Effects of fenfluramine on the behavior of autistic individuals

Dlsabrhrres, Research m Developmenrd Primed in the USA. All rights reserved.

Vol. 8. pp. 203.21 I, 1987 Copyright

6

0891-4222/87 13.00 + .M) 1987 Pergamon Journals Inc.

Effects of Fenfluramine on the Behavior of Autistic Individuals Gerald Groden, June Croden, Mitchell Dondey, and Thomas Zane Behavioral

Development

Center,

Rhode

Island

Siegfried M. Pueschel Child Development

Center, Rhode /s/and Hospital

Wayne Veliceur University of

Rhode k/and

The present report, part of a national, multicenter study to investigate the effects of fenfluramine on autistic behavior, describes findings on four autistic children ranging in age from 7 to 20 years. Additional performance and parental observation measures apart from those of the multicenter study are included. Results of this study which indicated no significant side effects, a reduction in some deviant behaviors and an improvement in activity level/attention span, provide support for earlier reports. The possibility that fenfluramine’s apparrently positive effects might be to simply reduce inappropriate behaviors via lethargy was examined and not supported.

INTRODUCTION

In 1961, Schain and Freedman reported that some autistic children showed elevated blood serotonin levels. In 1970, Ritvo et al. completed a more thorough controlled study where they reported that serotonin levels in autistic individuals were significantly higher than in the controls. Geller, Ritvo, Freeman, and Yuwiler (1982) postulated that this increased serotonin level might be a cause of autism. Fenfluramine, which had been previously approved for weight loss for adults and which is known to reduce blood serotonin concentration, and hypothesized to reduce brain serotonin levels, was administered by them to three autistic children. Corresponding to a decrease in serotonin level, the children also reportedly displayed improve-

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ments in IQ and behavior. Follow-up studies by Ritvo, Freeman, Geller, and Yuwiler (1983), Ritvo, Freeman, Yuwiler, Geller, Yokota, Schroth, and Novak (1984), and Ritvo et al., (1986) also reported a reduction of autistic symptomology in autistic children while on fenfluramine. Although the data for IQ changes were less clear, Ritvo et al. (1983) found only that a subgroup of the subjects showed any changes in IQ and these could be attributed to practice effects. In addition, while these changes were statistically significant, they were probably too small to be clinically significant. On the basis of these preliminary, but encouraging results, Ritvo initiated a multicenter study to evaluate the effects of this drug on a large number of autistic children. August, Raz, and Baird (1985) recently published initial findings from their portion of the study involving nine children and they reported a reduction in motor disturbances, as noted by staff during clinic visits, and a decrease in hyperactivity as observed by parents. Similar results were also noted by Klykylo, Feldis, O’Grady, Ross, and Halloran (1985) who like August, Raz, and Baird (1985) found no changes on intelligence tests. The present study, also performed as part of the multicenter effort, partially supports and extends previous reports. METHODS

Subjects Four individuals were found who met all selection criteria. All are participants in a day program at the Behavioral Development Center, a treatment and educational program in Providence, Rhode Island. The basis of selection was that the children met criteria of both the National Society for Autistic Children (Ritvo & Freeman, 1978) and the Diagnostic and Statistical Manual, III of the American Psychiatric Association (APA, 1980) definitions of autism as determined by the principal investigator of the multicenter collaborative project, Dr. Edward Ritvo, and a Behavioral Development Center investigator. All individuals were clinically seizure free and none were currently on any type of psychotropic medication. Parental consent was obtained. Table 1 contains descriptive information for each participant. Research Design A double-blind placebo cross-over design was used as specified by the mutlicenter research team at UCLA. The research began with a four week placebo-training period for all participants. During that time baseline data were obtained and individuals

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TABLE 1. Descriptive Information

Age

Sex

1

19

F

56.4

80

29

StanfordBinet

.390

2

13

M

34.1

40

45

WlSC-R

.144

3

20

M

72.3

80

33

Stanford-

.312

4

7

M

40.0

40

20

Cattell

.216

Child

Dosea (in mgs)

I.Q.

Baseline Serotonin LeveP

Weight (in kg)

I.Q. Test

‘Approximate dosages based on individual’s body weight was 1.5 mg/kg. When prescribed dosage did not conform to the use of whole pills, Dr. Edward Ritvo, Coordinator of the Multi-Center Study, made recommendations as to exact amounts of medication. bMicrograms per milliliter.

were trained by the parents to accept tablets twice daily, once in the morning at 9:00 a.m. and once in the afternoon at 3:00 p.m. The experimental phase followed with half of the participants receiving fenfluramine for four months while the other half remained on placebo. After 4 months there was a cross-over in which those who were in one condition changed to the other. Measurements Bio-medical monitoring. All participants were monitored weekly for height and weight, and daily for side effects by project personnel as well as by the parents of the participants. Blood serotonin and blood chemistry was monitored monthly as indicated by the research protocol. Serotonin assays were conducted according to methods described by Yuwiler, Plotkin, Geller, and Ritvo (1970) and were completed at The Neurobiochemistry Laboratory at the Veterans Administration Hospital in Los Angeles, California. Clinical Monitoring Side effects. All parents maintained a daily log wherein they indicated their observations of their child’s behavior. This included specific behaviors (e.g., increased finger tapping), emotional changes (e.g., increased laughing), and communication changes (e.g., increased verbal initiations). The daily diary used by all of the multicenter participants and designed by Dr. Edward Ritvo, was utilized for this purpose. Training sessions were initially con-

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ducted with parents to insure accurate recording of information. All parents met monthly with the principle investigator to go over the diary and the specific information included. Z.Q. Intelligence testing was conducted six times during the course of the study. Tests used were the Wechsler Intelligence Scale for Children Revised (Wechsler, 1974), and the Cattell (1960) or the Stanford-Binet Intelligence Scales (Thorndike, 1972). All tests were administered by a psychologist with extensive testing experience with autistic children and who was blind to treatment conditions. AI1 the participants were assigned to one instrument for the entire study based on their age and ability.

Adaptive Behavior All participants were rated by parents and designated center staff, trained by personnel experienced in administering the tests, six times during the course of the research on either the AAMD Adaptive Behavior Scale (AAMD, 1980) or the Alpern-Boll Development Profile (Alpern-Boll, 1980). Assignment was based on age and verbal abilities.

Social/Emotional

Behavior

Ritvo-Freeman Real Life Rating Scale for autism (RLRS). The Real Life Rating Scale (Ritvo et al., 1983) consists of 47 behaviors in the areas of motor, affect, language, social, and sensory functioning. Each participant was rated monthly by three trained observers during a 45 minute period. Participants were engaged in either lunch, free-time, or language activities that involved peers as well as other adults. Observers were trained prior to the beginning of the study and had reached an interrater reliability of .85 for the scale as a whole which was consistent through the entire study. The procedure used for interrater reliability was the number of intervals of agreement among observers divided by the total number of intervals. Behavioral Social Screening Scale (BSSS). Once per month parents completed a behavior scale designed by one of the project investigators (Groden, 1982). The scale, which has shown to have a test-retest reliability of .86, consists of 39 items and 5 categories-personality problems, conduct problems, tics, activity level/attention span difficulties, and atypical behaviors.

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of

Fenfluramine

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Academic/developmental task performance. Each child participated in an academic or developmental task each week with a teacher and his/her accuracy of performance was recorded. For three of the children, the task consisted of learning new sight words and for the fourth child, carrying out directions correctly was employed. Over-selectivity. Overselectivity was assessed by having children learn discriminations with multiple cues and then assessing the extent that they were guided by one or more cues. All children were taught to discriminate one picture from another. Each picture consisted of two components ranging in complexity from common objects to abstract Chinese symbols. Training sessions occurred daily until the discriminations were mastered. Once a child acquired the initial pair discriminations, they were tested on the individual components of the stimulus pairs to assess the control exerted by each of the two components of the reinforced stimulus pair.

RESULTS

Two different types of analysis were employed. The first was a two-way analysis of variance with repeated measure on the second factor. The first factor was order (A-B-A or A-A-B). The second factor was trials, representing each of the months of data gathering beginning after the placebo-training period. This analysis was employed for all data that was gathered monthly. A priori comparisons were employed to directly compare the drug and nondrug trials. The data that was gathered weekly was analyzed using time series analysis (Glass, Wilson, & Goltman, 1975). Because the number of data points did not permit identification of the specific series (Velicer & Harrop, 1983), an auto regressive order-one model was employed for all analyses. This model is robust across a wide variety of situations (Harrop & Velicer, 1985; Simonton, 1977). Side Effects No significant behavioral or physical problems were noted by parents as a result of fenfluramine administration. As in the August et al. report (1985), brief periods of lethargy were noted in some children at the onset of the drug phase. Parents also reported a modest decrease in appetite throughout this phase. This decrease was particularly appreciated by one family whose child was overweight. The largest weight loss during the course of the study was five pounds and all children returned to prestudy weight upon discontinuation of fenfluramine.

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Biochemical Data

Blood serotonin was noted to decrease for all four children following fenfluramine administration. Levels of fenfluramine were approximately one-half or less, levels prior to study onset or on placebo. Klykylo et al. (1985) and Ritvo et al. (1984) also found that the dosages selected uniformly decreased serotonin levels about 50% regardless of initial blood levels. The mean level of the serotonin for the nondrug phase was .24 mg/ml compared with .lO mg/ml for the drug phase (F (1, 16 = 80.48, p< .OOl). Serotonin returned to pretreatment levels following discontinuation of fenfluramine.

Behavioral Data

For analysis of drug effect on behavior, combined scores for each measure were compared for all four children for drug versus placebo phases and differences were analyzed for significance. No group differences were found for I.Q., adaptive behavior or overselectivity. Analysis of the group RLRS scores for drug versus nondrug phases revealed a significantly lower score, indicating less deviant behavior for the drug phase (drug mean 46, nondrug mean 82, F (1, 20) = 4.60, p< .05). Further analysis revealed this difference was accounted for by one of the five RLRS categories, sensory response, which was Significantly lower during the drug phase for the entire group (M drug 14.9, M nondrug 40.1, F (1, 20) = 9.49, p< .Ol) as well as for each child. Average individual changes from nondrug to drug phases ranged from 5 to 78. There were no group differences for the other four categories. The group score for one of the five parent completed Behavioral Social Screening Scale categories, activity level/attention span, was significantly different from the drug to nondrug phase showing fewer,problems in the drug phase (F (1, 6) = 9.94 p c .05). The mean for nondrug was 6.1 compared to 5.3 for the drug phase.

Academic Developmental

Task Performance

To assess for differences in learning rate, or level while carrying out teacher instructions, each child’s learning rate and level of performance accuracy was compared for drug versus nondrug conditions. A separate time series analysis was performed on each child. For three out of the four children, rate of learning (change in percent of correct response over trials) on drug was either equal (two children) or better (one child) to rate of learning on placebo. For one child, rate of learning was less on the drug than on the placebo. For this child, rate of learning for the first half of the drug

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condition was quite high, but then was negative during the last half. Also, the children’s learning on the tasks used to assess overselectivity was similar on both drug and nondrug conditions. DISCUSSION

The findings of this study are similar to those of August et al, (1985), Ritvo, et al. (1983), Klykylo’et al. (1985), Ritvo et al. (1984), and Ritvo et al. (1986) in indicating a lack of serious side effects of fenfluramine when administered over several months, a reductive and reversible effect on blood serotonin level, and positive behavioral changes. In light of the fact of significant drug/placebo differences in the RLRS sensory response and BSSS, activity level/attention span categories obtained in this study, it does appear that fenfluramine has a particular beneficial effect on atypical motor behaviors in children with autism. The findings are of special interest in that they derive from separate environments (Center and home) and observers (staff and parent). In spite of the different study design (matched drug/placebo cross over versus ABA), these findings are also similar to that of August et al. (1985) in that they indicate RLRS changes related to motor behavior as opposed to social, language or affective behaviors. Although August and coworkers (1985) reported changes on the sensory motor in contrast to the sensory response category, both differ from the other categories in their reflection of atypical motoric responses. Our findings are also similar to those of August et al. (1985) in that in our study parents reported an improvement in activity level/attention span and in the August et al. study (1985), parents also reported an improvement in activity level. The findings of the children’s functioning on learning and academic type tasks while on fenfluramine are of special interest. Because of August et al. (1985) and our observations of at least initial lethargy on fenfluramine, and the absence of evidence of its enhancing positive behaviors (e.g., language), the possibility existed that fenfluramine’s main effect might be lethargy, albeit less pronounced over time, which in turn reduced inappropriate behavior. If this were so, a similar retarding effect might also be seen on the academic/developmental tasks. As already indicated, this was not generally so, suggesting that fenfluramine’s ameliorating effect may be via other mechanisms. Also in agreement with August et al. (1985) and Klykylo et al. (1985), we observed no I.Q. increases. In light of the duration of the study and the fact that abilities reflected through I.Q. tests develop over time and experience, such increases were not expected. Although the number of children in this study was small, findings are considered to be worthy of note due to their internal consistency and similarity to earlier reports.

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et al.

It is hopeful that future reports will help to clarify and systematize our understanding of fenfluramine’s effects on persons afflicted with autism.

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