Integrating Treatment for Autism Spectrum Disorders Through the Life Cycle Robert L Hendren, DO Professor of Psychiatry and Behavioral Science Idaho Autism Summit November 2, 2019 Faculty Disclosure • Grants — Curemark, Roche, Otsuka • Advisory Board — Curemark, BioMarin, Janssen, Axial Biotherapeutics • Honoraria/Royalties: Oxford University Press, Taylor & Francis • Dr. Hendren does intend to discuss the use of off- label/unapproved use of drugs Learning Objectives • Identify successes and challenges in the developmental progression through the life cycle for people with developmental disabilities and their families • Identify and effectively treat comorbid medical, emotional and behavioral symptoms associated with autism spectrum disorders (ASD) • Consider integrating biomedical treatments for ASD including conventional psychotropic medication and what has been referred to as CAM/CIM into a comprehensive program. 2010 1 in 68; 2014 1 in 59 CDC Prevalence of Autism • Possible explanations include – Diagnostic expansion and substitution – Better reporting – Increased recognition – Increasing acceptability – Immigration for services – Environmental toxins – Infectious and immune vulnerability – Epigenetic processes Rutter M. Acta Pediatr. 2005;94(1):2-15. Centers for Disease Control and Prevention. Autism Spectrum Disorders. www.cdc.gov/ncbddd/autism. Accessed June 16, 2015. Hagerman R, Hendren RL (Eds). Treatment of Neurodevelopmental Disorders: Targeting Neurobiological Mechanisms. Oxford University Press; 2014. ASD Genetic Etiology (Levels 1 & 2) • Multiple genes: NRXN12q, 7q11.23, 15q11-13, 16p11.2, SHANK 3, 2, NLGN4, MTHFR 677>T, SEMA5A, 2Q22.1, GRIN2B, 5P14.1, CDH9, 10, FRX, PTEN • Identical twins: 60% to 90% – Fraternal twins: 0% to 36% – Siblings: 4% to 19% • Clear genetic etiology accounts for 25% of autism cases • Hundreds of genetic mutations, some de novo, lead to many ways to develop and treat autism • Is Precision Medicine Possible? Weiss KM, Issues Science and Technology in 2017 Levy D, et al. Neuron. 2011;70(5):886-897. Miles JH. Genet Med. 2011;13(4):278-294. Lossifov I, et al. Neuron. 2012;74(2):285-299. Murdoch JD, et al. Curr Opin Genet Dev. 2013;23(3):310-315. ASD and Environmental Risk • Documented: prenatal or early postnatal exposure to viral infections (rubella), valproic acid, thalidomide (Level 1) • Proposed: influence of mercury, lead, environmental toxins, vaccines, lack of vitamin D (Levels 3 & 4) • Parental age (older paternal and maternal; differences) (Level 1) • Maternal metabolic conditions (Level 2) • Influenza or fever during pregnancy (Level 2) • Environmental pollution (Level 2) Herbert MR. Curr Opin Neurol. 2010;23(2):103-110. Landrigan PJ. Curr Opin Pediatr. 2010;22(2):219- 225. Sandin S, et al. Mol Psychiatry. 2015;[Epub ahead of print]. Shelton JF, et al. Autism Res. 2010;3(1):30-39. Frans EM, et al. JAMA Psychiatry. 2013;70(5):516-521. Krakowiak P, et al. Pediatrics. 2012;129(5)e1121-e1128. Zerbo O, et al. J Autism Dev Disord. 2013;43(1):25-33. Schuler K, Institute for Agriculture and Trade Policy. www.iatp.org/files/2013_12_04_Autism_KS.pdf. Accessed June 16, 2015. Model for Autism Etiology • First hit – Genetic neurodevelopmental vulnerability • Second hit – Environmental “stressor” and interaction between the two • Third hit – Restricted development Translating from “Terroir”: Model Epigenetic Layer to Targeted Treatment Level 4 Level 3 Level 2 Level 1 Hagerman R, Hendren RL (Eds). Treatment of Neurodevelopmental Disorders: Targeting Neurobiological Mechanisms. Oxford University Press; 2014. Gene-Environment Interactions and Epigenetic Processes (Level 2) Immune abnormalities/ Oxidative stress Disturbed methylation inflammation Mitochondrial Free fatty acid Excitatory/inhibitory dysfunction metabolism imbalance Hormonal effects Microglia/Astrocytes Microbiome Goines P, et al. Curr Opin Neurol. 2010;23(2):111-117. James SJ, et al. Am J Clin Nutr. 2009;89(1):425-430. Frye RE, et al. Pediatr Res. 2011;69(5 Pt 2):41R-47R. Manji H, et al. Nat Rev Neurosci. 2012;13(5):293-307. Bell JG, et al. Br J Nutr. 2010;103(8):1160-1167. Rubenstein JL. Curr Opin Neurol. 2010;23(2):118-123. Harony H, et al. Neurosignals. 2010;18(2):82- 97. Cunningham CL. J Neurosci. 2013;33(10):4216-4233. Autism Through the Life Cycle Brain Growth and Development • Parental history and early developmental experiences also exert effects through epigenetic information not contained in the DNA sequence, which cause changes in gene expression – methylation and chromatin patterning – Histone acetylation – noncoding RNAs and mitochondria • Transgenerational epigenetic effects interact with conditions at conception to program the developmental trajectory of the embryo and fetus, ultimately affecting the lifetime health of the child Wells et al, 2016; Lane M, et al. Science. 2014;345(6198):756-760. Brain Growth and Development • We searched the MEDLINE database for studies published between January 1, 2005 and July 1, 2018 for perinatal risk factors and autism, risk factors such as infections, medications, and environmental factors including non-chemical stressors, chemical and nutritional factors. Then, we searched for interventions that may improve neurodevelopmental outcome including nutritional supplements during pregnancy, breastfeeding, and postpartum stress reduction. • Our review, in agreement with other reviews, supports the possibility that interventions to normalize or mitigate these processes, particularly in the preconception or perinatal period, could lead to resilience and health in the developing and newborn child. Cheng…Hendren, Medical Hypothesis, 127 (2019) 26-33 Hertz-Picciotto et al, 2018, Wang et al, 2017, Getahun et al., 2017, Hisle-Gorman et al., 2018 Pregnancy Autism Risk (Grade B Mod) • Maternal Infection and Inflammation (congenital rubella) • Environmental Toxicants (methylmercury, PCBs, Toluene, Arsenic) • Air Pollution • Pesticides • Bisphenols and Phthalates • Valproic Acid • Thalidomide • SSRIs • Acetaminophen • Heavy Metals Atladottir et al., 2010; Ornoy et al, 2016; Muzhe & Chou, 2017; Eskenazi et al, 2008; Kondolot et al, 2016; Christensen et al. 2013; Croen et al, 2011; Bourkhris et al, 2016; Avella-Garcia CB et al, 2016; Kern 2016 Can Autism be Prevented? (Grade C Mod) • Folic Acid and multivitamin Supplements before and during pregnancy associated with reduced risk of ASD (45,300 children; P<.001) • Omega -3 Polyunsaturated Fatty Acid • Vitamin D • Antioxidants • Iron • Choline/phosphatidylcholine • One practice minimized toxicant exposure; maximized breastfeeding; probiotics, nutritional counseling; limited antibiotics; minimized acetaminophen – Out of 294 general pediatric patients followed since 2005 there were 0 new cases of autism Levine SZ et al., 2018; Suren et al., 2013; Morgese & Trabace, 2016; Stubbs et al., 2016; Zhang et al, 2015; Schmidt et al., 2014; Ross et al, 2016; Mumper E. North American Journal of Medicine and Science. 2013;6(3):134-144 P2i – Preconception to Infancy • Goal is to establish a program that reduces miscarriages and helps ensure infants a healthy start in life • www.ForumP2i.com • University of Georgia Center for Excellence • Be Fruitful: The Essential Guide to Maximizing Fertility and Giving Birth to a Healthy Child, Victoria Maizes, MD, Scribner, NY, 2013 Early Intervention The majority of research and clinical programs are targeted at younger children where neurodevelopmental processes are more plastic Parental Concerns, Provider Response, and Timeliness of ASD Dx • Compared with children with ID/DD, children with ASD were younger when parents first had concerns and first discussed those concerns with a provider • Compared with parents of children with ID/DD, parents of children with ASD were less likely to receive proactive responses to their concerns and more likely to receive reassuring/passive responses • Among children with ASD, those with more proactive provider responses to concerns had shorter delays in ASD diagnosis compared with those with passive/reassuring provider responses • Although parents of children with ASD have early concerns, delays in diagnosis are common, particularly when providers’ responses are reassuring or passive, highlighting the need for targeted improvements in primary care ID/DD = intellectual disorder/developmental disorder. Zuckerman KE, et al. J Pediatr. 2015;166(6):1431-1439.e1. Later Intervention Is late adolescence and young adulthood too late to intervene? Development in ASD in Adolescence (Levels 2 & 3) • Microstructure of the thalamus, a key sensory and motor brain area, appears to develop differently in individuals with autism spectrum disorder with differences narrowing with age. • PEERS social skills treatment improves particular aspects of emotional, behavioral, and social functioning that may be necessary for developing and maintaining quality peer relationships and remediating social isolation in adolescents with ASD. Ecker C, et al. Lancet Neurol. 2015;S1474-4422(15)00050-2. Lainhart JE. Curr Opin Psychiatry. 2015;28(2):76-82. McLaughlin K et al, Autism Res. 2017; N Lordo D, J Autism Dev Disord. 2017 47(1):203-214. Postsecondary Employment Experiences among Young Adults with ASD • Approximately one-half (53.4%) of young adults with ASD had ever worked for pay outside the home since leaving high school, the lowest rate among disability groups • Young adults with an ASD earned an average of $8.10/hour, significantly lower than average wages for young adults in the comparison groups, and held jobs