The use of adrenocorticotrophic hormone (4–9) analog ORG 2766 in autistic children: Effects on the organization of behavior

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The Use of Adrenocorticotrophic Hormone (4-9) Analog ORG 2766 in Autistic Children: Effects on the Organization of Behavior Jan K. Buitelaar, Herman van Engeland, Kathy H. de Kogel, Han de Vries, Jan A.R.A.M. van Hooff, and Jan M. van Ree

In a double-blind placebo-controlled crossover trial, 14 autistic children were treated with the neuropeptide ORG 2766, a synthetic analog of adrenocorticotrophic hormone (ACTH) (4-9). ORG 2766 treatment (20 mg per day during 4 weeks) was associated with an increased amount and an improved quality of the social interaction of the autistic children with a familiar experimenter. These changes in interaction were clinically relevant. Following treatment with ORG 2766 gaze and smile behaviors of child and experimenter showed stronger temporal contingencies. Further, after ORG 2766, stereotypies were temporally disconnected from verbal initiatives. The data supported the notion of a stimulating effect of ORG 2766 on social interaction. The implications of these findings for the endogenous opioid theory of autism are discussed.

Introduction Autism is a neuropsychiatric disorder that is preeminently marked by deficits in social interaction. In addition, the disorder is characterized by repetitive stereotyped behavior patterns and a deviant development of cognitive, language, and communicative functions (Putter and Sch6pler 1987; Howlin 1986). Deficiencies in information processing have been established in autism by means of psychophysiological studies (Courchesne et al 1989; Verbaten et al 1991; Van Engeland et al 1991). ORG 2766, a synthetic adrenocorticotrophic hormone (ACTH) (4-9) analog, is a neuropeptide that is active on oral administration (Voortman and Timmer 1990) and that is devoid of substantial steroidogenic activity (Pigache and Rigter 1981). A study with ORG 2766 in autism was performed for the following reasons. First, ORG 2766 has been shown to counteract declines in social attention in aging rats (Spruyt 1991) and to modulate disturbances in social behavior of rats that are elicited by environmental manipulations (Niesink and van Ree 1983). For instance, both the increase in social interaction, induced

From the Depm'tmentof Child and Adolescent Psychiatry OKB, HvE, KHdK), Utrecht University Hospital; the Depsurtment of ComparativePhysiology(HdV, JARAMvA), and the Departmentof Psychopharmacology(JMvR) Universityof Utrecht, The Netherlanu.,. Address reprint requests to Jan K. Buitelaar, M.D., Ph.D., Depaztmentof Child and AdolescentPsychiatry, Utrecht University Hospital, P.O. Box 85500, 3508 GA Utxecht, The Netherlands. Received January 25, 1991; revised December 21, 1991. Presented in part at the Conference on the ExperimentalBiology of the Autistic Syndromes, held in Durham, U.K., March 29-31 1989, and at the 2]st International EtSologicaiConferencein Utrecht, August 9-17 1989. ~ 1992 Society of Biological Psychiatry

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by previous social isolation, and the decrease in interaction, induced by a high level of illumination, are counteracted by ORG 2766 when pairs of rats are tested. In human studies evidence appeared that administration of ORG 2766 is followed by an improvement of social behavior in elderly people with cognitive disorders and in mentally retarded adults (for review see van Ree in press; Sandman et al 1980). Second, ORG 2766 influences learning behavior in animal experiments (for review see De Wied and Jolles 1982; Fekete and de Wied 1982a,b), and influences both auditory and visual evoked response parameters in humans (Born et al 1984, 1985a, b, 1989; Sandman et al 1985). Finally, brain opioid systems have been implied in the neuroregulation of the autistic syndrome (Panksepp and Sahley 1987; Chamberlain and Herman 1990). ACTH peptides and endogenous opioids probably constitute a balanced system that modulates many brain functions (O'Donohue and Dorsa 1982). The effects of ORG 2766 in animal studies both on social behavior and on information processing could be demonstrated to be Naltrexone reversible (Niesink and van Ree 1983; Fekete et al 1983). This suggests that ORG 2766 exerts these effects via an interaction with endogenous opioid systems. In a previous report, beneficial behavioral effects were described of ORG 2766 in autistic children (Buitelaar et al 1990). Playroom observation data pointed to an increase in spontaneous activity. The autistic children manifested less stereotyped behaviors, and emitted more talk, locomotion, and changing-toy behaviors. No side effects were observed. Eight out of 14 children were identified as a clinical responder on the Clinical Global Impressions Scale (CGI, Psychopharmacol Bull 1985). The finding that ORG 2766 facilitates verbal communication and increases locomotor activity in autism leaves unanswered the question of whether ORG 2766 exerts positive effects in particular on the social behavior deficits in autism. In behavior-observation studies these deficits were found to pertain not so much to differences in frequencies of behaviors but rather to differences in the organization of social behavior (Van Engeland et al 1985; Buitelaar et al 1991). The organization of social behavior refers to the tempero-sequential patterning of behavior elements. Ethologists have developed concepts and methods enabling one to analyze the tempero-sequential patterning of behavior in quantitative terms (Van Hooff 1982; Van Engehmd et al 1985; Buitelaar et al 1991). T~,~s paper reports on the results of such an ethological analysis. The analysis was performed on the data from the task-related part of the playroom session in the first clinical trial wi~h ORG 2766 in autism (Buitelaar et al 1990).

Methods

Subjects and Procedure Subjects and procedures have been described earlier (Buitelaar et al 1990). In brief, 14 outpatient autistic children (12 boys and 2 girls, mean age +- SD ffi 8.7 +_ 2.7 year, IQ mean _ SD = 63.8 _+ 23.6) were enrolled in a double-blind placebo-controlled crossover design. Assignment to treatment-order groups ORG 2766-placebo or placebo-ORG 2766 was random. Each child received a tablet of 20 mg ORG 2766 (8 AM) for 4 consecutive weeks. Tablets of ORG 2766 or identical matching placebo tablets were provided by Organon lnternatio~::~~ ~.V. (Oss, the Netherlands). All subjects met the DSM-III-R criteria for autistic di~o~'der (APA 1987). Diagnosis was made in-

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dependently by two child psychiatrists UB,HvE) on the basis of all available information; this included a developmental history, a parent interview, and a child psychiatric observation. Subjects with neurological, internal, or endocrinological diumie~ were excluded. All children were free of other medications 3 months prior to or during the trial. Treatment-order groups did not differ in age or IQ. Drug effects were monitored in a semi-structured playroom session at baseline, following ORG 2766 treatment for 2 and 4 weeks, following placebo treatment for 2 and 4 weeks, and at follow-up after 4 weeks. As a reference, a group of l0 nonautistic retarded control children was also observed once in the same playroom procedure to be described below. Controls were matched on age (mean -- SD = 8.7 +_ 1.2 year)and IQ (mean - SD = 75.9 -+ 8.3). The data from the comparison of the controls with the autistics (in the baseline session) have been extensively reported elsewhere 'Buitelaar et al 1991).

Observation of Behavior in Playroom Session Behavioral observation daga were gathered in a semi-structured playroom session lasting 20 rain. The playroom session consisted of two parts, a first part (0-8 rain) of free play, and a second part in which the experimenter set the child four tasks. These tasks were a constructive task, a motor-imitation task, a drawing task, and a musical task, respectively. In subsequent sessions the children were offered alternative versions of the tasks with equal degree of difficulty. The whole study was carried out by the same experimenter (JB). We will report here only on the sequential patterning of behavior elements in the task-related part of the session. The time relationships of single behavior elements were registered by the same observer (CdK) throughout the study by means of an event recorder. The set of the behavior elements and their definitions is given in Table 1. Eight randomly chosen sessions were videotaped and recorded by the observer at the beginning and at the end of the study, 4 months later, as a check for intrarater drift. The mean intrarater reliability was 0.83, the range being from 0.68 (nonverbal behaviors) to 0.87 (stereotypies) (expressed in kappas, Cohen 1960). These eight randomly chosen sessions were also recorded by a second rater. The mean interrater reliability was 0.78, the range being from 0.68 (gaze behaviors) to 0.84 (stereotypies).

Data Analysis As a firststep in the analysis of the sequential paoeming of behavior, matrices of combination frequencieswere composed. A combination frequency points to behavioral elements occurring togetherwithin a time frame of 5 sec (Van Hoof 1982; Loots 1985; Buitelaaret al 1991). Secondly, the degree of interactionaldependency of the child'sbehavioron the behavior of the experimenter was calculatedaccording to the methods outlined in Steinberg and Conant (1974) and Steinberg (1977). This calculation is based on information-statistical principles. For instance, the, experimenter asks the child to sit down. Knowing this behavior of the experimenter, the issue is to predict the subsequent behavior of the child. When there is a strong interactional dependency, that is, when the transmission-efficiency

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Table 1. List of Behaviors Behavior of the child Face by C Nonface by C

Face directed toward face of experimenter Face not directed toward face of experimenter (includes all kinds of looking other than face) Verbal response All verbal communication by the child, including communicative speech, talking to self and answering Nonverbal response All nonverbal communication, including indicating and referencing gestures and nonverbal responding to tasks Stereotypy All stereotyped behaviors, including rocking, flapping, and stereotyped use of objects Smile by C The child smiles while facing the experimenter Vocalizing Includes all consonants, vowels, or other sounds made with lips, mouth, tongue, or nose. Behavior of the experimenter Set task Posing questions to or putting demands on the child that require either a nonverbal or a verbal response Face by E Face directed toward face of the child Nonface by E Face not directed toward face of the child Smile by E The experimenter smiles while facing the child C, child; E, experimenter,

(TE) child is high, there is little uncertainty in predicting that the child will manifest a certain response, for example, will gaze toward the experimenter, move toward the chair, and sit down. Thus, in this case there is a strong interaction of the child with the experimenter. Similarly, the TE-experimenter denotes the interaction of the experimenter with the child. Thirdly, in order to get a more detailed picture revealing the role of particular behavioral elements in the interactional dependencies, patterns of temporal contingencies of behavioral elements were analyzed (Van Hooff 1982). Before applying these descriptive techniques, differences between the matrices of combination frequencies in the baseline, placebo, and ORG 2766 conditions were explored with the recently developed matrix correlation test (Hemelrijk 1990). This test enables one to compare the complex information comprised in different matrices of combination frequencies. The temporal contingencies were expressed in terms of standardized residuals (Van Hooff 1982). These were obtained by comparing ~,,b~erved combination frequencies with the frequencies expected on the basis of the null hypothesis, which is that consecutive behavioral elements are independent. For each cell the standardized residual was calculated (R = (o - e)/V~e, where o represents the observed combination frequency and e the value that would be expected on the basis of a random distribution (Van Hooff 1970). For example, if the residual R of the temporal contingency between two behavioral elements turns out to be high, these two elements me occurring closer together in time far more often than should be expected on the basis of the frequencies of the single elements. Such a high R then indicates that there is a structural connection between these two behavioral elements. Changes in the frequencies of behavioral elements were most evident at the end of treatment, that is following 4 weeks on ORG 2766 (Buitelaar et al 1990). Hence the analysis of TE-values and temporal contingencies was focused on the comparison between the baseline condition, and the data of the crossover trial following 4 weeks on placebo and on ORG 2766, respectively.

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Table 2. Transmission-Efficiency(TE) Values (mean _+ SD) for the Baseline, Placebo (4 weeks), and ORG 2766 (4 weeks) Conditions. TIE- child TE- experimenter TE- child responders (n : 8) nonresponders (n = 6)

Baseline

Placebo

ORG 2766

Friedman

9.8 4. 2.0 17.4 4. 7.6

9.0 4. 2.2 17.1 4. 5.1

11.5 4. 5.0 18.5 4. 6.1

P < 0.05 B = P < O

9.7 4. 1.9 9.9 4. 2.0

9.6 4. 1.9 8.7 4. 2.6

12.8 4. 3.9 9.9 4. 6.3

P<0.05B

=P
B -- baseline, P = placebo (4 weeks), O = ORG 2766 (4 weeks). Compm/sions with Wilcoxon (two-tailed, alpha = 0.05). The TE values can be inteqxeted as a measure of the amount of interaction between child and experimenter. For example, a high "rE- child denotes a stnmg interaction of the child with the experimenter. TE values are based on individual matrices.

Results The TE-values of the matrices in the baseline, placebo, and ORG 2766 conditions are shown in Table 2. Analysis reveals that the TE-child values are significantly higher after ORG 2766. The enhanced TE-child values after treatment with ORG 2766 reflect an increase in the interaction of the children with the experimenter. No changes were detected in the TE-experimenter. The correlations with the matrix-correlation test (Table 3) indicate that the baseline and placebo matrices are rather similar, whereas the ORG 2766 matrix is somewhat different from the baseline and placebo matrices. The reference data from the comparison of the control group with the autistics in the baseline condition are presented in Figure I. The comparison reveals that face behaviors ~l the control group show high temporal contingencies, in contrast to the autistic group. A second main difference concerns the strong contingencies between stereotypies and nonverbal responding and vocalizing in the autistic group. The results from the temporal contingency analysis for the placebo and ORG 2766 conditions are shown in Figure 2. The main differences between the temporal contingencies of the behavioral elements following 4 weeks on placebo and 4 weeks on ORG 2766 will be described. First, and most interestingly, after ORG 2766 strong temporal associations are found between the face behaviors of child and experimenter. This association, which is lacking in the placebo condition, implies an improvement of eye contact. Second, it is apparent that following treatment with ORG 2766 stereotyped behaviors are temporally disconnected from all other behavioral elements. Third, the smile behaviors of child and experimenter reveal closer temporal connectedness following ORG 2766 treatment than after placebo; both smile behaviors are also strongly connected to vocalizing. This indicates that in the ORG 2766 condition, child and experimenter are smiling at each other; further that this mutual, interactive, smiling is accompanied by vocalizing of the child. Table 3. Correlation Coefficients (tan) with the Matrix Correlation Test of Matrices in Baseline, Placebo, and ORG 2766 Conditions B~.~: Placebo All correlations were significant, p < 0.01.

Placebo

ORG 2766

0.75

0.58 0.64

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Controls

Autistic children baseline -

m SET T A S K SMILE BY E l

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--,.., Figure 1. Pictogram of the temporal contingencies of behavioral elements from the comparison of a control group with the autistic group in the baseline condition (adapted from Buitelaar et al 1991). The contingencies are expressed as the standardized residuals between behavior elements. The re..iduals represent a measure of the strength of the temporal contingencies between behavior elements, corrected for chance. Strong contingencies (R> 10) are indicated by thick connecting lines, weak contingencies (5 < R < 10) by thin connecting lines. At left, the controls; at right, the autistics. C: behavioral elements emitted by the child, E: behavioral elements emitted by the experimenter. Read this figure from above, for example, for the controls as follows: E sets C a task; either E faces C, or not, When E faces C, in turn C faces E and gives a verbal response. When E does not face C, C does not face E, and gives a nonverbal response. When C faces E, this is frequently accompanied with smiling by C. Smiling by C is followed by smiling by E and by vocalizing. In particular vocalizing and nonverbal responding are frequently associated in time with stereotypies. Arrows point to main differences between both groups. For the autistics these differences include rather low contingencies between the face behaviors by C and E, smiling and vocalizing by C, and rather strong contingencies between nonverbal responding and stereotypy.

Behavioral changes after 2 weeks on ORG 2766 were intermediate between baseline and endpoint data; treatment effects were no longer visible after 4 weeks follow-up (data not shown).

Clinical Significance The investigators rated eight children as drug responders on the CGI (Buitelaar et al 1990). These children appeared more communicative and attentive. They were also more interested in social contact. When the information-statistical data of the responder and the nonresponder subgroups were analyzed separately (see Table 2) only the clinical responder subgroup showed the increases of the TE-child (increases in seven out of eight individual responOers and in three out of six nonresponders) after ORG 2766. Although it should be acknowledged that the effect size of the differences in TE-child values for the whole group in this study was rather small (0.3--0.5 SD) the effects were larger (0.51.0 SD) in the responder subgroup. Moreover, these responders could be identified as such independently on clinical grounds. A further validation of the clinical significance of the outcome of analysis of the organization was obtained by analyzing separately the temporal contingency aspects in the responder and nonresponder subgroups (data not shown). Only the responders manifested the increased associations between mutual face and smile behaviors after ORG 2766.

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Au~bc children O l ~ 27 66 SET TAM~

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Figure 2. The same picture as in Figure 1, here A is for the autistics following 4 weeks on placebo (at the left) and following 4 weeks on OR(] 2766 (at the right). C: behavior elements emitted by the child, E: behavior elements emitted by the experimenter. Arrows point to main differences between both of these groups. The placebo diagram is rather similar to the baseline diagram from Figure 1, with lacking temporal connections between the face behaviors of C and E, weak contingencies between smiling and vocalizing, and strong contingencies between nonverbal responding and stereotypy. In contrast, following OR(; 2766 there are strong contingencies between the face behaviors of C and E, and between smiling and vocalizing. Further, stereotypy is temporally disconnected from nonverbal responding and from vocalizing. Finally, there are strong associations between smiling by C and E, and between smilin? by E and vocalizing by C. B contains the diagrams following 2 weeks on placebo (left) and 2 weeks on ORG 2766 (right). Changes after 2 weeks on OR(3 2766 are intermediate between baseline an(! endpoint data.

Discussion The present data indicate that OR(] 2766 treatment is associated with changes in the social interaction of autistic children. The changes include both an in~:rease in the amount of interaction and an improvement in the quality of interaction. The latter result may be of special clinical importance. The improvement of the quality of social interaction is based on an improvement in the coordination of gaze behavior,; resulting in increased eye contact, an increase in mutual smiling, and a decrease in the interactional role of stereotyped behaviors. ORG 2766 trer, tment affected some of the temporal contingencies

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in particular, which formed chm~¢teristic differences between autisfics and controls (Figme 2; Buitelaar et al 1991). It is important to nolle that the ethological analyses applied provide evidence that ORG 2766 induced shifts in the sequential patterning of behavior that may be found in the absence of changes in ~,quencies of single behavioral elements. For no changes were found in the frequencies of gaze and smile behaviors following ORG 2766 treatment (Buitelaar et al 1990). This underscores the merits of a sequential behavioral analysis, supplementary to an analysis of frequency effects. With regard to the endogenous opioid hypothesis of autism, some beneficial effects have been observed after the administration of the opioid antagonist Naltrexone in autistic subjects. In open acute-dose studies Herman et al (1986) found a decrease in abnormal motor behaviors, but no effects on social and communicative behaviors, whereas Campbell et al (1989) reported on a combination of tranquilizing and social stimulating actions. Positive effects of Naltrexone on social behavior following subchronic dosages in open studies have been described by other research groups (Leboyer et al 1988; Lensing et al 1989; Lensing 1990). All these studies (except Campbell et al 1989) were pilot studies involving five or fewer subjects. In a first controlled trial, Naltrexone treatment in autism was associated with a decrease in hyperactivity. However, positive effects on social behavior could be substantiated only on a global clinical consensus rating but not on objective rating scales (Campbell et al 1990). The effects of ORG 2766 on ~ i a l behavior in animal studies proved to be Naitrexone reversible (Niesink and van Ree 1983). Other research findings suggest that these eftects of ORG 2766 originate in the amygdala by influencing the integration of sensory stimuli (Wolterink and van Ree 1989). Data from binding studies and social-interaction experiments also support the hypothesis that endogenous opioid systems in the amygdala are particularly important for social behavior (Panksepp and Bishop 1981; File and Rodgers 1979). As a consequence, a possible biochemical mechanism of action underlying the ORG 2766 effects could be the g:adual release of endogenous opioids in the amygdala. This possibility find,~ support in results from animal studies indicating that particularly low doses of beta-endorphin increase social approach behaviors in rats (van Ree and Niesink, 1983; Niesink and van Ree, 1984,1989); by contrast, higher dosages of beta-endorphin cause a reduction of social behavior in rats (e.g., Meyerson 1981; Niesink and van Ree 1989). All this creates a logical dilemma in view of the opioid excess hypothesis of autism (Panksepp 1979; Chamberlain and Herman 1990). It can, be anticipated either than Naltrexone could act by blocking brain-opioid receptors and consequently reduces the hyperfunction of endogenous opioid systems, or that Naltrexone, just by blocking, stimulates the presynaptic release of opioids. The time course of the effects of Naltrexone on social behavior of autistic children bears some suggestion for the last possibility, as social stimulating effects of Naltrexone were most clearly observed more than 24 hr after its administration in some studies (Lensing et al 1989; Lensing 1990). In any case, it seems worthwhile to explore in future studies in depth the neurochemical basis of the ORG 2766-induced behavioral effects. Among others, it is of interest to compare the behavioral effects of Naltrexone with those of ORG 2766 in the same patients, and to examine in great detail the effect of a combined treatment of ORG 2766 with an opioid antagonist. Some methodological aspects of this study merit attention. Behavior-observation data were gathered in only one experimental environment. Further, it cannot be ruled out that

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the described shifts in the sequential patterning of behavior followi~& the use of ORG 2766 are used by an interaction between ORG 2766 effects and repeated playroom experiences. Finally, the data are based on a small sample of autistic children. In conclusion the present findings reflect a social interaction stimulating influence of ORG 2766 on the behavior of autistic children. This may inspire further research into the role of neuropeptides and endogenous opioids in the pathophysiology of the autistic syndrome. The authors are grateful for the skillful help of Ineke den Hartog, Tilly Koolstra, Kees Koopman, and Ivan Komproe, and are indebted to Berry Spmyt for his suggestionto use the information-statisticalanalysis.

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