A randomized, placebo-controlled trial of extended-release guanfacine in children with autism spectrum disorder and ADHD symptoms: an analysis of secondary outcome measures

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In a prior report, we showed that extended-release guanfacine (GEXR) is safe and effective for children with autism spectrum disorder (ASD) accompanied by ADHD symptoms. Here, we examine the impact of GEXR on oppositional behavior, anxiety, repetitive behavior, and sleep disturbance. Sixty-two subjects with ASD (53 boys, 9 girls; ages 5–14 years) were randomly assigned to GEXR (n = 30) or placebo (n = 32) for 8 weeks. Outcomes include the Home Situation Questionnaire-Modified for ASD (HSQ-ASD), Anxiety scale of the Child and Adolescent Symptom Inventory (CASI), Children’s Yale-Brown Obsessive-Compulsive Scale-Modified for ASD (CYBOCS-ASD), and Children’s Sleep Habits Questionnaire (CSHQ). A repeated measures linear mixed model was used to determine the effects of treatment group and time on HSQ scores. For other measures, change from baseline was evaluated with Analysis of Covariance (ANCOVA).

After 8 weeks of treatment, parent ratings of oppositional behavior on the HSQ declined by 44% (per item mean from 3.4 to 1.9) in the GEXR group compared to 12% (from 3.3 to 2.9) for placebo (p = 0.004). Repetitive behavior on the CYBOCS-ASD showed a significantly greater decline in GEXR-treated participants compared to placebo (24% vs. <1%, p = 0.01). No group differences were observed on CASI Anxiety or CSHQ (p = 0.64 and 0.75, respectively). GEXR was effective in reducing oppositional behavior and, more modestly, repetitive behavior. GEXR was not superior to placebo for anxiety, though baseline anxiety ratings were low. GEXR did not significantly improve sleep habits. Future studies could focus on repetitive behavior or anxiety, symptoms with limited treatment options.

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  1. 1.

    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th edn. Washington, DC: American Psychiatric Publishing; 2013.

  2. 2.

    Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcin C, et al. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 2012;5:160–79.

  3. 3.

    Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009;65:591–8.

  4. 4.

    Accordino RE, Kidd C, Politte LC, Henry CA, McDougle CJ. Psychopharmacological interventions in autism spectrum disorder. Expert Opin Pharmacother. 2016;17:937–52.

  5. 5.

    Handen BL, Aman MG, Arnold LE, Hyman SL, Tumuluru RV, Lecavalier L, et al. Atomoxetine, parent training, and their combination in children with autism spectrum disorder and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2015;54:905–15.

  6. 6.

    Harfterkamp M, van de Loo-Neus G, Minderaa RB, van der Gaag RJ, Escobar R, Schacht A, et al. A randomized double-blind study of atomoxetine versus placebo for attention-deficit/hyperactivity disorder symptoms in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2012;51:733–41.

  7. 7.

    Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry. 2005;62:1266–74.

  8. 8.

    Pearson DA, Santos CW, Aman MG, Arnold LE, Casat CD, Mansour R, et al. Effects of extended release methylphenidate treatment on ratings of attention-deficit/hyperactivity disorder (ADHD) and associated behavior in children with autism spectrum disorders and ADHD symptoms. J Child Adolesc Psychopharmacol. 2013;23:337–51.

  9. 9.

    Reichow B, Volkmar FR, Bloch MH. Systematic review and meta-analysis of pharmacological treatment of the symptoms of attention-deficit/hyperactivity disorder in children with pervasive developmental disorders. J Autism Dev Disord. 2013;43:2435–41.

  10. 10.

    Scahill L, McCracken JT, King BH, Rockhill C, Shah B, Politte L, et al. Extended-release guanfacine for hyperactivity in children with autism spectrum disorder. Am J Psychiatry. 2015;172:1197–206.

  11. 11.

    Troost PW, Steenhuis MP, Tuynman-Qua HG, Kalverdijk LJ, Buitelaar JK, Minderaa RB, et al. Atomoxetine for attention-deficit/hyperactivity disorder symptoms in children with pervasive developmental disorders: a pilot study. J Child Adolesc Psychopharmacol. 2006;16:611–9.

  12. 12.

    Martinez-Raga J, Knecht C, de Alvaro R. Profile of guanfacine extended release and its potential in the treatment of attention-deficit hyperactivity disorder. Neuropsychiatr Dis Treat. 2015;11:1359–70.

  13. 13.

    Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007;129:397–410.

  14. 14.

    Findling RL, McBurnett K, White C, Youcha S. Guanfacine extended release adjunctive to a psychostimulant in the treatment of comorbid oppositional symptoms in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2014;24:245–52.

  15. 15.

    Strawn JR, Compton SN, Robertson B, Albano AM, Hamdani M, Rynn MA. Extended release guanfacine in pediatric anxiety disorders:a pilot, randomized, placebo-controlled trial. J Child Adolesc Psychopharmacol. 2017;27:29–37.

  16. 16.

    Connor DF, Grasso DJ, Slivinsky MD, Pearson GS, Banga A. An open-label study of guanfacine extended release for traumatic stress related symptoms in children and adolescents. J Child Adolesc Psychopharmacol. 2013;23:244–51.

  17. 17.

    Murphy TK, Fernandez TV, Coffey BJ, Rahman O, Gavaletz A, Hanks CE, Tillberg CS, Gomez LI, Sukhodolsky DG, Katsovich L, Scahill L. Extended-release guanfacine does not show a large effect on tic severity in children with chronic tic disorders. J Child Adolesc Psychopharmacol. 2017;27:762–70.

  18. 18.

    Efron D, Lycett K, Sciberras E. Use of sleep medication in children with ADHD. Sleep Med. 2014;15:472–5.

  19. 19.

    Rugino TA. Effect on primary sleep disorders when children with ADHD are administered guanfacine extended release. J Atten Disord. 2014;22:14–24.

  20. 20.

    Aman MG, Singh NN, Stewart AW, Field CJ. The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic. 1985;89:485–91.

  21. 21.

    Lord C, Rutter M, Goode S, Heemsbergen J, Jordan H, Mawhood L, et al. Autism diagnostic observation schedule: a standardized observation of communicative and social behavior. J Autism Dev Disord. 1989;19:185–212.

  22. 22.

    Rutter MBA, Lord C. The social communication questionnaire. Los Angeles, CA: Western Psychological Services; 2003.

  23. 23.

    Guy W. Clinical Global Impressions (CGI) Scale. In:Rush J, editors. Psychiatric measures. Washington, D.C: APA; 2000.

  24. 24.

    Barkley RA, Edelbrock C. Assessing situational variation in children’s problem behaviors: the Home and School Situations Questionnaires. In: Prinz R, editors. Advances in behavioral assessment of children and families. Greenwich, CT: JAI Press Inc.; 1987. pp. 157–76.

  25. 25.

    Chowdhury M, Aman MG, Lecavalier L, Smith T, Johnson C, Swiezy N, et al. Factor structure and psychometric properties of the revised Home Situations Questionnaire for autism spectrum disorder: the home situations questionnaire-autism spectrum disorder. Autism. 2016;20:528–37.

  26. 26.

    Aman MG, McDougle CJ, Scahill L, Handen B, Arnold LE, Johnson C, et al. Medication and parent training in children with pervasive developmental disorders and serious behavior problems: results from a randomized clinical trial. J Am Acad Child Adolesc Psychiatry. 2009;48:1143–54.

  27. 27.

    Bearss K, Johnson C, Smith T, Lecavalier L, Swiezy N, Aman M, et al. Effect of parent training vs parent education on behavioral problems in children with autism spectrum disorder: a randomized clinical trial. JAMA. 2015;313:1524–33.

  28. 28.

    Gadow KDSJ. Child symptom inventory-4. Stony Brook, NY: Checkmate Plus; 1994.

  29. 29.

    Gadow KDSJ. Adolescent Symptom Inventory-4 screening manual. Stony Brook, NY: Checkmate Plus; 1997.

  30. 30.

    Sprafkin J, Gadow KD, Salisbury H, Schneider J, Loney J. Further evidence of reliability and validity of the Child Symptom Inventory-4: parent checklist in clinically referred boys. J Clin Child Adolesc Psychol. 2002;31:513–24.

  31. 31.

    Hallett V, Lecavalier L, Sukhodolsky DG, Cipriano N, Aman MG, McCracken JT, et al. Exploring the manifestations of anxiety in children with autism spectrum disorders. J Autism Dev Disord. 2013;43:2341–52.

  32. 32.

    Scahill L, Riddle MA, McSwiggin-Hardin M, Ort SI, King RA, Goodman WK, et al. Children’s Yale-Brown obsessive compulsive scale: reliability and validity. J Am Acad Child Adolesc Psychiatry. 1997;36:844–52.

  33. 33.

    McDougle CJ, Scahill L, Aman MG, McCracken JT, Tierney E, Davies M, et al. Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology. Am J Psychiatry. 2005;162:1142–8.

  34. 34.

    Scahill L, McDougle CJ, Williams SK, Dimitropoulos A, Aman MG, McCracken JT, et al. Children’s Yale-Brown obsessive compulsive Scale modified for pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry. 2006;45:1114–23.

  35. 35.

    Owens JA, Spirito A, McGuinn M. The children’s sleep habits questionnaire (CSHQ): psychometric properties of a survey instrument for school-aged children. Sleep. 2000;23:1043–51.

  36. 36.

    Giannotti F, Cortesi F, Cerquiglini A, Vagnoni C, Valente D. Sleep in children with autism with and without autistic regression. J Sleep Res. 2011;20:338–47.

  37. 37.

    Malow BA, Marzec ML, McGrew SG, Wang L, Henderson LM, Stone WL. Characterizing sleep in children with autism spectrum disorders: a multidimensional approach. Sleep. 2006;29:1563–71.

  38. 38.

    Reed HE, McGrew SG, Artibee K, Surdkya K, Goldman SE, Frank K, et al. Parent-based sleep education workshops in autism. J Child Neurol. 2009;24:936–45.

  39. 39.

    Johnson CR, DeMand A, Lecavalier L, Smith T, Aman M, Foldes E, et al. Psychometric properties of the children’s sleep habits questionnaire in children with autism spectrum disorder. Sleep Med. 2016;20:5–11.

  40. 40.

    Posey DJ, Aman MG, McCracken JT, Scahill L, Tierney E, Arnold LE, et al. Positive effects of methylphenidate on inattention and hyperactivity in pervasive developmental disorders: an analysis of secondary measures. Biol Psychiatry. 2007;61:538–44.

  41. 41.

    Scahill L, Jeon S, Boorin SJ, McDougle CJ, Aman MG, Dziura J, et al. Weight gain and metabolic consequences of risperidone in young children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2016;55:415–23.

  42. 42.

    Fiks AG, Mayne SL, Song L, Steffes J, Liu W, McCarn B, et al. Changing patterns of alpha agonist medication use in children and adolescents 2009-2011. J Child Adolesc Psychopharmacol. 2015;25:362–7.

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The authors thank Courtney McCracken for her assistance with data analysis for this study.


The study was supported by NIMH grants to Dr. Scahill (R01MH083707), Dr. McDougle (RO1MH83739), Dr. McCracken (RO1MH083747), and Dr. King (R01MH86927); by a Yale Clinical and Transitional Science Award (UL1 RR024139) from the NIH National Center for Research Resources; and by Atlanta Clinical and Translational Science Institute, Emory University, which is supported by the NIH National Center for Advancing Translational Sciences under award UL1TR000454. Shire Pharmaceuticals provided active extended-release guanfacine and placebo. Dr. LCP receives research support from a Career Development Award with the North Carolina Translational and Clinical Sciences Institute, which is supported by NIH National Center for Advancing Translational Sciences under award UL1TR001111. Dr. LCP has received study drug from Nutramax, Inc. Dr. LS has served as a consultant for Bracket, Roche, and Shire, and he has served on the speaker’s bureau for the Tourette Syndrome Association. Dr. JTM has served as a consultant for Dart Neuroscience and Roche; he has received research support from Roche; he has received study drug and matching placebo from Shire; and he has served on the speaker’s bureau for the Tourette Syndrome Association. Dr. BK has received research support from Roche and Seaside Therapeutics.

Author information


  1. Department of Psychiatry, Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, 101 Renee Lynne Court, Carrboro, NC, 27510, USA

    • Laura C. Politte
  2. Department of Pediatrics, Marcus Autism Center, Emory University School of Medicine, Atlanta, USA

    • Lawrence Scahill
  3. Department of Pediatrics, Pediatrics Biostatistics Core, Emory University School of Medicine, Atlanta, USA

    • Janet Figueroa
  4. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, USA

    • James T. McCracken
  5. Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco School of Medicine, San Francisco, USA

    • Bryan King
  6. Department of Psychiatry, Lurie Center for Autism, Harvard Medical School, Boston, USA

    • Christopher J. McDougle


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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Laura C. Politte.

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