Biomedical Management of Autism: What Works? 8th Annual Developmental Disabilities: An Update for Health Professionals University of California, San Francisco Heidi Feldman, MD, PhD Lynne C. Huffman, MD Stanford University Department of Pediatrics Biomedical Management of Autism: What Works? Overview Clinical scenario (Dr. Feldman) al and Complementary-Alternative Medical (CAM) treatments (Dr. Huffman) Rationale and methods of comprehensive literature review Study quality and strength of evidence Questions and Discussion (Drs. Feldman and Huffman) 030609 2 Medical Management of Autism: What Works? Learning Objectives Participants will understand the scope of scientific evidence concerning pharmacologic and CAM treatments for autism Participants will be able to use scientific studies to support their thinking and decisionmaking about clinical issues 030609 3 Core Features of Autism Qualitative impairment of social interaction Impairment in eye-to-eye gaze, gestures Lack of social reciprocity Qualitative impairment of communication Delay in development of spoken language Idiosyncratic vocalization Restricted and repetitive behaviors Repetitive mannerisms Persistent preoccupation with parts of objects 030609 4 1
Associated Symptoms Behavior problems Aggression and oppositionality Hyperactivity Self-injury Dysregulation Irritability Emotional lability Depression and anxiety Odd responses to sensory stimuli Eating abnormalities Sleep problems GI disturbances 030609 5 Increasing Number of Reported Cases Studies over past decade 2-5 cases autism/10,000 (Bryson, 1997) 66 cases of ASD/10,000 (~1/150 children) (CDC, 2007) 030609 6 Current Treatment Options Goals of treatment Increase quality of life and functional independence Lessen associated deficits and family distress Mainstays of treatment Behavior management Intensive, sustained special education Limitations of behavior management and education Slow progress Labor intensive, expensive Difficult to take to scale Appeal of medication as adjunct treatment 030609 7 Use of Medications and CAM in Children with ASD is Increasing 52-57% taking psychotropic/ antiepileptic drugs Aman, et al. (2003) Oswald and Sonankar (2007) 32-74% using CAM Levy, et al. (2003) Hanson, et al. (2007) 030609 8 2
Issues in Choosing Medication Determining effectiveness Choice of target symptoms: core or associated Short versus long-term effects Balance between benefits and adverse effects Documenting change Target symptoms vary across children Variability within a child over time Current Status of the Field Many pharmacologic and CAM treatments have been proposed or tried There is one treatment that is FDA-approved for children with autism (risperidone) Some treatments have supporting scientific studies that demonstrate effectiveness for autism symptoms Some innovative treatment strategies reflect emerging scientific evidence Some treatments have scientific studies that demonstrate lack of effectiveness For many treatments, few or no studies 030609 9 030609 10 Current Status of the Field Beneficial effect or lack of effect? How can we determine which treatment fits in which category? We can begin with a systematic review of scientific literature. Comprehensive Review: Rationale Integrate existing information and support decision making Separate insignificant literature from salient studies Establish scientific consistency and generalizability Increase power and precision of estimates of treatment effects and exposure risks Limit bias and improve reliability/accuracy of conclusions 030609 11 030609 12 3
Research Questions How effective are pharmacologic and CAM interventions for children with ASD? Which interventions are useful for core symptoms of autism? Which interventions are useful for associated symptoms? What are adverse effects of medication? Approach Utilize stringent methodology Complete comprehensive search, applying clear inclusion/exclusion criteria to identified articles Review each study (2 independent reviewers) and assign quality rating (Scientific Merit Rating Scale score) Group studies by treatment and establish strength of evidence Develop evidence-based recommendations 030609 13 030609 14 Quality: Scientific Merit Rating Scale (SMRS) Scores Merit rating based on weighted domains Design (.30) Measurement of treatment effect/outcome (.30) Participant ascertainment (.15) Measurement of treatment (.15) Generalization of treatment effect (.10) SMRS score Very Poor Poor Weak Adequate Sound Rigorous Articles Identified in Search 85 Treatments 112 Articles Included in Review 27 CAM Treatments 841 Articles Identified as Potentially Relevant 114 Behavioral/Educational 729 Articles Excluded from Review 0 1 2 3 4 5 517 98 CAM 030609 15 030609 16 4
Included Medications 85 Articles on Medication Included CAM Treatment 27 Articles on CAM Treatment 29 Antipsychotic (Atypical) 15 Peptide Hormone 6 Dietary supplement: Vitamin 5 Dietary supplement: Protein/Amino Acid 11 Anti-depressant 7 Psychostimulant 1 Dietary supplement: Mineral 2 Dietary supplement: Hormone 7 Opioid antagonist 5 Anti-epileptic (Mood Stabilizer) 1 Dietary supplement: Digestive Enzymes 2 Dietary supplement: Fatty Acid 5 Anti-infective 3 Autonomic (Anti-Alzheimer) 6 Modified Diet 2 Neurofeedback 2 Anti-histamine 1 Anxiolytic 030609 17 1 Chelator 1 Oxygen 030609 18 Acceptable Evidence I Strongest Acceptable Evidence II Strong Insufficient Evidence I Early Investigation Insufficient Evidence II Unestablished Discredited Treatment I: Ineffective Discredited treatment II: Harmful Strength of Evidence Multiple acceptable studies (SMRS=5 or 4) with beneficial effects Multiple minimally acceptable studies (SMRS=3) with beneficial effects Few weaker studies (SMRS=2) with beneficial effects Very poorly controlled studies (SMRS=1 or 0) with beneficial effects OR Poorly controlled studies (SMRS=2, 1, or 0) with no beneficial effects or mixed effects or adverse effects Multiple acceptable/minimally acceptable studies (SMRS=5, 4, or 3) with no beneficial effects Multiple acceptable/minimally acceptable studies (SMRS=5, 4, or 3) with adverse effects and CAM: What Works? Acceptable evidence supporting clinical recommendations (Strongest/Strong) Core symptoms Associated symptoms Behavior problems Regulatory problems Insufficient evidence (Early Investigation/Unestablished) Discredited Treatment (Ineffective/Harmful) 030609 19 030609 20 5
Acceptable Evidence: ASD Core Symptoms Global Impaired social interaction Impaired communication Restricted repetitive behavior Strongest (atypical antipsychotic) Naltrexone (anti-opioid) Strong Atomoxetine/Tianeptine (anti-depressant, other) Escitalopram/Fluoxetine (anti-depressant, SSRI) Acceptable Evidence: ASD Behavior Problems General Hyperactivity Self-injury Aggression and oppositionality Strongest Methylphenidate (psychostimulant) Methylphenidate Strong Atomoxetine/Tianeptine Naltrexone Strongest = At least 2 acceptablestudies (SMRS=5 or 4) with beneficial effects Strongest = At least 2 acceptablestudies (SMRS=5 or 4) with beneficial effects Strong = At least 2 minimally acceptablestudies (SMRS=3) with beneficial effects 030609 21 Strong = At least 2 minimally acceptablestudies (SMRS=3) with beneficial effects 030609 22 Acceptable Evidence: ASD Regulatory Problems Strongest Strong Irritability/Anger Naltrexone Discredited Treatment: ASD Core Symptoms Ineffective Harmful Global Methylphenidate Emotional Lability Depression/Anxiety Sensory Abnormalities/ Self-stimulation Eating Problems Sleeping Problems GI Problems Methylphenidate Impaired social interaction Impaired communication Restricted repetitive behavior Ineffective = Multiple acceptable/minimally acceptable studies (SMRS=5, 4, or 3) with no beneficial effects Strongest = At least 2 acceptablestudies (SMRS=5 or 4) with beneficial effects Harmful = Multiple acceptable/minimally acceptable studies (SMRS=5, 4, or 3) with adverse effects 030609 Strong = At least 2 minimally acceptablestudies (SMRS=3) with beneficial effects 23 030609 24 6
Discredited Treatment: ASD Behavior Problems Discredited Treatment: ASD Regulatory Problems General Hyperactivity Aggression/ Oppositionality Self-injury DT/Ineffective DT/Harmful Irritability/Anger Emotional Lability Depression/Anxiety Sensory Abnormalities/ Self-stimulation Eating Problems Sleeping Problems GI Problems DT/Ineffective DT/Harmful Ineffective = Multiple acceptable/minimally acceptable studies (SMRS=5, 4, or 3) with no beneficial effects Harmful = Multiple acceptable/minimally acceptable studies (SMRS=5, 4, or 3) with adverse effects 030609 25 Ineffective = Multiple acceptable/minimally acceptable studies (SMRS=5, 4, or 3) with no beneficial effects Harmful = Multiple acceptable/minimally acceptable studies (SMRS=5, 4, or 3) with adverse effects 030609 26 Insufficient Evidence 1: Early Investigation Type and Class Autonomic (Anti-Alzheimer) Anti-depressant (SNRI; TCA) Autonomic (Anti-hypertensive) Anti-infective (Anti-microbial) Anti-infective (Anti-TB) Medications Galantamine Rivastigmine Venlafaxine Clomipramine Clonidine Guanfacine Propanolol Vancomycin Cycloserine Target Symptom Core symptoms; Impaired cognition Aggression Irritability Aggression; self-injury; hyperactivity Irritability Hyperactivity; self-injury Irritability; sleep problems Core symptoms Anxiolytic Buspirone Core symptoms Irritability Anti-infective (Immune enhancer) Immunoglobulin Core symptoms Hyperactivity GI symptoms Insufficient Evidence 1: Early Investigation CAM Type CAM Treatments Target Symptom Dietary supplement Dietary supplement Hormones -Melatonin Proteins/Amino Acids -Carnosine -Dimethylglycine (DMG) -Tetrahydrobiopterin (BH4) Sleep problems Core symptoms Impaired social interaction Dietary supplement Multi-vitamins Sleep problems; GI Problems Modified diet Gluten-free/Casein-free Depression/anxiety Oxygen Hyperbaric oxygen Core symptoms Impaired social interaction Mineral salt (Mood stabilizer) Lithium Aggression Irritability; emotional lability Early Investigation = Few weaker studies (SMRS=2) Early Investigation = Few weaker studies (SMRS=2) with beneficial effects 030609 with beneficial effects 27 030609 28 7
Insufficient Evidence 2: Unestablished Type and Class Medications Target Symptom Anti-infective (Anti-viral) Amantadine Behavior problem Regulatory problem Autonomic (Anti-Alzheimer) Memantine Behavior problem Regulatory problem Anti-depressant (SSRI) Fluvoxamine Core symptom Anti-depressant (NaSSA) Mirtazapine Behavior problem Regulatory problem Anti-epileptic (Mood stabilizer) Lamotrigine Levetiracetam Topiramate Valproate Behavior problem Regulatory problem Peptide Hormones ACTH analog Core symptoms Behavior problem Unestablished = Very poorly controlled studies (SMRS=1 or 0) with beneficial effects OR Poorly controlled studies (SMRS=2, 1, or 0) with no beneficial effects or mixed effects or adverse effects 030609 29 Insufficient Evidence 2: CAM Type CAM Treatments Target Symptoms Chelators Dimercaptosuccinic acid (DMSA) Core symptoms Dietary supplements Modified diets Digestive enzymes Fatty acids (fish oil, flaxseed oil) Minerals (magnesium, iron) Ketogenic Allergen-free Behavior problems Regulatory problems Core symptoms Behavior problems Regulatory problems Neurofeedback EEG biofeedback Core symptoms Behavior problems Immune enhancement Anti-fungal agents Colostrum Enzyme-potentiated desensitization Colloidal silver Garlic oil Probiotics Behavior problems Regulatory problems Behavior problems Regulatory problems Unestablished = Very poorly controlled studies (SMRS=1 or 0) with beneficial effects OR Poorly controlled studies (SMRS=2, 1, or 0) with no beneficial effects or mixed effects or adverse effects 030609 30 Summary: Medications and other atypical antipsychotics Acceptable evidence of benefit Improving core symptoms Decreasing behavior problems (hyperactivity, aggression) Decreasing regulatory problems (irritability) Adverse effects very common and limiting Somnolence Rhinitis, respiratory symptoms, dry mouth Increased appetite, unacceptable weight gain Naltrexone Acceptable evidence of benefit Improving core symptoms (general) Decreasing behavior problems (hyperactivity) Decreasing regulatory problems (irritability) Adverse effects Sedation Bitter taste, but patch now available and unstudied 030609 31 Summary: Medications Anti-depressants (SSRI) Acceptable evidence of benefit Improving core symptoms (repetitive behavior) Adverse effects Sedation Dry mouth, constipation Black box notice suicidality Anti-depressants (Other Atomoxetine, Tianeptine) Acceptable evidence of benefit Improving core symptoms (impaired social interaction) Decreasing behavior problems (hyperactivity) Adverse effects Sedation Loss of appetite Black box notice - suicidality 030609 32 8
Summary: Medications Methylphenidate Acceptable evidence of benefit Decreasing behavior problems (hyperactivity, aggression) Decreasing regulatory problems (irritability) Adverse effects Nervousness, insomnia Increased heart rate and blood pressure Loss of appetite Summary: CAM Treatments No published study of CAM treatments met criteria for acceptable evidence demonstrating beneficial effect 030609 33 030609 34 Conclusion Given rising numbers of documented autism, severity of symptoms, and frequency of pharmacologic medication/cam use, there is a notable lack of research Research Issues Randomized controlled trials: large samples with baseline measures Mixed interventions: behavioral + pharmacologic Practice-based evidence: using single-subject design methodology Collaboration of parents, child, and clinicians, with input from educators and therapists Specification of target outcomes and time frame Careful monitoring of effectiveness in multiple settings 030609 35 030609 36 9
Clinical Issues Use of single-subject design methodology Collaboration of parents and child, with input from educators and therapists Be willing to discontinue medication or CAM if not effective Minimize poly-pharmacy Reconsider medication at different developmental stages 030609 37 Project Background Stanford research team Lynne Huffman, MD, Principal Investigator Trenna Sutcliffe, MD, MSc Ima Tanner, BA Heidi Feldman, MD, PhD CA Department of Developmental Services and Napa County Office of Education Autistic Spectrum Disorders: Guidelines for Effective Interventions Project (2005) Systematic literature reviews and documentation Behavioral/educational interventions /CAM interventions www.asdguidelines.org 2009: planned public release of information 030609 38 Reflections and Questions 10