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Effects of Methylphenidate on Adolescents with Aggressive Conduct Disorder and ADDH: A Preliminary Report
Effects of Methylphenidate on Adolescents with Aggressive Conduct Disorder and ADDH: A Preliminary Report STUART L. KAPLAN , M.D ., JOAN BUSNER , PH.D., SAMUEL KUPIETZ, PH.D., EVELYN WASSERMANN, M.D., AND BORIS SEGAL, M.D .
Abstract. The effect of methylphenidate on aggression in adolescents diagnosed with both aggressive conduct disorder and attention deficit disorder with hyperacti vity was assessed in nine male adolescents . After three open trials, a placebo controlled double-blind design was used . During methylphenidate treatment of the six double-blind subjects, there was a significant reduction of aggressivity (P's < 0.05), as measured by the Adolescent Antisocial Behavior Checklist. Conners Teacher Rating Scale Hyperactivity and Aggression scores were in the predicted directions, but the differences were not statistically significant. J . Am . Acad. Child Adolesc. Psychiatry , 1990,29,5:719-723. Key Words: methylphenidate, aggressive conduct disorder , adolescents. Aggressive conduct disorder is a major reason for referral for psychiatric treatment for adolescents (Kazdin, 1987). Although there are a number of behavioral and psychopharmacological management approaches , a specific effective treatment for the disorder has yet to be developed (O'Donnell , 1985). Recent work concerned with etiology and treatment of the disorder supports attention deficit disorder as an important comorbid diagnosis of conduct disorder. In elementary school-aged children and adolescents , the two diagnoses frequently occur together (Stewart et aI., 1981; Biederman et aI., 1987; Szatmari et aI., 1989), and several authors have noted that the conduct disorder itself is more serious and has a poorer prognosis when it occurs together with attention deficit hyperactivity disorder (ADDH) than when it occurs alone (Magnusson et aI. , 1983; Walker et aI., 1987; Magnusson and Bergman, 1988). In elementary school-aged children, an unpublished report suggests that the symptoms of conduct disorder (CD) and ADDH occurring together may respond to stimulant medication (Gittlemen-Klein, 1987). Although stimulant treatment of adolescents with ADDH is increasing (Varley, 1985) and is reported to be efficacious, few studies address themselves to those adolescents who meet criteria for both aggressive conduct disorder and ADDH . Most of the reported studies were done more than a decade ago and employed dextroamphetamine as the stimu-
AcceptedFebruary13,1990. Dr. Kaplan is Executive Director of Rockland Children's Psychiatric Center , New York State Office ofMental Health, and Associate Clinical Professor ofPsychiatry, Columbia University College ofPhysicians and
Surgeons ; Dr . Busner is Associate Psy chologist , Rockland Children's Psychiatric Center. andInstructor in Clinical Psychology in Psychiatry, Columbia University College ofPhysicians and Surgeons; Dr. Kupietz is Research Scientist, Nathan Kline Institute for Psychiatric Research ; Dr. Wassermann and Dr. Segal are Staff Psychiatrists. R ockland Children's Psychiatric Center. The authors gratefully acknowledge the assistance of Helen Helper, M.D., andAnnPhillips, R .Ph. Reprint requests to Dr. Kaplan, Rockland Children's Psychiatric Center, Convent Road, Oran geburg, NY 10962. 0890-8567/90/2905-0719$02 .0010© 1990 by the American Academy of Child and Adolescent Psychiatry.
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lant. Korey (1944) published a single-blind study comparing benzedrine sulfate to placebo in 20 male adolescents consid ered to be among the "most delinquent" of a group of institutionalized federal delinquents. Although diagnosis was not specifically assessed, all subjects had long histories of delinquent offenses, and, today, would likely meet criteria for conduct disorder. Sixty-four percent of the 11 adolescents who received benzedrine sulfate, compared to 0% of the nine who received placebo, showed overall improvement in school performance, sociability, mood , and number of institutional rule infractions . Eisenberg et al. (1963), in a double-blind placebo-controlled study of dextroamphetamine, reported significant improvement in teacher, observer, and peer ratings of 14 institutionalized male delinquent adolescents (diagnoses not reported) who received dextroamphetamine, compared to matched delinquents who received either placebo (N = 14)or no treatment (N = 14). Similar findings for dextroamphetamine were reported in a double-blind placebo-controlled study by Maletzky (1974), who studied adolescents referred for outpatient treatment because of antisocial behavior; after 3 months' treatment, the 14 adolescents who received dextroamphetamine were significantly improved on parent and teacher ratings of aggressiveness and sociability, relative to the 14 adolescents who received placebo. A case report of a successful double-blind dextroamphetamine versus placebo trial in a 13-year-old, psychiatrically hospitalized , "hyperactive delinquent" is reported by Ostrov et al. (1980). Aggression on the ward was less during dextroamphetamine treatment than during placebo treatment. Allen and colleagues (Allen et aI., 1975; Safer and Allen, 1975) report reduction in aggressivity in six of seven aggressive hyperactive adolescents who were treated with methylphenidate on an open trial basis . There is a report of an open trial of methylphenidate in two inpatient male adults with antisocial personality disorder and childhood histories of ADDH (Stringer and Josef, 1983). Reduction of aggressivity was observed clinically during methylphenidate treatment; resumption of aggressivity occurred upon treatment cessation. In contrast to the above reports, recent review articles of
KAPLAN ET AL.
the treatment of aggression in childhood have commented in passing that stimulants are not an effective treatment for aggression (Campbell et al., 1982; Alessi and Wittekindt, 1989). The authors are aware of no double-blind study that has specifically examined stimulant treatment for the symptoms of aggression in adolescents meeting DSM-III criteria for aggressive conduct disorder, with or without ADDH. This paper reports preliminary data on three open trials, and on the first six cases of an ongoing double-blind placebo-controlled study of methylphenidate on adolescents with both ADDH and aggressive conduct disorder. Method Subjects
Subjects were nine adolescent males who currently met DSM-III criteria, based on structured interviews with patients (Diagnostic Interview for Children and Adolescents [DICA)), and parents (DICA-P), for both ADDH and aggressive conduct disorder, socialized type (N = 8) or unsocialized type (IV = 1). Six of the subjects were psychiatric inpatients on a locked "secure care" unit, specifically designed to handle only highly aggressive male adolescents. The remaining three subjects were outpatients at a psychiatric clinic based in a special education secondary school for emotionally handicapped youngsters; the outpatient subjects had been referred for their aggressiveness and impulsivity. On a measure of aggression, to be described below, the outpatients' scores were almost identical to the inpatients' (outpatient Adolescent Antisocial Behavior Checklist [AABC], X = 21.8, SD = 18.1; inpatient AABC, X = 22.6, SD = 12.2). Subjects were recruited by clinician referral; clinicians who believed they had a suitable candidate were queried briefly regarding diagnostic inclusionary and exclusionary (psychosis or drug abuse history) criteria, at which time patients were accepted or rejected for additional evaluation; the authors have no data as to number rejected. Of 13 inpatients accepted for additional evaluation, two were rejected for failing to meet DICA diagnostic criteria, two were rejected because the custodial social service agency involved refused to give consent, two were rejected because the parent refused to give consent, one was rejected because he was to be transferred from the hospital shortly, and six were admitted to the study. Of four outpatients accepted for additional evaluation, one was rejected because the parent refused to give consent, and three were admitted to the study. Clinical characteristics of the nine subjects were obtained from chart review. Seven of the nine had been previously diagnosed with ADDH or, in one case, Minimal Brain Damage; eight of the nine had been previously diagnosed with CD, and one had been diagnosed with oppositional disorder. Five of the nine had been treated previously with methylphenidate, for periods ranging from 1 week to 7 years. Four of the six inpatients had been hospitalized at least once before and had been placed out of the home in a variety of social service agencies at least once; none of the outpatients had ever been hospitalized, and one had been placed in an emergency foster setting due to his assaultiveness. The inpatients had been in
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and out of psychiatric outpatient treatment an average of 9.0 years (SD = 3.6 years); outpatients had been in and out of treatment an average of 5.7 years (SD = 3.2 years). Subjects ranged in age from 13 to 16 years; mean age = 14.4years;SD = 0.88 years. Tanner staging (Tanner, 1962) was conducted by a pediatrician highly experienced with the scale. Tanner staging provides an index of pubertal status based on secondary sex characteristics development; stages range from I (prepubertal) to V (adult). The mean Tanner stage was 3.4 (SD = 1.7); two subjects were Tanner stage I, one subject was Tanner stage II, three subjects were Tanner stage IV, and three subjects were Tanner stage V. Full scale WISC-R IQs ranged from 76 to 97, with a mean of86, SD = 6.0. Subjects' weights ranged from 53.4 kgs to 74.9 kgs (mean = 65kgs;SD = 1O.3kgs). Instruments DICA. The DICA is a widely used structured psychiatric interview from which DSM-III diagnoses can be made. The DICA-P is the parent version of the instrument. The DICA and DICA-P are reported to have acceptable levels of validity and reliability (Herjanic et al., 1975; Herjanic and Campbell, 1977; Herjanic and Reich, 1982; Herjanic, 1984). Adolescent Antisocial Behavior Checklist. The AABC is a 57-item checklist designed to be completed by ward staff at the end of an 8-hour shift. The instrument is divided into six scales: physical harm to self and others; physical threats of harm to self and others; verbal harm and verbal threats of harm to self and others; damage and threats to damage property; responsibility difficulties; and violations of unit norms and rules. Items are rated as to frequency of occurrence on a o to 3 scale. The AABC was selected because of its face validity and its specific delineation of a wide range of aggres-
sive behaviors. The instrument was developed for use on inpatient adolescent settings, and there is one report of its usefulness in measuring dextroamphetamine response (Ostrov et al., 1980). The instrument is reliable and valid (Curtiss et al., 1983). AABC ratings were completed twice a week by ward staff for inpatients or by the classroom teacher for outpatients. Conners Teacher Rating Scale (39 item). The CTRS (Conners, 1973) is an extensively used measure of classroom behavior that has been used in hundreds of studies on medication of hyperactive children. It includes a hyperactivity subscale and an aggression subscale. Items are rated on a 0 (' 'not at all' ') to 3 (" very much' ') scale. The CTRS has been shown repeatedly to be a reliable instrument that is sensitive to drug effects (Greenhill, 1985). For inpatients and outpatients, CTRS ratings were completed weekly by classroom teachers. In addition, for inpatients, CTRS ratings were completed weekly by the unit nurse. Design
The initial three subjects in the study were studied in an open design. These subjects were medicated with an incremental increase in dosage with the same schedule used in the full, blind study described below and then subjected to the J. Am. Acad. Child Adolesc. Psychiatry, 29:5, September 1990
METHYLPHENIDATE WITH AGGRESSIVE ADOLESCENTS TABLE
1. Mean Baseline, Methylphenidate, and Placebo Adolescent Antisocial Behavior Checklist Subscale Scores Baseline
Physical harm Physical threats Verbal harm Damage to property Responsibility difficulties Violations of rules
Methylphenidate
Placebo
X
SD
X
SD
X
SD
1.2
(0.9) (2.4) (3.2) (2.7) (2.2) (3.4)
0.5 1.5 2.8 0.5 1.1 1.7
(0.8) (1.8) (3.4)
1.6 3.7 8.7 2.7 4.8 5.8
(2.4) (2.8) (5.0) (3.5) (5.6) (4.7)
5.1 8.5 2.3 1.8 4.8
(1.2)
(2.2) (2.3)
F
Post Hoc Comparisons"
NS
7.8** 9.4**
b>mp>m b>mp>m
NS
4.2* 7.4*
bm b > mp > m
*p <0.05;*"]:1 <0.01. "b = baseline; m = methylphenidate; p = placebo.
same full dose and same measurement schedule. The subsequent six subjects were studied in a double-blind, placebocontrolled, crossover design. Each trial took 7 weeks; a I-week drug-free baseline was followed by a I-week period of increasing medication doses, which was followed by 2 weeks of full dose; the increasing medication dose week and 2-week, full dose condition was then repeated with the opposite condition (methylphenidate or placebo). Measurements taken during the increasing medication weeks were not used in data analyses. Due to an oversight, the assignment to methylphenidatefirst or placebo-first condition was made in the absence of a specific randomization formula. As determined after the fact, five of the six patients in the double-blind study received placebo for the first condition and methylphenidate for the second condition. Assignment to order condition was determined with no knowledge of the particular patients involved; thus patients did not receive one condition or other based on symptom picture or any other systematic bias. Medication
To minimize side effects in the evening and night, patients received the methylphenidate/placebo twice daily, at 8:00 A.M. and at noon. Clinicians were permitted to administer diphenhydramine, 50 mgs, in the evening to cover aggressive or unmanageable behavior. Patients were not on any other psychotropic medication during the study. Full methylphenidate dose was 0.6 mg/kg/dose with 30 mg as a ceiling, in accordance with Physicians' Desk Reference (1989) guidelines. Because of their weight, all patients received the full dose of30 mg/dose. Actual mg/kg full doses received ranged from 0.36 mg/kg to 0.56 mg/kg, with a mean of 0.47 mg/kg; SD = 0.07 mg/kg. During the medication increase week, patients moved from 10 mg b.i.d. to 30 mg b.i.d. within 5 days, with a 5 mg per dose, per day, increase. Results Open Trials Baseline versus full dose ratings were compared for the three open trials. AABC total score ratings wer~ lower (less aggression) in the methylphenidate condition (X ~ 7.3, SD = 10.0) than in the drug-free baseline condition (X = 15.3, SD = 14.5). The same pattern appeared on the CTRS l.Am.Acad. Child Adolesc. Psychiatry, 29:5, September 1990
hyperactivity factor (methylphenidate X = 0.9, SD = 0.7; baseline X = 1.3, SD = 0.7), and aggression factor (methylphenidate X = 0.6, SD = 1.2; baseline X = 1.1, SD = 0.9). Double-Blind Trials
For the six patients who completed the full double-blind trial, a series of repeated measures analyses of variance were conducted comparing baseline, methylphenidate, and placebo ratings. Multiple ratings were averaged to get one rating per patient, per instrument, and per condition (baseline, methylphenidate, placebo); statistically, using this averaged measure is more reliable than using the single measures (Lord and Novick, 1968). For the AABC analyses, total scores were examined as well as the six individual subscales. For the Conners, the hyperactivity and aggression factors were examined. Intwo cases, school vacations at the inpatient setting prevented the obtaining of teacher ratings during one condition of the study. In those two instances, the decision was made to use Conners ratings obtained from the unit nurse during both the condition for which there were no teacher ratings, and the condition for which there were teacher ratings; thus the comparisons were consistent in terms of rater. There were significant drug main effects on the Total AABC score and four (out of six) subscales; no other effects were significant (Fig. 1 and Table 1). Pairwise post hoc comparisons were conducted using the pooled estimate of error term following each significant drug main effect. The pattern was consistent; there was significantly less aggressive behavior during the methylphenidate condition than during the baseline condition or the placebo condition. The baseline and placebo conditions did not significantly differ, with one exception in which the baseline rating was significantly lower (less aggression) than the placebo rating. The two subscales that did not show significant main effects were both in the same direction as the other subscales. Conners hyperactivity and aggression mean scores are presented in Figure 2. As shown, means are in the expected direction, that is higher during the baseline and placebo conditions than during the methylphenidate condition. However, there were no significant effects when the scores were subjected to repeated measures analyses of variance. As measured by the Treatment Emergent Side Effect Scale
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KAPLAN ET AL.
(Guy, 1986), completed weekly by the treating psychiatrists, methylphenidate side effects of dizziness, appetite loss, and headache were reported in three of the nine youngsters. All side effects reported were considered to be mild in severity and did not result in alteration of the medication regimen. Discussion The findings provide preliminary evidence of the efficacy of methylphenidate in reducing aggression in aggressive conduct disordered adolescents also diagnosed with ADDH. In this study, the signficant effects on a measure that specifically deals with adolescent agressive behavior suggest that methylphenidate is useful for reducing verbal and physical aggressive symptoms in adolescents with ADDH and aggressive conduct disorder. That methylphenidate had a statistically significant effect on aggression, as measured by the AABC, with only six subjects, reflects the substantial magnitude of methylphenidate's effect on aggression. The lack of statistically significant effects on aggression and hyperactivity, as measured by the CTRS, reflects the small sample size of six subjects and what might be a lack of specificity of the CTRS for this age range, psychopathology, and clinical setting. However, the pattern ofthe results ofthe CTRS supports the potential efficacy of methylphenidate in treating hyperac-
tivity and aggression in this clinical sample. Clinically, it is of interest that all the youngsters were maintained by their clinicians on methylphenidate after the study ended. Parents, psychiatrists, and the adolescents themselves were impressed with the striking symptom improvement. A limitation of the present study is the fact that five of the six double-blind subjects studied received placebo for the first condition and methylphenidate for the second condition. This confounds length of time in treatment with receiving methylphenidate and raises the possibility that the improvement seen in the methylphenidate condition was a result of time spent in treatment, rather than methylphenidate itself. At present, the data do not allow the effects of time in treatment to be distinguished from methylphenidate treatment. But, it should be noted that one of the double-blind subjects did receive methylphenidate as the first treatment condition and did improve. Also, that improvement was based on receiving methylphenidate rather than time is suggested by the improvement under methylphenidate of the three "open" subjects, who received methylphenidate immediately following baseline, whereas the "blind" subjects did not improve in the placebo condition that immediately followed baseline. This will be further assessed once additional
Adolescent Antisocial Behavior Checklist Total Means by Condition 30
Conners Teacher Rating Scale Hyperactivity and Aggression Factor Means by Condition
--,--------------~-----_,
26,4 (22.6)
2,----------------------
1.8 (1.0)
25
20
15
10
0.5
5
o
Baseline
Methylphenidate
Placebo
o Baseline
Methylphenidate
Placebo
FIG. I. Double-blind study. N = 6. Repeated measures analysis of variance. Main effect for condition, F = 6.7, p < 0.05. Post hoc comparisons using pooled error term: baseline> methylphenidate; placebo > methylphenidate (P' s < 0.05).
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_
Hyperactivity
_
Aggression
FIG. 2. Double-blind study. N = 6. Separate repeated measures analyses of variance on hyperactivity factor and aggression factor. No significant effects.
J. Am. Acad. Child Adolesc. Psychiatry, 29:5, September 1990
METHYLPHENIDATE WITH AGGRESSIVE ADOLESCENTS
patients have been studied, counterbalancing for order. The study may have import for the classification of aggressive conduct disorders. Quay (1987), based on a review of factor analytic studies of traits of delinquent adolescents, describes a subgroup of delinquent adolescents who have attention deficits. If stimulant treatment is particularly efficacious in conduct disordered adolescents who have concurrent ADDH, then sub grouping conduct disordered adolescents by presence or absence of ADDH symptoms would be important for treating the disorder. To the authors' knowledge, this is the first placebo controlled, double-blind study of methylphenidate in aggressive conduct disordered adolescents also diagnosed with ADDH. Replication with a larger sample size is merited. An interesting question is whether the findings of decreased aggressiveness would occur in aggressive conduct disordered adolescents not diagnosed with ADDH. It is not known whether reduction in aggressivity occurs independent or of secondary to improvement in symptoms of ADDH. Additional study can address this issue by assessing methylphenidate treatment response in adolescents with aggressive conduct disorder without ADDH. References Alessi, N. E. & Wittekindt, J. (1989), Childhood aggressive behavior. Pediatr.Ann., 18:94-101. Allen, R. T., Safer, D. & Covi, L. (1975), Effects of psychostimulants on aggression. J.Nerv.Ment. Dis., 160:138-143. Biederman,J., Munir, K. & Knee, D. (1987), Conduct and oppositional disorder in clinically referred children with attention deficit disorder: a controlled family study. J. Am. Acad. ChildAdolesc. Psychiatry, 26:724-727. Campbell, M., Cohen, I. & Small, A. M. (1982), Drugs in aggressive behavior. J. Am. Acad. ChildAdolesc. Psychiatry, 21:107-117. Conners, C. K. (1973), Ratingscalesforusein drug studies with children. Psychopharmacol. Bull. ,21:243-250. Curtiss, G., Rosenthal, R., Marohn, R., Ostrov, E., Offer, D. & Trujillo, J. (1983), Measuring delinquent behavior in inpatient treatment settings: revision and validation of the Adolescent Antisocial Behavior Checklist, J. Amer. Acad. Child Psychiatry, 22:459-466. Eisenberg, L. ,Lachman, R. ,Molling,P. A. ,Lockner,A. ,Mizelle,J. D. & Conners, C. K. (1963), A psychopharmacologic experiment in a training school for delinquent boys. Am. J. Orthopsychiatry, 33:431447. Gittleman-Klein, R. (1987, January), Conduct disorder and hyperactivity: effects of stimulant treatment. Child Psychiatry Grand Rounds Presentation, New York Psychiatric Institute. Greenhill,L. (1985), The hyperkineticsyndrome. In: The Clinical Guide to Child Psychiatry, eds. D. Shaffer, A. A. Ehrhardt & L. Greenhill. New York: Free Press. Guy, W. (1986), Treatment emergentside effect scale. In: Early Clinical Drug Evaluation Manual, ed. W. Guy. Rockville, MD: National
J. Am. Acad. Child Adolesc .Psychiatry, 29:5, September 1990
Instituteof Mental Health. Herjanic, B. (1984), Systematic diagnostic interviewing of children: present state and future possibilities. (A review.) Psychiatr. Dev., 2. - - Reich, W. (1982), Development of a structured psychiatric interview for children: agreement between child and parent on individual symptoms. J.Abnorm. Child Psychol., 10:307-324. - - Campbell, W. (1977), Differentiating psychiatrically disturbed children on the basis of a structured interview. J. Abnorm. Child Psychol.,5: 127-134. --Herjanic, M., Brown,F. &Wheatt, T. (1975), Arechildren reliable reporters? J.Abnorm. Child Psychol, 3:41-48. Kazdin, A. E. (1987), Conduct Disorders in Childhood and Adolescence. New York: Sage. Korey, S. R. (1944), The effects of benzedrine sulfate on the behavior of psychopathic and neurotic juvenile delinquents.Psychiatr. Q., 18:127-137. Lord, F. M. & Novick, M. R. (1968), Statistical Theories ofMental Test Scores. Reading, MA: Addison-Wesley. Magnusson, D. & Bergman, L. R. (1988), Individual and variable-based approaches to longitudinal research on early risk factors. In: Studies ofPsychosocialRisk, ed. M. Rutter. New York:Cambridge University Press. - - Siottin, H. & Duner, A. (1983), Aggression and criminality in a longitudinalperspective. In: Antecedents ofAggression andAntisocial Behavior, eds. K. T. Van Dusen & S. A. Mednick. Boston: KluwerNijhoff. Maletzky, B. (1974), d-Amphetamine and delinquency: hyperkinesis persisting. Diseases ofthe Nervous System, 35:543-547. O'Donnell, D. 1. (1985), Conduct disorders. In: Diagnosis and Psychopharmacology ofChildhood and Adolescent Disorder, ed. J. Weiner. New York:Wiley. Ostrov, E., Marohn, R. C., Offer, D., Curtiss, G. & Feczko, M. (1980), The adolescent antisocial behavior checklist.J. Clin. Psychol., 36:594-601. . Physician's Desk Reference, 43rd Edition. (1989), Oradell, NJ: Medical EconomicsCo.• Inc. Quay, H. C. (1987), Patterns of delinquent behavior. In: Handbook of JuvenileDelinquency, ed. H. C. Quay. New York: Wiley. Safer, D. J. & Allen, R. (1975), Stimulant drug treatment of hyperactive adolescents. Diseases ofthe Nervous System, 36:454-457. Stewart, M. A., Cummings, C., Singer, S. & DeBlois, C. S. (1981), The overlap between hyperactive and unsocialized aggressive children. J. Child Psycho I. Psychiatry, 22:35-45. Stringer, A. Y. & Josef, N. (1983), Methylphenidate in the treatment of aggression in two patients with antisocial personality disorder. Am. J. Psychiatry, 140:1365-1366. Szatmari,P., Boyle,M. H. & Offord, D. R. (1989), ADDHandconduct disorders: degree of diagnostic overlap and differences among correlates. J. Am. Acad. ChildAdolesc. Psychiatry, 28:865-872. Tanner,J. M. (1962) ,Growth atAdolescence, Edition 2. Oxford: BlackwellScientific Publications. Varley, C. K. (1985), A review of studies of drug treatment efficacy for attention deficit disorder with hyperactivity in adolescents. Psychol. Bull. 21:216-221. Walker, J. L., Lahey, B. B., Hynd, G. W. & Frame, C. L. (1986), Comparison of specific patterns of antisocial behavior in children with conduct disorder with or without coexisting hyperactivity. Presented at American Psychological Association, Washington, DC.
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Abstract. The effect of methylphenidate on aggression in adolescents diagnosed with both aggressive conduct disorder and attention deficit disorder with hyperacti vity was assessed in nine male adolescents . After three open trials, a placebo controlled double-blind design was used . During methylphenidate treatment of the six double-blind subjects, there was a significant reduction of aggressivity (P's < 0.05), as measured by the Adolescent Antisocial Behavior Checklist. Conners Teacher Rating Scale Hyperactivity and Aggression scores were in the predicted directions, but the differences were not statistically significant. J . Am . Acad. Child Adolesc. Psychiatry , 1990,29,5:719-723. Key Words: methylphenidate, aggressive conduct disorder , adolescents. Aggressive conduct disorder is a major reason for referral for psychiatric treatment for adolescents (Kazdin, 1987). Although there are a number of behavioral and psychopharmacological management approaches , a specific effective treatment for the disorder has yet to be developed (O'Donnell , 1985). Recent work concerned with etiology and treatment of the disorder supports attention deficit disorder as an important comorbid diagnosis of conduct disorder. In elementary school-aged children and adolescents , the two diagnoses frequently occur together (Stewart et aI., 1981; Biederman et aI., 1987; Szatmari et aI., 1989), and several authors have noted that the conduct disorder itself is more serious and has a poorer prognosis when it occurs together with attention deficit hyperactivity disorder (ADDH) than when it occurs alone (Magnusson et aI. , 1983; Walker et aI., 1987; Magnusson and Bergman, 1988). In elementary school-aged children, an unpublished report suggests that the symptoms of conduct disorder (CD) and ADDH occurring together may respond to stimulant medication (Gittlemen-Klein, 1987). Although stimulant treatment of adolescents with ADDH is increasing (Varley, 1985) and is reported to be efficacious, few studies address themselves to those adolescents who meet criteria for both aggressive conduct disorder and ADDH . Most of the reported studies were done more than a decade ago and employed dextroamphetamine as the stimu-
AcceptedFebruary13,1990. Dr. Kaplan is Executive Director of Rockland Children's Psychiatric Center , New York State Office ofMental Health, and Associate Clinical Professor ofPsychiatry, Columbia University College ofPhysicians and
Surgeons ; Dr . Busner is Associate Psy chologist , Rockland Children's Psychiatric Center. andInstructor in Clinical Psychology in Psychiatry, Columbia University College ofPhysicians and Surgeons; Dr. Kupietz is Research Scientist, Nathan Kline Institute for Psychiatric Research ; Dr. Wassermann and Dr. Segal are Staff Psychiatrists. R ockland Children's Psychiatric Center. The authors gratefully acknowledge the assistance of Helen Helper, M.D., andAnnPhillips, R .Ph. Reprint requests to Dr. Kaplan, Rockland Children's Psychiatric Center, Convent Road, Oran geburg, NY 10962. 0890-8567/90/2905-0719$02 .0010© 1990 by the American Academy of Child and Adolescent Psychiatry.
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lant. Korey (1944) published a single-blind study comparing benzedrine sulfate to placebo in 20 male adolescents consid ered to be among the "most delinquent" of a group of institutionalized federal delinquents. Although diagnosis was not specifically assessed, all subjects had long histories of delinquent offenses, and, today, would likely meet criteria for conduct disorder. Sixty-four percent of the 11 adolescents who received benzedrine sulfate, compared to 0% of the nine who received placebo, showed overall improvement in school performance, sociability, mood , and number of institutional rule infractions . Eisenberg et al. (1963), in a double-blind placebo-controlled study of dextroamphetamine, reported significant improvement in teacher, observer, and peer ratings of 14 institutionalized male delinquent adolescents (diagnoses not reported) who received dextroamphetamine, compared to matched delinquents who received either placebo (N = 14)or no treatment (N = 14). Similar findings for dextroamphetamine were reported in a double-blind placebo-controlled study by Maletzky (1974), who studied adolescents referred for outpatient treatment because of antisocial behavior; after 3 months' treatment, the 14 adolescents who received dextroamphetamine were significantly improved on parent and teacher ratings of aggressiveness and sociability, relative to the 14 adolescents who received placebo. A case report of a successful double-blind dextroamphetamine versus placebo trial in a 13-year-old, psychiatrically hospitalized , "hyperactive delinquent" is reported by Ostrov et al. (1980). Aggression on the ward was less during dextroamphetamine treatment than during placebo treatment. Allen and colleagues (Allen et aI., 1975; Safer and Allen, 1975) report reduction in aggressivity in six of seven aggressive hyperactive adolescents who were treated with methylphenidate on an open trial basis . There is a report of an open trial of methylphenidate in two inpatient male adults with antisocial personality disorder and childhood histories of ADDH (Stringer and Josef, 1983). Reduction of aggressivity was observed clinically during methylphenidate treatment; resumption of aggressivity occurred upon treatment cessation. In contrast to the above reports, recent review articles of
KAPLAN ET AL.
the treatment of aggression in childhood have commented in passing that stimulants are not an effective treatment for aggression (Campbell et al., 1982; Alessi and Wittekindt, 1989). The authors are aware of no double-blind study that has specifically examined stimulant treatment for the symptoms of aggression in adolescents meeting DSM-III criteria for aggressive conduct disorder, with or without ADDH. This paper reports preliminary data on three open trials, and on the first six cases of an ongoing double-blind placebo-controlled study of methylphenidate on adolescents with both ADDH and aggressive conduct disorder. Method Subjects
Subjects were nine adolescent males who currently met DSM-III criteria, based on structured interviews with patients (Diagnostic Interview for Children and Adolescents [DICA)), and parents (DICA-P), for both ADDH and aggressive conduct disorder, socialized type (N = 8) or unsocialized type (IV = 1). Six of the subjects were psychiatric inpatients on a locked "secure care" unit, specifically designed to handle only highly aggressive male adolescents. The remaining three subjects were outpatients at a psychiatric clinic based in a special education secondary school for emotionally handicapped youngsters; the outpatient subjects had been referred for their aggressiveness and impulsivity. On a measure of aggression, to be described below, the outpatients' scores were almost identical to the inpatients' (outpatient Adolescent Antisocial Behavior Checklist [AABC], X = 21.8, SD = 18.1; inpatient AABC, X = 22.6, SD = 12.2). Subjects were recruited by clinician referral; clinicians who believed they had a suitable candidate were queried briefly regarding diagnostic inclusionary and exclusionary (psychosis or drug abuse history) criteria, at which time patients were accepted or rejected for additional evaluation; the authors have no data as to number rejected. Of 13 inpatients accepted for additional evaluation, two were rejected for failing to meet DICA diagnostic criteria, two were rejected because the custodial social service agency involved refused to give consent, two were rejected because the parent refused to give consent, one was rejected because he was to be transferred from the hospital shortly, and six were admitted to the study. Of four outpatients accepted for additional evaluation, one was rejected because the parent refused to give consent, and three were admitted to the study. Clinical characteristics of the nine subjects were obtained from chart review. Seven of the nine had been previously diagnosed with ADDH or, in one case, Minimal Brain Damage; eight of the nine had been previously diagnosed with CD, and one had been diagnosed with oppositional disorder. Five of the nine had been treated previously with methylphenidate, for periods ranging from 1 week to 7 years. Four of the six inpatients had been hospitalized at least once before and had been placed out of the home in a variety of social service agencies at least once; none of the outpatients had ever been hospitalized, and one had been placed in an emergency foster setting due to his assaultiveness. The inpatients had been in
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and out of psychiatric outpatient treatment an average of 9.0 years (SD = 3.6 years); outpatients had been in and out of treatment an average of 5.7 years (SD = 3.2 years). Subjects ranged in age from 13 to 16 years; mean age = 14.4years;SD = 0.88 years. Tanner staging (Tanner, 1962) was conducted by a pediatrician highly experienced with the scale. Tanner staging provides an index of pubertal status based on secondary sex characteristics development; stages range from I (prepubertal) to V (adult). The mean Tanner stage was 3.4 (SD = 1.7); two subjects were Tanner stage I, one subject was Tanner stage II, three subjects were Tanner stage IV, and three subjects were Tanner stage V. Full scale WISC-R IQs ranged from 76 to 97, with a mean of86, SD = 6.0. Subjects' weights ranged from 53.4 kgs to 74.9 kgs (mean = 65kgs;SD = 1O.3kgs). Instruments DICA. The DICA is a widely used structured psychiatric interview from which DSM-III diagnoses can be made. The DICA-P is the parent version of the instrument. The DICA and DICA-P are reported to have acceptable levels of validity and reliability (Herjanic et al., 1975; Herjanic and Campbell, 1977; Herjanic and Reich, 1982; Herjanic, 1984). Adolescent Antisocial Behavior Checklist. The AABC is a 57-item checklist designed to be completed by ward staff at the end of an 8-hour shift. The instrument is divided into six scales: physical harm to self and others; physical threats of harm to self and others; verbal harm and verbal threats of harm to self and others; damage and threats to damage property; responsibility difficulties; and violations of unit norms and rules. Items are rated as to frequency of occurrence on a o to 3 scale. The AABC was selected because of its face validity and its specific delineation of a wide range of aggres-
sive behaviors. The instrument was developed for use on inpatient adolescent settings, and there is one report of its usefulness in measuring dextroamphetamine response (Ostrov et al., 1980). The instrument is reliable and valid (Curtiss et al., 1983). AABC ratings were completed twice a week by ward staff for inpatients or by the classroom teacher for outpatients. Conners Teacher Rating Scale (39 item). The CTRS (Conners, 1973) is an extensively used measure of classroom behavior that has been used in hundreds of studies on medication of hyperactive children. It includes a hyperactivity subscale and an aggression subscale. Items are rated on a 0 (' 'not at all' ') to 3 (" very much' ') scale. The CTRS has been shown repeatedly to be a reliable instrument that is sensitive to drug effects (Greenhill, 1985). For inpatients and outpatients, CTRS ratings were completed weekly by classroom teachers. In addition, for inpatients, CTRS ratings were completed weekly by the unit nurse. Design
The initial three subjects in the study were studied in an open design. These subjects were medicated with an incremental increase in dosage with the same schedule used in the full, blind study described below and then subjected to the J. Am. Acad. Child Adolesc. Psychiatry, 29:5, September 1990
METHYLPHENIDATE WITH AGGRESSIVE ADOLESCENTS TABLE
1. Mean Baseline, Methylphenidate, and Placebo Adolescent Antisocial Behavior Checklist Subscale Scores Baseline
Physical harm Physical threats Verbal harm Damage to property Responsibility difficulties Violations of rules
Methylphenidate
Placebo
X
SD
X
SD
X
SD
1.2
(0.9) (2.4) (3.2) (2.7) (2.2) (3.4)
0.5 1.5 2.8 0.5 1.1 1.7
(0.8) (1.8) (3.4)
1.6 3.7 8.7 2.7 4.8 5.8
(2.4) (2.8) (5.0) (3.5) (5.6) (4.7)
5.1 8.5 2.3 1.8 4.8
(1.2)
(2.2) (2.3)
F
Post Hoc Comparisons"
NS
7.8** 9.4**
b>mp>m b>mp>m
NS
4.2* 7.4*
b
*p <0.05;*"]:1 <0.01. "b = baseline; m = methylphenidate; p = placebo.
same full dose and same measurement schedule. The subsequent six subjects were studied in a double-blind, placebocontrolled, crossover design. Each trial took 7 weeks; a I-week drug-free baseline was followed by a I-week period of increasing medication doses, which was followed by 2 weeks of full dose; the increasing medication dose week and 2-week, full dose condition was then repeated with the opposite condition (methylphenidate or placebo). Measurements taken during the increasing medication weeks were not used in data analyses. Due to an oversight, the assignment to methylphenidatefirst or placebo-first condition was made in the absence of a specific randomization formula. As determined after the fact, five of the six patients in the double-blind study received placebo for the first condition and methylphenidate for the second condition. Assignment to order condition was determined with no knowledge of the particular patients involved; thus patients did not receive one condition or other based on symptom picture or any other systematic bias. Medication
To minimize side effects in the evening and night, patients received the methylphenidate/placebo twice daily, at 8:00 A.M. and at noon. Clinicians were permitted to administer diphenhydramine, 50 mgs, in the evening to cover aggressive or unmanageable behavior. Patients were not on any other psychotropic medication during the study. Full methylphenidate dose was 0.6 mg/kg/dose with 30 mg as a ceiling, in accordance with Physicians' Desk Reference (1989) guidelines. Because of their weight, all patients received the full dose of30 mg/dose. Actual mg/kg full doses received ranged from 0.36 mg/kg to 0.56 mg/kg, with a mean of 0.47 mg/kg; SD = 0.07 mg/kg. During the medication increase week, patients moved from 10 mg b.i.d. to 30 mg b.i.d. within 5 days, with a 5 mg per dose, per day, increase. Results Open Trials Baseline versus full dose ratings were compared for the three open trials. AABC total score ratings wer~ lower (less aggression) in the methylphenidate condition (X ~ 7.3, SD = 10.0) than in the drug-free baseline condition (X = 15.3, SD = 14.5). The same pattern appeared on the CTRS l.Am.Acad. Child Adolesc. Psychiatry, 29:5, September 1990
hyperactivity factor (methylphenidate X = 0.9, SD = 0.7; baseline X = 1.3, SD = 0.7), and aggression factor (methylphenidate X = 0.6, SD = 1.2; baseline X = 1.1, SD = 0.9). Double-Blind Trials
For the six patients who completed the full double-blind trial, a series of repeated measures analyses of variance were conducted comparing baseline, methylphenidate, and placebo ratings. Multiple ratings were averaged to get one rating per patient, per instrument, and per condition (baseline, methylphenidate, placebo); statistically, using this averaged measure is more reliable than using the single measures (Lord and Novick, 1968). For the AABC analyses, total scores were examined as well as the six individual subscales. For the Conners, the hyperactivity and aggression factors were examined. Intwo cases, school vacations at the inpatient setting prevented the obtaining of teacher ratings during one condition of the study. In those two instances, the decision was made to use Conners ratings obtained from the unit nurse during both the condition for which there were no teacher ratings, and the condition for which there were teacher ratings; thus the comparisons were consistent in terms of rater. There were significant drug main effects on the Total AABC score and four (out of six) subscales; no other effects were significant (Fig. 1 and Table 1). Pairwise post hoc comparisons were conducted using the pooled estimate of error term following each significant drug main effect. The pattern was consistent; there was significantly less aggressive behavior during the methylphenidate condition than during the baseline condition or the placebo condition. The baseline and placebo conditions did not significantly differ, with one exception in which the baseline rating was significantly lower (less aggression) than the placebo rating. The two subscales that did not show significant main effects were both in the same direction as the other subscales. Conners hyperactivity and aggression mean scores are presented in Figure 2. As shown, means are in the expected direction, that is higher during the baseline and placebo conditions than during the methylphenidate condition. However, there were no significant effects when the scores were subjected to repeated measures analyses of variance. As measured by the Treatment Emergent Side Effect Scale
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KAPLAN ET AL.
(Guy, 1986), completed weekly by the treating psychiatrists, methylphenidate side effects of dizziness, appetite loss, and headache were reported in three of the nine youngsters. All side effects reported were considered to be mild in severity and did not result in alteration of the medication regimen. Discussion The findings provide preliminary evidence of the efficacy of methylphenidate in reducing aggression in aggressive conduct disordered adolescents also diagnosed with ADDH. In this study, the signficant effects on a measure that specifically deals with adolescent agressive behavior suggest that methylphenidate is useful for reducing verbal and physical aggressive symptoms in adolescents with ADDH and aggressive conduct disorder. That methylphenidate had a statistically significant effect on aggression, as measured by the AABC, with only six subjects, reflects the substantial magnitude of methylphenidate's effect on aggression. The lack of statistically significant effects on aggression and hyperactivity, as measured by the CTRS, reflects the small sample size of six subjects and what might be a lack of specificity of the CTRS for this age range, psychopathology, and clinical setting. However, the pattern ofthe results ofthe CTRS supports the potential efficacy of methylphenidate in treating hyperac-
tivity and aggression in this clinical sample. Clinically, it is of interest that all the youngsters were maintained by their clinicians on methylphenidate after the study ended. Parents, psychiatrists, and the adolescents themselves were impressed with the striking symptom improvement. A limitation of the present study is the fact that five of the six double-blind subjects studied received placebo for the first condition and methylphenidate for the second condition. This confounds length of time in treatment with receiving methylphenidate and raises the possibility that the improvement seen in the methylphenidate condition was a result of time spent in treatment, rather than methylphenidate itself. At present, the data do not allow the effects of time in treatment to be distinguished from methylphenidate treatment. But, it should be noted that one of the double-blind subjects did receive methylphenidate as the first treatment condition and did improve. Also, that improvement was based on receiving methylphenidate rather than time is suggested by the improvement under methylphenidate of the three "open" subjects, who received methylphenidate immediately following baseline, whereas the "blind" subjects did not improve in the placebo condition that immediately followed baseline. This will be further assessed once additional
Adolescent Antisocial Behavior Checklist Total Means by Condition 30
Conners Teacher Rating Scale Hyperactivity and Aggression Factor Means by Condition
--,--------------~-----_,
26,4 (22.6)
2,----------------------
1.8 (1.0)
25
20
15
10
0.5
5
o
Baseline
Methylphenidate
Placebo
o Baseline
Methylphenidate
Placebo
FIG. I. Double-blind study. N = 6. Repeated measures analysis of variance. Main effect for condition, F = 6.7, p < 0.05. Post hoc comparisons using pooled error term: baseline> methylphenidate; placebo > methylphenidate (P' s < 0.05).
722
_
Hyperactivity
_
Aggression
FIG. 2. Double-blind study. N = 6. Separate repeated measures analyses of variance on hyperactivity factor and aggression factor. No significant effects.
J. Am. Acad. Child Adolesc. Psychiatry, 29:5, September 1990
METHYLPHENIDATE WITH AGGRESSIVE ADOLESCENTS
patients have been studied, counterbalancing for order. The study may have import for the classification of aggressive conduct disorders. Quay (1987), based on a review of factor analytic studies of traits of delinquent adolescents, describes a subgroup of delinquent adolescents who have attention deficits. If stimulant treatment is particularly efficacious in conduct disordered adolescents who have concurrent ADDH, then sub grouping conduct disordered adolescents by presence or absence of ADDH symptoms would be important for treating the disorder. To the authors' knowledge, this is the first placebo controlled, double-blind study of methylphenidate in aggressive conduct disordered adolescents also diagnosed with ADDH. Replication with a larger sample size is merited. An interesting question is whether the findings of decreased aggressiveness would occur in aggressive conduct disordered adolescents not diagnosed with ADDH. It is not known whether reduction in aggressivity occurs independent or of secondary to improvement in symptoms of ADDH. Additional study can address this issue by assessing methylphenidate treatment response in adolescents with aggressive conduct disorder without ADDH. References Alessi, N. E. & Wittekindt, J. (1989), Childhood aggressive behavior. Pediatr.Ann., 18:94-101. Allen, R. T., Safer, D. & Covi, L. (1975), Effects of psychostimulants on aggression. J.Nerv.Ment. Dis., 160:138-143. Biederman,J., Munir, K. & Knee, D. (1987), Conduct and oppositional disorder in clinically referred children with attention deficit disorder: a controlled family study. J. Am. Acad. ChildAdolesc. Psychiatry, 26:724-727. Campbell, M., Cohen, I. & Small, A. M. (1982), Drugs in aggressive behavior. J. Am. Acad. ChildAdolesc. Psychiatry, 21:107-117. Conners, C. K. (1973), Ratingscalesforusein drug studies with children. Psychopharmacol. Bull. ,21:243-250. Curtiss, G., Rosenthal, R., Marohn, R., Ostrov, E., Offer, D. & Trujillo, J. (1983), Measuring delinquent behavior in inpatient treatment settings: revision and validation of the Adolescent Antisocial Behavior Checklist, J. Amer. Acad. Child Psychiatry, 22:459-466. Eisenberg, L. ,Lachman, R. ,Molling,P. A. ,Lockner,A. ,Mizelle,J. D. & Conners, C. K. (1963), A psychopharmacologic experiment in a training school for delinquent boys. Am. J. Orthopsychiatry, 33:431447. Gittleman-Klein, R. (1987, January), Conduct disorder and hyperactivity: effects of stimulant treatment. Child Psychiatry Grand Rounds Presentation, New York Psychiatric Institute. Greenhill,L. (1985), The hyperkineticsyndrome. In: The Clinical Guide to Child Psychiatry, eds. D. Shaffer, A. A. Ehrhardt & L. Greenhill. New York: Free Press. Guy, W. (1986), Treatment emergentside effect scale. In: Early Clinical Drug Evaluation Manual, ed. W. Guy. Rockville, MD: National
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Instituteof Mental Health. Herjanic, B. (1984), Systematic diagnostic interviewing of children: present state and future possibilities. (A review.) Psychiatr. Dev., 2. - - Reich, W. (1982), Development of a structured psychiatric interview for children: agreement between child and parent on individual symptoms. J.Abnorm. Child Psychol., 10:307-324. - - Campbell, W. (1977), Differentiating psychiatrically disturbed children on the basis of a structured interview. J. Abnorm. Child Psychol.,5: 127-134. --Herjanic, M., Brown,F. &Wheatt, T. (1975), Arechildren reliable reporters? J.Abnorm. Child Psychol, 3:41-48. Kazdin, A. E. (1987), Conduct Disorders in Childhood and Adolescence. New York: Sage. Korey, S. R. (1944), The effects of benzedrine sulfate on the behavior of psychopathic and neurotic juvenile delinquents.Psychiatr. Q., 18:127-137. Lord, F. M. & Novick, M. R. (1968), Statistical Theories ofMental Test Scores. Reading, MA: Addison-Wesley. Magnusson, D. & Bergman, L. R. (1988), Individual and variable-based approaches to longitudinal research on early risk factors. In: Studies ofPsychosocialRisk, ed. M. Rutter. New York:Cambridge University Press. - - Siottin, H. & Duner, A. (1983), Aggression and criminality in a longitudinalperspective. In: Antecedents ofAggression andAntisocial Behavior, eds. K. T. Van Dusen & S. A. Mednick. Boston: KluwerNijhoff. Maletzky, B. (1974), d-Amphetamine and delinquency: hyperkinesis persisting. Diseases ofthe Nervous System, 35:543-547. O'Donnell, D. 1. (1985), Conduct disorders. In: Diagnosis and Psychopharmacology ofChildhood and Adolescent Disorder, ed. J. Weiner. New York:Wiley. Ostrov, E., Marohn, R. C., Offer, D., Curtiss, G. & Feczko, M. (1980), The adolescent antisocial behavior checklist.J. Clin. Psychol., 36:594-601. . Physician's Desk Reference, 43rd Edition. (1989), Oradell, NJ: Medical EconomicsCo.• Inc. Quay, H. C. (1987), Patterns of delinquent behavior. In: Handbook of JuvenileDelinquency, ed. H. C. Quay. New York: Wiley. Safer, D. J. & Allen, R. (1975), Stimulant drug treatment of hyperactive adolescents. Diseases ofthe Nervous System, 36:454-457. Stewart, M. A., Cummings, C., Singer, S. & DeBlois, C. S. (1981), The overlap between hyperactive and unsocialized aggressive children. J. Child Psycho I. Psychiatry, 22:35-45. Stringer, A. Y. & Josef, N. (1983), Methylphenidate in the treatment of aggression in two patients with antisocial personality disorder. Am. J. Psychiatry, 140:1365-1366. Szatmari,P., Boyle,M. H. & Offord, D. R. (1989), ADDHandconduct disorders: degree of diagnostic overlap and differences among correlates. J. Am. Acad. ChildAdolesc. Psychiatry, 28:865-872. Tanner,J. M. (1962) ,Growth atAdolescence, Edition 2. Oxford: BlackwellScientific Publications. Varley, C. K. (1985), A review of studies of drug treatment efficacy for attention deficit disorder with hyperactivity in adolescents. Psychol. Bull. 21:216-221. Walker, J. L., Lahey, B. B., Hynd, G. W. & Frame, C. L. (1986), Comparison of specific patterns of antisocial behavior in children with conduct disorder with or without coexisting hyperactivity. Presented at American Psychological Association, Washington, DC.
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