The Adrenocorticotrophic Hormone (4–9) Analog ORG 2766 Benefits Autistic Children: Report on a Second Controlled Clinical Trial

The Adrenocorticotrophic Hormone (4-9) Analog ORG 2766 Benefits Autistic Children: Report on a Second Controlled Clinical Trial JAN K. BUITELAAR, M.D., PH.D., HERMAN VAN ENGELAND, M.D., PH.D., KATY HAN DE VRIES, JAN VAN HOOFF, PH.D., JAN VAN REE, PH.D.

DE

KOGEL,

Abstract. In a second controlled crossover trial, 20 autistic children received 40 mg/day of the neuropeptide ORG 2766, a synthetic analog of ACTH (4-9), for 8 weeks. Parents' checklist ratings (ABC) as well as clinicians' ratings (CGI) pointed to significant improvements after the course of treatment; improvements were clearest on the ABC social withdrawal subscale. The analysis of individual target symptoms and the parents' treatment preferences substantiated the beneficial effects of ORG 2766. In an ethologically analyzed playroom session, ORG 2766 treatment was associated with an improvement in the children's play behavior and a significant increase in the social interaction between child and experimenter. Gaze coordination between child and experimenter also was improved. J. Am. Acad. Child Adolesc. Psychiatry, 1992, 31, 6: 1149-1156. Key Words: autism, ORG 2766, social behavior, ethology.

The adrenocorticotrophic hormone (4-9) analog ORG 2766 is a neuropeptide that is active on oral administration; it is devoid of substantial steroidogenic activity (De Wied and Jolles, 1982; Greven and De Wied, 1973), and in animal and human studies it has been shown to improve information processing, adaptation, and social behavior (De Wied and Jolles, 1982; Niesink and Van Ree, 1983; Sandman et aI., 1980). Neuropeptides may exert their effects on the nervous system by acting as neurotransmitter, as neurohormone, or, most likely, as neuromodulator; i.e., by modulating the activity of the classic neurotransmitter systems (Gispen, 1980; Versteeg, 1980). In a controlled clinical trial involving 14 outpatient autistic children, ORG 2766 treatment for 4 weeks at a daily dose of 20 mg per child was found to be associated with increases in locomotion, talk, and changing-toy behaviors and with a decrease in stereotyped behaviors (Buitelaar et aI., 1990). The parents' general impressions also pointed to clinical improvements. However, the overall analysis of objective rating scales completed by the parents did not reveal significant effects. Inasmuch as the behavioral changes in the playroom session did not become apparent until the children had been treated for 4 weeks with rather a low dose of ORG 2766, it is concluded that the administered cumulative dose of ORG 2766 was too low to exert behavioral influences

Accepted November 19, 1991. Jan K. Buitelaar is a child and adolescent psychiatrist, Herman van Engeland is Professor of Child and Adolescent Psychiatry, and Katy de Kogel is a psychologist; all are with the Department of Child and Adolescent Psychiatry, Utrecht University Hospital. Han de Vries is a biostatistician, and Jan van Hoof! is Professor of Comparative Physiology; both are with the Department of Ethology, University of Utrecht. Jan van Ree is Professor of Psychopharmacology at the Rudolf Magnus Institute, University of Utrecht. The authors appreciate the suggestion by Berry Spruyt to use the information-statistical analysis. Address for correspondence: Dr. Buitelaar, Department of Child and Adolescent Psychiatry, Utrecht University Hospital, P.O. Box 85500, 3508 GA Utrecht, the Netherlands. 0890-8567/92/3106-1149$03.00/0©1992 by the American Academy of Child and Adolescent Psychiatry. J. Am. Acad. Child Adolesc. Psychiatry, 31:6, November 1992

unequivocally outside the more or less stable laboratory (i.e., playroom) situation. Therefore, a second study was designed to replicate and corroborate our earlier findings; this time a higher daily dosage of ORG 2766 (40 mg per child) was used, a longer treatment period (8 weeks) and a larger sample of autistic children. In addition to the Aberrant Behavior Checklist employed in the first study, a rating scale was used with items that pertained specificalll to possible behavioral effects of ORG 2766 and with items that were individual target symptoms for each child. The objectives of the present study were (1) to establish whether ORG 2766 exerts clinically meaningful effects on the social behavior of autistic children as measured by rating scales, and (2), if so, to characterize in detail the nature of the effects by means of an ethologically analyzed playroom session. Methods Sample

The subjects were 21 autistic children, 17 boys and 4 girls, all outpatients of the Utrecht University Hospital Department of Child Psychiatry. Their ages ranged from 5.33 years to 15.16 years (mean ± SD 10.33 ± 2.05). The diagnosis of infantile autism was made independently by two child psychiatrists according to DSM-III-R criteria (APA, 1987) on the basis of extensive diagnostic evaluations; these included a review of previous records, a parent interview, a child psychiatric observation and a complete medical diagnostic workup. All children met the DSM-III-R criteria for autistic disorder (299.00). The sample included 11 subjects who also had participated in our first study (Buitelaar et aI., 1990). Exclusion criteria employed earlier (Buitelaar et aI., 1990) were applied less strictly: this time we included two children who suffered from a convulsive disorder and who were being treated with antiepileptic medication (sodiumvalproate and ethosuximide), and one child known to have a congenital thyroid aplasia who received thyroid substitution therapy. The dosages remained fixed throughout the study. All children were in good general health and continued their 1149

BUITELAAR ET AL. TABLE 1. Time Schedule for Treatment Sequence

Weeks 0

2

6

14

10

ORO 2766 Placebo

18

20

24

28

Placebo ORO 2766

Follow-up

32

36

Follow-up

V

V

V

V

V

V

V

V

V

V

V

P A

P A

P A

P A

P A

P A

P

P A

P A

P A

P

A A A A A A Note: V = visit to Department of Child Psychiatry; P = playroom procedure + COl + Conners' PTQ; A = Aberrant Behavior Checklist (parents + teachers) + OAP. A

A

A

special educational or day care programs during the study. Subjects were characterized additionally by their IQ and by their Childhood Autism Rating Scale (CARS, see ScMpler et aI., 1980) scores. Four subjects were in the IQ range 22 to 40, four subjects in the IQ range 40 to 55, three subjects in the IQ range 55 to 70, and 10 subjects in the IQ range 70 to 85. Eleven subjects had a severe degree of autism (CARS ~ 37), and 10 subjects a moderate degree of autism. Written informed consent was obtained from the children's parents after the research procedure had been fully explained. Procedure

A double-blind and placebo-controlled crossover design was employed (Table 1). After a 2-week baseline period, the children were randomly assigned to their treatment sequence, group I: ORG 2766-placebo and group II: placeboORG 2766. Treatment order groups were matched by IQ and age. Treatment periods were 8 weeks on either ORG 2766 or placebo. After that, there was a 8-week follow-up; before the crossover, a new 2-week baseline period was established. Active treatment was 40 mg ORO 2766 per child per day. Tablets of ORG 2766 or identical matching placebo tablets were provided by Organon International B.V. and labeled by the local pharmacy. Evaluations (as indicated in Table 1) were made on the basis of behavior checklist ratings and an ethologically analyzed playroom observation. Behavior Checklist Ratings

Rating scales were completed independently by the parents and the teachers using the Aberrant Behavior Checklist (ABC) (Aman et aI., 1985a, b), by the parents using the Conners PTQ (Psychopharmacology Bulletin, 1985), and independently by a child psychiatrist and a psychologist using the Clinical Global Impressions Scale (COl) (Psychopharmacology Bulletin, 1985). Furthermore, the parents completed the General Assessment Parents Scale (GAP), which was designed particularly for this study on the basis of the experiences gained from the first trial. The GAP consists of five common items (general impression, stereotyped behaviors, social isolation, self-disclosure and communication, and general attentiveness). In addition, the scale includes one or more target symptoms that were specific for each child. All items had to be rated on a five-point scale. 1150

A

Finally, at the end of the trial, parents were required to fill out the treatment preference scale ("period 1," "period 2," or "no preference"). Playroom Session

Behavior elements of child and experimenter were monitored with an event recorder in a semistructured playroom session that lasted 20 minutes (Buitelaar et aI., 1991). The behavior elements included play behaviors and other forms of object manipulation, gaze and talk behaviors, gestures, stereotyped behaviors as well as responses to tasks set and requests made by the experimenter. The complete set of behavior elements and their definitions may be obtained from the first author on request. The playroom session consisted of two parts, a first part (0 to 8 minutes) of free play, and a second part in which the exper:imenter set the child four tasks. All scoring was done by the same observer (C.dK.). Eight randomly chosen sessions were videotaped and recorded by the observer at the beginning of the study and at the end of the study, 4 months later, as a check for intrarater drift. The mean intrarater reliability was .83, the range being from .68 (nonverbal behaviors) to .88 (activity behaviors) (expressed in K, Cohen, 1960). These eight randomly chosen sessions were also recorded by a second rater (J.B.). The mean interrater reliability was .78, the range being from .68 (gaze behaviors) to .84 (activity behaviors). Data Analysis of Playroom Session

The analysis of playroom data focused on changes in the frequencies of behavior elements and in the structure of behavior. Frequencies and durations of behavior elements were computed per session per child. In addition some compound parameters (e.g., face % = face / face + nonface) were calculated to correct for the number of times that some behavior elements were scored. The concept of the structure of behavior refers to the temporal-sequential relationships between various behavior elements (Van Engeland et aI., 1985; Van Hooff, 1982). The impact of ORG 2766 was examined on the interactional dependency of the behavior of child and experimenter, and on temporal contingencies of behavior elements. The structure of behavior was analyzed by composing matrices of combination frequencies, namely of behavior elements occurring together within a time period of 5 seconds (Buitelaar J. Am. Acad. Child Adolesc. Psychiatry, 31:6, November 1992

ORO 2766 AND AUTISM

et aI., 1991). Then the interactional dependency of the child's behavior on the behavior of the experimenter was calculated according to the information-theoretical methods outlined in Steinberg and Conant (1974) and Steinberg (1977). The interactional dependencies were expressed in transmission-efficiency (TE) values. For example, if the TE "interchild" turns out to be high, this can be interpreted as an increased interaction of the child with the experimenter. Next, the temporal contingencies were expressed in terms of residual values (Van Hooff, 1982). These residuals were obtained by comparing observed combination frequencies with the frequencies expected on the basis of the null hypothesis that combinations of behavior elements within time periods are random. For each cell, the residual value R was calculated (R = (0 - e)/e, where 0 represents the observed combination frequency and e the value that would be expected on the basis of random combination). Thus, the residual value is a measure of the strength of the temporal contingency, corrected for chance.

Statistical Methods Procedures for statistical analyses were established before the study. First, quantitative differences between the baseline, placebo, and ORG 2766 conditions were analyzed in the parallel study (weeks 0 to 18). Analyses (program SPSSPC 2.0) included repeated measures analyses with analysis of covariance for baseline with respect to the rating scale data, and nonparametric statistics for the playroom data. All testing was two-tailed with an a. level of .05. Second, the drug-placebo crossover design was analyzed according to recommendations of Hills and Armitage (1979) relating to the quantitative analysis of possible carry-over effects. Third, individual responders were identified from the checklist crossover data according to their improvement scores ([placebo score - ORG 2766 score]/ baseline score) on the ABC parents' and teachers' ratings, and according to their improvements on the CGI-improvement scale. The following algorithm was used: improvement score on ABC> 50%: 2 points; > 20% but < 50%: 1 point; > -20% but < 20%: 0 point; and < -20%: -1 point. Differences of 2 scales on the CGI-improvement scale: 2 points; of 1 scale: 1 point; of 0 scale: 0 point; and of -lor < -1 scale: -1 point. Definite responders should score ~ 3 points and probable responders 2 points when the points for ABCparents, ABC-teachers, and CGI improvements are summed. Finally, on the basis of the playroom crossover data, differences in the structure of behavior at group level between the baseline, placebo, and ORG 2766 conditions were analyzed. Results

Compliance and Untoward Effects One subject dropped out of the trial at the end of the parallel study because of gastrointestinal problems and an increase in epileptic seizures. It turned out that he had been on placebo. ABC-teachers' ratings were available for only 15 subjects. No physical side effects were reported by parJ. Am. Acad. Child Adolesc. Psychiatry, 31:6, November 1992

2. Results of Repeated Measures Analysis: MANCOVA and ANCOVAfor Simple Main Effects on Aberrant Behavior Checklist-Parents' Ratings as Dependent Variables in Parallel Study

TABLE

MANCOVA (Endpoint 8 weeks) ABC-parents Sum score Irritability Withdrawal Stereotypy Hyperactivity Speech

gr gr gr gr gr gr

X t F(3,57) t F(3,57) X t F(3,57) X

= 2.69* = 1.42

= 3.18*

2.18 X t F(3,57) = 1.08 X t F(3,57) = 0.16

X t F(3,57) =

ANCOVA (Endpoint) F(l,18) = 4.46* F(1,18) = 1.10 F(1,18) = 10.32** F(l,18) = 2.16 F(1,18) = 1.61 F(l,18) = 0.52

Note: MANCOVA = multiple analysis of covariance (baseline values as covariates); ANCOVA = analysis of covariance; ABC = Aberrant Behavior Checklist. * p < .05, ** P < .01.

ents or teachers, and we did not observe any physical side effects. During ORG 2766 treatment, four parents and two teachers reported increased lability of mood and increased inner tension in six subjects, whereas in the placebo condition, these features were reported in only two subjects.

Behavioral Checklist Data ABC-parents. At endpoint (after 8 weeks ORG 2766 treatment) the ABC-parents' sum score and subscale "social withdrawal" score revealed the predicted interaction between treatment group and treatment period (p < .05, see Table 2). Significant main effects were found on the ABCparents sum score and social withdrawal score after 8 weeks; these were in the direction of greater behavioral improvement with ORG 2766 than with baseline or placebo. Treatment effects were no longer visible after 8 weeks followup. GAP. Simple main effects for between-subject factors showed behavioral improvements in "stereotyped behavior" and in "social isolation" after 8 weeks ORG 2766, compared with baseline and placebo (p < .05), but not after 8 weeks follow-up (Table 3). CGl. On the CGI-severity scale, main effects analysis after 8 weeks ORG 2766 indicated that ORG 2766 treatment resulted in significantly lower severity of illness ratings (p < .05) compared with baseline and placebo (Table 3). The analysis of ABC-teachers' and Conners' data did not reveal significant differences between ORG 2766, baseline, and placebo ratings. Crossover effects. No significant carry-over effects were found in either of the behavioral ratings. Significant drug effects appeared in the crossover repeated measures analysis for baseline as covariate in the ABC-parents' sum score and social withdrawal subscale (drug effects F[l,17] = 4.72 and 5.14, respectively, withp < .05) and in the CGI severity and improvement ratings (drug effects F[ 1,17] = 6.12 and 4.80, respecti,vely, with p < .05, and time effect F[2,36] = 11.01 with p < .001 in the improvement rating). All drug effects were in the expected direction with improved ratings in the ORG 2766 condition. The crossover analysis on the GAP, 1151

BUITELAAR ET AL. TABLE 3. Results of ANCOVA for Simple Main Effects on Aberrant Behavior Checklist-Teachers', General Assessment Scale-Parents; Clinical Global Impressions, and Conners PTQ Ratings as Dependent Variables in Parallel Study

ANOVA (Endpoint) ABC-teachers· GAP General impression Stereotypy Social isolation Self-disclosure Attentiveness CGI Severity Improvement Conners PTQ

F(1,12) = 1.21 F(I,18) = 0.19 F(I,18) = 4.42* F(I,18) = 4.49* F(I,18) = 0.12 F(1,18) = 0.02 F(1,18) = 4.65* F(I,18) = 1.29 F(I,18) = 1.52

Note: ANCOVA = analysis of covariance, ABC = Aberrant Behavior Checklist, GAP = General Assessment Scale-Parents, CGI = Clinical Global Impressions. a ABC-teachers' ratings were completed for 15 subjects (placebo N = 7, ORG 2766 N = 8).

*p <

.05.

TABLE

4. Individual Target Symptoms (Rated by Parents)

ORG 2766 Compared with Placebo N Worse Same Improved Sleep disorder 7 5 4 3 Fears, anxiety Cognitive preoccupations 2 I Talks excessively 2 I Verbal aggression I I Physical aggression I Screaming I Depressed mood I Running away 1 Vocal tic I I Bizarre fantasies Note: 22 individual target symptoms were rated in IS children. The overall analysis is in accordance with an ORG 2766 treatment effect (chi-square [df = 2] = 8.3, p < .05)

Conners', and ABC-teachers' ratings did not show significant results. However, when ABC-teachers' ratings were analyzed separately for drug responders and nonresponders (see below), in the responder but not in the nonresponder subgroup improvements in ABC sum score and social withdrawal score were found on a p = .08 level. Parents treatment preferences completed at the end of the trial were for ORG 2766 treatment rather than for placebo (chi-square [df = 2] = 7.3, p < .05). The outcome of the individual target symptoms analysis is presented in Table 4. Conspicuously, parents reported that their children had fewer sleep difficulties, anxieties, and fears during ORG 2766 treatment.

Individual Responders According to the described algorithm for individual re-

sponders, seven subjects were identified as definite respond1152

ers and two subjects as probable responders. Response was not associated with IQ, CARS, weight, age, gender, participation in first trial, use of additional medication, treatment order, or baseline scores on any of the checklist (subscale) scores.

Playroom Data Frequencies of behavior elements. The behavior element "play" (representing functional object playing and/or symbolic play behavior) showed a consistent and significant difference between the baseline, placebo, and ORG 2766 conditions (see Fig. 1 and Table 5). No carry-over effects were found. In the crossover trial, ORG 2766 treatment was associated with significantly more play behavior. The increase in play behavior induced by O~G 2766 was more impressive in the subgroup of individual responders and was found to be associated with significant changes in the frequencies of other behavior elements in this subgroup (see below). Interaction between child and experimenter. ORG 2766 treatment was associated with a significant increase in the TE "interchild" (see Table 6) but not in the TE "interexperimenter." This indicates that the increased interaction between child and experimenter after treatment with ORG 2766 is to be ascribed to initiatives of the child. To locate more precisely the source of this difference, the analysis of the TE values subsequently was carried out for two clusters of child behavior elements separately, namely the (verbal) and (stereotypy) clusters (Table 6). After treatment with ORG 2766, a significant increase was found in the TE "interchild (verbal)" values compared with baseline and placebo values. This means that the child's verbal, gaze, and gesture behavior play an important part in the increased interaction with the experimenter. In contrast, the TE "interchild (stereotypy)" values did not show a signif400- sec

1

°1,_,_--..__ -2 0

1_--..__ 1_1 _ _ , _ _ 1_1 _ _ 1

8

16 18

22

26

30

34

time (wee ks) FIG. 1. Graphical display of the time spent on play behavior (mean ± SD) in the crossover trial (treatment group I N = II, treatment group II N = 9). Thick lines indicate the period of 8 weeks ORG 2766 treatment. Playing after treatment with ORG 2766 is increased compared with baseline and placebo (Wilcoxon, p < .05). J. Am. Acad. Child Ado/esc. Psychiatry, 31:6, November 1992

ORG 2766 AND AUTISM TABLE

5. Playroom Parameters (mean:±: SD) in Baseline, Placebo, and ORO 2766 (at Endpoint) Conditions Baseline 190 ± 37:±: 2.0 :±: ILl :±: 85 :±: 5.1 :±: 121 :±: 46:±: 14:±:

Play (sec) Locomotion (sec) Changing toy (fr) Talk (fr) Stereotypy (sec) Gestures (fr) Automanipulate (sec) React to task (%) Face (%) Note: sec

Placebo 215 ± 19:±: 1.6 :±: 11.5:±: 92:±: 4.1 :±: 116:±: 46:±: 10:±:

105 55 2.4 9.4 36 3.1 74 16 14

ORG 2766 295 ± 26:±: 2.0 ± 9.6:±: 78:±: 3.6:±: 93 :±: 48 ± 12:±:

98 19 2.0 10.4 32 3.5 223 15 10

135* 27 3.9 7.9 177 5.7 245 12 12

= seconds, fr = frequency, % = percentage of time that behavior was scored.

* Significant difference between baseline, placebo, and ORG 2766 (Friedman, p <

.05) and significant differences between ORG 2766 and

baseline, and between ORG 2766 and placebo (Wilcoxon, p < .05).

TABLE

6. Interaction between Child and Experimenter, Expressed in Transmission-Efficiency Values (mean ± SD) in Playroom Observation for Baseline, Placebo, and ORO 2766 Conditions. Based on Crossover Analysis (N = 20)

TE-%

Baseline X :±: SD

X :±: SD

ORG 2766 X :±: SD

Interchild Interexperimenter

3.3 :±: 2.5 5.8 ± 4.2

4.5:±: 2.9 8.8 :±: 7.5

7.2:±: 6.2 9.0:±: 7.0

Interchild (verbal) Interchild (stereo) Interexperimenter (verbal) Interexperimenter (stereo)

3.2 2.9 5.5 3.5

:±: :±: :±: :±:

1.7 2.6 3.3 6.3

Placebo

5.9 :±: 8.0:±: 12.6 :±: 5.8 :±:

5.2 7.6 20.3 5.8

12.5 9.0 8.8 6.5

:±: :±: :±: :±:

10.0 7.6 8.3 8.0

Friedman p < .01 B

= P< 0

< .001 B = P < 0 P <.01 B = P < 0

p

Note: TE = transmission efficiency, B = baseline, P = placebo, 0 = ORG 2766, comparisons with Wilcoxon (two-tailed, ex = .05). Parentheses indicate behavior elements included in that particular analysis: (verbal) = face by C, nonface by C, nod/shake, gestures, react, answer, ask, talk, smile specific; (stereo) = nonreact, smile unspecific, distress, automanipulate, stereotypy, touch by C, mouthing, vocalize; C = behavior element emitted by child. ".

icant difference between ORG 2766 and placebo. More insight into the role that particular behavior elements play in this increased interaction can be gained from the analysis of temporal contingencies. Temporal contingencies. The analysis of temporal contingencies of behavior elements is summarized in Table 7. (The complete behavior diagrams of this analysis are available from the first author on request.) In the analysis of the free activity part of the session, there are two main results to report. First, it is only after treatment with ORG 2766 that connections are found between "play" and the child's gaze behaviors, in particular TABLE

"face by C." This is an important finding because gaze behaviors of the child toward the experimenter in this part of the session were recorded during interactive or communicative events initiated by the child (e.g., the use of gestures). Second, after treatment with ORG 2766, "play" is sequentially less closely associated with the elements from the stereotypy cluster as "stereotypy," "manipulate" and/or "changing toy" than in the baseline/placebo conditions. This means that, after treatment with ORG 2766, "play" forms a separate behavioral system distinct from manipulating and! or stereotyped handling of objects. In the task-related part of the session, two findings are

7. Summary of Analysis of Changes in Temporal Contingencies between Behavior Elements in Baseline, Placebo, and ORO 2766 Playroom Observation. Data are Mean:±: SD of Residual Values R. Based on Crossover Data

Temporal Contingency

Baseline

Placebo

ORG 2766

Free activity part Play-face by C Play-nonface by C Play-stereotypy

-.09 ± .21 .04:±: .15 .60:±: .20

-.02 ± .23 .11 :±: .20 .56:±: .19

.34 ± .24 .25 :±: .18 .12:±: .25

p

.02:±: .31 .10:±: .12

-.II:±: .30 .23 :±: .16

.75:±: .38 .45 :±: .20

p

.56 :±: .30

.48 :±: .23

.02 :±: .16

P < .01 B = P> 0

Task-related part Face by C - face by E Gestures-verbal initiative Stereotypy-verbal initiative Note: B

= baseline, P "'" placebo, 0 = ORG 2766. Comparisons with Wilcoxon (two-tailed, ex =

J. Am. Acad. Child Adolesc. Psychiatry, 31:6, November 1992

Friedman

< .01 B = P < 0 P < .05 B < P = 0 P < .01 B = P> 0 < .01 B = P < 0 P < .05 B < P = 0

.05).

1153

BUITELAAR ET AL. TABLE

8. Differences in Playroom Parameters (mean ± SD)for Definite Responders (N

B Play (sec) Locomotion (sec) Change toys (fr) TE "interchild verbal" TE "interexperimenter verbal"

Responders P

94 (61) 37 (33) 3.3a (2.6)

154 (50) 16 (24) 2.7 (2.3)

2.la (1.6) 3.l a (1.8)

4.6 (4.0) 11.6 (22.7)

= 7) and Nonresponders (N = 6) B

Nonresponders P

ORG

(II) O.3 b (0.8)

135 (101) 18 (19) 1.5 (1.2)

317 (125) 23 (18) 1.8 (1.2)

293 (111) 26 (27) 4.2 (6.3)

l1.3 b (8.0) 7.7 (4.1)

4.5 (1.4) 8.8 (3.0)

6.5 (4.8) 11.5 (7.6)

12.5 (9.8) 10.9 (12.3)

ORG b

297 (112) ~

= baseline, P = placebo, 0 = ORG 2766, sec = seconds, fr = frequency, TE = transmission-efficiency values. Significant difference between baseline values of responders and non-responders (p < .05, Mann-Whitney). b Significant ORG 2766 effect in responder subgroup (Friedman, p < .05, and B = P, whereas 0 is different from Band P, Wilcoxon). Note: B

a

particularly important. First, after treatment with ORG 2766, there is an improvement in eye contact between child and experimenter, as is apparent from the closer temporal contingency between "face by C" and "face by E." Second, after ORG 2766, the child's verbal behavior has more communicative intention. This is evident from the closer connections of verbal initiatives (as "ask" and "talk") with "gestures" after treatment with ORG 2766. In contrast, in the baseline and placebo pictures verbal initiatives are sequentially more associated with "stereotypy." As a check, the temporal contingency analysis also was performed on split samples for both the free-activity part and the task-related part of the session and for all three conditions. The outcome confirmed the findings described above. In a further analysis, we tried to discover whether ORG 2766 differentially affected responders versus nonresponders on the playroom parameters (data and analysis are presented in Table 8). In the responder subgroup ORG 2766 treatment was associated with an increase in play behavior, a decrease in locomotion and changing-toy behavior, and an increase in the TE "interchild (verba!)." In the nonresponder subgroup, no ORG 2766 effects were found on any of the playroom parameters. Finally, temporal contingencies in both the placebo and ORG 2766 condition were analyzed separately for the responders and nonresponders. In both the free-activity and the task-related parts of the session, the ORG 2766-induced shifts in temporal contingencies were found to a much greater extent in the responder subgroup than in the nonresponder subgroup (data not shown). Discussion Checklist Ratings The principal objective of this study was to establish whether ORG 2766 exerts clinically meaningful effects on the social behavior of autistic children. Indeed, the parents' ABC-ratings and the clinicians' CGJ.ratings indicated significant ORG 2766 treatment effects after the administration of a higher cumulative dosage of ORG 2766 than in the 1154

first study. Most impressive was the reduction in social withdrawal behavior as reported by the parents. However, treatment effects subsided when ORG 2766 treatment ceased. The suggestion from the first trial that improvements on checklist ratings may continue after ORG 2766 treatment could not be confirmed. In this vein, it should be underlined that data on dose-response relationships of ORG 2766 are contradictory (Kragh-Sorensen and Lolk, 1987; Sandman et aI., 1980) and that the time course of ORG 2766 effects may be dose-dependent (Sandman et aI., 1985). The impression gained from the first trial that the children would become more attentive and show more interest in the "outside" world when treated with ORG 2766 could not be confirmed with the GAP. Furthermore, on the "general impression" item of the GAP, no treatment effects were found. Apparently, only detailed ratings (ABC-parents) during the trial reveal ORG 2766 treatment effects. No ORG 2766 effects were found on the Conners' rating scale. This is not surprising, because baseline Conners' ratings were within the normal range in the case of both treatment order groups. That ABC-teachers' ratings could not substantiate ORG 2766 effects is probably because of the smaller sample on which teachers' ratings were based and the much greater variance in the teachers' data. Another explanation, however, may be that the clinical effects of ORG 2766 are not robust enough to be perceived in a more complex group interaction situation. A less likely explanation is that teachers may be less familiar with or less sensitive to the autistic children's behavior. Individual Responders Nearly half the sample (9120) was found to be an individual responder. The responders, who were identified on crosssituational checklist ratings, also were characterized by specific improvements in playroom parameters, in contrast to the nonresponders. This is an interesting cross validation of the two methods for ascertaining an index of individual improvement because each was obtained independently of the other. Unfortunately, the attempt to find easily obtainable and potentially predictive chariicteristics of individual J. Am. Acad. Child Adolesc. Psychiatry, 31:6, November 1992

ORG 2766 AND AUTISM

responders failed. At the moment, the data suggest that responders are characterized by an initial lower level of interaction (lower baseline TE "inter [verbal]s" for both child and experimenter) and more initial activity (higher level of changing-toy behavior). The effect of ORG 2766 on biochemical and neurophysiological variables will have to be explored in future studies to obtain a better understanding of the neurobiological aspects. Playroom Data

The second objective of the study was to describe in detail the ORO 2766-induced behavioral effects by means of an ethologically analyzed playroom session. The behavioral changes after ORO 2766 seem to consist of two main components, stimulation of social interaction and enhancement of purposeful activity. With regard to the first component, ORO 2766 treatment was associated with an increase in the child-initiated interaction with the experimenter, as was appar,ent from the information-theoretical analysis. These effects of ORG 2766 on the TE "interchild" values were in accordance with the outcome of animal research, in which ORO 2766 was shown to block the progressive decline in sociability in aging rats (Spruyt, 1991a,b). A subsequent analysis of temporal contingencies indicated that improved coordination of mutual gaze behavior and heightened verbal communicative intention seem to play a key role in this increased interaction. The improvement in eye contact is of special clinical importance in view of the deficits of visual reciprocity behaviors that have been repeatedly reported in the autistic population (Buitelaar et aI., 1991). The second component, the enhancement of purposeful activity, was reflected as changes in play behavior. First, we found an increase in the time spent on play behavior; the finding, however, is almost at chance level (l of 9 playroom parameters changed with a p < .05). Second, and of greater importance, are the changes in the type and the quality of the children's play behavior. This can be extracted from the results of the analysis of temporal contingencies. This analysis reveals that, after treatment with ORO 2766, play behavior is less sequentially associated with and is less interrupted by locomotion or object manipulation and that there is increased social interaction during play. The results of the playroom data are in some respects at variance with· the outcome of the first trial (Buitelaar et aI., 1990). The increases in locomotion and changing-toy behavior found earlier were not replicated. However, this is not necessarily in contradiction to the increase in play behaviors in the present study. Locomotion and changingtoy behavior may be regarded as preliminary and supportive activities for the purpose of engaging in longer sustained play behavior. In the present study, the children were allowed a longer time for free activities. This, in combination with the higher cumulative dosage of ORO 2766 administered, may have facilitated the emergence of ORO 2766induced changes in play behavior, which were more or less incompatible (see the structure of behavior analysis) with increases in locomotion and changing-toy behavior. This line of reasoning is corroborated by the findings in the reJ. Am. Acad. Child Adolesc. Psychiatry, 31:6, November 1992

sponder subgroup, where a significant increase in play behavior is associated with significant decreases in changingtoy behavior and locomotion. Note that differences in play behaviors in the two studies are not due to differences in total or verbal IQ between the two samples of children or to differences in playing at baseline level. In this study no decrease in stereotyped behaviors was detected. This negative finding may be explained by differences in the baseline levels of stereotyped behaviors in the two studies (mean ± SD first trial 104 ± 159 seconds, second trial 85 ± 36 seconds). Concluding Remarks

The findings of this study need to be interpreted with caution. The data are based on rather a small sample of autistic children. Further, the patient population was rather diverse with regard to age, IQ, and severity of autism. This variation may have clouded to some extent the detection of clearcut drug effects. . It has been suggested that brain opioid systems may be involved in infantile autism (Chamberlain and Herman, 1990; Panksepp and Sahley, 1987). Initially, interesting effects have been reported after the administration of the opioid antagonist naltrexone in autistic subjects in open pilot studies, either in acute dosages (Campbell et aI., 1989; Herman et aI., 1986) or in subchronic dosages (Leboyer et aI., 1988; Lensing et aI., 1989). However, data from a first controlled trial with naltrexone in autistic subjects could not substantiate positive behavioral effects on objective rating scales (Campbell et aI., 1990). ACTH peptides and endogenous opioids probably constitute a balance system that modulates many brain functions (O'Donohue and Dorsa, 1982). The social behavior modulating effects of ORO 2766 in the rat dyad interaction model proved to be naltrexone reversible, which indicates that ORO 2766 exerts this effect via an interaction with endogenous opioid systems (Niesink and Van Ree, 1983). Hence the behavioral effects induced by ORO 2766 in these autistic children may be mediated by endogenous opioid systems. However, direct action of ORO 2766 on ACTH-specific binding sites (Oalina et aI., 1985) cannot be ruled out either. There are three alternative possibilities concerning the mechanism of action of ORG 2766 in the present study. First, social behavior may have been improved through reduction of fear. An anxiolytic activity of ORO 2766 has been suggested by an increased social interaction after ORO 2766 in the rat interaction model (File, 1981) and by some symptomatic improvement after ORO 2766 in patients with anxiety disorders (Den Boer et aI., 1989). The reduction in fears found in some subjects in the present study is in concordance with this possibility. Second, ORG 2766 may have exerted a positive impact directly on social motivation. This idea stems mainly from animal studies that indicate a stimulating effect of low doses of B-endorphin on approach behavior (Niesink and Van Ree, 1984; Van Ree and Niesink, 1983). Third, social interaction may have been promoted by enhanced concentration and attention. Data from the rat dyad interaction model suggest that the social behavior modulating effects of ORO 2766 originate in the amygdala by influ1155

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encing the integration of sensory stimuli (Wolterink and Van Ree, 1989). Because of the information processing deficits established in autism (Courchesne et al., 1985; Van Engeland et al., 1991; Verbaten et al., 1991) and the influence ORO 2766 has on information processing in humans (Sandman et al., 1985), this possiblity is further explored in a current study by evaluating both social behavior and information processing in autism after ORO 2766 treatment. The ORO 2766-induced behavioral effects, which can be summarized as a social interaction enhancing and activating influence, go to the core of the autistic symptomatology and merit further research. It should be emphasized, however, that ORO 2766 is not available on the market, and that, awaiting further studies of clinical efficacy and safety, it is too early to be recommended to routine practice.

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