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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
Arch Gen Psychiatry. 2001;58:775-782.
ABSTRACT
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Background We report on a controlled trial of a mixed amphetamine salts compound
(Adderall, dextroamphetamine sulfate, dextro-, levoamphetamine sulfate, dextroamphetamine
aspartate, levoamphetamine aspartate, and dextroamphetamine saccharate) in
the treatment of adult attention-deficit/hyperactivity disorder (ADHD).
Methods This was a 7-week, randomized, double-blind, placebo-controlled, crossover
study of Adderall in 27 well-characterized adults satisfying full DSM-IV criteria for ADHD of childhood onset and persistent symptoms into
adulthood. Medication was titrated up to 30 mg twice a day. Outcome measures
included the ADHD Rating Scale and the Clinical Global Impression Score. Comorbid
psychiatric disorders were assessed to test for potential effects on treatment
outcome.
Results Treatment with Adderall at an average oral dose of 54 mg (administered
in 2 daily doses) was effective and well tolerated. Drug-specific improvement
in ADHD symptoms was highly significant overall (42% decrease on the ADHD
Rating Scale, P<.001), and sufficiently robust to be detectable
in a parallel groups comparison restricted to the first 3 weeks of the protocol
(P<.001). The percentage of subjects who improved (reduction
in the ADHD rating scale of  30%) was significantly higher with Adderall
treatment than with a placebo (70% vs 7%; P = .001).
Conclusions Adderall was effective and well tolerated in the short-term treatment
of adults with ADHD. More work is needed to evaluate the long-term effects
of Adderall, or other amphetamine compounds, in the treatment of adults with
ADHD.
INTRODUCTION
IN CHILDREN with attention-deficit/hyperactivity disorder (ADHD), the
literature suggests that the percentage of responders is comparable between
the stimulants.1 However, crossover studies
of dextroamphetamine and methylphenidate (6 studies, 274 subjects) reveal
differences in response on the individual level. Of responders, 52% responded
equally well to both, 25% preferentially to amphetamine, and 23% to methylphenidate.2, 3, 4, 5, 6, 7
However, these differences in response may be because of either efficacy or
adverse effects.
In adults with ADHD, controlled studies have reported an average response
of 54% of subjects both to methylphenidate (6 studies, 139 subjects) and pemoline
(2 studies, 93 subjects).8 To our knowledge,
the only previous controlled trial of amphetamines in adults with ADHD was
a recent short-term study of dextroamphetamine in adults with broadly defined
ADHD indicating efficacy.9 In addition, there
is a controlled study in normal men10 as well
as several case studies11, 12 and
open series13, 14 in adults with
ADHD. For example, in a placebo-controlled, single-dose crossover study of
dextroamphetamine in normal men (N = 31), Rapoport et al10
reported improved cognitive performance. In an open, 6-week trial of dextroamphetamine
in 18 adults with ADHD, dramatic changes were reported in behavior, but not
on cognitive measures.13
Despite the well-documented efficacy of stimulant drugs in the treatment
of ADHD, their short duration of action commonly requires a 3-times-daily
dosing schedule to obtain a daylong clinical effect. In children with ADHD
the prevalence of after-school stimulant use has increased.15
Such after-school dosing has been recommended for ADHD-associated nonacademic
adaptive dysfunctions in daily living, communication, and socialization skills.16 Similar adaptive dysfunctions are salient in adults
with ADHD. Thus, a simplified dosing regimen with a longer-acting compound
could be particularly important for adults with ADHD.
There are sustained-release preparations available for both methylphenidate
and dextroamphetamine (spansules). While some reports have indicated an equal
response to methylphenidate immediate-release and sustained-release,4, 17, 18 others have not.19, 20, 21, 22 Dextroamphetamine
spansules may be more consistently effective4;
however, few studies have examined effectiveness beyond 4 hours.4, 23
While relatively long-acting, pemoline has been relegated to second-line status
because of concerns about hepatotoxicity.24
An additional longer-acting amphetamine product is the mixed amphetamine
salts compound, Adderall. Adderall consists of 25% levoamphetamine and 75%
dextroamphetamine in 4 salts. Recent controlled studies in children have reported
that Adderall is as effective as methylphenidate immediate-release in the
improvement of behavior in classroom and recreational settings and in increased
academic performance, and that the time course of the response is longer,
as shown in detailed pharmacodynamic studies.25, 26
While there has been no direct comparison between Adderall and dextroamphetamine,
there are theoretic reasons for potential differences. Previous reports comparing
levoamphetamine with dextroamphetamine have suggested that some children respond
preferentially to each isomer.27
We now report results of a randomized, placebo-controlled clinical trial
of an amphetamine (Adderall) in the treatment of adults with ADHD. We hypothesized
that a twice-daily dosing regimen of Adderall at clinically relevant doses
will be effective in the treatment of adults with ADHD and provide adequate
daylong coverage of their symptoms.
SUBJECTS AND METHODS
SUBJECTS
Subjects were 30 outpatient adults with ADHD between 19 and 60 years
of age ascertained from clinical referrals. To be included, subjects had to
satisfy full diagnostic criteria for DSM-IV ADHD
based on clinical assessment confirmed by structured diagnostic interview.
Attention-deficit/hyperactivity disorder diagnoses, including age of onset
by 7 years, were determined by self-report as well as school records and report
by others as available. We excluded potential subjects if they had any clinically
significant chronic medical conditions, abnormal baseline laboratory values,
IQ less than 80, delirium, dementia, or amnestic disorders, any other clinically
unstable psychiatric conditions (ie, bipolar disorder, psychosis), drug or
alcohol abuse or dependence within the 6 months preceding the study, previous
adequate trial of Adderall, or current use of psychotropics. We also excluded
pregnant or nursing females. This study was approved by the institutional
review board and all subjects completed a written informed consent before
inclusion in the study.
PROCEDURE
This was a double-blind, placebo-controlled, randomized, crossover trial,
comparing Adderall with placebo. There were two 3-week treatment periods separated
by 1 week of washout to minimize carryover effects of medication. During washout,
subjects received placebo pills to maintain the blind. The order of treatment
(Adderall, placebo, or placebo, Adderall) was randomized by the research pharmacy.
Weekly supplies of Adderall or placebo were dispensed by the pharmacy in identical-appearing
10-mg capsules. Study physicians prescribed medication under double-blind
conditions in twice-a-day dosing (7:30 AM, 2:30 PM). Compliance was monitored
by pill counts at each physician visit. Study medication was titrated up to
20 mg/d (10 mg twice daily) by week 1, 40 mg/d (20 mg twice daily) by week
2, and 60 mg/d (30 mg twice daily) by week 3, unless adverse effects emerged.
Although drug or placebo status was randomized, dose within each phase was
not. Study treatment was always titrated from low to high dose to avoid exposure
to high initial doses of active medication and to minimize adverse effects.
Other psychoactive medications were not permitted during the protocol.
ASSESSMENT
Before inclusion in the study, patients underwent a comprehensive clinical
assessment that included a psychiatric evaluation by a board-certified adult
and child psychiatrist (T.S., T.W., J.P., K.G., R.D., and A.P.), a structured
diagnostic interview, a medical history, and laboratory assessments (liver
function tests, complete blood counts, and electrocardiograms). The structured
diagnostic interview used was the Structured Clinical Interview for DSM-IV,28 supplemented for
childhood disorders by modules (DSM-IV ADHD and conduct
disorder) from the Kiddie Schedule for Affective Disorders and Schizophrenia
for School-Age Children (Epidemiologic Version).29
Diagnostic raters estimated a level of ADHD impairment (mild, moderate, or
severe) by assessing the degree of dysfunction (social, familial, academic,
and occupational) specifically attributable to the ADHD symptoms.
To have been given a full diagnosis of adult ADHD, the subject must
have (1) met full DSM-IV criteria (at least 6 of
9 symptoms) for inattentive or hyperactive/impulsive subtypes30
by the age of 7 years as well as currently (within the past month); (2) described
a chronic course of ADHD symptoms from childhood to adulthood; and (3) endorsed
a moderate or severe level of impairment attributed to the ADHD symptoms.
Diagnostic reliability of the structured interviews was established by having
3 experienced, board-certified child and adult psychiatrists diagnose the
conditions of 35 subjects from audiotaped interviews made by the assessment
staff. The mean  was 0.91. A of 1.0 was obtained for ADHD with
a 95% confidence interval of 0.8 to 1.0.
To assess intellectual functioning, we administered subtests of the
Wechsler Adult Intelligence Scale, Revised31
and the Wide Range Achievement Test, Revised.32
Learning disabilities33 were defined by the
procedure recommended by Reynolds34 that provides
a statistical method for operationalizing the difference between achievement
and intelligence scores. Family history was determined by questioning the
subject about the presence of psychiatric disorders in first- or second-degree
relatives. Socioeconomic status was measured by the Hollingshead Four-Factor
Index of Social Status,35 with low values indicating
high socioeconomic status.
To assess change during treatment, board-eligible or board-certified
psychiatrists used the following scales. Overall severity and change in severity
of ADHD was assessed with the Clinical Global Impression Scale.36
The Clinical Global Impression Scale includes global severity (1, not ill,
to 7, extremely ill) and global improvement (1, very much improved, to 7,
very much worse) scales. The ADHD Rating Scale,37
shown to be sensitive to drug effects in pediatric38
and adult39, 40, 41, 42
populations, assesses each of the 18 individual criteria symptoms of ADHD
in DSM-IV on a severity grid (0, not present; 3,
severe; overall minimum score, 0; maximum score, 54). Five raters independently
reviewed audiotaped interviews of 5 subjects. An intraclass correlation of
0.99 was obtained for interrater reliability of the ADHD symptom checklist.
For depression, we used the 17-item Hamilton Depression Scale (HAM-D) (minimum,
0; maximum, 52)43 and the Beck Depression Inventory
(minimum, 0; maximum, 63).44 For anxiety, we
used the Hamilton Anxiety Scale (HAM-A) (minimum, 0; maximum, 56).45 The presence of adverse experiences was elicited by
open-ended questions at each visit. We administered the HAM-D, HAM-A, and
Beck Depression Inventory before and after each arm of the study. All other
symptom rating scales were administered weekly. Raters were blind to treatment
assignment.
Since ADHD has been associated with cognitive impairments,46
we included neuropsychological measures to test for potential drug effects
on cognition. Based on our review of the literature and our previous neuropsychologic
studies with ADHD children and adults,46 we
selected neuropsychological tests that measure sustained attention, response
inhibition, set shifting and categorization, selective attention and visual
scanning, and organization and recall of visual constructions. The test battery
included an auditory version of the Continuous Performance Test,47, 48
the Stroop test,49
and the Rey-Osterrieth Complex Figure.50 This
neuropsychological battery was administered 3 times, at baseline and after
each arm of the study.
SUBJECT CHARACTERISTICS
One hundred three prospective participants applied for entry into the
study. Of these, 30 were enrolled. Of the 73 who were not enrolled, 17 did
not complete the initial evaluation; 14 were excluded because of current substance
or alcohol abuse; 12 did not meet full DSM-IV criteria
for ADHD; 11 met entry criteria but were unable to commit to the demands of
a controlled study; 12 were excluded for medical conditions and/or current
use of concomitant medications (4 seizures, 3 sensory motor impairment, 2
hypertension, and 3 other); and 7 were excluded for unstable psychiatric conditions
or current use of psychotropics (3 psychosis, 1 bipolar, and 3 depression).
Of the 30 subjects enrolled in the study, 27 (90%) completed it. Three
subjects did not complete the first treatment arm: 1 after the first week
and 2 after the second week, and were not included in the final analyses.
These 3 patients were receiving placebo and never received Adderall. Thus,
the final sample consisted of 15 men and 12 women (age: mean ± SD,
38 ± 9.3 years). Seventy-eight percent (21/27) met criteria for ADHD
combined type in childhood (44% [12/27] currently) and 22% (6/27) met criteria
for ADHD predominantly inattentive type in childhood (56% [15/27] currently).
No one met criteria for ADHD predominantly hyperactive-impulsive type. Ten
(37%) of the 27 subjects had been diagnosed as having ADHD previously and
had received other medications (8 other stimulants; 2 desipramine).
STATISTICAL ANALYSIS
The primary outcome measures were the ADHD Rating Scale and the Clinical
Global Impression Scale. Improvement was defined either as a 30% reduction
in the ADHD Rating Scale or "much" or "very much improved" on the Clinical
Global Impression Scale. For statistical tests of change between 2 points
in time, we used the McNemar test (for binary data), the paired t test (for continuous data), or the Wilcoxon signed rank test (for
ordinal data). For analyses that used all of the time points in our data set,
we used random effects, cross-sectional time-series models using the method
of generalized estimating equations (GEE) as described by Liang and Zeger51 and Zeger et al52 These
models estimated main effects of drug (Adderall vs placebo), time (week in
study), and order (Adderall first vs placebo first), as well as interactions
among these effects. Significance was set at the .05 level and all tests were
2-tailed.
RESULTS
As depicted in Table 1, 93%
(N = 25) of ADHD subjects had at least 1 lifetime comorbid psychiatric disorder.
The mean ± SD number of comorbid diagnoses was 2.9 ± 2.5 per
subject. Baseline ratings of depression (HAM-D, 4.3, and Beck Depression Inventory,
6.2) and anxiety (HAM-A, 6.0) were low. Using standard cutoff points for moderate
severity on ratings of depression (HAM-D, >16; Beck Depression Inventory,
>19) and anxiety (HAM-A, >21), only 11% (N = 3) of subjects had baseline scores
of depression or anxiety that were moderately severe or worse. Sixty-seven
percent of ADHD adults had 1 or more first- or second-degree relatives with
ADHD. Despite average to above-average intelligence (mean ± SD, 108
± 11), 37% of the subjects required tutoring in school and 19% had
repeated at least 1 grade.
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Table 1. Clinical and Demographic Characteristics of Sample (N = 27)*
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EFFICACY
Averaged across both periods, at week 1 the average daily doses of Adderall
and placebo were both 20 mg; by week 2, 38.5 mg and 40 mg; by week 3, 53.7
mg and 59.3 mg, respectively. Examining the first and second periods separately,
inspection of Figure 1 shows some
evidence of a carryover effect in that the mean value of the ADHD Rating Scale
of the medication-first group at week 4 (placebo-washout) did not fully return
to the baseline (Figure 1, B). However,
the order effect (medication first vs medication second) was not significant
(random effects: z = 0.99, P = .32). Despite the weak order effect, we found a significant effect of drug
for both the first period (week 0-3: Adderall, 15; placebo, 12; z = 5.5, P<.001) and the second period
(week 4-7: Adderall, 12; placebo, 15; z = 5.7, P<.001). In addition the average change scores (ADHD
Rating Scale) were similar in each period of the study (35% vs 51% decrease
while receiving Adderall and 5% vs 7% increase while receiving placebo; first
vs second period, respectively). While none of the subjects worsened while
receiving Adderall, 55% (15/27) worsened while receiving placebo.
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The controlled study of Adderall in adult attention-deficit/hyperactivity
disorder (ADHD). Fifteen participants were randomized to Adderall and 12 to
placebo during the first period (A). During the second period (B), the 15
participants who were given Adderall were crossed over to placebo, and the
12 participants who were given placebo were crossed over to Adderall.
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In addition, we analyzed the results after combining the first and second
period. Response to Adderall attained significance by the first week of treatment
(z = 3.1, P = .002), with
further improvement by week 2 (z = 5.6, P<.001) and week 3 (z = 6.3, P<.001). Overall, there was a very significant drug by time interaction
for ADHD symptoms (z = 6.4, P<.001)
without significant main effects of drug (Adderall or placebo) or time (baseline
and weeks 1, 2, and 3).
To further evaluate the absolute rate of improvement, we analyzed end-of-treatment
results (averaged across both periods) using a preestablished definition of
improvement of more than a 30% reduction on the ADHD Rating Scale (see the
"Subjects and Methods" section). Using this definition, 70.4% (19/27) of patients
showed improvement of ADHD symptoms while receiving Adderall compared with
only 7.4% (2/27) who were receiving placebo ( 21
= 13.8, P<.001). Similarly, when improvement was
defined as much or very much improved on the Clinical Global Improvement Scale,
66.7% (18/27) of patients receiving Adderall were rated as improved compared
with only 3.7% (1/27) receiving placebo (21 = 14.2, P<.001). In addition, Adderall treatment significantly
reduced the Global Severity Scale ratings of ADHD (4.7 ± 0.7 to 3.4
± 1.0; z = 4.3, P<.001).
In contrast, placebo did not (4.6 ± 0.7 to 4.4 ± 0.9; z = 0.8, P = .45).
Adderall treatment (averaged across both periods) was associated with
clinically and statistically significant improvement of all but 2 of the 18
individual ADHD symptoms, with the notable effects observed for symptoms in
both subclusters of hyperactivity/impulsivity and inattention (Table 2). However, fewer of the individual hyperactive/impulsivity
items would achieve significance when corrected for multiple comparisons.
In contrast, the effect of placebo on individual ADHD symptoms was negligible.
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Table 2. Individual Symptom Scores on the Attention-Deficit/Hyperactivity
Disorder Scale at Baseline and at the End of Treatment of the Placebo and
Adderall Conditions
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Other than race and socioeconomic status, our sample represented a group
of adults with diverse clinical characteristics (Table 1). Therefore, we examined each of these characteristics as
potential confounders. While we did not have sufficient power to fully examine
this issue, a detailed analysis revealed no effects of ADHD subtype (combined
vs predominately inattentive), sex, age, history of comorbid disorders, lifetime
history of treatment, current comorbid disorders, or positive family history
of psychiatric disorder on rates of improvement while receiving Adderall or
placebo. As mentioned earlier, baseline ratings of depression (HAM-D, BDI)
and anxiety (HAM-A) were very low and were not affected by treatment with
Adderall.
At baseline, adults with ADHD in this study performed comparably with
non-ADHD adults on some cognitive tests (Rey-Osterrieth Complex Figure, Stroop
[Interference condition]). On other tests (Stroop [Word and Color], and Continuous
Performance Test) adults with ADHD were found to have mild difficulty at baseline
with equal improvement while receiving medication and placebo (Table 3).
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Table 3. Neuropsychological Functioning at Baseline and at the End
of Treatment of the Placebo and Adderall Conditions*
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ADVERSE EFFECTS
Adverse effects were reported on the entire sample, at any time during
treatment and tabulated in Table 4.
Adderall was well tolerated and no serious adverse effects were observed.
Of individual adverse effects reported, only Adderall-associated appetite
suppression and agitation reached our threshold for significance (Table 4). All patients who received active
medication completed the study. Six patients receiving Adderall did not reach
or were not able to remain on the final target dose of 60 mg because of subjective
adverse effects that included anxiety (n = 3), fatigue (n = 1), increased
obsessive symptoms (n = 1), and confusion (n = 1). However, these patients
were able to tolerate a lower dose. One patient did not tolerate 60 mg of
placebo because of insomnia. In addition, significant but a clinically small
difference was observed with Adderall treatment in diastolic blood pressure
(76 vs 71 mm Hg) (t25 = 2.6, P = .02). While weight decreased an average of 1.8 kg (4 lb) (167 vs
163 lb [75 vs 73 kg]) (t25 = 5.8, P<.001), weight loss was not of clinical significance
in any individual patient.
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Table 4. Adverse Events While Receiving Adderall and Placebo
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COMMENT
In a double-blind study of amphetamines in adults with ADHD, we found
that treatment with the mixed amphetamine salts product Adderall, administered
twice daily at an average oral daily dose of 54 mg, was well tolerated and
effective. Although this was a crossover design, reduction in ADHD symptoms
was sufficiently robust to be detectable in a parallel group comparison during
the first 3 weeks of the protocol (P<.001). These
results confirm the study hypothesis and suggest that Adderall is a well-tolerated
and effective treatment for adults with ADHD.
Although the duration of drug action was not measured directly, our
results suggest that twice-daily dosing of Adderall may be comparable with
methylphenidate using a thrice-daily dosing.39
Subjects in our study indicated that twice-daily dosing was sufficient to
cover the entire day and there was no subjective sense of medication "wear-off"
in between doses.
These results extend to amphetamines other findings documenting a highly
similar pattern of drug responsivity between children and adults with ADHD
to anti-ADHD medications including methylphenidate,39
pemoline,42 desipramine,40
tomoxetine,41 and bupropion.53
The similarities in drug response across the life span provide further support
for the informativeness of trials of adults with ADHD in drug development
programs for ADHD.
Traditional analyses in clinical trials examine outcome using a cutoff
score. We used a 30% cutoff of ADHD symptoms (ADHD Rating Scale) to define
improvement. In another report, we have addressed the issue of cutoffs by
use of a novel analytic technique, the drug-placebo response curve, that examines
the entire range of symptom change scores.54
In addition, in this study the negligible overall response to placebo was
composed of individuals who improved and individuals who worsened. Another
pharmacotherapy study of adults with ADHD also revealed worsening while receiving
placebo.54
Although we evaluated a range of neuropsychological outcomes using a
battery of tests that measures executive functions, most subjects performed
well on this battery. The relative good function at baseline is consistent
with other studies showing adult ADHD to be associated with mild neuropsychological
deficits.46 This created a "ceiling" effect
that did not allow the detection of medication-associated cognitive improvements.
The development of tests that are more sensitive to neuropsychological dysfunction
in ADHD adults may be required to assess fully the effect of pharmacological
treatments.
The absence of meaningful associations between Adderall treatment and
ratings of anxiety and depression indicate that Adderall-associated ADHD improvement
was unlikely to be secondary to improvement in comorbid depression or anxiety
in our sample. They also indicate that Adderall treatment was not associated
with worsening of anxiety or depression in this sample that had a frequent
history of comorbidity with these disorders. While we did not have sufficient
statistical power to fully examine the effects of potential confounding factors,
the absence of sex and comorbidity effects in the treatment response of adults
with ADHD is consistent with prior studies with other medications, and does
not support the practice of excluding comorbid cases in clinical trials of
adults with ADHD.
Although none of our subjects suffered from pre-existing hypertension,
patients with poorly controlled hypertension may not be eligible for stimulant
treatment until their blood pressure is well controlled. Special monitoring
may be required in patients with borderline hypertension receiving Adderall
or other stimulant drugs. Until more is known about long-term treatment in
adults, periodic assessment of blood pressure may be warranted in patients
exposed to stimulants.
The results of this study should be viewed in light of methodological
limitations. These include the relatively small subject size, use of a crossover
design, and a relatively short exposure to medication. While studies in children
suggest a rapid response to stimulants, in clinical practice a more gradual
dose escalation is the rule. In our study, the dose was increased weekly;
thus we cannot disentangle dose and time effects. It is possible that continued
exposure would lead to increased effectiveness of long-term Adderall treatment.
While the use of a crossover design provides increased statistical power,
the evidence of a minor carryover effect would suggest that in future studies,
a longer washout period or a parallel design may be more optimal. Nevertheless,
reduction in ADHD symptoms was robust enough to be detectable in a parallel
group comparison. Despite their robustness, our results could not address
the impact of Adderall on functioning and quality of life. Such information
is critical to further inform the risk vs benefit analysis of treatment with
Adderall. Longer studies with appropriate instrumentation assessing these
domains will be needed to address these important issues.
Despite these limitations, this study has shown that Adderall significantly
improved ADHD symptoms and was well tolerated. These promising initial results
provide support for further studies of Adderall or other amphetamine compounds
in the treatment of adult ADHD using a wide range of doses over an extended
period of treatment and with more detailed assessment of functioning and quality
of life.
AUTHOR INFORMATION
Accepted for publication October 31, 2000.
Supported in part by funding from Shire Richwood Pharmaceuticals, and
grant R29MH57511 from the National Institutes of Mental Health, Bethesda,
Md (Dr Spencer).
Preliminary results were presented at the annual meeting of the American
Academy of Neurology,Toronto, Ontario, April 21, 1999, the annual meeting
of the American Psychiatric Association, Washington, DC, May 20, 1999, and
the annual meeting of the New Clinical Drug Evaluation Unit, Boca Raton, Fla,
June 2, 1999.
We thank John Vetrano, RPh, Harold Demonaco, MS, RPh, and other pharmacy
staff at the Massachusetts General Hospital, and Jeff Bostic, MD, for their
assistance with this project.
From the Pediatric Psychopharmacology Unit, Massachusetts General Hospital
(Drs Spencer, Biederman, Wilens, Faraone, Prince, Gerard, Doyle, and Parekh,
Mr Kagan, and Ms Bearman) and the Department of Psychiatry, Harvard Medical
School (Drs Spencer, Biederman, Wilens, Faraone, Prince, Gerard, Doyle, and
Parekh), Boston.
Reprints: Thomas Spencer, MD, Pediatric Psychopharmacology Unit (ACC-725),
Massachusetts General Hospital, Fruit Street, Boston, MA 02114.
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