An Open Trial of Risperidone in Young Autistic Children

An Open Trial of Risperidone in Young Autistic Children ROB NICOLSON, M.D., GEORGE AWAD, M.D.,

AND

LEON SLOMAN, M.D.

ABSTRACT ObJective: To assess the benefits and side effects of risperidone in young autistic children. Method: In this open,

prospective trial, subjects were treated with risperidone for 12 weeks. All subjects were started at 0.5 mg daily with individual titration to a maximum of 6 mg or 0.1 mg/kg daily. Behavioral ratings, completed by the investigators and the children's parents, included the Clinical Global Impressions (CGI), Children's Psychiatric Rating Scale, Conners ParentTeacher Questionnaire, Childhood Autism Rating Scale, and Abnormal Involuntary Movement Scale. Results: Ten boys, aged 4.5 to 10.8 years, were enrolled in the study and all completed the 12-week protocol. The mean final dose was 1.3

mg/day (range

= 1 to 2.5 mg/day). On the basis of CGI-rated

improvement, 8 of the 10 children were considered to be

responders. Improvement was also demonstrated on the other scales. Transient sedation was common, and the children gained an average of 3.5 kg over the 12 weeks of the study. There was no evidence of either extrapyramidal symptoms or tardive dyskinesia. Conclusions: These results suggest that risperidone may be safe and leads to improvements in several behavioral symptoms in young children with autism. Controlled studies of risperidone in young autistic children are warranted. J. Am. Acad. Child Ado/esc. Psychiatry, 1998, 37(4):372-376. Key Words: autistic disorder, risperidone, treatment.

Despite the use of a wide variety of pharmacological agents in the treatment of autistic disorder, no medication produces a marked and specific beneficial effect (Bailey et al., 1996). Nonetheless, some persons with autism display symptoms requiring pharmacotherapy, including stereotypies, hyperactivity, and aggressive behavior. In addition to ameliorating the difficulties caused by these behaviors, clinical experience and research have shown that effective pharmacotherapy can render persons with autism more amenable to special education or other psychosocial approaches and may facilitate learning (Campbell et al., 1996). Medications with primary effects on the dopaminergic and serotonergic systems have been shown to be beneficial in autistic disorder. Haloperidol, a dopamine receptor antagonist, has been shown to be superior to placebo in the treatment of autistic disorder (Locascio et al., 1991), as have the serotonin uptake inhibitors Accepted November 26. /997. From the Department ofPsychiatry, University of Toronto. Correspondence to Dr. Nicolson, Child Psychiatry Branch. NIMH, Building 10, Room 3N202, 10 Center Drive MSC 1600. Bethesda. MD 20892-1600. The authors thank Dr. judith Rapoport fOr her editorial comments and Mr. Peter Sansom of[anssen-Ortho Inc. fOr providing the risperidone used in this study. 0890-8S67/98/3704-0372/$03.00/0©1998 by the American Academy of Child and Adolescent Psychiatry.

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clomipramine (Gordon et al., 1993) and fluvoxamine (McDougle et al., 1996). Unfortunately, these medications are associated with a significant risk of side effects, particularly in young children (Sanchez et al., 1996). A significant proportion of autistic children treated with haloperidol develop dyskinesias (Campbell et al., 1997), which may limit treatment, and clomipramine was not found to be therapeutic in a sample of young autistic children and its use was associated with serious side effects (Sanchez et al., 1996). Risperidone is an atypical antipsychotic with potent dopamine-2 and serotonin-2A receptor antagonism as well as effects on a-adrenergic and histaminergic receptors (Janssen et aI., 1988; Leysen et al., 1988). It seems to produce fewer extrapyramidal side effects (EPS) than typical antipsychotics when used at low doses (Meltzer, 1995). As these may be related to the later development of tardive dyskinesia (Andrew, 1994), a decreased level of EPS may have clinical importance in children with autistic disorder. The therapeutic effect of risperidone in persons with pervasive developmental disorders has been described in several open trials (Findling et al., 1997; Horrigan and Barnhill, 1997; McDougle et al., 1997; Perry et aI., 1996). Improvements were often noted in withdrawal, stereotypies, and aggressive behavior, which are often

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RISP ERIDON E IN AUTISM

target sym pto ms for ph armacological int erven tion in autism . Side effects con sisted mostly of seda tion and weigh t gain, whil e EPS were reported rarely. In the se open stu dies, a significant proportion of the subjects were olde r childre n, ado lescents, and adults. As younger child ren may be more susceptible to side effects of psychoactive medi cations (Sanchez et al., 1996) and may deri ve less benefit from ph armacological treatment (Locascio et al., 1991), th e obj ective of this study was to explore th e effect iveness and safety of risperidone in a sample of young child ren with aut istic disord er within a fairly narrow age range using a pro spective, open- label design. METHOD

Subjects T he subjects were all referred to the Department of Psychiatry at th e Hosp ital for Sick Children or th e Chil d an d Family Stud ies Cent re at the C larke Institute of Psych iatry for outpa tient treatment . Behavior al sym pto ms included withdrawal. stereotypies, hyperactivity, temper tant rum s, and aggression . The part icipant s all met DSM- IV c rit e ria for aut istic d isord er (Ame rica n Psych iat ric Association, 199 4), an d the diagnosis was made by conse nsus of at least two of the investigators for each child . The parents of all childre n in th e study provided written informed consent . Excl usion criter ia inclu d ed a seizu re di so rder or history of seizures, includ ing febrile seizures, a histor y or clinical evidence of systemic d isease {e.g.. renal, liver, endocrino logical, or card iovascular), tard ive or withd rawal dyskinesia, or Tour ette 's disorder. One child had an XYY karyotype and an other had a balan ced translocation involving chro moso mes 19 and 2 1. None of the other children involved in the study had a diagnosed genetic, metabo lic, or neu rological cause for autist ic d isord er. All parti cipants were free of other psychoactive medic ation for at least I week before en rollment and for the duration of the study.

Design and Medication T he children were treated with risperidone in an open fashion for 12 weeks, starting at 0.5 mg daily. The medica tion was individually regulated with increm ents of up to 0 .5 mg daily no mo re often tha n weekly until optimal therapeuti c effects or un toward effects were ob served. A maximum dose of either 6 mg daily or 0.1 mg/kg daily, wh ichever was less, was no t exceeded .

Assessments Behav ioral ratin gs were co nd ucted four t imes by the same ph ysician (R,N .), prior to the initiation of risperidon e therap y and every 4 weeks the reafter unt il the end of the 12-week period. The children were rated on a variety of measures: the Ch ild ren's Psych iatri c Ratin g Scale (C P RS) (G uy, 197 6 ), t he C li n ica l G lo ba l Im pression s (CGI) (G uy, 1976), and the Abno rmal Invo luntary Movement Scale (AIMS) (Cam pb ell and Palij, 1985a). O nly the 14 items of th e C PRS that are most ap pro priate for ch ild ren wit h auti stic disorder were rated and analyzed , and four factors derived from these items (Autis m, Anger/ Uncoo pcrariveness, H yperactivity, and Speech Dev ian ce) (Overall an d Cam pbell. 19 88) were also

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AM. AC A D . CHI l. D AD O l. E SC. PSYC H IATRY. j7 : 4 , AP R I l. l 'i'!H

analyzed. In addi tion, the childre n were rated on the C hildhoo d Aut ism Rating Scale (CARS) (Schopler er al., 1980) at baseline and at the conclusion of the stu dy. Parents rated the child ren's behavior using th e Conn ers Parent-Teach er Questionnair e (PTQ) (Guy, 1976), which has been shown to be sensitive to changes in behavior associated with d rug treatment (Cam pbell and Palij, I985b ). Weight was measured at baseline and every 4 weeks th ereafter until the end of the study, wh ile blood pressure and heart rate were also measured at baseline an d at each visit to the clinic.

Statistical Analysis T he effective ness of risper idone o n behavioral measu res was assessed using matched-pairs t tests to com pare scores at baseline and on the monthl y ratings, or, for the CA RS, at the conclusio n of the study. As well, the effects of risperidone on heart rate, blood pressure, and weight were analyzed using matched-pairs t tests to com pare the baseline and the monthly results. A sign ificance level of .05 was set fo r all analyses, with all rests being two-tailed .

RESULTS

Sample

Ten children , all male s, participated in th e stu dy. Their ages ranged from 4. 5 to 10.8 years (mean ± SO = 7 .2 ± 2.2), and th eir int ellectual fun ctioning (based on the academic scale of the Developmental Profile II [Alpern et al., 198 4]) ranged from low average to severely retarded (Table 1). Eight children were Ca ucasian, one was African-American, and one was Asian. Three of th e ch ildren had previously received medication , including an t ipsychot ics, serotonin uptake inhibito rs, and cIonidine. Dosage and Untoward Effects

The final dose of risperidone for each child is noted in Table 1. The mean dose was 1.3 mg daily (SO = 0.5 rng), or 0.05 mg/kg (SO = 0.02 mg/kg). These doses are simi lar to those found to be effective with haloperidol (Ande rso n et al., 1984, 1989 ; C ampbell et al., 1978) and are within the range (both absolute and relat ive) at which risperidone produces fewer EPS than typical anti psychot ics such as haloperidol (Meltzer, 1995). A common side effect was weight gain . The children gain ed an average of 3.5 kg over the course of the course of th e study, representing an increase in weight of almost 13%. Weight was significantly higher after 12 week s than at baseline (30.9 ± 5.9 kg versus 27.4 ± 4.3 kg; t = 4. 1, df = 9, P = .00 3) . The weight gain noted here is similar to that reported in other open trials (Horrigan and Barnhill, 1997; McDougle er al., 1997) and translates to a 15-kg weight gain over the course of a year. Continued weight gain at th is rate could ult imately necessitate dis-

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NI COLSON ET AL.

TABLE 1 C linical C haracteristics of 10 Autisti c Children Treated W ith Risperidone Final Do se

(yr)

Level of Intellectual Functioning"

Previous Medication

Target Sympto ms

10.8

Moderately retarded

H yperactivity. stereo typ ies

2.5

0.08

2 3 4 5

7.5 4 .8 5.4 10.1

Moderatel y retard ed Mi ld ly retard ed Mildly retarded Moderately retarded

Hal op eridol. paroxetin e, met hylphenidate None No ne None Thior idazine. paroxeri ne,

1.0 1.5 1.5 1.5

0 .04 0.06 0.07 0 .06

6

6.9

Moderately retarded

None

1.0

0.03

7 8 9 10

7 .6 8.8 5.8 4.5

Low average Severely retarded Moderately retard ed Borderline

Fluoxet ine None None None

Hyper activity, tantrums Tantrums , withdrawal H ypera ctivity H ypera ctivity. tantrums. self-injur ious behav ior Aggression . tantrums. self-injurious behav ior Hyperactivity. stereotypies Aggression. tantrums Aggression . stereotypies Stereo typies

1.0 1.0 1.0 1.0

0.0 4 0.03 0.03 0.04

Age Subject

clonidine

mg mg/kg

" Intellectual funct io ning based o n the academic scale of the Developmental Profile II (Alpern er al., 1984).

continuation. Sedation was also common and was seen in three children. This was transient in all cases and was most obvious shortly after the initiation of risperidone or an increase in the dose. One child experienced a brief period of constipation, which was alleviated by increased fiber intake, and a second experienced transient sialorrhea and occasional urin ary incontinence (he had previously been continent for more than 6 months) . There was no clinical evidence of extrap yramidal symptoms and no abnormal movements were detected with th e AIMS . Blood pressure and heart rate did not sign ificantly change over the course of the study. Behavioral Assessments

Clinical Global Impressions. On the basis of a rating of "much improved" or "very much improved" on the

Global Improvement item of the CGI , 8 of the 10 children were classified as responders. The two children who failed to respond were the two oldest child ren in the study, with one being rated minimally improved and the other unchanged. The mean baseline rating of severity of illness, based on the CGI Severity item , was 5.0 (SO = 0.9), with four rated moderately ill, two rated markedl y ill, and four rated severely ill. There was a significant improvement in the rating of illness severity after 12 weeks of treatment (Table 2). Children's Psychiatric RatingScale. Mean baseline and end-of-treatment ratings for th e sum of the 14 rated CPRS items as well as four factors derived from these items (Autism, Anger/Uncooperativeness, Hyperactivity, and Speech Deviance) are shown in Table 2. The sum of

TABLE 2 Behavioral Rat ings: Mean Baseline an d End-of-Treatment Scores for Nin e Autistic C hildren Treated W ith Risperidone Baseline Score

End -of-Treatment Sco re

Behavioral Rat ings

Mean

SO

Mean

SO

CGI Severity Sum of 14 CPRS items CPRS Autism factor C PRS H yperactivity factor C PRS Anger/ Un coop erat iveness facto r C PRS Speech Dev iance facto r CARS PTQ total sco re

5.0 45.0 22.2 7.0 9.4 4.2 41.3 19.6

0.9 10.0 5.2 3.1 5.7 2.4 4.0 4.6

4. 0 31. 9 15.4 4 .5 6.4 3.0 3 1.9 10.8

10.0 6.5 2.6 3. 1 1.1 7. 1 5.8

1.2

p t Sco re

df

Value

4.7 6.2 5.0 2.8 1.9 1.7 6 .2 8. 1

9 9 9 9 9 9 9 9

.00 1 <.001 .001 .02 .10 . 12 <.001 <.00 1

N ote: CGI = C linical G lobal Impression s; C PRS = Child ren's Psych iatr ic Rat ing Scale; CARS Scale; PTQ = Connors Parent- Teache r Questionnaire.

374

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= C hild hoo d Autism

Rating

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RI SP ERID O N E IN AUT ISM

the rated CPRS items and two of the four factors (Autism and Hyperactivity) showed significant changes. Childhood Autism Rating Scale. Mean baseline and end-of-treatment CARS ratings are shown in Table 2. Over the course of the study, there was a decrease of more than 20% in the mean total score on the CARS. Conners Parent- Teacher Questionnaire. Mean PTQ total scores for baseline and the conclusion of the study period are shown in Table 2. The PTQ total score is the sum of the 10 items rated at home by children's parents. There was a significant decrease in the total PTQ scores, and the comments by many parents, that their children seemed happier and that life at home was easier for everyone, corroborated the changes in the PTQ. The score on item 10, "temper outbursts (explosive and unpredictable behavior)" decreased by more than 50% over the course of the study (2.0 + 1.1 versus 0.8 + 0.6; t = 3.9, df= 9, P = .004). DISCUSSION

In this open trial with young autistic children, the use of risperidone was associated with a decrease in several target behaviors in a majority of th e participants. Using a definition of meaningful response as a score of "much improved" or "very much improved" on the Global Improvement item of the CGI, 8 of the 10 participants were rated as responders after 12 weeks of risperidone th erapy. Other than weight gain and mild sedation, risperidone was well tolerated. Importantly, there was no evidence of EPS or tardive dyskinesia, which arc often found in autistic children using traditional antipsychotics (Campbell et al., 1997) and which may have limited the willingness of clinicians to use anti psychotics in the past. It is interesting to note that the two child ren who d id not respond to risperidone were the two oldest subjects. These boys had previously failed trials of typical antipsychotics, serotonin uptake inhibitors, and clonidine. As another subject who previously had been treated with fluoxetine showed a good response to risperidone, the lack of improvement in these two patients may be more indicative of their general lack of response to pharmacological intervention than an association between previous medication trials and response to risperidone. One of th e most common presenting problems in this group was aggression. Over the course of the study, the parents of many of the children for whom aggression had been a problem noted a reduction in aggressive

] . AM. ACA D , C H I L O ADOL ESC. PSYC H I AT RY, .>7 :4 . APRIL 1')98

behavior, and the sign ificant decrea se in the PTQ item related to temper outbursts reflects thi s. Several teachers also commented on the reduced levels of aggression. The decrease in aggression noted in this study is consistent with prior reports of risperidone use in people with pervasive developmental disorders (Horrigan and Barnhill, 199 7; McDougle et al., 199 7) and d evelopmental disabilities (Vanden Borre et al., 1993). In the latter double-blind, placebo-controlled crossover study of risperidone in addition to regul ar medication, decreases in aggressive behaviors were significantly greater during the risperidone phase than during the placebo phase. While improvements were noted in overactivity and aggression, risperidone use also resulted in a decrea se in other sym p toms commonly seen in autistic disorder. The Auti sm factor of the CPRS, which includes item s such as withdrawal, rhythmic motions, and abnormal object relationships , showed a significant decrease over the course of the study. Although there have previously been reports of increa sed obsessive-compulsive symptoms in adults with schizophrenia treated with risperidone (Dodr et al., 1997; Kopala and Honer, 1994) , there wa s no evidence of increased stereotypies or repetitive behavior in thi s sample. In addition to the stati stically significant changes that occurred in the behavioral ratings used in this study, clinically significant changes oc curred in the functioning of several responders. One of the ch ild ren who had previously been unable to attend school because of aggression was accepted into a special education class in a regular school after his aggression decreased. Another child who had been transported to school alone in a taxi because of his disruptive behaviors was able to ride the school bu s with other child ren. The parents of mo st of the responders reported that their children seemed happier and easier to engage in interactions. Teachers also noted that the responders were more likely to participate in group activities than previously and were also able to focus better on their work at school. Several methodological limitations restrict the conclusions that can be drawn from this study. First , because this was an open study, possible bias cannot be excluded as a possible explanation for the improvement on the various assessment scales used . Other factors th at could account for the improvement cou ld include a placebo effect and the natural fluctu ation in the symptoms of autistic disorder. The small sample size also

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Alpern GD. Boll TJ. Shearer MS (1984). Developmental Profile 11. Los Angeles: Western Psychological Services American Psychiatric Association (1994). Diagnostic and StatisticalManual of Mental Disorders. 4th edition (DSM-IV). Washington. DC: American Psychiatric Association Anderson LT.Campbell M. Adams P, Small AM. Perry R. Shell J (1989). The effects of haloperidol on discrimination learning and behavioral symptoms in autistic children.] Autism Deu Disord 19:227-239 Anderson LT. Campbell M. Grega DM. Perry R. Small AM. Green WH (1984). Haloperidol in the treatment of infantile autism: effects on learning and behavioral symptoms. Am] Psychiatry 141:1195-1202 Andrew HG (1994). Clinical relationship of extrapyramidal symptoms and tardive dyskinesia. Can] Psychiatry 39(suppl 2):S76-S80

Bailey A. Phillips W. Rutrer M (1996). Autism: towards an integration of clinical. genetic. neuropsychological, and neurobiological perspectives.] Child Psycho! Psychiatry 37:89-126 Campbell M. Anderson LT. Meier M er al. (1978). A comparison of haloperidol and behavior therapy and their interaction in autistic children.] Am Acad Gild Psychiatry 17:641-655 Campbell M. Armenteros JL. Malone RP,Adams PB. Eisenberg ZW. Overall JE (1997). Neuroleptic-related dyskinesias in autistic children: a prospective. longitudinal srudy.] Am Acad Child Adolesc Psychiatry 36:835-843 Campbell M. Palij M (l985a). Measurement of side effects including tardive dyskinesia. Psychopharmacol Bull 21:1063-1082 Campbell M. Palij M (l985b). Behavioral and cognitive measures used in psychopharmacological srudies of infantile autism. Psychopharmacol Bull 21: 1047-1053 Campbell M. Schopler E. Cueva JE. Hallin A (1996), Treatment of autistic disorder.] Am Acad Child Adolesc Psychiatry 35: 134-143 Dodr JE. Byerly MJ. Cuadros C, Christensen RC (1997), Treatment of risperidone-induced obsessive-compulsive symptoms with semaline. Am] Psychiatry 154:582 Findling RL. Maxwell K. Wiznitzer M (1997). An open clinical trial of risperidone monotherapy in young autistic children. Psychopharmacol Bull 33:155-159 Gordon CT. State RC. Nelson JE. Hamburger SD. Rapoport JL (1993). A double-blind comparison of clomipramine. desipramine. and placebo in the treatment of autistic disorder. Arch Gen Psychiatry 50:441-447 Guy W (1976). ECDEU Assessment Manual [or Psychopharmacology. Revised. Rockville. MD: US Department of Health. Education. and Welfare Horrigan JP, Barnhill LJ (1997), Risperidone and explosive aggressiveautism. ] Autism Dev Disord27:313-323 Janssen PAJ. Niemegeers C)E. Awouters F.Schellekens KHL. Megens AAHP, Meert TF (1988). Pharmacology of risperidone (R64766). a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties.] PharmacalExp Ther 244:685-693 Kopala L. Honer WG (1994). Risperidone, serotonergic mechanisms. and obsessive-compulsive symptoms. Am] Psychiatry 151:1714-1715 Le sen JE. Gommern W. Eens A. De Chaffoy De Courcelles D. Sroof JC, Janssen PAJ (1988). Biochemical profile of risperidone, a new antipsychotic.] PharmacolExp Ther 247:661-670 Locascio JJ. Malone RP, Small AM er al. (199 I). Factors related to haloperidol response and dyskinesias in autistic children. Psychopharmacol Bull 21:119-126 McDougle C). Holmes JP, Bronson MR er al. (1997). Risperidone treatment of children and adolescents with pervasive developmental disorders: a prospective, open-label trial. ] Am Acad Child Adolesc Psychiatry 36: 685-693 McDougle C). Naylor ST. Cohen DJ. Volkmar FR. Heninger GR. Price LH (1996). A double-blind. placebo-controlled study of fluvoxamine in adulrs wirh autistic disorder. Arch Gen Psychiatry 53:1001-1008 Meltzer HY (1995). Arypical antipsychotic drugs. In: Psychopharmacology: The Fourth Generation ofProgress. Bloom FE. Kupfer DJ, eds. New York: Raven Press. pp 1277-1286 Overall JE. Campbell M (1988). Behavioral assessment of psychopathology in children: infantile autism.] Clin PsychoI44:708-716 Perry RI. Pataki CS. Munoz DM. Armenteros JL. Silva RR (1996). Pilot trial of risperidone in children and adolescents with pervasive developmental disorder. Presented ar rhe 149rh annual meeting of the American Psychiatric Association. New York Sanchez LE. Campbell M. Small AM. Cueva JE. Armenteros JL. Adams PB (1996). A pilot study of clomipramine in young autistic children.] Am Acad Child Adolesc Psychiatry 35:537-544 Schopler E. Reichler RJ. DeVellis RF. Daly K (1980). Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS).] Autism Deu Disord 10:91-103 Vanden Borre R. Verrnote R. Burriens M er al. (1993). Risperidone as addon therapy in behavioural disturbances in mental retardation: a doubleblind placebo-controlled cross-over study. Acta Psychiatr Scand 87: 167-171

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limits the conclusions that can be drawn, as does the fact that all of the participants were male. Although each of the four youngest children in the study, all of whom were younger than 6 years of age, had a good response to risperidone, the age range of the subjects makes it difficult to interpret the results with regard to very young patients. As side effects (Sanchez et al., 1996) and response to medication (Locascio et al., 1991) may be different in very young children with autism, future studies of risperidone will need to include larger numbers of very young subjects to determine whether their response or side effect profile differs from that of older children. Despite these limitations, the use of risperidone resulted in significant improvements in a majority of the young autistic children who participated in this study. The results in this sample of young children mirror those reported previously (Findling et al., 1997; Horrigan and Barnhill, 1997; McDougle et al., 1997; Perry et al., 1996). While weight gain was significant and transient sedation was also common, other significant adverse effects, including extrapyramidal symptoms, were not noted. Controlled studies are needed in this population to permit a more definitive investigation of risperidone. Clinical Implications

In this small sample of young children with autistic disorder, risperidone administration resulted in improvement in several behavioral symptoms. Although there was significant weight gain, adverse effects were minimal and there was no evidence of extrapyramidal symptoms or dyskinetic movements. Further controlled studies are needed to delineate fully the therapeutic effects of risperidone in this population.

REFERENCES

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