ORIGINAL ARTICLE Efficacy of a Mixed Amphetamine Salts Compound in Adults With Attention-Deficit/ Hyperactivity Disorder Thomas Spencer, MD; Joseph Biederman, MD; Timothy Wilens, MD; Stephen Faraone, PhD; Jefferson Prince, MD; Kristine Gerard, MD; Robert Doyle, MD; Asha Parekh, MD; Jake Kagan, BA; Sarah Kate Bearman, BA Background: We report on a controlled trial of a Results: Treatment with Adderall at an average oral dose mixed amphetamine salts compound (Adderall, dextro- of 54 mg (administered in 2 daily doses) was effective and amphetamine sulfate, dextro-, levoamphetamine sul- well tolerated. Drug-specific improvement in ADHD symp- fate, dextroamphetamine aspartate, levoamphetamine toms was highly significant overall (42% decrease on the aspartate, and dextroamphetamine saccharate) in the ADHD Rating Scale, P,.001), and sufficiently robust to treatment of adult attention-deficit/hyperactivity disor- be detectable in a parallel groups comparison restricted der (ADHD). to the first 3 weeks of the protocol (P,.001). The percent- age of subjects who improved (reduction in the ADHD rat- Methods: This was a 7-week, randomized, double- ing scale of $30%) was significantly higher with Adderall blind, placebo-controlled, crossover study of Adderall treatment than with a placebo (70% vs 7%; P=.001). in 27 well-characterized adults satisfying full DSM-IV criteria for ADHD of childhood onset and persistent Conclusions: Adderall was effective and well tolerated symptoms into adulthood. Medication was titrated up in the short-term treatment of adults with ADHD. More to 30 mg twice a day. Outcome measures included the work is needed to evaluate the long-term effects of Adder- ADHD Rating Scale and the Clinical Global Impres- all, or other amphetamine compounds, in the treatment sion Score. Comorbid psychiatric disorders were of adults with ADHD. assessed to test for potential effects on treatment out- come. Arch Gen Psychiatry. 2001;58:775-782 N CHILDREN with attention-deficit/ example, in a placebo-controlled, single- hyperactivity disorder (ADHD), dose crossover study of dextroamphet- the literature suggests that the per- amine in normal men (N=31), Rapoport centage of responders is compa- et al10 reported improved cognitive per- rable between the stimulants.1 formance. In an open, 6-week trial of dex- IHowever, crossover studies of dextroam- troamphetamine in 18 adults with ADHD, phetamine and methylphenidate (6 stud- dramatic changes were reported in behav- ies, 274 subjects) reveal differences in ior, but not on cognitive measures.13 response on the individual level. Of re- sponders, 52% responded equally well to See also page 784 both, 25% preferentially to amphetamine, and 23% to methylphenidate.2-7 However, Despite the well-documented effi- these differences in response may be be- cacy of stimulant drugs in the treatment of cause of either efficacy or adverse effects. ADHD, their short duration of action com- In adults with ADHD, controlled monly requires a 3-times-daily dosing From the Pediatric studies have reported an average re- schedule to obtain a daylong clinical ef- Psychopharmacology Unit, sponse of 54% of subjects both to meth- fect. In children with ADHD the preva- Massachusetts General Hospital ylphenidate (6 studies, 139 subjects) and lence of after-school stimulant use has in- (Drs Spencer, Biederman, pemoline (2 studies, 93 subjects).8 To our creased.15 Such after-school dosing has been Wilens, Faraone, Prince, knowledge, the only previous controlled recommended for ADHD-associated non- Gerard, Doyle, and Parekh, trial of amphetamines in adults with ADHD academic adaptive dysfunctions in daily liv- Mr Kagan, and Ms Bearman) was a recent short-term study of dextro- ing, communication, and socialization and the Department of amphetamine in adults with broadly de- skills.16 Similar adaptive dysfunctions are Psychiatry, Harvard Medical 9 School (Drs Spencer, fined ADHD indicating efficacy. In addi- salient in adults with ADHD. Thus, a sim- Biederman, Wilens, Faraone, tion, there is a controlled study in normal plified dosing regimen with a longer- Prince, Gerard, Doyle, men10 as well as several case studies11,12 and acting compound could be particularly im- and Parekh), Boston. open series13,14 in adults with ADHD. For portant for adults with ADHD. (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 58, AUG 2001 WWW.ARCHGENPSYCHIATRY.COM 775 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 SUBJECTS AND METHODS to avoid exposure to high initial doses of active medica- tion and to minimize adverse effects. Other psychoactive medications were not permitted during the protocol. SUBJECTS ASSESSMENT Subjects were 30 outpatient adults with ADHD between 19 and 60 years of age ascertained from clinical referrals. To Before inclusion in the study, patients underwent a com- be included, subjects had to satisfy full diagnostic criteria prehensive clinical assessment that included a psychiatric for DSM-IV ADHD based on clinical assessment con- evaluation by a board-certified adult and child psychia- firmed by structured diagnostic interview. Attention-deficit/ trist (T.S., T.W., J.P., K.G., R.D., and A.P.), a structured hyperactivity disorder diagnoses, including age of onset by diagnostic interview, a medical history, and laboratory as- 7 years, were determined by self-report as well as school sessments (liver function tests, complete blood counts, and records and report by others as available. We excluded po- electrocardiograms). The structured diagnostic interview tential subjects if they had any clinically significant chronic used was the Structured Clinical Interview for DSM-IV,28 medical conditions, abnormal baseline laboratory values, supplemented for childhood disorders by modules (DSM- IQ less than 80, delirium, dementia, or amnestic disor- IV ADHD and conduct disorder) from the Kiddie Sched- ders, any other clinically unstable psychiatric conditions ule for Affective Disorders and Schizophrenia for School- (ie, bipolar disorder, psychosis), drug or alcohol abuse or Age Children (Epidemiologic Version).29 Diagnostic raters dependence within the 6 months preceding the study, pre- estimated a level of ADHD impairment (mild, moderate, vious adequate trial of Adderall, or current use of psycho- or severe) by assessing the degree of dysfunction (social, tropics. We also excluded pregnant or nursing females. This familial, academic, and occupational) specifically attribut- study was approved by the institutional review board and able to the ADHD symptoms. all subjects completed a written informed consent before To have been given a full diagnosis of adult ADHD, the inclusion in the study. subject must have (1) met full DSM-IV criteria (at least 6 of 9 symptoms) for inattentive or hyperactive/impulsive sub- PROCEDURE types30 by the age of 7 years as well as currently (within the past month); (2) described a chronic course of ADHD symp- This was a double-blind, placebo-controlled, randomized, toms from childhood to adulthood; and (3) endorsed a mod- crossover trial, comparing Adderall with placebo. There were erate or severe level of impairment attributed to the ADHD two 3-week treatment periods separated by 1 week of wash- symptoms. Diagnostic reliability of the structured inter- out to minimize carryover effects of medication. During views was established by having 3 experienced, board- washout, subjects received placebo pills to maintain the certified child and adult psychiatrists diagnose the condi- blind. The order of treatment (Adderall, placebo, or pla- tions of 35 subjects from audiotaped interviews made by the cebo, Adderall) was randomized by the research phar- assessment staff. The mean k was 0.91. A k of 1.0 was ob- macy. Weekly supplies of Adderall or placebo were dis- tained for ADHD with a 95% confidence interval of 0.8 to 1.0. pensed by the pharmacy in identical-appearing 10-mg To assess intellectual functioning, we administered sub- capsules. Study physicians prescribed medication under tests of the Wechsler Adult Intelligence Scale, Revised31 and double-blind conditions in twice-a-day dosing (7:30 AM, the Wide Range Achievement Test, Revised.32 Learning dis- 2:30 PM). Compliance was monitored by pill counts at each abilities33 were defined by the procedure recommended by physician visit. Study medication was titrated up to 20 mg/d Reynolds34 that provides a statistical method for operation- (10 mg twice daily) by week 1, 40 mg/d (20 mg twice daily) alizing the difference between achievement and intelli- by week 2, and 60 mg/d (30 mg twice daily) by week 3, gence scores. Family history was determined by question- unless adverse effects emerged. Although drug or placebo ing the subject about the presence of psychiatric disorders status was randomized, dose within each phase was not. in first- or second-degree relatives. Socioeconomic status Study treatment was always titrated from low to high dose was measured by the Hollingshead Four-Factor Index of There are sustained-release preparations available havior in classroom and recreational settings and in in- for both methylphenidate and dextroamphetamine creased academic performance, and that the time course (spansules). While some reports have indicated an equal of the response is longer, as shown in detailed pharma- response to methylphenidate immediate-release and sus- codynamic studies.25,26 While there has been no direct tained-release,4,17,18 others have not.19-22 Dextroamphet- comparison between Adderall