Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease http://dx.doi.org/10.1016/B978-0-12-410529-4.00018-8 197 © 2015 Elsevier Inc. All rights reserved.

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Autism Spectrum Disorders: Clinical Considerations

Patricia Evans, Sailaja Golla, and Mary Ann Morris The University of Texas Southwestern Medical Center, Dallas, TX, USA

INTRODUCTION

Autism spectrum disorders (ASD) are a group of neurodevelopmental disabilities that typically first appear in childhood and are characterized by significant difficulties in social, communicative, and behavioral functioning. Although no one single cause has been found, it is suspected that many etiologies have a common final pathway within early neurologic development. Bearing a diagnosis of an ASD typically causes an individual and his/her family difficult financial, emotional, and at times, physical burdens over the individual’s lifespan. New bur-dens are being experienced by state and federal agencies as communities seek ways to medically and financially support the increasing volume of adults with ASD. Consequently, research continues to better understand the complex process of ASD, find disease-specific interventions, and better ways to enable communities to provide resources for families.

OVERVIEW

Identifying individuals with an ASD ideally starts in infancy, and requires two levels of surveillance, each ad-dressing a distinct component of patient management. Routine developmental surveillance and screening specif-ically for ASD has been recommended to be performed on all children, with subsequent in-depth investigation specific for ASD as needed. Such an approach ensures that all children with risk for any type of atypical development are screened, and within that group, specifically identifying those children with a possible ASD, with appropriate referral. Specific information about the recommended developmental screening and diagnostic tools can be found at the American Academy of Neurology (AAN) website (http://www.aan.com).1

The American Academy of Pediatrics as well as the AAN recommend developmental surveillance at all well-child visits from infancy through school age, and at any time afterwards in the context of concerns regarding social accep-tance, learning, or behavior.2–4 A child has failed level one surveillance if he or she fails to meet any of the following specific milestones: no evidence of babbling by 12 months; no gesturing by 12 months; the lack of single words by 16 months; no two-word spontaneous phrases by 24 months; and finally, loss of any previously acquired language or social skills at any age.3,4 Additionally, siblings of children with an ASD should be carefully monitored for acqui-sition of social, communication, and play skills, and the occurrence of maladaptive behaviors. Screening should be performed not only for ASD-related symptoms but also for language delays, learning difficulties, social problems, and anxiety or depressive symptoms.

Screening specifically for an ASD should be performed on all children failing routine developmental surveillance procedures using one of the validated instruments. A release for all school records as well as any private, individ-ualized assessment is important to attain pertinent information. A child having failed initial surveillance typically requires assessment by practitioners with particular interest and training in ASD.

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CLINICAL FEATURES AND DIAGNOSTIC EVALUATION

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)2 was released in May 2013. The changes from the previous Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)3 have been as dramatic as they have been controversial: DSM-5 no longer contains the subdiagnoses of Autistic Disorder, Asperger Syndrome, Pervasive Developmental – Not Otherwise Specified, Childhood Disintegrative Disorder, or Rett Disorder. The DSM-IV-TR’s autistic symptoms were divided into three areas, specifically, social reciprocity, communicative intent, restricted and repetitive behaviors; while the new DSM-5’s diagnostic criteria has been reduced into two areas, specifically, social communication/interaction and restricted/repetitive behaviors. If the diagnostic criteria for ASD are met, then the diagnosis must also specify if it is with or without accompanying intellectual impairment and/or language impairment, as well as noting if the diagnosis is associated with a known medical or genetic condition and/or environmental factor. Additionally, the ASD diagnosis must also be specified by severity levels (Level 1 – Requiring Support, Level 2 – Requiring Substantial Support, and Level 3 – Requiring Very Substantial Support).2,4 Children who have deficits only in social communication should be considered for the new DSM-5 diagnostic category of Social Communication Disorder (SCD).4,5

Clinical Diagnostic Procedures and Methods

Interview MethodThe Autism Diagnostic Interview – Revised (ADI-R)6 is a structured interview conducted with the parent or care-

taker of a child and adult with a mental age of at least 2 years old and who has been referred for the evaluation of a possible ASD. The ADI-R is useful for diagnosing ASD, planning treatment, and distinguishing ASD for other developmental disorders.6–8

The ADI-R typically takes 1–2 hours and focuses on the child’s current behavior or behavior at a certain point in the areas of reciprocal social interaction, communication and language, and patterns of behavior.7 The interview is divided into five sections: opening questions, communication questions, social development and play questions, repetitive and restricted behavior questions, and questions about general behavior problems. Due to the lengthy interview, the ADI-R is primarily used in clinical or research settings.8

Observational MethodsThe Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) is a semi-structured set of observations

and series of activities involving the referred individual and a trained examiner.9 This revision improves an instru-ment already viewed as “the gold standard” for observational assessment of an ASD. With updated protocols, re-vised algorithms, a new Comparison Score, and a Toddler Module,10 the ADOS-2 provides a highly accurate picture of current symptoms, unaffected by language. It can be used to evaluate almost anyone suspected of having ASD, as young as a 12 months old with no language to verbally fluent adults.

Like its predecessor, the ADOS,11 the ADOS-2 is a semi-structured, standardized assessment of communication, social interaction, play, and restricted and repetitive behaviors. It presents various activities that elicit behaviors directly related to a diagnosis of ASD. By observing and coding these behaviors, information can be attained for diagnosis, treatment planning, and educational placement.

In Modules 1 through 4, algorithm scores are compared with cut-off scores to yield one of three classifications: Autism, Autism Spectrum, and Non-Spectrum. The difference between Autism and Autism Spectrum classifications is one of severity, with the former indicating more pronounced symptoms.9 In the Toddler Module, algorithms produce “ranges of concern” rather than classification scores.10

The Childhood Autism Rating Scale, Second Edition (CARS2) is a widely used autism assessment tool.12 The revised second edition expands its responsiveness to individuals that are high functioning on the autism spectrum with average and above cognitive abilities, as well as better verbal skills, and more subtle social and behavioral deficits.

The CARS2 includes the Standard Version Rating Booklet, for use with individuals younger than 6 years of age with communication challenges or below-average cognitive abilities, and the High-Functioning Version Rating Booklet, for the assessment of verbally fluent individuals, 6 years of age and older, with cognitive abilities above 80. Rating values for all items are summed to produce a total raw score that is converted to a standard score or percentile rank, as well as guidelines for score interpretation and suggestions for intervention.12

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Checklist and Rating Scale MethodsThe Social Responsiveness Scale, Second Edition (SRS-2) can be completed in approximately 15 minutes and iden-

tifies social impairment associated with ASD, as well as quantifying its severity.13 The SRS-2 has a Preschool Form (for ages 2.5–4.5 years) and the School-Age Form (for ages 4–18 years), which are completed by a parent/guardian or teacher. The Adult (Relative/Other Report) Form is for ages 19 years and up and is completed by a relative or friend and the Adult (Self-Report) Form is completed by the individual and begins at 19 years of age through adulthood.

The SRS-2 generates scores for Social Awareness, Social Cognition, Social Communication, Social Motivation, Restricted Interests, and Repetitive Behavior treatment scales that are useful in determining appropriate treatment and intervention.13

The Social Communication Questionnaire (SCQ) is a brief, 35-item, true/false questionnaire, completed by par-ents or guardians regarding the communication skills and social functioning of children who may be suspected of having ASD.14 It parallels the ADI-R in content and is used for brief screening to determine the need to conduct a full ADI-R interview and/or the ADOS-2.7,9 Because the SCQ is brief, quick, and easily completed by a parent or caregiver in less than 10 minutes, it allows clinicians and educators to routinely screen children for ASD, as well as determine the need for comprehensive diagnostic evaluation.

The Gilliam Autism Rating Scale, Third Edition (GARS-3) assists parents/guardians, teachers, and clinicians in identifying ASD in individuals, as well as estimating its severity.13 The GARS-3 items are based on the DSM-5 di-agnostic criteria for ASD.2 The GARS-3 yields standard scores, percentile ranks, severity levels, and the probability of an ASD. The GARS-3 is normed for ages 3-22 years, and takes approximately 10 minutes to rate. The instrument consists of 56 clearly stated items describing the characteristic behaviors of persons with ASD. The items are grouped into six subscales: Restrictive, Repetitive Behaviors, Social Interaction, Social Communication, Emotional Responses, Cognitive Style, and Maladaptive Speech.15

Medical Assessment

A detailed and careful history is imperative, and should include probes into family history with potential risk for consanguinity, postnatal deaths, and perinatal issues.16 Family prevalence is important: family studies note a 50–100-fold increase in the rate of ASD in first-degree relatives of autistic children.17 For all referrals of individuals with an ASD, a careful review of psychometric measures is critical, which has been detailed above. Children with ASD have an increased rate of larger head circumferences, often noted over the first few years of life rather than at birth, although only a few will have a true macrocephaly.1,18,19 There are well-known associations with a range of genetic disorders, including, but not limited to, tuberous sclerosis complex, fragile X syndrome, Angelman Syndrome, and a wide range of DNA genetic variations.20–25

The physical exam should include the graphing of height, weight, and head circumference, particularly in young children, as well as simply observing the child’s interaction with his family and caregivers during history gathering. In particular, attention should be given to possible dysmorphology, curvature of spine, the shape and size of the head, and the appearance of any birth marks.1,18,19 The degree to which a child can make and sustain eye contact with family members as well as with the examiners should be specifically described, and adjectives such as fleeting, brief, intermittent, and others, may all be appropriate to the exam. The mental status exam should include a description of the speech patterns, if present; the level of social maturity relative to age; and the capacity to engage with the exam-iner.26–28 Attention should be also given to the range and quality of speech; language deficits may range from mutism to verbal fluency, but with other pragmatic and receptive language difficulties.27,28 The neurologic examination may be quite limited depending upon the anxiety or timidity of the child; however, attempts should be made to assess optic discs, visual fields, strength, tone, at least a general sensory exam, gait, and coordination.1,19

Laboratory investigations that are recommended in the context of developmental delay, with or without elements of an ASD, typically include a formal audiology examination as well as lead screening for children who have had an extended oral–motor stage of play, even in the absence of true pica.4,18 Additional laboratory investigations will be guided by findings on exam; however, genetic testing yields abnormalities in more than 1% of children with an au-tistic phenotype, including abnormalities in the proximal long arm of chromosome 15q, such as Angelman Syndrome and Prader–Willi syndrome, disorders typically associated with moderate to severe intellectual impairment.22,23 Less than 5% of all children with an ASD phenotype have inborn errors of metabolism; however, assessing serologies for abnormalities in amino acid, carbohydrate, purine, peptide, and mitochondrial metabolism must be made based on each individual case.4,18,30 Electrophysiological testing is dictated by the history and physical. The prevalence of epilepsy in autistic children has been estimated at 7%18 to 14%,28 whereas the cumulative prevalence by adulthood is estimated at 20–35%.31,32 Seizure onset peaks in early childhood and again in adolescence. Intellectual disability, with

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or without motor abnormalities or family history of epilepsy, is a significant risk factor for the development of sei-zures in individuals with an ASD.31–33 A higher incidence of epileptiform electroencephalogram (EEG) abnormalities in autistic children whose presentation includes a history of regression has been reported when compared to autistic children without clinical regression.34,35 Seizures or epileptiform discharges were more prevalent in children with re-gression who demonstrated cognitive deficits. Regression in cognition and language in adolescence associated with seizure onset has also been observed, but little is known about its cause or prevalence. There may be a causal rela-tionship between a subgroup of children with autistic regression and EEG-defined benign focal epilepsies, although there has not yet been consensus on how to treat.35 Radiographic images are rarely indicated in children with an autistic phenotype unless there is evidence for focal findings by exam or by EEG. Prevalence of lesions on magnetic resonance imaging (MRI) in children with an ASD is similar to normal control subjects.1,4,30,36 Computed tomography (CT) and MRI studies of autistic subjects screened to exclude those with disorders other than ASD have confirmed the absence of significant structural brain abnormalities.36,37 There is no evidence to support a role for functional neu-roimaging studies in the clinical diagnosis of an ASD at the present time.1,4,30

There is insufficient evidence to support the use of other tests such as hair analysis for trace elements, celiac an-tibodies, allergy testing for gluten, casein, candida, and other molds, immunologic or neurochemical abnormalities, micronutrients such as vitamin levels, intestinal permeability studies, stool analysis, urinary peptides, mitochondrial disorders, thyroid function tests, or erythrocyte glutathione peroxidase studies.4

THERAPEUTIC APPROACHES

Because of the complexity of the ASD condition, reducing the social and emotional discomfort for an individual with an ASD requires a multidisciplinary approach. Such approaches typically include providing supportive envi-ronments at home, school, and where applicable, work. Additionally, therapeutics that involve behavior modifica-tion and enhancement of effective communication are important. Finally, the use of psychopharmacologic agents can be helpful in reducing troublesome issues of disruptive, aggressive, or anxious behaviors.

Environmental Approaches

After a diagnosis of an ASD has been made, it is optimal to invite all caregivers to participate in a relaxed and sup-portive conference with the medical team to review specific challenges. Although predictability and consistent rou-tines are often difficult for many 21st century families, such qualities are key to an individual’s successful outcome.38 Evidence continues to reinforce that the earlier and more inclusive the intervention, the more successful individuals are. The individual’s environment must include consistency in schedules and physical space as well as supportive relationships between all caregivers.38–40

Nonpharmacologic Therapeutic Options

In addition to environmental supports and structure, the addition of formal therapies has been shown to be crit-ically important for many children and teenagers. Although speech and occupational therapies are particularly im-portant for infants and young children, the introduction of appropriate therapies at any point in development, from childhood to the adult years, can yield significant improvement in an individual’s independence and capacity for interaction with others. Of these, five are the most commonly used, and include speech and language therapy; occu-pational therapy; behavior therapy; social skills therapy; and virtual reality therapeutics.

Speech and language therapies include a wide range of techniques and methods, and may include didactic and naturalistic behavioral therapy: verbal behavior, natural language paradigm, pivotal response training, and milieu teaching have been studied.19,29,38,41 Augmentative and alternative communication modalities, such as American Sign Language, picture and communication boards, and even the child’s best gestural commands, can all be effective in building communication skills.41–44

Occupational therapy has been the cornerstone of addressing many of the sensory issues found in this population of children. While there are many approaches, the general goals seek to reduce sensory overstimulation and provide improved focus for learning tasks, both cognitively and for visual motor skills.45–47

Behavioral and social skills therapies are also important, and can range in goals from better navigating the prag-matics of conversation to simply not being as aggressive when feeling anxious, and include the use of discrete trial teaching (DTT) and applied behavioral analysis (ABA). Certainly the use of practicing scripted dialogue, particularly with improved eye contact, can provide individuals with tools to better understand their social environments.41,43,44,48

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Finally, individuals with an ASD can be greatly assisted by the emerging field of virtual reality therapeutics. Although often expensive, immersive virtual reality (VR) has the potential to be very helpful in coaching socializa-tion and self-confidence. Some studies have observed an increase in gaze duration, vocalizations, as well as signifi-cant reduction in social anxiety. Further research is needed in this very promising field.49,50

Pharmacologic Interventions

Patients with ASD typically present with impairments associated with social interaction, communication difficul-ties, and stereotyped behaviors. These difficulties most often manifest as relative degrees of aggression, self-injurious behaviors, irritability, sleep problems, anxiety, mood disorders, obsessive–compulsive behaviors, inattention, overactivity, and impulsiveness. Such behavioral problems may be responsive to the combination of environmental support, nontherapeutic interventions as reviewed, and adjunctive pharmacological intervention as well. Research into the pharmacotherapy of ASD and related disorders have been ongoing since the middle of the 20th century. But the utility of earlier research is limited by methodological flaws. Behavioral heterogeneity, over interpretation of case studies, and lack of appropriate outcome measures have been some of the major problems.51 Most current pharmaco-therapies target one or more of the several major biochemical pathways, most commonly through the dopaminergic and serotonergic pathways.52,53 A comprehensive review of psychopharmacology is beyond the scope of this chapter. Readers are referred to the ninth edition of Kaplan and Sadock’s Comprehensive Textbook of Psychiatry for a detailed discussion of psychopharmacology referenced below.54

Neuroleptics (Antipsychotics)Neuroleptics typically block D2 receptors in the dopaminergic system. In addition to D2 antagonistic effects,

neuroleptics also block serotonin receptors, with newer generations of atypical neuroleptics demonstrating greater selectivity of receptors.54 The use of atypical antipsychotics in children with ASD is based, in part, on their efficacy in the treatment of psychiatric disorders that have behavioral symptoms similar to the core symptoms seen with ASD, as well as their relatively safe adverse effect profile in comparison with older, conventional antipsychotics, and the possible role of dopamine in the etiology of ASD.55–57

Typical neuroleptics are less selective than atypical neuroleptics, and because the typical neuroleptics more often block dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway, typical neuroleptics such as haloperidol provoke frequent side effects, which include sedation, headaches, dizziness, hyperprolactinemia, sexual dysfunction, osteoporosis, weight gain, and orthostasis.54,58 Neuroleptics also produce an-ticholinergic effects, including angle-closure glaucoma, constipation, dry mouth, and reduced perspiration. Tardive dyskinesias occur more often for individuals taking high-potency first-generation neuroleptics such as haloperidol, and also appear after chronic, rather than acute, exposure to the drug. Tardive dyskinesias are manifest by repetitive, involuntary, and purposeless movements, most often of the face, lips, legs or torso; they tend to resist treatment and are frequently irreversible.54 Neuroleptic malignant syndrome is a potentially fatal condition characterized by au-tonomic instability, which can manifest with tachycardia, nausea, vomiting, diaphoresis, and hyperthermia; mental status alteration; and muscle rigidity, any of which may be associated with laboratory abnormalities, including ele-vated creatinine kinase, reduced iron plasma levels, and electrolyte derangements.54 Finally, the use of neuroleptics has also been associated with pancreatitis, pharyngitis, and changes on electrocardiogram, specifically a QT interval prolongation. Seizures have been observed, especially in the context of chlorpromazine and clozapine. Finally, other cardiac complications may include thromboembolism, myocardial infarction, stroke, and torsades de pointes.

Haloperidol, a typical neuroleptic, was one of the first medications studied systematically as a treatment for ASD-related symptoms. The effects of typical neuroleptics, such as haloperidol and chlorpromazine, are primarily me-diated through dopamine-receptor (D2) antagonism, and have been shown to be effective in targeting a range of maladaptive behavioral symptoms, withdrawal, and stereotypy, especially in school-age children.55,56 However, sig-nificant adverse effects including dose-related sedative effects and extrapyramidal symptoms such as dystonias and dyskinesias limit the use of haloperidol primarily to treatment-refractory patients.56 Hence, atypical neuroleptics, with significantly less severe extrapyramidal side effects, have emerged as the first-line drugs in the management of children with ASD.

Atypical neuroleptics, by contrast, are potent serotonin-receptor as well as dopamine-receptor antagonists, and these include aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone.54,59 The serotonin receptor antag-onism decreases the propensity for tardive dyskinesias and extrapyramidal symptoms. Risperidone is one of the most commonly used medications in this group. In 2003, the US Food and Drug Administration (FDA) approved risperidone for the short-term treatment of the mixed and manic states associated with bipolar disorder. In 2006,

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the FDA approved risperidone for the treatment of irritability in children and adolescents with autism. The FDA’s decision was based, in part, on a study of autistic people with severe and enduring problems of violent meltdowns, aggression, and self-injury. Risperidone is not recommended for autistic people with mild aggression and explosive behavior without an enduring pattern. Weight gain is a major adverse effect of this drug. Hence, it is important to regularly monitor body mass index, lipid panel and blood glucose in patients receiving risperidone.58–60 Aripiprazole is another commonly used atypical neuroleptic. Weight gain is considered less severe with aripiprazole compared to risperidone, although some of the more recent studies have shown significant weight gain with it.59,61,62 Ziprasidone is found to be weight neutral, but can potentially cause QTc prolongation on the electrocardiogram.63

StimulantsHyperactivity, inattention, and impulsiveness are common traits among individuals with ASD. Stimulants have

been shown to decrease these symptoms in a significant proportion of such patients, although these agents can be problematic in this group of patients because of the propensity to exacerbate anxiety, a feature common in ASD.64,81 Stimulants exert their effects through a number of different pharmacological mechanisms, the most prominent of which include facilitation of norepinephrine, or dopamine, or both; adenosine receptor antagonism; and nicotinic acetylcholine receptor agonism.65 Commonly used stimulants in the ASD population include amphetamines; meth-ylphenidate; and dopamine and/or norepinephrine reuptake inhibitors.66

Amphetamines are a group of phenylethylamine stimulants such as amphetamine, methamphetamine, Dexedrine and levoamphetamine (Adderall). Amphetamines increase the levels of norepinephrine and dopamine in the brain via reuptake inhibition; however, the more important mechanism by which amphetamines cause stimulation is through the direct release of these catecholamines from storage vesicles in cells. Amphetamines are known to cause elevated mood and euphoria as well as rebound depression and anxiety, the latter a particular challenge for many individuals with an ASD.54,66

Methylphenidate (MPH; Ritalin, Concerta, Metadate, or Methylin) is a drug approved for treatment of attention- deficit hyperactivity disorder (ADHD), postural orthostatic tachycardia syndrome, and narcolepsy.65 It belongs to the piperidine class of compounds and increases the levels of dopamine and norepinephrine in the brain through reuptake inhibition of the monoamine transporters. It also increases the release of dopamine and norepinephrine. MPH possesses structural similarities to amphetamine, and, although it is less potent, its pharmacological effects are even more closely related to those of cocaine.65 A recent meta-analysis reviewed seven randomized-controlled trials looking at the effects of MPH on ADHD symptoms in children with pervasive developmental delay.64 This review found MPH to be an effective treatment for ADHD symptoms in these children, but noting that weight loss and car-diac toxicity are two of the major side effects associated with its use.

Norepinephrine and/or dopamine reuptake inhibitors (NRIs) also function as stimulants, and inhibit the reuptake of norepinephrine and/or dopamine, resulting in increased extracellular levels and, therefore, enhanced neurotrans-mission, ultimately producing a stimulant effect. Among individuals with an ASD, the NRI atomoxetine (Strattera) is commonly used in this population of patients. Limited studies have demonstrated its use in ASD as being both effective and safe.64–66

Also used is bupropirone (Wellbutrin), which blocks dopamine primarily, and to a much lesser extent, nor-epinephrine. Both drugs have a considerably lower abuse potential in comparison to other stimulants like the amphetamines.67,68

Alpha Adrenergic AgonistsClonidine and guanfacine are among the most commonly used alpha adrenergic agents in ASD in which inat-

tention and impulsivity prominently feature. The mechanism of action in the treatment of ADHD is to increase noradrenergic tone in the prefrontal cortex (PFC) directly by binding to postsynaptic α2A adrenergic receptors and indirectly by increasing norepinephrine input from the locus coeruleus.69,70 Alpha 2 agonists have been used as stimulant-treatment extenders in the context of immediate-release methylphenidate or amphetamine, when the goal is to limit both the number of stimulant doses given per day and extend the duration of therapeutic action in com-bination with a stimulant.71,72 Also, alpha 2 agonists, with their pronounced sedative side effects, are used to reduce the delay in sleep onset, a problem common in children with ADHD and impulse control problems.73 In contrast to clonidine, guanfacine is more selective for the alpha 2A receptor,74 with less alpha 2B activity, making it less sedating than clonidine. The use of these agents as adjunctive sleep aids should be short term at most.75,76

Alpha 2 adrenergic agonists are additionally used with a stimulant to enhance the stimulant efficacy. The use of combination of alpha 2 adrenergic agonists with a stimulant is often used in presence of ADHD with comorbid features, specifically oppositional defiant disorder, Giles de Tourette syndrome, and aggressive/impulsive behavior.

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The rationale for combination therapy in these cases has been that the primary effects of stimulants and alpha 2 agonists are mediated by different neurotransmitter systems. Functional neuroimaging studies78 demonstrate that guanfacine produces selective and circumscribed activation of frontal and frontal association areas while at the same time “turning down” or inhibiting striatal activity. Research suggests that stimulants such as methylphenidate im-prove working memory and regulate attention primarily through alpha 2A receptors to enhance norepinephrine tone in the prefrontal cortex.79 These effects of methylphenidate on prefrontal cortical function can be prevented by blocking either norepinephrine alpha 2 receptors or dopamine D1 receptors,79 establishing that both D1 and alpha 2A receptors are essential to the optimum functioning of the prefrontal cortex.

Anxiolytics and Selective Serotonin Reuptake Inhibitors (SSRIs)Selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitors (SSRIs) are a class of compounds

typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. SSRIs are believed to increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor.80

Buspirone is a serotonin agonist that is used primarily to treat anxiety disorders but has recently proven to be useful to treat ASD, as these children have alteration in brain serotonin synthesis during critical periods of brain develop-ment.82 Serotonin receptor inhibitors (SRIs) have been beneficial for obsessive–compulsive behaviors and repetitive behaviors with ASD. The most commonly used are fluoxetine, fluoxamine, and clomipramine.83–92 Further research is needed to better understand mechanisms affected by SSRIs and serotonin agonists during brain development in ASD.

AnticonvulsantsAnticonvulsants such as valproic acid,93 lamictal,94,95 carbamazepine and oxcarbamazapine96 have shown improve-

ment in a range of symptoms in ASD, particularly as mood stabilizers with mixed results. Overall very few studies and limited evidence limits the use of these medications. Some studies demonstrated some improvement in attention span and impulsivity.

Other Medications and Experimental TherapiesAMANTADINE HYDROCHLORIDE

The psychotropic effect of amantadine is related to its antagonism of the N-methyl-D-aspartate (NMDA) receptor. By decreasing the toxic effects of the glutamatergic neurotransmitter system, amantadine is thought to ameliorate issues particularly related to ASD. Two randomized controlled trials of amantadine were identified in children and adolescents. One reported beneficial effects in controlling the symptoms of irritability and hyperactivity in ASD and the other described a significant impact in ADHD. Studies in adults, with relevance to children and adolescents, re-ported effectiveness in resistant depression, obsessive–compulsive disorder and in counteracting side effects of some psychotropic medications. Available data for such use, although promising, require further confirmation.97

CHOLINESTERASE INHIBITORS

Cholinesterase inhibitors increase acetylcholine levels in the brain and have been used for a long time in the treatment of Alzheimer disease. Some of the commonly used agents are donepezil,98 galantamine,99 and rivastigmine tartrate.100 Very few studies have been attempted on ASD that have shown some improvement with hyperactivity and irritability.

SECRETIN

Evidence from seven randomized controlled trials supports a lack of effectiveness of secretin for the treatment of ASD symptoms. Secretin has been studied extensively in multiple randomized controlled trials, with clear evidence that it lacks any benefit. Given the high strength of evidence for a lack of effectiveness, secretin as a treatment ap-proach for ASDs warrants no further study.101 Other therapies like gluten-free diet102 and hyperbaric oxygen103 also have not shown any significant beneficial effect for children with ASD.

Treatment and Future Research

The goal of all current therapies in ASD is to relieve the core symptoms, most often anxiety, aggression, impulsiv-ity, and inattention. Many patients with ASD receive some form of pharmacotherapy, much of it off-label, with the primary therapeutic aim being to improve behaviors that interfere with behavioral and educational therapies.104–106 Because of the difficulties inherent in conducting randomized, placebo-controlled studies in pediatric populations, evidence of the benefits of this strategy is limited, and most such studies have been small and of short duration.1,30 There remains a great need for research into the long-term benefits and risks of pharmacotherapy in ASD.1,30

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