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Comparative Effectiveness of Therapies for Children with Autism Spectrum Disorders
Open for comment through 31 Aug 2009

Background
Disorders within the autism spectrum include Autistic Disorder, Asperger’s Syndrome, and Pervasive Developmental Disorder, Not Otherwise Specified (PDD-NOS). Rett Syndrome and Childhood Disintegrative Disorder are included in the Pervasive Developmental Disorders category but are typically considered as separate from the Autism Spectrum Disorders. ASD is characterized by significant impairments in social interaction, behavior, and communication (3). Impairments include a lack of reciprocal social interaction and joint attention; dysfunctional or absent communication and language skills; lack of spontaneous or pretend play; intense preoccupation with particular concepts or things; and repetitive behaviors or movements. Children with ASD may also exhibit impaired cognitive skills and sensory perception (1, 3). ASD is often accompanied by comorbid conditions such as seizure disorders, hyperactivity, and anxiety (4).

The manifestation and severity of symptoms of ASD differ widely, and treatments comprise a range of behavioral, psychosocial, educational, medical, and complementary approaches (5-7) that vary given a child’s age and developmental status. Goals of treatment often focus on alleviating core deficits in communication, social interactions, or behavior; however treatment is frequently complicated by emergent symptoms such as irritability and other common comorbid conditions. Given the complexity of ASD and associated therapies, clinicians and families need guidance in selecting appropriate treatments. There is no cure for autism spectrum disorders and no global consensus regarding which intervention strategy is most effective. Chronic management is often required, and the goals of treatment are to maximize the child’s ultimate functional independence and quality of life by minimizing the core autism spectrum disorder features, facilitating development and learning, promoting socialization, reducing maladaptive behaviors, and educating and supporting families. Early, appropriate, and sustained behavioral and educational intervention may be associated with improved short-term outcomes and quality of life, although specific strategies vary. Management strategies consist of a diverse set of interventions that vary in their modality and the degree to which they are supported by the evidence. Nominations for a comprehensive systematic review of therapies for ASD, submitted by a member of the Medicaid Medical Director’s Learning Network and on behalf of the Autism Speaks advocacy organization, emphasized the need to understand the effectiveness and comparative effectiveness of various treatment modalities.

Overall state of the literature
A significant body of literature reports on aspects of ASD treatment; initial searches in the PubMed, PsycInfo, and ERIC systems identified more than 3,600 papers with an estimated 20% relevant to ASD therapies. The literature reports a wide variety of interventions in the behavioral, medical, allied health, and complementary arenas aimed at treating either ASD core symptoms or associated symptoms such as gastrointestinal distress. The ages of children included in studies generally range from preschool to 18, with a number of studies assessing 3-12 year olds and fewer examining young toddlers or older adolescents. Many modalities lack a systematic evidence base and are instead supported by small case series, single cases, or small, short-term trials. The following sections broadly survey recent reports of ASD therapies.

Behavioral and psychosocial interventions
Case reports and case series comprise a substantial portion of the ASD literature describing behavioral therapies. Such reports generally describe treatment of a single subject or a limited number of subjects using multiple baseline designs, though group designs are also used. Commonly described behavioral interventions employ elements of applied behavioral analysis (ABA), and a recent review of several ABA studies and some psycho-educational reports noted the potential effectiveness of ABA in younger children (8). A number of studies address aspects of treatment such as parent and teacher training (9, 10); methods of reinforcement and cueing (11-14); and discrete trial training (15-17). Reciprocal Imitation Training (18-21) and the Lovaas/Early Intensive Behavioral Treatment method (22-25) are also described. Recent reviews of early behavioral intervention have reported potential gains in IQ (26-28). Some investigators have employed controlled and/or randomized trials to assess the Picture Exchange Communication System (PECS) (29-31), noting increases in communication and joint attention. Milieu teaching (31-34) has also shown some effectiveness in promoting communication responses in trials and case reports. Reports of behavioral interventions generally note some amelioration of targeted symptoms.

A number of other investigations have addressed more developmentally-based interventions to improve communication or social skills in ASD. The DIR (developmental, individual-difference, relationship-based model)/Floortime (35-37) articulates social and communication-related milestones and caregiver-initiated techniques to help children progress appropriately, and case studies employing Floortime have reported some developmental gains. Some research has employed treatment modalities such as structured teaching/TEACCH (38-40) and the Denver model (41, 42) or therapeutic aids including LEGO play (43-45), virtual reality (46), and robots (47). Social stories have also been used in case series and controlled trials to minimize disruptive behaviors and improve social skills with some effectiveness (48-50). Peer training and social skills groups have also been reported to improve social interactions (51-54).

Though not a focus of this review, the literature also describes interventions aimed at parents, teachers, and other caregivers. Such interventions typically include training to help participants understand more about ASD as well as counseling sessions to help individuals cope with caring for a child with ASD (55, 56).

Allied health interventions

Allied health interventions including occupational, physical, and speech therapy techniques have also been studied as treatments for aspects of ASD and have shown some utility (57-60). Some research employs sensory/auditory integration techniques (60-63), and speech therapy studies have addressed aspects of language use (64-66). Physical therapy studies have also examined topics such as aquatic therapy (67) and benefits of exercise in autism (68).

Medical interventions
In the last several years, the atypical antipsychotic risperidone has been studied in randomized, controlled clinical trials, assessing its short-term utility in treating irritability, aggression, self-injury, and repetitive and other behavioral problems (69-83). As the result of these studies, risperidone was the first medication to receive approval for treatment of irritability in autism, although significant side effects limit its use. The use of other atypical and typical antipsychotics has also been studied (75, 80, 84-92) with some support. Other medications have also been investigated, such as serotonin reuptake inhibitors for symptoms including irritability and repetitive behavior, with mixed results (93-96). Medications targeting hyperactivity or impulsivity have also been studied (97-101) with some support. A few studies have examined the potential behavioral benefits of anticonvulsants (102-104) or medications developed to target dementia (70, 105-107). Treatment with secretin infusion has been the most-studied medical intervention in autism, albeit with no significant evidence supporting its use across multiple studies (108-110). A number of studies have also investigated the efficacy and safety of non-prescription interventions within the medical setting. For example, a number of recent trials have evaluated melatonin for sleep disturbances (111-115).

Complementary interventions
While some complementary therapies may be referred to as “biomedical,” such terminology can be confusing; therefore, this review will classify such reports as “complementary.” The literature reports several studies of complementary interventions using varied study designs, with an emphasis on uncontrolled designs. Dietary intervention is common; although a 2008 systematic review of gluten free-casein free diets to treat autism found poor quality evidence for the diet’s utility (116). Recent studies have also examined acupuncture (117, 118); massage (119-121); and hyperbaric oxygen therapy (122-124). Omega-3, Omega-6, and polyunsaturated fatty acid supplementation have been examined using varied designs (125-127), and vitamin supplementation has also been studied in controlled trials and cohort studies (128-130). Other interventions include music therapy (131-133) and biofeedback (134). Finally, some have targeted heavy metal chelation as a potential treatment despite significant safety risks associated with the practice (135, 136).

Summary

Previous reviews of the literature have noted limited quality and consistency in studies assessing ASD therapies (6, 25, 137-140), and an umbrella review found methodological weaknesses in systematic reviews of psychosocial interventions (7). While controlled trials seem to be increasing, much research is observational, generally with small sample sizes, limited follow-up, and limited discussion of the durability of treatment gains once active therapy ends. As the prevalence of ASD has increased, the available treatment options have also increased, but evidence overall for many interventions can only be considered preliminary. It is clear that there is a real need for synthesized research that evaluates the evidence base for various treatments and identifies gaps in the current literature that may drive the research agenda.

While advances have been made in early diagnosis and the promotion of early intervention for ASD, there are no current guidelines for comparing the benefits and harms of treatment interventions. Clinicians and families are left to choose among the interventions in part based on what is available to them, what is covered by commercial insurance or Medicaid, or what they can afford out of pocket. The bottom line is that parents and caregivers are not given consistent advice on how to treat and manage this condition. Often, clinical recommendations are based on the most common or most popular treatments at a given time. Many therapies are not covered by insurance, and a primary reason for insurance denial from private insurers is that there are no evidence-based guidelines for this condition. Additionally, insurers may find it confusing to distinguish among therapies or to sort out which approaches have an evidence base and which are still experimental.

The delivery and organization of care for ASD is very fragmented, with pieces scattered about in the primary care, school, and specialty clinical settings. It is left to the families and caregivers of patients with ASD to find and assemble these pieces. Patients and caregivers are ultimately left with a “laundry list” of treatment and management strategies that appear to have equal weighting, without prioritization among the choices. This situation presents many challenges not only to patients and families, but also to health policy and decision makers.

Policy issues

Policy activities related to care for ASD include:

The Combating Autism Act of 2006 (S.843) - This Act authorizes expanded activities related to autism research, prevention, and treatment through FY 2011.

Medicaid Autism Waiver Program - Several states including Colorado, Indiana, Massachusetts, Maryland, and Wisconsin are currently participating in the Medicaid Autism Waiver Program covering home- and community-based services specifically for people with autism. Pennsylvania just received approval by CMS in May of 2008. All are limited to children except Pennsylvania, whose waiver program aims to provide services to autistic adults and children. According to a recent Government Accountability Office (GAO) report, state autism waiver programs generally offer the same services as their Developmental Disability (DD) waivers, but the primary difference is that the autism waiver may offer early intervention behavioral therapies targeted to young children.

Population(s) Children ages 2 – 12 who are diagnosed with an autism spectrum disorder (ASD) and children under age 2 at risk for diagnosis of an ASD


Interventions Behavioral, educational, family, medical, allied health or CAM treatment approaches to addressing core and commonly associated symptoms of ASD. Therapies addressed will depend on the availability of the literature and may include:
Behavioral Interventions, including variations of applied behavioral analysis as well as developmentally-based models such as DIR/Floortime, among others
Educational interventions, including the TEACCH program
Allied health interventions, including occupational, physical, and speech therapy
Medical interventions, including prescription and non-prescription treatments
CAM approaches, including music therapy and nutritional therapies


Outcomes
Primary outcomes

Changes in short-term targeted outcome areas, including social skills/interaction, language and communication, repetitive and other maladaptive behaviors, psychological distress, adaptive skills development and academic skills development
Secondary outcomes

Changes in long-term functional outcome areas, including adaptive independence/self care, academic/occupational engagement and attainment, psychological well-being, and interpersonal relationships/community involvement
Adverse events

Adverse behavioral or psychosocial reactions to behavioral or other therapies (e.g. increased aggression or anxiety)
Regression of language, skills, or behaviors
Increases in/worsening of co-morbid symptoms
Adverse reactions to drug therapies (e.g. somnolence, weight gain)
Reduction in/negative influences on quality of life
TimingShort-term outcomes will be considered as those that occur ? 6mos
Long-term outcomes will be considered as those that occur >6mos


Setting
Settings include medical, other clinical therapy settings, the home, and the educational setting

Definition of TermsN/A
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