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Treatment Effects of Methylphenidate on Behavioral Adjustment in Children With Mental Retardation and ADHD
Treatment Effects of Methylphenidate on Behavioral Adjustment in Children With Mental Retardation and ADHD DEBORAH A. PEARSON, PH.D., CYNTHIA W. SANTOS, M.D., JOHN D. ROACHE, PH.D., CHARLES D. CASAT, M.D., KATHERINE A. LOVELAND, PH.D., DAVID LACHAR, PH.D., DAVID M. LANE, PH.D., LAURA P. FARIA, M.A., AND LYNNE A. CLEVELAND
ABSTRACT Objective: The effects of stimulant medication treatment were investigated in children with mental retardation (MR) and attention-deficit/hyperactivity disorder (ADHD). Method: Parent and teacher behavioral ratings and reports of side effects were obtained for children (N = 24, mean age = 10.9 years, SD = 2.4) during a placebo-controlled, double-blind, crossover treatment trial with 0.15 mg/kg, 0.30 mg/kg, and 0.60 mg/kg b.i.d. dosages of methylphenidate. Results: The most significant improvements occurred at the 0.60 mg/kg methylphenidate dose for teacher ratings of inattention (p = .024), hyperactivity (p < .001), aggression (p < .001), and asocial behavior (p = .009). No significant improvements, relative to placebo, occurred at the 0.15 mg/kg dosage. Of interest, nearly all significant medication-related behavioral improvements were detected by teachers. However, parents were sensitive raters of side effects, noting more sleeping problems and loss of appetite at the 0.60 mg/kg dose compared with placebo. Conclusions: These results suggest that symptoms of ADHD can be treated successfully in children with ADHD/MR, and consistent with MTA study results, higher doses were most effective. Furthermore, these improvements were not accompanied by increases in symptoms such as staring, social withdrawal, or anxiety. J. Am. Acad. Child Adolesc. Psychiatry, 2003, 42(2):209–216. Key Words: methylphenidate, mental retardation, attention-deficit/hyperactivity disorder, behavior.
Attention-deficit/hyperactivity disorder (ADHD) (DSMIII-R, DSM-IV: 314.01) (American Psychiatric Association, 1987, 1994), the most commonly diagnosed behavioral disturbance of childhood, is characterized by symptoms of inattention, hyperactivity, and impulsivity. Findings from the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/ Accepted September 11, 2002. From the Department of Psychiatry, University of Texas Medical School at Houston (Pearson, Santos, Loveland, Lachar, Faria, Cleveland); Department of Psychology, Rice University, Houston (Lane); Department of Psychiatry, UT-San Antonio (Roache); and Carolinas HealthCare System, Charlotte, NC (Casat). Drs. Pearson, Santos, and Lachar are also with the University of Texas Harris County Psychiatric Center. This research was supported by NIMH grant R29 MH48212. The authors thank the parents, teachers, and children who participated in this study. The authors are indebted to John E. Overall, Ph.D., who provided additional statistical consultation. Correspondence to Dr. Pearson, Department of Psychiatry, University of Texas Medical School at Houston, 1300 Moursund, Houston, TX 77030-3497, e-mail: [email protected]. 0890-8567/03/4202–0209䉷2003 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.CHI.0000037009.34553.36
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Hyperactivity Disorder (MTA) suggest that school-age children with ADHD (with IQs of 80+) who received higher and more frequent doses of stimulant medication had generally better outcomes than those treated with lower and less frequent doses (Jensen et al., 2001; MTA Cooperative Group, 1999). Although findings such as these suggest that higher doses of carefully monitored stimulant treatment are associated with better outcomes with regard to ADHD symptomatology, others (e.g., Gan and Cantwell, 1982; Sprague and Sleator, 1977) have noted a curvilinear response to stimulant medication, such that lower doses of stimulants produced initial improvements relative to placebo, followed by declines in performance at higher doses. Until recently, few studies had investigated either the nature of ADHD in mental retardation (MR) or the response of these children to stimulants. Indeed, subaverage intelligence (i.e., IQ ≤ 80) has often been an exclusion criterion in these treatment studies (Gadow and Poling, 1988). Fortunately, in recent years, studies have appeared suggesting that ADHD is manifested in mild to moderate MR 209
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in a similar way as it is in children without MR (e.g., Aman et al., 1996; Fee et al., 1994; Pearson et al., 1996b, 2000) and that these children show behavioral improvements with stimulant treatment (e.g., Aman et al., 1991, 1993, 1997; Hagerman et al., 1988; Handen et al., 1990, 1992, 1994; Payton et al., 1989; Varley and Trupin, 1982). However, several investigators have noted a more variable or idiosyncratic response to methylphenidate (MPH) in children with ADHD and MR (ADHD/MR), particularly lower-functioning children (Handen et al., 1991) or children whose MR was associated with genetic syndromes (Hagerman et al., 1988; Power et al., 1997). Of particular concern are reports suggesting that children with ADHD/MR may be more prone to experiencing serious side effects of MPH such as staring spells and social withdrawal (e.g., Feldman et al., 1989; Handen et al., 1991). This apparent sensitivity to MPH in children with ADHD/MR has also been noted by Aman et al. (1991, 1993), using only a single morning dose of MPH (0.4 mg/kg). Given that children with MR are often heavily medicated (Gadow, 1985), these studies suggest that there is a significant risk that children with ADHD/MR will be overmedicated, relative to a dose that would lead to optimal functioning. Given the potential for increased stimulant side effects in children with MR, the purpose of this study was to determine whether low doses of MPH (which might have a lower risk of side effects) could produce significant improvements in ADHD symptomatology. Most studies of stimulant treatment in ADHD/MR have used doses in the 0.30–0.60 mg/kg (typically b.i.d.) range. In this study, we assessed parent and teacher ratings of treatment response in children with ADHD/MR to placebo and to MPH 0.15 mg/kg, 0.30 mg/kg, and 0.60 mg/kg b.i.d. A second aim of this study was to assess whether medication treatment response followed a linear pattern (i.e., successively higher doses producing increasingly better behavior) or a curvilinear pattern (i.e., initial improvement at lower doses, followed by declines at higher doses). We hypothesized that ADHD symptomatology would decrease in a linear fashion with ascending doses but that children would also experience significantly more side effects at successively higher doses. METHOD PARTICIPANTS Twenty-four children with ADHD/MR (18 boys and 6 girls) participated in this study. The mean chronological age of these children was 10.9 years (SD = 2.4), the mean IQ (Stanford-Binet, 4th edition)
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(Thorndike et al., 1986) was 56.5 (SD = 10.24), and the mean mental age (estimated using the Stanford-Binet) was 5.7 years (SD = 1.2). Seventeen children had mild (50+) MR; seven had moderate MR. The ethnic breakdown of these children was as follows: 9 white, 14 African American, and 1 Hispanic. The mean Hollingshead fourfactor social class for this sample was 3.39 (SD = 1.16) (Hollingshead, 1975). The mean education level was 12.35 (SD = 2.6) years for mothers and 12.24 (SD = 2.7) years for fathers. Participants met DSM-III-R criteria for ADHD (as determined by parent interview, using the Diagnostic Interview for Children and Adolescents-Revised [DICA-R]) (Reich et al., 1991); they did not meet criteria for any other DSM-III-R diagnoses. Data collection began in 1993 (i.e., before DSM-IV) and continued for nearly 7 years; 1,328 children were screened during this time, in search of children with ADHD/MR who did not have comorbid psychiatric conditions. We retained the DSM-III-R structured interview for consistency with previously collected data but also used the strategy of Biederman et al. (1997) of collecting sufficient information (e.g., behavioral questionnaires, parent interviews) to allow for both DSM-III-R and DSMIV diagnoses. All patient files were reviewed independently by two licensed psychologists (D.A.P. and K.A.L.), and one child and adolescent psychiatrist (C.W.S.) to confirm each child’s relevant DSMIV ADHD subtype. This process allowed us to determine, with 100% interrater reliability, that 22 children met DSM-IV criteria for ADHD, combined type, and two for ADHD, predominantly inattentive type. To further assess severity of ADHD symptoms, the children were assessed with the Parent and Teacher versions of the Conners Abbreviated Symptom Questionnaire (CASQ), sometimes called the Hyperactivity Index (Conners, 1989). The mean Parent CASQ score for this group was 20.9 (mean T score = 84.3), and the mean Teacher CASQ score for this group was 20.0 (mean T score = 77.0). All of the children participating in this study had familial MR; no other etiologies of MR (e.g., Down syndrome, fragile X) were identified (by reviewing medical and school records, parent interview, and physician assessment of phenotype during the physical examination done prior to entry into the medication trial). All were communitybased and lived at home; they were recruited from special education classrooms of a large metropolitan public school district. Exclusion criteria included psychosis, autistic behaviors, and mood disorders (these conditions were ruled out with the DICA-R). No children were taking psychotropic medication at their entry into this study; however, four had taken MPH, one had taken pemoline, and one had taken dextroamphetamine prior to study entry. Previous medication was discontinued at least 1 week prior to entry into the medication trial. It should be noted that some data from 13 of these participants were discussed in a preliminary report from this project (Pearson et al., 1996a). DESIGN The effectiveness of the various dosages of MPH (placebo, 0.15 mg/kg, 0.30 mg/kg, 0.60 mg/kg b.i.d.) in children with ADHD/MR was investigated using a within-subject, crossover, placebo-controlled design. The order of dosage administration was counterbalanced across subjects using a digram-balanced Latin squares procedure which controls for both order and sequence Wagenarr (1969). Prior to the start of the drug trials, all participants were given a single-blind week of placebo baseline (the staff was unblinded); this period served as a time during which the pill-taking regimen could be firmly established at home and at school. During the actual medication trial period, each child received 1 week each of placebo (cornstarch), MPH 0.15 mg/kg, MPH 0.3 mg/kg, and MPH 0.6 mg/kg; medication was given before breakfast and at lunchtime. MPH was prepared by crushing and blending white generic MPH tablets with cornstarch and filling two opaque,
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size 1 gelatin capsules. The study director, physician, research assistants, teachers, parents, and children were all blind with respect to dosages given during the drug trial; the study pharmacologist (J.D.R.)— who had no patient contact—ran the double-blind. PROCEDURE Participants were recruited to the medication treatment trial after completing a comprehensive assessment that included a standardized neuropsychological test battery (including Stanford-Binet) and psychiatric interview (Pearson et al., 1996a). Potential participants were given a physical examination by the study physician (C.W.S.) to confirm medical eligibility to take MPH. The children were seen at the end of the placebo baseline week and at the end of each week of the drug trial for both a medication check with the study physician and an interview with the study psychologist (D.A.P.). Parents completed behavioral questionnaires each week (i.e., for each dosage) and were urged to base their ratings on weekend behaviors (when they would have seen their children under the influence of the medication). Parents also completed a medication side effects questionnaire each week, which addressed common side effects associated with MPH treatment (Physician’s Desk Reference, 1991). In addition to the symptoms listed in the checklist, there was also an open-ended question at the end of the questionnaire about “other atypical behaviors that you may have noticed this week.” Behavioral questionnaires and medication side effects questionnaires were also collected from the teachers each week.
Revised Behavior Problem Checklist. The Revised Behavior Problem Checklist (RBPC) (Quay and Peterson, 1987) includes six subscales: Conduct Disorder, Socialized Aggression, Attention ProblemsImmaturity, Anxiety-Withdrawal, Psychotic Behavior, and Motor Tension-Excess. It has been shown to be sensitive to MPH in children with ADHD in the general school-age population (Pelham et al., 1989) and in children with ADHD/MR (Aman et al., 1993, 1997). Personality Inventory for Children-Revised. The Personality Inventory for Children-Revised (PIC-R) (Wirt et al., 1984) is a 280-item multidimensional measure of child behavior, affect, and ability. There are 12 clinical subscales on the PIC-R, including Hyperactivity and Delinquency, which were used in this investigation. COMPLIANCE Compliance with the study medication regimen was assessed by having the parents and the school nurse each complete a dose administration form, documenting the date and time that each dose was dispensed. Parents were also asked about any missed or late doses during their weekly clinic interview (with D.A.P.); teachers were also queried by the research assistant during the weekly school visit. The number of pills remaining in the returned home and school bottles was counted and verified against the parent and teacher dose administration forms. If any discrepancy was found, the parent or teacher was asked for additional information.
INSTRUMENTS
RESULTS
Teacher Questionnaires
The data were analyzed using SPSS-PC (version 10.0) repeated-measures one-way analysis of variance (ANOVA) procedures, with MPH dosage as the within-subjects variable. Because preliminary analyses revealed no significant effects of gender or dose order, these factors were dropped from subsequent analyses. For significant effects, post hoc Student-Newman-Keuls analyses were performed to determine which doses of medication were significantly different from one another (p ≤ .05). Because the purpose of these analyses was to detect treatment-related reductions in absolute levels of symptomatology, only the raw scores from teacher and parent indices are presented (e.g., Aman et al., 1993). The teacher behavioral ratings are summarized in Table 1; parent behavioral ratings are summarized in Table 2.
ADD-H Comprehensive Teacher Rating Scale. The ADD-H Comprehensive Teacher Rating Scale (ACTeRs) (Ullmann et al., 1985) contains subscales measuring attention, hyperactivity, social skills, and oppositional behavior. Unlike all other behavior questionnaire subscales reported in this investigation, higher scores on the Attention and Social Skills subscales of the ACTeRS are indicative of better symptomatology. The ACTeRS has been found to be sensitive to stimulant effects in the general school-age population (Ullmann and Sleator, 1985) and in children with ADHD/MR (Hagerman et al., 1988). Conners Teacher Rating Scale. The Conners Teacher Rating Scale (CTRS) (Conners, 1989) includes seven subscales: Hyperactivity, Conduct Problem, Emotional-Overindulgent, Anxious-Passive, Asocial, Daydream-Attention Problem, and the Hyperactivity Index. The CTRS has been found to be sensitive to MPH response in children with ADHD in the general school-age population (e.g., Sprague and Sleator, 1977) and in children with ADHD/MR (e.g., Aman et al., 1993, 1997; Handen et al., 1992). Parent Questionnaires Conners Parent Rating Scale. The Conners Parent Rating Scale (CPRS; 48-item revision) (Conners, 1989) includes six subscales: Conduct Problem, Learning Problem, Psychosomatic, ImpulsiveHyperactive, Anxiety, and the Hyperactivity Index. The CPRS has been found to be sensitive to MPH in children with ADHD in the general school-age population (e.g., Solanto and Conners, 1982), as well as in children with ADHD/MR (Varley and Trupin, 1982). Aberrant Behavior Checklist. The Aberrant Behavior Checklist (ABC; Community version) (Marshburn and Aman, 1992), specifically developed for individuals with MR, includes subscales measuring Irritability, Lethargy, Stereotypic Behavior, Hyperactivity, and Inappropriate Speech. The ABC has been shown to be sensitive to MPH in children with ADHD/MR (e.g., Aman et al., 1993).
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Teacher Behavioral Ratings
Significant declines in ADHD symptomatology with MPH treatment were found with both scales. Symptoms of inattention declined steadily with ascending MPH doses (ACTeRS: p = .024; CTRS: p = .022), as did symptoms of hyperactivity (ACTeRS: p < .001; CTRS: p < .001). There was a similar decline in oppositional behavior (p = .012) and conduct problems (p < .001). These decreases in aggressive symptoms were accompanied by decreases in asocial behaviors (p = .009), although this decrease was 211
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TABLE 1 Effects of Methylphenidate on Teacher Behavioral Ratings Variable ACTeRS Attention Hyperactivity Social Skills Oppositional CTRS Hyperactivity Conduct Problem Emotional Overindulgent Anxious-Passive Asocial Daydream-Attention Hyperactivity Index
Placebo
0.15 mg/kg (Low)
0.30 mg/kg 0.60 mg/kg (Medium) (High)
15.88 17.67 21.63 13.08
16.46 15.83 22.96 12.25
18.54 13.79 23.17 11.25
19.75 11.08 24.42 9.17
3.35 7.83 1.79 3.93
.024 <.001 .157 .012
P:H P:M, P:H, L:H
26.75 12.42 8.42 6.42 3.63 3.88 16.29
22.75 11.00 7.29 6.00 3.42 3.17 14.08
19.25 9.21 6.67 6.17 3.17 2.92 11.92
10.75 3.96 4.04 4.88 1.67 2.17 6.58
13.53 8.74 4.57 1.51 4.13 3.42 12.89
<.001 <.001 .006 .221 .009 .022 <.001
P:M, P:H, L:H, M:H P:H, L:H, M:H P:H, L:H, M:H
F3,69
Source of Significance
pa
P:H, L:H
P:H, L:H, M:H P:H P:M, P:H, L:H, M:H
Note: ACTeRS = ADD-H Comprehensive Teacher Rating Scale; CTRS = Conners Teacher Rating Scale. Values in boldface type are significant.
a
not accompanied by significant gains in social skills (p = .15), at least not within the short timeframe of this study. Teachers noted no increases in symptoms of anxiety with MPH treatment (p = .22); indeed their ratings of anxiety were actually lowest at the highest MPH dose.
Post hoc Student-Newman-Keuls analyses revealed that without exception, the most consistent and effective reductions in inattentive, hyperactive, aggressive, and asocial behaviors occurred at the highest (0.60 mg/kg) dose. No significant behavioral improvements were noted
TABLE 2 Effects of Methylphenidate on Parent Behavioral Ratings Variable CPRS Conduct Problem Learning Problem Psychosomatic Impulsive-Hyperactive Anxiety Hyperactivity Index ABC Irritability Lethargy Stereotypic Behavior Hyperactivity Inappropriate Speech RBPC Conduct Disorder Socialized Aggression Attention Problems Anxiety-Withdrawal Psychotic Motor Tension-Excess PIC-R Delinquency Hyperactivity
Placebo
0.15 mg/kg (Low)
0.30 mg/kg (Medium)
0.60 mg/kg (High)
F3,69
pa
6.38 6.92 0.25 5.96 2.25 13.92
5.54 6.46 0.21 5.96 1.75 12.88
4.83 6.46 0.46 5.00 1.79 12.33
5.17 6.17 0.71 4.50 1.71 11.67
1.42 0.68 0.92 3.59 0.83 1.41
.245 .567 .438 .018 .483 .248
9.96 4.42 1.83 18.54 2.71
9.33 4.67 2.17 21.00 2.71
8.42 5.92 2.79 18.33 3.04
9.17 6.46 1.54 16.46 2.79
0.58 1.30 2.01 1.75 0.27
.627 .283 .121 .165 .845
14.29 2.25 12.96 4.04 2.00 3.96
13.13 2.71 12.21 4.33 1.96 4.29
12.71 3.33 12.75 3.75 2.38 3.96
13.75 2.21 13.17 4.38 2.33 3.71
0.25 1.34 0.29 0.32 0.41 0.72
.862 .269 .832 .813 .745 .544
12.33 14.96
12.71 14.67
11.88 14.29
12.79 14.29
0.74 0.42
.530 .738
Source of Significance
P:H, L:H
Note: CPRS = Conners Parent Rating Scale; ABC = Aberrant Behavior Checklist; RBPC = Revised Behavior Problem Checklist; PIC-R = Personality Inventory for Children-Revised. a Value in boldface type is significant.
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between the placebo and the 0.15 mg/kg dose in any of these behaviors, suggesting that the low dose was insufficient to produce a detectable behavioral response. Symptoms of hyperactivity showed significant declines between the placebo and the 0.30 mg/kg dose on both the ACTeRs and CTRS subscales. For the ACTeRS, no further significant improvement in hyperactivity was noted between the 0.30 mg/kg dose and the 0.60 mg/kg dose; but a further significant decline in symptoms of hyperactivity was noted on the CTRS between the medium and high doses. Symptoms of inattention only showed significant improvements (relative to placebo) at the 0.60 mg/kg dosage on both teacher instruments; no improvements were noted between the placebo and the lower two doses. Similarly, the most effective treatment of aggressive symptoms occurred at the highest dose.
parents reported headache at the 0.60 mg/kg dose, and one at the 0.30 mg/kg dose. Compliance
Compliance was quite high, as indicated that overall, fewer than one dose was missed each week. For the placebo condition, the mean number of missed doses (of 14 possible doses) each week was 0.50 (96.4% compliance); for the 0.15 mg/kg MPH condition, it was 0.25 (98.2% compliance); for the 0.30 mg/kg MPH condition, it was 0.63 (95.5% compliance); and for the 0.6 mg/kg condition, it was 0.42 doses per week (97% compliance). No significant differences emerged among these dose conditions (F3,69 = 1.03, p = .39). Furthermore, it was the impression of the study staff that our families were highly responsible with regard to their adherence to the prescribed dosing schedules.
Parent Questionnaires
In contrast to the numerous medication-related declines in behavioral problems reported by teachers, the only parent rating that showed significant treatment-related declines was the CPRS Impulsive-Hyperactive subscale. Consistent with the teacher ratings, the most effective reduction in symptoms was noted at the highest MPH dosage. Also, like the teachers, the parents noted no significant increases in behavioral ratings of anxiety with increasing medication dosage on either the CPRS or the RBPC. Ratings of Side Effects
There were no significant effects of medication dose on any of the teacher reports of side effects. In comparison, parents reported significant increases in loss of appetite (F3,69 = 3.54, p = .02) and sleeping problems (F3,69 = 4.60, p = .005) at higher doses of MPH. Four parents (of 24) reported insomnia at the high dose, relative to none at placebo (p ≤ .05), and seven parents noted significant symptoms of loss of appetite at the 0.60 mg/kg dose, relative to one at placebo (p ≤ .05). No other side effect symptoms showed statistically significant dosage-related changes. Although it is interesting to note that teachers of five children and parents of four children reported staring behaviors at the highest dose, there were no significant dose-related increases in these behaviors because five teachers and three parents had also reported staring in the placebo condition. A review of the open-ended question at the end of the questionnaire revealed that two teachers reported unresponsive, “zombie” like behaviors at the 0.60 mg/kg dose (no such symptoms were reported at lower doses). Three J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 2 , F E B RU A RY 2 0 0 3
DISCUSSION
Our findings of decreases in ADHD symptomatology with MPH treatment in children with ADHD/MR are consistent with those of previous investigations (e.g., Aman et al., 1991, 1993, 1997; Hagerman et al., 1988; Handen et al., 1990, 1992). Our results extend previous findings by confirming that there is little efficacy of a 0.15 mg/kg dose (relative to placebo); they also suggest that MPH treatment produces concomitant declines in aggressive and asocial behaviors in children with ADHD/MR. Unlike the children studied by Handen et al. (1991), our participants did not experience significant increases in serious side effects such as staring, social withdrawal, and anxiety at the 0.6 mg/kg dose. In fact, the 0.6 mg/kg b.i.d. MPH dose produced the maximum treatment benefit, but it was also associated with the typical MPH side effects of insomnia and loss of appetite for some children. Thus our findings of a steady improvement with MPH treatment in the 0.15 to 0.6 mg/kg dose range are consistent with those of the MTA study, with the best behavioral outcome being associated with the highest dose. Limitations
We are sensitive to the fact that our sample was collected using a structured interview geared to DSM-IIIR. This was inevitable, given the protracted recruitment period. Fortunately, as Biederman et al. (1997) have noted, the change from DSM-III-R to DSM-IV results in considerable diagnostic continuity between these classification systems. Given that DSM-IV criteria have actually 213
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been found to identify more children with ADHD than did DSM-III-R criteria (Wolraich et al., 1996) and that our charts were reviewed independently by three licensed mental health professionals, we feel confident that our children meet DSM-IV criteria for ADHD. A second possible limitation might be that only 75% of the sample was stimulant-naïve; i.e., the presence of the children who had previously taken stimulants might have unduly influenced these results. To address this issue, the ANOVAs were rerun after removing the six children who had previously taken stimulants. With one exception, all the subscales that had been significant with the entire sample remained significant (the p value associated with the ACTeRS Oppositional subscale became p = .069). These findings strongly suggest that the children who had previously taken stimulants were not driving the results of this investigation. Another possible limitation of the current study lies in its inherent experimental rigor, i.e., the use of “ADHD simplex” children. We recruited children without comorbid psychiatric diagnoses to avoid potential confounding effects of these comorbid conditions in studying MPH efficacy in children with ADHD/MR. Given that the findings of the MTA study suggest that optimal treatment for children with ADHD may depend on comorbid disorders (Jensen et al. 2001), it will be important for future studies to systematically explore the efficacy of MPH in subgroups of children with ADHD/MR who have comorbid psychiatric conditions (e.g., anxiety). Clinical Implications
The implications of our findings for clinical treatment are that children with mild to moderate MR can benefit from MPH and that the moderate dose of 0.6 mg/kg is well tolerated. These results also suggest that patients who develop unacceptable symptoms such as severe social withdrawal at the 0.6 mg/kg dose can be treated using a 0.3 mg/kg dose. The preliminary report of our in-progress study (Pearson et al., 1996a) did not have sufficient statistical power (given its partial sample size) to detect improvement in the 0.3 mg/kg dose, relative to placebo. However, with the complete sample in place, we were able to detect significant reduction in hyperactivity, but not in inattention, at the 0.3 mg/kg dose (relative to placebo), although further reduction in symptoms is possible at the 0.6 mg/kg dose for children who can tolerate it, given that there is considerable variability in individual responses to MPH (Rapport et al., 1985). 214
These results strongly suggest that if at all possible, titration of MPH treatment in children with ADHD/MR should be conducted when a teacher informant is available. Our findings of greater teacher sensitivity (in comparison to parents) to changes in ADHD symptomatology with MPH treatment has been found both with children with ADHD/MR (e.g., Aman et al., 1991, 1997; Hagerman et al., 1988) and with children with ADHD in the general school-age population (e.g., Sleator and Sprague, 1978). This finding may reflect the fact that teachers have more opportunity to observe the core symptoms of ADHD in a setting in which they would be most problematic. It is also consistent with previous findings that parents and teachers often perceive behavioral adjustment in the same children quite differently, given that the domains of school and home place different demands on children (Gould et al., 1981). Perhaps the most parsimonious explanation for the differences between parent and teacher ratings is that parents had less opportunity to see their children during the medicated state, i.e., the MPH would have worn off by the time the children got home from school, leaving the weekends as their only time to observe medication-related behavioral changes. Although teachers saw the children more in the medicated state, parents were urged to base their behavioral ratings on weekend behavior, when they would observe their child while he or she was in the medicated state. This explanation is also inconsistent with the steady (albeit mostly statistically insignificant) declines in a number of parent subscale ratings of ADHD symptomatology at successively higher MPH doses. Furthermore, parents were sensitive raters of dose-related MPH side effects. Still another possible explanation for this difference is that parents of children with familial ADHD/MR may have been unable to effectively detect and report behavioral changes in their children. This possibility seems unlikely because our parents were sensitive reporters of side effects, were highly compliant with the treatment regimen, had an average educational level of high school graduates, and, on average, functioned on the “skilled craftsmen, clerical, and sales workers” social-class level (Hollingshead, 1975, p. 23). This explanation would also be inconsistent with the fact that the same discrepancy has been found in studies of children with ADHD in the general school-age population (Sleator and Sprague, 1978). Another potential explanation for the discrepancy between parent and teacher ratings may have been the possible insensitivity of our parent measures in this population. This posJ . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 2 , F E B RU A RY 2 0 0 3
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sibility seems unlikely because significant differences emerged on the teacher Conners but not on the parallel parent form of the Conners. To our knowledge, there is only one other double-blind, placebo-controlled crossover study of MPH efficacy in children with ADHD/MR which used both the CPRS and the CTRS as outcome measures (Varley and Trupin, 1982, who reported the 10-item Hyperkinesis Index from both). Using parallel parent- and teacher-completed ABCs, Aman et al. (1997) found the same discrepancy we found in this study using the Conners, although both parent- and teacher-completed ABCs had yielded similar results in an earlier study (Aman et al., 1993). Although it is difficult to compare parent- and teacher-completed versions of a particular scale across different studies, it is interesting to note that only one (25%) in four previous double-blind, placebo-controlled crossover studies of stimulant efficacy in children with ADHD/MR which used the parent Conners found significant differences in ADHD symptomatology between placebo and MPH conditions (Varley and Trupin, 1982), while seven (78%) of nine studies using the teacher Conners found such differences (Aman et al., 1991, 1993, 1997; Feldman et al., 1989; Handen et al., 1990, 1992, 1999; Varley and Trupin, 1982). Although relatively few double-blind, placebo-controlled crossover studies of stimulant efficacy have been done in children with ADHD/MR, the pattern of results generated to date suggests that teacher ratings are often more sensitive to MPH dose-related behavioral changes than are parent ratings. At this point, we are only beginning to understand the role of stimulant treatment in children with ADHD/MR. There is a need to study dose-related changes in cognitive response to MPH in children with ADHD/MR (Pearson et al., manuscript in preparation). There is also a need for more systematic study of medication treatment in children whose MR is caused by common genetic syndromes such as Down syndrome. In addition to studying groups of children with ADHD/MR with different comorbid psychiatric conditions, it will be important to examine possible differences in MPH response among different subtypes of ADHD. The efficacy of the newer long-acting stimulants in children with ADHD/MR has yet to be explored, and they might prove beneficial for children who have a tendency to forget lunchtime dosing. Another obvious avenue for future research in this area is to explore the relative contributions of behavioral and medication treatment factors to the long-term outcome of children with ADHD/MR. Given that long-term follow-up studies of these children have found that they are at high risk for J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 2 , F E B RU A RY 2 0 0 3
enduring psychiatric, legal, and educational problems (Aman et al., 1996; Handen et al., 1997), further study into effective treatment for them is clearly warranted. REFERENCES Aman MG, Kern RA, McGhee DE, Arnold LE (1993), Fenfluramine and methylphenidate in children with mental retardation and ADHD: clinical and side effects. J Am Acad Child Adolesc Psychiatry 32:851–859 Aman MG, Kern RA, Osborne P, Tumuluru R, Rojahn J, del Medico V (1997), Fenfluramine and methylphenidate in children with mental retardation and borderline IQ: clinical effects. Am J Ment Retard 101:521–534 Aman MG, Marks RE, Turbott SH, Wilsher CP, Merry SN (1991), Clinical effects of methylphenidate and thioridazine in intellectually subaverage children. J Am Acad Child Adolesc Psychiatry 30:246–256 Aman MG, Pejeau C, Osborne P, Rojahn J, Handen B (1996), Four-year followup of children with low intelligence and ADHD. Res Dev Disabil 17:417–432 American Psychiatric Association (1987), Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSM-III-R). Washington, DC: American Psychiatric Association American Psychiatric Association (1994), Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Washington, DC: American Psychiatric Association Biederman J, Faraone SV, Weber W, Russell RL, Rater M, Park K (1997), Correspondence between DSM-III-R and DSM-IV attention-deficit/ hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 36:1682–1687 Conners CK (1989), Conners’ Rating Scales Manual. North Tonawanda, NY: Multi-Health Systems Fee VE, Matson JL, Benavidez DA (1994), Attention deficit-hyperactivity disorder among mentally retarded children. Res Dev Disabil 15:67–79 Feldman H, Crumrine P, Handen BL, Alvin R, Teodori J (1989), Methylphenidate in children with seizures and attention-deficit disorder. Am J Dis Child 143:1081–1086 Gadow KD (1985), Prevalence and efficacy of stimulant drug use with mentally retarded children and youth. Psychopharmacol Bull 21:291–303 Gadow KD, Poling AG (1988), Pharmacotherapy and Mental Retardation. Boston: Little, Brown Gan J, Cantwell DP (1982), Dosage effects of methylphenidate on paired associate learning: positive/negative placebo responders. J Am Acad Child Psychiatry 21:237–242 Gould MS, Wunsch-Hitzig R, Dohrenwend B (1981), Estimating the prevalence of childhood psychopathology: a critical review. J Am Acad Child Psychiatry 20:462–476 Hagerman RJ, Murphy MA, Wittenberger MD (1988), A controlled trial of stimulant medication in children with the fragile X syndrome. Am J Med Genet 30:377–393 Handen BL, Breaux AM, Gosling A, Ploof DL, Feldman H (1990), Efficacy of methylphenidate among mentally retarded children with attention deficit hyperactivity disorder. Pediatrics 86:922–930 Handen BL, Breaux AM, Janosky J, McAuliffe S, Feldman H, Gosling A (1992), Effects and noneffects of methylphenidate in children with mental retardation and ADHD. J Am Acad Child Adolesc Psychiatry 31:455–461 Handen BL, Feldman H, Gosling A, Breaux AM, McAuliffe S (1991), Adverse side effects of methylphenidate among mentally retarded children with ADHD. J Am Acad Child Adolesc Psychiatry 30:241–245 Handen BL, Feldman HM, Lurier A, Murray PJH (1999), Efficacy of methylphenidate among preschool children with developmental disabilities and ADHD. J Am Acad Child Adolesc Psychiatry 38:805–812 Handen BL, Janosky J, McAuliffe S (1997), Long-term follow-up of children with mental retardation/borderline intellectual functioning and ADHD. J Abnorm Child Psychol 25:287–295 Handen BL, Janosky J, McAuliffe S, Breaux AM, Feldman H (1994), Prediction of response to methylphenidate among children with ADHD and mental retardation. J Am Acad Child Adolesc Psychiatry 33:1185–1193 Hollingshead AB (1975), Four Factor Index of Social Status. New Haven, CT: Yale University Department of Sociology
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Jensen PS, Hinshaw SP, Kraemer HC et al. (2001), ADHD comorbidity findings from the MTA study: comparing comorbid subgroups. J Am Acad Child Adolesc Psychiatry 40:147–158 Marshburn EC, Aman MG (1992), Factor validity and norms for the Aberrant Behavior Checklist in a community sample of children with mental retardation. J Autism Dev Disord 22:357–373 MTA Cooperative Group (1999), A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder: the MTA Cooperative Group Multimodal Treatment Study of Children With ADHD. Arch Gen Psychiatry 56:1073–1086 Payton JB, Burkhart JE, Hersen M, Helsel WJ (1989), Treatment of ADDH in mentally retarded children: a preliminary study. J Am Acad Child Adolesc Psychiatry 28:761–767 Pearson DA, Lachar D, Loveland KA et al. (2000), Patterns of behavioral adjustment and maladjustment in mental retardation: a comparison of children with and without ADHD. Am J Ment Retard 105:236–251 Pearson DA, Santos CW, Roache JD et al. (1996a), Effects of methylphenidate on behavioral adjustment in children with mental retardation and ADHD: preliminary findings from a study in progress. J Dev Phys Disabil 8:313–333 Pearson DA, Yaffee LS, Loveland KA, Lewis KR (1996b), A comparison of sustained and selective attention in children who have mental retardation with and without attention deficit hyperactivity disorder. Am J Ment Retard 100:592–607 Pelham WE, Walker JL, Sturges J, Hoza J (1989), Comparative effects of methylphenidate on ADD girls and ADD boys. J Am Acad Child Adolesc Psychiatry 28:773–776 Physician’s Desk Reference (1991), Oradell, NJ: Medical Economics Company Power TJ, Blum NJ, Jones SM, Kaplan PE (1997), Brief report: response of methylphenidate in two children with Williams syndrome. J Autism Dev Disord 27:79–87 Quay HC, Peterson DR (1987), Manual for the Revised Behavior Problem Checklist. Available from HC Quay, Box 240074, U Miami, Coral Gables, FL 33124
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Rapport MD, Stoner G, DuPaul GJ, Birmingham BK, Tucker S (1985), Methylphenidate in hyperactive children: differential effects of dose on academic, learning, and social behavior. J Abnorm Child Psychol 13:227–244 Reich W, Welner Z, Herjanic B (1991), Diagnostic Interview for Children and Adolescents-Revised. North Tonawanda, NY: Multi-Health Systems Sleator EK, Sprague RL (1978), Pediatric psychopharmacology. In: Principles of Psychopharmacology, 2nd ed, Clark WG, del Giudice J, eds. New York: Academic Press, pp 573–591 Solanto MV, Conners CK (1982), A dose-response and time-action analysis of autonomic and behavioral effects of methylphenidate in attention deficit disorder with hyperactivity. Psychophysiology 19:658–667 Sprague RL, Sleator EK (1977), Methylphenidate in hyperkinetic children: differences in dose effects in learning in social behavior. Science 198:1274–1276 Thorndike RL, Hagen EP, Sattler JM (1986), Guide for Administering and Scoring the Stanford-Binet Intelligence Scale, 4th ed. Chicago: Riverside Publishing Ullmann RK, Sleator EK (1985), Attention deficit disorder children with or without hyperactivity: which behaviors are helped by stimulants? Clin Pediatr (Phila) 24:547–551 Ullmann RK, Sleator EK, Sprague RL (1985), Introduction to the use of the ACTeRS Psychopharmacol Bull 21:915–920 Varley CK, Trupin EW (1982), Double-blind administration of methylphenidate to mentally retarded children with attention deficit disorder: a preliminary study. Am J Ment Defic 86:560–566 Wagenarr WA (1969), Note on the construction of digram-balanced Latin squares. Psychol Bull 72:384–386 Wirt RD, Lachar D, Klinedinst JK, Seat D (1984), Multidimensional Description of Child Personality: A Manual for the Personality Inventory for Children, revised. Los Angeles: Western Psychological Services Wolraich ML, Hannah JN, Pinnock TY, Baumgaertel A, Brown J (1996), Comparison of diagnostic criteria for attention-deficit hyperactivity disorder in a county-wide sample. J Am Acad Child Adolesc Psychiatry 35:319–324
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ABSTRACT Objective: The effects of stimulant medication treatment were investigated in children with mental retardation (MR) and attention-deficit/hyperactivity disorder (ADHD). Method: Parent and teacher behavioral ratings and reports of side effects were obtained for children (N = 24, mean age = 10.9 years, SD = 2.4) during a placebo-controlled, double-blind, crossover treatment trial with 0.15 mg/kg, 0.30 mg/kg, and 0.60 mg/kg b.i.d. dosages of methylphenidate. Results: The most significant improvements occurred at the 0.60 mg/kg methylphenidate dose for teacher ratings of inattention (p = .024), hyperactivity (p < .001), aggression (p < .001), and asocial behavior (p = .009). No significant improvements, relative to placebo, occurred at the 0.15 mg/kg dosage. Of interest, nearly all significant medication-related behavioral improvements were detected by teachers. However, parents were sensitive raters of side effects, noting more sleeping problems and loss of appetite at the 0.60 mg/kg dose compared with placebo. Conclusions: These results suggest that symptoms of ADHD can be treated successfully in children with ADHD/MR, and consistent with MTA study results, higher doses were most effective. Furthermore, these improvements were not accompanied by increases in symptoms such as staring, social withdrawal, or anxiety. J. Am. Acad. Child Adolesc. Psychiatry, 2003, 42(2):209–216. Key Words: methylphenidate, mental retardation, attention-deficit/hyperactivity disorder, behavior.
Attention-deficit/hyperactivity disorder (ADHD) (DSMIII-R, DSM-IV: 314.01) (American Psychiatric Association, 1987, 1994), the most commonly diagnosed behavioral disturbance of childhood, is characterized by symptoms of inattention, hyperactivity, and impulsivity. Findings from the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/ Accepted September 11, 2002. From the Department of Psychiatry, University of Texas Medical School at Houston (Pearson, Santos, Loveland, Lachar, Faria, Cleveland); Department of Psychology, Rice University, Houston (Lane); Department of Psychiatry, UT-San Antonio (Roache); and Carolinas HealthCare System, Charlotte, NC (Casat). Drs. Pearson, Santos, and Lachar are also with the University of Texas Harris County Psychiatric Center. This research was supported by NIMH grant R29 MH48212. The authors thank the parents, teachers, and children who participated in this study. The authors are indebted to John E. Overall, Ph.D., who provided additional statistical consultation. Correspondence to Dr. Pearson, Department of Psychiatry, University of Texas Medical School at Houston, 1300 Moursund, Houston, TX 77030-3497, e-mail: [email protected]. 0890-8567/03/4202–0209䉷2003 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.CHI.0000037009.34553.36
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Hyperactivity Disorder (MTA) suggest that school-age children with ADHD (with IQs of 80+) who received higher and more frequent doses of stimulant medication had generally better outcomes than those treated with lower and less frequent doses (Jensen et al., 2001; MTA Cooperative Group, 1999). Although findings such as these suggest that higher doses of carefully monitored stimulant treatment are associated with better outcomes with regard to ADHD symptomatology, others (e.g., Gan and Cantwell, 1982; Sprague and Sleator, 1977) have noted a curvilinear response to stimulant medication, such that lower doses of stimulants produced initial improvements relative to placebo, followed by declines in performance at higher doses. Until recently, few studies had investigated either the nature of ADHD in mental retardation (MR) or the response of these children to stimulants. Indeed, subaverage intelligence (i.e., IQ ≤ 80) has often been an exclusion criterion in these treatment studies (Gadow and Poling, 1988). Fortunately, in recent years, studies have appeared suggesting that ADHD is manifested in mild to moderate MR 209
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in a similar way as it is in children without MR (e.g., Aman et al., 1996; Fee et al., 1994; Pearson et al., 1996b, 2000) and that these children show behavioral improvements with stimulant treatment (e.g., Aman et al., 1991, 1993, 1997; Hagerman et al., 1988; Handen et al., 1990, 1992, 1994; Payton et al., 1989; Varley and Trupin, 1982). However, several investigators have noted a more variable or idiosyncratic response to methylphenidate (MPH) in children with ADHD and MR (ADHD/MR), particularly lower-functioning children (Handen et al., 1991) or children whose MR was associated with genetic syndromes (Hagerman et al., 1988; Power et al., 1997). Of particular concern are reports suggesting that children with ADHD/MR may be more prone to experiencing serious side effects of MPH such as staring spells and social withdrawal (e.g., Feldman et al., 1989; Handen et al., 1991). This apparent sensitivity to MPH in children with ADHD/MR has also been noted by Aman et al. (1991, 1993), using only a single morning dose of MPH (0.4 mg/kg). Given that children with MR are often heavily medicated (Gadow, 1985), these studies suggest that there is a significant risk that children with ADHD/MR will be overmedicated, relative to a dose that would lead to optimal functioning. Given the potential for increased stimulant side effects in children with MR, the purpose of this study was to determine whether low doses of MPH (which might have a lower risk of side effects) could produce significant improvements in ADHD symptomatology. Most studies of stimulant treatment in ADHD/MR have used doses in the 0.30–0.60 mg/kg (typically b.i.d.) range. In this study, we assessed parent and teacher ratings of treatment response in children with ADHD/MR to placebo and to MPH 0.15 mg/kg, 0.30 mg/kg, and 0.60 mg/kg b.i.d. A second aim of this study was to assess whether medication treatment response followed a linear pattern (i.e., successively higher doses producing increasingly better behavior) or a curvilinear pattern (i.e., initial improvement at lower doses, followed by declines at higher doses). We hypothesized that ADHD symptomatology would decrease in a linear fashion with ascending doses but that children would also experience significantly more side effects at successively higher doses. METHOD PARTICIPANTS Twenty-four children with ADHD/MR (18 boys and 6 girls) participated in this study. The mean chronological age of these children was 10.9 years (SD = 2.4), the mean IQ (Stanford-Binet, 4th edition)
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(Thorndike et al., 1986) was 56.5 (SD = 10.24), and the mean mental age (estimated using the Stanford-Binet) was 5.7 years (SD = 1.2). Seventeen children had mild (50+) MR; seven had moderate MR. The ethnic breakdown of these children was as follows: 9 white, 14 African American, and 1 Hispanic. The mean Hollingshead fourfactor social class for this sample was 3.39 (SD = 1.16) (Hollingshead, 1975). The mean education level was 12.35 (SD = 2.6) years for mothers and 12.24 (SD = 2.7) years for fathers. Participants met DSM-III-R criteria for ADHD (as determined by parent interview, using the Diagnostic Interview for Children and Adolescents-Revised [DICA-R]) (Reich et al., 1991); they did not meet criteria for any other DSM-III-R diagnoses. Data collection began in 1993 (i.e., before DSM-IV) and continued for nearly 7 years; 1,328 children were screened during this time, in search of children with ADHD/MR who did not have comorbid psychiatric conditions. We retained the DSM-III-R structured interview for consistency with previously collected data but also used the strategy of Biederman et al. (1997) of collecting sufficient information (e.g., behavioral questionnaires, parent interviews) to allow for both DSM-III-R and DSMIV diagnoses. All patient files were reviewed independently by two licensed psychologists (D.A.P. and K.A.L.), and one child and adolescent psychiatrist (C.W.S.) to confirm each child’s relevant DSMIV ADHD subtype. This process allowed us to determine, with 100% interrater reliability, that 22 children met DSM-IV criteria for ADHD, combined type, and two for ADHD, predominantly inattentive type. To further assess severity of ADHD symptoms, the children were assessed with the Parent and Teacher versions of the Conners Abbreviated Symptom Questionnaire (CASQ), sometimes called the Hyperactivity Index (Conners, 1989). The mean Parent CASQ score for this group was 20.9 (mean T score = 84.3), and the mean Teacher CASQ score for this group was 20.0 (mean T score = 77.0). All of the children participating in this study had familial MR; no other etiologies of MR (e.g., Down syndrome, fragile X) were identified (by reviewing medical and school records, parent interview, and physician assessment of phenotype during the physical examination done prior to entry into the medication trial). All were communitybased and lived at home; they were recruited from special education classrooms of a large metropolitan public school district. Exclusion criteria included psychosis, autistic behaviors, and mood disorders (these conditions were ruled out with the DICA-R). No children were taking psychotropic medication at their entry into this study; however, four had taken MPH, one had taken pemoline, and one had taken dextroamphetamine prior to study entry. Previous medication was discontinued at least 1 week prior to entry into the medication trial. It should be noted that some data from 13 of these participants were discussed in a preliminary report from this project (Pearson et al., 1996a). DESIGN The effectiveness of the various dosages of MPH (placebo, 0.15 mg/kg, 0.30 mg/kg, 0.60 mg/kg b.i.d.) in children with ADHD/MR was investigated using a within-subject, crossover, placebo-controlled design. The order of dosage administration was counterbalanced across subjects using a digram-balanced Latin squares procedure which controls for both order and sequence Wagenarr (1969). Prior to the start of the drug trials, all participants were given a single-blind week of placebo baseline (the staff was unblinded); this period served as a time during which the pill-taking regimen could be firmly established at home and at school. During the actual medication trial period, each child received 1 week each of placebo (cornstarch), MPH 0.15 mg/kg, MPH 0.3 mg/kg, and MPH 0.6 mg/kg; medication was given before breakfast and at lunchtime. MPH was prepared by crushing and blending white generic MPH tablets with cornstarch and filling two opaque,
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size 1 gelatin capsules. The study director, physician, research assistants, teachers, parents, and children were all blind with respect to dosages given during the drug trial; the study pharmacologist (J.D.R.)— who had no patient contact—ran the double-blind. PROCEDURE Participants were recruited to the medication treatment trial after completing a comprehensive assessment that included a standardized neuropsychological test battery (including Stanford-Binet) and psychiatric interview (Pearson et al., 1996a). Potential participants were given a physical examination by the study physician (C.W.S.) to confirm medical eligibility to take MPH. The children were seen at the end of the placebo baseline week and at the end of each week of the drug trial for both a medication check with the study physician and an interview with the study psychologist (D.A.P.). Parents completed behavioral questionnaires each week (i.e., for each dosage) and were urged to base their ratings on weekend behaviors (when they would have seen their children under the influence of the medication). Parents also completed a medication side effects questionnaire each week, which addressed common side effects associated with MPH treatment (Physician’s Desk Reference, 1991). In addition to the symptoms listed in the checklist, there was also an open-ended question at the end of the questionnaire about “other atypical behaviors that you may have noticed this week.” Behavioral questionnaires and medication side effects questionnaires were also collected from the teachers each week.
Revised Behavior Problem Checklist. The Revised Behavior Problem Checklist (RBPC) (Quay and Peterson, 1987) includes six subscales: Conduct Disorder, Socialized Aggression, Attention ProblemsImmaturity, Anxiety-Withdrawal, Psychotic Behavior, and Motor Tension-Excess. It has been shown to be sensitive to MPH in children with ADHD in the general school-age population (Pelham et al., 1989) and in children with ADHD/MR (Aman et al., 1993, 1997). Personality Inventory for Children-Revised. The Personality Inventory for Children-Revised (PIC-R) (Wirt et al., 1984) is a 280-item multidimensional measure of child behavior, affect, and ability. There are 12 clinical subscales on the PIC-R, including Hyperactivity and Delinquency, which were used in this investigation. COMPLIANCE Compliance with the study medication regimen was assessed by having the parents and the school nurse each complete a dose administration form, documenting the date and time that each dose was dispensed. Parents were also asked about any missed or late doses during their weekly clinic interview (with D.A.P.); teachers were also queried by the research assistant during the weekly school visit. The number of pills remaining in the returned home and school bottles was counted and verified against the parent and teacher dose administration forms. If any discrepancy was found, the parent or teacher was asked for additional information.
INSTRUMENTS
RESULTS
Teacher Questionnaires
The data were analyzed using SPSS-PC (version 10.0) repeated-measures one-way analysis of variance (ANOVA) procedures, with MPH dosage as the within-subjects variable. Because preliminary analyses revealed no significant effects of gender or dose order, these factors were dropped from subsequent analyses. For significant effects, post hoc Student-Newman-Keuls analyses were performed to determine which doses of medication were significantly different from one another (p ≤ .05). Because the purpose of these analyses was to detect treatment-related reductions in absolute levels of symptomatology, only the raw scores from teacher and parent indices are presented (e.g., Aman et al., 1993). The teacher behavioral ratings are summarized in Table 1; parent behavioral ratings are summarized in Table 2.
ADD-H Comprehensive Teacher Rating Scale. The ADD-H Comprehensive Teacher Rating Scale (ACTeRs) (Ullmann et al., 1985) contains subscales measuring attention, hyperactivity, social skills, and oppositional behavior. Unlike all other behavior questionnaire subscales reported in this investigation, higher scores on the Attention and Social Skills subscales of the ACTeRS are indicative of better symptomatology. The ACTeRS has been found to be sensitive to stimulant effects in the general school-age population (Ullmann and Sleator, 1985) and in children with ADHD/MR (Hagerman et al., 1988). Conners Teacher Rating Scale. The Conners Teacher Rating Scale (CTRS) (Conners, 1989) includes seven subscales: Hyperactivity, Conduct Problem, Emotional-Overindulgent, Anxious-Passive, Asocial, Daydream-Attention Problem, and the Hyperactivity Index. The CTRS has been found to be sensitive to MPH response in children with ADHD in the general school-age population (e.g., Sprague and Sleator, 1977) and in children with ADHD/MR (e.g., Aman et al., 1993, 1997; Handen et al., 1992). Parent Questionnaires Conners Parent Rating Scale. The Conners Parent Rating Scale (CPRS; 48-item revision) (Conners, 1989) includes six subscales: Conduct Problem, Learning Problem, Psychosomatic, ImpulsiveHyperactive, Anxiety, and the Hyperactivity Index. The CPRS has been found to be sensitive to MPH in children with ADHD in the general school-age population (e.g., Solanto and Conners, 1982), as well as in children with ADHD/MR (Varley and Trupin, 1982). Aberrant Behavior Checklist. The Aberrant Behavior Checklist (ABC; Community version) (Marshburn and Aman, 1992), specifically developed for individuals with MR, includes subscales measuring Irritability, Lethargy, Stereotypic Behavior, Hyperactivity, and Inappropriate Speech. The ABC has been shown to be sensitive to MPH in children with ADHD/MR (e.g., Aman et al., 1993).
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Teacher Behavioral Ratings
Significant declines in ADHD symptomatology with MPH treatment were found with both scales. Symptoms of inattention declined steadily with ascending MPH doses (ACTeRS: p = .024; CTRS: p = .022), as did symptoms of hyperactivity (ACTeRS: p < .001; CTRS: p < .001). There was a similar decline in oppositional behavior (p = .012) and conduct problems (p < .001). These decreases in aggressive symptoms were accompanied by decreases in asocial behaviors (p = .009), although this decrease was 211
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TABLE 1 Effects of Methylphenidate on Teacher Behavioral Ratings Variable ACTeRS Attention Hyperactivity Social Skills Oppositional CTRS Hyperactivity Conduct Problem Emotional Overindulgent Anxious-Passive Asocial Daydream-Attention Hyperactivity Index
Placebo
0.15 mg/kg (Low)
0.30 mg/kg 0.60 mg/kg (Medium) (High)
15.88 17.67 21.63 13.08
16.46 15.83 22.96 12.25
18.54 13.79 23.17 11.25
19.75 11.08 24.42 9.17
3.35 7.83 1.79 3.93
.024 <.001 .157 .012
P:H P:M, P:H, L:H
26.75 12.42 8.42 6.42 3.63 3.88 16.29
22.75 11.00 7.29 6.00 3.42 3.17 14.08
19.25 9.21 6.67 6.17 3.17 2.92 11.92
10.75 3.96 4.04 4.88 1.67 2.17 6.58
13.53 8.74 4.57 1.51 4.13 3.42 12.89
<.001 <.001 .006 .221 .009 .022 <.001
P:M, P:H, L:H, M:H P:H, L:H, M:H P:H, L:H, M:H
F3,69
Source of Significance
pa
P:H, L:H
P:H, L:H, M:H P:H P:M, P:H, L:H, M:H
Note: ACTeRS = ADD-H Comprehensive Teacher Rating Scale; CTRS = Conners Teacher Rating Scale. Values in boldface type are significant.
a
not accompanied by significant gains in social skills (p = .15), at least not within the short timeframe of this study. Teachers noted no increases in symptoms of anxiety with MPH treatment (p = .22); indeed their ratings of anxiety were actually lowest at the highest MPH dose.
Post hoc Student-Newman-Keuls analyses revealed that without exception, the most consistent and effective reductions in inattentive, hyperactive, aggressive, and asocial behaviors occurred at the highest (0.60 mg/kg) dose. No significant behavioral improvements were noted
TABLE 2 Effects of Methylphenidate on Parent Behavioral Ratings Variable CPRS Conduct Problem Learning Problem Psychosomatic Impulsive-Hyperactive Anxiety Hyperactivity Index ABC Irritability Lethargy Stereotypic Behavior Hyperactivity Inappropriate Speech RBPC Conduct Disorder Socialized Aggression Attention Problems Anxiety-Withdrawal Psychotic Motor Tension-Excess PIC-R Delinquency Hyperactivity
Placebo
0.15 mg/kg (Low)
0.30 mg/kg (Medium)
0.60 mg/kg (High)
F3,69
pa
6.38 6.92 0.25 5.96 2.25 13.92
5.54 6.46 0.21 5.96 1.75 12.88
4.83 6.46 0.46 5.00 1.79 12.33
5.17 6.17 0.71 4.50 1.71 11.67
1.42 0.68 0.92 3.59 0.83 1.41
.245 .567 .438 .018 .483 .248
9.96 4.42 1.83 18.54 2.71
9.33 4.67 2.17 21.00 2.71
8.42 5.92 2.79 18.33 3.04
9.17 6.46 1.54 16.46 2.79
0.58 1.30 2.01 1.75 0.27
.627 .283 .121 .165 .845
14.29 2.25 12.96 4.04 2.00 3.96
13.13 2.71 12.21 4.33 1.96 4.29
12.71 3.33 12.75 3.75 2.38 3.96
13.75 2.21 13.17 4.38 2.33 3.71
0.25 1.34 0.29 0.32 0.41 0.72
.862 .269 .832 .813 .745 .544
12.33 14.96
12.71 14.67
11.88 14.29
12.79 14.29
0.74 0.42
.530 .738
Source of Significance
P:H, L:H
Note: CPRS = Conners Parent Rating Scale; ABC = Aberrant Behavior Checklist; RBPC = Revised Behavior Problem Checklist; PIC-R = Personality Inventory for Children-Revised. a Value in boldface type is significant.
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between the placebo and the 0.15 mg/kg dose in any of these behaviors, suggesting that the low dose was insufficient to produce a detectable behavioral response. Symptoms of hyperactivity showed significant declines between the placebo and the 0.30 mg/kg dose on both the ACTeRs and CTRS subscales. For the ACTeRS, no further significant improvement in hyperactivity was noted between the 0.30 mg/kg dose and the 0.60 mg/kg dose; but a further significant decline in symptoms of hyperactivity was noted on the CTRS between the medium and high doses. Symptoms of inattention only showed significant improvements (relative to placebo) at the 0.60 mg/kg dosage on both teacher instruments; no improvements were noted between the placebo and the lower two doses. Similarly, the most effective treatment of aggressive symptoms occurred at the highest dose.
parents reported headache at the 0.60 mg/kg dose, and one at the 0.30 mg/kg dose. Compliance
Compliance was quite high, as indicated that overall, fewer than one dose was missed each week. For the placebo condition, the mean number of missed doses (of 14 possible doses) each week was 0.50 (96.4% compliance); for the 0.15 mg/kg MPH condition, it was 0.25 (98.2% compliance); for the 0.30 mg/kg MPH condition, it was 0.63 (95.5% compliance); and for the 0.6 mg/kg condition, it was 0.42 doses per week (97% compliance). No significant differences emerged among these dose conditions (F3,69 = 1.03, p = .39). Furthermore, it was the impression of the study staff that our families were highly responsible with regard to their adherence to the prescribed dosing schedules.
Parent Questionnaires
In contrast to the numerous medication-related declines in behavioral problems reported by teachers, the only parent rating that showed significant treatment-related declines was the CPRS Impulsive-Hyperactive subscale. Consistent with the teacher ratings, the most effective reduction in symptoms was noted at the highest MPH dosage. Also, like the teachers, the parents noted no significant increases in behavioral ratings of anxiety with increasing medication dosage on either the CPRS or the RBPC. Ratings of Side Effects
There were no significant effects of medication dose on any of the teacher reports of side effects. In comparison, parents reported significant increases in loss of appetite (F3,69 = 3.54, p = .02) and sleeping problems (F3,69 = 4.60, p = .005) at higher doses of MPH. Four parents (of 24) reported insomnia at the high dose, relative to none at placebo (p ≤ .05), and seven parents noted significant symptoms of loss of appetite at the 0.60 mg/kg dose, relative to one at placebo (p ≤ .05). No other side effect symptoms showed statistically significant dosage-related changes. Although it is interesting to note that teachers of five children and parents of four children reported staring behaviors at the highest dose, there were no significant dose-related increases in these behaviors because five teachers and three parents had also reported staring in the placebo condition. A review of the open-ended question at the end of the questionnaire revealed that two teachers reported unresponsive, “zombie” like behaviors at the 0.60 mg/kg dose (no such symptoms were reported at lower doses). Three J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 2 , F E B RU A RY 2 0 0 3
DISCUSSION
Our findings of decreases in ADHD symptomatology with MPH treatment in children with ADHD/MR are consistent with those of previous investigations (e.g., Aman et al., 1991, 1993, 1997; Hagerman et al., 1988; Handen et al., 1990, 1992). Our results extend previous findings by confirming that there is little efficacy of a 0.15 mg/kg dose (relative to placebo); they also suggest that MPH treatment produces concomitant declines in aggressive and asocial behaviors in children with ADHD/MR. Unlike the children studied by Handen et al. (1991), our participants did not experience significant increases in serious side effects such as staring, social withdrawal, and anxiety at the 0.6 mg/kg dose. In fact, the 0.6 mg/kg b.i.d. MPH dose produced the maximum treatment benefit, but it was also associated with the typical MPH side effects of insomnia and loss of appetite for some children. Thus our findings of a steady improvement with MPH treatment in the 0.15 to 0.6 mg/kg dose range are consistent with those of the MTA study, with the best behavioral outcome being associated with the highest dose. Limitations
We are sensitive to the fact that our sample was collected using a structured interview geared to DSM-IIIR. This was inevitable, given the protracted recruitment period. Fortunately, as Biederman et al. (1997) have noted, the change from DSM-III-R to DSM-IV results in considerable diagnostic continuity between these classification systems. Given that DSM-IV criteria have actually 213
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been found to identify more children with ADHD than did DSM-III-R criteria (Wolraich et al., 1996) and that our charts were reviewed independently by three licensed mental health professionals, we feel confident that our children meet DSM-IV criteria for ADHD. A second possible limitation might be that only 75% of the sample was stimulant-naïve; i.e., the presence of the children who had previously taken stimulants might have unduly influenced these results. To address this issue, the ANOVAs were rerun after removing the six children who had previously taken stimulants. With one exception, all the subscales that had been significant with the entire sample remained significant (the p value associated with the ACTeRS Oppositional subscale became p = .069). These findings strongly suggest that the children who had previously taken stimulants were not driving the results of this investigation. Another possible limitation of the current study lies in its inherent experimental rigor, i.e., the use of “ADHD simplex” children. We recruited children without comorbid psychiatric diagnoses to avoid potential confounding effects of these comorbid conditions in studying MPH efficacy in children with ADHD/MR. Given that the findings of the MTA study suggest that optimal treatment for children with ADHD may depend on comorbid disorders (Jensen et al. 2001), it will be important for future studies to systematically explore the efficacy of MPH in subgroups of children with ADHD/MR who have comorbid psychiatric conditions (e.g., anxiety). Clinical Implications
The implications of our findings for clinical treatment are that children with mild to moderate MR can benefit from MPH and that the moderate dose of 0.6 mg/kg is well tolerated. These results also suggest that patients who develop unacceptable symptoms such as severe social withdrawal at the 0.6 mg/kg dose can be treated using a 0.3 mg/kg dose. The preliminary report of our in-progress study (Pearson et al., 1996a) did not have sufficient statistical power (given its partial sample size) to detect improvement in the 0.3 mg/kg dose, relative to placebo. However, with the complete sample in place, we were able to detect significant reduction in hyperactivity, but not in inattention, at the 0.3 mg/kg dose (relative to placebo), although further reduction in symptoms is possible at the 0.6 mg/kg dose for children who can tolerate it, given that there is considerable variability in individual responses to MPH (Rapport et al., 1985). 214
These results strongly suggest that if at all possible, titration of MPH treatment in children with ADHD/MR should be conducted when a teacher informant is available. Our findings of greater teacher sensitivity (in comparison to parents) to changes in ADHD symptomatology with MPH treatment has been found both with children with ADHD/MR (e.g., Aman et al., 1991, 1997; Hagerman et al., 1988) and with children with ADHD in the general school-age population (e.g., Sleator and Sprague, 1978). This finding may reflect the fact that teachers have more opportunity to observe the core symptoms of ADHD in a setting in which they would be most problematic. It is also consistent with previous findings that parents and teachers often perceive behavioral adjustment in the same children quite differently, given that the domains of school and home place different demands on children (Gould et al., 1981). Perhaps the most parsimonious explanation for the differences between parent and teacher ratings is that parents had less opportunity to see their children during the medicated state, i.e., the MPH would have worn off by the time the children got home from school, leaving the weekends as their only time to observe medication-related behavioral changes. Although teachers saw the children more in the medicated state, parents were urged to base their behavioral ratings on weekend behavior, when they would observe their child while he or she was in the medicated state. This explanation is also inconsistent with the steady (albeit mostly statistically insignificant) declines in a number of parent subscale ratings of ADHD symptomatology at successively higher MPH doses. Furthermore, parents were sensitive raters of dose-related MPH side effects. Still another possible explanation for this difference is that parents of children with familial ADHD/MR may have been unable to effectively detect and report behavioral changes in their children. This possibility seems unlikely because our parents were sensitive reporters of side effects, were highly compliant with the treatment regimen, had an average educational level of high school graduates, and, on average, functioned on the “skilled craftsmen, clerical, and sales workers” social-class level (Hollingshead, 1975, p. 23). This explanation would also be inconsistent with the fact that the same discrepancy has been found in studies of children with ADHD in the general school-age population (Sleator and Sprague, 1978). Another potential explanation for the discrepancy between parent and teacher ratings may have been the possible insensitivity of our parent measures in this population. This posJ . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 2 , F E B RU A RY 2 0 0 3
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sibility seems unlikely because significant differences emerged on the teacher Conners but not on the parallel parent form of the Conners. To our knowledge, there is only one other double-blind, placebo-controlled crossover study of MPH efficacy in children with ADHD/MR which used both the CPRS and the CTRS as outcome measures (Varley and Trupin, 1982, who reported the 10-item Hyperkinesis Index from both). Using parallel parent- and teacher-completed ABCs, Aman et al. (1997) found the same discrepancy we found in this study using the Conners, although both parent- and teacher-completed ABCs had yielded similar results in an earlier study (Aman et al., 1993). Although it is difficult to compare parent- and teacher-completed versions of a particular scale across different studies, it is interesting to note that only one (25%) in four previous double-blind, placebo-controlled crossover studies of stimulant efficacy in children with ADHD/MR which used the parent Conners found significant differences in ADHD symptomatology between placebo and MPH conditions (Varley and Trupin, 1982), while seven (78%) of nine studies using the teacher Conners found such differences (Aman et al., 1991, 1993, 1997; Feldman et al., 1989; Handen et al., 1990, 1992, 1999; Varley and Trupin, 1982). Although relatively few double-blind, placebo-controlled crossover studies of stimulant efficacy have been done in children with ADHD/MR, the pattern of results generated to date suggests that teacher ratings are often more sensitive to MPH dose-related behavioral changes than are parent ratings. At this point, we are only beginning to understand the role of stimulant treatment in children with ADHD/MR. There is a need to study dose-related changes in cognitive response to MPH in children with ADHD/MR (Pearson et al., manuscript in preparation). There is also a need for more systematic study of medication treatment in children whose MR is caused by common genetic syndromes such as Down syndrome. In addition to studying groups of children with ADHD/MR with different comorbid psychiatric conditions, it will be important to examine possible differences in MPH response among different subtypes of ADHD. The efficacy of the newer long-acting stimulants in children with ADHD/MR has yet to be explored, and they might prove beneficial for children who have a tendency to forget lunchtime dosing. Another obvious avenue for future research in this area is to explore the relative contributions of behavioral and medication treatment factors to the long-term outcome of children with ADHD/MR. Given that long-term follow-up studies of these children have found that they are at high risk for J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 2 : 2 , F E B RU A RY 2 0 0 3
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