1. Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness of Therapies for Children With Autism Spectrum Disorders
Prepared for:
Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness of Therapies for Children With Autism Spectrum Disorders This slide set is based on a comparative effectiveness review titled, Comparative Effectiveness of Therapies for Children With Autism Spectrum Disorders, that was developed by the Vanderbilt University Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ Contract No I) and is available online at CERs represent comprehensive systematic reviews of the literature and usually compare two or more types of treatment, such as different drugs, for the same condition. For the CER on therapies for children with autism spectrum disorders, primary clinical trials published between January 1, 2000, through May 30, 2010, were identified from searches of MEDLINE®, PsycINFO (psychology and psychiatry literature), and the Education Resources Information Center (ERIC). A search of the Web sites of the U.S. Food and Drug Administration, Health Canada, and ClinicalTrials.gov was also conducted for information on aripiprazole and risperidone. This CER included 159 unique studies.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.

2. Background: Autism Spectrum Disorders (1 of 2)
Autism spectrum disorders (ASDs):
Are common neurodevelopmental disorders.
Include the following conditions:
Autistic disorder
Asperger syndrome
Pervasive developmental disorder—not otherwise specified
(PPD-NOS)
Have multiple etiologies involving both genetic and environmental factors.
Environmental factors that may contribute to risk for ASDs are:
Advanced parental age
Prematurity
Background: Autism Spectrum Disorders (1 of 2)
Autism spectrum disorders (ASDs) are common neurodevelopmental disorders. ASDs have multiple etiologies involving both genetic and environmental risk factors. Among the environmental risk factors that may contribute to ASD risk are advanced parental age and prematurity. Disorders within the autism spectrum include autistic disorder, Asperger syndrome, and pervasive developmental disorder–not otherwise specified (PDD-NOS).
References:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Autism and Developmental Disabilities Monitoring Network Surveillance Year 2006 Principal Investigators for the Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, United States, MMWR Surveill Summ 2009;58(SS10):
Johnson CP, Myers SM, for the American Academy of Pediatrics Council on Children with Disabilities. Identification and evaluation of children with autism spectrum disorders. Pediatrics 2007;120:
Shelton JF, Tancredi DJ, Hertz-Picciotto I. Independent and dependent contributions of advanced maternal and paternal ages to autism risk. Autism Res 2010;3:
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

3. Background: Autism Spectrum Disorders (2 of 2)
The expression and severity of symptoms associated with ASDs differ widely.
Individuals with ASDs may have:
Impairments in social interaction.
Dysfunctional or absent communication and language skills.
Lack of spontaneous or pretend play.
Intense preoccupation with particular concepts or things.
Repetitive behaviors and movements and other behavioral impairment.
Impaired cognitive skills and sensory perception.
Autism Spectrum Disorders (2 of 2) Individuals with ASDs have significant impairments in social interactions, behavior, and communication. These impairments include a lack of reciprocal social interaction and joint attention (i.e., the ability of the child to use nonverbal means, like pointing, to direct others’ attention to something in which the child is interested); 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 ASDs may also have impaired cognitive skills and sensory perception. References:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; Autism and Developmental Disabilities Monitoring Network Surveillance Year 2006 Principal Investigators for the Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, United States, MMWR Surveill Summ 2009;58(SS10):1-20.
Myers SM. Management of autism spectrum disorders in primary care. Pediatr Ann 2009;38:42-9.
Myers SM, Johnson CP, for the American Academy of Pediatrics Council on Children with Disabilities. Management of children with autism spectrum disorders. Pediatrics 2007;120:
Zwaigenbaum L, Bryson S, Lord C, et al. Clinical assessment and management of toddlers with suspected autism spectrum disorder: insights from studies of high-risk infants. Pediatrics 2009;123:
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

4. Background: Autism Spectrum Disorders — Associated Conditions
Autism spectrum disorders are often accompanied by other conditions, such as:
Seizure disorders
Hyperactivity
Anxiety
Background: Autism Spectrum Disorders — Associated Conditions
Children with ASDs often experience coexisting conditions, such as seizure disorders, hyperactivity, and anxiety. The expression and severity of each child’s ASD symptoms differ. Treatments include a range of behavioral, psychosocial, educational, medical, and complementary approaches that vary by a child’s age and developmental status.
References:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Myers SM. Management of autism spectrum disorders in primary care. Pediatr Ann 2009;38:
Myers SM, Johnson CP, for the American Academy of Pediatrics Council on Children with Disabilities. Management of children with autism spectrum disorders. Pediatrics 2007;120:
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

5. Background: Autism Spectrum Disorders — Prevalence and Treatment
Autism spectrum disorders have an estimated prevalence of 1 in 110 children in the United States.
There is no cure for ASDs and currently no global consensus regarding which intervention strategy is most effective.
Background: Autism Spectrum Disorders — Prevalence and Treatment
Autism spectrum disorders (ASDs) are common neurodevelopmental disorders, with an estimated prevalence of 1 in 110 children in the United States. There is no cure for ASDs and no global consensus about which intervention strategy is most effective. References:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Autism and Developmental Disabilities Monitoring Network Surveillance Year 2006 Principal Investigators for the Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, United States, MMWR Surveill Summ 2009;58(SS10):
Committee on Educational Interventions for Children with Autism, for the National Research Council. Lord C and McGee JP, eds. Educating children with autism. Washington DC: National Academies Press;
National Autism Center. National standards report: the National Standards Project—addressing the need for evidence-based practice guidelines for autism spectrum disorders. Randolph, MA: National Autism Center;
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

6. Background: Autism Spectrum Disorders — Treatment
Treatments include a range of behavioral, psychosocial, educational, medical, and complementary approaches.
Treatment options vary by age and developmental status.
Chronic management is often required to maximize functional independence and quality of life by:
Minimizing core ASD deficits in social skills and communication.
Facilitating development and learning.
Promoting socialization.
Reducing maladaptive behaviors.
Educating and supporting families.
Background: Autism Spectrum Disorders — Treatment
Treatment is frequently complicated by emergent symptoms such as irritability and other comorbid conditions that may warrant targeted treatment. Chronic management is often required to maximize functional independence and quality of life. Goals of ASD therapy include: minimizing the core deficits in social skills and communication, facilitating development and learning, promoting socialization, and reducing maladaptive behaviors. Educating and supporting families is also a primary concern of treatment plans for children with ASDs. Individual goals for treatment vary for different children and may include combinations of medical and related therapies, behavioral therapies, educational therapies, allied health therapies, and complementary and alternative medicine (CAM) therapies.
References:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Myers SM. Management of autism spectrum disorders in primary care. Pediatr Ann 2009;38:
Myers SM, Johnson CP, for the American Academy of Pediatrics Council on Children with Disabilities. Management of children with autism spectrum disorders. Pediatrics 2007;120:
Zwaigenbaum L, Bryson S, Lord C, et al. Clinical assessment and management of toddlers with suspected autism spectrum disorder: insights from studies of high-risk infants. Pediatrics 2009;123:
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

7. Background: Goals of Treatment
Goals of treatment focus on improving core deficits in communication, social interactions or restricted behaviors.
Individual goals for treatment vary for different children and may include combinations of medical and related therapies, behavioral therapies, educational therapies, allied health therapies, and complementary and alternative medicine (CAM) therapies.
Background: Goals of Treatment
The goals of treatment for ASDs focus on improving communication and social interactions or on restricting behaviors may help children develop greater functional skills and independence. In the 1980s, comprehensive treatment programs were developed that target behaviors and development more broadly instead of focusing on a specific behavior of interest. There has been suggestion that intensive therapy (25 to 30 hours/week) at an earlier age may lead to greater improvements.
References:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Bryson SE, Rogers SJ, Fombonne E. Autism spectrum disorders: early detection, intervention, education, and psychopharmacological management. Can J Psychiatry 2003;48:
Committee on Educational Interventions for Children with Autism, for the National Research Council. Lord C and McGee JP, eds. Educating children with autism. Washington DC: National Academies Press;
Myers SM, Johnson CP, for the American Academy of Pediatrics Council on Children With Disabilities. Management of children with autism spectrum disorders. Pediatrics 2007;120:
Rogers SJ, Vismara LA. Evidence-based comprehensive treatments for early autism. J Clin Child Adolesc Psychol 2008;37:
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

8. Treatment: Interventions Included in This Report
This report examined the evidence available on the following types of interventions:
Behavioral interventions
Educational interventions
Medical and related interventions
Allied health interventions
CAM interventions
Treatment: Interventions Included in This Report
This review includes specifically: behavioral interventions, educational interventions, medical and related interventions, allied health interventions, and CAM interventions.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

9. Behavioral Interventions Addressed in This Report (1 of 2)
The following behavioral interventions aimed at the core symptoms of ASDs were addressed in the report:
Early intensive behavioral and developmental interventions
UCLA/Lovaas-based approaches
Early Start Denver Model and other developmental and relational approaches
Parent training approaches
Social skill interventions
Social skills training
Play- and interaction-based interventions
Joint attention interventions
Symbolic play and play-based interventions
Behavioral Interventions Aimed at Core Symptoms (1 of 2)
In this review, behavioral interventions were categorized into early intensive behavioral and developmental interventions, social skills interventions, and play- and interaction-based interventions. Early intensive behavioral and developmental interventions include UCLA/Lovaas-based approaches, the Early Start Denver Model, and those using the principles of applied behavioral analysis to focus on key pivotal behaviors rather than on global improvements (e.g., Pivotal Response Training, Hanen More than Words, social pragmatic intervention, etc.). Social skills interventions address core social impairments and utilize approaches such as direct instruction within individual (e.g., Social Stories) or group (e.g., Skillstreaming, Children’s Friendship Training) formats and structured interactions with peers (e.g., Lego therapy). Play- and interaction-based interventions use interactions between children and adults (either parents or researchers) to improve outcomes such as imitation or joint attention skills or the ability of the child to engage in symbolic play. They include teaching parents how to interact differently with their children within daily routines and interactions, often using standard behavior-management strategies. They also include foci on generic day-to-day interactions outside of the family.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

10. Behavioral Interventions Addressed in This Report (2 of 2)
The following behavioral interventions aimed at symptoms commonly associated with ASD were addressed in this report:
Cognitive behavioral therapy
Neurofeedback
Sleep interventions
Behavioral Interventions Addressed in This Report (2 of 2)
This slide reviews behavioral interventions aimed at symptoms commonly associated with ASD that were considered in the systematic review. Challenging behaviors, such as noncompliance, tantrums, self-injury, and aggression, are also common among children with ASDs. Several behavioral interventions target symptoms like anger and anxiety, which are often present with ASDs. Cognitive behavioral therapy has been adapted for and applied to children with ASDs, particularly children with higher IQs. This approach focuses on teaching cognitive skills and relaxation strategies, helping children recognize anxious feelings, and providing them with behavioral exposures in which to practice coping skills in the face of anxiety-provoking situations. It aims to reduce generalized and specific anxiety symptoms over time. Parent training protocols are used to teach behavior prevention, intervention, and management strategies, enabling parents to act as “cotherapists.” Parent training interventions may also improve parental feelings of self-efficacy and decrease parental stress. Additional interventions include techniques such as sleep workshops and neurofeedback.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

11. Educational Interventions Addressed in This Report
Treatment and Education of Autistic and Communication related handicapped CHildren (TEACCH) program
Broad-based approaches
Computer-based approaches
Educational Interventions Addressed in This Report
Educational interventions are the primary treatment for ASDs and, for the most part, are intended to be administered in educational settings. In general, these interventions focus on improving educational and cognitive skills; however, they may also be used to address core areas of social, cognitive, and behavioral impairment. The systematic review examined literature on the TEACHH program, broad-based early intervention center- or classroom-based instruction, and computer-based approaches to educational intervention.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

12. Medical and Related Interventions Addressed in This Report
Medication
Application for ASDs
Antipsychotics
Problem/challenging behaviors including irritability, aggression, and self-injurious behavior
Serotonin-reuptake inhibitors
Repetitive behaviors and challenging behavior
Stimulants and other medications for hyperactivity
Hyperactivity
Secretin
Language, gastrointestinal symptoms, adaptive behavior, cognitive impairments, and social and fine motor skills
Dietary supplements/
restrictive diets
Behavioral symptoms (magnesium, vitamin B6, l-carnosine, dimethylglycine, polyunsaturated fatty acid, and ketogenic diet) and associated comorbidities including sleep difficulties (melatonin and iron)
Other medical
interventions
Cognition (piracetam, donepezil, and rivastigmine), gastrointestinal symptoms (immunoglobulin), and behavior (hyperbaric oxygen, amantadine, and pentoxifylline)
Medical and Related Interventions Addressed in This Report
The table on this slide lists specific medical interventions and outcomes considered in the systematic review. Medical interventions that were considered include: antipsychotics, psychostimulants, and serotonin-reuptake inhibitors. Therapeutic diets, supplements, hormonal supplements, immunoglobulin, hyperbaric oxygen, and chelating agents have also been employed to treat the symptoms of ASDs.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

13. Other Interventions Addressed in This Report
Allied Health Interventions
Speech and language development
Picture exchange communication system (PECS) and responsive education and prelinguistic milieu teaching (RPMT)
Sensory and auditory integration and music therapy
Occupational therapy techniques
Animal-assisted interventions (e.g., horseback riding therapy)
Movement therapy
CAM Interventions
Massage
Acupuncture
Other Interventions Addressed in This Report
Several allied health approaches have been applied toward improving core symptoms of ASDs and associated characteristics. Allied health interventions considered in this report include those that focus on language, use sensory or auditory integration, and use techniques such as horseback riding or occupational therapy. CAM interventions examined in this report include massage and acupuncture.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

14. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review Development
Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others.
A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.
The results of these reviews are summarized into Clinician Guides and Consumer Guides for use in decisionmaking and in discussions with patients. The Guides and the full report, with references for included and excluded studies, are available at
Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review Development
Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others. A systematic review of all relevant clinical studies is conducted by independent researchers, who are funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment. The results of these reviews are summarized into Clinician Guides and Consumer Guides for use in decisionmaking and in discussions with patients. The Guides and the full report, with references for included and excluded studies, are available at
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.

15. Key Question 1
Among children ages 2–12 years with ASDs, what are the short- and long-term effects of available behavioral, educational, family, medical, allied health, or CAM treatment approaches?
KQ 1a: What are the effects on core symptoms (e.g., social deficits, communication deficits, and repetitive behaviors) in the short term (≤6 months)?
KQ 1b: What are the effects on commonly associated symptoms (e.g., motor, sensory, medical, mood/anxiety, irritability, and hyperactivity) in the short term (≤6 months)?
KQ 1c: What are the longer term effects (>6 months) on core symptoms (e.g., social deficits, communication deficits, and repetitive behaviors)?
KQ 1d: What are the longer term effects (>6 months) on commonly associated symptoms (e.g., motor, sensory, medical, mood/anxiety, irritability, and hyperactivity)?
Key Question 1
Among children ages 2–12 years with ASDs, what are the short- and long-term effects of available behavioral, educational, family, medical, allied health, or CAM treatment approaches? Specifically:
KQ 1a: What are the effects on core symptoms (e.g., social deficits, communication deficits, and repetitive behaviors), in the short term (≤6 months)?
KQ 1b: What are the effects on commonly associated symptoms (e.g., motor, sensory, medical, mood/anxiety, irritability, and hyperactivity) in the short term (≤6 months)?
KQ 1c: What are the longer term effects (>6 months) on core symptoms (e.g., social deficits, communication deficits, and repetitive behaviors)?
KQ 1d: What are the longer term effects (>6 months) on commonly associated symptoms (e.g., motor, sensory, medical, mood/anxiety, irritability, and hyperactivity)?
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

16. Key Question 2
Among children ages 2–12 years with ASDs, what are the modifiers of outcome for different treatments or approaches?
KQ 2a: Is the effectiveness of the therapies reviewed affected by the frequency, duration, and intensity of the intervention?
KQ 2b: Is the effectiveness of the therapies reviewed affected by the training and/or experience of the individual providing the therapy?
KQ 2c: What characteristics, if any, of the child modify the effectiveness of the therapies reviewed?
KQ 2d: What characteristics, if any, of the family modify the effectiveness of the therapies reviewed?
Key Question 2
Among children ages 2–12 years with ASDs, what are the modifiers of outcome for different treatments or approaches? Specifically:
KQ 2a: Is the effectiveness of the therapies reviewed affected by the frequency, duration, and intensity of the intervention?
KQ 2b: Is the effectiveness of the therapies reviewed affected by the training and/or experience of the individual providing the therapy?
KQ 2c: What characteristics, if any, of the child modify the effectiveness of the therapies reviewed?
KQ 2d: What characteristics, if any, of the family modify the effectiveness of the therapies reviewed?
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

17. Key Questions 3–7
KQ 3: Are there any identifiable changes early in the treatment phase that predict treatment outcomes?
KQ 4: What is the evidence that effects measured at the end of the treatment phase predict long-term functional outcomes?
KQ 5: What is the evidence that specific intervention effects measured in the treatment context generalize to other contexts (e.g., people, places, materials)?
KQ 6: What evidence supports specific components of treatment as driving outcomes, either within a single treatment or across treatments?
KQ 7: What evidence supports the use of a specific treatment approach in children under the age of 2 years who are at high risk of developing autism based upon behavioral, medical, or genetic risk factors?
Key Questions 3–7
KQ 3: Are there any identifiable changes early in the treatment phase that predict treatment outcomes?
KQ 4: What is the evidence that effects measured at the end of the treatment phase predict long-term functional outcomes?
KQ 5: What is the evidence that specific intervention effects measured in the treatment context generalize to other contexts (e.g., people, places, materials)?
KQ 6: What evidence supports specific components of treatment as driving outcomes, either within a single treatment or across treatments?
KQ 7: What evidence supports the use of a specific treatment approach in children under the age of 2 years who are at high risk of developing autism based upon behavioral, medical, or genetic risk factors?
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

18. The Studies Key inclusion criteria:
Studies of children ages 2–12 years with ASDs or ages 0–2 years at risk for an ASD diagnosis.
Any study design except case study reports.
Studies were excluded if they:
Included ≤10 total participants for studies of behavioral, educational, allied health, or CAM interventions or ≤30 total participants for medical studies.
Did not report information pertinent to the Key Questions.
Were published prior to the year 2000.
Were not original research.
Did not present aggregated results (i.e., included data for individual participants only) or presented graphical data only.
The Studies
Key inclusion criteria: studies of children ages 2–12 years with ASDs or ages 0–2 years at risk for diagnosis of an ASD; any study design except case study reports.
Studies were excluded if they: included < 10 total participants for studies of behavioral, educational, allied health, or CAM interventions; included < 30 total participants for medical studies; did not report information pertinent to the Key Questions; were published prior to the year 2000; were not original research; did not present aggregated results (i.e., included data for individual participants only) or presented graphical data only.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

19. Strength of Evidence Ratings
The strength of evidence is classified into four broad ratings:
High
●●●
There are consistent results from good-quality studies. Further research is very unlikely to change the conclusions.
Moderate
●●○
Findings are supported, but further research could change the conclusions.
Low
●○○
There are very few studies, or existing studies are flawed.
Insufficient
○○○
Evidence is either unavailable or does not permit estimation of an effect.
Strength of Evidence Ratings Throughout this slide set, strength of evidence ratings are assigned to findings of the report. Strength of evidence is typically assigned to reviews of medical treatments after assessing four domains: risk of bias, consistency, directness, and precision. Available evidence for each Key Question was assessed for each of these four domains; the domains were combined qualitatively to develop the strength of evidence for each Key Question.
References:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality, March AHRQ Publication No. 10(11)-EHC063-EF. Chapters available at:
Owens DK, Lohr KN, Atkins D, et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions—Agency for Healthcare Research and Quality and the Effective Health-Care Program. J Clin Epidemiol 2010;63:
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

20. Key Question 1: Clinical Bottom Line — Behavioral Interventions
Early intensive behavioral and developmental interventions such as approaches based on the UCLA/Lovaas Model improve cognitive, language, and adaptive outcomes in certain subgroups of children.
Strength of evidence: Low
The evidence is insufficient to understand the effectiveness, benefits, or adverse events from any other behavioral interventions.
Strength of evidence: Insufficient
Key Question 1: Clinical Bottom Line — Behavioral Interventions
There is some evidence to guide choices among early intensive behavioral interventions. Early intensive behavioral and developmental interventions such as UCLA/Lovaas-based approaches improve cognitive, language, and adaptive outcomes in certain subgroups of children (strength of evidence: low). There is insufficient evidence to estimate the effectiveness, benefits, or adverse events from any other behavioral interventions.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

21. Key Question 1: Clinical Bottom Line — Benefits Associated With Medical Interventions
Aripiprazole and risperidone reduce challenging and repetitive behaviors when compared with placebo.
Strength of evidence for aripiprazole: High
Strength of evidence for risperidone: Moderate
The evidence clearly shows that secretin does NOT improve language, cognition, behavior, communication, autism symptom severity, or socialization.
Strength of evidence: High
The evidence is insufficient to understand the effectiveness of and benefits from all other medical interventions.
Strength of evidence: Insufficient
Key Question 1: Clinical Bottom Line — Benefits Associated With Medical Interventions
Aripiprazole reduces challenging and repetitive behaviors when compared with placebo (strength of evidence: high). Risperidone reduces challenging and repetitive behaviors when compared with placebo (strength of evidence: moderate). Secretin does not improve language, cognition, behavior, communication, autism symptom severity, or socialization (strength of evidence: high).
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

22. Key Question 1: Clinical Bottom Line — Harms Associated With Medical Interventions
Aripiprazole and risperidone are associated with significant weight gain, sedation, and extrapyramidal effects that may limit their use to patients with severe impairment or with risk of injury.
Strength of evidence: High
There was insufficient evidence to understand the adverse events from all other medical interventions, including serotonin-reuptake inhibitors and stimulants.
Strength of evidence: Insufficient
Key Question 1: – Clinical Bottom Line: Harms Associated With Medical Interventions
Aripiprazole and risperidone are associated with significant weight gain, sedation, and extrapyramidal effects that may limit their use to patients with severe impairment or with risk of injury (strength of evidence: high). Other than for aripiprazole and risperidone, there was insufficient evidence to estimate the severity and frequency of potential adverse events associated with any interventions, including serotonin-reuptake inhibitors and stimulants (strength of evidence: insufficient).
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

23. Outcomes of Risperidone and Aripiprazole for Irritability
Change in Aberrant Behavior Checklist-Community Version Irritability Subscale Score
Risperidone
Placebo
Aripiprazole (15 mg)
Shea et al
RUPP
2002
Marcus et al
Owen et al
-20
-15
-10 -5 * † ‡ †
*p ≤ 0.001
†p < 0.001
‡p = 0.001
Outcomes of Risperidone and Aripiprazole for Irritability
This review included four randomized clinical trials (RCTs) that compared risperidone to placebo and two RCTs that compared aripiprazole to placebo. Risperidone: Two of the four RCTs of risperidone focused on challenging behavior as their primary outcomes and included a combined total of 180 subjects. Both studies used a graduated-dose titration design over 8 weeks; the average risperidone dose ranged from 1.5–1.8 mg per day. In these two studies, baseline ratings of irritability were measured with the Irritability Subscale of the Aberrant Behavior Checklist–Community Version (ABC-C) and were similar across the risperidone (18.9–26.2) and the placebo (21.2–25.5) arms. Decreases in the ABC-C Irritability Subscale were significantly greater for the risperidone arms in both studies (12.2–14.9) when compared with the placebo arms (3.6–6.5). Aripiprazole: Each of the two aripiprazole RCTs focused on the primary outcome of challenging behavior indexed by the ABC-C Irritability Subscale. Combined, the trials included 213 subjects in the aripiprazole arm and 103 subjects in the placebo arms. The study by Marcus et al. (2009) was a fixed-dose design with one placebo arm and three arms corresponding to 5, 10, and 15 mg doses of aripiprazole per day. Only the results for the 15 mg per day versus placebo arm are shown in the figure, although improved outcomes were noted for all three aripiprazole arms and increased response with increased dose was observed. In both RCTs, baseline ratings of irritability were similar across the aripiprazole and the placebo arms (ABC-C Irritability Subscale, 28.0–30.8). Decreases in ABC-C Irritability Subscale scores were significantly greater for the aripiprazole arms in both studies, with improvements of 12.4–14.4 as opposed to 5.0–8.4 for the placebo arm. References:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Aman MG, Arnold LE, McDougle CJ, et al. Acute and long-term safety and tolerability of risperidone in children with autism. J Child Adolesc Psychopharmacol 2005;15: Aman MG, Hollway JA, McDougle CJ, et al. Cognitive effects of risperidone in children with autism and irritable behavior. J Child Adolesc Psychopharmacol 2008;18:
Anderson GM, Scahill L, McCracken JT, et al. Effects of short- and long-term risperidone treatment on prolactin levels in children with autism. Biol Psychiatry 2007;61: Arnold LE, Vitiello B, McDougle C, et al. Parent-defined target symptoms respond to risperidone in RUPP autism study: customer approach to clinical trials. J Am Acad Child Adolesc Psychiatry 2003;42: Marcus RN, Owen R, Kamen L, et al. A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry 2009;48: Martin A, Scahill L, Anderson GM, et al. Weight and leptin changes among risperidone-treated youths with autism: 6-month prospective data. Am J Psychiatry 2004;161: McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002;347: McDougle CJ, Scahill L, Aman MG, et al. Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology. Am J Psychiatry 2005;162: Owen R, Sikich L, Marcus RN, et al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics 2009;124: Pandina GJ, Bossie CA, Youssef E, et al. Risperidone improves behavioral symptoms in children with autism in a randomized, double-blind, placebo-controlled trial. J Autism Dev Disord 2007;37: Shea S, Turgay A, Carroll A, et al. Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics 2004;114:e Williams SK, Scahill L, Vitiello B, et al. Risperidone and adaptive behavior in children with autism. J Am Acad Child Adolesc Psychiatry 2006;45:431-9.
1The study by Marcus et al. (2009) had a four-arm fixed-dose design with a placebo arm and three
aripiprazole arms (5, 10, or 15 mg/day). Only the results for the 15 mg/day versus placebo arm are shown.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

24. Outcomes of Risperidone and Aripiprazole for Hyperactivity/Noncompliance
Change in Aberrant Behavior Checklist-Community Version Hyperactivity Subscale Score
-18
-14
-10 -4
Shea et al.
2004
RUPP
2002
Marcus et al
Owen et al -2 -6 -8
-12
-16
Risperidone
Placebo
Aripiprazole (15 mg) † * †
Outcomes of Risperidone and Aripiprazole for Hyperactivity/Noncompliance
This review included four RCTs that compared risperidone to placebo and two RCTs that compared aripiprazole to placebo.
Risperidone: Two of the four RCTs of risperidone focused on challenging behavior as their primary outcomes and included a combined total of 180 subjects. Both studies used a graduated-dose titration design over 8 weeks; the average risperidone dose ranged from 1.5–1.8 mg per day. In these two studies, baseline ratings of hyperactivity and noncompliance were measured with the Hyperactivity Subscale of the Aberrant Behavior Checklist-Community Version (ABC-C) and were similar across the risperidone (27.3–31.8) and placebo (30.9–32.3) arms. Decreases in ABC-C Hyperactivity Subscale were significantly greater for the risperidone arms in both studies (14.8–14.9) when compared with the placebo arms (4.7–7.4).
Aripiprazole: Each of the two aripiprazole RCTs indexed a primary outcome of challenging behavior by the ABC-C Hyperactivity Subscale and together included 213 subjects in the aripiprazole arm and 103 subjects in the placebo arms. The study by Marcus et al. (2009) was a fixed-dose design with one placebo arm and three arms corresponding to 5, 10, and 15 mg per day of aripiprazole. Only the results for the 15 mg/day versus placebo arm are shown in the figure in this slide, although improvements in challenging behaviors were noted for all three aripiprazole arms. An increased response with an increased dose was observed. In both RCTs, baseline ratings of hyperactivity/noncompliance were similar across the aripiprazole arms (ABC-C Hyperactivity Subscale 32.2–34.1) and the placebo arms (ABC-C Hyperactivity Subscale 31.0–34.7). Decreases in ABC-C Hyperactivity Subscale scores were significantly greater for the aripiprazole arms in both studies, with improvements of 12.7–16.3 as opposed to 2.8–7.7 for the placebo arms.
References:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Aman MG, Arnold LE, McDougle CJ, et al. Acute and long-term safety and tolerability of risperidone in children with autism. J Child Adolesc Psychopharmacol 2005;15:
Aman MG, Hollway JA, McDougle CJ, et al. Cognitive effects of risperidone in children with autism and irritable behavior. J Child Adolesc Psychopharmacol 2008;18:
Anderson GM, Scahill L, McCracken JT, et al. Effects of short- and long-term risperidone treatment on prolactin levels in children with autism. Biol Psychiatry 2007;61:
Arnold LE, Vitiello B, McDougle C, et al. Parent-defined target symptoms respond to risperidone in RUPP autism study: customer approach to clinical trials. J Am Acad Child Adolesc Psychiatry 2003;42:
Marcus RN, Owen R, Kamen L, et al. A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry 2009;48:
Martin A, Scahill L, Anderson GM, et al. Weight and leptin changes among risperidone-treated youths with autism: 6-month prospective data. Am J Psychiatry 2004;161:
McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002;347:
McDougle CJ, Scahill L, Aman MG, et al. Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology. Am J Psychiatry 2005;162:
Owen R, Sikich L, Marcus RN, et al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics 2009;124:
Pandina GJ, Bossie CA, Youssef E, et al. Risperidone improves behavioral symptoms in children with autism in a randomized, double-blind, placebo-controlled trial. J Autism Dev Disord 2007;37:
Shea S, Turgay A, Carroll A, et al. Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics 2004;114:e
Williams SK, Scahill L, Vitiello B, et al. Risperidone and adaptive behavior in children with autism. J Am Acad Child Adolesc Psychiatry 2006;45:
Key words: outcomes, strength of evidence, treatment, therapy, interventions, medical, harmsor the 15 mg/day versus placebo arm are shown.
*p ≤ 0.001
†p < 0.001 *
1The study by Marcus et al. (2009) had a four-arm fixed-dose design with a placebo arm and three
aripiprazole arms (5, 10, or 15 mg/day). Only the results for the 15 mg/day versus placebo arm are shown.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

25. Adverse Events Experienced by Patients Taking Risperidone or Aripiprazole
Placebo
Risperidone
Aripiprazole
Percentage (range) of subjects
with adverse events (Number of studies)
Appetite changes/ weight gain
3.0–25.0 (6)
7.9–89.5 (7)
12.1–14.9 (2)
Somnolence/sedation/drowsiness
(4)
3.2–72.5 (7)
17.0–23.6 (2)
Extrapyramidal symptoms
0–12.8 (5)
1.6–27.5 (6)
10.3–14.9 (2)
Adverse Events Experienced by Patients Taking Risperidone and Aripiprazole
Among the studies included in this report, common side effects experienced by patients taking the antipsychotics risperidone or aripiprazole include weight gain, sedation, and extrapyramidal effects.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

26. Key Question 1: Clinical Bottom Line — Other Types of Interventions
The evidence is insufficient to understand the effectiveness, benefits, or adverse events from any educational, allied health, or CAM intervention.
Strength of evidence: Insufficient
Key Question 1: Clinical Bottom Line — Other Types of Interventions
Overall, the available body of evidence does not provide guidance on the effectiveness, benefits, or harms associated with any educational, allied health, or CAM intervention considered in this report.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

27. Key Question 2: Modifiers of Treatment Outcomes
Few studies were designed or powered to identify modifiers of treatment effect.
True treatment modifiers were only demonstrated in one included study.
Many other studies failed to find a relationship between autism symptoms and treatment response.
The evidence report identified several potential correlates that warrant future study:
Pretreatment IQ and language skills
Age at initiation of treatment
Social skills, imitation skills, and aloofness (UCLA/Lovaas)
Diagnosis
Key Question 2: Modifiers of Treatment Outcomes
Few studies were designed or powered to identify modifiers of treatment effect. True treatment modifiers were only demonstrated in one included study. Many other studies failed to find a relationship between autism symptoms and treatment response. The evidence report identified several potential correlates that warrant future study, including: pretreatment IQ and language skills; age at initiation of treatment; social skills, imitation skills, and aloofness (UCLA/Lovaas); and diagnosis.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

28. Key Questions 3 and 4: Early Treatment Results and End-of-Treatment Effects That Predict Outcomes
There is almost no information about specific observations of children that might be made early in treatment to predict long-term outcomes.
No studies addressed end-of-treatment effects to predict longer range outcomes.
Key Question 4
Feasibility of such studies was established in one language study that reported outcomes 12 months postintervention.
Key Questions 3 and 4: Early Results During Treatment and End-of-Treatment Effects That Predict Outcomes
The literature offers almost no information about whether long-term outcomes can be predicted from any specific observations of children made early in treatment. No studies addressed whether end-of-treatment effects predict longer range outcomes. The feasibility of performing these types of studies was established in one language study that reported outcomes 12 months postintervention.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

29. Key Questions 5 and 6: Generalization of Treatment Effects and Drivers of Treatment Effects
Few studies measured the generalization of effects seen in treatment conditions to either different conditions or locations.
Key Question 6
No studies were identified to answer questions about drivers of treatment effects.
Key Questions 5 and 6: Generalization of Treatment Effects and Drivers of Treatment Effects
Few studies measured the generalization of effects seen in treatment conditions to either different conditions or locations. No studies were identified to answer questions about drivers of treatment effects.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

30. Key Question 7: Treatment Approaches in Children Under Age 2 Years and at Risk for ASDs
Research on young children is preliminary, with only four studies identified.
One good-quality randomized clinical trial suggested benefit for the use of the Early Start Denver Model in young children, with improvements in adaptive behavior, language, and cognitive outcomes.
Overall, the body of evidence related to this Key Question does not provide any guidance on whether any intervention improves outcomes in children who are under age 2 years and at risk for ASDs.
Key Question 7: Treatment Approaches in Children under Age Two at Risk for ASDs
Research on young children is preliminary, with only four studies identified. One good-quality randomized clinical trial suggested benefit for the use of the Early Start Denver Model in young children with improvements in adaptive behavior, language, and cognitive outcomes. Overall, the body of evidence related to this Key Question does not provide any guidance on whether any intervention improves outcomes in children who are under age 2 years and at risk for ASDs.
Reference: Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

31. Conclusions (1 of 2)
Efforts toward early intervention for ASDs have been encouraging.
Promising results on the effectiveness of therapies for ASDs need to be replicated and expanded.
There is some evidence to guide choices among early intensive behavioral interventions and medical interventions (for challenging and repetitive behaviors).
There is little or no comparative evidence on which to make decisions about: medical interventions for social or communication symptoms; most behavioral interventions; and educational, allied health, and CAM interventions.
Conclusions (1 of 2)
There have been encouraging advances in the promotion of early diagnosis and intervention for ASDs. Since this is a young field, existing studies need to be replicated and expanded. Evidence on the comparative effectiveness and safety of most specific interventions for children with ASDs is limited and inconclusive. There is some evidence to guide choices among early intensive behavioral interventions and medical interventions for challenging behaviors. Little evidence exists to guide choices among medical interventions for social or communication symptoms. There is little or no comparative evidence upon which to make decisions about behavioral, educational, allied health, and CAM interventions.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

32. Conclusions (2 of 2)
For most interventions, the evidence is insufficient to permit an estimate of their benefits or harms.
This finding does not mean that these interventions are not associated with benefits or harms but that further study is required.
Evidence also suggests that there is an undefined subgroup of children for whom early and intensive behavioral interventions may elicit robust gains while others may not demonstrate marked improvement.
Conclusions
The evidence on certain medical and behavioral interventions is promising across several outcomes. For most interventions, however, the evidence is insufficient to permit an estimate of their benefits or harms. This finding does not mean that these interventions are not associated with benefits or harms but that further study is required. Evidence also suggests that there is a subgroup of children for whom early and intensive behavioral interventions may elicit robust gains while others may not demonstrate marked improvement.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

33. Note Regarding Possible Harms
Adverse events were not reported for most interventions.
Other than for risperidone and aripiprazole, there was not enough evidence to permit conclusions to be drawn about the severity and frequency of potential adverse events associated with any of the interventions.
According to the U.S. Food and Drug Administration, there are serious safety issues associated with chelation products. Even when used under medical supervision, these products may cause serious harm, including dehydration, kidney failure, and death.
Note Regarding Possible Harms
Adverse events were not reported for most interventions. They were reported, however, for the antipsychotics risperidone and aripiprazole (see clinical bottom line), serotonin-reuptake inhibitors (decreased sleep, increased energy), guanfacine, and stimulants. Other than for risperidone and aripiprazole, there was not enough evidence to permit conclusions to be drawn about the severity and frequency of potential adverse events associated with any of the interventions. According to the U.S. Food and Drug Administration, there are serious safety issues associated with chelation products. Even when used under medical supervision, these products may cause serious harm, including dehydration, kidney failure, and death.
References:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
U.S. Food and Drug Administration Web site. FDA Consumer Health Information. FDA Warns Marketers of Unapproved ‘Chelation’ Drugs. Available at: Accessed May 17, 2011.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

34. Gaps in Knowledge
There are no or few studies that describe the following:
Direct comparisons of the effects of different treatment approaches and their practical effectiveness or feasibility beyond research studies.
Which children are likely to benefit from particular interventions.
Generalization of treatment effects to contexts outside of the treatment context (e.g., settings), components of multicomponent therapies that drive effectiveness, and predictors of treatment success.
Which specific treatment approaches to use in children under 2 years of age who are at high risk of developing an ASD based on behavioral, medical, or genetic risk factors.
Whether there are any harms associated with behavioral, educational, allied health, or CAM interventions.
Gaps in Knowledge
There are no or few studies that describe the following:
Direct comparisons of the effects of different treatment approaches (e.g., no direct comparison of UCLA/Lovaas and the Early Start Denver Model), and there are few data on practical effectiveness or feasibility beyond research studies.
Which children are likely to benefit from particular interventions.
Generalization of treatment effects to contexts outside of the treatment context (e.g., settings), components of multicomponent therapies that drive effectiveness, and predictors of treatment success.
Which specific treatment approaches to use in children under 2 years of age who are at high risk of developing an ASD based upon behavioral, medical, or genetic risk factors.
Whether there are any harms associated with behavioral, educational, allied health, or CAM interventions.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

35. Future Research Needs
Continuing improvements in methodological rigor in the field, including:
Consistent use of standardized, validated outcome measure(s) for each target of therapy.
Thorough descriptions of study participants and interventions.
Large, publicly funded, multisite studies of existing interventions across all treatment types and studies with extended followup times.
Standardized and validated outcome measures for each target of therapy.
Research on medical interventions for which no research has been conducted and on atypical antipsychotics that are less associated with adverse events than are aripiprazole and risperidone.
Future Research Needs
Continuing improvements in methodological rigor in the field, including the following:
Consistently used standardized, validated outcome measure(s) for each target of therapy.
Thorough descriptions of study participants and interventions.
Large, publicly funded, multisite studies of existing interventions across all treatment types and studies with extended followup times.
Standardized and validated outcome measures for each target of therapy.
Research on medical interventions for which no research has been conducted and on atypical antipsychotics that are less associated with adverse events than are risperidone and aripiprazole.
Reference:
Warren Z, Veenstra V-W, Stone W, et al. Therapies for Children With Autism Spectrum Disorders. Comparative Effectiveness Review No. 26 (Prepared by the Vanderbilt University Evidence-based Practice Center under Contract No I). Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 11-EHC029-EF.
Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26.
Available at:

36. What To Discuss With Your Patient’s Parent or Caregiver
Types of therapies and specialists to consider.
Educational options, given the severity of the ASD.
Treatment goals and realistic expectations.
Side effects of medications and the longevity of those side effects.
Daily routine.
Support groups, local services, and sources of trusted information.
Experience of the treatment team in working with children who have ASDs.
Insurance coverage.
What To Discuss With Your Patient’s Parent or Caregiver
Clinicians should discuss with parents of their patients: types of therapies and specialists to consider; educational options (given the severity of the ASD); treatment goals and realistic expectations; side effects of medications and the longevity of those side effects; daily routine; issues related to diet modification; support groups, local services, and sources of trusted information; the experience of treatment team in working with children who have ASDs; and insurance coverage.