Current Drug Therapy, 2007, 2, 97-103 97

Autism Spectrum Disorders: Etiology and Pharmacotherapy

Mohammad-Reza Mohammadi and Shahin Akhondzadeh*

Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran

Abstract: Autism is a complex neurodevelopmental disorder that forms part of a spectrum of related disorders referred to
as Autism Spectrum Disorders (ASD). Like other complex neurodevelopmental disorders (e.g., schizophrenia), ASD is
thought to be the final common pathway of multiple etiological (largely genetic) and neuropathological mechanisms. In
the absence of a biological marker, ASD is defined behaviorally, its clinical presentation characterized by impairments in
reciprocal social interaction and in communication with others, and by a preference for repetitive, stereotyped behaviors.
Our understanding of autism has changed dramatically over the past decade. We now know that autism is not one disor-
der, but several closely related “disorders”, including Asperger syndrome, atypical autism, and disintegrative disorder.
They may involve a range of behaviors at different ages and degrees of functioning, thus the term “autism spectrum disor-
der”. Along with these changes in classification, there has been a greater understanding of the causes of autism. Develop-

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mental delay, epilepsy, minor facial and bodily abnormalities, increased rate of obstetrical complications, an unequal sex

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ratio, and extremes of head size represent subtle, but still not clearly defined, signs that autism is a neuropsychiatric disor-
der. It appears that pharmacological interventions may have a limited role to play in the overall therapy of the autistic
child. Medications may be most helpful in reducing hyperactivity, impulsivity, and aggressive and obsessive behaviors.

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For the development of everyday life skills, one-on-one behavioral therapy seems to be mandatory.

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INTRODUCTION edition (ICD-10)], and the American Psychiatric Associa-

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tion’s “Diagnostic and Statistical Manual”, 4th edition
ASDs are diagnosed on the basis of qualitative abnor-

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(DSM-IV) [4, 5]. These reflect agreement in the field that

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malities in social, communicative and imaginative behaviors,
ASDs are characterized by early emerging (before 3 years
and the presence of repetitive and stereotyped patterns of old), qualitative (i.e. abnormal and not merely delayed de-

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interests and activities. Diagnosis is complicated by the var-
velopment) impairments in social interaction, communica-
ied manifestation of these core deficits, by wide variation in

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tion (and imagination), with restricted and repetitive interests
ability level, and by developmental changes. There is con-
and activities [6].

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siderable heterogeneity, and subgroups might be usefully
distinguished. There are now systematic tools for diagnosis,

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DIAGNOSIS
through parental interview and direct observation – and these

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should allow greater comparability of research samples Diagnosis is complicated by the range of manifestations
of each of the triad of impairments. Therefore, an individual

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across studies in the future. Population-based screening for
ASDs is complicated by the need to check negative findings, may show qualitative impairment of social interaction in the

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and ethical issues in identifying undiagnosed individuals at form of aloof and indifferent response to others, passivity,
the high-ability end of the autism spectrum. This paper re- or over-friendly ‘active-but-odd’ behavior. Communication
views the etiology and pharmacotherapy of ASD. impairments, too, may vary from complete muteness to over-
literal and pedantic, but verbally fluent and erudite, lan-
In the absence of a specific biological marker (e.g. blood guage. People with ASDs, in a similar way to people with-
test) for ASDs, autistic disorder is defined by behavioral out, show individual differences as a function of personality,
criteria. These criteria have evolved over the almost 65 years family and social environment, educational and vocational
since Kanner and Asperger first introduced the term autism opportunities, and so forth. Also contributing to the chal-
for childhood disorders of social interaction [1]. In response lenge of diagnosis is the change in manifestation with age,
to research findings, there has been a progressive widening autism, even in the same individual, may look very different
of diagnostic criteria: Kanner and Eisenberg identified as the at 5 and at 15 years of age. For example, lack of pretend play
two key features of autism, social aloofness and insistence is a striking manifestation of the imagination impairment in
on sameness, and to these Rutter added impairment in lan- childhood, but in adulthood the same impairment is often
guage development [2]. Wing and Gould introduced the no- seen instead in lack of interest in fiction, and fascination
tion of an autism spectrum, covering a range of ability levels with facts (e.g. memorizing dates or timetables). It is clear
and severities, but characterized by qualitative impairments that ASDs persist and those children with ASD become
in social, communicative and imaginative development [3]. adults with ASD, with their own complex needs [7, 8].
It is this ‘triad’ of impairments that is captured in current
international classification systems [the World Health Orga- The course of development into old age is as yet un-
nization’s “International Classification of Diseases”, 10th known, and further research is needed. To date most at-
tempts to define subgroups have been at the behavioral level.
*Address correspondence to this author at the Roozbeh Psychiatric Hospital, The diagnostic manuals (DSM-IV, ICD-10) identify various
Tehran University of Medical Sciences, South Kargar Street, Tehran 13337, subtypes, three of which are currently considered part of the
Iran; Tel: +98-21-55412222; Fax: +98-21-55419113;
E-mail: [email protected]
autism spectrum (autistic disorder, Asperger syndrome, and

1574-8855/07 $50.00+.00 ©2007 Bentham Science Publishers Ltd.

 98 Current Drug Therapy, 2007, Vol. 2, No. 2 Mohammadi and Akhondzadeh

atypical autism or ‘Pervasive Developmental Disorder, not spectrum disorders far more common than was previously
otherwise specified’ (PDD-NOS) [6]. Other attempts to de- generally recognized [14-17].
fine subtypes include 1) Wing’s passive, aloof, active but
odd [1], 2) low, medium and high functioning and, 3) non- The average prevalence from all studies published by the
regressive and regressive subtypes differentiated by age of year 2000 is 10 per 10,000 for autistic disorder, and 2.5 per
onset. At present, none of the proposed subdivisions of ASDs 10,000 for Asperger syndrome. Estimates from more recent
have been validated at the cognitive, neurobiological, or etio- studies have been higher, reflecting better ascertainment. For
logical level. The distinction between high-functioning example, prevalence estimates based on the two most recent
autism and Asperger syndrome, currently made on the basis studies in the UK using active case ascertainment and a two
of language delay in the former only, is contentious; groups stage ‘screen’ with similar criteria for caseness are consis-
so defined seem far more alike than different when examined tent. Baird reported a combined prevalence of 57.9 per
in adolescence [9, 10]. 10,000 in children by the age of 7 which accords with the
figure of 62.6 per 10,000 for all pervasive developmental
It is important to note, also, that because ASDs are pre- disorders reported by Chakrabarti and Fombonne in their
eminently developmental disorders, an individual may fit survey of 4 to 7-year-olds in Staffordshire. Baird estimated a
one sub grouping at one stage of development and another at prevalence of 27.1 per 10,000 for Asperger syndrome which
a later developmental stage. Behaviorally defined subgroups is higher than 8.4 per 10,000 reported by Chakrabarti; this

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therefore do not, at least as yet, appear to relate to etiology or may reflect some differences in age groups studied [14-18].
prognosis. However, behaviorally defined subtypes have

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practical usefulness and may be helpful for individuals with A male excess is generally observed and this is especially
ASDs, parents and service providers [9, 10]. pronounced at the high ability end of the spectrum. Wing has

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speculated that this pattern reflects both greater male suscep-
Systematic assessment tools have been developed in re- tibility to developing ASDs as well as a requirement for

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cent years, lessening the reliance on clinical judgment, which more severe brain involvement in girls before they express
was up until now the only gold standard. History taking and the ASD phenotype. This theory remains to be tested. It is

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direct observation have different strengths and weaknesses, also possible that ASDs may be harder to recognize in
and are best used in combination although it is unclear how

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women, at least using current diagnostic criteria which may

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to balance these sources of information if they conflict. The identify abnormal behaviors for men more successfully than
new assessment tools allow clinicians to measure degree of for women [19].

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impairment, as well as deciding whether an individual passes
a threshold for diagnosis [11-13]. Use of these instruments in

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THE ROLE OF GENETICS
the future should ensure that different research studies are

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including comparable groups of people with ASDs. Even in Twin and family studies show that ASDs are highly heri-
the presence of agreed broad diagnostic criteria for ASDs, table, although the mechanisms are likely to be complex and

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the methods by which information has been obtained when a involve the interaction of many genes. At present, these

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child or adult comes to the clinic have varied. In the past, complex genetic influences are thought to operate in most
cases of ASD, while single gene disorders and chromosomal

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parental interview and direct observation have been unstan-
dardised, with clinical judgment (of what constitutes, for abnormalities may affect a small (5-10%) proportion of those
with ASDs [20-24].

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example, qualitative impairment in social interaction, given a
child’s age and intellectual level) remaining crucial. More In approximately 90% of individuals with ASDs, there is
recently, complex diagnostic instruments have been devel-
good evidence to indicate that complex genetic influences
oped, to allow systematic collection of developmental data
are contributing to pathogenesis. However, these estimates
relevant to diagnosis. Examples of such instruments are the
are based on studies of relatively small samples of twins that
Autism Diagnostic Interview – Revised (ADI-R), the Autism
were ascertained using relatively narrowly defined and strin-
Diagnostic Observational Schedule (ADOS), and the Diag-
gent diagnostic criteria. Moreover, to varying extents the
nostic Interview for Social and Communication disorders samples are likely to have been subject to ascertainment bias
(DISC). These instruments are to be administered by inter-
[20-24].
viewers who have good knowledge and understanding of the
features of autism spectrum disorders (in part, based on di- A variety of possible risk factors for ASDs have been
rect observation of the clinical manifestations) and additional suggested, In general, there is insufficient evidence to date to
specific training in the use of these instruments [11-13]. allow firm conclusions. Perinatal complications are thought
PREVALENCE more likely to be consequences rather than causes of a
child’s ASD, and no specific prenatal exposures have been
Prevalence estimates will depend on exact assessment established as contributory. A small number of cases have
tools and ascertainment methods, and variations across stud- been reported in which viral infection may have played a
ies will likely reflect such methodological differences. How- role [25].
ever, according to recent reviews, there appears fairly good
agreement that the autism spectrum disorders affect ap- It must be stressed that the term “environmental” implies
proximately, and narrowly-defined autism 10-30, per 10,000 all factors other than genetic susceptibility. At present there
children under 8. The prevalence of autism among adult is little, if any, direct evidence in support of these potential
populations is not known. These estimates make autism factors.
 Autism Spectrum Disorders: Etiology and Pharmacotherapy Current Drug Therapy, 2007, Vol. 2, No. 2 99

NEUROBIOLOGICAL CAUSES PHARMACOTHERAPY

Several environmental risk factors have been established Antipsychotics
for the development of autism. These include in utero expo-
sure to rubella, as well as teratogenic agents such as ethanol, Although there is no strong evidence of dopamine in-
valproic acid, and thalidomide. The observation that autism volvement in autism, neuroleptics have been used for a long
is much more common among persons exposed to thalido- time to decrease aggressivity, stereotypic behaviors, and
mide has led some researchers to postulate that the develop- impulsivity. Low-potency neuroleptics were soon abandoned,
ment of autism may, for some, begin as early as gestational owing to their cognitive and sedative side effects. Among
day 20 to 24, when the motor neurons of the cranial nerves high-potency neuroleptics, haloperidol has been studied most.
are being formed [26-33]. These cell bodies are located in Several controlled studies showed benefits over placebo
the brain stem. It has been hypothesized that cranial nerve among young children treated with dosages in the range of 1
dysfunction may somehow interfere with the proper devel- to 2 mg daily to improve attention and to reduce hyperactiv-
opment or wiring of that region of the brain. Specifically, ity, anger outbursts, and stereotypies [45, 46]. However,
some studies have revealed that the brains of some autistic problematic side effects in the form of acute dystonic reac-
individuals lack the superior olive, and fewer cell bodies are tions, withdrawal dyskinesias, and tardive dyskinesias were
found in the facial nucleus and the trapezoid body. In other noted. Typical neuroleptics have been replaced with atypical
antipsychotics that combine dopamine (D2) and serotonin

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words, the brain stem of a person with autism is shorter than
the brain stem of a normal person [34]. The structures at the (5-HT2) receptor antagonist actions [45-48]. Following sev-

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junction of the pons and medulla (such as the facial nucleus eral open-label studies suggesting the efficacy of risperidone,
and trapezoid body) are closer to the structures of the lower a 12-week, double-blind, placebo-controlled trial was con-
ducted with 31 adults (mean age 28 years) with autism and

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medulla (the hypoglossal nucleus and inferior olive). It has
been reported that this appearance as if a band of cerebral PDD NOS. Significantly, at a man dosage of 2.9 mg daily,

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tissue had been removed and the two remaining pieces were more responders (57% vs 0%) were found in the risperidone
simply sown together without a seam where the tissue was than in the placebo group, and improvements were noted for

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missing. This has led us to opine that “many cases of autism, irritability, anxiety or nervousness, aggression, repetitive
behaviors, and depression. There were no improvements on

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if not all, are initiated very early in gestation” [34]. Several

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other studies have also implicated developmental damage to objective measurements of social behavior and language,
the cerebellum, or reduction in the number of cerebellar suggesting that the drug targets nonspecific behavioral prob-

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Purkinje cells as causative. Paradoxically, megaloencephaly lems associated with autism [49, 50]. The drug was well tol-
erated. More recently, a multicentric, 8-week, double- blind,

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(as measured by head circumference) is observed in one-fifth
of autistic persons especially in the occipital and parietal placebo-controlled trial of risperidone (dosage range 0.5 to

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regions of the brain. Still others posit that autism may in- 3.5 mg daily) was completed on 101 children with autism
aged 5 to 17 years (mean age 8.8 years) presenting with

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volve cellular abnormalities of the hippocampus, amygdala
or other structures of the limbic system. Other authorities clinical levels of tantrums, aggression, and self-injurious

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have identified a reduction in brain perfusion to the temporal behavior. Significant benefits of the active medication were

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area of the brain among autistic children [35-39]. Gillberg observed for the 2 primary outcome measures of reduced
has interpreted these and other findings as indicating that Irritability scores (57% vs 14%) and a rating of “much im-

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autism may originate from two different pathways: one con- proved” or “very much improved” on a Clinical Global Im-
nected to primary temporofrontal dysfunction (caused by late provement (CGI) scale (69% vs 12%). Side effects such as
prenatal or early postnatal insults) and another linked to pri- fatigue, drowsiness, increased appetite, and drooling were
mary brain stem dysfunctions (caused by early prenatal ori- more common in the risperidone group, as was a signifi-
gins) [40]. cantly higher weight gain (2.7 vs 0.8 kgs). Promising open-
label studies have been conducted with olanzapine, quetiap-
INFECTIONS ine, clozapine, and ziprasidone; several randomized studies
No cases have been reported of direct bacterial, parasitic are currently under way. Atypical neuroleptics therefore ap-
or other non-viral infection in the CNS that were associated pear to be promising agents to treat behavioral symptoms
with patients displaying ASD symptoms. In contrast, a role often occurring among autism patients. Yet, despite their
for viral infection in triggering ASDs has been proposed in a good tolerance, these drugs are associated with some unde-
number of studies. ASDs has occasionally been associated sirable adverse effects, such as tachycardia in young children
with cases of perinatal cytomegalovirus infection in children taking risperidone and sedation for all atypicals, the most
as well as with cases of congenital rubella infection [41, 42]. serious of which is substantial weight gain. There are no
A small number of cases have been described associated with long-term studies of the drugs’ efficacy and tolerability [48-
herpes simplex virus encephalitis [43, 44]. All these viral 52].
infections have many other detrimental effects on the brain LITHIUM
of infected patients and hence it is probably not surprising
that some of the affected children displayed symptoms asso- Lithium has been reported to have a mood-reducing ef-
ciated with autism spectrum disorders. With the disappear- fect on manic disorder in adults with autism. It may also re-
ance of congenital rubella the number of reports of associ- duce aggressiveness and hyperactivity in some individuals.
ated ASD has decreased substantially. The cases were spo- The role of lithium in children is unclear; results from only a
radic and rare and hence it is unlikely that these viruses act few controlled studies are available. It seems that lithium is
as triggers for the majority of individuals with ASDs [41, 44]. effective in reducing aggressive behavior in children of nor-
 100 Current Drug Therapy, 2007, Vol. 2, No. 2 Mohammadi and Akhondzadeh

mal intelligence diagnosed as having conduct disorder. There ment had fewer Peptostroptoccal species than adult controls.
are uncontrolled studies that suggest lithium may have an Vancomycin provides broad coverage for anaerobic bacteria.
anti aggressive effect in children with mental retardation [48, Colitis is a known side effect. Widespread use of vancomy-
49]. cin is discouraged to prevent the emergence of resistant
strains of bacteria [57].

BLOCKERS
CYPROHEPTADINE
 blockers are medications that block  –adrenergic re-
ceptors and reduce overall norepinephrine neurotransmis- Cyproheptadine is an antihistamine that is a 5-HT2 re-
sion. It has been reported that propranolol (a  blocker) was ceptor antagonist with reported antipsychotic activity. Stud-
effective in reducing severe and treatment resistant aggres- ies have described elevated blood levels of 5-HT which is
siveness directed against others or oneself. These reports, now determined to be associated with increased levels of
however, are based on uncontrolled trials or case reports serotonin in platelets [58]. As in other therapeutic innova-
involving diagnostically heterogeneous nonautistic subjects. tions of treatment in autism, information obtained from trials
In an open trial of propranolol in eight hospitalized adults of adults with schizophrenia paved the way for trials in
with autism, it has been reported that a reduction in aggres- autism. Several open clinical trials of ritanserin, a selective
sive, impulsive, and self-injurious behaviors and improve- 5-HT2/1C antagonist; showed promising results in reduction
ment in speech and socialization. However, seven of the of symptoms. A double-blind, placebo-controlled 8-week

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eight patients were receiving concomitant neuroleptic or trial of oral cyproheptadine compared to haloperidol and

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mood-stabilizing drugs during the trial [48, 49]. placebo in 40 children between 3 and 11 years of age with
severely disruptive behavioral symptoms was completed
CLONIDINE
[58]. Children who received cyproheptadine and haloperidol

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Clonidine is an
2-adrenergic receptor agonist that de- had better outcomes as measured by the Aberrant Behavior

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creases norepinephrine neurotransmission. It has been re- Checklist-Community and the Childhood Autism Rating
ported that clonidine has therapeutic value in Tourette disor- Scale (CARS). The authors suggested confirmation with a

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der [53]. It is less effective in reducing tics than haloperidol larger population. Side effects noted included sleepiness and
increased appetite. This represents an off-label use of an ap-

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and pimozide but has fewer side effects than haloperidol. It

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was tried in autism because of its behavioral effects. In a proved medication, taking advantage of actions (e.g., 5-HT
double-blind, placebo controlled crossover study, clonidine antagonism) other than the primary one as an antihistamine.

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(0.15–0.20 mg/d) was given to eight autistic boys, aged 5 to It is possible that the combination of cyproheptadine with an
13 years, who had been previously treated with methylphe- atypical neuroleptic rather than haloperidol might be more

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nidate, neuroleptics, or desipramine without effect. Teacher effective [58].

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and parent ratings indicated modest improvement in hyper-
D-CYCLOSERINE

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activity and irritability. Sedation and decreased blood pres-
sure were the most frequent side effects, and many of the D-cycloserine, an antibiotic that is a partial agonist at the

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children eventually developed tolerance to the therapeutic glycine binding site of N-methyl-D-aspartate (NMDA) glu-

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effects of clonidine [54]. tamate receptor, has been proposed as a treatment for autism
[59-61]. Several reports have related GABA receptor genes
GUANFACINE

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and the GABA system to pathophysiology of autism. Earlier
Guanfacine is another
-adrenoceptor agonist with a studies of adults with schizophrenia [60] demonstrated a
longer excretion half-life, decreased sedative side effects, decrease in disruptive symptoms with D-cycloserine in com-
and more selective binding profile than those of clonidine. It bination with a neuroleptic. Posey et al. [61] published a 2-
has been reported to show effectiveness in treating children week single-blind placebo lead-in phase to treatment with
with attention deficit hyperactivity disorder and in children three different doses of D-cycloserine. Subjects (n=10) were
with both attention deficit hyperactivity disorder and aged 5–27 years. Outcome measures included the Clinical
Tourette disorder [55, 56]. Global Impression scale and Aberrant Behavior Checklist.
On the highest dose, subjects had statistically significant
ANTIBIOTIC THERAPY improvement in social withdrawal. Adverse effects reported
Anecdotal reports of the recognition of symptoms of included motor tics and increased echolalia in two subjects.
ASD after antibiotic use led Sandler et al. to suggest that an Nevertheless, it should be considered the limitations of this
alteration in intestinal flora may have precipitated symptoms study including the wide age range, lack of clinician blind-
of autism. When the stools of children with autism were ing, absence of a control group, and small number of sub-
compared to children without autism, colonization with clos- jects. The order of treatments was not randomized. This is an
tridium species were different [57]. The relationship of al- intriguing idea that might deserve further pursuit, pending
tered colonic flora and neurological symptoms on the basis documentation of an association between glutametergic neu-
of toxins and/or alteration of the integrity of the intestinal rotransmission and autism [59-61].
lining is suggested. Oral vancomycin was given in an open OPIATE ANTAGONISTS
label study to 11 children with ASD who had a history of
behavioral regression and diarrhea. Outcome parameters The potential role of opiod-excess in autism, and relevant
included blinded videotape evaluations and non blinded be- clinical observations, led to the use of naltrexone, an opiate
havior and communication assessments. Eight of 10 children antagonist. Although there are several controlled studies re-
had significant improvement. Stool samples prior to treat- porting its efficacy in reducing hyperactivation, inattention,
 Autism Spectrum Disorders: Etiology and Pharmacotherapy Current Drug Therapy, 2007, Vol. 2, No. 2 101

and self-injury behaviors, at least in a subgroup of children lems are viewed as challenging behaviors if they represent a
with autism, a critical appraisal of the current literature pro- serous risk for the individual or others or when they further
vides mixed results [62, 63]. burden their effective education and interfere with their so-
cial adaptation. In addition, comorbid conditions, such as
STIMULANTS
anxiety, tics, depression, and epilepsy can complicate the
Methylphenidate is proven to be efficacious in children effective management of the main disorder. Such difficulties
with attention-deficit hyperactivity disorder (ADHD). Meth- should be promptly identified through constant monitoring,
ylphenidate was also introduced to children with ASD to and appropriate behavioral and/or educational problems fail
target symptoms of hyperactivity, impulsiveness, and inat- to respond to such modifications, drug treatments represent a
tention. Stimulants seem to help only a subgroup of children feasible alternative or even a necessity. Drugs should be used
with autism, particularly those with higher functioning only to facilitate behavior management and to treat specific
autism and comorbid ADHD [64, 65]. symptoms, in order to enhance the child’s benefits from a
comprehensive behavioral/educational intervention and not
CHOLINESTERASE INHIBITORS to replace it. The decision of when and which drug should be
Donepezil, a cholinesterase inhibitor used for treating used is not always clear cut. Current literature, however,
dementing illnesses such as dementia of the Alzheimer’s offers data concerning both the efficacy and safety of phar-
macotherapeutic agents in the treatment of persons with

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type, has been investigated in an open study in autism, but
data to support such use are limited [66]. autism and rational protocols for their use. Antipsychotics,

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including both the conventional and atypical agents, are the
GLUTEN/CASEIN-FREE DIET class of drugs that have been the most studied in autism. As
The most frequently cited diet in the treatment of autism is the case for all drug treatments in autism, antipsychotics

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is the gluten/casein-free diet. Gluten and Casein are dietary are not curative but can be used to reduce symptoms, there

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proteins found in wheat/barley and cow’s milk, respectively. by enhancing the effects of other ongoing psychosocial and
It is hypothesized that toxins released with the incomplete educational treatments.

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breakdown of gluten and casein cause autism. By excluding REFERENCES

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Received: June 19, 2006 Revised: January 04, 2007 Accepted: January 04, 2007

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