Olaf Kraus de Camargo@DevPeds

Update on ASD Research

April 25th 2016

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DisclaimerThis is a biased selection based on my

non-systematic readings, clinical practice and small involvement in some of the

studies without any financial gains

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First: some definitions!• Statistically Significant: usually means that the chance that an observed effect is related to an

intervention is at least 95% - it does not tell if this effect is big or small!• Clinically Significant: describes how meaningful is the effect• Evidence level: refers to the type of studies done to describe a certain effect and the likelihood that

the results can be trusted.• Randomized: it is a lottery to determine which child gets which treatment• Double-blind: neither patient/caregiver nor experimenter knows who is being treated

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Causes for ASD

Bourgeron, T., 2015. The genetics and neurobiology of ESSENCE: The third Birgit Olsson lecture. Nord. J. Psychiatry 9488, 1–9. doi:10.3109/08039488.2015.1042519

Genetic: 600 -700 candidate genetic alterations

“The recent advances in genomics have demonstrated that an identical genetic variant may increase the risk for a wide range of diagnoses formerly thought of as distinct”

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ASD & Genes

Bourgeron, T., 2015. The genetics and neurobiology of ESSENCE: The third Birgit Olsson lecture. Nord. J. Psychiatry 9488, 1–9. doi:10.3109/08039488.2015.1042519

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ASD & Genes &…...

Zhao, Y., Castellanos, F.X., 2016. Annual Research Review: Discovery science strategies in studies of the pathophysiology of child and adolescent psychiatric disorders: promises and limitations. J. Child Psychol. Psychiatry n/a–n/a. doi:10.1111/jcpp.12503

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ASD & Prematurity

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ASD & Prematurity

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International Classification of Functioning, Disability and Health (WHO)

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Research Domain Criteria (NIH)

Domain Genes Cells Circuits Physiology Behaviour SelfReport Paradigm

Negative Valence Systems

Positive Valence Systems

Cognitive Systems

Systems for Social Processes

Arousal and Regulatory Systems

Environment

Dev

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https://www.nimh.nih.gov/research-priorities/rdoc/index.shtml

Body Functions and Body StructuresActivities and Participation

Environmental Factors

Omega-3-fatty acid supplementation

“To date there is no high quality evidence that omega-3 fatty acids supplementation is effective for improving core and associated symptoms of ASD.”

Two double-blind randomized trials - 37 patients

2011

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Gluten-free, Casein-free Diet

“Evidence to date on the effectiveness of gfcf-d for children with ASD has been inconclusive due to methodologic limitations. Preliminary data suggest there may be a subgroup of children with ASD who respond to a gfcf-d.”

Many low quality studies, only two double-blind randomized trials

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Social Groups

“There is some evidence that social skills groups can improve social competence for some children and adolescents with ASD.”

Five randomized controlled studies, only children and adolescents with IQ > 70 (196 participants)

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Risperidone

“There is some limited evidence of efficacy of risperidone reducing aggression and conduct problems in children aged 5 to 18 with disruptive behaviour disorders in the short term.

For aggression, the difference in scores of 6.49 points on the ABC Irritability subscale (range 0 to 45) may be clinically significant. For conduct problems, the difference in scores of 8.61 points on the NCBRF-CP (range 0 to 48) is likely to be clinically significant.”Eight randomized controlled trials, over 200

patients 14

Melatonin

“Melatonin administration in ASD is associated with improved sleep parameters, better daytime behavior, and minimal side effects.”

Five randomized double-blind studies

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IBI“We found that children receiving the EIBI treatment performed better than children in the comparison groups after about two years of treatment on tests of adaptive behavior (behaviors that increase independence and the ability to adapt to one’s environment), intelligence, social skills, communication and language, autism symptoms, and quality of life. The evidence supports the use of EIBI for some children with ASD. However, the quality of this evidence is low as only a small number of children were involved in the studies and only one study randomly assigned children to groups.”

One randomized trial, four non-randomized trials, 203 children

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Joint Attention

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• Analyzed 16 studies• About 750 children• Different approaches were analyzed

(behavioural and developmental)• No RCT’s

Joint Attention

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• The results of this meta-analysis provide strong support for explicit joint attention interventions for young children with ASD with most comparisons showing a statistically significant 2/3 standard deviation treatment effect increase for the experimental group compared with the control/comparison group.

• No specific type of approach was superior

Research at Mac & HHS

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• Riluzole: is a substance that reduces the action of glutamate on synapses in the brain

• Has been proposed in ALS, Alzheimer, Depression, Anxiety

• Has been used in a multi-site trial in adolescents with ASD

• Data collection is finished, Analysis is in progress

Research at Mac & HHS

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• Tideglusib: is a substance that reduces the action of an enzyme (GSK-3β) identified as modulating pathways and reversing symptoms in animal models of fragile-X and congenital myotonic dystrophy

• Recruitment is ongoing (multi-site trial): 12-17 years old with ASD

• Double-blind, placebo-controlled, randomized study

Research at Mac & HHS

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Research at Mac & HHS

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• Why is this important?• Is a meaningful concept for ASD as it focusses on a core symptom (not IQ)

• Better description of level of functioning

• Opens the possibility to compare data from different studies

• Will help to identify what works for which children and what does not work!

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Conclusion• Different types of lesions and exposures to the

brain can result in similar behavioural manifestations

• Despite decades of high level basic research we still lack effective treatments for the majority of children with ASD

• ASD is an example for a spectrum condition - case-control studies are difficult to replicate – need for better description of study populations

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Conclusion• Understanding complex systems requires

“explorative science” (Big Data)• Effective treatment of spectrum conditions

requires a personalized approach• Future developments will depend on close

cooperations between basic sciences, clinical research, clinical practice and patients with their families

macautism.ca

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References1.Bourgeron, T., 2015. The genetics and neurobiology of ESSENCE: The third Birgit Olsson lecture. Nord. J. Psychiatry 9488, 1–9.

doi:10.3109/08039488.2015.10425192.Zhao, Y., Castellanos, F.X., 2016. Annual Research Review: Discovery science strategies in studies of the pathophysiology of child

and adolescent psychiatric disorders: promises and limitations. J. Child Psychol. Psychiatry n/a–n/a. doi:10.1111/jcpp.125033.Kuzniewicz, M.W., Wi, S., Qian, Y., Walsh, E.M., Armstrong, M.A., Croen, L. a., 2014. Prevalence and neonatal factors associated

with autism spectrum disorders in preterm infants. J. Pediatr. 164, 20–25. doi:10.1016/j.jpeds.2013.09.0214.Webb, S.J., 2014. Neonatal factors associated with autism spectrum disorders in infants. Evid. Based. Ment. Health 17, 106–106.

doi:10.1136/eb-2014-1017635.James, S., Montgomery, P., Williams, K., 2011. Omega-3 fatty acids supplementation for autism spectrum disorders (ASD).

Cochrane Database Syst Rev Cd007992. doi:10.1002/14651858.CD007992.pub26.Reichow, B., Barton, E.E., Boyd, B.A., Hume, K., 2012. Early intensive behavioral intervention (EIBI) for young children with autism

spectrum disorders (ASD). Cochrane Database Syst Rev 10, Cd009260. doi:10.1002/14651858.CD009260.pub27.Dosman, C., Adams, D., Wudel, B., Vogels, L., Turner, J., Vohra, S., 2013. Complementary, holistic, and integrative medicine:

autism spectrum disorder and gluten- and casein-free diet. Pediatr Rev 34, e36–41. doi:10.1542/pir.34-10-e368.Reichow, B., Steiner, A.M., Volkmar, F., 2013. Cochrane review: social skills groups for people aged 6 to 21 with autism spectrum

disorders (ASD). Evid Based Child Heal. 8, 266–315. doi:10.1002/ebch.19039.Reichow, B., Barton, E.E., Boyd, B.A., Hume, K., 2012. Early intensive behavioral intervention (EIBI) for young children with autism

spectrum disorders (ASD). Cochrane Database Syst Rev 10, Cd009260. doi:10.1002/14651858.CD009260.pub210.Loy, J.H., Merry, S.N., Hetrick, S.E., Stasiak, K., 2012. Atypical antipsychotics for disruptive behaviour disorders in children and

youths. Cochrane Database Syst Rev 9, Cd008559. doi:10.1002/14651858.CD008559.pub211.Rossignol, D.A., Frye, R.E., 2011. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med

Child Neurol 53, 783–792. doi:10.1111/j.1469-8749.2011.03980.x12.Wainer, A.L., Hepburn, S. & McMahon Griffith, E., 2016. Remembering Parents in Parent-Mediated Early Intervention: An

Approach to Examining Impact on Parents and Families. Autism, March 7(Online), pp.1–13.13.Murza, K.A. et al., 2016. Joint attention interventions for children with autism spectrum disorder: a systematic review and meta-

analysis. International Journal of Language & Communication Disorders, p.n/a–n/a.

Collection of ASD papers: https://www.mendeley.com/groups/8628801/asd/