Hostname: page-component-7c8c6479df-r7xzm Total loading time: 0 Render date: 2024-03-29T05:03:25.481Z Has data issue: false hasContentIssue false

Emerging concepts in therapies for autism spectrum disorder

Commentary on… Drug Treatment of Autism Spectrum Disorder and its Comorbidities in Children and Adolescents

Published online by Cambridge University Press:  02 January 2018

Rights & Permissions [Opens in a new window]

Summary

Autism spectrum disorder (ASD) is a heterogeneous disorder with clearly recognisable core features, but without reliable biomarkers as yet. It has a high rate of comorbid psychiatric disorders which need to be identified and appropriately treated. Emerging concepts in genetics, pathobiology and outcome measurement have potential to significantly advance the treatment of both ASD and its comorbidities over the following decades.

Type
Commentary
Copyright
Copyright © The Royal College of Psychiatrists 2016 

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with no established biomarkers. The condition brings with it high morbidity and cost to the individual, their family and services (Reference Buescher, Cidav and KnappBuescher 2014). Santosh & Singh (2016, this issue) give a timely review of the evidence for therapies in ASD. ASD has associated psychiatric comorbidities with aggregated rates estimated at 72–94% and these have a significant impact on adaptive function (Reference Simonoff, Pickles and CharmanSimonoff 2008; Reference Mattila, Hurtig and HaapsamoMattila 2010). It is important to correctly identify common co-occurring conditions, including attention-deficit hyperactivity disorder (ADHD), behaviour that challenges owing to aggression, oppositional defiant disorder (ODD), anxiety disorders, depression and obsessive–compulsive disorder (OCD). The prescription of psychotropic medication to individuals with ASD has been increasing over the past decade, and it has been estimated that approximately one-third of patients (aged 0–24 years old) with the disorder in the UK now receive it (Reference Murray, Hsia and GlaserMurray 2014). National Institute for Health and Care Excellence (NICE) guidelines and quality standards on ASD in children and young people state that antipsychotic medication should be considered for managing challenging behaviour if behavioural interventions are insufficient or could not be delivered because of the severity of symptoms (Reference Kendall, Megnin-Viggars and GouldKendall 2013). The clinical equipoise in ASD is such that data are often extrapolated from studies of other psychiatric or neurodevelopmental disorders and, as highlighted by Santosh & Singh, more trials for the treatment of comorbidities in ASD itself are required.

Syndromic ASD: guidance for future therapies

Santosh & Singh also stress that the development of therapies has been hindered because specific biomarkers have not yet been identified for the classic ASD phenotypes. Developmental synaptopathies are an example of a group of rare genetic disorders of syndromic ASD and intellectual disability that converge on common pathways involved in synaptic development and signalling (Reference De Rubeis, He and GoldbergDe Rubeis 2014; Reference Pinto, Delaby and MericoPinto 2014; Reference Ebrahimi-Fakhari and SahinEbrahimi-Fakhari 2015). Despite the heterogeneity in ASD, patients present with characteristic impairments (American Psychiatric Association 2013). Tuberous sclerosis complex (mutations in the TSC1 or TSC2 gene), Phelan–McDermid syndrome (SHANK3 gene) and PTEN hamartoma tumour syndrome (PTEN gene), which cause syndromic ASD, exemplify this rare disease group, collectively responsible for less than 1% of cases of ASD with or without intellectual disability. These conditions share common genetic and molecular pathways. The study of these synaptic abnormalities has allowed the identification of potential therapeutic targets. For example, excessive signalling of the protein ‘mammalian target of rapamycin’ (mTOR) has been found to explain the molecular basis of tuberous sclerosis complex. Behavioural and molecular abnormalities in TSC-deficient mice are reversible by treatment with mTOR inhibitors such as everolimus (Reference Tang, Gudsnuk and KuoTang 2014). Similar studies of molecular pathways have shown insulin-like growth factor 1 (IGF-1) to be a candidate therapy in SHANK3 mouse models (Reference Shcheglovitov, Shcheglovitova and YazawaShcheglovitov 2013) and rapamycin in PTEN mouse models (Reference Butler, Dasouki and ZhouButler 2005; Reference Zhou, Blundell and OgawaZhou 2009; Reference Conti, Condo and PosarConti 2012). The Genomics England 100,000 Genomes Project is likely to identify more children with mutations contributing to syndromic ASD (such as the SYNGAP1 gene, and the neuroligin genes). By further characterising the neurodevelopmental phenotype of syndromic ASD, biomarkers and surrogate markers may be developed that help predict risk for symptom severity and response to treatment. Overlapping pathophysiology would suggest that treatments developed for one condition may be translatable to others. This knowledge may eventually be beneficial in translating therapies to ‘idiopathic’ ASD.

Environment, the immune system and the microbiome: implications for therapies in ASD

Santosh & Singh note that several papers have indicated that genetic predisposition and environmental factors might be among the mechanisms underlying the pathophysiology of ASD. There is indeed a growing interest, for example, in the role of the immune system in the neurobiology of the disorder. Genome-wide expression studies and post-mortem brain analysis indicate abnormalities in immune system gene transcripts in patients with ASD (Reference Lintas, Sacco and PersicoLintas 2012). Animal and initial human point to activation and active inflammation of microglia (resident central nervous system macrophage cells) in ASD (Reference Zhan, Paolicelli and SforazziniZhan 2014). There has also been an increasing interest in activation of the maternal immune system and childhood ASD (Reference Knuesel, Chicha and BritschgiKnuesel 2014). Vitamin D, a hormone with increasingly recognised immunomodulatory effects on disease, has also been implicated as having a role in ASD (Reference Mostafa and Al-AyadhiMostafa 2012; Reference Patrick and AmesPatrick 2014). Small case–control studies investigating the intestinal microbiome in people with ASD compared with healthy controls have reported differences, including increased clostridial species, which may result from a number of environmental factors, such as antibiotic usage and improved sanitation. The microbiome is postulated to make a significant contribution to the immune function of individuals, and hence therapies aimed at improving intestinal health may have an effect on symptoms (Reference BuieBuie 2015).

Although the study of the contributions of environment, the immune system and the microbiome in ASD is at a very early stage, the identification of potentially suitable biomarkers in a subset of patients with ASD may guide future developments for disease monitoring and therapeutics.

Pharmacogenetics and ASD

The article by Santosh & Singh also illustrates challenges faced by clinicians in identifying treatments that have suitably balanced safety and efficacy profiles for treating comorbid psychiatric disorders. Specific adverse drug reactions have been reported commonly in young people with ASD receiving psychotropic medication, and there is evidence that young people with ASD may have more frequent and troubling adverse drug reactions (Reference Owley, Brune and SaltOwley 2010). Dosing is complicated by the fact that there appears to be no relationship between weight and effective dose, and only a weak correlation between age and effective dose.

Pharmacogenetics can show how genetic determinants affect an individual's response to a medication. Applying its techniques has the potential, on an individual level, to achieve better response to prescribed medicines and lessen the risk of adverse drug reactions. At the population level, it will increase the risk–benefit ratio associated with this widely used group of drugs. The application of pharmacogenetics in psychiatry is gaining increasing interest (Reference Hawcutt, Thompson and SmythHawcutt 2013), but it has yet to be shown whether pharmacogenetics offers meaningful advantages over clinical titration in psychiatric conditions. A position paper by the European Medicines Agency (Committee for Medicinal Products for Human Use 2013) recommends that further trials are conducted in order to guide the use of medication in young people in ASD. Small studies in which physicians used pharmacogenetic tests to guide their prescribing of psychotropics for various disorders have reported improved treatment efficacy and reduced adverse drug reactions, but the beneficial effects of testing have been inadequately studied in larger groups or specifically in patients with ASD and psychiatric comorbidities. Pharmacogenetic testing is hence rarely used in clinical practice in the UK. A recent genome-wide association expression study (Reference Malhotra, Correll and ChowdhuryMalhotra 2012) assessing weight gain associated with 12 weeks of antipsychotic treatment implicates the MC4R gene in extreme weight gain and related metabolic disturbances. A priori identification of patients at high risk of such drug side-effects could be beneficial in clinical practice.

Treatment of core ASD features

Finally, as emphasised by Santosh & Singh, there is a lack of effective treatments for the core symptoms of ASD and a need for a range of interventions. Effective interventions early in life may make long-term differences in the trajectory of the condition. Sulforaphane, for example, has been shown in a recent double-blind placebo-controlled randomised trial (n = 44, randomisation roughly 2:1, White males aged 13–27 years) to target core clinical features (social responsiveness) with a very favourable safety profile (Reference Singh, Connors and MacklinSingh 2014). Larger confirmatory trials are needed.

Conclusions

Autism spectrum disorder is a common neurodevelopmental disorder that affects adaptive functioning from early childhood and is associated with a high rate of neuropsychiatric comorbidity. Given that there are likely to be ASD-specific differences in therapeutic response, high-quality evidence for treatment of psychiatric comorbidity such as anxiety is still needed from both pharmacological trials and well-controlled trials of psychological therapies. In addition, as a result of breakthroughs in technology, biology and the genetics of ASD, there has been an increasing interest in therapies for core ASD features. Recent interest in objective outcome measures, including advancement of the field of ASD biomarkers, has potential to benefit the design of ASD clinical trials.

Footnotes

See pp. 151–161, this issue.

DECLARATION OF INTEREST

None

References

American Psychiatric Association (2013) Neurodevelopmental disorders. In Diagnostic and Statistical Manual of Mental Disorders (5th edn) (DSM-5): 31-86. American Psychiatric Association.Google Scholar
Buescher, AV, Cidav, Z, Knapp, M et al (2014) Costs of autism spectrum disorders in the United Kingdom and the United States. JAMA Pediatrics, 168: 721–8.Google Scholar
Buie, T (2015) Potential etiologic factors of microbiome disruption in autism. Clinical Therapeutics, 37: 976–83.Google Scholar
Butler, MG, Dasouki, MJ, Zhou, XP et al (2005) Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. Journal of Medical Genetics, 42: 318–21.Google Scholar
Committee for Medicinal Products for Human Use (2013) Concept Paper on the Development of Medicinal Products for the Treatment of Autism Spectrum Disorder. European Medicines Agency.Google Scholar
Conti, S, Condo, M, Posar, A et al (2012) Phosphatase and tensin homolog (PTEN) gene mutations and autism: literature review and a case report of a patient with Cowden syndrome, autistic disorder, and epilepsy. Journal of Child Neurology, 27: 392–7.CrossRefGoogle Scholar
De Rubeis, S, He, X, Goldberg, AP et al (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 515: 209–15.Google Scholar
Ebrahimi-Fakhari, D, Sahin, M (2015) Autism and the synapse: emerging mechanisms and mechanism-based therapies. Current Opinion in Neurology, 28: 91-102.Google Scholar
Hawcutt, DB, Thompson, B, Smyth, RL et al (2013) Paediatric pharmacogenomics: an overview. Archives of Disease in Childhood, 98: 232–7.Google Scholar
Kendall, T, Megnin-Viggars, O, Gould, N et al (2013) Management of autism in children and young people: summary of NICE and SCIE guidance. BMJ, 347: f4865.Google Scholar
Knuesel, I, Chicha, L, Britschgi, M et al (2014) Maternal immune activation and abnormal brain development across CNS disorders. Nature Reviews Neurology, 10: 643–60.Google Scholar
Lintas, C, Sacco, R, Persico, AM (2012) Genome-wide expression studies in autism spectrum disorder, Rett syndrome, and Down syndrome. Neurobiology of Disease, 45: 57-68.Google Scholar
Malhotra, AK, Correll, CU, Chowdhury, NI et al (2012) Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Archives of General Psychiatry, 69: 904–12.Google Scholar
Mattila, ML, Hurtig, T, Haapsamo, H et al (2010) Comorbid psychiatric disorders associated with Asperger syndrome/high-functioning autism: a community- and clinic-based study. Journal of Autism and Developmental Disorders, 40: 1080–93.Google Scholar
Mostafa, GA, Al-Ayadhi, LY (2012) Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. Journal of Neuroinflammation, 9: 201.Google Scholar
Murray, ML, Hsia, Y, Glaser, K et al (2014) Pharmacological treatments prescribed to people with autism spectrum disorder (ASD) in primary health care. Psychopharmacology (Berlin), 231: 1011–21.Google Scholar
Owley, T, Brune, CW, Salt, J et al (2010) A pharmacogenetic study of escitalopram in autism spectrum disorders. Autism Research, 3: 1-7.Google Scholar
Patrick, RP, Ames, BN (2014) Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB Journal, 28: 2398–413.Google Scholar
Pinto, D, Delaby, E, Merico, D et al (2014) Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. American Journal of Human Genetics, 94: 677–94.Google Scholar
Santosh, P, Singh, J (2016) Drug treatment of autism spectrum disorder and its comorbidities in children and adolescents. BJPsych Advances, 21: 151–61.Google Scholar
Shcheglovitov, A, Shcheglovitova, O, Yazawa, M et al (2013) SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature, 503: 267–71.Google Scholar
Simonoff, E, Pickles, A, Charman, T et al (2008) Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. Journal of the American Academy of Child & Adolescent Psychiatry, 47: 921–9.Google Scholar
Singh, K, Connors, SL, Macklin, EA et al (2014) Sulforaphane treatment of autism spectrum disorder (ASD). Proceedings of the National Academy of Sciences of the United States of America, 111: 15550–5.Google Scholar
Tang, G, Gudsnuk, K, Kuo, SH et al (2014) Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron, 83: 1131–43.Google Scholar
Zhan, Y, Paolicelli, RC, Sforazzini, F et al (2014) Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nature Neuroscience, 17: 400–6.Google Scholar
Zhou, J, Blundell, J, Ogawa, S et al (2009) Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. Journal of Neuroscience, 29: 1773–83.Google Scholar
Submit a response

eLetters

No eLetters have been published for this article.