1. Comparative Effectiveness of Therapies for Children With Autism Spectrum Disorders Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

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) Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

3.  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. Background: Autism Spectrum Disorders (2 of 2) Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

4.  Autism spectrum disorders are often accompanied by other conditions, such as:  Seizure disorders  Hyperactivity  Anxiety Background: Autism Spectrum Disorders — Associated Conditions Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

5.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

6.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

7.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

8.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

9.  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 Addressed in This Report (1 of 2) Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

10.  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) Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

11.  Treatment and Education of Autistic and Communication related handicapped CHildren (TEACCH) program  Broad-based approaches  Computer-based approaches Educational Interventions Addressed in This Report Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

12. Medical and Related Interventions Addressed in This Report Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

13.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

14.  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 www.effectivehealthcare.ahrq.gov. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review Development

15.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

16.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

17.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

18.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

19.  The strength of evidence is classified into four broad ratings: Strength of Evidence Ratings Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

20.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

21.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

22.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

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. 2004 RUPP 2002 Marcus et al. 2009 1 Owen et al. 2009 -20 -15 0 -10 -5 1 The 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. * † ‡ † * p ≤ 0.001 † p < 0.001 ‡ p = 0.001 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

24. Outcomes of Risperidone and Aripiprazole for Hyperactivity/Noncompliance Change in Aberrant Behavior Checklist-Community Version Hyperactivity Subscale Score -18 -14 0 -10 -4 Shea et al. 2004 RUPP 2002 Marcus et al. 2009 1 Owen et al. 2009 -2 -6 -8 -12 -16 Risperidone Placebo Aripiprazole (15 mg) 1 The 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. * † * † * p ≤ 0.001 † p < 0.001 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

25. Adverse Events Experienced by Patients Taking Risperidone or Aripiprazole Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

26.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

27.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

28.  Key Question 3  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 Treatment Results and End-of-Treatment Effects That Predict Outcomes Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

29.  Key Question 5  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

30.  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 2 Years and at Risk for ASDs Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

31.  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) Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

32.  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 (2 of 2) Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

33.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

34.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

35.  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 Warren A, Veenstra V-W, Stone W, et al. AHRQ Comparative Effectiveness Review No. 26. Available at: http://www.effectivehealthcare.ahrq.gov/autism1.cfm.

36.  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