Hyperactivity Disorder

Differential Effectiveness of Methylphenidate and Adderall" in School-Age Youths With AttentionDeficidHyperactivity Disorder MICHAEL J. MANOS, PH.D.,ELIZABETH J. SHORT, PH.D., AND ROBERT L. FINDLING, M.D.

ABSTRACT Objective: To compare the effectiveness of a single dose of Adderall@(q.d.) with that of 2 daily doses of methylphenidate (b.i.d.; MPH) as a treatment for attention-deficiUhyperactivity disorder (ADHD) in youths ranging in age from 5 to 17 years. Forty-two youths treated with MPH were compared with 42 youths treated with [email protected] were matched for age, sex, and DSM-IV diagnostic subtype. Method: Youths were assigned to the Adderalla or MPH condition by their prescribing physician.All youths were evaluated under 5 conditions, including baseline, placebo, 5 mg, 10 rng, and 15 mg. The best dose was assigned prior to breaking the medication blind and was assigned by the consensus of the psychologist and psychiatrist.Subjective ratings by both teachers and parents were examined for dosage level effects and medication type effects. Results: Best dose was always superior to baseline and placebo conditions. No differences between MPH and Adderall@were observed on either teacher or parent ratings of behavior. Conclusions: Both MPH and Adderall@have been shown to be effective treatments for children with ADHD. Both medications appear to improve teachers' and parents' ratings of behavior. Single-dose treatments of Adderall" appear to be as effective as 2 daily doses of MPH and therefore increase the possibility of managing treatment without involving the school in medication administration. In addition, youths who have previously been unsuccessfully treated with MPH because of adverse side effects or poor response may be successfully treated with Adderall". J. Am. Acad. Child Adolesc. Psychiatry, 1999, 38(7):813419. Key Words: attention-deficiUhyperactivity disorder, Adderall@,methylphenidate, stimulant, dose.

Accepted January 7,1999. Dr. Manos was Assistant Projkor of Pychiatry, Case Western Reserve Universig (CWRU) Jchool of Medicine, Cleveland,and Clinical Director of the Pediatric Assessment and Evaluation Service (PAES) during this study. Currently he is Director of the ADHD Center, The ClevelandFoundation. Dr. Short is Associate Profissor of Psychology at CWRU and was Research Director of PAES. Dr. Findling is Assistant Profism of Pqcbiawy, CWRU School of Medicine, and was Medical Director of PMS. The authors acknowledge partial support to the second author from NIDA (grants ROI-DA07957and MCJ-390592) andfiom the Maternal and Child Health Program, Health Resources and Service Administration, Department of Health and Human Services (grant 390715), and to the third authorfrom the Stanley Foundation. Special thanks to participatingfamilies, Barb DePasquale, Ed Chang, and Shelly Lowry. Reprint requests to Dr. Manos, Division of Pediatrics, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. 0890-8567/99/38O7-0813O 1999 by the American Academy of Child and Adolescent Psychiatry.

pemoline provide significant salutary effects in this population (see reviews by Findling and Dogin, 1998; Spencer et d., 1996). MPH is the most commonly prescribed psychostimulant (Wolraich et al., 1990). It provides safe, effective treatment for A D H D in most youths for whom it is prescribed (Elia et al., 1991). MPH is currently available in the United States in 2 forms: an immediate- and slowrelease preparation. In clinical practice, the immediaterelease preparation of MPH is usually prescribed twice a day (with breakfast and lunch), with an afternoon dose given as needed. The sustained-release preparation is usually prescribed once a day (with breakfast), thereby making dosing during the hours while the child is at school unnecessary. However, a second dose of the sustained-release preparation is sometimes administered after lunch. Although logistical and clinical benefits may be gained from treatment with the slow-release formulation of MPH because it obviates the need for inschool medication dosing, others have raised concerns that slow-release MPH may not be as effective as the

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Psychostimulants are the mainstays of pharmacotherapy for attention-deficidhyperactivity disorder (ADHD) in children. There are numerous double-blind, placebocontrolled trials that have demonstrated that the psychostimulants methylphenidate (MPH), amphetamine, and

M A N O S ET AL.

immediate-release formulation (see review by Findling and Dogin, 1998). Adderall@is a recently reintroduced psychostimulant preparation consisting of equal parts amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate that was previously marketed under the name Obetrol as a treatment for obesity (Popper, 1994). A recent double-blind study showed that Adderall@ is not only safe and effective for the treatment of ADHD, but may have a longer duration of action than MPH (Swanson et al., 1998). The primary purpose of this study was to compare the effectiveness of Adderall@given once in the morning and that of MPH given in the morning and at noon under double-blind titration (i.e., blind to dose, not to medication), placebo-controlled conditions in children with a confirmed diagnosis of ADHD. METHOD Subjects This sample is a subset of a clinic-based population referred for diagnosis and treatment of ADHD to the Pediatric Assessment and Evaluation Service of a large, urban, teaching hospital. As a result of the hospital infrastructure, this sample systematically caters to managed care patients not requiring immediate intervention. Of the 600 patients referred for evaluation to date, 159 have participated in a medication trial. Of the 159 subjects receiving medication, MPH was administered to 117 and Adderall@to 42.

were run simultaneously,with medication assigned to subjects based on physician’s discretion and familiarity with the medication. The 42 patients who received Adderall@ exhausted our sample of children receiving this medication. In an effort to control for differences on dependent measures due to age, diagnostic category, and gender and instead to focus attention on effects of medication only, subjects were matched on these measures. That is, we selected subjects from the MPH group (n = 117) who had been assigned the same diagnostic category, were approximately the same age (+6 months), and were the same gender as those enrolled in the Adderall@group.

PharmacologicalProtocol All subjects in this study were evaluated using a 4-week, doubleblind titration, placebo-controlled protocol. That is, parents were aware of the medication their child received (i.e., whether the child was assigned MPH or Adderall@) but were blind to dosage level. Each child’s pediatrician determined whether MPH or Adderall@was to be used. Type of medication administered was based on physicians’ familiarity with the agent (i.e., often related to the number of times they had previously prescribed the medication), as well as whether they wanted a child to receive a single dose (Adderall@)or twice-daily dose (MPH) of medication for treatment of ADHD. This latter decision was usually based on a parent‘s concern about the child taking medication in school. Fifteen of the Adderall@subjects had previously used MPH but had discontinued its use because of a failure to respond ( n = 7) or negative side effects ( n = 8). None of the MPH patients had used Adderall@previously. Subjects received each of 4 MPH (b.i.d.) or Adderall@(q.d.) doses in a randomly assigned sequence. The 4 stimulant drug conditions for both MPH (b.i.d.) and Adderall@(q.d.) were placebo (Al), 5 mg (low dose; Bl), 10 mg (moderate dose; B2), and 15 mg (high dose; BJ. Six dose orders were used such that the highest dose (15 mg) was given only when preceded by the moderate dose (10 mg). Dose orders were assigned to subjects in a random fashion. The possible dose orders were the following:

Diagnostic Criteria

All children with ADHD met full DSM-Ndiagnostic criteria for this disorder. These are (1) the presence of at least 6 symptoms of inattention and/or at least 6 symptoms of hyperactivity/impulsivity; (2) symptoms significantly interfered with functioning at home and at school as noted during structured (Computerized Diagnostic Interview Schedule for Children) (Shaffer, 1997) or semistructured clinical interviews; (3) symptom severity on broad-band (i.e., Conners Abbreviated Symptoms Questionnaire; A S Q (Conners, 1969) and narrow-band (i.e., ADHD Rating Scale; A R S ) (DuPaul, 1991) rating scales was at threshold or above (i.e., rated 2 or 3); (4) multiple raters (e.g., parents and teachers) agreed to the presence of the symptoms; and (5) empirical comparison to norms indicated at least a 1.5 SD cutoff on at least one rating scale. It should be noted that when the presence of symptoms was identified, behaviors across informants were not pooled observations. Behaviors were considered significant only if 2 informants agreed to the presence of the symptom on rating scales or in interviews. The use of multiple informants and the necessity of agreement between informants increase the probability that we have ruled out alternative causes for the presence of ADHD symptoms.

Fixed doses (versus mglkg) were prescribed because they reflect typical pediatric practice, and MPH dosage has been shown to be independent of body weight (Rapport et al., 1989). Also, fixed doses provide increased flexibility in comparing data sets with previous studies, providing more information about A D H D children’s response to stimulants. All MPH, Adderall@, and placebo capsules were prepared by licensed pharmacists and packaged in white gelatin capsules to avoid detection of placebo or active medicine by taste. Capsules were sealed in individual bottles dated by week to control for accurate dose administration. Parents were given one bottle of capsules every week and were asked to return bottles at the end of the week with unused capsules to ensure compliance with the protocol. MPH capsules were given in the morning (at 8:OO A.M.) and at noon each day. Adderall@capsules were administered in the morning only. While both the clinician and parent knew which medication condition each child had been assigned, the clinician, teacher, and parent were blind to the weekly dose administered.

Matching Procedures

Measures

Adderall@was administered to only 42.MPH and Adderall@protocols

ADHD Rating Scale. The ARS (DSM-III-R and DSM-Nversions) (DuPaul, 1991; C.J. DuPaul, A.D. Anastopoulos, T.J. Powers, R.

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As noted previously, MPH was administered to 117 subjects, while

EFFECTIVENESS O F ADDERALL@A N D MPH

Reid, M.J. Ikeda, K.E. McGoey, unpublished normative data for the home version of the AD/HD Rating Scale IV, 1996) is composed of items assessing the symptoms of the ADHD diagnostic category. For this study, items on the DSM-ZZZ-R version were revised to reflect the new symptom criteria of the DSM-ZK The severity of symptoms is rated on a problem scale of 0 (not at all) to 3 (very much). The sum of items scored 2 or higher determines whether a child meets the formal diagnostic criteria for ADHD. The A R S has been shown to discriminate children with A D H D from learning-disabled and non-learning-disabled children, to differentiate children with hyperactivity from children without, and to be sensitive to stimulant drug effects (Barkley et al., 1990). Abbreviated Symptoms Questionnaire. The ASQ is a parent and teacher rating form developed by Keith Conners (1969). The 10-item rating scale is similar to the ARS in format. That is, parents and teachers rate children’s symptoms on a scale of 0 to 3, with 0 indicating that the symptom is not present at all and 3 indicating that the symptom is very much present. The ASQ is considered to be the “gold standard of rating scales and was included for validation purposes. Composite Ratings. Using parental report of weekly behavior problems, the primary clinician rated the child’s behavior at the end of each week on a scale of -5 (significant deterioration) to +5 (significant improvement). These weekly composite ratings reflected both clinicians’ (M.J.M. and R.L.F.) summary based on a review of standardized data, parental report, and anecdotal data. School Situations Questionnaire-Revised. The School Situations Questionnaire-Revised (SSQ-R) (DuPaul, unpublished, 1990) is an 8-item measure assessing specific problems with attention and concentration at school. Respondents first rate whether a child has problems in a given situation, then they rate the severity of that problem from 1 (mild) to 9 (severe).The scale has adequate test-retest reliability and correlates highly with other teacher ratings scales of ADHD symptomatology. The SSQ-R has been found to be sensitive to the effects of stimulant medication interventions (Barkley, 1990) and discriminates children with A D H D from normal children (Barkley et al., 1990). “Part scores” used in analyses excluded items for which teacher ratings were consistently unavailable (e.g., “during movies, filmstrips”; “on field trips”). Side Effects Behavior Monitoring Scale. Side effects were noted on the Side Effects Behavior Monitoring Scale (SE/BMS) (Manos, 1996). The SElBMS is based in part on previously published scales (Barkley, 1990) and clinical experience. Norms and reliability data are currently being collected. Parents were asked to rate 16 possible side effects each week. Side effects were rated on a scale of 0 to 10, with 0 indicating “not a problem” and 10 indicating a “significant problem” (i.e., symptom was intolerable). To be conservative, symptoms were considered problematic if parents rated them as 5 or greater.

Procedure With the exception of body weight, which was collected only at the beginning and end of the trial, all other data were collected on the seventh day of each week‘s dose, beginning with the baseline week. For the purposes of this report, comparisons were made between placebo and best dose unless otherwise noted. It should be noted that 7 MPH and 4 Adderall@youths did not receive the 15-mg dose of medication. The decision to forgo the 15-mg condition was based on the pediatrician’s assessment that the child was too young or underweight for this high dose and our assessment that best dose had already been achieved at a lower dose. Appointments were scheduled at the same time and day each week for the 4-week double-blind, placebo-controlled medication trial.

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Parents completed the questionnaires during their scheduled appointment each week, and ratings were based on their 7-day observation of their child and on anecdotal information gathered from other sources (e.g., day-care providers, baby-sitters). Teachers completed questionnaires and rating scales on the day before the child’s weekly appointment. Parents returned teacher observation rating scales at the scheduled appointment.

Data Analysis Strategy All data were analyzed using a multivariate and univariate repeated-measures analysis of variance strategy, with dosage level (best dose versus placebo) as the within-subject variable and medication type (Adderall@and MPH) as the between-subject variable. Significant multivariate main effects and interactions were explored using univariate analyses of variance. In addition, best-dose data were examined for order effects. Because of the small sample size, the 6 orders were collapsed into 3 with comparisons made between children who received placebo first (MPH = 12; Adderall@= IS), 5 mg first (MPH = 21; Adderall@ = 12), and 10 mg first (MPH = 9; Adderall@= 15). No significant order effects were observed for any of the dependent variables ( p > .lo). Therefore, the analyses reported below exclude order as a between-subject variable.

RESULTS

As previously noted, 42 children who received MPH and 42 children who received Adderall@ during the pharmacological intervention served as subjects for the following investigation. While the 42 Adderall@subjects exhausted our sample receiving this medication, the subjects in the MPH group were hand-selected from the larger sample ( n = 117) who had completed this trial. The Adderall@and MPH youths were matched on age (mean = 10.1; range 5-17 years), sex (33 males, 9 females), and diagnostic category (inattentive type, n = 19; combined type, n = 23) to control for differential responsiveness to medication type. For a complete description of the sample, the reader is referred to Table 1. As can be seen in Table 1, the present sample was predominantly white, well educated, and without significant comorbid disorders. During the medication trial, children were classified as responders or nonresponders on the basis of changes in scale scores. Children showing a rating change in Tscores of 1 SD or more on at least one rating scale were considered responders. Those not showing at least this change were nonresponders ( n = 2; both from the Adderall@group) and were referred to an appropriate health professional for more in-depth consultation. Both nonresponders had previously failed to respond to MPH. Best-Dose Classification

A best dose was assigned prior to the medication blind being broken for each patient. This best dose was deter-

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TABLE 1 Sample Characteristics Methylphenidate Primary diagnosis ADHD inattentive type ADHD combined type Secondary diagnosis Mood disorder Anxiety disorder Learning disability Oppositional defiant disorder None Age Young (<9 years) Old 29 years) Race White African-American Hispanic Sex Male Female Education" (motherlfather) Some high school High school diploma Some college College diploma or greater

Adderall@'

19 23

19 23

0

1

2

11 5 24

2 9 4 26

17 25

16 26

39 3 0

39 1 2

33 9

33 9

212 1318 513 18114

1I0 919 318 20114

of behavior would be better for the group as a whole on their best dose of medication than under the placebo condition. In addition, we assessed whether the benefit of a single dose of Adderall@was comparable with that obtained with 2 daily doses of MPH. To examine the individual differences in response to medication, we performed analyses to ascertain whether optimal dose varied as a function of medication type or age. No differences were observed in the analyses involving medication type or age (Table 2). It should be noted that 2 children in the Adderall@ condition were classified as nonresponders and therefore were not considered in subsequent analyses. From Table 2 it can be seen that the average daily best dose of MPH was 19.5 mg/day and the mean daily best dose of Adderall@was 10.6 mg/day. These data provide evidence suggesting that Adderall@is substantially more potent than MPH. These findings are consistent with prior work by Elia et al. (1991). Elia et al. (1991) noted that youths with suboptimal response to MPH may have superior salutary effects with dextroamphetamine therapy. Similarly, the 13 youths in our study who had previously been treated with MPH were able to receive therapeutic benefit from Adderall@.

x2

Note: ADHD = attention-deficitlhyperactivity disorder. a Education data available for a portion of the sample only.

Safety Data

mined on the basis of rating scales, parent interviews, patient report, teacher ratings, and clinical observation. Best dose was assigned by the consensus of a clinical child psychologist (M.J.M.) and a board-certified child and adolescent psychiatrist (R.L.F.). We compared clinical ratings of optimal dose to the placebo condition. It was hypothesized that both parent and teacher ratings

Data were available for weight at entry into the treatment and upon conclusion. In contrast, data for resting and seated blood pressure and for pulse were gathered weekly when children were under the effects of each medication dosage level (i.e., placebo, 5, 10, 15 mg). Separate repeated-measures analyses of variance were conducted for all 3 measures. In all cases, no significant

TABLE 2 Best Dose Response by Medication Type, Diagnostic Category, and Age Best Dose" Placebo

TDD MPH (mg) TDD ADL (mg) Methylphenidate (n) Adderall@(n) Inattentive type (n) Combined type (n) Age-young (n) Age-old (n)

2 1 3 1 0 3

Note: T D D = total daily dose; MPH

5 mg

10 mg

15 mg

10 5 10 8 5 13 9

20 10 18 16 19 15 18 16

30 15 12 15 10 17 11 16

9 =

Nonresponse

0 2

methylphenidate; ADL = Adderalla.

" Best dose of methylphenidate administered b.i.d. with breakfast and lunch. Best dose of Adderall@given once per day with breakfast.

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EFFECTIVENESS O F ADDERALL@A N D MPH

TABLE 3 Parent Ratings of Symptoms on Best Dose and Placebo

ASQ Parent Best dose Placebo ARS Parent Best dose Placebo Composite ratings Best dose Placebo

Methylphenidate

Adderall@

50.64 (10.64) 67.00 (17.32)

49.83 (13.95) 62.31 (l7.W

10.10 (6.71) 18.61 (11.86)

11.79 (9.86) 20.01 (11.68)

3.31 (0.52) 0.50 (1.27)

3.50 (0’64) 0.82 (1.44)

Note: Values represent mean (SD).ASQ = Abbreviated Symptoms Questionnaire; ARS = ADHD Rating Scale.

main or interaction effects for dosage level, medication VPe, Or a dosage level medication We interaction were noted (maximum FI,80 = o.680, P *41)*No tically or clinically significant change in weight, blood pressure, and pulse occurred across the treatment or as a result of medication type.

’

Parent Ratings

Best-dose comparisons on the ASQ-P revealed signif= 87.83, p < .OOI). icant effect for dosage level (F1,71 Parents reported less symptomatic behavior in their child at hidher optimal dose of medication compared with the placebo condition (Table 3).No differences were observed as a function of medication type, nor was there a significant dosage level by medication type interaction. Regardless of whether a youth received M P H or Adderall@, parents rated subjects as less symptomatic on medication than on the placebo. That is, parents rated their children’s behavior in the medicated condition as better than in the placebo condition for both MPH and Adderall@. Best-dose comparisons on the A R S revealed significant effects for dosage level ( F 1 , 7 6 = 76.80, p < .OOI). Consistent with their reports on the ASQ-R parents rated their children’s behavior as more oDtimal under conditions of best dose than under the placebo condition. It should be noted that ratings under the placebo condition are approximately 1 S D higher than those obtained for typical peers (mean = 11.4, SD = 10.0; see DuPaul et al., unpublished normative data for the home version of the AD/HD Rating Scale IV, 1996). For both MPH and Adderall@best-dose conditions, parent ratings on the ARS were slightly better than the norms obtained for typical peers. Thus, best-dose conditions appear to normalize the

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ADHD children’s behavior according to parental report (Table 3).Overall weekly composite ratings by the primary rating clinician (M.J.M.) revealed a significant dosage level effect as well ( F l , 8 0 = 317.56, p < .001). Again ratings of children’s behavior under best-dose conditions were superior to behavioral ratings under conditions of placebo. No differences between MPH and Adderall@were observed, nor was there a medication type by dosage level interaction (Table 3).Thus, regardless of which medication children were given, parents reported less symptomatic behavior during ” the best-dose week than the placebo week. Teacher Ratings

Comparisons on the ASQ-T revealed significant effects for dosage level only ( F ~= 34-15, , ~ ~ < .001). Teacher ratings under best dose were superior to teacher ratings of behavior under placebo conditions. The efficacy of MPH was not different from that ofAdderall@, nor was there a medication type by dosage level interaction (Table 4). Thus, the picture is quite consistent across reporters (i.e., parents and teachers) and across measures (ASQ and ARS) in that ratings under the best-dose condition were superior to those with placebo (F1,79= 55.26, p < .001), with no differences emerging between MPH and Adderall@(Table 4). Best-dose comparisons on both the SSQ-R total and part score revealed a similar pattern of findings. That is, teachers rated children’sbehavior as inferior in the placebo condition compared with the best-dose condition (minimum F,,,, = 33.41, p < .OOl). Like parent ratings, no differences between the efficacy of Adderall@and M P H in managing youths’ behavior was observed in teachers’ ratings (Table 4). TABLE 4 Teacher Ratings on Best Dose and Placebo

ASQ teacher Best dose Placebo SSQ-R, total Best dose Placebo SSQ-R, part Best dose Placebo

Methylphenidate

Adderall@

56.12 (11.81) 64.38 (15.41)

5 1.47 (10.37) 62.03 (13.62)

1.92 (2.11) 2.62 (2.86)

1.67 (1.65) 2.80 (1.88)

2.68 (2.56) 4.30 (2.84)

2.23 (2.27) 4.00 (2.73)

Note: Values represent mean (SD).ASQ = Abbreviated Symptoms Questionnaire; SSQ-R = School Situations Questionnaire-Revised.

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Taken together, the best dose of a single dose of Adderall@and 2 daily doses of MPH appear to be equally effective in managing the behavioral symptoms in children and adolescents with ADHD according to both parents and teachers. Best-dose condition was superior to placebo under both teacher and parent ratings. While our MP H and Adderall@groups did not differ in rated behavior under either placebo or best-dose conditions, both MPH and Adderall@ children demonstrated noteworthy improvement under medicated conditions. Side Effects

Although behavioral ratings showed decreased symptomatology by both parent and teacher report, behavioral improvement is often mitigated by side effects. To assess side effects, parents were queried weekly on the SE/BMS about the side effects exhibited by their child (for a complete description of these side effects see Table 5). Few parents reported severe side effects for their children on the best dose of medication (Table 5). The most commonly reported side effects for MPH were “staring a lot,” “being sadhnhappy,” “anxiety,”and “perseveration.”The most commonly reported side effects for Adderall@were “. insomnia,” “being sad/unhappy,” and “prone to cry.” The repeated-measures analysis of the side effects data revealed no differences between dosage level (placebo

versus best dose) and medication type (MP H versus Adderall@)(minimum F3,81= 2 . 9 7 , ~ > .09). O n average, the MP H group experienced 1.4 side effects and the Adderall@ group experienced 1.6 side effects when administered the best dose of medication. It is interesting that these same children experienced more side effects while not on medication (MPH = 2.4 and Adderall@= 2. l), but differences were not statistically significant. Very few children experienced any of the side effects during their best-dose week (Table 5). Results strongly indicate that both MPH (b.i.d.) and Adderall@(q.d.) decrease behavioral symptoms of inattention and hyperactivity according to parental and teacher report. The effectiveness of Adderall@as a viable treatment for children with ADHD does not appear to differ from MPH in this sample. Given our sample, there is evidence that Adderall@,in some cases, has a superior effect. As noted above, 15 youths in the Adderall@sample had been tried on MPH prior to enrollment in this medication trial. Because of lack of response ( n = 7 ) or serious side effects ( n = 8; i.e., severe loss of appetite or severe difficulty sleeping), these children discontinued using MPH. Thirtyseven percent of the Adderall@sample subsequently was composed of children who had unsuccesshlly used MPH but successfully responded to Adderall@. DISCUSSION

Nonresponders were included in this table as they also experienced side effects.

The primary purpose of this study was to examine the effectiveness of Adderall@as a viable treatment alternative for youths with A D H D . This goal was accomplished in a double-blind titration, placebo-controlled study of Adderall@(q.d.) and MPH (b.i.d.) in a clinicbased sample of youths. The Adderall@and MPH youths were matched on age, sex, and diagnostic classification. The Adderall@ and MP H youths did not differ from each other in symptomatology reported under the placebo condition, and, when given their best dose of Adderall@ and MPH, these groups did not differ from each other in behavioral symptoms reported by parents and teachers. Although neither Adderall@nor MPH differed in effectiveness, all youths’ behavioral symptoms were reduced under medicated conditions versus placebo. Side effects were examined for both medications, with no statistically significant differences emerging. No statistically or clinically significant safety issues emerged for this sample as well. That is, pulse, blood pressure, and weight remained stable across the assessment period and differential side effects were unremarkable.

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TABLE 5 Frequency of Side Effects on Best Dose Side Effect Insomnia Nightmares Stares a lot Decreased appetite Irritability Stomach ache Headache Drowsiness Sadlunhappy Prone to cry Anxious Perseverative Bites nails Euphoric Dizziness Ticslnervousness Overfocused Rebound

Methylphenidate ( n = 42) 2/42 0142 4/42 1I42 2/42 0142 1142 3/42 4/42 3/42 7/42 5/42 3/42 2/42 0142 0142 0142 1I42

Adderall@‘“ ( n = 42)

5/42 0142 1I42 0142 3/42 0142 2/42 0142 5/42 5/42 1I42 1I42 2/42 1142 0142 0142 0142 0142

EFFECTIVENESS OF ADDERALL@ A N D M P H

Potential Limitations

Although the study is the first to compare several dosage levels of Adderall@ (q.d.) with several dosage levels of MPH (b.i.d.) in a double-blind titration, placebocontrolled study, choice of medication was left to the discretion of the referring physician. As such, random assignment of medication was not an option in this study. Although efforts were made to equate children on all potential confounding demographic variables, future studies should examine the differential effectiveness of these medications under conditions of random assignment. A second limitation of this study is the fact that the sample is a clinic-based sample which caters to primarily middle-class families. While this is an unusual ADHD sample and unlike many in the literature (though similar to patients in many private practices), the availability of normative data on the measures used allows for confidence in the change in behavior observed under conditions of best dose. While significant behavioral changes were noted by both parents and teachers, it would be helpful to obtain behavioral observations and academic data from a classroom setting to supplement the ratings obtained on this sample. Future research using an analog classroom setting might enable an examination of the duration of action of both Adderall@and MPH. Clinical Implications

Similar to the findings of Swanson et al. (1998), Adderall@appeared to be as effective as MPH in reducing behavioral symptoms in this sample. We support Swanson and colleagues’ study, and we extend the findings on Adderall@in that we have shown in our sample that oncea-day dosing with Adderall@was comparablewith twice-aday dosing with MPH in reducing behavioral symptoms. Although caution should be exercised with all new findings, our conclusions are strengthened by the fact that 15 MPH nonresponders benefited behaviorally from [email protected] possible explanation for this finding could be that these MPH nonresponders were benefiting not from the Adderall@ per se, but rather the increased attention given in this formal medication trial. Although we are not able to rule this explanation out completely in the present investigation, this conclusion seems unlikely because the attention component was a constant across

J . A M . A C A D . C H I L D A D O L E S C . PSYCHIATRY, 3 8 : 7 , JULY 1999

both placebo and best-dose conditions, yet differences favoring best dose consistently emerged. Future research should examine cognitive, personality, and physiological factors that indicate differential responsivity to MPH and [email protected] addition, it would be useful to know what percentage of children are nonresponders to Adderall@and whether they benefit from MPH, dextroamphetamine, or Dexedrine@Spansules@. This study provides evidence in support of the use of a stimulant (Adderall@)administered once a day to children with ADHD. Medical management of children in schools is always a concern to both families and school personnel. The ability to manage the medical regimen of a child outside the parameters of the school appears to be quite beneficial to the child in terms of privacy and to the school in terms of time savings.

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