• When should treatments or interventions be started?
• What are the medical issues I need to know about?
• How do I know that treatments are both safe and effective?

What Do We Know?

Although autism is defined and diagnosed by deficits in core behaviors, accumulating evidence suggests that the breadth of this disorder extends well beyond the behavioral diagnosis. There is increasing recognition that the multiple systemic issues in children with ASD may influence vulnerability, onset, and severity of symptoms and behaviors. The systemic component of autism supports the possibility that both the core behaviors and medical issues have a convergent mechanistic basis that, if identified, could provide new insights into treatment targets, candidate genes, and strategies for prevention.

A wide range of treatment and intervention options are available for children and adults with ASD that can target core symptoms, ameliorate associated symptoms, and prevent further disability. For example, interventions such as speech therapy facilitate language development, pragmatic communication, and social interaction. Occupational therapy can improve functioning in everyday activities (e.g., eating, bathing, and learning) as well as sensory integration. Both types of therapy can promote the development of life skills, which help people with ASD to gain more independence. People with ASD can benefit from adaptive technologies, such as the use of keyboards and computers that promote expressive communication skills, and visual representation tools such as the Picture Exchange Communication System (PECS) that assist those with little or no language to communicate more effectively. For preschool and school-age children, public school systems and private schools can provide essential interventions including curricula that are individualized to the child, testing for cognitive and academic strengths and weaknesses, and special education services with lower teacher-to-student ratios, to name a few. For all of these interventions, there is a range of improvement, with some people making profound gains and others showing little response. We do not know how to predict which people will benefit from any of the available treatments.

Of the numerous behavioral interventions currently in use, little scientific evidence from randomized controlled trials (RCTs) supports their efficacy. Behavioral therapies, such as applied behavior analysis (ABA) based therapies, which use the principles of reinforcement and repetition, have been used since the 1960s and have been studied most extensively. Controlled trials have shown ABA to be effective for improving social skills and language when provided for at least 25 to 40 hours per week for 2 years (Lord & McGee, 2001). Efficacy is greatest when behavioral interventions are used early, but improved skills have been reported with adolescents and adults (McClannahan, MacDuff & Krantz, 2002; Weiss & Harris, 2001).

Medications to improve some of the symptoms associated with autism have been studied. However, thus far, no medication has been shown in controlled trials to enhance social behavior or communication. In 2006, risperidone became the first Food and Drug Administration (FDA) approved pharmacologic therapy for certain symptoms of autism. First introduced in 1993 as a medication used to treat symptoms of schizophrenia, risperidone has now been shown to be effective as a treatment of irritability and aggression seen in some children with ASD (McDougle et al, 2005). Selective serotonin reuptake inhibitors have had mixed results in decreasing certain repetitive and stereotyped behaviors (Kolevzon, Mathewson & Hollander, 2006; King et al., 2009). Other biological and pharmacological treatments that have been investigated in small studies and may warrant fuller attention include omega-3 fatty acids, memantine, oxytocin, and pioglitazone (Amminger et al., 2007; Chez et al., 2007; Hollander et al., 2007; Boris et al., 2007).

There are other treatments in wide use that have not been studied in randomized controlled trials. These include nutritional supplements and diets (e.g., probiotics, mitochondrial cocktails, CoQ10, carnitine, and gluten-casein free diets), and chelation. One such treatment, the neuropeptide secretin, that had been reported to improve symptoms of ASD, was studied in a placebo-controlled trial and found to be ineffective (Esch & Carr, 2004). Some parents and therapists suggest that these treatments are effective, that recovery is possible, and that further studies are needed. Others are concerned that these treatments involve more than minimal risks and urge caution before recommending large-scale studies.

What Do We Need?

Safe and effective interventions are needed across the lifespan, from early development shortly after the detection of risk or diagnosis through childhood, school age, adolescent, adult, and senior phases of life. Going forward, research needs to be balanced between two poles. On the one hand, there is a need for novel, targeted interventions based on an understanding of the molecular mechanisms of ASD. These interventions, analogous to ongoing efforts in cancer and cardiovascular research, will require a successful commitment to earlier elements of this Strategic Plan. On the other hand, there is a need for rigorous studies to develop and safely test the efficacy of current interventions, identifying which elements are most effective in reducing or ameliorating symptoms for which people. Intervention research should collect information about the mode of delivery, intensity, duration, and dose, as well as unique characteristics of the people with ASD (e.g., behavioral, biological, genetic) in an effort to develop more personalized interventions, treatments, services, and supports, and to help inform basic research about additional targets for study. This research will require large-scale multidisciplinary randomized controlled trials.

The identification of biomarkers—for instance in plasma, saliva, cerebrospinal fluid (CSF), or tissue—is necessary to provide insights into targeted treatment strategies designed to improve or reverse autistic symptoms, as well as insights into preventive measures. Further, if biomarkers present in children with ASD are found to be present in infants and toddlers at high risk of developing autism, then targeted intervention strategies to normalize these biomarkers could be tested for the potential to arrest or reverse the symptoms and progression of autism.

Decision makers (people with ASD, families, clinicians, and payors) frequently lack critical information about which treatment is best for an individual person. While there are many interventions in wide use, the field lacks comparative studies of their value or how these various interventions should be staged or combined. Comparative effectiveness research yields information from head-to-head comparisons of interventions or policies that, when combined with a personalized approach, can inform decision makers about health care choices. This approach, already helpful for cardiovascular and cancer research, needs to be developed to inform ASD interventions.

Special attention is needed on treatment of co-occurring medical conditions, developing pharmacological treatments, and testing interventions that are in wide use (e.g., nutritional supplements), but for which little rigorous efficacy data exist (Levy & Hyman, 2003). Co-occurring conditions, such as gastrointestinal symptoms and sleep disorders, may influence the effectiveness of interventions designed to affect the core symptoms of ASD. Similarly, interventions that focus on co-occurring conditions may also affect or reduce core symptoms. Animal models and/or cell lines relevant to autism are needed to develop new or test existing pharmacological agents for ASD, understand the mechanisms of action, and serve as a first-step in testing drug safety. Such model systems research may be crucial in leveraging the pharmaceutical industry to develop medications that target the core symptoms of ASD.

While some people with ASD have been reported to show marked improvement, little is known about the characteristics of these people or the types of interventions they have received that may help to explain these changes. Studies of these people may provide an opportunity for discovering important clues with regard to risk factors and intervention strategies for specific ASD subgroups.

2011 Addendum To Question 4: Which Treatments and Interventions will Help?

What Is New in This Research Area, and What Have We Learned This Past Year?

Several notable studies and reviews on the efficacy of specific interventions for improving outcomes of individuals with ASD were published in 2010. These include a study showing that medications such as risperidone are most effective for reducing irritability and aggression when they are combined with intensive behavioral intervention (Frazier et al., 2010). A study of psychotropic medication use over time in youth and adults with ASD showed an increasingly high likelihood of staying medicated across the life course (Esbensen et al., 2009).

Recent research also supports the benefits of social skills training for people with ASD. A 2010 study showed improved levels of social interaction and peer relationships (Frankel et al., 2010), while a randomized controlled trial (RCT) evaluating a social skills group intervention found improvements in social behavior for children with ASD who had high cognitive ability (Derosier et al., 2010).

In other notable work conducted in 2010, a systematic review concluded that modified cognitive behavioral interventions are efficacious for reducing anxiety in individuals with Asperger syndrome (Lang et al., 2010). In addition, a RCT of a caregiver-mediated joint engagement intervention for toddlers showed positive results; it represents the first controlled data to suggest that short-term parent-mediated intervention can be efficacious for improving joint attention and functional play acts with maintenance of skills one year post-intervention (Kasari et al., 2010).

An environmental scan study, supported by the Centers for Medicare & Medicaid Services (CMS), examined interventions for children, youth, and adults with ASD (Young et al., 2010 (PDF – 2.44 MB)). The scan included services addressing the core impairments associated with ASD, as well as other support services, such as behavioral interventions, peer training, and supported employment. For children, 15 interventions met the "evidence-based" criteria established, while the other 16 interventions studied met only the criteria for emerging or unestablished interventions. Far less evidence was available on services and supports for transitioning youth and adults, underscoring the need for more research in this area.

In the area of early behavioral interventions, a randomized controlled trial demonstrated the efficacy of a comprehensive early intensive behavioral intervention, based on the Early Start Denver Model, which integrates developmental approaches with principles of applied behavioral analysis (ABA) for improving IQ, language, and adaptive behavior and reducing severity of autism diagnosis in toddlers with ASD (Dawson et al., 2010). In addition, three reviews of the effectiveness of early intensive behavioral intervention based on ABA were published. The Institute of Education Sciences reviewed findings specific to the Lovaas model of ABA, concluding that this model has been shown to have potentially positive effects on cognitive development but had no discernable effect on communication/language competencies, social-emotional development and behavior, or functional abilities (Institute of Education Sciences, 2010). In the Annual Review of Clinical Psychology, Vismara and Rogers (2010) concluded that both comprehensive and targeted early intervention programs based on ABA are effective for improving communication, social skills, and management of behavioral challenges.

Finally, results of a meta-analysis showed that long-term, comprehensive ABA interventions for children with ASD lead to medium to large positive effects in intellectual functioning, language development, acquisition of daily living skills, and social functioning (Virues-Ortega, 2010). Effects for language-related outcomes (e.g., IQ, receptive and expressive language, communication) were more robust than nonverbal IQ, social functioning, and daily living skills.

What Gap Areas Have Emerged Since Last Year?

Recent data indicate that several rare and highly penetrant gene variants and copy-number variations (e.g., NLGN3, NLGN4, NRXN1, SHANK2, SHANK3, PTCHD1, maternally inherited 15q11-q13, among others) are involved in ASD (Pinto et al., 2010). There is a need for translational research that can take advantage of these new genetic findings to (1) identify subgroups of individuals with ASD who respond well to specific medications and intervention approaches, (2) inform which molecular signaling pathways are affected in ASD, (3) develop animal models to explore the downstream effects of these genetic variants on brain function, and (4) discover targets for development of therapeutics. In order to develop effective medical and behavioral interventions, there is a continuing need for autism intervention networks that can provide platforms for conducting clinical trials and comparative effectiveness research using genetic and other biomarkers for specific subtypes, other individual characteristics, and their relationship to response to specific treatments for people with ASD.

In a 2010 presentation to the IACC, data were presented from the Autism Speaks–supported Autism Treatment Network (ATN), a system of 14 academic health centers throughout the United States and Canada that provide care to more than 5,000 individuals with ASD, which showed that 65% of individuals with ASD experience sleep disturbances and 14% of those with sleep problems also have seizures (Presentation to the IACC on the Autism Treatment Network, 2010). Gastrointestinal problems were also reported in 50%, and those with gastrointestinal problems were more likely to have sleep disturbances, behavioral problems, and a lower health-related quality of life. Other health issues identified include seizures, food sensitivities, anxiety, and depression. It is not known whether these medical conditions are a primary aspect of some forms of autism or whether they are secondary features. Recent consensus statements and expert reviews indicate that assessment and treatment of such conditions can lead to improvement in behavior and quality of life (Buie et al., 2010a,b; Coury, 2010) and represent a critical unmet need and great opportunity for improving overall health and quality of life for people with ASD. The existence of co-occurring medical conditions in ASD underscores the importance of identifying subgroups of individuals with specific medical conditions who might respond favorably to a particular targeted treatment. In addition, it will be necessary to develop and test multifaceted treatment approaches (e.g., combined behavioral and medical interventions) that address co-occurring medical conditions.

In April 2010, an NIH-sponsored workshop identified the urgent need for more research on children with ASD who have not developed functional verbal language by 5 years of age (Summary of NIH Workshop on Nonverbal School-Aged Children with Autism, 2010). Among the topics discussed was the development of new intervention approaches that directly teach spoken communication skills and augmentative and alternative communication (AAC). More research is needed on the efficacy of novel service provision, education, and treatment approaches that facilitate communication skills in people with ASD who are nonverbal and in individuals with challenges in verbal ability, including the need for evidence on the utility of AAC for specific subpopulations of people with ASD. Potential areas of investigation include oral-motor skills, auditory/speech processing, social attention mechanisms, and impairments in intentional communication. In addition, research is needed on ways to improve access to AAC and the most appropriate means of AAC to utilize with specific subpopulations of individuals on the autism spectrum, including both individuals who are nonspeaking and individuals with speech that is partially or periodically limited. Comprehensive studies focusing on both adults and children on the autism spectrum should address the components of the most effective AAC approaches and factors that enhance or moderate improvements in communication, behavior and quality of life as a result of AAC usage.

Additional focus is needed to identify and address health disparities for people with ASD. While attention has been given to closing disparities in access to health care and health outcomes on the basis of race and income, little has been done to close this gap for people with developmental and intellectual disabilities, including autism (Presentation to IACC on the Eunice Kennedy Shriver National Institute of Child Health and Human Development Workshop "Disparities in the Identification of Children with ASD," 2010 (PDF – 172 KB); Videocast of NICHD Workshop on Disparities in Diagnosing ASD). Recent legislative initiatives, including the Children's Health Insurance Program Reauthorization Act (CHIPRA) and the Affordable Care Act support this research, as well as the refinement of quality-of-life measures for children, and the development of quality-of-life measures for adults (CHIPRA, 2009 (PDF – 424 KB); Patient Protection and Affordable Care Act, 2010 (PDF – 2.41 MB)). The National Core Indicators (NCI) Project (PDF – 1.64 MB), sponsored by the National Association of State Directors of Developmental Disabilities Services (NASDDDS), has collected some data regarding quality of life specifically for people with ASD enrolled in State programs (National Core Indicators Project website). NCI-participating States are using the data to inform their quality management processes and to improve the delivery of services and supports to people with intellectual disabilities and other developmental disabilities.

Aspirational Goal: Interventions Will Be Developed That Are Effective For Reducing Both Core And Associated Symptoms, For Building Adaptive Skills, And For Maximizing Quality Of Life And Health For People With ASD.

Research Opportunities

• Large-scale studies that directly compare interventions and combinations of interventions (e.g., pharmaceutical, educational, and behavioral interventions) to identify what works best for which people and how much it will cost.
  • Best practice models that are being used in community-based ASD intervention programs.
  • Clinical trials that assess the safety and efficacy of widely used interventions that have not been rigorously studied for use in ASD populations.
  • Studies in diverse populations.
• Interventions that improve functioning and quality of life for people with ASD across the lifespan, including older children, adolescents, and adults with ASD.
• Early interventions that aim to prevent the development of ASD in very young "at-risk" children and reduce family burden.
• Innovative treatments that specifically target core symptom clusters unique to ASD.
• Development of emerging technologies, such as assisted communication, that provide opportunities for people with ASD to become more engaged in the community.
• Animal models and/or cellular lines that can be used to test efficacy and/or safety of ASD interventions and treatments.
• Strategies that facilitate rapid translation of promising basic scientific discoveries and community practices into clinical research and trials.
• Methods of treating coexisting medical or psychiatric conditions and assessment of how such treatments affect ASD symptoms and severity.
• Interventions that may enhance neural plasticity and adaptive brain reorganization in children, adolescents, and adults with ASD, thereby promoting significant improvement of ASD.
• Outcome studies of the effectiveness of behavioral, developmental, and cognitive therapies and approaches.
• Methods for measuring changes in core symptoms of ASD from treatment.
• Dissemination research (coordinated with subsequent objectives) to ensure that evidence-based interventions are implemented in diverse communities with fidelity and efficiency.
• Investigation of the use of medications to control challenging behaviors in people with ASD, particularly adults.

Short-Term Objectives

Note: Dates that appear next to the objectives indicate the year that the objective was added to the Strategic Plan. If the objective was revised in subsequent editions of the Plan, the revision date is also noted.

Dates 2009	A.	Support at least three randomized controlled trials that address co-occurring medical conditions associated with ASD by 2010. IACC Recommended Budget: $13,400,000 over 3 years.
Dates 2009	B.	Standardize and validate at least 20 model systems (e.g., cellular and/or animal) that replicate features of ASD and will allow identification of specific molecular targets or neural circuits amenable to existing or new interventions by 2012. IACC Recommended Budget: $75,000,000 over 5 years.
Dates 2009	C.	Test safety and efficacy of at least five widely used interventions (e.g., nutrition, medications, assisted technologies, sensory integration, medical procedures) that have not been rigorously studied for use in ASD by 2012. IACC Recommended Budget: $27,800,000 over 5 years.
Dates 2009	D.	Complete two multi-site randomized controlled trials of comprehensive early intervention that address core symptoms, family functioning and community involvement by 2013. IACC Recommended Budget: $16,700,000 over 5 years.
Dates 2010	E.	Convene a workshop to advance the understanding of clinical subtypes and treatment personalization (i.e., what are the core symptoms to target for treatment studies) by 2011. IACC Recommended Budget: $50,000.
Dates 2010	F.	Launch randomized controlled trials of interventions including biological signatures and other measures to predict response, and monitor quality of life and functional outcomes in each of the following groups: Five trials in infants and toddlers by 2013. IACC Recommended Budget: $30,000,000 over 5 years. Three trials in school-aged children and/or adolescents by 2013. IACC Recommended Budget: $18,000,000 over 5 years. Three trials in adults by 2014. IACC Recommended Budget: $18,000,000 over 5 years.
Dates 2011	G.	Support at least five studies on interventions for nonverbal individuals with ASD by 2012. Such studies may include: Projects examining service-provision models that enhance access to augmentative and alternative communication (AAC) supports in both classroom and adult service-provision settings, such as residential service-provision and the impact of such access on quality of life, communication, and behavior; Studies of novel treatment approaches that facilitate communication skills in individuals who are nonverbal, including the components of effective AAC approaches for specific subpopulations of people with ASD; and Studies assessing access and use of AAC for children and adults with ASD who have limited or partially limited speech and the impact on functional outcomes and quality of life. IACC Recommended Budget: $3,000,000 over 2 years.
Dates 2011	H.	Support at least two studies that focus on research on health promotion and prevention of secondary conditions in people with ASD by 2012. Secondary conditions of interest include weight issues and obesity, injury, and co-occurring psychiatric and medical conditions. IACC Recommended Budget: $5,000,000 over 3 years.

Long-Term Objectives

Note: Dates that appear next to the objectives indicate the year that the objective was added to the Strategic Plan. If the objective was revised in subsequent editions of the Plan, the revision date is also noted.

Dates 2009	A.	Complete at least three randomized controlled trials on medications targeting core symptoms in people with ASD of all ages by 2014. IACC Recommended Budget: $22,200,000 over 5 years.
Dates 2009	B.	Develop interventions for siblings of people with ASD with the goal of reducing the risk of recurrence by at least 30% by 2014. IACC Recommended Budget: $6,700,000 over 5 years.
Dates 2010	C.	Conduct at least one study to evaluate the safety and effectiveness of medications commonly used in the treatment of co-occurring conditions or specific behavioral issues in people with ASD by 2015. IACC Recommended Budget: $10,000,000 over 5 years.
Dates 2011	D.	Support at least five community-based studies that assess the effectiveness of interventions and services in broader community settings by 2015. Such studies may include comparative effectiveness research studies that assess the relative effectiveness of: Different and/or combined medical, pharmacological, nutritional, behavioral, service-provision, and parent- or caregiver-implemented treatments; Scalable early intervention programs for implementation in underserved, low-resource, and low-literacy populations; and Studies of widely used community intervention models for which extensive published data are not available. Outcome measures should include assessment of potential harm as a result of autism treatments, as well as positive outcomes. IACC Recommended Budget: $37,500,000 over 5 years.