Placebo-Controlled Evaluation of Amphetamine Mixture—Dextroamphetamine Salts and Amphetamine Salts (Adderall): Efficacy Rate and Side Effects Peter A. Ahmann, MD*; Fred W. Theye, PhD‡; Richard Berg, MS§; Ann J. Linquist, BA§; Alayne J. Van Erem, MDʈ; and Lois R. Campbell, MD* ABSTRACT. Objective. The primary objective of this and insomnia were rated as worse by parents while chil- study was to determine the efficacy rate of Adderall in dren were receiving either dose of Adderall; headaches children newly diagnosed with attention-deficit/hyperac- were rated as worse when children were receiving the tivity disorder (ADHD). A secondary objective was to higher dose of Adderall. Parents rated certain side ef- address the severity of side effects associated with fects, including staring/daydreaming, sadness, euphoria, Adderall treatment in children with ADHD using the and anxious/irritable, as worse during placebo regimens. Barkley Side Effects Questionnaire (BSEQ). Conclusions. We found that Adderall is highly effi- Design. Randomized, double-blind, placebo-con- cacious in our population of youth diagnosed with trolled crossover trial. ADHD. In addition, Adderall is well-tolerated with a Setting. A large rural tertiary care clinic. side effect profile similar to that reported for other Patients. Participants were prospectively recruited psychostimulants. Pediatrics 2001;107(1). URL: http:// from children 5 to 18 years of age referred for academic www.pediatrics.org/cgi/content/full/107/1/e10; attention- and/or attention problems; 154 children who met the deficit/hyperactivity disorder, side effects, efficacy rate, Diagnostic and Statistical Manual of Mental Disorders, Adderall. Fourth Edition criteria for ADHD were enrolled. Interventions. Two doses of Adderall (0.15 mg/kg/ dose and 0.3 mg/kg/dose) were compared with placebo in ABBREVIATIONS. ADHD, attention-deficit/hyperactivity disor- separate 2-week trials. Participants received each dosage der; ACTeRS, ADD-H Comprehensive Teachers’ Rating Scale; regimen twice daily for 7 consecutive days. CTRS-28, Conners’ Teachers’ Rating Scale (28 items); CPRS-48, Measurements and Main Results. Efficacy rates were Conners’ Parent Rating Scale (48 items); BSEQ, Barkley Side Ef- fects Questionnaire; CBCL, Child Behavior Checklist; SD, stan- determined by comparing Adderall with placebo during dard deviation. the low-dose crossover sequence and also during the high-dose crossover sequence. The criteria that defined a positive response to Adderall relative to placebo (with ttention-deficit/hyperactivity disorder (ADHD) each patient serving as their own control) included an is the most commonly diagnosed neurobe- indication of response by at least 1 of 2 parent measures havioral disorder of childhood and is esti- of children’s behavior or at least 2 of 5 teacher measures A 1 mated to affect 5% to 11% of school-aged children. of children’s behavior. The Adderall efficacy rate was determined based on parent criteria alone, teacher crite- Although various specialists may be involved in the ria alone, and by a more stringent definition of response care of children with ADHD during the continuum that required concurrence between parent and teacher of diagnosis and management, the primary care phy- criteria. The Adderall response rate in this study ranged sician frequently performs the initial evaluation of a from 59% when requiring concurrence between parent child with the disorder. Therefore, pediatricians and teacher observers, to 82% when based on parent should be cognizant of the efficacy rates and side criteria alone. Overall, 137 of 154 participants (89%) effect profiles of all currently available psychostimu- showed a positive response by either the parent or lant medications. teacher response criteria. Parents completed a modified version of the BSEQ Psychostimulants have served as the primary during each week of the trial. Appetite, stomachaches, mode of treatment of ADHD with reported efficacy rates of ϳ70%.2 For the past 2 decades, methylpheni- date (Ritalin, Novartis, East Hanover, NJ) and dex- ʈ From the Departments of *Neurology, ‡Neuropsychology, and Pediatrics, troamphetamine (Dexedrine, SmithKline Beecham, Marshfield Clinic, and the Department of §Clinical Research, Marshfield Medical Research Foundation, Marshfield, Wisconsin. Philadelphia, PA; DextroStat, Shire Richwood Inc, Preliminary results of this study were presented at the following meetings: Florence, KY) have been used for the management of American Academy of Neurology; April 6, 1999; Toronto, Canada; Child ADHD. A product comprised of mixed amphet- Neurology Society; October 22–24, 1998; Montreal, Canada; CHADD’s An- amine salts (Adderall, Shire Richwood Inc) has been nual International Conference on ADHD; October 15–17, 1999; Washington, DC; and the American Academy of Child and Adolescent Psychiatry; marketed for the treatment of ADHD since 1994. October 21, 1999; Chicago, IL. Abstract of preliminary results was published Each Adderall tablet contains equal milligram por- in Neurology. 1999;52(suppl 2):A154 tions of d-amphetamine saccharate, d,l-amphetamine Received for publication Feb 10, 2000; accepted Sep 7, 2000. aspartate, d-amphetamine sulfate, and d,l-amphet- Reprint requests to (P.A.A.) Department of Neurology, Marshfield Clinic, 3 1000 N Oak Ave, Marshfield, WI 54449. E-mail: [email protected] amine sulfate. This combination of salts and isomers 4 PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad- results in a 3:1 ratio of dextro to levoamphetamine. emy of Pediatrics. In Ͼ4000 patients with ADHD enrolled in an open- http://www.pediatrics.org/cgi/content/full/107/1/Downloaded from www.aappublications.org/newse10 by PEDIATRICSguest on September Vol. 24,107 2021 No. 1 January 2001 1of11 label trial of Adderall, reported side effects were ticipants 7 years of age and younger were given a modified typical of other psychostimulant medications and “Assent Form” to sign, written in age-appropriate language. At the time of initial appointment, an extensive medical history included decreased appetite, insomnia, and head- form was completed by the family. The Child Behavior Checklist 4 aches. No research has been conducted to address (CBCL)18 served as an initial screening measure for comorbid the differences between mixed salts of amphetamine conditions during this portion of the examination. The results of and dextroamphetamine spansules. the CBCL are given in Table 1. The physician and the neuropsy- The prevalence of ADHD among school-aged chil- chologist each interviewed the family independently, framing their interview questions around the 18 behavioral items from the dren as well as the recently recognized persistence of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition the disorder into adolescence and adulthood requir- criteria for ADHD. The physician also completed a physical and ing long-term treatment with psychostimulant med- neurological examination. The neuropsychologist evaluated the ications have contributed to the inclusion of Adderall patient for comorbid disorders of mood, anxiety, and conduct. Consultation then occurred between the physician and neuropsy- in the “Top 200” list of most frequently prescribed chologist regarding their findings. Both physician and neuropsy- 5 medications in the United States. Recent compara- chologist reviewed the results from previsit questionnaires sent to tive trials indicate that Adderall is at least as effica- the family (CTRS, CPRS, and ACTeRS) to ensure that the results cious as Ritalin.6–10 Potential advantages to the use were consistent with eligibility criteria. (See Table 2 for these of Adderall in the treatment of ADHD include baseline test data.) To be categorized as either ADHD subtype impulsive or com- the following: a longer duration of action than bined (impulsive and inattentive), at least 3 of the following 5 Ritalin6; a dose-dependent duration of action8; a re- criteria had to be met: duction in the need for in-school dosing of a psycho- 9–11 1. ACTeRS Attention Score at or below the 25th percentile; stimulant ; and a smoother course of clinical ac- 2. ACTeRS Hyperactivity Score at or below the 25th percentile; 12 tion. At the conclusion of a comparison trial of 3. CTRS-28 Inattention/Passivity Scale 2 or more standard devi- Adderall and Ritalin, Pelham and colleagues6 recom- ations (SDs) above the mean; mended Adderall by a ratio of 3:1 for continued 4. CTRS-28 Hyperactivity Index 2 or more SDs above the mean; medication treatment in children with ADHD. How- 5. CPRS-48 Hyperactivity Index 2 or more SDs above the mean. ever, review of the literature reveals that no study To be categorized as ADHD subtype inattentive, the child had involving large numbers of children in a naturalistic to also meet at least 2 of the following 3 criteria: setting has systematically and prospectively ad- 1. ACTeRS Attention Score at or below the 25th percentile; dressed efficacy rates and side effects associated with 2. CTRS-28 Inattention/Passivity scale Ͼ1.5 SDs above the mean; this mixture of amphetamine salts, compared with 3. Teacher narrative that suggests problems with careless mis- placebo in a randomized, double-blind manner. takes, organization skills, maintenance of routines, loss of ma- terials, and failure to finish work. This prospective study was initiated in 1997 to determine the efficacy rate and side effect profile of Children with a history of seizures, mental retardation, or other Adderall in the treatment