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Versus Dexamphetamine in Children With Deficit Hyperactivity Disorder: A Double-blind, Crossover Trial

Daryl Efron, FRACP; Frederick Jarman, FRACP; and Melinda Barker, Grad Dip Ed Psych

ABSTRACT. Objective. To compare methylphenidate behavioral, academic, and social functioning. Many (MPH) and dexamphetamine (DEX) in a sample of chil- well-designed, placebo-controlled studies have dem- dren with attention deficit hyperactivity disorder onstrated beyond doubt the benefits of in (ADHD). the vast majority of children with ADHD.2–4 In a Method. A total of 125 children with ADHD received review of 110 studies on the effects of both MPH (0.3 mg/kg twice daily) and DEX (0.15 mg/kg drugs on more than 4200 children with ADHD, twice daily) for 2 weeks a double-blind, crossover study. 4 ϳ Outcome measures were Conners’ Parent Rating Scale– Barkley found that 75% of subjects were regarded Revised, Conners’ Teacher Rating Scale–Revised, a Par- as improved on stimulants. The mean placebo re- ent Global Perceptions questionnaire, the Continuous sponse was 39%. Performance Test, and the Barkley Rating Methylphenidate (MPH) and dexamphetamine Scale. (DEX) are the two stimulants prescribed most fre- Results. There were significant group mean im- quently and have been shown to have similar types provements from baseline score on all measures for of positive effects in children with ADHD. However, both stimulants. On the Conners’ Teacher Rating Scal- it is not known whether one is more efficacious than e–Revised, response was greater on MPH than DEX on the other in terms of probability of producing a the conduct problems and hyperactivity factors, as well positive response, magnitude of response, quality of as on the hyperactivity index. On the Conners’ Parent Rating Scale–Revised, was the only factor to improved performance, or side-effect profile. Some differ significantly, in favor of MPH. Parents rated authors suggest that the two stimulants are equally 5 73% of subjects as globally improved on MPH and 69% effective or that “there is little to choose between improved on DEX, compared with baseline. Overall, them,”6 whereas a number of clinicians have the 46% of parents chose MPH as the preferred drug, com- impression that MPH is the more efficacious of the pared with 37% who chose DEX. On the Continuous two and has fewer associated adverse effects. MPH is Performance Test, there was no difference in the num- often designated the drug of first choice in psycho- ber of correct responses or errors between the two pharmacology texts, despite the absence of support- drugs. ing evidence.7 Conclusions. Most children with ADHD improve Clinical experience suggests that although most significantly on both MPH and DEX. There was a slight advantage to MPH on most measures. Pediatrics children respond equally well to either of these 1997;100(6). URL: http://www.pediatrics.org/cgi/ stimulants, a subgroup of children seem to re- content/full/100/6/e6; attention deficit hyperactivity spond better to one than the other. However, there disorder, stimulant medication, methylphenidate, dex- has been surprising little research published exam- . ining the question of relative efficacy and toxicity of the two most commonly used drugs in child- ABBREVIATIONS. ADHD, attention deficit hyperactivity disor- hood behavior disturbance. No advantage to either der; MPH, methylphenidate; DEX, dexamphetamine; DSM–IV, drug has been demonstrated to date in the sparse Diagnostic and Statistical Manual of Mental Disorders, 4th ed; literature directly comparing MPH with DEX. CBCL, Child Behavior Checklist; TRF, Teacher Report Form; Hence, the choice of drug is often made on the CPRS–R, Conners’ Parent Rating Scale–Revised; CTRS–R, Con- basis of previous anecdotal experience, trial and ners’ Teacher Rating Scale–Revised; CPT, Continuous Perfor- mance Test; SERS, rating scale. error, and/or cost. In the present study, we set out to compare systematically MPH and DEX in a sam- ple of children with ADHD. timulant medication is the most effective treat- ment for children with attention deficit hyper- METHODS activity disorder (ADHD).1,2 Stimulants have S Subjects been shown to induce short-term enhancement of Subjects were selected from ambulatory patients referred to the Royal Children’s Hospital, Melbourne, Australia, for an assess- From the Centre for Community Child Health and Ambulatory Paediatrics, ment for possible ADHD. Referral sources included pediatricians, Royal Children’s Hospital, Melbourne, Australia. family practitioners, school nurses, and psychologists. In addition, Received for publication May 1, 1997; accepted Jul 14, 1997. many parents self-referred by calling the hospital, usually at the Reprint requests to (D.E.) Centre for Community Child Health and Ambu- suggestion of a relative, friend, the child’s teacher, or the state latory Paediatrics, Royal Children’s Hospital, Flemington Rd, Parkville, ADHD parent support group. Victoria, 3052, Australia. Criteria for enrollment in the trial were 1) age between 5 and 15 PEDIATRICS (ISSN 0031 4005). Copyright © 1997 by the American Acad- years; 2) satisfy Diagnostic and Statistical Manual of Mental Dis- emy of Pediatrics. orders, 4th ed (DSM–IV) criteria for ADHD.8 The DuPaul ADHD http://www.pediatrics.org/cgi/content/full/100/6/Downloaded from www.aappublications.org/newse6PEDIATRICS by guest on October Vol. 2, 1002021 No. 6 December 1997 1of7 rating scale9 a was used in which each DSM–IV ADHD symptom number of commission errors (false alarms) is thought to reflect was marked on a four-point scale: “never or rarely,” “sometimes,” the degree of . “often,” or “very often”; only symptoms rated often or very often Subjects attempted the CPT at baseline and again on the final were considered present and counted toward the diagnosis; 3) T day of each medication cycle, 1 to 2 hours after ingestion of their score of at least 1.5 SD units above the mean on the attention morning dose (ie, at a time coinciding with peak behavioral problems scale of the Child Behavior Checklist (CBCL)10 or effects). Teacher Report Form (TRF)11; 4) no history of intellectual disabil- Side effects were evaluated using the Barkley Side Effects Rat- ity, gross neurologic abnormality, or Tourette’s syndrome; and 5) ing Scale (SERS). This questionnaire assesses the frequency and decision made to undertake stimulant medication trial on clinical severity of 17 common side effects of stimulants, rated on a scale grounds. from 0 (absent) to 9 (severe).9 Because children with ADHD often display some of these apparent side effects before receiving med- Procedure ication, this questionnaire was also administered at baseline, so This study used a double-blind, crossover design. Subjects were that true medication effects were able to be measured. IQ was estimated using a short form of the Wechsler Intelli- randomized to receive either DEX or MPH for the first 2 weeks of 14 the study. After a 24-hour washout period, they were crossed over gence Scale for Children, 3rd ed, comprising two verbal (simi- to receive the other stimulant for the 3rd and 4th weeks. Each drug larities and vocabulary) and two performance (block design and was administered twice a day, after breakfast and after lunch, at a object assembly) scale subtests. standardized dose. The dose was 0.15 mg/kg/dose for DEX and 0.3 mg/kg/dose for MPH, rounded off to the nearest size. Data Analysis Both drugs were presented in identical form, as a crushed powder The methods used to analyze the CPRS–R and CTRS–R were in opaque gelatin capsules (2.5 mg for DEX and 5 mg for MPH). identical. Data were analyzed by factor. The principal measure The investigators, families, subjects, and teachers were blind to the used was the difference in T score from baseline to the end of the randomization order throughout the study period. The study treatment period (ie, baseline T score Ϫ treatment T score). protocol was approved by the Ethics in Human Research Com- Initially within-subject analysis of variance (ANOVA) for re- mittee of the Royal Children’s Hospital, and written informed peated measures was computed for the means of all factors (ie, consent was obtained from parents. comparison of scores at three trial conditions: baseline, DEX, and MPH). Because all F values were significant, planned comparisons Measures were conducted to define differences, using paired-samples t tests The following four principle measures of response to stimulant (Table 1). T medication were used in this study. The change in score for each factor was then submitted to the Hills and Armitage analysis for data from crossover trials.15 Data 12 were first tested for period effects and treatment-by-period inter- Conners’ Parent Rating Scale–Revised (CPRS–R) action effects, and finally the magnitudes of the effects of the two This 48-item questionnaire yields five factors: conduct prob- interventions were compared. lems, learning problems, psychosomatic, impulsive–hyperactive, Subjects were then classified into responders and nonre- and anxiety. In addition, a composite hyperactivity index has been sponders to each stimulant. This enabled a categorical analysis of derived from the 10 items with the highest loading from the factor response, using the same three measures. On the CPRS–R and scales. Each item is rated on a four-point scale (not at all ϭ 0, just CTRS–R, subjects were grouped according to the change in hyper- a little ϭ 1, pretty much ϭ 2, and very much ϭ 3). Raw scores for activity index T score from the baseline score. The cutoff point was each factor are transformed by age and sex into T scores, with a chosen so as to classify response in a meaningful way, both mean of 50 and an SD of 10. The CPRS–R was completed by clinically and statistically. Subjects whose T score decreased by parents at baseline and at the completion of each trial period. Ն10 points (1 SD) were classified as responders. All others were classified as nonresponders. On the Parent Global Perceptions Conners’ Teacher Rating Scale–Revised (CTRS–R)12 questionnaire, subjects rated “better” or “much better” at the This 28-item questionnaire complements the CPRS–R, and scor- completion of a cycle were classified as responders to that medi- ing is identical. It was completed at the same time as the CPRS–R. cation, and those rated “about the same,” “worse,” or “much The CTRS–R has the following three factors: conduct problem, worse” were classified as nonresponders. hyperactivity, and inattentive–passive. A hyperactivity index has A number of child and family variables were analyzed for their again been derived from the 10 highest loading. hypothesized association with response to each stimulant. The degrees of change from baseline in CPRS–R and CTRS–R factor T Parental Global Perceptions Questionnaire scores on each stimulant were used as the outcome measures for evaluation of predictors. Pearson product moment correlations Parents of study subjects were asked to rate their child in were calculated to examine the following continuous variables: comparison with his/her usual self at the completion of each age, gender, deviation IQ, self-perception, parent-rated behavior medication cycle. Two attributes, activity and concentration, as (CBCL), teacher-rated behavior (TRF), socioeconomic status, fam- well as overall perceptions each were rated on a five-point scale. ily functioning, and maternal mental health. The following cate- At the completion of both study cycles (before unblinding), par- gorical variables were examined as predictors using independent ents were asked which medication they thought was the most samples t tests: aggressive–delinquent behavior (CBCL T score helpful, taking everything into account. Ն67 on both aggressive behavior and delinquent behavior syn- drome scales), anxiety–depression (CBCL T score Ն67 on anx- Continuous Performance Test (CPT)13 ious/depressed syndrome scale), learning disability (reading), The CPT is a computerized test of sustained attention and and DSM–IV category. Because multiple analyses were conducted, impulsivity. In this study, we used the A–X paradigm. This is a a variable was not considered a predictor unless the P value of the Ͻ successive discrimination task, in which the subject responds to a correlation coefficient or t test score was .01. designated target only when it occurs after a specified warning signal. The target stimulus was an “X,” and the warning signal RESULTS was an “A.” Single letters were randomly displayed in the center Sample Characteristic of a monitor for 500 msec, with an interstimulus interval of 1500 msec. A 10-minute task was used, during which there were 60 A total of 125 subjects (114 boys and 11 girls) met targets within 300 presentations. The number of omission errors the inclusion criteria and were enrolled in the trial (missed targets) is thought to be a measure of inattention, and the between April 1995 and August 1996. Age ranged from 60 months to 179 months, with a mean age overall of 104.8 months (SD ϭ 27.6 months). Mean a Reference 9 contains the previous version of the rating scale based on DSM–III–R. The updated version used in this study was based on DSM–IV age for boys was 105 months, and for girls 102.4 and has not yet been formally published. It was provided in Russell months. Barkley’s lecture notes, September 1995. All subjects satisfied DSM–IV diagnostic criteria

2of7 STIMULANTS INDownloaded ATTENTION from www.aappublications.org/news DEFICIT HYPERACTIVITY by guest DISORDER on October 2, 2021 TABLE 1. Comparisons of T scores on CPRS-R and CTRS-R Factors at Three Conditions: Baseline, DEX, and MPH Mean T Score (SD) ANOVA Paired t Tests Baseline DEX MPH F (df) P Baseline–DEX Baseline–MPH Mean Difference P Mean Difference P (95% CI) (95% CI) CPRS-R Conduct problems 74.12 62.39 60.66 60.51 Ͻ.001 11.49 Ͻ.001 13.63 Ͻ.001 (16.91) (16.80) (14.93) (2,120) (8.84,14.14) (10.96,16.30) Learning problems 89.09 69.16 68.79 152.42 Ͻ.001 19.80 Ͻ.001 20.23 Ͻ.001 (10.28) (15.65) (15.09) (2,120) (16.87,22.73) (17.62,22.83) Psychosomatic 61.19 55.94 53.86 7.49 .001 4.81 .007 7.25 Ͻ.001 (19.31) (16.01) (15.33) (2,120) (1.31,8.31) (3.76,10.74) Impulsive–hyperactive 73.46 57.33 57.39 152.46 Ͻ.001 16.03 Ͻ.001 16.00 Ͻ.001 (9.85) (11.22) (10.53) (2,120) (13.91,18.15) (13.80,18.20) Anxiety 55.56 48.67 47.77 48.34 Ͻ.001 6.67 Ͻ.001 7.58 Ͻ.001 (12.6) (10.08) (9.59) (2,120) (5.05,8.28) (6.07,9.09) Hyperactivity index 84.63 64.89 64.28 192.92 Ͻ.001 19.55 Ͻ.001 20.30 Ͻ.001 (10.19) (13.74) (13.46) (2,120) (17.02,22.09) (17.78,22.81) CTRS-R Conduct problems 69.31 58.39 55.16 57.88 Ͻ.001 10.94 Ͻ.001 14.52 Ͻ.001 (16.43) (13.69) (11.99) (2,116) (8.18,13.71) (11.93,17.10) Hyperactivity 71.26 58.88 56.20 105.73 Ͻ.001 12.41 Ͻ.001 15.29 Ͻ.001 (13.24) (11.08) (11.02) (2,116) (10.27,14.54) (13.14,17.43) Inattentive–passive 64.87 55.69 54.09 102.46 Ͻ.001 9.21 Ͻ.001 10.58 Ͻ.001 (8.80) (8.90) (7.61) (2,116) (7.60,10.81) (9.10,12.06) Hyperactivity index 71.46 58.76 56.14 125.57 Ͻ.001 12.71 Ͻ.001 15.36 Ͻ.001 (11.45) (10.57) (10.17) (2,116) (10.71,14.72) (13.38,17.34) CI indicates interval.

for ADHD. Of the subjects, 101 (80.8%) were ADHD– Parent Global Perceptions Questionnaire mixed type, 22 (17.6%) ADHD–predominantly inat- The five-point scales were dichotomized to repre- tentive, and 2 (1.6%) ADHD–predominantly hyper- sent positive or negative responses in that domain. active/impulsive, according to the diagnostic criteria Parental perceptions of their children’s reduced ac- for ADHD. Mean IQ was estimated to be 98.9 (SD ϭ tivity (DEX, 41.6%; MPH, 37.9%; P ϭ .57) and im- 13.8). proved concentration (DEX, 70.4%; MPH, 74.2%; P ϭ Highest group mean [SD] T scores on the CBCL .59) did not differ between the two drugs (McNe- were the attention problems (75.9 [8.4]), aggressive mar’s modified ␹2 test). The parents of 68.8% of sub- behavior (73.4 [11.2]), and total problems (72.0 [6.8]) jects rated them as “better” or “much better” overall scores. A similar pattern was seen on the TRF (atten- (responders) during the period in which they took tion problems 70.2 [9.8], aggressive 67.4 [10.5], and DEX, compared with 72.6% during the MPH period. total problems 67.0 [7.4]). There was no significant difference in the proportion of responders to the two drugs (McNemar’s test, ␹2 ϭ Response to Stimulant Medication .27; P ϭ .60). The CPRS–R and CTRS–R are considered together, followed by the Parental Global Perceptions ques- Parents’ Comparison of the Two Trial Periods tionnaire. The parents of 104 (83.2%) of the 125 study subjects indicated that one trial period was clearly superior to CPRS–R and CTRS–R the other for their child. The parents of 46 subjects Mean T scores for every factor of the CPRS–R and (36.8%) specified the period in which their child was CTRS–R were significantly lower on each drug, com- taking DEX as the preferred period, compared with pared with scores at baseline (Table 1). Largest ef- the parents of 58 subjects (46.4%) who specified the fects were found for the learning problems and im- MPH period. The ␹2 (goodness-of-fit) statistic was pulsive–hyperactive factors of the CPRS–R and the 1.38 (P Ͼ .1). hyperactivity and inattentive–passive factors of the CTRS–R for both drugs. Responders Versus Nonresponders The results of the Hills and Armitage analysis of Table 3 classifies the sample by combinations of each factor of the CPRS–R and CTRS–R are presented response and nonresponse to the two stimulants, by in Table 2. There was a systematic trend toward the criteria described above, on each of the main MPH having a larger treatment effect than DEX. outcome measures. There was only one nonre- Differences were of small magnitude on the CPRS–R, sponder to both stimulants by all three measures. with the anxiety factor being the only one with a P In Table 4, these data are presented in a slightly value Ͻ.05. On the CTRS–R, however, T scores were different way to address the important clinical ques- improved to a significantly greater degree on MPH tion: If a child does not respond to one stimulant, than on DEX on all three factors, as well as on the what is the likelihood of response to the alternative hyperactivity index. stimulant?

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/100/6/ by guest on October 2, 2021 e6 3of7 TABLE 2. Comparison of the Effects of DEX and MPH, by Conners’ Rating Scales Factors (Change in T Scores From Baseline) Factor Period Effect Treatment-by-Period Difference in Treatment Effect (Period A–Period B) Interaction (MPH Effect–DEX Effect) Difference in Improvement P Value P Value Difference in Improvement P Value (95% CI) (95% CI) CPRS-R Conduct problems Ϫ.98 .50 .06 2.18 .13 (Ϫ3.81,1.85) (Ϫ.65,5.01) Learning problems Ϫ3.46 .03 .54 .79 .62 (Ϫ6.58,Ϫ.33) (Ϫ2.34,3.91) Psychosomatic Ϫ3.94 .01 .04 2.12 .17 (Ϫ6.96,Ϫ.92) (Ϫ.90,5.14) Impulsive–hyperactive Ϫ1.83 .13 .63 .21 .87 (Ϫ4.23,.55) (Ϫ2.18,2.61) Anxiety Ϫ.97 .06 .83 1.20 .02 (Ϫ1.98,.04) (.19,2.20) Hyperactivity index Ϫ2.58 .10 .90 1.03 .51 (Ϫ5.64,.49) (Ϫ2.03,4.10) CTRS-R Conduct problems Ϫ2.59 .02 .08 3.31 Ͻ.01 (Ϫ4.79,Ϫ.40) (1.11,5.50) Hyperactivity Ϫ1.73 .10 .93 2.78 Ͻ.01 (Ϫ3.81,.35) (.70,4.86) Inattentive–passive Ϫ1.2 .07 .94 1.61 .02 (Ϫ2.52,.11) (.30,2.92) Hyperactivity index Ϫ2.13 .03 .58 2.60 Ͻ.01 (Ϫ4.04,Ϫ.22) (.69,4.51) CI indicates .

TABLE 3. Number (%) of Responders and Nonresponders to DEX and MPH, by Parent Global Perceptions, CPRS-R, and CTRS-R Measure Responders to Both Responders to DEX Responders to MPH Nonresponders P Value* but not to MPH but not to DEX to Both Parent Global Perceptions 58 (46.4) 27 (21.6) 32 (25.6) 7 (5.6) .60 CPRS-R† 72 (57.6) 21 (16.8) 19 (15.2) 10 (8) .87 CTRS-R† 52 (41.6) 16 (12.8) 25 (20) 25 (20) .21 * McNemar’s modified ␹2 test, comparing the proportion of subjects responding to DEX with the proportion responding to MPH. † Hyperactivity index.

TABLE 4. Proportion of Nonresponders to One Stimulant Who Responded to the Alternative Stimulant Measure Nonresponders to DEX No. (%) of DEX Nonresponders Nonresponders to MPH No. (%) of MPH Nonresponders (% Total) Who Responded to MPH (% Total) Who Responded to DEX Parent Global 39 (31.2) 32 (82) 34 (27.2) 27 (79.4) Perceptions CPRS-R* 29 (23.2) 19 (65.5) 31 (24.8) 21 (67.7) CTRS-R* 50 (40) 25 (50) 41 (32.8) 16 (39) * Hyperactivity index.

Continuous Performance Test DEX was associated with a significantly greater sever- Subjects achieved a higher number of correct re- ity of side effects than MPH, particularly negative emo- sponses on DEX compared with baseline score (P Ͻ tional side effects (eg, , tearfulness, anxiety). .01), with a similar trend during the MPH phase (P ϭ .06). Compared with the baseline score, subjects Predictors of Response made fewer commission errors and omission errors The severity of baseline parental behavior rating on both DEX and MPH (P Ͻ .001). There was no (CBCL), severity of baseline teacher behavior rat- significant difference between DEX and MPH on any ing (TRF), and aggressive–delinquent behavior of these measures. predicted a greater response to both stimulants. Subjects with the DSM–IV category ADHD–com- Side Effects bined type responded to a greater degree than The data concerning the relative side effects of these those with predominantly inattentive type. Com- two drugs from the present study has been reported pared with subjects with an IQ Ն85, those with IQ previously.16 There were two main findings: 1) Many Ͻ85 had a significantly less marked response to symptoms commonly considered to be side effects of DEX, but not to MPH. Response to the two drugs stimulant medication were present at baseline and, in was then compared directly for the subgroup with fact, diminished with medication treatment; and 2) IQ Ͻ85 (n ϭ 16), but no differences were found.

4of7 STIMULANTS INDownloaded ATTENTION from www.aappublications.org/news DEFICIT HYPERACTIVITY by guest DISORDER on October 2, 2021 Age, gender, socioeconomic status, and anxiety– measures, 124 of 125 subjects were rated as respond- depression were not predictive of a greater or ers on at least one measure. This is consistent with lesser response to either drug. earlier work. Winsberg et al19 conducted a random- order intrasubject comparative study of MPH, DEX, DISCUSSION and placebo, and found that equal proportions (60%) Reviews of separate trials of individual drugs (ie, of subjects responded to either drug, but that a small MPH studies and DEX studies) were published in number of children responded selectively to one or 196717 and 1977.4 However, only seven published the other. More recently, Elia et al1 measured the studies have compared these two drugs directly (Ta- response of 48 boys with ADHD to DEX and MPH in ble 5). As part of a recent review, Richters et al2 a well-designed and comprehensive study. A total of tallied the subjects from such comparative studies of 79% of subjects responded to MPH and 88% to DEX, the two major stimulants. Of a total of 141 subjects, and all but 2 responded to one or the other stimulant 50 were rated globally as better on DEX, 37 re- by global rating. Overall, 47 of 48 boys were consid- sponded preferentially to MPH, and most of the ered to have responded to one or the other stimulant remainder did well on both. No advantage to either and were discharged on that drug (22 on MPH, 25 on drug has been demonstrated to date. DEX). Vyborova et al20 reported a higher proportion This study is the first to report differential efficacy of subjects to be responsive to DEX, although the between the two stimulants MPH and DEX. Differ- mean magnitude of effect was greater with MPH. ences were most marked by teacher report (CTRS–R). Unfortunately the same dose was used for both DEX The degree of response as measured by the CTRS–R and MPH in this single-blind, crossover study. The was greater for MPH than for DEX. Mean improve- finding of similar efficacy between long-acting forms ment on the hyperactivity index was 2.6 T score of MPH and DEX21 has limited applicability to the points greater with MPH than with DEX. Thus, the use of the standard DEX preparation. differences were not only statistically significant but On the CPT, subjects made more correct responses clinically important as well. Categorical analysis of and fewer errors on both DEX and MPH relative to these data demonstrated that almost 8% more sub- baseline performance. These results are consistent jects were rated as responders to MPH than to DEX with the improvement in CPT performance found by CTRS–R. previously with stimulant medication.22,23 No differ- By parental rating (CPRS–R), the differences in ences between the two stimulants were seen on these efficacy between the two stimulants were in the same primary CPT measures. direction as with teacher report (ie, greater benefit The main finding from analysis of predictors of from MPH than from DEX), although not as marked. response was that the magnitude of response was In addition, almost 10% more parents said they pre- related to the severity of baseline symptoms. This ferred MPH to DEX (46.4% vs 36.8%), all things phenomenon has been reported previously24,25 and considered. It is important to note that these findings may be considered a true clinically useful predictive were seen with a twice-daily dosing regimen. Par- factor. However, regression to the mean artifact may ents would possibly have reported greater differ- partly account for this; that is, subjects with the most ences had an after-school dose been used. This was statistically deviant scores at baseline tend to display not given because it was felt that an afternoon dose the greatest change in score with treatment. The find- of DEX would have caused a great deal of sleep ing of a greater response among aggressive subjects disturbance. may be another expression of the phenomenon of Approximately 60% of subjects were rated by their more severe children improving by a greater margin. parents as “the same” or “more than usual” for ac- ADHD subjects with comorbid aggressive–delin- tivity for both drugs. This may have reflected varia- quent behavior may be considered a more severe tion in parents’ interpretation of the question. In- group and, therefore, have the most room to move creased activity may be seen as a positive reaction, ie, toward the normal range. The data from this study more productive.18 This may be particularly so for suggest that children with ADHD–combined type those subjects with ADHD–predominantly inatten- may show a greater degree of response than those tive type, in which overactivity was not a presenting with ADHD–predominantly inattentive type. This problem. Parents felt that the child’s concentration finding may reflect the problem of adequately mea- was improved in 70.4% of subjects while taking DEX, suring change in children with ADHD–predomi- and in 74.2% with MPH. These figures are remark- nantly inattentive type. In children without hyperac- ably similar to the proportions seen by parents as tivity, short-term change may be harder to discern, improved overall, suggesting that impaired concen- and multiple measures or repeated measures over tration was the primary symptom in the eyes of longer intervals may be needed to demonstrate parents. equivalent benefits from medication. Because the The categorical analysis of nonresponders demon- subgroup of girls studied was small, the power to strated that if a child with ADHD does not do well detect gender differences was limited. on one stimulant, he has a good chance of respond- Several authors have discussed the lack of reliable ing to the alternative. Depending on the measure predictor variables,1,2,4 and their identification re- examined, between 50% and 82% of nonresponders mains one of the most elusive aspects of stimulant to DEX responded to MPH, and between 39% and drug research. There are a number of possible rea- 79.4% of nonresponders to MPH responded to DEX. sons why specific predictors of response were not By trying both drugs and using a range of outcome defined in this study. First, the number of subjects

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/100/6/ by guest on October 2, 2021 e6 5of7 6of7 TMLNSI TETO EII YEATVT DISORDER HYPERACTIVITY DEFICIT ATTENTION IN STIMULANTS Downloaded from TABLE 5. Previous Studies Comparing DEX and MPH Author (Year) Experimental Design Dosage n (Boys) Age (Mean) Outcome Measures Primary Findings Weiss et al (1971) Results of two separate parallel Individualized to maximum of DEX, 38 (32) 6–12 (8.1) Mothers’ global judgment, Both stimulants superior to group, double-blind, placebo- DEX 20 mg qid, MPH 50 mg MPH, 51 (44) various cognitive measures placebo, and roughly controlled studies of DEX and qid equivalent www.aappublications.org/news MPH Conners (1972) Parallel group, double-blind Individualized to DEX 15 mg 75 (70) 6–13 (9.3) Various psychometric tests, CPT Similar overall efficacy study bid, MPH 30 mg bid Winsberg et al (1974) Placebo-controlled double-blind Individualized to DEX 20 mg 18 (15) 5–11 (8.5) CTRS Both drugs superior to placebo; crossover study bid, MPH 30 mg bid equal proportions of subjects responded to each Arnold et al (1978) Placebo-controlled double-blind Individualized to DEX 5–30 29 (22) 5–12 (8) Various parent-, teacher-, and Both more effective than crossover study mg/d, MPH 10–60 mg/d psychiatrist-completed rating placebo; no significant scales differences; 89% responded well to one or other Vyborova et al (1984) Single-blind crossover Mean 38 mg/d for both DEX 28 (25) 6–14 (NA) Cerny scale 63% responded to DEX, 53% to byguest on October2,2021 and MPH MPH; mean improvement greater with MPH Pelham et al (1990) Placebo-controlled, double-blind, DS 10 mg mane, SR-20 20 mg 22 (22) 8–13 (10.4) Frequencies of certain behaviors, No significant group differences crossover study comparing mane, MPH 10 mg bid ACTRS, academic productivity between the three drug sustained-release DEX (DS), and accuracy, daily report conditions, all of which were sustained-release MPH (SR- card, CPT superior to placebo 20), and standard MPH Elia et al (1991) Placebo-controlled, double-blind, Based on body weight; increased 48 (48) 6–12 (8.6) ACTRS, CTRS, CPRS, CPT, PAL, Both drugs superior to placebo; crossover study weekly to DEX 1.3 mg/kg/d, truncal activity monitor no significant group MPH 2.5 mg/kg/d differences; 98% responded well to one or other stimulant ACTRS indicates Abbreviated Conners’ Teacher Rating Scale; PAL, paired associate learning task. may not have been sufficient to determine predictive multimodal treatment study of children with ADHD. I. Background and utility. The second possible explanation is that the rationale. J Am Acad Child Adolesc Psychiatry. 1995;34:987–1000 3. Jacobvitz D, Sroufe LA, Stewart M, Leffert N. Treatment of attentional relevant or important influences on response to stim- and hyperactivity problems in children with sympathomimetic drugs: a ulant medication were not examined. Finally, there comprehensive review. J Am Acad Child Adolesc Psychiatry. 1990;29: may not actually be any factors that inform the cli- 677–688 nician of which children are likely to respond favor- 4. Barkley RA. A review of stimulant drug research with hyperactive children. J Child Psychol Psychiatry. 1977;18:137–165 ably to stimulant medication. In ADHD, there are so 5. Conners CK. Recent drug studies with hyperkinetic children. J Learn many interrelated influences on the child’s presenta- Disabil. 1971;4:476–483 tion and response to therapy that it may be impos- 6. Eisenberg L. The clinical use of stimulant drugs in children. Pediatrics. sible to anticipate response to stimulant medication 1972;49:709–715 based on any one attribute or feature of the case. The 7. Barkley RA, DuPaul GJ, Costello A. Stimulants. In: Werry JS, Aman MG, eds. Practitioner’s Guide to Psychoactive Drugs for Children and Adolescents. short-term trial, which is used by practitioners in New York, NY: Plenum Publishing Corporation; 1993:205–237 everyday clinical practice, may ultimately be the best 8. American Psychiatric Association Co. Diagnostic and Statistical Manual of mean of determining the suitability of stimulant Mental Disorders. 4th ed. Washington, DC: American Psychiatric drug treatment for an individual child. Association; 1994 9. Barkley RA. Attention-Deficit Hyperactivity Disorder: A Handbook for Di- Children with ADHD with comorbid anxiety dis- agnosis and Treatment. New York, NY: Guilford Press; 1990 orders have been reported to respond less consis- 10. Achenbach TM. Manual for the Child Behavior Checklist/4–18 and 1991 tently and less dramatically to MPH than those with- Profile. Burlington, VT: University of Vermont; 1991 out anxiety.26 In this study, however, subjects with or 11. Achenbach TM. Manual for the Teacher’s Report Form and 1991 Profile. without anxiety responded equally well. It is unclear Burlington, VT: University of Vermont; 1991 12. Goyette CH, Conners CK, Ulrich RF. Normative data on revised why this finding should contrast with earlier work. Conners parent and teacher rating scales. J Abnorm Child Psychol. 1978; The dose of 0.3 mg/kg twice daily for MPH used 6:221–236 in this study has been commonly used in research 13. Rosvold HE, Mirsky AF, Sarason I, Bransome ED, Beck LH. A contin- studies, because this moderate dose has been shown uous performance test of brain damage. J Consult Clin Psychol. 1956;20: 343–350 to induce maximal improvements in distractibility 14. Wechsler D. Manual for the Wechsler Intelligence Scale for Children. 3rd ed. and performance on memory tasks (speed and accu- San Antonio, TX: Psychological Corporation; 1991 racy), with a relatively low risk of adverse effects.27 15. Hills M, Armitage P. The two-period cross-over . Br J Clin Less is known about the optimal dose of DEX, be- Pharmacol. 1979;8:7–20 cause there has been much less investigation into this 16. Efron D, Jarman FC, Barker MJ. “Side effects” of methylphenidate and dexamphetamine in children with attention deficit hyperactivity drug than into MPH. The recommended dose of DEX disorder: a double-blind, crossover trial. Pediatrics. 1997;100:662–666 7,28 is half that of MPH. However, there is wide vari- 17. Millichap JG, Fowler GW. Treatment of minimal brain dysfunction ation in the individual dose required to achieve max- syndromes. Pediatr Clin North Am. 1967;14:767–777 imal effect,29,30 and a proportion of nonresponders 18. Loney J, Ordona TT. Using cerebral stimulants to treat minimal brain dysfunction. Am J Orthopsychiatry. 1975;45:564–572 would possibly have done better on a higher dose. 19. Winsberg BG, Press M, Bialer I, Kupietz M. Dextroamphetamine and The use of a varying dosage regimen in future stud- methylphenidate in the treatment of hyperactive/aggressive children. ies might shed more light on the question of the Pediatrics. 1974;53:236–241 optimal doses of these two stimulants. 20. Vyborova L, Nahunek K, Drtilkova I, Balastikova B, Misurec J. Intrain- This study provides strong evidence of a group dividual comparison of a twenty-one day application of amphetaminil and methylphenidate in hyperkinetic children. Act Nerv Super. 1984;26: mean superiority of MPH over DEX from the teach- 268–269 ers’ point of view, and some evidence that parents 21. Pelham WE Jr, Greenslade KE, Vodde-Hamilton M, et al. Relative also prefer MPH over DEX. This is the first research efficacy of long-acting stimulants on children with attention deficit- data to indicate that one of these stimulants may hyperactivity disorder: a comparison of standard methylphenidate, sus- tained-release methylphenidate, sustained-release dextroamphetamine, have a general advantage over the other. However, it and . Pediatrics. 1990;86:226–237 needs to be emphasized that DEX was the preferred 22. Sykes DH, Douglas VI, Weiss G, Minde KK. Attention in hyperactive drug for more than one third of subjects. Because children and the effect of Ritalin. J Child Psychol Psychiatry. 1971;12: DEX is substantially less expensive and there ap- 129–139 pears to be no reliable predictors of which children 23. Koelega HS. Stimulant drugs and vigilance performance: a review. Psychopharmacology. 1993;111:1–16 will do better on which stimulant, it would seem 24. Taylor E, Schachar R, Thorley G, Wieselberg HM, Everitt B, Rutter M. reasonable to prescribe DEX as the first-line agent for Which boys respond to stimulant medication? A controlled trial of children with ADHD in whom a trial of medication methylphenidate in boys with disruptive behaviour. Psychol Med. 1987; is considered clinically appropriate. If the child is not 17:121–143 25. McBride MC. An individual double-blind crossover trial for assessing greatly improved or experiences unacceptable ad- methylphenidate response in children with attention deficit disorder. verse effects with DEX, then MPH should be tried. J Pediatr. 1988;113:137–145 26. Pliszka SR. Effect of anxiety on cognition, behavior, and stimulant ACKNOWLEDGMENTS response in ADHD. J Am Acad Child Adolesc Psychiatry. 1989;28:882–887 Dr Efron was supported by a Clinical Research Scholarship 27. Barkley RA, Fischer M, Newby RF, Breen MJ. Development of a mul- from the Royal Children’s Hospital Research Foundation. We timethod clinical protocol for assessing stimulant drug response in thank Dr John Carlin for assistance with data analysis and Zeffie children with attention deficit disorder. J Clin Child Psychiatry. 1988;17: Poulakis for helpful advice. 14–24 28. American Academy of Pediatrics. Medication for children with an Pediatrics. REFERENCES attention deficit disorder. 1987;80:758–760 29. Barkley RA, McMurray MB, Edelbrock CS, Robbins K. The response of 1. Elia J, Borcherding BG, Rapoport JL, Keysor CS. Methylphenidate and aggressive and nonaggressive ADHD children to two doses of methyl- dextroamphetamine treatments of hyperactivity: are there true nonre- phenidate J Am Acad Child Adolesc Psychiatry. 1989;28:873–881 sponders? Psychiatry Res. 1991;36:141–155 30. Rapport MD, DuPaul GJ. Hyperactivity and methylphenidate: rate- 2. Richters JE, Arnold LE, Jensen PS, et al. NIMH collaborative multisite dependent effects on attention. Int Clin Psychopharmacol. 1986;1:45–52

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Downloaded from www.aappublications.org/news by guest on October 2, 2021 Methylphenidate Versus Dexamphetamine in Children With Attention Deficit Hyperactivity Disorder: A Double-blind, Crossover Trial Daryl Efron, Frederick Jarman and Melinda Barker Pediatrics 1997;100;e6 DOI: 10.1542/peds.100.6.e6

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