Journal of Autism and Developmental Disorders, VoL 21, No.

3, 1991

Brief Report: Effects of Fenfluramine on

Communicative, Stereotypic, and Inappropriate
Behaviors of Autistic-Type Mentally Handicapped
Individuals
Pieter C. Duker, 2 Karin Welles, Daniel Seys,
Hanneke Rensen, and Agnes Vis
Winckelsteegh, Nijmegen, and University of Nijmegen, The Netherlands

Gerard van den Berg

Hondsberg Observation Center, The Netherlands

In spite of many positive findings, controversy remains about the effective-

ness of fenfluramine with hyperserotonergic autistic individuals (e.g., Camp-
bell, 1988; Verglas, Banks, & Guyer, 1988). The controversy may be partially
due to methodological flaws in the studies in this area.
First, in several studies data were collected using an A-B design only (e.g.,
Campbell et al., 1988). Claims for validity of differences between experimen-
tal conditions are then heavily threatened by rival explanations. Double-blind
placebo controlled crossover designs, in which subjects are randomly assigned
to conditions, have also been used (e.g., Beisler, Tsai, & Stiefel, 1986; Cog-
gins et al., 1988). However, in these studies it was not clear whether observ-
ers/raters were informed or held naive with respect to the exact time point
of alternating or continuing experimental conditions. Side effects, which are
reported with fenfluramine, such as drowsiness, lethargy, decreased appe-

~This study was conducted at the Winckelsteegh, Nijmegen. We thank the ward staff and the
teachers for their contribution to the study. B. Rimland is acknowledged for providing diag-
nostic facilities. G. Lancioni is acknowledged for his suggestions to improve the manuscript.
We thank C. van Wychen for her assistance during the study. This study was supported by
a grant of SAMIVOZ to the first author.
2Address all correspondence to Pieter C. Duker, University of Nijmegen, PROCESS Research
Group, Erasmusgeb. 6500 HD Nijmegen, The Netherlands.
355
0162-3257/91/0900-0355506.50/0 9 1991 PlenumPublishingCorporation
356 Duker, Welles, $eys, Rensen, Vis, and van den Berg

rite, weight loss, social withdrawal, and irritability (e.g., Barthelemy et al.,
1989; Yarbrough, Santat, Perel, Webster, & Lombardi, 1987) may have in-
formed observers/raters (parents, teachers, ward staff) about the experimental
protocol. Observers/raters can, therefore, easily predict who receives the active
drug and who receives the placebo at any point during the study. In addi-
tion, an increase or decrease of side effects when experimental conditions
change, as evidenced by contrast effects, may have informed observers/raters
about individuals' placebo-drug schedule (see August, Raz, & Baird, 1985;
Groden et al., 1987).
Second, a threat to validity also pertains to the recording procedures
used. Only Yarbrough et al. (1987), Coggins et al. (1988), and Reiss, Egel,
Feinstein, Goldsmith, and Borengasser-Caruso (1988) employed naturalistic
observations. Other investigators used rating scales and IQ tests to assess
treatment effectiveness. Rating scales produce data that are easily influenced
by processes such as observer bias and halo effects. When using IQ scores
as a dependent variable (e.g., August et al., 1985; Ritvo & Freeman, 1986),
it should be noted that (a) there is a weak conceptual tie between the hypothe-
sized drug effect and IQ scores, (b) statistical regression may account for
differences, (c) changes in IQ scores may be attributed to repeated testing,
and (d) IQ changes may be mediated by observers'/raters' awareness of the
protocol.
Third, in several studies (e.g., August et al., 1985) data that were ordi-
nal (e.g., ratings) were analyzed as if they were of an interval type.
Fourth, recording of reliability (inter- and intraobserver agreement) has
only been occasionally performed. Yarbrough et al. (1987) trained observ-
ers to attain a criterion of 80~ reliability of recording prior to formal data
collection. No data on reliability were collected during the study itself. Au-
gust et al. (1985) mentioned that following each session of reliability record-
ing observers informed each other about their performance, whereas in a
later study (August, Raz, & Baird, 1987) reliability for recording was assessed
during baseline only. Observer drift will occur when observers inform each
other about their performances during data collection, thereby posing a threat
to internal validity. Also, as far as we know, none of the studies evaluating
the effects of fenfluramine with autistic individuals used intraobserver in-
dices of reliability to strengthen validity.
In the present study we attempted to circumvent the above problems
by (a) using videotaped recordings of individuals' behaviors in that observ-
ers remained naive with respect to the occurrence of any of individuals' side
effects and their medication status, (b) using naturalistic observations (of
videotaped recordings) instead of rating scales, and (c) using interobserver
agreement assessments for recording throughout the study, while prevent-
ing the observers from informing each other about their performance.
Effects of Fenfluramine 357

Moreover, (d) time-series analysis was used as a statistical procedure to en-

sure that within-subject variability would be taken into account. Finally,
videotaped sessions allowed us to assess intraobserver agreements for
recording.

METHOD

Subjects

Twenty-eight subjects who met the D S M - I I I - R (American Psychiatric

Association, 1987) definition o f autistic disorders (299.00) were selected in
a residential facility for mentally handicapped individuals. Two physicians
and two psychologists who were familiar with the residents selected these
subjects. Parent consent was obtained for assessing subjects' peripheral blood
serotonin levels exceeding 3.6 nmol/109 platelets (i.e., these values exceed-
Criterion for elevated serotonin level was based on the data o f 46 individu-
als with normal levels of intelligence. It was decided that subjects with blood
serotonin levels exceeding 3.6 mmol/109 platelets (i.e., these values exceed-
ed the third quartile o f the values obtained with the above sample) would
participate, which resulted in 11 subjects' participation (see Table I). Two
o f them were epileptic, but no changes in medication occurred during the
course o f the study.

Recording

Subjects' behaviors were videotaped. Video recordings of 10 minutes

were taken at arbitrarily chosen time points, two or three times each week.

Table I. Characteristics of the Subjects

Subject Age (years) Sex Levelof retardation ~
G.A. 17 M Severe
S.C. 30 F Profound
R.C. 30 M Profound
M.H. 18 M Severe
R.K. 14 F Profound
M.Ma. 6 M Severe
M.Me. 27 M Severe
E.S. 13 F Severe
R.V. 10 M Severe
R.W. 25 M Profound
B.W. 12 F Profound
~Estimated according to AAMD classification on basis of
Vineland Social Maturity Scale.
358 Duker, Welles, Seys, Rensen, Vis, and van den Berg

There were no limitations imposed as to the situation of recording subjects'

behaviors, apart from when they were on the toilet, or when bathing. Record-
ings were taken on the living group, in the classroom, on the playground,
in the bathroom, when they were walking with ward staff, and so on. While
recording, observers withheld interaction with ward staff and subjects. Data
collection did not begin until all videorecordings had been made. Also it was
only after all data recording and reliability assessments had been conducted
that the code pertaining to the experimental design (see below) was broken.
Data were collected using a computer (Repp, Harman, Felce, Van Acker,
& Karsh, 1989). Each response to be recorded (see Behavior Categories) had
been allocated a key on the computer. Assessments of blood serotonin level,
using high-pressure liquid chromatography (Anderson, Young, Cohen,
Schlicht, & Patel, 1981), occurred in a laboratory not associated with the
facility once during the conditionins of baseline and fenfluramine.

Behavior Categories

Three behavior categories were defined.

Communicative Behaviors. This category encompassed any oral be-
havior (i.e., spontaneously and elicited), including echolalia (delayed and im-
mediate), vocalizations, but also communicative gesturing. Verbally
inappropriate behaviors (e.g., screaming, yelling) were recorded as Inap-
propriate Behaviors (see below). This category was recorded for the seven
subjects who were known to have communicative behaviors.
Stereotypic Behaviors. This category encompassed all repetitive be-
haviors, such as hand flapping, body rocking, rubbing, tapping, and so on.
We provided concise descriptions in this respect. For example, body rocking
was defined as subject is sitting, standing, or lying and moves upper torso
front-to-back or side-to-side at a frequency of at least one time per second,
the angle between torso and lower body part being at least 30 degrees. Be-
haviors of all subjects were recorded.
Inappropriate Behaviors. This category encompassed behaviors such
as aggression, head banging, head hitting, spitting, and screaming. This
category was recorded for the three subjects who were known to have inap-
propriate behaviors.
Subjects' behaviors were assigned to the above response categories in
terms of rate per minute (e.g., bangs head, hits self), or percentage of dura-
tion (e.g., rocks body) for each session. Response definitions were neither
mutually exclusive nor exhaustive.
Effects of Fenfluramine 359

Reliability of Recording

Data were obtained by having the observer record the videotapes two
times in order to calculate intraobserver reliability coefficients. To control
for observer drift, observers were not informed as to their performance on
previous recordings. Indices of interobserver reliability were assessed by hav-
ing a second observer record videotapes of four subjects.

Procedure

There were three experimental conditions.

Baseline. No drug or placebo was given to the subjects during a 4-week
period. Standard programs for each of the subjects remained in effect, such
as drug treatment for seizures, speech training, training of gestural commu-
nication, perceptual-motor training, physical therapy, recreation, and occupa-
tional therapy.
Fenfluramine. While standard programs continued, each subject
received 1.5 mg of fenfluramine/kg/per day. The medication, in tablet form,
was taken in two divided doses.
Placebo. While standard programs continued, each subject received 1.5
mg of avicel (cellulose)/kg/per day. The placebo, in a similar tablet form
as the fenfluramine, was taken in two divided doses.

Experimental Design

After the baseline period, each subject was assigned either to a condi-
tion of fenfluramine or to placebo using standard randomization procedures.
After a point of time, which was different for each subject (see below), the
condition would switch. Decisions regarding assignment and switching were
taken by one of the physicians, prior to data collection. Observers, parents,
and direct care staff only knew that during the period following baseline,
each subject would have at least one condition of fenfluramine and one of
placebo, but they remained naive with respect to order and length of condi-
tions. Length of fenfluramine conditions ranged from 5 to 12 weeks and of
placebo from 3 to 6 weeks across the 11 subjects. The above measure were
taken to enhance methodological control.
360 Duker, Welles, Seys, Rensen, Vis, and van den Berg

RESULTS

Assessment of blood serotonin 5-HT levels occurred once during base-

line and fenfluramine. Using paired t tests, two-tailed testing of differences
revealed a statistically significant difference of means of blood serotonin
5-HT (nmol/109 platelets) levels between baseline and fenfluramine, t(10)
= 10.73, p = .0001, with respective means o f 5.52 (SD = 1.30) and 1.77
(SD = 1.37).
Intraclass coefficients of intraobserver reliability of behavioral record-
ings averaged .94 (range .87-.99). As an estimation of reliability o f record-
ing, interobserver reliabilities were calculated for four subjects, yielding an
average of .94 (range .90-.99).
For purposes of statistical analysis, data were transformed into Z values
as scores within each of the three categories were collected either as rate per
minute or as percentage duration. T I D A , a time-series program (Oud, 1991),
was used to test differences. T I D A uses M A N O V A to describe interrupted
time-series across subjects utilizing polynomial curves. The program has been
designed to test changes in the trend of the curve at the starting point of
the intervention, taking into account serial dependency between the scores.
The statistic used is the F transformation of Wilk's lambda.
With respect to communicative behaviors, four subjects' behaviors
(R.V., R.C., R.K., M.Ma) were c o m p a r e d in the order baseline versus fen-
fluramine and fenfluramine versus placebo, with F(1, 3) = 4.433, p = . 13
and F(1, 3) = .004, p = .95, respectively, indicating the absence of differ-
ences. Three subjects' communicative responses (G.A., M . H . , E.S.) were
compared in the order baseline versus placebo and placebo versus fenflura-
mine. The values o f F ( l , 2) = 5.95, p = .393 and F(1, 2) = 0.119, p =
.763 for the respective comparisons, indicate that no differences were found.
Six subjects' stereotypic behaviors (R.W., M.M., R.V., R.C., R. K.,
M.Ma.) were compared in the order baseline versus fenfluramine and fen-
fluramine versus placebo. Time-series analysis, revealing F(1, 5) = 0.644,
p = .459, and F(1, 5) = 4.072, p = .097 for the respective conditions, indi-
cate that there were no differences. For the remaining five subjects, com-
parisons of scores were made in the order baseline versus placebo and placebo
versus fenfluramine. Analysis of the time-series data, revealing F(1, 4) =
0.492, p = .522, and F(1, 4) = 0.627, p = .473, for the respective condi-
tions, indicate that there existed no differences. Finally, the inappropriate
behaviors of three subjects (R.W., R.C., R.K.) were c o m p a r e d in the order
baseline versus fenfluramine and fenfluramine versus placebo. Analysis rev-
ealed no differences, with F(1, 2) = 2.31, p = .08 and F(1, 2) = 1.147,
p = .397, respectively. No adverse side effects were reported.
Effects of Fenfluramine 361

DISCUSSION

The difference in whole blood serotonin levels between baseline and

treatment was statistically significant. This finding is in agreement with other
findings (e.g., August et al., 1985; Coggins et al., 1988; Ritvo & Freeman,
1986).
The results suggest that the administration of fenfluramine with the
present sample fails to increase communicative behaviors and to decrease
stereotypic behaviors and inappropriate behaviors. Also, the serotonergic ef-
fect is not related to the behavioral improvement. The failure to affect in-
dividuals' communicative behaviors is in accordance with results found by
Beisler et al. (1986) and Coggins et al. (1988). The results with respect to
stereotypic behaviors, however, are in contrast to the findings of Campbell
et al. (1986) and Ritvo and Freeman (1986), relying on the Children's Psy-
chiatric Rating Scale, the Real Life Rating Scale (RLRS), and parents' subjec-
tive comments. The present results are also in contrast with results of Groden
et al. (1987), who found a decrease of self-stimulation on the RLRS during
the drug phase. Although Groden et al. (1987) trained their observers to rate
subjects' behaviors, no information was given whether these observers were par-
ents or ward staff.
An increasing number of studies are appearing documenting the ab-
sence of any behavioral (Beeghly, Kuperman, Perry, Wright, & Tsai, 1987;
Reiss et al., 1988; Stubbs, Budden, Jackson, Terdal, & Ritvo, 1986), or cog-
nitive (Ho, Lockitch, Eaves, & Jacobson, 1986; Yarbrough et al., 1987) ef-
fects of fenfluramine with autistic individuals. Even retarding or paradoxical
effects of this drug have been documented (Campbell, 1988; Campbell et
al., 1988; Coggins et al., 1988). A parallel-group design with random assign-
ment of 28 autistic children to either a condition of fenfluramine or placebo
failed to reveal significant differences on a large number of behavioral meas-
ures, except for fidgetiness and withdrawal (Campbell et al., 1988).
An explanation of conflicting evidence on the effects of fenfluramine
might be that studies differ in their attempts to control for observational
bias and other artifacts. As noted, side effects of a drug treatment may in-
form observers and create expectancy with regard to the effect. O'Leary and
Kent (1977) demonstrated that global evaluations of individuals' behaviors
can be influenced by expectations alone. It might be that observers/raters,
who are involved with the individual to be observed, are more susceptible
to bias. It might also be that fenfluramine is differentially effective across in-
dividuals, the characteristics of whom have not been represented in the
present sample.
362 Duker, Welles, Seys, Rensen, Vis, and van den Berg

At least two methodological limitations should be imposed on the

results of this study. First, the high reliability scores obtained may be inflat-
ed, in that the recording technique did not allow us to identify the degree
of overlap between the occurrences of behavior that these scores represent.
A second limitation refers to the low power of the statistical tests of this study.
However, the small effect sizes obtained may have reduced the likelihood
that we failed to reject the null hypothesis when it was false.

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