Oppositional defiant disorder in children is characterized

Transcription

1 Original Article Methylphenidate in Children With Oppositional Defiant Disorder and Both Comorbid Chronic Multiple Tic Disorder and ADHD Journal of Child Neurology Volume 23 Number 9 September Sage Publications / hosted at Kenneth D. Gadow, PhD, Edith E. Nolan, PhD, Jeffrey Sverd, MD, Joyce Sprafkin, PhD, and Jayne Schneider, PhD Our primary objective was to determine if immediate-release methylphenidate is an effective treatment for oppositional defiant disorder diagnosed from mother s report in children with both chronic multiple tic disorder and attention-deficit hyperactivity disorder (ADHD). Children (n = 31) aged 6 to 12 years received placebo and 3 doses of methylphenidate twice daily for 2 weeks each under double-blind conditions and were assessed with ratings scales and laboratory measures. Results indicated significant improvement in both oppositional and ADHD behaviors with medication; however, the magnitude of treatment effect varied considerably as a function of disorder (ADHD > Oppositional behaviors), informant (teacher > mother), assessment instrument, and specific oppositional behavior (rebellious > disobeys rules). Drug response was comparable with that in children (n = 26) who did not have diagnosed oppositional defiant disorder, but comorbidity appeared to alter the perceived benefits for ADHD according to mother s report. Methylphenidate is an effective short-term treatment for oppositional behavior in children with comorbid ADHD and chronic multiple tic disorder. Keywords: oppositional defiant disorder; attention-deficit hyperactivity disorder; chronic multiple tic disorder; Tourette syndrome; methylphenidate; aggression Oppositional defiant disorder in children is characterized by an inappropriate level of argumentative, hostile, and defiant behavior toward authority figures, typically parents and teachers. The symptomatic presentation of oppositional defiant disorder is relatively common in the general population. The findings from several studies in different countries indicate that parents and teachers each rate approximately 5% of elementary school children as meeting DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th ed.) symptom criteria for oppositional defiant disorder. 1-3 Prevalence rates are higher in older children (8-12 years) than in younger children (5-7 years) and in boys than girls; however, in the absence of comorbid attention-deficit hyperactivity From the Department of Psychiatry and Behavioral Science, State University of New York, Stony Brook (KDG, EEN, J Sprafkin, J Schneider), and John T. Mather Memorial Hospital, Port Jefferson, New York (J Sverd). Address correspondence to: Kenneth D. Gadow, Department of Psychiatry, Division of Child and Adolescent Psychiatry, Putnam Hall, South Campus, State University of New York, Stony Brook, NY ; kenneth.gadow@stonybrook.edu. Gadow KD, Nolan EE, Sverd J, Sprafkin J, Schneider J. Methylphenidate in children with oppositional defiant disorder and both comorbid chronic multiple tic disorder and ADHD. J Child Neurol. 2008;23: disorder (ADHD), gender differences are less apparent. 1 Oppositional defiant disorder generally co-occurs (overlaps) with ADHD. For example, in one community-based study, of the children who met symptom criteria for oppositional defiant disorder according to teachers, 91% of the younger and 76% of the older boys also met symptom criteria for ADHD, but this was less the case for girls ( 30%). 1 In children with ADHD, disruptive behavior plays an important role in prompting clinical referral 4 and subsequent treatment with psychotropic medication, and oppositional behavior in elementary school children with ADHD often continues and remains problematic in adulthood. 5,6 Evidence supports both genetic and environmental determiners of oppositional defiant disorder, 7,8 and in children with ADHD, oppositional defiant disorder is predictive of later development of more severe antisocial pathology. 9,10 Oppositional defiant disorder also commonly co-occurs with chronic multiple tic disorder, presumably through its association with ADHD, 11 all of which greatly complicates clinical management. Stimulants are now recognized as safe and effective treatment for ADHD in many children with comorbid chronic multiple tic disorder, and therapeutic benefits appear to be identical to those observed in children without chronic tic disorder. Research with samples with no tic disorder suggests that stimulants are also 981

2 982 Journal of Child Neurology / Vol. 23, No. 9, September 2008 effective for diagnosed oppositional defiant disorder, 16 but there are no controlled studies of this disorder in children with comorbid chronic multiple tic disorder. Although it is reasonable to assume that the extant literature should also apply to children with chronic tic disorder, there continues to be considerable controversy as to whether ADHD and other behavioral disturbances in these patients are etiologically distinct from phenotypically similar presentations in children without tic disorder. 17 Comings and Comings 18 suggested that ADHD and Tourette syndrome were pleiotropic manifestations of the same gene(s), whereas the findings of one family history study seem to suggest that ADHD in some patients with chronic tics may be genetically different. 19 Others emphasize the many biological and behavioral similarities to garden variety ADHD in this clinical population. 20 It has also been noted that patients with chronic multiple tic disorder are particularly vulnerable to a variety of antisocial behaviors, 21 including explosive outbursts, 22 especially individuals with psychiatric comorbidities, but their etiology is presumed to be diverse. 23 This raises many questions about the exact nature of oppositional behavior in children with chronic tic disorder, and the types of therapies that are most appropriate. It has been suggested, for example, that multiple drug therapy may be necessary for disruptive behavior in children with Tourette syndrome, 24,25 although this is at variance with what is generally recommended for the management of similar behavior in ADHD children without tic disorder. For all the aforementioned reasons, the primary objective of the present study was to determine if immediaterelease methylphenidate is an effective therapy for oppositional defiant disorder diagnosed from the mother s report in children with comorbid chronic tic disorder and ADHD. Data analyses included drug effects on specific types of oppositional behavior, potential tic exacerbation, adverse events, and comparison of drug response with children who did not have diagnosed oppositional defiant disorder. A secondary objective was to examine whether mothers and teachers perceived the therapeutic benefits of medication differently. Prior research has shown disagreements between mother and teacher ratings about which children have oppositional behavior problems. As a result, mother- versus teacher-defined oppositional defiant disorders differ in terms of clinical features, associated mental health risk factors, and characteristics that distinguish oppositional defiant disorder from similar behavioral syndromes Methods Participants The primary study sample comprised 31 children who met DSM-III-R 31 or DSM-IV 32 diagnostic criteria for oppositional defiant disorder as well as ADHD and either chronic multiple tic disorder or Tourette s disorder. Four of these children also met criteria for conduct disorder. For comparative purposes, some analyses included a second group of 26 children who did not have diagnosed oppositional defiant disorder but who did meet diagnostic criteria for both ADHD and chronic multiple tic disorder. Both groups of children are described in Table 1. All children participated in a previously described placebo-controlled, double-blind study of the safety and efficacy of methylphenidate for ADHD in children with chronic tic disorder. 15 All participants were recruited from a variety of sources, including referrals from clinicians, schools, media advertisements, and parent support groups. All children who met entry criteria were given an opportunity to participate in the study regardless of their prior experiences with medication. This study was approved by a university institutional review board. Prior to enrollment, parents were repeatedly warned of the possible risk of irreversible tic exacerbation consequent to methylphenidate treatment. Parents and children ( 11 years) provided written informed consent and assent, respectively. Diagnostic criteria. A diagnosis of oppositional defiant disorder was confirmed in a semistructured interview with each child s mother using either the DSM-III-R 31 or DSM-IV 32 version of the Diagnostic Interview for Children and Adolescents (DICA). 33 In addition to a clinical diagnosis of ADHD, most children were above cutoff on 2 out of 3 mother- or teacher-completed ADHD behavior rating scales: Abbreviated Teacher/Parent Rating Scale, 34 the IOWA Conners Teacher s Rating Scale, 35 the Conners (48- item) Parent Rating Scale, 36 the Mothers Objective Method for Subgrouping (MOMS) checklist, 37 and the parent and teacher versions of the Child Symptom Inventory. 1 In other words, they evidenced significant problems at both home and school. The tic measures completed for the diagnostic evaluation included the Yale Global Tic Severity Scale, 38 mother- and teacher-completed Global Tic Rating Scale, 39 and direct observation (Simulated Classroom, Clinic Office). All children met research diagnostic criteria 40 for either Tourette syndrome definite or by history (n = 54) or chronic multiple tic disorder, definite (n = 3). At least 2 reliable examiners in different settings witnessed motor tics in all patients. Exclusion criteria. Children who exhibited one or more of the following were excluded from consideration for the study if (a) their tics were the major clinical management concern; (b) they were too severely ill (dangerous to self or others), psychotic, or mentally retarded (IQ < 70); or (c) had a seizure disorder, major organic brain dysfunction, major medical illness, medical or other contraindication to medication (other than tics), or pervasive developmental disorder. Medication history. Many of the children with oppositional defiant disorder had a prior history of drug therapy for either ADHD (n = 8), Tourette syndrome (n = 2), or both disorders

3 Methylphenidate in Children With Oppositional Defiant Disorder / Gadow et al 983 Table 1. Patient Characteristics: Children With (ODD+) and Without (ODD ) Oppositional Defiant Disorder ODD+ (n = 31) ODD (n = 26) Demographics M (SD) M (SD) t (χ 2 ) P Effect Size Age 8.8 (1.9) 9.2 (1.8) Male (F/%) 25 (81) 19 (73) (0.82).366 IQ (n = 49) (11.9) (9.0) Age tic onset 5.9 (2.1) 5.6 (1.9) Caucasian (F/%) 26 (84) 25 (96) (0.02).889 Socioeconomic status 35.7 (8.3) 36.8 (11.9) Parent rating scales Child Symptom Inventory ADHD Inattentive 20.6 (5.5) 20.9 (4.8) ADHD Hyperactive-Impulsive 18.1 (4.9) 15.3 (8.0) ODD 13.2 (5.7) 7.9 (5.3) Conners Abbreviated Scale 18.9 (4.5) 15.4 (5.5) Peer Conflict Scale 9.5 (6.9) 3.6 (4.6) Teacher rating scales Child Symptom Inventory ADHD Inattentive 20.4 (4.5) 19.0 (5.6) ADHD Hyperactive-Impulsive 14.7 (6.5) 11.5 (7.5) ODD 9.1 (6.3) 3.4 (4.0) Abbreviated Conners Scale 18.9 (5.3) 15.0 (6.8) IOWA Conners Inattention-Overactivity 11.1 (2.8) 9.7 (3.5) Oppositional-Defiant 7.0 (4.6) 2.8 (3.5) Peer Conflict Scale 7.6 (6.1) 3.2 (4.4) Simulated Classroom On task 81.3 (16.5) 89.0 (13.1) Fidgets 20.3 (12.2) 22.3 (23.8) Worksheets (80.5) (75.7) Motor tics 15.2 (9.9) 16.8 (7.1) Continuous performance test Inattention 5.6 (1.0) 6.1 (5.8) Impulsivity 2.8 (4.0) 4.0 (5.6) Dyscontrol 5.3 (5.9) 6.5 (10.0) YGTSS Overall impairment 17.4 (13.2) 11.5 (12.9) Global Severity Score 40.0 (17.8) 31.7 (17.2) Special Education Full-time 13 (42) 8 (31) (0.76).384 Part-time 7 (23) 8 (31) None 11 (35) 10 (38) Prior history of medication (F/%) 11 (35) 10 (38) NOTE: M = mean; SD = standard deviation; ADHD = attention-deficit hyperactivity disorder; ODD = oppositional defiant disorder; F = frequency; YGTSS = Yale Global Tic Severity Scale. (n = 1): stimulants, n = 6; nonstimulants, n = 5. Of the 6 children previously treated with stimulants, undocumented tic exacerbation was reported by parents in none of the cases and tic onset after drug exposure in 2 cases. Procedure Participants received placebo and 3 doses of methylphenidate (0.1 mg/kg [mean, M = 4.5 mg; standard deviation, SD = 1.6], 0.3 mg/kg [M = 9.3 mg; SD = 3.0], and 0.5 mg/kg [M = 14.3 mg; SD = 3.3]) for 2 weeks each under doubleblind conditions. The upper limit for the 0.5 mg/kg dose was 20 mg. All children received Novartis Brand Ritalin-IR (ie, generic substitutions were not permitted). Dose schedules were counter-balanced and assigned on a random basis. Medication was administered twice daily, approximately 3.5 hours apart, 7 days a week. To assess compliance, medication was dispensed in dated, sealed envelopes at 2-week intervals. Detailed descriptions of the procedure and all measures were previously published. 14,15 Once the medication evaluation began, each child and at least 1 parent (typically the mother) were required to come to the clinic at 2-week intervals for interviews with the physician (J Sverd) that included observations of tics and assessment of clinical status and cardiovascular/weight measurements (n = 57). All children were observed in a clinic classroom and then tested with a computerized vigilance task. Parents and teachers completed a battery of rating

4 984 Journal of Child Neurology / Vol. 23, No. 9, September 2008 scales for each child s behavior, 2 days per week for the duration of the drug evaluation. Teachers rated child behavior during periods of maximum drug efficacy (specific time duration for the morning), and mothers completed their ratings for a specific time duration during the day on Saturday and Sunday. Most teacher and mother ratings were completed in school or at home, respectively, with 1 exception, the MOMS checklist, which was filled out in the clinic and reflected the mother s overall impression for each 2-week, dose interval. Measures Oppositional defiant disorder symptoms. The primary outcome measures were teacher (IOWA Conners) and parent (MOMS) ratings of oppositional defiant disorder symptoms. Teachers completed the 5-item Oppositional-Defiant (O-D) subscale of the IOWA Conners Teacher s Rating Scale. Items are rated on a 4-point scale: 0 = not at all, 3 = very much. The primary measure for mothers was the 5-item Aggression subscale from the MOMS checklist. Items are rated as yes/no. Secondary measures of oppositional behavior were factor 2 (4 items: demands must be met immediately, cries easily and often, mood changes, temper outbursts) 41 of the Abbreviated Conner s Rating Scale completed by both mothers and teachers. For individual item analyses, nonoverlapping items from the aforementioned scales were examined as well as individual items from the 10-item Peer Conflict Scale (annoys others) 42 and the Stimulant Side Effects Checklist (irritable). 43 ADHD symptoms. Teacher ratings of ADHD included the 5-item Inattention-Overactivity subscale of the IOWA Conners Teacher s Rating Scale and factor 1 of the Abbreviated Conners Teacher Rating Scale. Parent ADHD ratings were the Hyperactivity subscale from the MOMS checklist and factor 1 of the Abbreviated Conners Parent Rating Scale. Additional ADHD measures were 2 child-completed laboratory tasks: the Simulated Classroom 44 and the Continuous Performance Test. 45 The 15-minute, videotaped, Simulated Classroom variables were on task and fidgets (all coded for occurrence in 180 five-second intervals) and number of worksheet items completed. Tics and adverse events. The primary physician tic measure was the Yale Global Tic Severity Scale, which includes 4 behaviorally anchored subscales: Total Motor Tic Score, Total Phonic Tic Score, Overall Impairment Rating, and Global Severity Score. The physician also recorded heart rate, blood pressure, and weight changes. Mothers and teachers completed the Global Tic Rating Scale, which assesses frequency, severity, and impairment as well as Stimulant Side Effects Checklist. The Simulated Classroom was also used to evaluate the frequency of motor tics (all coded for occurrence in 180 five-second intervals). Statistical Analyses The first step in the analyses was to determine how children with and without oppositional defiant disorders differed in terms of variables that might be important to understanding differences in response to medication (Table 1). χ 2 and t tests were used for dichotomous and continuous variables, respectively. The next step involved separate Gender Age Dose MANOVAs (multivariate analyses of covariance) conducted for the oppositional defiant disorder and ADHD measures for the oppositional defiant disorder group only. When the main effect of dose was significant (P <.01, Wilks s λ), univariate Age Gender Dose ANOVAs (analyses of variance) were conducted. Age and gender were dropped from these analyses if the appropriate interaction term was nonsignificant. The data sets for a few children were incomplete for a few measures because care providers did not complete them. (Unless noted otherwise, all reported significant main effects are also significant using the Greenhouse- Geisser correction.) Tests for trend were also conducted to provide information about the form of the relation between doses of methylphenidate and the dependent variable. To localize the source of statistically significant dose effects, post hoc Newman-Keuls tests were performed. Effect sizes were calculated using Cohen s d, pooled SD formula, 46 the magnitudes of which were classified as small (0.2), medium (0.5), and large (0.8). 47 The ANOVAs, tests for trend, Newman-Keuls tests, and effect-size calculations were repeated to determine if methylphenidate exacerbated tics in children with oppositional defiant disorder. Given our concern about the possibility of making a Type II error (ie, erroneously concluding that methylphenidate did not have an adverse effect on tics), univariate ANOVAs were performed for each tic measure without first conducting a MANOVA. To address the question as to whether children with (n = 31) and without (n = 26) comorbid oppositional defiant disorder responded differently to medication, exploratory Group Gender Age Dose MANOVAs were conducted according to the same guidelines as the primary analyses with the inclusion of group (with or without oppositional defiant disorder) as a between-subjects factor. Results How Do Children With and Without Oppositional Defiant Disorder Differ at Baseline? Children with and without oppositional defiant disorder did not differ in terms of demographics or treatment history (special education, medication). However, as indicated in Table 1, they were highly different according to both mothers and teachers in terms of the severity of oppositional defiant

5 Methylphenidate in Children With Oppositional Defiant Disorder / Gadow et al 985 Table 2. Symptom and Laboratory Measures by Dose of Methylphenidate in Children With Diagnosed Oppositional Defiant Disorder (n = 31) Placebo 0.1 mg/kg 0.3 mg/kg 0.5 mg/kg Trend Effect Variable a M (SD) M (SD) M (SD) M (SD) F ratio P Post hocs Tests Size c ODD measures IOWA O-D (T) 3.9 (3.8) 2.4 (3.0) 2.4 (2.7) 1.6 (2.1) PL >.1,.3,.5 L.75 MOMS Aggression (P) 2.1 (1.8) 1.6 (1.5) 1.5 (1.5) 1.3 (1.5) PL >.5 L.48 ACRS factor 2 (T) 2.4 (2.7) 1.6 (2.0) 1.9 (1.8) 1.1 (1.8) PL >.5 L.48 ACRS factor 2 (P) 3.6 (3.1) 3.2 (2.3) 3.6 (2.4) 2.7 (2.4) N/A.33 Peer aggression Peer Conflict Scale (T) 4.5 (5.1) 2.6 (3.8) 2.0 (2.5) 1.5 (2.3) 8.4 <.0001 PL >.1,.3,.5 L.76 Peer Conflict Scale (P) 5.4 (5.2) 3.9 (4.9) 4.4 (3.8) 2.8 (3.1) PL >.5 L.61 ADHD ACRS factor 1 (T) 9.7 (5.0) 6.7 (4.6) 6.8 (4.3) 4.7 (3.9) 14.6 <.0001 PL >.1,.3 >.5 L, Q 1.1 ACRS factor 1 (P) 7.5 (4.8) 6.3 (4.6) 6.4 (3.7) 5.0 (3.2) PL >.5 L.61 IOWA I-O scale (T) 7.6 (4.2) 5.2 (3.6) 5.2 (3.5) 3.7 (3.1) 15.3 <.0001 PL >.1,.3 >.5 L, Q 1.1 MOMS Hyperactivity (P) 2.8 (1.6) 2.5 (1.5) 2.4 (1.4) 1.8 (1.6) PL >.5 L.63 Laboratory measures CPT b Inattention 6.3 (6.7) 6.1 (5.6) 5.1 (6.0) 4.7 (5.1) N/A.27 Impulsivity 2.5 (3.2) 2.3 (3.4) 1.3 (2.2) 1.9 (4.4) N/A.16 Dyscontrol 4.8 (6.7) 4.7 (6.3) 2.4 (2.5) 1.7 (3.2) PL,.1 >.5 L.59 Clinic Classroom On task 78.7 (23.1) 85.3 (19.1) 90.5 (11.2) 88.7 (20.4) ,.5 > PL L, C.46 Fidgets 20.6 (13.8) 21.1 (16.9) 18.3 (18.4) 15.0 (14.3) N/A.40 Worksheet items 249 (123) 285 (123) 287 (103) 288 (130) ,.3,.5 > PL L.31 NOTE: M = mean; SD = standard deviation; ADHD = attention-deficit hyperactivity disorder; ODD = oppositional defiant disorder; MOMS = Mothers Objective Method for Subgrouping; P = parent; T = teacher; IOWA I-O = IOWA Conners Inattention-Overactivity; IOWA O-D = IOWA Conners Oppositional/Defiant; ACRS = Abbreviated Conners Rating Scale; CPT = continuous performance test; PL = placebo; N/A = not applicable; L = linear; Q = quadratic; C = cubic. a. Lower scores indicate less severe symptoms or impaired performance except Clinic Classroom (On task, Worksheets). b. Untransformed means. c. Cohen s d (modified) for placebo vs 0.5 mg/kg. disorder symptoms (MOMS Aggression, IOWA O-D) and peer aggression (Peer Conflict Scale). Mothers also rated the oppositional group as having more severe hyperactivity-impulsivity symptoms. There were also marginally significant indications that the oppositional group was less on task (P =.06) and completed less work (P =.09) in the Simulated Classroom and had more severe tics (P =.08). Does the Severity of Oppositional Defiant Disorder Improve With Methylphenidate? Both teacher (IOWA O-D subscale) and mother (MOMS Aggression subscale) ratings clearly indicated that methylphenidate reduced oppositional defiant disorder symptoms (Table 2). However, the perceived magnitude of therapeutic improvement for placebo versus the 0.5 mg/kg dose was somewhat larger for teacher (.75) than mother (.48) ratings. Moreover, the 0.1 mg/kg and 0.3 mg/kg treatment effects were significant for teacher ratings only. Power analyses indicate that the study had 92% power to detect treatment effects as large as those seen for the teacher-completed IOWA O-D subscale. The comparable figure for the MOMS Aggression subscale was 82%. As for the secondary measures of negativistic behavior where mothers and teachers were responding to exactly the same items (Abbreviated Conners factor 2, Peer Conflict Scale), teacher Conners factor 2 ratings indicated significant treatment effects for the 0.5 mg/kg dose; however, both informants indicated improvement in peer aggression, teachers for all 3 doses and parents for the 0.5 mg/kg dose only. Do All Symptoms of Oppositional Defiant Disorder Improve Equally? Analyses of individual items from the teacher rating scales presented in Table 3 indicate a significant difference between placebo and the 0.5 mg/kg dose for all but 2 lowfrequency items (acts smart, mood changes). Nevertheless, effect sizes (placebo vs 0.5 mg/kg) ranged from small (.33) to large (.89). Items that evidenced the largest treatment effects were the following: annoys others, uncooperative, and quarrelsome. Although the mean severity of all mother-rated items decreased with increasing dose, only 2 items (explosive, rebellious) evidenced significant placebo

6 986 Journal of Child Neurology / Vol. 23, No. 9, September 2008 Table 3. Effects of Methylphenidate for Ratings of Specific Behaviors in Children With Diagnosed Oppositional Defiant Disorder (n = 31) Placebo 0.1 mg/kg 0.3 mg/kg 0.5 mg/kg Effect Variable a M (SD) M (SD) M (SD) M (SD) F ratio P Post hocs Trend Tests Size b Parent ratings MOMS Disobeys rules 0.6 (0.5) 0.4 (0.5) 0.4 (0.5) 0.5 (0.5) N/A N/A.20 Explosive 0.4 (0.5) 0.2 (0.4) 0.3 (0.5) 0.2 (0.4) PL >.1,.5 Q.44 Irritable 0.6 (0.5) 0.5 (0.5) 0.4 (0.5) 0.4 (0.5) N/A N/A.40 Quick-tempered 0.5 (0.5) 0.4 (0.5) 0.5 (0.5) 0.3 (0.5) N/A N/A.40 Rebellious 0.5 (0.5) 0.2 (0.4) 0.3 (0.5) 0.2 (0.4) PL >.1,.3,.5 L.66 Abbreviated Conners Mood changes 0.8 (1.0) 0.8 (0.8) 0.9 (0.8) 0.7 (0.8) N/A N/A.11 Temper outbursts 0.8 (0.9) 0.8 (0.8) 0.9 (0.9) 0.6 (0.6) N/A N/A.26 Peer Conflict Scale Annoys others 0.8 (0.7) 0.7 (0.6) 0.8 (0.6) 0.5 (0.6) N/A N/A.42 Teacher ratings IOWA O-D Temper outbursts 0.6 (0.9) 0.4 (0.5) 0.4 (0.6) 0.2 (0.4) PL >.5 L.57 Quarrelsome 0.9 (0.9) 0.6 (0.7) 0.6 (0.8) 0.3 (0.6) PL >.1,.3,.5 L.79 Acts smart 0.5 (0.7) 0.4 (0.6) 0.3 (0.5) 0.3 (0.4) NS L.35 Defiant 0.6 (0.7) 0.3 (0.6) 0.4 (0.6) 0.2 (0.4) PL >.5 L.70 Uncooperative 1.0 (0.9) 0.7 (0.8) 0.6 (0.8) 0.4 (0.5) PL >.1,.3,.5 L.82 Abbreviated Conners Mood changes 0.5 (0.7) 0.4 (0.5) 0.5 (0.6) 0.3 (0.5) N/A N/A.33 Peer Conflict Scale Annoys others 1.0 (1.0) 0.6 (0.7) 0.5 (0.6) 0.3 (0.5) PL >.1,.3,.5 L.89 SSEC Irritable 0.8 (0.8) 0.5 (0.5) 0.5 (0.5) 0.4 (0.5) PL >.1,.3,.5 L.60 NOTE: M = mean; SD = standard deviation; O-D = Oppositional/Defiant; MOMS = Mothers Objective Method for Subgrouping; SSEC = Stimulant Side Effects Checklist; PL = placebo; N/A = not applicable; L = linear; Q = quadratic; C = cubic; NS = nonsignificant;n/a = not applicable. a. Lower scores indicate less severe symptoms. b. Cohen s d (modified) for placebo vs 0.5 mg/kg. versus 0.5 mg/kg differences. As was the case with teacher ratings, effect sizes for mother-rated items were also variable. Do ADHD Behaviors Improve With Methylphenidate in Oppositional Children? According to teacher ratings, all 3 doses of methylphenidate were superior to placebo in reducing the severity of ADHD behaviors (Abbreviated Conners factor 1, IOWA Inattention-Overactivity subscale), and the 0.5 mg/kg dose was superior to all other doses (Table 2). For mother ratings (factor 1, MOMS Hyperactivity), only the difference between placebo and 0.5 mg/kg was significant. Teacher ratings indicated large ( 1.0) treatment effects for placebo versus the 0.5 mg/kg dose, whereas the effect sizes for mother ratings were moderate. Although laboratory measures of ADHD clearly indicated treatment effects, their magnitude was low to moderate. Does Medication Exacerbate Tics? Treatment with methylphenidate did not increase the severity or degree of impairment associated with tics in children with oppositional defiant disorder. Teacher ratings actually indicated improvement in tic symptoms with medication. There was a marginally significant (P =.06) main effect of dose for motor tic frequency in the Simulated Classroom. A full report of findings for methylphenidate and tics appears in Gadow et al. 15 What Adverse Events Are Associated With Methylphenidate in Oppositional Children? Teacher Mood, Attention/Arousal, and Motor Movement scores of the Stimulant Side Effects Checklist indicated fewer troublesome reactions with methylphenidate versus placebo in children with oppositional defiant disorder (Table 4). Parents, however, rated physical complaints as being more severe with methylphenidate than placebo. All parameters of cardiovascular function were higher on the 0.5 mg/kg dose than placebo, as was weight loss. Do Children With or Without Oppositional Defiant Disorder Respond Similarly to Medication? There was very little evidence that children with or without comorbid oppositional defiant disorder differed in their response to methylphenidate; however, owing to concerns about small sample size, these analyses must be considered exploratory. The interaction term was significant for only 1

7 Methylphenidate in Children With Oppositional Defiant Disorder / Gadow et al 987 Table 4. Measures of Adverse Events by Dose of Methylphenidate in Children With Diagnosed Oppositional Defiant Disorder (n = 31) Placebo 0.1 mg/kg 0.3 mg/kg 0.5 mg/kg Trend Effect Variable M (SD) M (SD) M (SD) M (SD) F ratio P Post hocs Tests Size a Teacher SSEC b Mood Index 3.7 (3.1) 2.5 (3.1) 2.9 (2.4) 2.5 (2.4) PL >.1,.3,.5 L, Q.45 Atten/Arousal Index 1.7 (1.3) 1.4 (1.4) 1.6 (1.3) 1.1 (1.3) PL,.3 >.1,.5 Q.45 Physical complaints 0.3 (0.6) 0.2 (0.5) 0.3 (0.4) 0.2 (0.5) N/A N/A.04 Motor movements 1.4 (1.3) 1.0 (1.1) 0.9 (1.0) 0.8 (1.1) PL >.1,.3,.5 L.50 Parent SSEC b Mood Index 1.9 (2.0) 2.1 (1.8) 2.2 (2.1) 2.1 (2.0) N/A N/A.04 Atten/Arousal Index 0.8 (0.8) 1.1 (1.5) 0.7 (0.8) 1.2 (1.3) N/A N/A.35 Physical complaints 1.1 (1.4) 2.1 (1.8) 1.7 (1.9) 2.2 (2.2) ,.3,.5 > PL L, Q.61 Motor movements 1.4 (0.9) 1.1 (1.0) 1.3 (0.9) 1.0 (0.7) N/A N/A.54 Cardiovascular Systolic 95.3 (18.7) 99.1 (14.0) (12.5) (16.2) > PL L.50 Diastolic 58.5 (7.4) 58.7 (9.6) 58.9 (10.5) 65.1 (10.6) > PL,.1,.3 L, C.73 Heart rate 84.2 (12.5) 88.4 (13.3) 88.6 (14.6) 92.1 (14.1) > PL L.59 Weight 80.3 (32.6) 79.8 (32.7) 79.3 (32.8) 78.6 (32.0) PL >.5 L.05 NOTE: M = mean; SD = standard deviation; SSEC = Stimulant Side Effects Checklist; PL = placebo; N/A = not applicable; L = linear; Q = quadratic; C = cubic. a. Cohen s d (modified) for placebo vs 0.5 mg/kg. b. Lower scores indicate less severe symptoms. behavioral symptom measure, the teacher-rated Peer Conflict Scale. Follow-up simple effects analyses indicated significant linear dose effects for both groups but post hoc analyses revealed a slight but predictable difference for the oppositional defiant disorder group (placebo >.1,.3,.5) versus the nonoppositional group (placebo.1, >.3,.5). In other words, teachers perceived an improvement in peer aggression for all doses of methylphenidate as compared with placebo for the children with comorbid oppositional defiant disorder; however, improvement was noted only for the 0.3 mg/kg and 0.5 mg/kg doses for children without oppositional defiant disorder. With regard to tics, the only significant Group Dose interaction was for parent tic severity ratings; however, follow-up simple effects analyses were not significant. There were 2 significant interactions for adverse events assessed with the Stimulant Side Effects Checklist, Mood Index ratings (teacher), and Physical Complaints Index (mother). For the teacher Mood Index, ratings were worse for placebo compared with 3 doses of methylphenidate in both groups, but trend analyses were significant only for the oppositional defiant disorder group (linear, cubic). For the mothercompleted Physical Complaints Index, ratings were worse for all 3 doses of methylphenidate versus placebo for both groups, but findings for trend analyses were different: nonoppositional (linear) and oppositional defiant disorder (linear, cubic). Discussion In general, the results of this study indicate that methylphenidate administered morning and noon is effective for the short-term treatment of oppositional behavior and peer aggression in children with both ADHD and chronic multiple tic disorder. Obtained effects sizes (placebo vs 0.5 mg/kg) were moderate according to both mothers and teachers, though larger according to the latter. Compared with obtained effect sizes reported by others in studies of children with ADHD and oppositional defiant disorder but not chronic tic disorder, 16 the findings from the present study appear to be similar. More detailed analyses examining treatment response for specific types of oppositional behavior revealed considerable within-sample variability in size of the treatment effect as a function of informant, measure, and specific type of symptom, all of which gives pause to the interpretation of findings from meta-analytic strategies and monofactorial conceptualizations of child aggression. For example, whereas teachers perceived a big decrease in defiant, quarrelsome, and annoying behaviors consequent to methylphenidate treatment (placebo vs 0.5 mg/kg), they saw much less improvement in mood changes and acts smart, but these behaviors were rated by teachers as being of relatively low frequency on placebo (ie, less room for improvement). Mothers indicated that rebellious and explosive were the symptoms showing the biggest change with methylphenidate, yet these behaviors were no more common during placebo than the other behaviors for which treatment effects were not significant. Nevertheless, the mean rating for all mother and teacher items was generally lowest with the 0.5 mg/kg dose. One likely explanation for the variability in obtained findings is that the clinical phenotype is heterogeneous, resulting in considerable within- and between-child differences in response to treatment at the

8 988 Journal of Child Neurology / Vol. 23, No. 9, September 2008 individual symptom level. In other words, because there are 8 different DSM-IV symptoms of oppositional defiant disorder (of which only 4 need to be problematic for a diagnosis), few patients with this disorder will behave exactly alike. It is well established that mothers and teachers often rate the frequency of oppositional defiant disorder symptoms differently, with mothers generally giving higher scores, 1,15,26 and that stimulant treatment effect sizes are generally larger for teacher- than mother-completed ratings. 15,16 Given this situation, we were curious to see how the informant affected our findings. First, although mother report was the basis for diagnosing oppositional defiant disorder in this study, at intake, teachers also rated our O-D group as being much more oppositional and aggressive than the nonoppositional group. Second, the treatment effect size for mother ratings of oppositional defiant disorder was clearly lower than that for teacher ratings. Third, and most interesting, the effect sizes for mother and teacher ratings of improvement in ADHD behaviors (placebo vs 0.5 mg/kg) in both groups of children were very similar (.92 to 1.2) with 1 exception: mother ADHD ratings for children with oppositional defiant disorder was lower (.63). When we tested this statistically with an Informant Group ANOVA, the interaction term was in fact marginally significant (P <.06). Because both children with and without oppositional defiant disorder showed similar improvement with methylphenidate for laboratory measures of ADHD symptoms, this finding appears to suggest that mother but not teacher ratings may actually underestimate clinical improvement in children with comorbid oppositional defiant disorder. With regard to possible differences in response to methylphenidate in children with and without diagnosed oppositional defiant disorder, both groups of children showed comparable improvement in oppositional behavior consequent to treatment with methylphenidate; neither group was at risk of tic exacerbation (group data); and in both groups, adverse events included increases in heart rate, blood pressure, weight loss, and physical complaints. Nevertheless, children without oppositional defiant disorder did not evidence decreased peer aggression (according to teachers) at the 0.1 mg/kg dose, whereas youngsters with oppositional defiant disorder did. Moreover, it is also likely that future studies with larger samples of children will reveal even more differences in response to treatment in children with and without comorbid oppositional defiant disorder. Limitations Generalization of study findings are subject to several qualifications. All patients received Novartis brand methylphenidate; therefore, results for specific measures may be somewhat different for other types of stimulants (eg, long-acting preparations). Because controversy remains concerning the etiology of ADHD and oppositional defiant disorder in children with chronic tic disorder, it is possible that response to methylphenidate in child patients without tic disorder may be different; however, the evidence does not appear to support this interpretation. Although our prior research examined direct observation of oppositional behaviors at school, 13 this was not done at home. It is possible that oppositional behavior did improve to a greater extent at home, but mother-completed rating scales are not a good method for measuring treatment response for this type of behavior. Alternatively, the drug effect may be less evident at home because the pathogenesis of home versus school oppositional defiant disorder is different and possibly less responsive to stimulant medication. This interpretation is supported by the fact that parent ratings clearly indicated that methylphenidate did improve ADHD and, importantly, peer aggression at home. The current study did not investigate oppositional defiant disorder in the absence of comorbid ADHD, larger doses of methylphenidate, or a thrice-a-day dosing schedule; nor does it address relative efficacy versus other drugs shown to be effective for oppositional defiant disorder (eg, atomoxetine, OROS-MPH, Adderall XR) or parent management training, reviewed by Connor. 48 Clinical Implications It is well established that children with both ADHD and chronic multiple tic disorder are at significantly greater risk of clinical impairment than either disorder singly. 17,49,50 Fortunately, short-term methylphenidate therapy appears to be effective for decreasing their oppositional symptoms; however, it is unclear why informant perceptions of the magnitude of benefit are not more consistent. There is an emerging literature that indicates that children with mother- versus teacher-defined oppositional defiant disorder are different in terms of mental health risk factors, psychosocial correlates, and clinical course, which underscores the importance of considering informant differences in treatment response evaluations. For instance, the disparity between mother and teacher reports unavoidably affects numerous treatment decisions, including the optimal dose of medication, preference for longer-acting preparations, or multiple drug therapy, criteria for treatment and dose adjustment, and inclusion of home- and schoolbased behavioral interventions as alternatives or adjuncts to pharmacotherapy. 51 Further confounding the selection of treatment strategies is the fact that mother child interaction and family variables are often associated with the development, maintenance, and/or exacerbation of oppositional behaviors, and these relations differ for mother versus teacher-defined oppositional defiant disorder. Acknowledgment The authors wish to thank Dr Joseph Schwartz for assisting us with the data analyses, Linda Volkersz for conducting clinic evaluations, Michele and Michael De Angelis for providing pharmacy services, CIBA Pharmaceutical Company for supplying methylphenidate placebos, and Dr Daniel

9 Methylphenidate in Children With Oppositional Defiant Disorder / Gadow et al 989 Connor and anonymous reviewers for their many helpful comments. We are particularly indebted to the courageous families who made this study possible. This study was supported, in part, by a research grant from the Tourette Syndrome Association, Inc, and P.H.S. grant No. MH from the National Institute of Mental Health. Accepted: November 27, References 1. Gadow KD, Sprafkin J. Child Symptom Inventory-4 Screening and Norms Manual. Stony Brook, NY: Checkmate Plus; Gadow KD, Nolan EE, Litcher L, et al. Comparison of attentiondeficit/hyperactivity disorder symptom subtypes in Ukrainian schoolchildren. J Am Acad Child Adolesc Psychiatry. 2000;39: Nolan EE, Gadow KD, Sprafkin J. Teacher reports of DSM-IV ADHD, ODD, and CD symptoms in schoolchildren. J Am Acad Child Adolesc Psychiatry. 2001;40: Schneider H, Eisenberg D. Who receives a diagnosis of attentiondeficit/hyperactivity disorder in the United States elementary school population. Pediatrics. 2006;117:e601-e Gadow KD, Sprafkin J, Schneider J, Nolan EE, Schwartz J, Weiss MD. ODD, ADHD, versus ODD+ADHD in clinic and community adults. J Attention Disorders. 2007;11: Murphy KR, Barkley RA. Attention deficit hyperactivity disorder adults: comorbidities and adaptive impairments. Compr Psychiatry. 1996;37: Dick DM, Viken RJ, Kaprio J, Pulkkinen L, Rose RJ. Understanding the covariation among childhood externalizing symptoms: genetic and environmental influences on conduct disorder, attention deficit hyperactivity disorder, and oppositional defiant disorder symptoms. J Abnorm Child Psychol. 2005;33: Hudziak JJ, Derks EM, Althoff RR, Copeland W, Boomsma DI. The genetic and environmental contributions to oppositional defiant behavior: a multi-informant twin study. J Am Acad of Child Adolesc Psychiatry. 2005;44: August GJ, Realmuto GM, Joyce T, Hektner JM. Persistence and desistence of oppositional defiant disorder in a community sample of children with ADHD. J Am Acad Child Adolesc Psychiatry. 1999;38: Biederman J, Faraone SV, Milberger S, et al. Is childhood oppositional defiant disorder a precursor to adolescent conduct disorder? Findings from a four-year follow-up study of children with ADHD. J Am Acad Child Adolesc Psychiatry. 1996;35: Comings DE. The role of genetic factors in conduct disorder based on studies of Tourette syndrome and attention-deficit hyperactivity disorder probands and their relatives. J Dev Behav Pediatr. 1995;16: Gadow KD, Sverd J. Stimulants for ADHD in child patients with Tourette s syndrome: the issue of relative risk. J Dev Behav Pediatr. 1990;11: Gadow KD, Nolan EE, Sprafkin J, Sverd J. School observations of children with attention deficit hyperactivity disorder and comorbid tic disorder: effects of methylphenidate treatment. J Dev Behav Pediatr. 1995;16: Gadow KD, Sverd J, Sprafkin J, Nolan EE, Ezor SN. Efficacy of methylphenidate for attention-deficit hyperactivity disorder in children with tic disorder. Arch Gen Psychiatry. 1995;52: Gadow KD, Sverd J, Nolan EE, Sprafkin J, Schneider J. Immediate-release methylphenidate for ADHD in children with comorbid chronic multiple tic disorder. J Am Acad Child Adolesc Psychiatry. 2007;46: Connor DF, Glatt SJ, Lopez ID, Jackson D, Melloni RH. Psychopharmacology and aggression. I: Meta-analysis of stimulant effects on overt/covert aggression-related behaviors in ADHD. J Am Acad Child Adolesc Psychiatry. 2002;41: Shapiro A, Shapiro E, Young J, Feinberg TE. Gilles de la Tourette Syndrome. New York, NY: Raven Press; Comings DE, Comings BG. Tourette syndrome and attention deficit disorder with hyperactivity: are they genetically related? J Am Acad Child Psychiatry. 1984;23: Pauls DL, Leckman JF, Cohen DJ. Familial relationship between Gilles de la Tourette s syndrome, attention deficit disorder, learning disabilities, speech disorders, and stuttering. J Am Acad Child Adolesc Psychiatry. 1993;32: Denckla MB. Attention-deficit hyperactivity disorder (ADHD) comorbidity: a case for pure Tourette syndrome. J Child Neurol. 2006;21: Comings DE, Comings BG. A controlled study of Tourette syndrome. II. Conduct. Am J Hum Genet. 1987;41: Budman CL, Bruun RD, Park KS, Lesser M, Olson M. Explosive outbursts in children with Tourette s disorder. J Am Acad Child Adolesc Psychiatry. 2000;39: Budman CL, Rockmore L, Stokes J, Sossin M. Clinical phenomenology of episodic rage in children with Tourette syndrome. J Psychosom Res. 2003;55: TSSG (Tourette Syndrome Study Group). Treatment of ADHD in children with tics. Neurology. 2002;58: Zinner SH. Tourette syndrome much more than tics: moving beyond misconceptions to a diagnosis. Contemp Pediatr. 2004; 21: Drabick DAG, Gadow KD, Loney J. Source-specific oppositional defiant disorder: comorbidity and risk factors in referred elementary school boys. J Am Acad Child Adolesc Psychiatry. 2007;46: Drabick DAG, Gadow KD, Carlson GA, Bromet EJ. ODD and ADHD symptoms in Ukrainian children: external validators and comorbidity. J Am Acad Child Adolesc Psychiatry. 2004;43: Drabick DAG, Gadow KD, Loney J. Co-occurring ODD and GAD symptom groups: source-specific syndromes and crossinformant comorbidity. J Clin Child Adolesc Psychol. In press. 29. Gadow KD, Nolan EE. Differences between preschool children with ODD, ADHD, and ODD+ADHD symptoms. J Child Psychol Psychiatry. 2002;43: Offord DR, Boyle MH, Racine Y, et al. Integrating assessment data from multiple informants. J Am Acad Child Adolesc Psychiatry. 1996;35: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSM-III-R). Washington, DC: American Psychiatric Association; American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Washington, DC: American Psychiatric Association; Reich W. Diagnostic Interview for Children and Adolescents (DICA). J Am Acad Child Adolesc Psychiatry. 2000;39: Conners CK. Rating scales for use in drug studies with children. Psychopharm Bull. 1973;9(special issue): Loney J, Milich R. Hyperactivity inattention, and aggression in clinical practice. In: Wolraich M, Routh DK, eds. Advances in

10 990 Journal of Child Neurology / Vol. 23, No. 9, September 2008 Developmental and Behavioral Pediatrics. Vol 3. Greenwich, CT: JAI Press; 1982: Goyette CH, Conners CK, Ulrich RF. Normative data on revised Conners Parent and Teacher Rating Scales. J Abnorm Child Psychol. 1978;6: Loney J. A short parent scale for subgrouping childhood hyperactivity and aggression. Paper presented at: Annual meeting of the American Psychological Association; August 1984; Toronto, Ontario, Canada. 38. Leckman JF, Riddle MA, Hardin MT, et al. The Yale Global Tic Severity Scale: Initial testing of a clinic-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry. 1989;28: Nolan EE, Gadow KD, Sverd J. Observations and ratings of tics in school settings. J Abnorm Child Psychol. 1994;22: Kurlan R. Tourette s syndrome: current concepts. Neurology. 1989;39: Epstein MH, Cullinan D, Gadow KD. Teacher ratings of hyperactivity in learning disabled, emotionally disturbed, and mentally retarded children. J Spec Educ. 1986;20: Nolan EE, Gadow KD. Relation between ratings and observations of stimulant drug response in hyperactive children. J Clin Child Psychol. 1994;23: Gadow KD, Sprafkin J. ADHD Symptom Checklist-4 Manual. Stony Brook, NY: Checkmate Plus; Roberts MA, Ray RS, Roberts RJ. A playroom observational procedure for assessing hyperactive boys. J Pediatr Psychol. 1984;9: Halperin JM, Matier K, Bedi G, Sharma V, Newcorn JH. Specificity of inattention, impulsivity, and hyperactivity to the diagnosis of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1992;31: Rosnow RL, Rosenthal R. Computing contrasts, effect sizes, and counternulls on other people s published data: general procedures for research consumers. Psychol Methods. 1996;1: Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Mahwah, NJ: Lawrence Erlbaum; Connor DF. Pharmacological treatment of ODD symptoms in ADHD children: a brief review. ADHD Rep. 2007;15: Comings DE. Tourette Syndrome and Human Behavior. Duarte, CA: Hope Press; Pierre CB, Nolan EE, Gadow KD, Sverd J, Sprafkin J. Comparison of internalizing and externalizing symptoms in children with attention-deficit hyperactivity disorder with and without comorbid tic disorder. J Dev Behav Pediatr. 1999;20: Kolko DJ, Bukstein OG, Barron J. Methylphenidate and behavior modification in children with ADHD and comorbid ODD or CD: main and incremental effects across settings. J Am Acad Child Adolesc Psychiatry. 1999;38: