Articles
Double-Blind, Placebo-Controlled Study of Amantadine Hydrochloride in the Treatment of Children With Autistic Disorder

https://doi.org/10.1097/00004583-200106000-00010Get rights and content

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.

Section snippets

Subjects

Forty-three subjects, aged 5 to 19 years, were recruited and enrolled in this multicenter study. Four subjects withdrew before baseline (three did not meet continued eligibility criteria and one required additional treatment for a preexisting condition); otherwise all patients completed the study. The study was conducted at six university medical centers following approval by the institutional review boards governing each site and was subject to informed consent (witnessed, written, and signed)

Parent-Rated ABC-CV Scores

The percentage of responders (reduction of at least 25% in subscale scores for the ABC-CV for irritability and/or hyperactivity at the end of treatment) in the group treated with amantadine hydrochloride was higher than in the placebo-treated group, 9/19 (47%) versus 7/19 (37%), respectively, but this difference was not statistically significant (p = .511). Exploratory analyses looking at the percentage of responders at 7, 14, 21, and 28 days showed that the response rate was slightly higher

DISCUSSION

There was no statistically significant difference in parent-rated categorical treatment responder rates. However, amantadine was associated with statistically significant improvements in certain investigator-rated ABC-CV subscales (e.g., Hyperactivity) and a trend (p < .1) toward improvements in outcome on the CGI scale. An unexpected finding was that, in contrast to recent clinical trials of other drugs in adults (McDougle et al., 1996, McDougle et al., 1998), treatment of children in this

REFERENCES (36)

  • M Bauman et al.

    Neuroanatomic observations of the brain in autism

  • KM Belsito et al.

    Lamotrigine therapy for childhood autism: a randomized, double-blind, placebo-controlled trial

    Neurology

    (1998)
  • ME Blue et al.

    Development of amino acid receptors in frontal cortex from girls with Rett syndrome

    Ann Neurol

    (1999)
  • M Campbell et al.

    The effects of haloperidol on learning and behavior in autistic children

    J Autism Dev Disord

    (1982)
  • M Campbell et al.

    Response to triiodothyronine and dextroamphetamine: a study of preschool, schizophrenic children

    J Autism Child Schizophr

    (1972)
  • M Campbell et al.

    Levodopa and levoamphetamine: a crossover study in young schizophrenic children

    Curr Ther Res Clin Exp

    (1976)
  • M Chandler et al.

    Amantadine: profile of use in the developmentally disabled

  • CD Elliot

    Differential Abilities Scale (DAS)

    (1990)
  • Cited by (0)

    This study was funded by Cerebrus plc, Winnersh, U.K. The authors thank H. Eddine, J. Lainhart, D. Macarchick, A. Malekpour, and S. Smalley for their assistance.

    View full text