effects of fenfluramine on communicative, stereotypic and inappropriate behaviors of autistic-type...

8/8/2019 Effects of Fenfluramine on Communicative, Stereotypic And Inappropriate Behaviors of Autistic-Type Mentally Handi

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Journal o f Au tism and Developmen tal Disorders, VoL 21, No. 3, 1991

Brief Report: Effects of Fenfluramine onCommunicative, Stereotypic, and InappropriateBehaviors of Autistic-Type Mentally HandicappedIndividualsPieter C. Duk er, 2 Karin W elles, D aniel Seys,Hanneke Rensen, and Agnes VisWinckelsteegh, Nijmegen, and University o f Nijmegen, The NetherlandsGerard van den BergHondsberg 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 partiallydue 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-blindplacebo controlled crossover designs, in which subjects are randomly assignedto 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 pointof alternating or continuing experimental conditions. Side effects, which arereported with fenfluramine, such as drowsiness, lethargy, decreased appe-

~This study was conducted at the Winckelsteegh, Nijmegen. We thank the ward sta ff and theteachers 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 bya grant of SAMIVOZ to the first author.

2Address all correspondence to Pieter C. Duker, University of Nijmegen, PROCESS ResearchGroup, Erasmusgeb. 6500 HD Nijmegen, The Netherlands.355

0162-3257/91/0900-0355506.50/0 9 1991 Plenum PublishingCorporation


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356 Duker, Welles, $eys, Rensen, Vis, and van den Bergri te, weight loss, social withdrawal, and irri tabili ty (e.g. , Barthelemy et al . ,1989; Yarbrough, Santat , Perel, Webster, & Lombardi, 1987) may have in-forme d observe rs/raters (parents, teachers, w ard staff) abou t the experimentalprotoco l. O bserve rs/raters can, therefore, easily predict who receives the activedrug and who receives the placebo at any point during the study. In addi-t ion, an increase or decrease of s ide effects when exper imental condi t ionschange, as evidenced by contrast effects, ma y have informed observers/ratersabou t individuals ' p laceb o-dru g schedule (see Augu st , Raz, & Baird, 1985;Groden et al. , 1987).

Second, a threat to validity also pertains to the recording proceduresused. Only Yarbrough et al . (1987), Coggins et al . (1988), and Reiss, Egel,Feinstein, Goldsmith, and Borengasser-Caruso (1988) employed naturalist icobservations. Other investigators used rating scales and IQ tests to assesstreatme nt effectiveness. Rating scales prod uce d ata that are easily influencedby processes such as observer bias and halo effects . When using IQ scoresas a depe nden t variable (e.g. , Aug ust et al ., 1985; Ritvo & Free ma n, 1986),i t should be noted that (a) there is a weak conceptual t ie between the hypothe-sized drug effect and IQ scores, (b) statist ical regression may account fordifferences, (c) changes in IQ scores may be attr ibuted to repeated testing,and (d) IQ changes ma y be mediated by observers ' / ra ters ' awareness of theprotocol .Third, in several studies (e.g., A ugu st et al. , 1985) dat a tha t were ordi-nal (e.g. , ratings) were analyzed as if they were of an interval type.

Fourth, recording of reliability (inter- and intraobserver agreement) hasonly been occasional ly performed. Yarbrough et a l . (1987) t ra ined observ-ers to attain a criterion of 80~ reliabili ty of recording prior to fo rma l datacollection. No data on reliabili ty 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 alater study (A ugust, Raz, & Baird, 1987) reliability for reco rding w as assessedduring baseline only. Observer drift will occur when observers inform eachother a bou t their perform ances during d ata collection, thereby posing a threatto internal validity. Also, as far as we know, none of the studies evaluatingthe effects of fenfluramine with autist ic individuals used intraobserver in-dices of reliabili ty to strengthen validity.

In the present s tudy we at tempted to c ircumvent the above problemsby (a) using videotaped recordings of individuals ' behaviors in that observ-ers remained naive with respect to the occurrence of any of individuals' sideeffects and their med ication status, (b) using naturalist ic ob servatio ns (ofvideotaped recordings) instead of rating scales, and (c) using interobserveragreement assessments for recording throughout the s tudy, while prevent-ing the observers f rom informing each other about their performance.


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Effects of Fenfluramine 357

M o r e o v e r , ( d ) t i m e - s e ri e s an a l y s i s w a s u s e d a s a s t a ti s ti c a l p r o c e d u r e t o e n -s u r e t h a t w i t h i n - s u b j e c t v a r i a b i l i t y w o u l d b e t a k e n i n t o a c c o u n t . F i n a l ly ,v i d e o t a p e d s e s s i o ns a l l o w e d u s t o a s s es s i n t r a o b s e r v e r a g r e e m e n t s f o rr e c o r d i n g .

M E T H O D

SubjectsT w e n t y - e i g h t s u b je c ts w h o m e t t h e D S M - I I I - R ( A m e r i c a n P s y c h i a tr i c

Ass oc ia t ion , 1 987) de f in i t ion o f au t i s t i c d i sorde r s (299 .00) were se l ec ted ina r e s id e n t i al f a c i l i ty f o r m e n t a l l y h a n d i c a p p e d i n d i v i d u a ls . T w o p h y s i c i a n sa n d t w o p s y c h o l o g i s t s w h o w e r e f a m i l i a r w i t h t h e r e s i d e n t s s e l e c t e d t h e s esub jec t s . Pa r en t consen t was ob ta ined fo r a s se ss ing sub jec t s ' pe r iphe ra l b loodserotonin levels exceeding 3.6 nmol/109 platelets ( i .e . , these values exceed-C r i t e r i o n f o r e l e v a t e d s e r o t o n i n l ev e l w a s b a s e d o n t h e d a t a o f 4 6 i n d i v i d u -a l s w i th n orm a l l eve ls o f in t el l igence . I t was dec ided th a t su b jec t s w i th b lo odse ro ton in l eve l s exceed ing 3 .6 m m ol /1 09 p la t e l e t s ( i . e . , t he se va lues exceed-e d t h e t h i r d q u a r t i l e o f t h e v a l u e s o b t a i n e d w i t h t h e a b o v e s a m p l e ) w o u l dp a r t i c i p a t e , w h i c h r e s u l t e d i n 11 s u b j e c t s ' p a r t i c i p a t i o n ( se e T a b l e I ) . T w oo f t h e m w e r e e p i l e p t i c , b u t n o c h a n g e s i n m e d i c a t i o n o c c u r r e d d u r i n g t h ec o u r s e o f t h e s t u d y .

RecordingS u b j e c t s ' b e h a v i o r s w e r e v i d e o t a p e d . V i d e o r e c o r d i n g s o f 1 0 m i n u t e s

w e r e t a k e n a t a r b i t r a r i l y c h o s e n t i m e p o i n t s , t w o o r t h r e e t im e s e a c h w e e k .Table I. Characteristics of the Subjects

Subject Age (years) Sex L ev elof retardation ~G.A. 17 M Sev ereS.C. 30 F ProfoundR.C. 30 M ProfoundM.H. 18 M Sev ereR.K. 14 F ProfoundM.Ma. 6 M SevereM.Me. 27 M Sev ereE.S. 13 F Se ve reR.V. 10 M Sev ereR.W. 25 M ProfoundB.W. 12 F Profound~Estimated according to AAM D classification on basis ofVineland Social Maturity Scale.


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358 Duker, Welles, Seys, Rensen, Vis, and van den Berg

There were no limitations imposed as to the s ituation 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. Whilerecording, observers withheld interaction with ward s taff and subjects. Datacollection did not begin until all videorecordings had been made. Also it wasonly after all data recording and reliability assessments had been conductedthat 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) hadbeen 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 thefacility once during the conditionins of baseline and fenfluramine.

Behavior CategoriesThree 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. Verballyinappropriate behaviors (e.g., screaming, yelling) were recorded as Inap-propriate Behaviors (see below). This category was recorded for the sevensubjects 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 rockingwas defined as subject is sitting, standing, or lying and moves upper torsofront-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 suchas aggression, head banging, head hitting, spitting, and screaming. Thiscategory was recorded for the three subjects who were known to have inap-propriate behaviors.

Subjects' behaviors were assigned to the above response categories interms 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 neithermutually exclusive nor exhaustive.


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Reliability of RecordingData were obtained by having the observer record the videotapes twotimes in order to calculate intraobserver reliability coefficients. To controlfor 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.

ProcedureThere 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, suchas 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 subjectreceived 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 1.5mg of avicel (cellulose)/kg/per day. The placebo, in a similar tablet formas the fenfluramine, was taken in two divided doses.

Experimental DesignAfter the baseline period, each subject was assigned either to a condi-tion of fenfluramine or to placebo using standard randomization procedures.

After a point o f time, which was different for each subject (see below), thecondit ion would switch. Decisions regarding assignment and switching weretaken 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 ofplacebo, but they remained naive with respect to order and length of condi-tions. Length of fenfluramine conditions ranged from 5 to 12 weeks and ofplacebo from 3 to 6 weeks across the 11 subjects. The above measure weretaken to enhance methodological control.


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R E S U L T SA s s e s s m e n t o f b l o o d s e r o t o n i n 5 - H T l e ve ls o c c u rr e d o n c e d u r i n g b a s e -l in e a n d f e n f l u r a m i n e . U s i n g p a i r e d t t e st s , t w o - t a i l e d t e s ti n g o f d i f f e r e n c e s

revea led a s ta t i s t ica l ly s igni f icant d i f fe rence of means of blood serotonin5 - H T ( n m o l / 1 0 9 p l a te l e ts ) le v el s b e t w e e n b a s e l i n e a n d f e n f l u r a m i n e , t (1 0 )= 10.73, p = .0001 , wi th respec t iv e me an s o f 5 .52 (SD = 1.30) an d 1.77(SD = 1.37).

I n t r a c l a s s c o e f f i ci e n t s o f i n t r a o b s e r v e r r e l i a b il i ty o f b e h a v i o r a l r e c o r d -i n gs a v e r a g e d . 94 ( r an g e . 8 7 - .9 9 ) . A s a n e s t i m a t i o n o f r e l i a b il i ty o f r e c o r d -ing , in t e robse rve r r e l i ab i l i t i e s were ca lcu la t ed fo r four sub jec t s , y i e ld ing ana v e r a g e o f . 9 4 ( r a n g e . 9 0 - . 9 9 ) .For purposes o f s t a t i s t i ca l ana lys i s , da t a were t r ans form ed in to Z va luesas score s wi th in each o f the th r ee ca t egor i e s were co l l ec t ed e i the r a s r a t e pe rm i n u t e o r a s p e r c e n t a g e d u r a t i o n . T I D A , a t im e - s e ri e s p r o g r a m ( O u d , 1 99 1),w a s u s e d t o t e s t d i f f e r e n c e s . T I D A u s e s M A N O V A t o d e s c r i b e i n t e r r u p t e dt im e-se r ie s ac ross sub jec ts u t il iz ing po lyn om ia l curves . The p r og ram has beend e s i g n e d t o t e st c h a n g e s i n th e t r e n d o f t h e c u r v e a t t h e s t a r t i n g p o i n t o ft h e i n t e r v e n t i o n , t a k i n g i n t o a c c o u n t s e r i a l d e p e n d e n c y b e t w e e n t h e s c o r e s .Th e s t a t i s ti c used i s t he F t r an s form a t ion o f W i lk 's l am bda .

W i t h r e sp e c t t o c o m m u n i c a t i v e b e h a v i o r s , f o u r s u b j e c t s ' b e h a v i o r s( R . V . , R . C . , R . K . , M . M a ) w e r e c o m p a r e d i n t h e o r d e r ba s e li n e ve r su s f e n-f lu r a m in e and f enf lu r am ine ve r sus p lac ebo , w i th F (1 , 3 ) = 4 .433 , p = . 13and F(1 , 3 ) = . 004 , p = . 95, re spec t ive ly , i nd ica t ing the abse nce o f d i f f e r -e n ce s. T h r e e s u b j e ct s ' c o m m u n i c a t i v e r e s p o n s e s ( G . A . , M . H . , E . S . ) w e rec o m p a r e d i n t h e o r d e r b a s e l i n e v e r s u s p l a c e b o a n d p l a c e b o v e r s u s f e n f l u r a -m ine . Th e va lues o f F ( l , 2 ) = 5 .95 , p = . 393 and F(1 , 2 ) = 0 .1 1 9 , p =.7 63 f o r t h e r e s p e c t iv e c o m p a r i s o n s , i n d i ca t e t h a t n o d i f f e r en c e s w e r e f o u n d .

S ix s u b j e c t s ' s t e r e o t y p i c b e h a v i o r s ( R . W . , M . M . , R . V . , R . C . , R . K . ,M . M a . ) w e r e c o m p a r e d i n t h e o r d e r b a s e l i n e v e r s u s f e n f l u r a m i n e a n d f e n -f lu r a m in e ve r sus p lacebo . T im e - se r i e s ana lys i s , r evea l ing F(1 , 5 ) = 0 .644 ,p = . 459 , an d F(1 , 5 ) = 4 .072 , p = . 097 fo r the r e spec t ive con di t ion s , i nd i -c a t e t h a t t h e r e w e r e n o d i f f e re n c e s . F o r t h e r e m a i n i n g f i v e s u b j e c t s , c o m -p a r i s o n s o f s c o re s w e r e m a d e i n th e o r d e r b a s el in e v e r su s p l a c e b o a n d p l a c e b ov e r s u s f e n f l u r a m i n e . A n a l y s i s o f th e t i m e - se r i e s d a t a , r e v e a l in g F ( 1 , 4 ) =0.492, p = .522, an d F( 1 , 4) = 0 .62 7, p = .473, for the resp ec t iv e con di-t i o n s , i n d i c a t e t h a t t h e r e e x i s t e d n o d i f f e r e n c e s . F i n a l l y , t h e i n a p p r o p r i a t eb e h a v i o r s o f th r e e s u b je c ts ( R . W . , R . C . , R . K . ) w e r e c o m p a r e d i n th e o r d e rb a s e l in e v e rs u s f e n f l u r a m i n e a n d f e n f l u r a m i n e v e r su s p l a c e b o . A n a l y s i s r e v -ea led no di f fe renc es , wi th F( 1 , 2) = 2 .31 , p = .08 an d F(1 , 2) = 1 .147,p = . 397 , re spec t ive ly . No adve r se s ide e f f ec t s we re r epo r t ed .


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DISCUSSIONThe difference in whole blood serotonin levels between baseline andtreatment 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 thepresent sample fails to increase communicative behaviors and to decreasestereotypic 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 byBeisler et al. (1986) and Coggins et al. (1988). The results with respect tostereotypic behaviors, however, are in contrast to the findings of Campbellet 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 Grodenet al. (1987), who found a decrease of self-stimulation on the RLRS duringthe drug phase. Although Groden et al. (1987) trained their observers to ratesubjects' 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 paradoxicaleffects o f this drug have been documented (Campbell, 1988; Campbell etal., 1988; Coggins et al., 1988). A parallel-group design with random assign-ment o f 28 autistic children to either a condition of fenfluramine or placebofailed 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 fenfluraminemight be that studies differ in their attempts to control for observationalbias 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 andKent (1977) demonstrated that global evaluations of individuals' behaviorscan be influenced by expectations alone. It might be that observers/raters,who are involved with the individual to be observed, are more susceptibleto bias. It might also be that fenfluramine is differentially effective across in-dividuals, the characteristics of whom have not been represented in thepresent sample.


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At least two methodological l imitations should be imposed on theresults of this study. First , the high reliabil ity scores ob tain ed m ay b e inflat-ed, in that the recording technique did not allow us to identify the degreeof overlap between the occurrences of behavior that these scores represent.A second limitation refers to the low powe r o f the statistical tests of this study.However , the smal l e f fect s izes obta ined may have reduced the l ike l ihoodthat we failed to reject the null hypothesis when it was false.

R E F E R E N C E SAm erican Psychiatr ic Assoc iat ion. (1987). Diagnostic and statistical manual of mental disor-ders (3rd ed. , rev.) . Washington, DC: Author.And erson , G. M., Y oung, J . G. , Cohe n, D. J . , Schlicht , K. R. , & Patel , N. (1981). Liquid-chromatographic de terminat ion of sero tonin and t ryptophan in whole b lood and p las-m a. Clinical Chemistry, 27, 775-776.August , G. J . , Raz, N ., & Baird, T. D. (1985). Brief report : Effects of fen fluram ine on be-havioral , cognit ive, and affect ive disturbances in autist ic children. Journal of Autismand Developmental Disorders, 15, 97-107.August , G. J . , Raz, N., & Baird, T. D. (1987). Fenfluramine response in high and low func-t ioning autist ic children. Journal of the American Academy of Child and AdolescentPsychiatry, 26, 342-346.Barthelemy, C. , Bruneau , N., Jouve, J . , Mar t ineau , J . , M uh, J . P . , & Lelord, G. (1989). U ri-nary dopam ine metaboli tes as indicators of the responsiveness to fenflu ramine treatm entin children with autist ic behavio r. Journal o f A utism and Developmental Disorders, 19,241-254.Beeghly, J . H. L . , Ku perm an, S. , Perry, P. J . , W right , G. J . , & Tsai , L. Y. (1987). Fenflu ra-mine t rea tment of au t i sm: Rela t ionship of t rea tm ent response to b lood leve ls of fen-f luramine and norfenf luramine . Journal of Autism and Developmental Disorders, 17,541-548.Beisler, J. M ., Tsai, L . Y., & Stiefel, B. (1986). Brief report: T he effects of fen flura mi ne oncommunication skil ls in autist ic children. Journal of Autism and Developmental Dis-orders, 16, 227-233.Campbell, M. (1988). Fenfluramine treatment of autism. Journal of Child Psychology and Psy-chiatry, 29, 1-10.Campbell , M., Perry, R. , Polonsky, B. B. , Deutsch, S. I . , Pali j , M., & Lukasok, D. (1986).Brief report: An open study of fenfluramine in hospitalized young autistic children.Journal of Autism and Developmental Disorders, 16, 495-506.Campbell , M., Ada ms, P. , Small , A. M ., Curren, E. L. , Overall , J . E. , Ande rson, L. T. , Lynch,N., & Perry, R. (1988). Efficacy and safety of fen fluram ine in autist ic children. Journalof the American Academy o f Child and Adolescent Psychiatry, 27, 434-439.Coggins, T. E. , Morisset , C. , Krasney, L. , Frederickson, R. , Holm, V. A., & Raisys, V. A.(1988). Brief report : D oes fenfluram ine treatmen t enhance the cognit ive and comm unica-t ive functioning o f autist ic children? Journal of Autism and Developmental Disorders,18, 425-434.Gro den, G ., Grod en, J . , Dond ey, M., Z ane, T. , Pu eschel , S. M., & Veliceur, W. (1987). Ef-fects of fenf luram ine on the beha vior of au t is t ic indiv iduals . Research in Developmen-tal Disabilities, 8, 203-211.Ho, H . H ., Lockitch, G ., Eaves, L. , & Jaco bson , B. (1986). Blood seroton in conce ntrat ionsand fenf luramine therapy in aut is t ic ch i ldren . Journal of Pediatrics, 108, 465-469.O'Leary, K. D., & Kent, R. N. (1977). Sources of bias in observational recording. In B. C.Etzel , J . M. LeBlanc, & D. M. Baer (Eds.) . New developments in behavioral research,theory, and application. Hillsdale, N J: Erlba um .


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Oud, J. H. (1991). TIDA: A computer program for analyzing interrupted time-series or multi-ple subjects. Manuscr ip t submit ted for publ ica t ion .Reiss, A. L., Egel, A. L., Feinstein, C., Goldsmith, B., & Borengasser-Caruso, M. (1988). Ef-fects of fenflu ram ine on social behavio r in autist ic children. Journal of Autism andDe-velopmental Disorders, 18, 617-625.Repp, A., H arm an, M. L. , Felce, D., Van Acker, R. , & Karsh, K. G. (1989). C ondu cting be-havioral assessments on computer-collected data. Behavior Assessment, 11, 249-268.Ritvo, Eo R., & Freem an, B. J . (1986). Fen fluram ine therapy for autism: pro mise and precau-t ion. Psychopharmacology Bulletin, 22, 133-140.Stubbs, E. G., Budden, S. S. , Jackson, R. H., Terdal , L. G., & Ritvo, E. R. (1986). Effectsof fenf luramine on e ight outpa t ien ts wi th the syndrome o f au t i sm. DevelopmentalMedi-cine and Child Neurology, 28, 229-235.

Verglas, du G., Banks, S. R., & Guyer, K. E. (1988). Clinical effects of fenfluramine on chil-dren with autism: A review of the research. Journal of Autism and Developmental Dis-orders, 18, 297-308.Yarbroug h, E. , San tat , U. , Perel , I . , Webster , C. , & Lom bardi , R. (1987). Effects of fenflura-mine on autist ic individuals residing in a state developm ental center . Journal o f Autismand Developmental Disorders, 17, 303-314.

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