GW320659 for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children

Attention-deficit/hyperactivity disorder (ADHD) is oneof the most common childhood mental disorders. Theprevalence of ADHD, reported in epidemiological stud-ies using standardized diagnostic criteria, ranges from 3%

to 6% in the school-age population. Although a few stud-ies have suggested a lower prevalence, studies using newer,broader criteria show prevalence rates to be even higherthan 6% (Goldman et al., 1998). The NIH ConsensusStatement (National Institutes of Health, 1998) refers toADHD as a costly major public health problem, withsufferers experiencing pronounced impairments and pos-sible long-term adverse effects on academic performance,vocational success, and social-emotional development.These impairments can have a profound impact on affectedindividuals, their families, schools, and society.

Pharmacotherapy for children with ADHD, especiallythe use of psychostimulants for short- and long-termtreatment, is controversial. Although the most commonlyused stimulants such as methylphenidate and the amphet-amines have efficacy rates as high as 70% in controlledstudies, they do not work for all patients with ADHD(Stein et al., 1996). Furthermore, their use is associated

Accepted March 12, 2002.Drs. Laurenza, Barrows, Webster, Stotka, and Asgharnejad are with GlaxoSmithKline,

Research Triangle Park, NC; Drs. Conners and DeVeaugh-Geiss are with DukeUniversity Medical Center, Durham, NC; Dr. Sarkis is with Alachua Family Psychiatry,Gainesville, FL; Dr. Winner is with Premiere Research Institute at Palm BeachNeurology, West Palm Beach, FL; Dr. Ginsberg is with Red Oak Psychiatric Associates,Houston; and Dr. Hemphill is with Georgia Neurological Institute, Savannah. Dr.DeVeaugh-Geiss was with GlaxoSmithKline when this research was conducted.

This study was presented at the NCDEU Annual Meeting, May 30–June 2, 2000,in Boca Raton, FL; the AACAP Annual Meeting, October 24–29, 2000, in NewYork; and the ECNP Congress, September 9–13, 2000, in Munich.

This study (protocol ADDA2002) was sponsored by Glaxo Wellcome Inc. Theauthors thank Ruby Terracciano for writing and editing assistance.

Reprint requests to Dr. Asgharnejad, GlaxoSmithKline, Five Moore Drive,P.O. Box 13398, Research Triangle Park, NC 27709.

0890-8567/02/4108–0914�2002 by the American Academy of Child andAdolescent Psychiatry.

GW320659 for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children

JOSEPH DEVEAUGH-GEISS, M.D., C. KEITH CONNERS, PH.D., ELIAS H. SARKIS, M.D., PAUL K. WINNER, D.O.,LAWRENCE D. GINSBERG, M.D., J. MICHAEL HEMPHILL, M.D., ANTONIO LAURENZA, M.D.,

CATHLEEN F. BARROWS, PH.D., CHRISTOPHER J. WEBSTER, B.S., CHRISTOPHER J. STOTKA, PHARM.D., AND MAHNAZ ASGHARNEJAD, PHARM.D.

ABSTRACT

Objective: To assess the safety, tolerability, and efficacy of GW320659, a chemically novel inhibitor of norepinephrine

and dopamine reuptake, in pediatric attention-deficit/hyperactivity disorder (ADHD). Method: This was a multicenter,

open-label, dose-titration study of seven daily dose levels of GW320659: 1.25, 2.5, 5, 7.5, 10, 12.5, and 15 mg.Treatment

began with the lowest dose of GW320659 and increased weekly until subjects (mean age 9.1 years) achieved a maxi-

mum acceptable dose. Subjects remained at their maximum acceptable dose for a 4-week treatment period. The key

efficacy end-point was clinical response (Clinical Global Impressions of Improvement score of 1 or 2 and an improvement

of 5 or more points on at least one of the Conners Parent or Teacher Rating Scales T score). Other end-points included

assessments of safety and of quality of life using the Child Health Questionnaire Parent Form 28 (CHQ-PF28). Results:

Fifty-one subjects entered the titration phase and 46 subjects completed the study. During the treatment phase, these 46

subjects received a mean dose of 14.2 mg/day and the maximum exposure to GW320659 was 11 weeks. At the end of

the treatment period, 76% of subjects showed improvement with GW320659 and there were significant improvements

in 7 of the 12 subscales of the CHQ-PF28 compared with baseline (p < .05). Adverse events were generally mild; only

five subjects required downward titration because of adverse events (three psychiatric, one neurological and urological,

one cardiovascular), and no subject withdrew because of adverse events. Conclusions: GW320659 may have clinically

relevant efficacy in pediatric ADHD and was well tolerated in this short-term initial study in children. J. Am. Acad. Child

Adolesc. Psychiatry, 2002, 41(8):914–920. Key Words: GW320659, attention-deficit/hyperactivity disorder.

914 J . AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 41 :8 , AUGUST 2002

with adverse events including appetite loss, abdominalpain, insomnia, and nervousness (Ahmann et al., 1993;Efron et al., 1997). Stimulants also have abuse potentialand are controlled substances.

Other pharmacotherapies such as bupropion, tricyclicantidepressants, and monoamine oxidase inhibitors havebeen evaluated in clinical trials but have not been approvedby the Food and Drug Administration for use in treat-ing ADHD. Studies show that these antidepressants,which enhance noradrenergic and/or dopaminergic neu-rotransmission, may be effective treatments for ADHD(Barrickman et al., 1995; Biederman et al., 1986, 1989;Conners et al., 1996; Wender and Reimherr, 1990; Wilenset al., 1996). In particular, the efficacy of bupropion hasbeen shown in clinical trials of ADHD in both childrenand adults (Barrickman et al., 1995; Conners et al., 1996;Wender and Reimherr, 1990, Wilens et al., 2001).GW320659 is a chemically novel inhibitor of catecholaminereuptake that, like bupropion, inhibits norepinephrineand dopamine reuptake. With this pharmacological mech-anism, GW320659 may be potentially effective in thetreatment of ADHD.

The present dose-titration study was designed to assessthe effects of GW320659 in children with ADHD. Theobjective of the study was assessment of drug safety andtolerability.

METHOD

Study Design

This was a multicenter, open-label, dose-titration study beginningwith up to 4 weeks of screening/washout for subjects receiving med-ications which were excluded by the protocol criteria. All subjects thenentered a dose-titration phase of up to 7 weeks’ duration, followed bya 4-week treatment period and a 1-week follow-up period. All subjectsbegan the study on the lowest dose of 1.25 mg of GW320659, anddoses were titrated each week to a higher dose level (2.5 mg, 5 mg, 7.5mg, 10 mg, 12.5 mg, 15 mg) up to the maximum dose of 15 mg/dayor, if the subject experienced unacceptable adverse events (requiring adose reduction), to the highest tolerated dose. GW320659 was givenas a round, white tablet taken orally twice a day. The first dose wastaken when the subject awoke in the morning and the second doseapproximately 8 to 10 hours later. For observation and measurementof vital signs, subjects received the first dose of medication at each newdose level in the clinic and were required to remain in the clinic for aminimum of 3 hours after receiving each new dose level. Subjects con-tinued to take their maximum tolerated dose for a 4-week treatmentperiod. After completing the treatment period, subjects returned tothe clinic for a 1-week posttreatment follow-up visit. The study pro-tocol was approved by an institutional review board at each study cen-ter, and the trial was conducted according to Good Clinical PracticeGuidelines in accordance with the Declaration of Helsinki (1996).

Study Population

Subjects eligible for inclusion in the study were males and females(6–12 years old) with ADHD. Diagnosis of ADHD was according toDSM-IV criteria (American Psychiatric Association, 1994), based onan interview conducted by suitably qualified and trained psychiatricprofessionals. To be included, subjects had to have a minimum scoreof 4 (moderately ill) on the Clinical Global Impressions of Severity(CGI-S) scale, with functional impairment in at least the school andhome domains; subjects were required to have a Total T score of at least65 on both the Conners Parent Rating Scale (CPRS) and the ConnersTeacher Rating Scale (CTRS) at visit 2 (Conners, 1998). All parentsgave written informed consent for their children to participate in thestudy before their inclusion. Also, where approved by the institutionalreview board, subjects gave their assent to participate in the study.

Exclusion criteria included current or recent (<1 year) diagnosis ofmajor depression, panic disorder, bipolar disorder, conduct disorder,posttraumatic stress disorder, obsessive-compulsive disorder, suicidalbehavior, antisocial or borderline personality disorders. Other exclu-sion criteria included a history or current diagnosis of psychotic disor-der, anorexia nervosa, or bulimia; history of alcohol or substance abusewithin the past 6 months; use of any psychoactive drug or stimulant inthe week prior to visit 2; use of benzodiazepines, antihypertensives,antidepressants, monoamine oxidase inhibitors, fluvoxamine, anticon-vulsants, St John’s Wort, or lithium 2 weeks prior to visit 2; use of fluox-etine 4 weeks prior to visit 2; an IQ of less than 70; a history of seizuredisorder or any other unstable medical disorder or a known hypersen-sitivity to bupropion; home-schooled or without a teacher willing andable to complete the CTRS; and a body weight of less than 25 kg.

Study End-Points

The key efficacy end-point was clinical response at the end of thetreatment period defined as the subject having a CGI-Improvementscore of 1 or 2 (very much or much improved) and a clinically sig-nificant improvement (a decrease of at least 5 points) on either theCPRS T score or the CTRS Total T score compared with the base-line score. CPRS subscale T scores include the subscales Oppositional,Cognitive Problems/Inattention, Hyperactivity, Anxious-Shy,Perfectionism, Social Problems, Psychosomatic, Conners ADHDIndex, Conners Global Index Restless-Impulsive, Conners GlobalIndex Emotional Lability, Conners Global Index Total, DSM-IVInattentive, DSM-IV Hyperactive-Impulsive, and DSM-IV Total.CTRS subscale T scores include the subscales Oppositional, CognitiveProblems/Inattention, Hyperactivity, Anxious-Shy, Perfectionism,Social Problems, Conners ADHD Index, Conners Global IndexRestless-Impulsive, Conners Global Index Emotional Lability, ConnersGlobal Index Total, DSM-IV Inattentive, DSM-IV Hyperactive-Impulsive, and DSM-IV Total. Semistructured interviews, in whichinterviewers used the standard questionnaires but could vary the inter-view content as necessary during the interview, were used. Other end-points included changes in the CGI-Severity, the CPRS subscale Tscores, and the CTRS subscale T scores.

Health Outcomes Measures

The impact of ADHD and its subsequent treatment with GW320659on subjects’ quality of life was assessed by the 28-item Child HealthQuestionnaire Parent Form 28 (CHQ-PF28) (Health Institute, 1996)by the parent, at screening and at the end of the study. The CHQ-PF28includes the following 13 dimensions of child health: physical func-tioning, ability of the child to participate in social activities because ofphysical health, general health perception, bodily pain, parent’s time

GW320659 IN PEDIATRIC ADHD

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 41 :8 , AUGUST 2002 915

limitation because of child’s health, emotional impact on parents dueto child’s health, child’s limitations in activities due to emotional prob-lems, child’s limitations due to behavior problems, child’s self-esteem,child’s mental health, child’s general behavior, limitation and interrup-tion of family activities because of child’s health, and family cohesion.

Safety Measurements

Medical history, baseline characteristics, and a physical examinationwere done at screening. Other assessments made during the screeningand treatment phases included analyses of hematology, clinical chem-istry, urinalysis, blood pressure, heart rate, and electrocardiographic data.

Adverse events (AEs) noted by the investigators or reported bypatients spontaneously or during open-ended questioning were col-lected during the study and rated for severity and relationship to med-ication. A treatment-emergent AE was any AE that occurred for thefirst time after taking the first dose of study medication, or that hadoccurred prior to taking study medication but occurred at a higherintensity after taking study medication, and began prior to 24 hoursafter the last dose of study medication.

Sample Size and Statistical Analysis

Statistical and safety analyses were done on the intent-to-treat pop-ulation, which consisted of all subjects who received at least one doseof study medication. The health outcomes population consisted ofall subjects in the intent-to-treat population who completed (at least80% of questions answered) the CHQ-PF28 questionnaire at thescreening visit and at the end of treatment.

The last observation carried forward principle was used for missingefficacy data after a subject had been taking active drug for at least 3weeks. Change scores were calculated for the appropriate efficacy mea-sures by subtracting the baseline value from the visit value. In the Connersrating scales, T scores were derived from a table of raw scores, whichwere normalized based on a normally distributed population of childrenand adjusted for age and sex. The T scores allow each scale to be nor-malized in such a way that a mean of 50 represents normal, and devia-tions from normal are based on a standard deviation of 10. An improvementof one half of a standard deviation (5 points) was considered to be clin-ically significant. For the assessment of health outcomes, change wasassessed for individual CHQ-PF28 using a paired t test, comparing eachsubject’s screen values to end-of-treatment values.

RESULTS

Study Population

A total of 75 subjects were screened, of whom 24 with-drew before taking study medication. Eighteen of the with-drawn subjects failed to meet the inclusion/exclusion criteriafor the study, five withdrew consent, and one was lost tofollow-up. There were 51 subjects in the intent-to-treatpopulation who entered the titration phase of the studyand received at least one dose of open-label study med-ication. Five subjects withdrew during the titration phase,although none of these withdrawals was due to AEs. All46 subjects who entered the treatment phase completedthe study. Of these subjects, 43 were titrated up to the max-imum dose of 15 mg/day, 2 subjects to 12.5 mg/day, 1 sub-

ject to 7.5 mg/day, 1 subject to 5 mg/day, and 1 subject to2.5 mg/day. During the treatment phase, these 46 subjectsreceived a mean dose of 14.2 mg/day and the maximumexposure to GW320659 was 11 weeks. The characteristicsof the subjects at baseline are summarized in Table 1. Of51 subjects, 24 (47%) reported having never received phar-macological treatment for ADHD symptoms. Of the remain-ing 27 subjects, 53% reported that they had been treatedfor their ADHD; 25 had used stimulants. Nonstimulantmedications were previously used by 12 subjects (24%).

Clinical Response

As shown in Figure 1, 65% of subjects responded totreatment with GW320659 at the end of the titrationphase and 76% responded to GW320659 at the end ofthe treatment phase. (Treatment response was defined asthe subject having a CGI-Improvement score of 1 or 2[very much or much improved] and a clinically signifi-cant improvement [a decrease of at least 5 points] oneither the CPRS T score or the CTRS Total T score com-pared with the baseline score.) Subpopulation analysis(data not shown; no formal statistical analyses conducted)suggested that subjects who weighed ≥35 kg had higherresponse rates (85%) than subjects weighing <35 kg (69%).Higher response rates were also obtained in subjects whowere treatment-naive (95%) than in subjects previouslytreated (58%). Similarly, higher response rates wereobtained in subjects not previously treated with a stim-ulant (96%) than in subjects previously treated with astimulant (55%).

DEVEAUGH-GEISS ET AL.


TABLE 1Baseline Characteristics of Subjects in the Intent-to-Treat

Population (N = 51 Subjects)

Age (mean years ± SD) 9.1 ± 1.9Height (mean cm ± SD) 137.6 ± 10.8Sex: n (%)

Male 35 (69)Female 16 (31)

Race: n (%)White 43 (84)Black 5 (10)American Hispanic 3 (6)

Weight (mean kg ± SD) 35.19 ± 10.2Body mass index (mean ± SD) 18.3 ± 3.4ADHD subtype: n (%)

Combined 37 (73)Hyperactive-impulsive 5 (10)Inattentive 9 (18)

Note: ADHD = attention-deficit/hyperactivity disorder.



Conners Parent Rating Scale

The mean baseline Total T score for the CPRS was 83(the upper limit for normal is 65). This score was reducedto 61 at the end of the titration phase (95% confidenceinterval 57.7, 63.5) and to 59 at the end of the treatmentphase (95% confidence interval 55.8, 62.0). This reduc-tion constitutes a reduction of greater than 2 SD and isclinically significant. Similar results were obtained for theparent-rated Inattentive T score and the Hyperactive-Impulsive T score. Mean data are shown in Figure 2.

Conners Teacher Rating Scale

The mean baseline Total T score for the CTRS was 75(the upper limit of normal is 65). This score was reducedto 58 at the end of titration and to 60 at the end of treat-ment. This constitutes a reduction of 1.5 SD and is clin-ically significant. Similar results were obtained for theteacher-rated Inattentive T scores and the Hyperactive-Impulsive T scores. Mean data are shown in Figure 3.

Health Outcomes Results

A total of 41 subjects who completed the study hadCHQ-PF28 questionnaires that were at least 80% com-

plete. In the majority of cases, the questionnaire was com-pleted by the mother of the subject. A statistically sig-nificant improvement was observed in the psychosocialsummary score (p < .001) but not in the physical sum-mary score (p = .545). Subjects showed statistically sig-nificant improvements in 7 of the 12 subscales of theCHQ-PF28 at the end of treatment compared with base-line as follows: Role-Emotional/Behavior (p < .01),Behavior (p < .001), Mental Health (p < .001), Self-Esteem (p < .001), Parent Impact Emotional (p < .05),Parent Time Impact (p < .05), and Family Activities(p < .001). The subscales that had no significant changewith treatment were Physical Functioning, Role-Physical,Bodily Pain, General Health, and Family Cohesion.

Safety

Treatment-emergent AEs were reported by 92% of sub-jects. The majority of events were mild to moderate innature. The most commonly occurring drug-related, treat-ment-emergent AEs (reported by ≥10% of subjects) areshown in Table 2. Five subjects (10%) experienced AEsthat resulted in a dose reduction during the titration phase.Psychiatric AEs, reported by three of these subjects, included

Fig. 1 Percentage of clinical responders by week from baseline in the intent-to-treat population. Titr = titrationphase; Tmt = treatment phase; F/U = posttreatment follow-up visit.



Fig. 2 Effects of treatment with GW320659 on the Conners parent-ratedTotal T score, the parent-rated Inattentive T score, and the parent-ratedHyperactive-Impulsive T score. In each case the shadowed area represents 1.5SD around the norm.

Fig. 3 Effects of treatment with GW320659 on the Conners teacher-ratedTotal T score, the teacher-rated Inattentive T score, and the teacher-ratedHyperactive-Impulsive T score. In each case the shadowed area represents 1.5SD around the norm.

crying/emotional lability (n = 20) and mood elevations(n = 1). Increased blood pressure (from 100/64 mm Hgat screening to a maximum on-treatment blood pressureof 128/92 mm Hg) was observed in one subject who oftendrank highly caffeinated, carbonated beverages that, studypersonnel reported, may have contributed to the increase.Sleep disorder and nocturia were reported by one subject.Subject weight of <35 kg was the most consistent factorpredictive of the occurrence of AEs. Overall, no seriousAEs were reported and no subjects withdrew from the

study because of AEs. There were no clinically relevantchanges in laboratory parameters or electrocardiographicfindings after treatment with GW320659. Vital sign datashowed a mean increase of 10 beats per minute (bpm) instanding and supine heart rate at the end of treatmentcompared with baseline heart rates (90.6 bpm [SD = 11.9]to 100.3 bpm [SD = 13.5] for standing heart rate and 80.2bpm [SD = 9.0] to 89.8 [SD = 11.0] for supine heart rate).Supine systolic blood pressure also showed a mean increasefrom baseline of approximately 5 to 6 mm Hg (101.9 mm

Hg [SD = 11.7] to 107.2 mm Hg [SD = 107.2]). Theseincreases in heart rate and blood pressure were partiallyresolved at the 1-week posttreatment follow-up visit.

DISCUSSION

The results of this open-label study showed thatGW320659 appeared to be effective in treating childrenwith ADHD. There was considerable improvement (1–2SD) in both the CPRS and the CTRS scores, with bothscores falling to within the normal range at the end ofthe titration period and remaining in the normal rangethroughout the treatment period. These score improve-ments suggest that GW320659 works at home as well asat school. CPRS and CTRS subscales for Inattentive andHyperactive-Impulsive symptoms also improved con-siderably to within the normal range at the end of thetitration period and throughout the treatment period.Such results suggest that GW320659 improves both theinattentive and the hyperactive-impulsive symptoms ofADHD, so that behavior is similar to that of childrenwho do not suffer from ADHD.

Overall response rates were lower and the incidence ofAEs was higher in subjects with a baseline weight of <35kg compared with subjects with a baseline weight of ≥35kg. The lower-weight subpopulation may have received ahigher milligram-per-kilogram dose of study drug, whichmay have led to a higher plasma concentration ofGW320659. This in turn may have led to increased AEs,such as agitation, that may have lowered the perceivedefficacy of the treatment. Further work may be requiredto assess the effects of body weight on efficacy of GW320659.

Response rates were higher in treatment- or stimulant-naive subjects than in subjects who had previously receivedtreatment for ADHD. Subjects with previous treatment

may have been refractory to their past treatments (i.e., treat-ment failures). These subjects may be more likely to fail torespond to any subsequent treatments, including GW320659.

The response rates achieved in this study are compara-ble with efficacy rates achieved with currently marketedADHD medications such as methylphenidate and theamphetamines (Barkley, 1977; Klein, 1987; Wilens andBiederman, 1992). Although these stimulant medicationsare still the first choice in the treatment of ADHD, for somesubjects there is a stigma attached to taking a schedule IIcontrolled substance. Alternative treatments include drugssuch as bupropion, clonidine, and guanfacine and the tri-cyclic antidepressants (Cyr and Brown, 1998; Silver, 1999).Such treatments, which enhance noradrenergic and/or dopa-minergic neurotransmission, may also be effective treat-ments for ADHD. GW320659 is a chemically novel inhibitorof catecholamine reuptake that, like bupropion, inhibitsnorepinephrine and dopamine reuptake. With this phar-macological mechanism, GW320659 may be useful as anonstimulant treatment alternative for children with ADHD.

The results of the CHQ-PF28 showed the positive impactof GW320659 on the quality of life of children with ADHD.Health outcomes parameters improved after GW320659treatment, with significant improvements in 7 of the 12subscales of the CHQ-PF28. In particular, there was a sig-nificant improvement in the psychosocial summary scale,which is an aspect likely to be affected by ADHD. Suchprosocial benefits should improve family interactions anddecrease their stress levels. Although the CHQ-PF28 hasbeen used in populations of pediatric subjects with ADHD,the questionnaire is not specifically designed to measurequality of life in such children. Therefore, not all of the sub-scales are designed to measure areas of life affected by ADHD.For example, ADHD is not associated with pain or a reduc-tion in physical abilities so the lack of change in the phys-ical summary scale was expected.

GW320659 was well tolerated at all doses during thetitration phase and during the treatment phase. Treatment-emergent AEs were generally mild or moderate and resolvedwithout sequelae. AEs reported such as mood disorders,sleep disorders, and feeding problems are consistent withthe sympathomimetic pharmacological profile ofGW320659. Overall, the tolerability of GW320659 com-pared well with currently marketed ADHD medications.

Limitations

As this study was an open-label trial, the degree towhich improvements in patients’ symptoms are attrib-



TABLE 2Summary of Drug-Related, Treatment-Emergent Adverse Events

Occurring With a Frequency of ≥10%

% of SubjectsAdverse Event (N = 51)

Headaches 31Gastrointestinal discomfort and pain 25Crying, emotional lability 20Feeding problems (anorexia) 18Sleep disorders (insomnia) 14Nausea and vomiting 12Gastrointestinal signs and symptoms 10



utable to study medication or other factors such as regres-sion to the mean cannot be determined. A second limi-tation of the study is the relatively short treatment period;it is of interest to determine whether a more or less robustresponse rate to study medication would be obtained witha longer treatment period. Furthermore, the study wasconducted in a predominantly white sample.

Clinical Implications

In conclusion, this initial study in children suggeststhat GW320659 may have clinically relevant efficacy inADHD. The drug was well tolerated and the clinicalresponse rates were comparable with those of currentmedications, suggesting that GW320659 may be usefulas a nonamphetamine treatment alternative for childrenwith ADHD. Randomized, placebo-controlled trials willbe needed to confirm the results of this study.

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GW320659 for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children