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Double-Blind, Placebo-Controlled Study of Amantadine Hydrochloride in the Treatment of Children With Autistic Disorder
Double-Blind, Placebo-Controlled Study of Amantadine Hydrochloride in the Treatment of Children With Autistic Disorder BRYAN H. KING, M.D., D. MARK WRIGHT, PH.D., BENJAMIN L. HANDEN, PH.D., LINMARIE SIKICH, M.D., ANDREW W. ZIMMERMAN, M.D., WILLIAM MCMAHON, M.D., ERIN CANTWELL, B.S., PABLO A. DAVANZO, M.D., COLIN T. DOURISH, PH.D., SC.D., ELISABETH M. DYKENS, PH.D., STEPHEN R. HOOPER, PH.D., CATHERINE A. JASELSKIS, M.D., BENNETT L. LEVENTHAL, M.D., JENNIFER LEVITT, M.D., CATHERINE LORD, PH.D., MARTIN J. LUBETSKY, M.D., SCOTT M. MYERS, M.D., SALLY OZONOFF, PH.D., BHAVIK G. SHAH, M.D., MICHAEL SNAPE, PH.D., ELISA W. SHERNOFF, B.A., KWANNA WILLIAMSON, M.S., R.N., C.S., AND EDWIN H. COOK, JR., M.D.
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, singleblind 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. J. Am. Acad. Child
Adolesc. Psychiatry, 2001, 40(6):658–665. Key Words: N-methyl-D-aspartate (NMDA), hyperactivity, irritability, placebo.
Accepted January 23, 2001. Dr. King is with Dartmouth Medical School, Hanover, NH; Drs. Wright, Snape, and Dourish are with Vernalis Group plc, Winnersh, U.K.; Ms. Cantwell and Drs. Davanzo, Dykens, Shah, and Levitt are with the UCLA Neuropsychiatric Institute; Drs. Handen and Lubetsky are with the University of Pittsburgh School of Medicine; Ms. Williamson and Drs. Sikich and Hooper are with the University of North Carolina, Chapel Hill; Drs. Zimmerman and Myers are with Kennedy Krieger Institute, Baltimore; Drs. McMahon and Ozonoff are with the University of Utah, Salt Lake City; Ms. Steele and Drs. Leventhal, Lord, Jaselskis, and Cook are with the University of Chicago. 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. Reprint requests to Dr. King, Department of Psychiatry, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756-0001; e-mail: [email protected]. 0890-8567/01/4006–0658䉷2001 by the American Academy of Child and Adolescent Psychiatry.
Autism, a pervasive developmental disorder, is characterized by qualitative impairments in social interaction and in communication, and restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. Currently there are no approved or well-established pharmacotherapies for autism or problematic behavior that may occur in the context of pervasive developmental disorders. One obstacle has been that the pathophysiology of autism, or of accompanying maladaptive behaviors, has not been sufficiently understood to provide an adequate basis for rational drug development. Research into the mechanisms underlying the development and maturation of the CNS, as well as new insights regarding the mechanism of action of psychotropic drugs, will inform therapeutic strategies.
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There is a growing body of evidence that suggests that excitatory amino acids may be involved in the regulation of neuronal survival, dendritic and axonal structure, synaptogenesis, and activity-dependent synaptic plasticity (McDonald and Johnston, 1990). During ontogenesis, the sensitivity of the N-methyl-D-aspartate (NMDA) subclass of the glutamatergic receptor changes, and different cell groups exhibit temporal fluctuations in sensitivity (Ikonomidou et al., 1989). At an early stage in development, NMDA receptors may suppress neuronal sprouting (Lin and Constantine-Paton, 1998) and play an important role in shaping the developing circuitry. Thus it has been postulated that a pathological event involving NMDA receptors could produce different patterns of neuronal abnormalities depending on the developmental stage reached (Olney, 1989). Accordingly, the event may be manifest in later life in disorders such as cerebral palsy, attention-deficit/hyperactivity disorder, schizophrenia, or pervasive development disorders such as autism. Indeed, areas of the brain found to exhibit cellular abnormalities associated with autism (Bauman and Kemper, 1994) show a high degree of NMDA binding sites (McDonald and Johnston, 1990). In keeping with these theories suggesting glutamatergic involvement in developmental disorders, abnormalities in the NMDA system have been highlighted in Rett syndrome (Johnston et al., 1995; Wenk et al., 1993), another of the pervasive developmental disorders. Elevated levels of glutamate in the cerebrospinal fluid of children with Rett syndrome have been reported (Hamberger et al., 1992; Lappalainen and Riikonen, 1996), as have elevated levels of NMDA receptors in postmortem brains (Blue et al., 1999; Wenk et al., 1993). Magnetic resonance spectroscopy also demonstrates increased glutamate levels in vivo in Rett syndrome (Pan et al., 1999). Manipulation of NMDA systems thus may represent a useful therapeutic approach to autism. However, drugs such as the noncompetitive NMDA antagonists are often associated with severe psychological side effects including hallucinations (Javitt and Zukin, 1991). Thus clinical development efforts initially have been directed at competitive antagonists that may have a more favorable side effect profile. However, not all noncompetitive NMDA antagonists share the limitation of psychotomimetic side effects, and novel compounds may open promising new therapeutic avenues (Rogawski, 1993). Amantadine hydrochloride has been found to have noncompetitive NMDA antagonist activity (Kornhuber
et al., 1994) at doses routinely used for its prescribed indications for the treatment of influenza, herpes zoster, and Parkinson disease. While limited, there are also reports of amantadine being used effectively in the treatment of behavioral disturbance. For example, Gualtieri et al. (1989) treated 30 patients (aged between 5 and 59 years) who had traumatic brain injury, with amantadine for periods of up to 1 year. Improvement in symptoms of agitation, hyperactivity, self-injury, and irritability were reported in more than half of the patients treated. Mattes (1980) reported favorable responses to amantadine in two of nine hyperkinetic children (aged 10 to 13 years). Similarly, Masters (1997) recently reported his personal experience that hyperactivity and irritability in the context of attention deficit disorder were improved in more than 30 children who had previously not responded to stimulant trials. These findings are of interest because hyperactivity and irritability (and, in addition, aggressive, self-injurious, and impulsive behaviors) are commonly associated with autistic disorder and often account for psychiatric referral of children with autism. More recently, King and colleagues (2001) used amantadine to treat eight children with hyperactivity, impulsivity, and aggression. These behaviors occurred in the context of various developmental disabilities including autism, epilepsy, tuberous sclerosis complex, and mental retardation. In this open trial all of the patients improved, with half showing marked clinical improvement. The open-label studies highlighted above support the concept that NMDA antagonists may be useful in the treatment of behavioral problems associated with autistic disorder. The aim of the present study was to conduct a randomized, double blind, and placebo-controlled study to test this hypothesis.
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METHOD 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) by the parents and, where possible, the child. The key inclusion criteria were a diagnosis of autistic disorder according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised (Lord et al., 1994) and the Autism Diagnostic
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Observation Schedule-Generic (ADOS-G) (Lord et al., 2000). To ensure that assessment tests were appropriate and valid for use on the subject population, additional threshold criteria were set for inclusion and exclusion. First, subjects were screened with the Vineland Adaptive Behavior Scales (Sparrow et al., 1984), and only those with composite age equivalents greater than 18 months were selected for further consideration. Second, subjects were excluded if they had an IQ (ratio, nonverbal) score of less than 35 as measured on the Mullen Scales of Early Learning (Mullen, 1995) or the Differential Ability Scale (Elliot, 1990). In addition, subjects were included only if Aberrant Behavior Checklist-Community Version (ABC-CV) (Aman et al., 1985) subscale scores for irritability (subscale I) and hyperactivity (subscale IV) were equal to or greater than the age-adjusted 75th percentile. In an attempt to select for a subject population as representative as possible, enrollment was limited to idiopathic autism. Thus patients with fragile X syndrome and tuberous sclerosis complex (both of which may predispose to autistic symptoms) were specifically excluded. Subjects were also excluded if they were receiving neuroleptic, anticonvulsant, or stimulant medication, or showed evidence for any clinically important medical illness. Subjects were not excluded if they were taking selective serotonin reuptake inhibitors provided the dose had been stable for greater than 1 month prior to entry, and the dose did not change during the study period. The intention-to-treat population consisted of 39 patients, of whom 19 were randomly assigned to receive amantadine hydrochloride and 20 were randomly assigned to receive placebo. Subject characteristics are summarized in Table 1. Some subjects received psychopharmacological agents during the course of the study, of which selective serotonin reuptake inhibitors (e.g., fluoxetine and fluvoxamine) were the largest category being coadministered to four subjects in the amantadine hydrochloride group (21%) and to six subjects in the placebo group (30%). The treatment groups were comparable with regard to medical history and physical examination. Study Design and Procedures The study design was of a randomized, double-blind, parallel-group, placebo-controlled type with a target of 40 evaluable patients with autistic disorder diagnosed according to DSM-IV and ICD-10 criteria. TABLE 1 Subject Characteristics by Group
The study had three phases: (1) screen (subject screening and recruitment, visit 0); (2) baseline (visit 1, end of 1-week placebo run-in); (3) treatment (visits 2, 3, 4, and 5). The baseline phase was of 1 week’s duration during which the subject was to receive placebo (single blind). At the end of the baseline phase the subject’s compliance was assessed and eligibility in relation to ABC-CV threshold criteria reconfirmed. After successful completion of this phase, the subject was randomly assigned for entry into the treatment phase. The treatment phase was of 4 weeks’ duration, during which the subject was to receive either placebo or amantadine. The dosing regimen for the first week of the treatment period was once a day, but thereafter the regimen was bid. Treatment Treatment allocation was randomized and supplied in a blind manner. The treatments administered were amantadine hydrochloride (Symmetrel威 syrup) and taste- and color-matched placebo. During the baseline phase (1 week), placebo was given at a single dose of 0.25 mL/kg per day; thus on average seven doses were administered to complete this phase. After successful completion of the baseline phase (including meeting criteria for entry to treatment phase), subjects were assigned treatment according to randomization. During the first week of the treatment phase, under double-blind conditions, subjects received either amantadine hydrochloride, at a single dose of 2.5 mg/kg per day (i.e., 0.25 mL/kg per day), or placebo at a single dose of 0.25 mL/kg per day. Thus during this period each subject was scheduled to receive seven doses of either amantadine hydrochloride or placebo. For each of the three remaining weeks of the treatment phase, the subject was given either placebo as two doses of 0.25 mL/kg (i.e., 0.5 mL/kg per day) or amantadine hydrochloride as two doses of 0.25 mL/kg (i.e., 5 mg/kg per day). In total during the trial the subject was scheduled to receive 49 doses of trial treatment. The parent or care provider was instructed to give each single dose at breakfast time. When two doses were administered each day, these were given at breakfast time and in the afternoon. The dose (5 mg/kg per day) was selected as a result of our previous experience with the use of amantadine hydrochloride in the treatment of a range of target behaviors, largely in the context of developmental disabilities (King et al., 2001). Treatment doses used previously ranged from 3.7 to 8.2 mg/kg per day (mean 5.3 mg/kg per day) and had been judged by the clinical team to be beneficial and well tolerated. Efficacy and Safety Measures
Placebo
Amantadine
20 7 (range 5–15) 1 28.2 75 6
19 7 (range 5–11) 4 26.9 79 4
1 11 7 18.7 (3–33) 32.7 (17–46)
0 11 8 19.1 (3–38) 29.4 (16–42)
Note: SSRI = selective serotonin reuptake inhibitor; CGI = Clinical Global Impressions; ABC = Aberrant Behavior Checklist.
The efficacy variables were obtained by use of two instruments: (1) the ABC-CV (Aman et al., 1985, 1995) and (2) the Clinical Global Impressions (CGI) scale (National Institute of Mental Health, 1988). For the ABC-CV, the parent, or care provider, was instructed to complete this instrument (which consists of a 58-item questionnaire with a 4-point rating scale and is used to measure behavior) at visits 0 (screen), 1 (baseline), and 2–5 inclusive (treatment). Instructions were given to ensure that the same rater was used throughout. The investigator also completed the ABC-CV on the basis of behaviors observed during the ADOS-G sessions, which were performed at screen (visit 0) and at the end of treatment (visit 5); ADOS-G sessions were videotaped. The CGI scale (National Institute of Mental Health, 1988), designed to assess severity of illness, global improvement, and efficacy index, was completed at visit 1 (baseline) and visits 2–5 inclusive (treatment). Instructions were given to ensure that the same observer (investigator) was used throughout. Variables used for the assessment of safety were derived from the use of (1) laboratory monitoring from blood and urine samples taken at screen (visit 0) and end of treatment (visit 5); and (2) adverse event
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Total Age (years) Females Median weight (kg) White (%) Concomitant SSRI (n) CGI-rated illness severity Mild Moderate Severe ABC irritability at baseline (parent) ABC hyperactivity at baseline
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(side effects) reporting, which was recorded at visits 1–5 inclusive. Adverse events were recorded on a specific form in which any potential side effects since the previous visit were recorded with date of onset and offset, and their nature, intensity, and outcome. Likelihood of association with the study drug was also assessed (e.g., is there a reasonable probability that this upper respiratory tract infection is study drug–related?). For serious adverse events, a supplementary form was provided for further characterization of the event. In addition, a full medical history and physical examination (including vital signs, height, and weight) was conducted at the screening visit (visit 0).The laboratory studies obtained included (1) hematology (complete blood cell count, differential); (2) clinical chemistries (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatine kinase, γ-glutamyltransferase, lactate dehydrogenase, bilirubin, blood urea nitrogen, cholesterol, creatinine, calcium, chloride, potassium, sodium); and (3) urinalysis. Statistical Analysis A total of 40 evaluable subjects (20 per treatment group) were deemed sufficient to detect, with at least 90% power, a difference in response rate between the two treatment groups of 50% (based on a two-sided test using a significance level of 5%). The primary efficacy variable was a binary outcome derivative of the parent-rated ABC-CV, and the analysis compared percentage of responders in the amantadine hydrochloride and placebo groups. This primary outcome variable was proposed as a means of identifying a difference that would represent improvements in behavior that would be meaningful to parents and would be considered of clinical relevance. A subject was defined as a “responder” if there had been a reduction of at least 25% in parentrated subscale scores for the ABC-CV for irritability and/or hyperactivity at the end of treatment (visit 5) compared with the baseline assessment (visit 1). The ABC-CV response rate for each treatment group was defined as the percentage of responders. The CGI responder (treatment success) definition was the percentage of subjects per group rated as showing moderate or marked improvement. For comparisons of ABC-CV subscales, estimates of treatment differences were expressed in adjusted least square means together with the associated 95% confidence interval. The statistical methods used included Pearson χ2, analysis of covariance, and summary statistics.
Fig. 1 Parent-rated Aberrant Behavior Checklist-Community Version mean Irritability subscale plotted against time. Week 1 represents the baseline assessment after 1 week of single-blind placebo treatment and the subsequent start of randomized treatment; week 2 represents 1 week of single-dose treatment; week 5 represents the final assessment after 3 additional weeks of bid treatment. There were no statistically significant differences between treatments.
estimated difference between treatments and 95% confidence intervals indicated a greater reduction from baseline with amantadine hydrochloride compared with placebo. For example, for the Hyperactivity subscale the estimated (least square means) treatment difference was –4.81 (mean change from baseline: –4.9 for amantadine hydrochloride compared with –1.6 for placebo), with the 95% confidence interval –11.63 to 2.00. Investigator-Rated ABC-CV Scores
Analysis of the investigator-rated ABC-CV scores at visits 0 and 5 revealed significant treatment differences.
RESULTS 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 for amantadine hydrochloride at all time points except 14 days. There were no statistically significant differences between ABCCV subscale scores for irritability (p = .178), lethargy (p = .960), or any of the other parent-rated ABC-CV subscale scores (Figs. 1 and 2). In three of the five subscales the
Fig. 2 Parent-rated Aberrant Behavior Checklist-Community Version mean Hyperactivity subscale plotted against time. Week 1 represents the baseline assessment after 1 week of single-blind placebo treatment and the subsequent start of randomized treatment; week 2 represents 1 week of single-dose treatment; week 5 represents the final assessment after 3 additional weeks of bid treatment. There was no statistically significant difference between treatments.
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These treatment differences were evident in comparisons of the subscale scores of Hyperactivity (p = .046) and Inappropriate Speech (p = .008). In addition, there was a trend toward significance for Stereotypy (p = .086). For Irritability (p = .141) and Lethargy (p = .353), differences were not significant. For Hyperactivity (Fig. 3) the estimated treatment difference (–5.75) showed that the reduction from baseline was greater for amantadine hydrochloride than placebo (95% confidence interval: –11.39 to –0.10). For Inappropriate Speech (Fig. 4) the estimated treatment difference (–2.24) showed that the reduction from baseline was greater for amantadine hydrochloride than placebo (95% confidence interval: –3.85 to –0.63). For Stereotypy the estimated treatment difference (–2.20) indicated that the reduction from baseline was greater for amantadine hydrochloride than placebo (95% confidence interval: –4.74 to 0.33). Clinical Global Impressions
Twice as many subjects in the amantadine hydrochloride group were considered to be responders, i.e., were rated as showing moderate or marked improvement, than in the placebo group (Fig. 5, visit 5). The success rate was 53% after amantadine hydrochloride compared with 25% for placebo (p = .076). The estimated treatment difference was 27.6 percentage points in favor of amantadine hydrochloride (95% confidence interval: 57.0% to –1.8%). Ratings of “marked improvement” were applied to 5/19 (26%) children receiving amantadine hydrochloride and
only 1/20 (5%) receiving placebo. As is evident in Fig. 5, it would appear that this difference in percentage of marked responders largely accounts for the overall trend toward improved CGI outcome for amantadine. There were no significant differences in the assessment of “severity of illness” at the final visit. In both treatment groups most patients had moderate severity of illness (53% for amantadine hydrochloride and 50% for placebo). The overall percentage of responders (moderate + marked) at 7, 14, 21, and 28 days (visits 2 through 5) was higher for amantadine hydrochloride within the first week and at all subsequent time points (Fig. 5). Safety Evaluation
Similar numbers of patients in both active and placebo groups experienced side effects. Fourteen (74%) patients on amantadine hydrochloride reported at least one side effect, compared with 14 (70%) patients on placebo. There were no serious adverse events. There were no adverse events that started prebaseline and worsened. The side effect reported most often was insomnia, which was reported in 4 subjects (21%) in the amantadine hydrochloride treatment group and 2 subjects (10%) in the placebo group. In all but one case the insomnia was rated as mild, the exception being a report of moderate insomnia in a subject in the placebo group. Two subjects in the amantadine hydrochloride group were reported to have somnolence. In the placebo group there were more
Fig. 3 Investigator-rated changes in Aberrant Behavior Checklist-Community Version hyperactivity derived from Autism Diagnostic Observation ScheduleGeneric videotapes (p = .046).
Fig. 4 Investigator-rated changes in Aberrant Behavior Checklist-Community Version inappropriate speech derived from Autism Diagnostic Observation Schedule-Generic videotapes at study entry versus completion (p = .008).
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reports of adverse events involving difficult or antisocial behaviors (broadly grouped as “personality disorder” within the Coding Symbols for Thesaurus of Adverse Reaction Terms [COSTART] terminology [US Food and Drug Administration, 1995] and including, for example, “increased self stimulation”): four reports versus two reports in the amantadine hydrochloride group. There were no reports of hallucinations, a side effect attributed to amantadine at high doses (King et al., 2001).
by Belsito and coworkers (1998). In their trial with lamotrigine, using the same 25% response definition, their responder rate in the placebo group ranged from 39% to 54% (P. Law, personal communication, 1998). Quintana and coworkers (1995) also noted that autistic children receiving placebo showed a decrease in hyperactivity scores in comparison with their respective baseline score. In that study, statistically significant improvement from baseline occurred in the placebo-treated group according to both the ABC and Conners Parent questionnaires. The evidence accumulating from our experiences and those of others suggests that placebo responses in studies involving children may be distinct from placebo responses in adults and deserves particular attention. Among the possible reasons for this finding, one might consider natural oscillations in behavior (perhaps more marked in children than adults), a true placebo effect, or regression to the mean. Expectancy effects, perhaps greater in parents of young children than in caregivers of autistic adults, or beneficial behavioral modification as a result of study participation, may also be important factors. Future studies will need to address and allow for these possibilities, by enrolling more subjects, or perhaps by extending the length of both placebo and active treatment phases of study and recruiting additional informants. Additional options might be to consider changing the threshold for inclusion and/or to use a crossover rather than parallel-group design.
DISCUSSION
Limitations
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, 1998), treatment of children in this study with placebo was associated with significant improvements in behavioral ratings. Thus, although 47% of children in the amantadine hydrochloride–treated group were rated by their parents as responders, so too were 37% of children in the placebo group. It was notable that the mean ABC-CV score data for this group also indicated a decrease from baseline in all subdomains (with the possible exception of Inappropriate Speech). With regard to the placebo response rate in children with autism, similar findings have also been made recently
The number of subjects in this study did not provide sufficient statistical power to confirm the effectiveness of amantadine over placebo across all of the outcome measures examined. Numbers of subjects are also insufficient to examine the response in subgroups, for example, children with more severe cognitive disabilities, females, or children receiving concurrent treatment with a serotonin reuptake inhibitor. All of these factors may also have influenced treatment response. Demonstrating efficacy for amantadine in this study is also limited by the singledose design. Amantadine hydrochloride was well tolerated at the 5mg/kg dose administered. In retrospect, it was perhaps “too well tolerated” given that there were no dropouts from the active treatment arm nor any statistically significant differences in side effects in comparison with placebo. The mean and median doses of amantadine were 168.3 mg and 134.5 mg, respectively, and the dose range was 90 to 200 mg. These doses are below the recommended 200-mg
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Fig. 5 Percentage of moderate and marked responders from Clinical Global Improvement ratings for amantadine (A) (n = 19) and placebo (P) (n = 20) by visit.
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amantadine dose for prophylactic treatment of children for influenza. At least one “nonresponder” was converted to a responder in an open-label extension of the study following a dosage increase. A follow-up study with a higher dose of amantadine might be justified. Our findings of a modest improvement in behavioral problems are consistent with previous open studies reporting improvements in symptoms such as hyperactivity, agitation, irritability, and self-injury following treatment of nonautistic children with amantadine (Chandler et al., 1991; King et al., 2001; Masters, 1997; Mattes, 1980). The mechanism underlying these behavioral improvements remains to be determined. In addition to its glutamatergic properties, amantadine interacts with dopaminergic systems, and there is evidence for dopaminergic influence on behavioral problems in autism such as hyperactivity. It is interesting, however, that both dopaminergic agonists and antagonists have been reported to be effective in this context (Birmaher et al., 1988; Campbell et al., 1982; McDougle et al., 1998). Furthermore, controlled trials have suggested that dopamine agonism may exacerbate some behaviors in autism including social withdrawal, hyperactivity, and stereotypy (Campbell et al., 1972, 1976).
autism or the expression of maladaptive behaviors in this context. Additional study will be important to clarify the role for NMDA antagonism as an approach to the treatment of this population and the safety and efficacy of amantadine or related compounds in treatment of hyperactivity in children, adolescents, and adults with autistic disorder. REFERENCES
In this study it was found that children with autism treated with amantadine hydrochloride, at a final daily dose of 5 mg/kg for 3 weeks, showed modest improvements in hyperactive behavior without significant adverse events. The CGI scale, perhaps influenced by reports from family or teachers in addition to direct observation, accorded significant improvement to active drug. But parent ratings alone did not statistically differentiate drug from placebo. Future trials in this population may benefit by inclusion of more systematic data from multiple informants or the use of a CGI-equivalent for parents. It is possible, for example, that improvement in behaviors such as “disturbs others” or “disobedient” is diluted and lost by inclusion with arguably less clinically significant items in the ABC such as “does not pay attention to instructions” or “restless.” In the same vein, because a substantial number of children showed behavioral improvements when treated with placebo, appreciation of the potential magnitude of a placebo response should be an important consideration in the design of drug trials for the treatment of children with autism. Glutamatergic dysfunction may be an important pathophysiological mechanism involved in
Aman MG, Burrow WH, Wolford PL (1995), The Aberrant Behavior Checklist-Community: factor validity and effect of subject variables for adults in group homes. Am J Ment Retard 100:283–292 Aman MG, Singh NN, Stewart AW, Field CJ (1985), The Aberrant Behavior Checklist. Am J Ment Defic 89:492–502 Bauman M, Kemper TL (1994), Neuroanatomic observations of the brain in autism. In: The Neurobiology of Autism, Bauman ML, Kemper TL, eds. Baltimore: Johns Hopkins University Press, pp 119–145 Belsito KM, Kirk KS, Landa RJ, Law PA, Zimmerman AW (1998), Lamotrigine therapy for childhood autism: a randomized, double-blind, placebo-controlled trial. Neurology 50:A85 Birmaher B, Quintana H, Greenhill LL (1988), Methylphenidate treatment of hyperactive autistic children. J Am Acad Child Adolesc Psychiatry 27:248–251 Blue ME, Naidu S, Johnston MV (1999), Development of amino acid receptors in frontal cortex from girls with Rett syndrome. Ann Neurol 45:541–545 Campbell M, Anderson LT, Small AM, Perry R, Green W, Caplan R (1982), The effects of haloperidol on learning and behavior in autistic children. J Autism Dev Disord 12:167–175 Campbell M, Fish B, Shapiro DR, Collins P, Koch C (1972), Response to triiodothyronine and dextroamphetamine: a study of preschool, schizophrenic children. J Autism Child Schizophr 2:343–358 Campbell M, Small AM, Collins PJ, Friedman E, David R, Genieser M (1976), Levodopa and levoamphetamine: a crossover study in young schizophrenic children. Curr Ther Res Clin Exp 19:70–86 Chandler M, Barnhill L, Gualtieri CT (1991), Amantadine: profile of use in the developmentally disabled. In: Mental Retardation: Developing Pharmacotherapies, Ratey JJ, ed. Washington, DC: American Psychiatric Press, pp 139–162 Elliot CD (1990), Differential Abilities Scale (DAS). San Antonio, TX: Psychological Corporation Gualtieri T, Chandler M, Coons TB, Brown LT (1989), Amantadine: a new clinical profile for traumatic brain injury. Clin Neuropharmacol 12:258–270 Hamberger A, Gillberg C, Palm A, Hagberg B (1992), Elevated CSF glutamate in Rett syndrome. Neuropediatrics 23:212–213 Ikonomidou C, Mosinger JL, Shahid Salles K, Labruyere J, Olney JW (1989), Sensitivity of the developing rat brain to hyperbaric/ischemic damage parallels sensitivity to N-methyl-D-aspartate neurotoxicity. J Neurosci 9:2809–2818 Javitt DC, Zukin SR (1991), Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308 Johnston MV, Hohmann C, Blue ME (1995), Neurobiology of Rett syndrome. Neuropediatrics 26:119–122 King BH, Wright DM, Snape M, Dourish CT (2001), Case series: amantadine open-label treatment of impulsive and aggressive behavior in hospitalized children with developmental disabilities. J Am Acad Child Adolesc Psychiatry 40:654–657 Kornhuber J, Weller M, Schoppmeyer K, Riedereer P (1994), Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm Suppl 14:91–104 Lappalainen R, Riikonen RS (1996), High levels of cerebrospinal fluid glutamate in Rett syndrome. Pediatr Neurol 15:213–216 Lin S, Constantine-Paton M (1998), Suppression of sprouting: an early function of NMDA receptors in the absence of AMPA/kainate receptor activity. J Neurosci 18:3725–3737
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Lord C, Risi S, Lambrecht L et al. (2000), The ADOS-G (Autism Diagnostic Observation Schedule-Generic): a standard measure of social and communication deficits associated with autism spectrum disorder. J Autism Dev Disord 30:205–223 Lord C, Rutter M, Le Couteur A (1994), Autism Diagnostic InterviewRevised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 24:659–685 Masters KJ (1997), Alternative medications for ADHD (letter). J Am Acad Child Adolesc Psychiatry 36:301 Mattes J (1980), A pilot trial of amantadine in hyperactive children. Psychopharmacol Bull 16:67–69 McDonald JW, Johnston MV (1990), Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Rev 15:41–70 McDougle CJ, Holmes JP, Carlson DC, Pelton GH, Cohen DJ, Price LH (1998), A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive development disorders. Arch Gen Psychiatry 55:633–641 McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR, Price LH (1996), A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry 53:1001–1008
Mullen E (1995), Mullen Scales of Early Learning. Circle Pines, MN: American Guidance Service National Institute of Mental Health (1988), Rating scales and assessment instruments for use in pediatric psychopharmacology research. Psychopharmacol Bull 21:839–842 Olney JW (1989), Excitatory amino acids and neuropsychiatric disorders. Biol Psychiatry 26:505–525 Pan JW, Lane JB, Hetherington H, Percy AK (1999), Rett syndrome: 1H spectroscopic imaging at 4.1 Tesla. J Child Neurol 14:524–528 Quintana H, Birmaher B, Stedge D et al. (1995), Use of methylphenidate in the treatment of children with autistic disorder. J Autism Dev Disord 25:283–294 Rogawski MA (1993), Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines. Trends Pharmacol Sci 14:325–331 Sparrow SS, Balla DA, Cicchetti DV (1984), Survey Form Manual (Interview Edition) of the Vineland Adaptive Behavior Scales. Circle Pines, MN: American Guidance Service US Food and Drug Administration (1995), COSTART: Coding Symbols for Thesaurus of Adverse Reaction Terms, 5th ed. Washington, DC: US Department of Health and Human Services Wenk GL, O’Leary M, Nemeroff CB, Bissett G, Moser H, Naidu S (1993), Neurochemical alterations in Rett syndrome. Dev Brain Res 74:67–72
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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, singleblind 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. J. Am. Acad. Child
Adolesc. Psychiatry, 2001, 40(6):658–665. Key Words: N-methyl-D-aspartate (NMDA), hyperactivity, irritability, placebo.
Accepted January 23, 2001. Dr. King is with Dartmouth Medical School, Hanover, NH; Drs. Wright, Snape, and Dourish are with Vernalis Group plc, Winnersh, U.K.; Ms. Cantwell and Drs. Davanzo, Dykens, Shah, and Levitt are with the UCLA Neuropsychiatric Institute; Drs. Handen and Lubetsky are with the University of Pittsburgh School of Medicine; Ms. Williamson and Drs. Sikich and Hooper are with the University of North Carolina, Chapel Hill; Drs. Zimmerman and Myers are with Kennedy Krieger Institute, Baltimore; Drs. McMahon and Ozonoff are with the University of Utah, Salt Lake City; Ms. Steele and Drs. Leventhal, Lord, Jaselskis, and Cook are with the University of Chicago. 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. Reprint requests to Dr. King, Department of Psychiatry, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756-0001; e-mail: [email protected]. 0890-8567/01/4006–0658䉷2001 by the American Academy of Child and Adolescent Psychiatry.
Autism, a pervasive developmental disorder, is characterized by qualitative impairments in social interaction and in communication, and restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. Currently there are no approved or well-established pharmacotherapies for autism or problematic behavior that may occur in the context of pervasive developmental disorders. One obstacle has been that the pathophysiology of autism, or of accompanying maladaptive behaviors, has not been sufficiently understood to provide an adequate basis for rational drug development. Research into the mechanisms underlying the development and maturation of the CNS, as well as new insights regarding the mechanism of action of psychotropic drugs, will inform therapeutic strategies.
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There is a growing body of evidence that suggests that excitatory amino acids may be involved in the regulation of neuronal survival, dendritic and axonal structure, synaptogenesis, and activity-dependent synaptic plasticity (McDonald and Johnston, 1990). During ontogenesis, the sensitivity of the N-methyl-D-aspartate (NMDA) subclass of the glutamatergic receptor changes, and different cell groups exhibit temporal fluctuations in sensitivity (Ikonomidou et al., 1989). At an early stage in development, NMDA receptors may suppress neuronal sprouting (Lin and Constantine-Paton, 1998) and play an important role in shaping the developing circuitry. Thus it has been postulated that a pathological event involving NMDA receptors could produce different patterns of neuronal abnormalities depending on the developmental stage reached (Olney, 1989). Accordingly, the event may be manifest in later life in disorders such as cerebral palsy, attention-deficit/hyperactivity disorder, schizophrenia, or pervasive development disorders such as autism. Indeed, areas of the brain found to exhibit cellular abnormalities associated with autism (Bauman and Kemper, 1994) show a high degree of NMDA binding sites (McDonald and Johnston, 1990). In keeping with these theories suggesting glutamatergic involvement in developmental disorders, abnormalities in the NMDA system have been highlighted in Rett syndrome (Johnston et al., 1995; Wenk et al., 1993), another of the pervasive developmental disorders. Elevated levels of glutamate in the cerebrospinal fluid of children with Rett syndrome have been reported (Hamberger et al., 1992; Lappalainen and Riikonen, 1996), as have elevated levels of NMDA receptors in postmortem brains (Blue et al., 1999; Wenk et al., 1993). Magnetic resonance spectroscopy also demonstrates increased glutamate levels in vivo in Rett syndrome (Pan et al., 1999). Manipulation of NMDA systems thus may represent a useful therapeutic approach to autism. However, drugs such as the noncompetitive NMDA antagonists are often associated with severe psychological side effects including hallucinations (Javitt and Zukin, 1991). Thus clinical development efforts initially have been directed at competitive antagonists that may have a more favorable side effect profile. However, not all noncompetitive NMDA antagonists share the limitation of psychotomimetic side effects, and novel compounds may open promising new therapeutic avenues (Rogawski, 1993). Amantadine hydrochloride has been found to have noncompetitive NMDA antagonist activity (Kornhuber
et al., 1994) at doses routinely used for its prescribed indications for the treatment of influenza, herpes zoster, and Parkinson disease. While limited, there are also reports of amantadine being used effectively in the treatment of behavioral disturbance. For example, Gualtieri et al. (1989) treated 30 patients (aged between 5 and 59 years) who had traumatic brain injury, with amantadine for periods of up to 1 year. Improvement in symptoms of agitation, hyperactivity, self-injury, and irritability were reported in more than half of the patients treated. Mattes (1980) reported favorable responses to amantadine in two of nine hyperkinetic children (aged 10 to 13 years). Similarly, Masters (1997) recently reported his personal experience that hyperactivity and irritability in the context of attention deficit disorder were improved in more than 30 children who had previously not responded to stimulant trials. These findings are of interest because hyperactivity and irritability (and, in addition, aggressive, self-injurious, and impulsive behaviors) are commonly associated with autistic disorder and often account for psychiatric referral of children with autism. More recently, King and colleagues (2001) used amantadine to treat eight children with hyperactivity, impulsivity, and aggression. These behaviors occurred in the context of various developmental disabilities including autism, epilepsy, tuberous sclerosis complex, and mental retardation. In this open trial all of the patients improved, with half showing marked clinical improvement. The open-label studies highlighted above support the concept that NMDA antagonists may be useful in the treatment of behavioral problems associated with autistic disorder. The aim of the present study was to conduct a randomized, double blind, and placebo-controlled study to test this hypothesis.
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METHOD 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) by the parents and, where possible, the child. The key inclusion criteria were a diagnosis of autistic disorder according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised (Lord et al., 1994) and the Autism Diagnostic
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Observation Schedule-Generic (ADOS-G) (Lord et al., 2000). To ensure that assessment tests were appropriate and valid for use on the subject population, additional threshold criteria were set for inclusion and exclusion. First, subjects were screened with the Vineland Adaptive Behavior Scales (Sparrow et al., 1984), and only those with composite age equivalents greater than 18 months were selected for further consideration. Second, subjects were excluded if they had an IQ (ratio, nonverbal) score of less than 35 as measured on the Mullen Scales of Early Learning (Mullen, 1995) or the Differential Ability Scale (Elliot, 1990). In addition, subjects were included only if Aberrant Behavior Checklist-Community Version (ABC-CV) (Aman et al., 1985) subscale scores for irritability (subscale I) and hyperactivity (subscale IV) were equal to or greater than the age-adjusted 75th percentile. In an attempt to select for a subject population as representative as possible, enrollment was limited to idiopathic autism. Thus patients with fragile X syndrome and tuberous sclerosis complex (both of which may predispose to autistic symptoms) were specifically excluded. Subjects were also excluded if they were receiving neuroleptic, anticonvulsant, or stimulant medication, or showed evidence for any clinically important medical illness. Subjects were not excluded if they were taking selective serotonin reuptake inhibitors provided the dose had been stable for greater than 1 month prior to entry, and the dose did not change during the study period. The intention-to-treat population consisted of 39 patients, of whom 19 were randomly assigned to receive amantadine hydrochloride and 20 were randomly assigned to receive placebo. Subject characteristics are summarized in Table 1. Some subjects received psychopharmacological agents during the course of the study, of which selective serotonin reuptake inhibitors (e.g., fluoxetine and fluvoxamine) were the largest category being coadministered to four subjects in the amantadine hydrochloride group (21%) and to six subjects in the placebo group (30%). The treatment groups were comparable with regard to medical history and physical examination. Study Design and Procedures The study design was of a randomized, double-blind, parallel-group, placebo-controlled type with a target of 40 evaluable patients with autistic disorder diagnosed according to DSM-IV and ICD-10 criteria. TABLE 1 Subject Characteristics by Group
The study had three phases: (1) screen (subject screening and recruitment, visit 0); (2) baseline (visit 1, end of 1-week placebo run-in); (3) treatment (visits 2, 3, 4, and 5). The baseline phase was of 1 week’s duration during which the subject was to receive placebo (single blind). At the end of the baseline phase the subject’s compliance was assessed and eligibility in relation to ABC-CV threshold criteria reconfirmed. After successful completion of this phase, the subject was randomly assigned for entry into the treatment phase. The treatment phase was of 4 weeks’ duration, during which the subject was to receive either placebo or amantadine. The dosing regimen for the first week of the treatment period was once a day, but thereafter the regimen was bid. Treatment Treatment allocation was randomized and supplied in a blind manner. The treatments administered were amantadine hydrochloride (Symmetrel威 syrup) and taste- and color-matched placebo. During the baseline phase (1 week), placebo was given at a single dose of 0.25 mL/kg per day; thus on average seven doses were administered to complete this phase. After successful completion of the baseline phase (including meeting criteria for entry to treatment phase), subjects were assigned treatment according to randomization. During the first week of the treatment phase, under double-blind conditions, subjects received either amantadine hydrochloride, at a single dose of 2.5 mg/kg per day (i.e., 0.25 mL/kg per day), or placebo at a single dose of 0.25 mL/kg per day. Thus during this period each subject was scheduled to receive seven doses of either amantadine hydrochloride or placebo. For each of the three remaining weeks of the treatment phase, the subject was given either placebo as two doses of 0.25 mL/kg (i.e., 0.5 mL/kg per day) or amantadine hydrochloride as two doses of 0.25 mL/kg (i.e., 5 mg/kg per day). In total during the trial the subject was scheduled to receive 49 doses of trial treatment. The parent or care provider was instructed to give each single dose at breakfast time. When two doses were administered each day, these were given at breakfast time and in the afternoon. The dose (5 mg/kg per day) was selected as a result of our previous experience with the use of amantadine hydrochloride in the treatment of a range of target behaviors, largely in the context of developmental disabilities (King et al., 2001). Treatment doses used previously ranged from 3.7 to 8.2 mg/kg per day (mean 5.3 mg/kg per day) and had been judged by the clinical team to be beneficial and well tolerated. Efficacy and Safety Measures
Placebo
Amantadine
20 7 (range 5–15) 1 28.2 75 6
19 7 (range 5–11) 4 26.9 79 4
1 11 7 18.7 (3–33) 32.7 (17–46)
0 11 8 19.1 (3–38) 29.4 (16–42)
Note: SSRI = selective serotonin reuptake inhibitor; CGI = Clinical Global Impressions; ABC = Aberrant Behavior Checklist.
The efficacy variables were obtained by use of two instruments: (1) the ABC-CV (Aman et al., 1985, 1995) and (2) the Clinical Global Impressions (CGI) scale (National Institute of Mental Health, 1988). For the ABC-CV, the parent, or care provider, was instructed to complete this instrument (which consists of a 58-item questionnaire with a 4-point rating scale and is used to measure behavior) at visits 0 (screen), 1 (baseline), and 2–5 inclusive (treatment). Instructions were given to ensure that the same rater was used throughout. The investigator also completed the ABC-CV on the basis of behaviors observed during the ADOS-G sessions, which were performed at screen (visit 0) and at the end of treatment (visit 5); ADOS-G sessions were videotaped. The CGI scale (National Institute of Mental Health, 1988), designed to assess severity of illness, global improvement, and efficacy index, was completed at visit 1 (baseline) and visits 2–5 inclusive (treatment). Instructions were given to ensure that the same observer (investigator) was used throughout. Variables used for the assessment of safety were derived from the use of (1) laboratory monitoring from blood and urine samples taken at screen (visit 0) and end of treatment (visit 5); and (2) adverse event
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Total Age (years) Females Median weight (kg) White (%) Concomitant SSRI (n) CGI-rated illness severity Mild Moderate Severe ABC irritability at baseline (parent) ABC hyperactivity at baseline
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(side effects) reporting, which was recorded at visits 1–5 inclusive. Adverse events were recorded on a specific form in which any potential side effects since the previous visit were recorded with date of onset and offset, and their nature, intensity, and outcome. Likelihood of association with the study drug was also assessed (e.g., is there a reasonable probability that this upper respiratory tract infection is study drug–related?). For serious adverse events, a supplementary form was provided for further characterization of the event. In addition, a full medical history and physical examination (including vital signs, height, and weight) was conducted at the screening visit (visit 0).The laboratory studies obtained included (1) hematology (complete blood cell count, differential); (2) clinical chemistries (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatine kinase, γ-glutamyltransferase, lactate dehydrogenase, bilirubin, blood urea nitrogen, cholesterol, creatinine, calcium, chloride, potassium, sodium); and (3) urinalysis. Statistical Analysis A total of 40 evaluable subjects (20 per treatment group) were deemed sufficient to detect, with at least 90% power, a difference in response rate between the two treatment groups of 50% (based on a two-sided test using a significance level of 5%). The primary efficacy variable was a binary outcome derivative of the parent-rated ABC-CV, and the analysis compared percentage of responders in the amantadine hydrochloride and placebo groups. This primary outcome variable was proposed as a means of identifying a difference that would represent improvements in behavior that would be meaningful to parents and would be considered of clinical relevance. A subject was defined as a “responder” if there had been a reduction of at least 25% in parentrated subscale scores for the ABC-CV for irritability and/or hyperactivity at the end of treatment (visit 5) compared with the baseline assessment (visit 1). The ABC-CV response rate for each treatment group was defined as the percentage of responders. The CGI responder (treatment success) definition was the percentage of subjects per group rated as showing moderate or marked improvement. For comparisons of ABC-CV subscales, estimates of treatment differences were expressed in adjusted least square means together with the associated 95% confidence interval. The statistical methods used included Pearson χ2, analysis of covariance, and summary statistics.
Fig. 1 Parent-rated Aberrant Behavior Checklist-Community Version mean Irritability subscale plotted against time. Week 1 represents the baseline assessment after 1 week of single-blind placebo treatment and the subsequent start of randomized treatment; week 2 represents 1 week of single-dose treatment; week 5 represents the final assessment after 3 additional weeks of bid treatment. There were no statistically significant differences between treatments.
estimated difference between treatments and 95% confidence intervals indicated a greater reduction from baseline with amantadine hydrochloride compared with placebo. For example, for the Hyperactivity subscale the estimated (least square means) treatment difference was –4.81 (mean change from baseline: –4.9 for amantadine hydrochloride compared with –1.6 for placebo), with the 95% confidence interval –11.63 to 2.00. Investigator-Rated ABC-CV Scores
Analysis of the investigator-rated ABC-CV scores at visits 0 and 5 revealed significant treatment differences.
RESULTS 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 for amantadine hydrochloride at all time points except 14 days. There were no statistically significant differences between ABCCV subscale scores for irritability (p = .178), lethargy (p = .960), or any of the other parent-rated ABC-CV subscale scores (Figs. 1 and 2). In three of the five subscales the
Fig. 2 Parent-rated Aberrant Behavior Checklist-Community Version mean Hyperactivity subscale plotted against time. Week 1 represents the baseline assessment after 1 week of single-blind placebo treatment and the subsequent start of randomized treatment; week 2 represents 1 week of single-dose treatment; week 5 represents the final assessment after 3 additional weeks of bid treatment. There was no statistically significant difference between treatments.
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These treatment differences were evident in comparisons of the subscale scores of Hyperactivity (p = .046) and Inappropriate Speech (p = .008). In addition, there was a trend toward significance for Stereotypy (p = .086). For Irritability (p = .141) and Lethargy (p = .353), differences were not significant. For Hyperactivity (Fig. 3) the estimated treatment difference (–5.75) showed that the reduction from baseline was greater for amantadine hydrochloride than placebo (95% confidence interval: –11.39 to –0.10). For Inappropriate Speech (Fig. 4) the estimated treatment difference (–2.24) showed that the reduction from baseline was greater for amantadine hydrochloride than placebo (95% confidence interval: –3.85 to –0.63). For Stereotypy the estimated treatment difference (–2.20) indicated that the reduction from baseline was greater for amantadine hydrochloride than placebo (95% confidence interval: –4.74 to 0.33). Clinical Global Impressions
Twice as many subjects in the amantadine hydrochloride group were considered to be responders, i.e., were rated as showing moderate or marked improvement, than in the placebo group (Fig. 5, visit 5). The success rate was 53% after amantadine hydrochloride compared with 25% for placebo (p = .076). The estimated treatment difference was 27.6 percentage points in favor of amantadine hydrochloride (95% confidence interval: 57.0% to –1.8%). Ratings of “marked improvement” were applied to 5/19 (26%) children receiving amantadine hydrochloride and
only 1/20 (5%) receiving placebo. As is evident in Fig. 5, it would appear that this difference in percentage of marked responders largely accounts for the overall trend toward improved CGI outcome for amantadine. There were no significant differences in the assessment of “severity of illness” at the final visit. In both treatment groups most patients had moderate severity of illness (53% for amantadine hydrochloride and 50% for placebo). The overall percentage of responders (moderate + marked) at 7, 14, 21, and 28 days (visits 2 through 5) was higher for amantadine hydrochloride within the first week and at all subsequent time points (Fig. 5). Safety Evaluation
Similar numbers of patients in both active and placebo groups experienced side effects. Fourteen (74%) patients on amantadine hydrochloride reported at least one side effect, compared with 14 (70%) patients on placebo. There were no serious adverse events. There were no adverse events that started prebaseline and worsened. The side effect reported most often was insomnia, which was reported in 4 subjects (21%) in the amantadine hydrochloride treatment group and 2 subjects (10%) in the placebo group. In all but one case the insomnia was rated as mild, the exception being a report of moderate insomnia in a subject in the placebo group. Two subjects in the amantadine hydrochloride group were reported to have somnolence. In the placebo group there were more
Fig. 3 Investigator-rated changes in Aberrant Behavior Checklist-Community Version hyperactivity derived from Autism Diagnostic Observation ScheduleGeneric videotapes (p = .046).
Fig. 4 Investigator-rated changes in Aberrant Behavior Checklist-Community Version inappropriate speech derived from Autism Diagnostic Observation Schedule-Generic videotapes at study entry versus completion (p = .008).
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reports of adverse events involving difficult or antisocial behaviors (broadly grouped as “personality disorder” within the Coding Symbols for Thesaurus of Adverse Reaction Terms [COSTART] terminology [US Food and Drug Administration, 1995] and including, for example, “increased self stimulation”): four reports versus two reports in the amantadine hydrochloride group. There were no reports of hallucinations, a side effect attributed to amantadine at high doses (King et al., 2001).
by Belsito and coworkers (1998). In their trial with lamotrigine, using the same 25% response definition, their responder rate in the placebo group ranged from 39% to 54% (P. Law, personal communication, 1998). Quintana and coworkers (1995) also noted that autistic children receiving placebo showed a decrease in hyperactivity scores in comparison with their respective baseline score. In that study, statistically significant improvement from baseline occurred in the placebo-treated group according to both the ABC and Conners Parent questionnaires. The evidence accumulating from our experiences and those of others suggests that placebo responses in studies involving children may be distinct from placebo responses in adults and deserves particular attention. Among the possible reasons for this finding, one might consider natural oscillations in behavior (perhaps more marked in children than adults), a true placebo effect, or regression to the mean. Expectancy effects, perhaps greater in parents of young children than in caregivers of autistic adults, or beneficial behavioral modification as a result of study participation, may also be important factors. Future studies will need to address and allow for these possibilities, by enrolling more subjects, or perhaps by extending the length of both placebo and active treatment phases of study and recruiting additional informants. Additional options might be to consider changing the threshold for inclusion and/or to use a crossover rather than parallel-group design.
DISCUSSION
Limitations
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, 1998), treatment of children in this study with placebo was associated with significant improvements in behavioral ratings. Thus, although 47% of children in the amantadine hydrochloride–treated group were rated by their parents as responders, so too were 37% of children in the placebo group. It was notable that the mean ABC-CV score data for this group also indicated a decrease from baseline in all subdomains (with the possible exception of Inappropriate Speech). With regard to the placebo response rate in children with autism, similar findings have also been made recently
The number of subjects in this study did not provide sufficient statistical power to confirm the effectiveness of amantadine over placebo across all of the outcome measures examined. Numbers of subjects are also insufficient to examine the response in subgroups, for example, children with more severe cognitive disabilities, females, or children receiving concurrent treatment with a serotonin reuptake inhibitor. All of these factors may also have influenced treatment response. Demonstrating efficacy for amantadine in this study is also limited by the singledose design. Amantadine hydrochloride was well tolerated at the 5mg/kg dose administered. In retrospect, it was perhaps “too well tolerated” given that there were no dropouts from the active treatment arm nor any statistically significant differences in side effects in comparison with placebo. The mean and median doses of amantadine were 168.3 mg and 134.5 mg, respectively, and the dose range was 90 to 200 mg. These doses are below the recommended 200-mg
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Fig. 5 Percentage of moderate and marked responders from Clinical Global Improvement ratings for amantadine (A) (n = 19) and placebo (P) (n = 20) by visit.
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amantadine dose for prophylactic treatment of children for influenza. At least one “nonresponder” was converted to a responder in an open-label extension of the study following a dosage increase. A follow-up study with a higher dose of amantadine might be justified. Our findings of a modest improvement in behavioral problems are consistent with previous open studies reporting improvements in symptoms such as hyperactivity, agitation, irritability, and self-injury following treatment of nonautistic children with amantadine (Chandler et al., 1991; King et al., 2001; Masters, 1997; Mattes, 1980). The mechanism underlying these behavioral improvements remains to be determined. In addition to its glutamatergic properties, amantadine interacts with dopaminergic systems, and there is evidence for dopaminergic influence on behavioral problems in autism such as hyperactivity. It is interesting, however, that both dopaminergic agonists and antagonists have been reported to be effective in this context (Birmaher et al., 1988; Campbell et al., 1982; McDougle et al., 1998). Furthermore, controlled trials have suggested that dopamine agonism may exacerbate some behaviors in autism including social withdrawal, hyperactivity, and stereotypy (Campbell et al., 1972, 1976).
autism or the expression of maladaptive behaviors in this context. Additional study will be important to clarify the role for NMDA antagonism as an approach to the treatment of this population and the safety and efficacy of amantadine or related compounds in treatment of hyperactivity in children, adolescents, and adults with autistic disorder. REFERENCES
In this study it was found that children with autism treated with amantadine hydrochloride, at a final daily dose of 5 mg/kg for 3 weeks, showed modest improvements in hyperactive behavior without significant adverse events. The CGI scale, perhaps influenced by reports from family or teachers in addition to direct observation, accorded significant improvement to active drug. But parent ratings alone did not statistically differentiate drug from placebo. Future trials in this population may benefit by inclusion of more systematic data from multiple informants or the use of a CGI-equivalent for parents. It is possible, for example, that improvement in behaviors such as “disturbs others” or “disobedient” is diluted and lost by inclusion with arguably less clinically significant items in the ABC such as “does not pay attention to instructions” or “restless.” In the same vein, because a substantial number of children showed behavioral improvements when treated with placebo, appreciation of the potential magnitude of a placebo response should be an important consideration in the design of drug trials for the treatment of children with autism. Glutamatergic dysfunction may be an important pathophysiological mechanism involved in
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