Advances in the Treatment of Autism Spectrum Disorders

1. Susan E. Swedo, M.D. Chief, Pediatrics & Developmental Neuroscience Branch National Institute of Mental Health National Institutes of Health Department of Health & Human Services Advances in the Treatment of Autism Spectrum Disorders

2. Social Deficits Communication Deficits Repetitive Behaviors & Restricted Interests Core Symptom Domains of Autism

3. Social Deficits Repetitive Behaviors & Restricted Interests Communication Deficits Core Symptoms + Associated Features Anxiety and other symptoms Behavioral Problems Many Others Receptive & Expressive Language Deficits Neurologic Signs & Symptoms Motor & Sensory Issues Intellectual Disability Feeding Problems Sleep Problems

4. Co-occurring Conditions Genetic Disorders GI Disorders Epilepsy Immune Dysfunction Sleep Disorders AUTISM SPECTRUMDISORDERS ADHD +/- Learning Disabilities OCD & Other Psychiatric Disorders Multitude of Possibilities

5. Therapeutic Interventions for Autism – Behavioral, Educational & Others • Applied Behavior Analysis (ABA) • Animal Therapy • Art Therapy • Auditory Integration Therapy Tomatis, Berard, Fast Forward and Earobics • Augmentative & Alternative Comm. • Bonding (Attachment) Therapies • Developmental Therapies (e.g. SCERTS) • Developmentally-based Individual-difference Relationship-based Intervention (DIR) Floor time; Greenspan Method • Early Intensive Behavioral Intervention Rx Early Start Denver Model • Facilitated Communication • Holding Therapy • Music Therapy • Oral-Motor Training Kaufman, PROMPT • Patterning • Picture Exchange Communication System (PECS) • Project TEACCH (Treatment & Education of Autistic and Related Communication-Handicapped Children) • Psychoanalytic & Humanistic Play Therapy • Rapid Prompting Method (RPM) • Recreational Sports/Exercise • Relationship Development Intervention (RDI) • Sensory Integrative Therapy • Sensory-motor Therapies • Socialization related Classes • Social Skills Groups • Social Stories • Video modeling • Vision Therapy Irlen lenses, glasses, eye exercises, rapid eye therapy, ambient lenses, yoked prisms

6. Therapeutic Interventions for Autism – Biomedical, Dietary and Pharmcotherapy • Anti-fungal medications • Chelation Therapy • Craniosacral Therapy • Herbs & Natural Interventions • Homeopathic Treatments • Hyperbaric Oxygen Therapy • Magnets • Probiotics & Prebiotics • Secretin and other hormone • Special Diets • Allergen-free (e.g. dye-free) • Gluten -free • Casein-free • Gluten & Casein free (GfCf) • Specific Carbohydrates • Specialized & Individualized • Vitamin and Supplement Therapy • Vitamin A • Vitamin B6 • Vitamin B12 • Vitamin C • Vitamin D • Magnesium • Dimethylglycerine (DMG) • Calcium • Omega 3 Fatty Acids • Pharmacotherapy • Risperidone & dopaminergic agents (for aggression and disruptive behaviors) • SSRI’s (for RRB’s and anxiety) • Methylphenidate & Stimulants (for ADHD sx’s) • Others – e.g. Pathyway-targeted medications such as mGluR5 blockers

7. Therapeutic Interventions –What is the target? • Core symptoms of autism • Associated features of autism • Co-occurring conditions

8. Social Deficits Communication Deficits Repetitive Behaviors & Restricted Interests Core Symptom Domains

9. Therapeutic Interventions Targeting Core Symptoms of ASD • What is success? • No social communication deficits and no impairments from restricted interests, repetitive behaviors – “cure” • Improvements are also beneficial, but require objective, valid, reliable and feasible assessments across various ages, developmental stages and cognitive functioning. • Difficult to measure gains in function • “Optimum functioning” (i.e. 100% improvement) is unknown • Natural (untreated) history may have been equivalent • Particularly problematic for Early Intervention studies since they are done during period of maximal developmental gains • Lack of improvements may be due to an unrelated, intervening events or acquired condition (e.g., epilepsy) • Need for controlled trials that can produce generalizable results • Ethical concerns about withholding beneficial treatments • Feasibility constraints (expensive, time-consuming, difficult to design and implement, recruitment and retention are challenging)

10. Behavioral Interventions Targeting the Core Symptoms of ASD • Widely used with numerous reports of benefit – especially when started early. • Variety of approaches are being used, with ABA appearing to have the greatest support from clinicians and community. • Surprisingly, only two RCTs have been done for behavioral interventions (one for ABA and one for the Early Start Denver Model). The remaining literature consists of case series and single case reports; most of which contain insufficient information to judge true benefits of the intervention. (Reviewed by Warren et al, Pediatrics, on-line publication on 4/4/11) • It may be too late to conduct controlled trials of the various behavioral interventions, given current ethical concerns and feasibility constraints. However, comparison trials may be useful in providing • Information about superiority of one approach against another • Determining predictors of response/lack of response • Identifying therapies that provide the greatest benefit:cost ratio

11. Biomedical Interventions Targeting the Core Symptoms of ASD • Open-label trials are often reported to be helpful, but controlled trials fail to demonstrate benefits or superiority over placebo • Secretin – dozens of cases reported to have received benefit (in many different settings). However, a double-blind, placebo-controlled trial proved negative. • Hyperbaric Oxygen Therapy (HBOT) – also reported to be helpful in open-label case series. However, several placebo-controlled trials recently failed to demonstrate significant benefits Lerman 2008; Rossignol 2009 (one behavioral rating was positive); Granpeesheh 2010; Jepson 2011 • Theoretical basis for the interventions is sometimes unclear, but active area for novel proposals and research.

12. Biomedical Interventions Targeting the Core Symptoms of ASD • Dietary interventions • Typically involve restriction of certain foods or class of foods (e.g. GfCf diet; Specific carbohydrate diet, etc) • Requires careful attention to nutritional status of the child in order to avoid diseases related to dietary deficiencies, such as rickets, anemia, failure to thrive and others • Vitamins and supplements • Theoretically quite interesting, given the key role that various vitamins and minerals play in neuronal functions. • However, caution is warranted even with “natural” compounds, as toxicity can result from unbalanced excesses. • E.g., Neurotoxicity from pyridoxine (Vitamin B6) excess produces sensory neuropathies (manifest as hyper-/hypo-sensitivities)

13. Pharmacological Interventions Targeting the Core Symptoms of ASD • Social Communication Deficits • Oxytocin – • One case series and a small RCT demonstrated benefits on some components of social communication. • Short half-life and difficulty getting drug into brain limit utility at present. • Additional trials with syntocin are underway, including an NIMH study using fMRI to assess prosocial effects of oxytocin and vasopressin vs. placebo. • Restricted interests and repetitive behaviors • SSRI’s – Positive open-label reports but to date, evidence for benefit is insufficient to support use (McPheeters et al, Pediatrics, on-line publication on 4/4/11) • Risperidone and aripiprazole – Significantly greater reduction in troublesome, repetitive behaviors with active drugs than placebo, but significantly more adverse effects as well. Risk:benefit ratio is not clearly positive, particularly given that both medications put children at risk of chronic problems with metabolic syndrome.

14. Novel Pharmacologic Targets for ASD • Glutamate • Amantadine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, was found to be effective for some symptoms in young autistic subjects in a small RCT. • D-cycloserine, a partial NMDA agonist, produced significantly greater symptom improvements than placebo in a small group of children with autism, including changes in a core symptom, social responsiveness. • Lamotrigine, a drug that reduces glutamate release, was not significantly better than placebo. • Riluzole, a drug that reduces glutamatergic effects via inhibition of its release (among other mechanisms), has proven benefits for repetitive behaviors in childhood-onset OCD and is currently being tested in a double-blind, placebo-controlled trial at NIMH.

15. Treatment of the Core Symptoms of ASD -- Exciting News about Glutamatergic Therapies • Studies of Fragile X - • Genetic defect of X chromosome which results in abnormalities of the metabotropic glutamate receptor (mGluR) • Neurodevelopmental disorder characterized by intellectual disabilities and variety of neuropsychiatric symptoms, including autistic behaviors • Studies in animal models revealed striking improvements in core deficits associated with down-regulation of the mGluR5 receptor • Pilot studies of mGluR5 antagonists are underway

16. Social Deficits Repetitive Behaviors & Restricted Interests Communication Deficits Core Symptoms + Associated Features Anxiety and other symptoms Behavioral Problems Many Others Receptive & Expressive Language Deficits Neurologic Signs & Symptoms Motor & Sensory Issues Intellectual Disability Feeding Problems Sleep Problems

17. Treatment of the Associated Features of ASD • Much more progress in this area than for core symptoms • Better measures of change • Lessons learned in other disorders apply in ASD • Can have major impact on the overall functioning of the affected individuals and sometimes, improvements are seen in core symptoms in association with Rx of associated sx’s. • Reported treatment benefits for: • Anxiety – SSRI’s have documented benefits (Start low & go slow!) • Feeding problems – Behavioral techniques and attention to sensory issues can produce dramatic improvements • Behavioral problems – • Risperdol and other atypical antipsychotics for aggression and irritability • Hyperactivity – Stimulant medications better than placebo and recent RCT suggests Omega-3 fatty acids may be of benefit Bent et al, J Autism Dev Disord2011; 41:545-554.

18. Rxfor Sleep Disturbances Associated with ASD • Sleep problems reported in association with ASD • Initial insomnia (trouble falling asleep) • Middle insomnia (waking in the night) • Terminal insomnia (waking up too early in the morning) • Parasomnias (nightmares, night terrors, sleepwalking, etc) • Decreased need for sleep (?) • Sleep problems found in NIMH Subtyping study • Sleep difficulties weren’t reported frequently by parents of children (ages 2-5 yrs) in the study. • Polysomnography revealed abnormalities in most children • Decreased sleep efficiency (decreased time spent sleeping) • Prolonged latency to REM sleep • Decreased total time spent in REM sleep • Increased time spent in slow wave sleep AW Buckley et al, Arch PediatrAdolesc Med 2010; 164(11):1032-1037.

19. Results of Sleep Studies at NIMH Administration of donepezil (Aricept) normalizes %REM sleep in ASD (Pilot data from dose finding study with 1.25, 2.5 and 5mg per day)2 Children with autism have significantly decreased %REM, compared with children with typical or delayed development (DD)1 Data provided by Ashura W. Buckley, M.D. – NIMH and NYU Child Study Center 1Arch Pediatr Adolesc Med 2010; 164(11):1032-1037; 2 Under review; personal communication 4/11.

20. Co-occurring Conditions Genetic Disorders GI Disorders Epilepsy Immune Dysfunction Sleep Disorders AUTISM SPECTRUMDISORDERS ADHD +/- Learning Disabilities OCD & Other Psychiatric Disorders Multitude of Possibilities

21. Advances in Rx of Co-Occurring Conditions • Significant improvements in recognition of co-occurring medical and psychiatric conditions • GI Disorders – particularly GE reflux (Buie) • Immunologic disorders (Pardo, VanDeWater, Ashwood and others) • Sleep disorders and epilepsy • ADHD, anxiety and other psychiatric disorders • Treatment of co-occurring conditions is essential to minimizing impairment and maximizing outcome • Formation of Autism Treatment Network (ATN) has focused attention on providing a competent “medical home” for individuals with ASD • Collaborations between PDN and ATN sites allow for rapid translation of pilot study data into efficacy and effectiveness trials, as well as providing for “proof of concept” studies (e.g., assessment of sleep disorders)