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A comprehensive systematic review and meta-analysis of pharmacological and dietary supplement interventions in paediatric autism: moderators of treatment response and recommendations for future research

  • A. Masi (a1), A. Lampit (a2), M. M. DeMayo (a1), N. Glozier (a1), I. B. Hickie (a1) and A. J. Guastella (a1)...
Abstract
Background

Autism spectrum disorders (ASDs) are pervasive and multifactorial neurodevelopmental conditions, characterized by impairments in social communication and interaction, and restricted, repetitive patterns of behaviour, interests or activities. Treatment options to ameliorate symptoms of ASDs are limited. Heterogeneity complicates the quest for personalized medicine in this population. Our aim was to investigate if there are baseline characteristics of patients that moderate response or trial design features that impede the identification of efficacious interventions for ASDs.

Method

Literature searches of EMBASE, MEDLINE and PsycINFO identified 43 studies for qualitative assessment of baseline characterization of participants and 37 studies for quantitative analysis of moderators of treatment response. Criteria included blinded randomized controlled trials (RCTs) in paediatric ASD, with at least 10 participants per arm or 20 overall, of oral treatments, including pharmacological interventions and dietary supplements.

Results

Random-effects meta-analysis of 1997 participants (81% male) identified three moderators associated with an increase in treatment response: trials located in Europe and the Middle-East; outcome measures designated primary status; and the type of outcome measure. Inconsistent reporting of baseline symptom severity and intellectual functioning prevented analysis of these variables. Qualitative synthesis of baseline characteristics identified at least 31 variables, with only age and gender reported in all trials. Biological markers were included in six RCTs.

Conclusions

Few trials reported adequate baseline characteristics to permit detailed analysis of response to treatment. Consideration of geographical location, baseline severity and intellectual function is required to ensure generalizability of results. The use of biological markers and correlates in ASD trials remains in its infancy. There is great need to improve the application of baseline characterization and incorporation of biological markers and correlates to permit selection of participants into homogeneous subgroups and to inform response to treatment in ASD.

Copyright
Corresponding author
*Address for correspondence: A. J. Guastella, Ph.D., Brain and Mind Centre, University of Sydney, 100 Mallett Street, Camperdown, NSW 2050, Australia. (Email: adam.guastella@sydney.edu.au)
References
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Aman MG, McDougle CJ, Scahill L, Handen B, Arnold L, Johnson C, Stigler KA, Bearss K, Butter E, Swiezy NB, Sukhodolsky DD, Ramadan Y, Pozdol S, Nikolov R, Lecavalier L, Kohn AE, Koenig K, Hollway JA, Korzekwa P, Gavaletz A, Mulick JA, Hall KL, Dziura J, Ritz L, Trollinger S, Yu S, Vitiello B, Wagner A (2009). Medication and parent training in children with pervasive developmental disorders and serious behavior problems: results from a randomized clinical trial. Journal of the American Academy of Child and Adolescent Psychiatry 48, 11431154.
Aman MG, Novotny S, Samango-Sprouse C, Lecavalier L, Leonard E, Gadow KD, King BH, Pearson DA, Gernsbacher MA, Chez M (2004). Outcome measures for clinical drug trials in autism. CNS Spectrums 9, 3647.
American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association: Washington, DC.
American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th edn. American Psychiatric Association: Washington, DC.
Arnold L, Farmer C, Kraemer HC, Davies M, Witwer A, Chuang S, DiSilvestro R, McDougle CJ, McCracken J, Vitiello B, Aman MG, Scahill L, Posey DJ, Swiezy NB (2010). Moderators, mediators, and other predictors of risperidone response in children with autistic disorder and irritability. Journal of Child and Adolescent Psychopharmacology 20, 8393.
Borenstein M, Hedges LV, Higgins JP, Rothstein HR (2009). Introduction to Meta-Analysis. John Wiley & Sons, Ltd: Hoboken, NJ.
Borenstein M, Higgins JPT (2013). Meta-analysis and subgroups. Prevention Science 14, 134143.
Carrasco M, Volkmar FR, Bloch MH (2012). Pharmacologic treatment of repetitive behaviors in autism spectrum disorders: evidence of publication bias. Pediatrics 129, e1301e1310.
Chaidez V, Hansen RL, Hertz-Picciotto I (2014). Gastrointestinal problems in children with autism, developmental delays or typical development. Journal of Autism and Developmental Disorders 44, 11171127.
Charman T, Pickles A, Simonoff E, Chandler S, Loucas T, Baird G (2011). IQ in children with autism spectrum disorders: data from the Special Needs and Autism Project (SNAP). Psychological Medicine 41, 619627.
Ching H, Pringsheim T (2012). Aripiprazole for autism spectrum disorders (ASD). Cochrane Database of Systematic Reviews, issue 5, CD009043.
Cohen J (2013). Statistical Power Analysis for the Behavioral Sciences. Routledge Academic: London.
Cohen S, Conduit R, Lockley SW, Rajaratnam SMW, Cornish KM (2014). The relationship between sleep and behavior in autism spectrum disorder (ASD): a review. Journal of Neurodevelopmental Disorders 6, 44.
De Vries M, Geurts H (2015). Influence of autism traits and executive functioning on quality of life in children with an autism spectrum disorder. Journal of Autism and Developmental Disorders 45, 27342743.
Egger M, Davey Smith G, Schneider M, Minder C (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ 315, 629634.
El Achkar CM, Spence SJ (2015). Clinical characteristics of children and young adults with co-occurring autism spectrum disorder and epilepsy. Epilepsy and Behavior 47, 183190.
Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A (2002). Meta-analyses involving cross-over trials: methodological issues. International Journal of Epidemiology 31, 140149.
Eldevik S, Hastings RP, Hughes JC, Jahr E, Eikeseth S, Cross S (2009). Meta-analysis of early intensive behavioral intervention for children with autism. Journal of Clinical Child and Adolescent Psychology 38, 439450.
Feldman MA, Bosett J, Collet C, Burnham-Riosa P (2014). Where are persons with intellectual disabilities in medical research? A survey of published clinical trials. Journal of Intellectual Disability Research 58, 800809.
Frazier TW, Youngstrom EA, Haycook T, Sinoff A, Dimitriou F, Knapp J, Sinclair L (2010). Effectiveness of medication combined with intensive behavioral intervention for reducing aggression in youth with autism spectrum disorder. Journal of Child and Adolescent Psychopharmacology 20, 167177.
Fung LK, Mahajan R, Nozzolillo A, Bernal P, Krasner A, Jo B, Coury D, Whitaker A, Veenstra-Vanderweele J, Hardan AY (2016). Pharmacologic treatment of severe irritability and problem behaviors in autism: a systematic review and meta-analysis. Pediatrics 137, S124S135.
Ghanizadeh A, Sahraeizadeh A, Berk M (2014). A head-to-head comparison of aripiprazole and risperidone for safety and treating autistic disorders, a randomized double blind clinical trial. Child Psychiatry and Human Development 45, 185192.
Guastella AJ, Hickie IB (2016). Oxytocin treatment, circuitry, and autism: a critical review of the literature placing oxytocin into the autism context. Biological Psychiatry 79, 234242.
Handen BL, Melmed RD, Hansen RL, Aman MG, Burnham DL, Bruss JB, McDougle CJ (2009). A double-blind, placebo-controlled trial of oral human immunoglobulin for gastrointestinal dysfunction in children with autistic disorder. Journal of Autism and Developmental Disorders 39, 796805.
Harfterkamp M, Buitelaar JK, Minderaa RB, Van De Loo-Neus G, Van Der Gaag R-J, Hoekstra PJ (2014). Atomoxetine in autism spectrum disorder: no effects on social functioning; some beneficial effects on stereotyped behaviors, inappropriate speech, and fear of change. Journal of Child and Adolescent Psychopharmacology 24, 481485.
Higgins JPT, Green S (2011). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011 (http://www.cochrane-handbook.org/).
Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003). Measuring inconsistency in meta-analyses. BMJ 327, 557560.
Hozo SP, Djulbegovic B, Hozo I (2005). Estimating the mean and variance from the median, range, and the size of a sample. BMC Medical Research Methodology 5, 13.
Huguet G, Ey E, Bourgeron T (2013). The genetic landscapes of autism spectrum disorders. Annual Review of Genomics and Human Genetics 14, 191213.
Hurwitz R, Blackmore R, Hazell P, Williams K, Woolfenden S (2012). Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents. Cochrane Database of Systematic Reviews, issue 3, CD008372.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ (1996). Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 17, 112.
Jesner OS, Aref-Adib M, Coren E (2007). Risperidone for autism spectrum disorder. Cochrane Database of Systematic Reviews, issue 1, CD005040.
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT (2008). Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Medicine 5, e45.
Knapp G, Hartung J (2003). Improved tests for a random effects meta-regression with a single covariate. Statistics in Medicine 22, 26932710.
Kraemer HC, Wilson GT, Fairburn CG, Agras WS (2002). Mediators and moderators of treatment effects in randomized clinical trials. Archives of General Psychiatry 59, 877883.
Mandell DS, Wiggins LD, Carpenter LA, Daniels J, Diguiseppi C, Durkin MS, Giarelli E, Morrier MJ, Nicholas JS, Pinto-Martin JA, Shattuck PT, Thomas KC, Yeargin-Allsopp M, Kirby RS (2009). Racial/ethnic disparities in the identification of children with autism spectrum disorders. American Journal of Public Health 99, 493498.
Mankad D, Dupuis A, Smile S, Roberts W, Brian J, Lui T, Genore L, Zaghloul D, Iaboni A, Marcon PM, Anagnostou E (2015). A randomized, placebo controlled trial of omega-3 fatty acids in the treatment of young children with autism. Molecular Autism 6, 18.
Masi A, Lampit A, Glozier N, Hickie IB, Guastella AJ (2015). Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis. Translational Psychiatry 5, e640.
Matson JL, Shoemaker M (2009). Intellectual disability and its relationship to autism spectrum disorders. Research in Developmental Disabilities 30, 11071114.
Mattila T, Wohlfarth T, Koeter M, Storosum J, Van Den Brink W, De Haan L, Leufkens H, Denys D (2014). Geographic variation in efficacy of atypical antipsychotics for the acute treatment of schizophrenia – an individual patient data meta-analysis. European Neuropsychopharmacology 24, 10671077.
McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, Arnold E, Lindsay R, Nash P, Hollway J, McDougle CJ, Posey D, Swiezy N, Kohn A, Scahill L, Martin A, Koenig K, Volkmar F, Carroll D, Lancor A, Tierney E, Ghuman J, Gonzalez NM, Grados M, Vitiello B, Ritz L, Davies M, Robinson J, McMahon D; Research Units on Pediatric Psychopharmacology Autism Network (2002). Risperidone in children with autism and serious behavioral problems. New England Journal of Medicine 347, 314321.
McDougle CJ, Scahill L, Aman MG, McCracken JT, Tierney E, Davies M, Arnold LE, Posey DJ, Martin A, Ghuman JK, Shah B, Chuang SZ, Swiezy NB, Gonzalez NM, Hollway J, Koenig K, McGough JJ, Ritz L, Vitiello B (2005). Risperidone for the core symptom domains of autism: results from the study by the Autism Network of the Research Units on Pediatric Psychopharmacology. American Journal of Psychiatry 162, 11421148.
McPheeters ML, Warren Z, Sathe N, Bruzek JL, Krishnaswami S, Jerome RN, Veenstra-Vanderweele J (2011). A systematic review of medical treatments for children with autism spectrum disorders. Pediatrics 127, e1312e1321.
Miral S, Gencer O, Inal-Emiroglu FN, Baykara B, Baykara A, Dirik E (2008). Risperidone versus haloperidol in children and adolescents with AD: a randomized, controlled, double-blind trial. European Child and Adolescent Psychiatry 17, 18.
Moher D, Liberati A, Tetzlaff J, Altman DG (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals of Internal Medicine 151, 264269, w64.
Nagaraj R, Singhi P, Malhi P (2006). Risperidone in children with autism: randomized, placebo-controlled, double-blind study. Journal of Child Neurology 21, 450455.
Ousley O, Cermak T (2014). Autism spectrum disorder: defining dimensions and subgroups. Current Developmental Disorders Reports 1, 2028.
Perry A, Flanagan HE, Dunn Geier J, Freeman NL (2009). Brief report: the Vineland Adaptive Behavior Scales in young children with autism spectrum disorders at different cognitive levels. Journal of Autism and Developmental Disorders 39, 10661078.
Persico AM, Napolioni V (2013). Autism genetics. Behavioral Brain Research 251, 95112.
Rossignol DA, Frye RE (2012). Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Molecular Psychiatry 17, 290314.
Saad K, Eltayeb AA, Mohamad IL, Al-Atram AA, Elserogy Y, Bjorklund G, El-Houfey AA, Nicholson B (2015). A randomized, placebo-controlled trial of digestive enzymes in children with autism spectrum disorders. Clinical Psychopharmacology and Neuroscience 13, 188193.
Scahill L, Lord C (2004). Subject selection and characterization in clinical trials in children with autism. CNS Spectrums 9, 2232.
Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G (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 and Adolescent Psychiatry 47, 921929.
Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, Carpenter J, Rucker G, Harbord RM, Schmid CH, Tetzlaff J, Deeks JJ, Peters J, Macaskill P, Schwarzer G, Duval S, Altman DG, Moher D, Higgins JP (2011). Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 343, d4002.
Thase ME, Mahableshwarkar AR, Dragheim M, Loft H, Vieta E (2016). A meta-analysis of randomized, placebo-controlled trials of vortioxetine for the treatment of major depressive disorder in adults. European Neuropsychopharmacology 26, 979993.
Trivedi MH, McGrath PJ, Fava M, Parsey RV, Kurian BT, Phillips ML, Oquendo MA, Bruder G, Pizzagalli D, Toups M, Cooper C, Adams P, Weyandt S, Morris DW, Grannemann BD, Ogden RT, Buckner R, McInnis M, Kraemer HC, Petkova E, Carmody TJ, Weissman MM (2016). Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC): rationale and design. Journal of Psychiatric Research 78, 1123.
Vivanti G, Barbaro J, Hudry K, Dissanayake C, Prior M (2013). Intellectual development in autism spectrum disorders: new insights from longitudinal studies. Frontiers in Human Neuroscience 7, 354.
Voigt RG, Mellon MW, Katusic SK, Weaver AL, Matern D, Mellon B, Jensen CL, Barbaresi WJ (2014). Dietary docosahexaenoic acid supplementation in children with autism. Journal of Pediatric Gastroenterology and Nutrition 58, 715722.
Welten CC, Koeter M, Wohlfarth T, Storosum J, Van Den Brink W, Gispen-De Wied C, Leufkens H, Denys D (2015). Efficacy of drug treatment for acute mania differs across geographic regions: an individual patient data meta-analysis of placebo-controlled studies. Journal of Psychopharmacology 29, 923932.
Williams K, Brignell A, Randall M, Silove N, Hazell P (2013). Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database of Systematic Reviews, issue 8, CD004677.
Williams LM, Rush AJ, Koslow SH, Wisniewski SR, Cooper NJ, Nemeroff CB, Schatzberg AF, Gordon E (2011). International Study to Predict Optimized Treatment for Depression (iSPOT-D), a randomized clinical trial: rationale and protocol. Trials 12, 4.
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