Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder

Bryan H. King, D. Mark Wright, Benjamin L. Handen, Linmarie Sikich, Andrew W. Zimmerman, William McMahon, Erin Cantwell, Pablo A. Davanzo, Colin T. Dourish, Elisabeth M. Dykens, Stephen R. Hooper, Catherine A. Jaselskis, Bennett L. Leventhal, Jennifer Levitt, Catherine Lord, Martin J. Lubetsky, Scott M. Myers, Sally J Ozonoff, Bhavik G. Shah, Michael SnapeElisa W. Shernoff, Kwanna Williamson, Edwin H. Cook

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

Objective: To test the hypothesis that amantadine hydrochloride is a safe and effective treatment for behavioral disturbances - for example, hyperactivity and irritability - in children with autism. Method: Thirty-nine subjects (intent to treat; 5-19 years old; IQ > 35) had autism diagnosed according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. The Aberrant Behavior Checklist-Community Version (ABC-CV) and Clinical Global Impressions (CGI) scale were used as outcome variables. After a 1-week, single-blind placebo run-in, patients received a single daily dose of amantadine (2.5 mg/kg per day) or placebo for the next week, and then bid dosing (5.0 mg/kg per day) for the subsequent 3 weeks. Results: When assessed on the basis of parent-rated ABC-CV ratings of irritability and hyperactivity, the mean placebo response rate was 37% versus amantadine at 47% (not significant). However, in the amantadine-treated group there were statistically significant improvements in absolute changes in clinician-rated ABC-CVs for hyperactivity (amantadine -6.4 versus placebo -2.1; p = .046) and inappropriate speech (-1.9 versus 0.4; p = .008). CGI scale ratings were higher in the amantadine group: 53% improved versus 25% (p = .076). Amantadine was well tolerated. Conclusions: Parents did not report statistically significant behavioral change with amantadine. However, clinician-rated improvements in behavioral ratings following treatment with amantadine suggest that further studies with this or other drugs acting on the glutamatergic system are warranted. The design of these and similar drug trials in children with autistic disorder must take into account the possibility of a large placebo response.

Original languageEnglish (US)
Pages (from-to)658-665
Number of pages8
JournalJournal of the American Academy of Child and Adolescent Psychiatry
Volume40
Issue number6
StatePublished - 2001
Externally publishedYes

Fingerprint

Amantadine
Autistic Disorder
Placebos
Therapeutics
Checklist
Drug Design
International Classification of Diseases
Diagnostic and Statistical Manual of Mental Disorders
Appointments and Schedules
Parents
Observation
Interviews

Keywords

  • Hyperactivity
  • Irritability
  • N-methyl-D-aspartate (NMDA)
  • Placebo

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Developmental and Educational Psychology

Cite this

King, B. H., Mark Wright, D., Handen, B. L., Sikich, L., Zimmerman, A. W., McMahon, W., ... Cook, E. H. (2001). Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 40(6), 658-665.

Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. / King, Bryan H.; Mark Wright, D.; Handen, Benjamin L.; Sikich, Linmarie; Zimmerman, Andrew W.; McMahon, William; Cantwell, Erin; Davanzo, Pablo A.; Dourish, Colin T.; Dykens, Elisabeth M.; Hooper, Stephen R.; Jaselskis, Catherine A.; Leventhal, Bennett L.; Levitt, Jennifer; Lord, Catherine; Lubetsky, Martin J.; Myers, Scott M.; Ozonoff, Sally J; Shah, Bhavik G.; Snape, Michael; Shernoff, Elisa W.; Williamson, Kwanna; Cook, Edwin H.

In: Journal of the American Academy of Child and Adolescent Psychiatry, Vol. 40, No. 6, 2001, p. 658-665.

Research output: Contribution to journalArticle

King, BH, Mark Wright, D, Handen, BL, Sikich, L, Zimmerman, AW, McMahon, W, Cantwell, E, Davanzo, PA, Dourish, CT, Dykens, EM, Hooper, SR, Jaselskis, CA, Leventhal, BL, Levitt, J, Lord, C, Lubetsky, MJ, Myers, SM, Ozonoff, SJ, Shah, BG, Snape, M, Shernoff, EW, Williamson, K & Cook, EH 2001, 'Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder', Journal of the American Academy of Child and Adolescent Psychiatry, vol. 40, no. 6, pp. 658-665.
King, Bryan H. ; Mark Wright, D. ; Handen, Benjamin L. ; Sikich, Linmarie ; Zimmerman, Andrew W. ; McMahon, William ; Cantwell, Erin ; Davanzo, Pablo A. ; Dourish, Colin T. ; Dykens, Elisabeth M. ; Hooper, Stephen R. ; Jaselskis, Catherine A. ; Leventhal, Bennett L. ; Levitt, Jennifer ; Lord, Catherine ; Lubetsky, Martin J. ; Myers, Scott M. ; Ozonoff, Sally J ; Shah, Bhavik G. ; Snape, Michael ; Shernoff, Elisa W. ; Williamson, Kwanna ; Cook, Edwin H. / Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. In: Journal of the American Academy of Child and Adolescent Psychiatry. 2001 ; Vol. 40, No. 6. pp. 658-665.
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T1 - Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder

AU - King, Bryan H.

AU - Mark Wright, D.

AU - Handen, Benjamin L.

AU - Sikich, Linmarie

AU - Zimmerman, Andrew W.

AU - McMahon, William

AU - Cantwell, Erin

AU - Davanzo, Pablo A.

AU - Dourish, Colin T.

AU - Dykens, Elisabeth M.

AU - Hooper, Stephen R.

AU - Jaselskis, Catherine A.

AU - Leventhal, Bennett L.

AU - Levitt, Jennifer

AU - Lord, Catherine

AU - Lubetsky, Martin J.

AU - Myers, Scott M.

AU - Ozonoff, Sally J

AU - Shah, Bhavik G.

AU - Snape, Michael

AU - Shernoff, Elisa W.

AU - Williamson, Kwanna

AU - Cook, Edwin H.

PY - 2001

Y1 - 2001

N2 - Objective: To test the hypothesis that amantadine hydrochloride is a safe and effective treatment for behavioral disturbances - for example, hyperactivity and irritability - in children with autism. Method: Thirty-nine subjects (intent to treat; 5-19 years old; IQ > 35) had autism diagnosed according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. The Aberrant Behavior Checklist-Community Version (ABC-CV) and Clinical Global Impressions (CGI) scale were used as outcome variables. After a 1-week, single-blind placebo run-in, patients received a single daily dose of amantadine (2.5 mg/kg per day) or placebo for the next week, and then bid dosing (5.0 mg/kg per day) for the subsequent 3 weeks. Results: When assessed on the basis of parent-rated ABC-CV ratings of irritability and hyperactivity, the mean placebo response rate was 37% versus amantadine at 47% (not significant). However, in the amantadine-treated group there were statistically significant improvements in absolute changes in clinician-rated ABC-CVs for hyperactivity (amantadine -6.4 versus placebo -2.1; p = .046) and inappropriate speech (-1.9 versus 0.4; p = .008). CGI scale ratings were higher in the amantadine group: 53% improved versus 25% (p = .076). Amantadine was well tolerated. Conclusions: Parents did not report statistically significant behavioral change with amantadine. However, clinician-rated improvements in behavioral ratings following treatment with amantadine suggest that further studies with this or other drugs acting on the glutamatergic system are warranted. The design of these and similar drug trials in children with autistic disorder must take into account the possibility of a large placebo response.

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KW - Hyperactivity

KW - Irritability

KW - N-methyl-D-aspartate (NMDA)

KW - Placebo

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