
for use with MAO inhibitors
Avoid combining with other
antihypertensives (additive effects);
mirtazapine decreases levels; rare
reports of sudden cardiac death when
Interactions
combined with stimulants; additive
effects with digoxin; tricyclics
exaggerate BP swings with use of
clonidine
C - Safety for use during pregnancy
Pregnancy
has not been established.
Patch form not recommended for
young childreningested patch may
Precautions lead to coma; abrupt withdrawal may
precipitate a hypertensive crisis;
sedation from medication is common

Drug Category: Beta-blockers -- Inhibit chronotropic, inotropic, and

vasodilatory responses to beta-adrenergic stimulation.

Propranolol (Inderal) -- May be useful

Drug Name for treatment of aggression and self-
injurious behavior.
Adult Dose 10-120 mg PO bid
 0.6-1.5 mg/kg/d divided q8h, not to
Pediatric Dose
exceed 4 mg/kg/d
Documented hypersensitivity;
uncompensated congestive heart
Contraindications
failure; bradycardia, cardiogenic
shock; A-V conduction abnormalities
Coadministration with aluminum salts,
barbiturates, NSAIDs, penicillins,
calcium salts, cholestyramine, and
rifampin may decrease propranolol
effects; calcium channel blockers,
Interactions
cimetidine, loop diuretics, and MAOIs
may increase toxicity of propranolol;
toxicity of hydralazine, haloperidol,
benzodiazepines, and phenothiazines
may increase with propranolol
C - Safety for use during pregnancy
Pregnancy
has not been established.
Beta-adrenergic blockade may
decrease signs of acute hypoglycemia
and hyperthyroidism; abrupt
Precautions withdrawal may exacerbate symptoms
of hyperthyroidism, including thyroid
storm; withdraw drug slowly and
monitor closely.

Drug Category: Opioid antagonist -- Mostly experimental for this indication.

Naltrexone (ReVia) -- Although

previously thought to be helpful for its
opiate-blocking activities, conflicting
reports on naltrexone's efficacy in
autism now exist. One study showed
more rapid deterioration in patients
Drug Name
with Rett disorder on naltrexone. It is a
cyclopropyl derivative of oxymorphone
that acts as a competitive antagonist at
opioid receptors. Not commonly used
for this indication, considered
experimental.
Adult Dose 25-100 mg PO qd
 Pediatric Dose 1 mg/kg/d PO
Documented hypersensitivity; acute
hepatitis or liver failure; Rett disorder;
Contraindications patients receiving opioid analgesics,
going through acute opioid withdrawal,
or opioid dependent
Interactions Inhibits effects of opiates
C - Safety for use during pregnancy
Pregnancy
has not been established.
Precautions Caution in hepatic impairment

Further Outpatient Care:

Monitor for adverse effects to medication. Autistic individuals tend to

have a higher incidence of adverse effects from medications, so use
extra caution. No research guidance exists for the long-term use of
medications. Risk of long-term adverse effects with these medications,
apart from tardive dyskinesia with neuroleptics, is very low; therefore,
clinical impressions must be used in determining long-term use.

Monitor for other causes of deterioration of behavior and functioning,

including concurrent illness, change in psychosocial environment, and
other external stressors.

Transfer:

When self-injurious behavior escalates to the point of severe self-harm,

transfer to a specialized facility may be necessary in order to review
medication and behavioral treatments, enhance physical protection,
and reassess needs for placement or housing.

Deterrence/Prevention:

No evidence of any effective deterrence or prevention strategies exists.

Early intensive intervention may decrease ultimate functional

impairment.

Federal Early Intervention Program (up to age 3) is often the first

source of treatment for these children. After age 3, local school districts
 have the legal mandate to take over and place these children on an
individualized educational plan (IEP).

Complications:

Detection of Asperger disorder often is delayed until well into

adulthood. Failure to detect this illness and implement appropriate
social, educational, and vocational interventions may result in
exacerbation of the disability through an accumulation of academic,
social, and vocational failures. These, in turn, can increase the risk of
secondary major depression or other adjustment reactions.

Prognosis:

Most children with autistic spectrum disorders have difficulties

throughout life.

Intensive, individualized behavior and treatment programming

beginning early in childhood can result in significant improvement in
functioning.

Improvement in early adolescence is frequent.

Individuals without mental retardation who are found to have Asperger

syndrome frequently improve enough to live independent adult lives,
and they may marry.

Depending on the population studied, 2-15% of patients achieve a

nonretarded level of cognitive and adaptive function.

IQ below 50 at school age and lack of communicative speech by age 5-

6 years is correlated with poor long-term outcome.

The presence of epilepsy and other comorbid disorders is predictive of

poorer outcome.

Patient Education:

Patient and family education about the causes, impact, treatments,

symptoms, and prognosis is an essential part of ongoing treatment.
Involvement of family as participants in the treatment is essential.
Family-to-family support can greatly decrease the adverse impact of
autistic spectrum disorder on youth and family functioning. Other
families of children with autism, who have learned many things about
 how to work best with local care providers, can be excellent local
resources.
Families have strong reactions to the diagnosis of autism and often
need time to grieve the loss of their ideal image for their child.

For excellent patient education resources, visit eMedicine's Brain and

Nervous System Center. Also, see eMedicine's patient education
articles Autism and Asperger Syndrome.

A good book for family education is The Autism Sourcebook by Karen

Siff Exhorn (2005).

Medical/Legal Pitfalls:

All children aged 3-21 years who are diagnosed with autism or PDD
must by law receive an appropriate education within the public
educational system. Services for children aged younger than 3 years
must be provided, but they may be provided by an agency with
individualized education programs and individualized family service
plans, generally through early intervention programs.