SPECIAL SECTION

Effects of Stimulant Medication on Growth Rates

Across 3 Years in the MTA Follow-up
JAMES M. SWANSON, PH.D., GLEN R. ELLIOTT, PH.D., M.D.,
LAURENCE L. GREENHILL, M.D., TIMOTHY WIGAL, PH.D., L. EUGENE ARNOLD, M.D.,
BENEDETTO VITIELLO, M.D., LILY HECHTMAN, M.D., JEFFERY N. EPSTEIN, PH.D.,
WILLIAM E. PELHAM, PH.D., HOWARD B. ABIKOFF, PH.D., JEFFREY H. NEWCORN, M.D.,
BROOKE S.G. MOLINA, PH.D., STEPHEN P. HINSHAW, PH.D., KAREN C. WELLS, PH.D.,
BETSY HOZA, PH.D., PETER S. JENSEN, M.D., ROBERT D. GIBBONS, PH.D.,
KWAN HUR, PH.D., ANNAMARIE STEHLI, M.P.H., MARK DAVIES, M.S.,
JOHN S. MARCH, M.D., M.P.H., C. KEITH CONNERS, PH.D., MARK CARON, PH.D.,
AND NORA D. VOLKOW, M.D.

ABSTRACT
Objective: To evaluate the hypothesis of stimulant medication effect on physical growth in the follow-up phase of the
Multimodal Treatment Study of Children With ADHD. Method: Naturalistic subgroups were established based on patterns of
treatment with stimulant medication at baseline, 14-, 24-, and 36-month assessments: not medicated (n = 65), newly
medicated (n = 88), consistently medicated (n = 70), and inconsistently medicated (n = 147). Analysis of variance was used to
evaluate effects of subgroup and assessment time on measures of relative size (z scores) obtained from growth norms.
Results: The subgroup  assessment time interaction was significant for z height (p < .005) and z weight (p < .0001), due
primarily to divergence of the newly medicated and the not medicated subgroups. These initially stimulant-naı̈ve subgroups
had z scores significantly 90 at baseline. The newly medicated subgroup showed decreases in relative size that reached
asymptotes by the 36-month assessment, when this group showed average growth of 2.0 cm and 2.7 kg less than the not
medicated subgroup, which showed slight increases in relative size. Conclusions: Stimulant-naı̈ve school-age children with
Combined type attention-deficit/hyperactivity disorder were, as a group, larger than expected from norms before treatment but
show stimulant-related decreases in growth rates after initiation of treatment, which appeared to reach asymptotes within 3
years without evidence of growth rebound. J. Am. Acad. Child Adolesc. Psychiatry, 2007;46(8):1015Y1027. Key Words:
attention-deficit/hyperactivity disorder, growth, methylphenidate, side effects, long-term outcome.

The use of stimulant medications (see American

Accepted January 8, 2007.
Please see end of text for author affiliations.
The work reported was supported by cooperative agreement grants and contracts
from the National Institute of Mental Health to the following: University of
California, Berkeley: U01 MH50461 and N01MH12009; Duke University:
U01 MH50477 and N01MH12012; University of California, Irvine: U01
MH50440 and N01MH 12011; Research Foundation for Mental Hygiene
(New York State Psychiatric Institute/Columbia University): U01 MH50467.
The opinions and assertions contained in this report are the private views of
the authors and are not to be construed as official or as reflecting the views of the
National Institute of Mental Health, the National Institutes of Health, or the
Department of Health and Human Services.
Correspondence to Dr. James M. Swanson, UCI Child Development Center,
19722 MacArthur Blvd., Irvine, CA 92612; e-mail: jmswanso@uci.edu.
8567/07/4608-1015Ó2007 by the American Academy of Child and
Adolescent Psychiatry.
DOI:10.1097/chi.0b013e3180686d7e
Academy of Child and Adolescent Psychiatry, 2002)
to treat children with attention-deficit/hyperactivity
disorder (ADHD) has increased dramatically since
1990 (Olfson et al., 2002; Swanson et al., 1995),
despite limited information on long-term effects
(Charach et al., 2004; Gillberg et al., 1997). The
Multimodal Treatment Study of Children With
ADHD (MTA) was intended to fill this gap (see
Arnold et al., 1997). The primary reports of outcome in
the MTA focused on efficacy, with assessment of
outcome at the end of the initial 14-month treatment
phase (MTA Cooperative Group, 1999) and at the first
follow-up 10 months later, 24 months after initiation

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 46:8, AUGUST 2007 1015

Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
SWANSON ET AL.
of treatment (MTA Cooperative Group, 2004a).
The companion reports in this special section (Jensen
et al., 2007; Molina et al., 2007; Swanson et al., 2007)
focus on efficacy and changes in effectiveness at the end
of the second follow-up phase, 36 months after
initiation of treatment. The secondary analyses reported
here focus on a possible side effect of stimulant
medication on growth rates of school-age children
with ADHD.
The hypothesis of a stimulant-related decrease in
physical growth rates (a slowing in the gain of height
and weight) was proposed by Safer et al. (1972).
Consensus reviews and statements decades apart (see
NIH Consensus Committee, 1998; Roche et al., 1979)
discounted the clinical significance of this hypothesis,
based on prevailing views that short-term growth
suppression may occur but does not result in long-
term effects on ultimate size. Two hypotheses that offer
explanations for this discrepancy of short- and long-
term effects on growth and relative size are the growth
rebound hypothesis (Safer et al., 1975) and the delayed
maturation hypothesis (Spencer et al., 1996).
The evidence of growth rebound is inconsistent and
mostly circumstantial. Safer et al. (1975) reported that
when children were treated with stimulant medications
(D-amphetamine or methylphenidate) during the school
year, then growth rates for both height and weight were
less than expected based on norms, but if medication was
discontinued during the summer, growth rates then
appeared to be greater than expected, suggesting growth
rebound. Satterfield et al. (1979) reported that growth
suppression was manifested in the first year of treatment
but was followed by growth rebound (greater than
expected growth) whether or not stimulant medication
was discontinued in the summer. However, multiple
studies have not replicated this effect of growth rebound
during continued treatment with stimulant medication.
Mattes and Gittelman (1983) evaluated groups of
children with continuous treatment for 1 to 4 years and
documented stimulant-related growth deficit that accu-
mulated with the duration of treatment. It was still
present during the final year of observation in the group
treated for 4 years with methylphenidate, suggesting that
growth slowing did not abate during continuous
treatment.
Apparently, the growth rebound hypothesis gained
prominence and acceptance based on long-term follow-
up studies that suggested that ultimate height in
1016
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adulthood was not affected by childhood treatment
with stimulants. Klein and Mannuzza (1988) followed
the Mattes and Gittelman (1983) sample into adult-
hood and compared their average size to a nonclinical
control group. No difference in height or weight was
observed. Kramer et al. (2000) followed the Loney et al.
(1981) sample into adulthood and compared height
and weight to control groups drawn from family
members (unmedicated brothers and fathers), the
community (randomly selected classmates), and clinical
groups (individuals with clinical problems but never
medicated). No differences in self-reported height or
weight were documented. Because ultimate height
appeared not to be compromised in adults who had
shown growth slowing during treatment as children, the
implication of these studies was that growth rebound
must have occurred. However, growth rebound was not
measured directly in these influential studies.
Spencer et al. (1996) proposed that maturational lag
characterized the clinical condition of ADHD, which
produced a reduction in growth rate that was correlated
with but not necessarily a result of treatment with
stimulant medication. This hypothesis was based on
data from a 4-year follow-up of a longitudinal study of
a group of 124 boys with ADHD, all but 10 with a
lifetime history of treatment with medication, com-
pared to a control group of 109 boys without ADHD.
However, growth measures were obtained only at one
point in time in the longitudinal study, providing only
cross-sectional evaluation of size. The key findings of
the study were that height and weight deficits were
evident in the younger but not the older adolescent
children with ADHD and that there was no association
between height deficits and treatment with various drug
classes (stimulant or other), various dose regimens
(robust or mild), and duration of treatment. Based on
this, they proposed that slow growth in ADHD
children was due primarily to early but temporary
manifestations of the ADHD itself and may be disorder
related rather than treatment related. Using the same
design, Biederman et al. (2003) described the growth of
a group of 140 girls with ADHD, most (70%) with a
lifetime history of treatment with medication, com-
pared with a control group of 122 non-ADHD girls.
They reported a similar pattern as Spencer et al. (1996)
reported for boys: the group of preadolescent but not
adolescent girls was shorter than the control group, but
this difference was not significant for relative size
J. AM. ACAD. CH ILD ADOLESC. PSYCHIAT RY, 46:8, AUGUST 2007

adjusted for age and was not related to medication
history. Comparisons of the two samples showed no
significant effect of sex. Based on this, they concluded
that treatment with stimulant medication does not have
an adverse impact on growth of children with ADHD.
In recent studies of possible effects of stimulant
medication on growth, the findings are inconsistent.
Two recent chart-review studies of children treated with
stimulant medication in clinical practices in the United
States (Lisska and Rivkees, 2003) and Australia
(Poulton and Cowell, 2003) have shown reductions
in growth rates for up to 3 years without evidence of
growth rebound. In two other recent chart-review
studies, no evidence was found to support the
hypothesis that clinical treatment with stimulant
medications reduced the growth rates of children with
ADHD (Pliszka et al., 2006; Spencer et al., 2006).
However, in both of these studies, the treatment
regimens allowed for medication holidays, so they did
not evaluate the effects of continuous treatment. A
recent prospective study of the initiation of methyl-
phenidate treatment in preschool children, the Pre-
school ADHD Treatment Study, did evaluate effects of
stimulant medication on growth when treatment was
monitored frequently and was maintained for the initial
period of 1 year, and under these conditions, significant
reductions in growth rates were documented for both
height and weight (Swanson et al., 2006).
When the MTA was initiated (see Arnold et al.,
1997) and when the initial analyses were performed (see
MTA Cooperative Group, 1999), there was a strong
consensus (NIH Consensus Committee, 1998; Roche
et al., 1979) that growth suppression either was
clinically insignificant (due to a temporary effect of
initial treatment with stimulant medication followed by
growth rebound) or was an artifact of a characteristic of
the clinical condition that resulted in slow growth that
was correlated with the use of stimulants but not a
consequence of this treatment. Based on this consensus,
the possible risk of stimulant-related growth suppres-
sion was not a consideration (e.g., it was not mentioned
in the consent forms for the MTA), and a test of the
hypothesis of stimulant-related growth suppression was
not addressed as a specific aim of the MTA.
It is not surprising, then, that the initial evaluations of
outcome emphasized characterization of long-term
efficacy (MTA Cooperative Group, 1999) and that the
evaluation of the measures of height and weight were not
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 46:8, AUGUST 2007
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EFFECTS OF STIMULANT MEDICATION ON GROWTH
included in the initial report of the effects of treatment.
The first evaluation of growth in the MTA was part of a
report of outcome at the first follow-up 2 years after
initiation of treatment (MTA Cooperative Group,
2004b). In this report the intent-to-treat evaluation of
assigned treatment revealed that at 14 months the two
groups assigned to systematic stimulant medication
showed an initial reduction in growth rate for height
(j1.23 cm/year) and weight (j2.48 kg/year), which
dissipated by the 24-month assessment. However, this
dissipation was apparently due to differences between
assigned and actual treatment. Changes in height and
weight in naturalistic subgroups defined by consistent
treatment (i.e., with stimulant medication at both the
14- and 24-month assessments or no treatment at either
assessment) revealed continued stimulant-related reduc-
tions in annual growth rates in the second year for height
(j1.04 cm/year) and weight (j1.22 kg/year).
However, in the 24-month evaluation of growth in
the MTA, we did not evaluate growth in terms of
normed relative size (z scores) or the effect of previous
treatment with stimulant medication on initial size
upon entry into the MTA. Here we focus on the
evaluation of the hypothesis of long-term growth
slowing, this time with more rigorous methods and a
longer follow-up period than in the previous report
(MTA Cooperative Group, 2004b).
METHOD
The characteristics of the clinical sample and the general methods
of the MTA are described in previous publications (MTA
Cooperative Group, 1999, 2004a) and in one of the companion
papers in this issue (Jensen et al., 2007), so only a brief description is
provided here. For the MTA, 579 children between 7.0 and 9.9
years of age (80% males, 61% white, 20% African American, and
8% Hispanic) with confirmed diagnosis of ADHD Combined type
were recruited from a variety of sources at seven sites in North
America and randomly assigned to one of four treatment
conditions: medication management (MedMgt), behavior therapy
(Beh), the combination of these two modalities (Comb), and usual
community care (CC). The MTA Medication Algorithm was used
to manage stimulant medications for most of the participants in the
MedMgt and Comb groups over the initial 14-month treatment
phase (Greenhill et al., 2001; Vitiello et al., 2001), and some
participants in the CC (67%) and Beh (26%) received stimulant
medication from clinicians in the community. Compliance with
initial randomly assigned treatment conditions was not perfect
during the treatment phase, and adherence to these conditions
waned during the follow-up phases of the MTA, which made the
evaluation of actual as well as assigned treatment advisable (MTA
Cooperative Group, 2004b). A record of actual treatment was
provided by parental reports on the Services for Children and
AdolescentsYParent Interview (SCA-PI; Hoagwood et al., 2004;
1017
SWANSON ET AL.

TABLE 1
Naturalistic Subgroups Based on SCA-PI Reports of Use of Stimulant Medication
Previous 14 Mo 24 Mo 36 Mo
Not (n = 65) No Med No Med No Med No Med
Newly (n = 88)a No Med Med Med Med
Consistently (n = 70)b Med Med Med Med
Inconsistently (n = 147) 58:89 80:67 68:79 74:73
(n = 13) Med No Med No Med No Med
(n = 18) No Med Med No Med No Med
(n = 2) No Med No Med Med No Med
(n = 9) No Med No Med No Med Med
(n = 23)b No Med No Med Med Med
(n = 6)b Med Med No Med No Med
(n = 5) Med No Med Med No Med
(n = 6)b Med No Med No Med Med
(n = 18) No Med Med Med Med
(n = 19) No Med Med No Med Med
(n = 11) Med Med Med No Med
(n = 8) Med Med No Med Med
(n = 9) Med No Med Med Med
Note: SCAPI = Services for Children and Adolescents-Parent Interview.
a
One missing value for weight at baseline assessment.
b
One missing value for weight at 36-mo assessment.

Jensen et al., 2004) at each assessment, which provided information
to estimate how many days stimulant medication was used since the
previous assessment and the doses administered, which were
expressed in methylphenidate equivalents for amphetamine ( 2)
and pemoline ( 5), which were the other stimulants that were
available and in use during this trial. From this record, we
determined the total number of days treated and total cumulative
dose consumed during the study, as well as whether medication was
administered during the 30 days before each assessment. In all three
subgroups treated with medication, the primary drug used was
methylphenidate at all assessment points, with the percentage
ranging from 95.4% to 73.5%. At the baseline and 14-, 24-, and 36-
month assessment points, respectively, the percentages of medicated
children taking methylphenidate were the following: consistently
(85.4%, 79.7%, 76.8%, and 73.5%; newly (not available, 95.4%,
93.0%, and 85.9%), and inconsistently (94.9%, 93.1%, 92.4%,
and 85.1%).
In other publications on the MTA outcomes, two definitions of
positive medication status have been used. In the secondary analysis
of changes in effectiveness and growth at the 24-month assessment,
medication use during the previous 30 days (MTA Cooperative
Group, 2004b) was the criterion for positive medication status. In
the assessment of effectiveness at the 36-month assessment,
medication use more than 50% of the days since the previous
assessment was the criterion for positive medication use (Jensen
et al., 2007; Swanson et al., 2007). To maintain consistency with
the previous article on growth (MTA Cooperative Group, 2004b),
here we used the 30-day definition; therefore, if medication was
used within a 30-day period before the assessment medication status
was positive (Med) and otherwise negative (No Med). If an
individual_s medication status changed at any assessment point,
then they were placed in the inconsistently medicated group. For
this binary designation of medication status at four assessment
points, there are 24 patterns of medication use that define 16
possible naturalistic subgroups at the 36-month assessment.
The most recent growth norms provided by the U.S. Centers for
Disease Control and Prevention (Kuczmarski et al., 2000) were used
to transform the raw scores (centimeters and kilograms) into
standard scores (z height and z weight). Based on an assumption of
normal size at entry to the MTA, the baseline z scores are expected
to be near zero, and based on the assumption of normal growth rates
during the MTA implementation of the MTA protocol, the z scores
for height and weight are expected to remain constant over time. A
two-way analysis of variance, with a significance level of p < .05, was
used to evaluate the effects of the between group factor (naturalistic
subgroups), the within group factor (assessment time), and the
interaction on measures of z height and z weight.
RESULTS
Complete information was obtained at each time
point for 370 of the 485 children in the MTA follow-
up (Jensen et al., 2007). These cases were spread across
the 16 possible naturalistic subgroups defined by the
patterns of medication status (Med or No Med) across
the four assessment points (Table 1), but were
concentrated in three of these subgroups that repre-
sented consistent patterns over time: not medicated
(65 stimulant-naı̈ve children at entry who were not
receiving stimulant medication at any assessment
point), newly medicated (88 children stimulant naı̈ve
at entry who started stimulant medication in the MTA

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 EFFECTS OF STIMULANT MEDICATION ON GROWTH

and were receiving medication at each assessment point
after baseline), and consistently medicated (70 children
receiving stimulant medication during the 30-day
period before entry, although the length of the previous
treatment was not determined, and at each assessment
point). The other subgroups were collapsed into a single
group to form a fourth subgroup who were incon-
sistently medicated (147 children, with reports of
medication at some but not all of the assessment points,
with ratios of Med to No Med of 58:89, 80:67, 68:79,
and 74:73, respectively, across the four assessment
points). At the 24-month and 36-month assessment
points, we also obtained height and weight measures
from 213 of the 279 classmates of the ADHD cases who
were recruited from the local normative comparison
group (LNCG), which became part of the MTA follow-
up at the 24-month assessment point.
Both randomization and self-selection operated to
form these naturalistic subgroups. To check whether
they differed on some relevant factors at baseline, we
used the MTA database to obtain information on 26
child, parent, pregnancy, birth, and infant variables.
We used one-way analysis of variance to compare the
four naturalistic subgroups on each of these variables.
As would be expected by chance for 26 F tests, each
with 3 and 366 df and an unadjusted significance level of
p < .05, 1 (pregnancy length) showed a small but
statistically significant between-group difference. After
adjustment for multiple tests (0.05/26 = 0.002), none of
these tests were statistically significant. It is notable that
the four subgroups did not differ on initial size at birth
(birth weight), age, parent or teacher ratings of ADHD
symptoms, sex, expected adult size (mid-parent size),
welfare status, or maternal smoking (Table 2).
The analyses of variance of our measures of physical
size produced significant interactions of naturalistic
subgroup  assessment time (Fig. 1 and Table 3) for z
height (F 9,1083 = 3.88; p < .005) and z weight (F 9,1,068 =
8.88; p < .0001). The overall interaction was
decomposed into two orthogonal components to
evaluate the impact of starting medication (the not
medicated versus the newly medicated subgroups) and
consistency of medication (the consistently medicated
versus the inconsistently medicated subgroups). To
complete the set of three orthogonal comparisons, the
third was derived from a combination of the conditions
(Not + Newly vs. Consistently + Inconsistently). This
decomposition of variance into nonoverlapping com-
ponents revealed that the overall interaction was due
primarily to the starting medication component,
which accounted for 92% of the interaction for height
(F3,441 = 11.77; p < .0001) and 72.8% for weight
(F3,438 = 21.76; p < .0001). The profiles shown by
dashed lines in Figure 1A (for height) and B (for
weight) suggest that this effect was due to the sig-
nificant divergence of the unmedicated clinical control
group (the not medicated subgroup) and prospectively
medicated group (the newly medicated subgroup).
The consistency of medication contrast was also
significant, but this was due to a main effect of group
without an interaction with assessment time. At the
baseline assessment, the consistently medicated sub-
group was smaller than the inconsistently medicated
subgroup, and this difference was maintained over time,

TABLE 2
Baseline Demographic and Clinical Variables Across the Four Naturalistic Medication Subgroups
ANOVA With 3 df (Group) and 369 df (Error) Not Newly Inconsistently Consistently p
Child variables
Birth weight, kg 3.42 3.35 3.30 3.46 .0990
Age at baseline, y 7.94 7.75 7.91 8.04 .8449
SNAP parent compositea 1.91 1.92 2.00 2.04 .5060
SNAP teacher compositea 1.87 1.89 1.91 2.08 .4840
Sex, % male 74 74 78 90 .0580
Parent variables
Parent average height z score 0.17 0.28 0.20 0.24 .6155
% Welfare 15.38 13.64 17.81 8.57 .3426
% Mother smoked during pregnancy 18.52 32.10 33.33 16.05 .2362
Note: ANOVA = analysis of variance; SNAP = Swanson, Nolan, and Pelham.
a
SNAP composites were ratings in unmedicated state of 18 DSM-IV attention-deficit/hyperactivity disorder symptoms on 0Y3 metric.

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SWANSON ET AL.

as shown by the parallel profiles for these two subgroups
for both height and weight (see solid lines in Fig. 1A, B).
In Figure 1C the average SNAP scores for the four
naturalistic subgroups are presented to provide infor-
mation on the effectiveness of treatment along with the
information on effects related to growth presented in
Figure 1A (for height) and B (for weight). In the
companion articles (Jensen et al., 2007; Swanson et al.,
2007), the effects of actual as well as assigned
medication status over time were addressed in detail,
with different methods (e.g., time-varying covariates),
and at the 36-month assessment, there were no group
differences apparent. The analysis of this measure of
effectiveness for the naturalistic subgroups confirms the
results reported in the companion articles.
Using information from the SCAPI, we estimated
the number of days treated with stimulant medication
and the ending milligrams/kilogram dose of stimulant
medication (in methylphenidate equivalents) for each
child. Regression analyses were used to relate these
measures to relative size at the 36-month assessment.
The fitted equations had negative slopes indicating sig-
nificant exposure-related reduction in relative height
(z height 0.589 Y 0.218[years of treatment], F1,369 =
19.18; p 9 .0001) and relative weight (z weight 0.776 Y
0.183[years of treatment], F1,365 = 12.68; p < .0004)
and significant dose-related reduction in relative
height (z height 0.493 j 0.0117[mg/kg], F1,365 =
11.04; p .0010) but not relative weight (z weight
0.547 j 0.0045[mg/kg], F1,365 = 1.34; p 9 .2486).

Fig. 1 Profiles for the naturalistic subgroup  assessment time interaction, showing standardized measures of size (z height [A] and z weight [B]) and efficacy
(average SNAP ratings [C]) for the four subgroups formed on the basis of history of medication use before entry into the MTA (baseline), at the end of the MTA
treatment phase (14 months), at the first follow-up (24 months) and at the second follow-up (36 months). LNCG = local normative comparison group; SNAP =
Swanson, Nolan, and Pelham.

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 EFFECTS OF STIMULANT MEDICATION ON GROWTH

TABLE 3
Means, SDs, and SEs for the Naturalistic Subgroups
Base 14 Mo 24 Mo 36 Mo
No. Mean SD SE Mean SD SE Mean SD SE Mean SD SE
Height z score
Not med 65 0.357 0.892 0.111 0.415 0.870 0.108 0.491 0.913 0.113 0.541 0.894 0.111
Newly 88 0.178 1.12 0.119 0.072 1.08 0.115 0.0435 1.11 0.118 0.0725 1.09 0.116
Incons 147 0.239 1.02 0.084 0.248 1.02 0.084 0.282 1.12 0.092 0.310 1.05 0.087
Consis 70 j0.140 0.905 0.108 0.165 0.905 0.108 j0.159 1.04 0.124 j0.12 0.894 0.107
LNCG 260 0.229 0.945 0.014 0.234 0.924 0.015
Weight z score
Not med 65 0.617 0.915 0.113 0.621 0.954 0.118 0.652 0.975 0.121 0.756 1.01 0.125
Newly 88 0.616 0.999 0.106 0.113 1.14 0.122 0.181 1.09 0.116 0.293 1.15 0.123
Incons 147 0.430 1.05 0.087 0.311 1.16 0.096 0.35 1.21 0.100 0.519 1.25 0.103
Consis 70 0.312 0.999 0.119 0.037 1.05 0.125 0.071 1.03 0.123 0.156 1.200 0.143
LNCG 259 0.427 1.04 0.026 0.425 1.07 0.026
SNAP
Not med 39 1.66 0.406 0.050 1.04 0.565 0.070 1.08 0.508 0.063 1.01 0.545 0.068
Newly 63 1.87 0.424 0.045 0.811 0.509 0.054 1.02 0.521 0.056 1.12 0.555 0.059
Incons 106 1.76 0.398 0.033 1.10 0.524 0.043 1.16 0.497 0.041 1.09 0.516 0.043
Consis 55 1.92 0.405 0.048 1.04 0.410 0.049 1.19 0.427 0.051 1.10 0.382 0.046
LNCG 251 0.444 0.945 0.028 0.38 0.924 0.024

Note: Not med = not medicated; LNCG = local normative comparison group; Newly = newly medicated; Incons = inconsistently medicated;
Consis = consistently medicated; SNAP = Swanson, Nolan, and Pelham Rating Scale.

At the 36-month assessment, the average relative size
(z height and z weight) of the naturalistic subgroups
were negatively related to the average cumulative
exposure to stimulant medication. As shown in Figure
2 the totals for the naturalistic subgroups, which were
formed using the 30-day criteria at each assessment
point, varied as expected: not medicated (28 days and
529 mg), inconsistently medicated (603 days and
16,183 mg), newly medicated (983 days and 31,797 mg),
and consistently medicated (1,022 days and 33,576 mg).
The stimulant-untreated clinical control group was
taller and heavier than average (not medicated: z height
0.541 and z weight 0.765), whereas the two groups
that were medicated for about 1,000 days and received

Fig. 2 Size (z height and z weight) at the 36-month assessment time point for the four naturalistic subgroups that differed in exposure (total milligrams and total
number of days) to stimulant medication in the MTA. LNCG = local normative comparison group.

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SWANSON ET AL.
930,000 mg methylphenidate over the 3 years of the
MTA follow-up were just slightly above or below
expected relative size based on norms (newly medi-
cated: z height 0.073 and z weight 0.293; consistently
medicated: z height j0.120 and z weight 0.156) and
well below the average relative height and weight of
the LNCG.
The average population SDs for 7- to 12-year-old
children, 6.5 cm for height and 5.5 kg for weight,
were used to transform the average z scores at the 36-
month assessment into absolute units (centimeters
and kilograms) for comparisons to the stimulant-
untreated clinical control group as well as the
classmate nonclinical control group. These compar-
isons revealed that the newly medicated subgroup
(which had been only 1.1 cm shorter than the not
medicated group at baseline) was at 36 months 3.04
cm shorter and 2.71 kg lighter than the not
medicated subgroup and 1.1 cm shorter and 0.7 kg
lighter than the LNCG. The consistently medicated
subgroup was 2.3 cm shorter and 1.5 kg lighter than
the LNCG and 4.21 cm shorter and 3.51 kg lighter
than the not medicated subgroup.
DISCUSSION
The MTA provides an excellent opportunity to
address two key methodological issues in the literature
that were identified by Spencer et al. (1996), who
recommended Bto differentiate disorder from treatment-
related growth effects, studies must compare treated
children with ADHD with untreated children, and not
with unaffected control subjects,[ and that this Bshould
be evaluated in future longitudinal studies.[
In this prospective longitudinal study of school-age
children with diagnoses of ADHD Combined type, one
of the naturalistic self-selected subgroups (derived
largely from those randomly assigned to Beh) provided
a stimulant-untreated clinical control group. Compared
to this not medicated subgroup, we documented a
significant stimulant-related decrease in growth rate in
the newly medicated subgroup consisting of initially
stimulant-naı̈ve individuals (at least for 30 days before
entering the study) for whom treatment was initiated
and maintained for 3 years of the MTA protocol. These
subgroups did not differ in severity of ADHD
symptoms or initial relative size at the baseline
assessment. The comparison of these two subgroups
1022
Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
in terms of growth velocity after initiating medication
revealed the time course of stimulant-related reduction
in annual growth rate, which was maximal in the first
year, decreased in the second year, and absent in the
third year of treatment.
We did not document a decrease in relative size in
the group of participants with a history of treatment
before entry into the MTA protocol during subsequent
treatment with stimulant medication over the 3 years.
However, this group (the consistently medicated
naturalistic subgroup) was smaller than the stimulant-
naı̈ve group (the newly medicated naturalistic sub-
group) at entry, suggesting that early treatment of
children (before the ages of 7Y9 years) with stimulant
medication may have produced a reduction of growth
rate before entry into the MTA protocol. Of course,
other possibilities exist, such as selective early treatment
of individuals who are smaller than normal. Similarly,
the participants without continuous treatment with
stimulant medication (the inconsistently medicated
subgroup) did not manifest a decrease in relative size
during the MTA protocol but was slightly smaller at
baseline and did not increase in relative size as much as
the not medicated group over the 3-year follow-up. By
the 36-month assessment, this subgroup was signifi-
cantly smaller than the stimulant-untreated clinical
control group (not medicated), even though it was
nominally larger than the LNCG. The definition of
inconsistent treatment here was not based on a
systematic variation of planned medication holidays
on the weekend or in summer as in some previous
studies (Gittelman-Klein et al., 1988; Safer et al., 1975;
Satterfield et al., 1979).
Our findings do not support the hypothesis of
growth rebound when treatment is continued, as
suggested by Satterfield et al. (1979). The newly
medicated subgroup manifested a slight increase in
relative size from the 24- to 36-month assessment. This
suggests an increase in growth rate to a level that is
greater than expected based on population norms,
which may be interpreted as growth rebound. However,
the stimulant-untreated clinical control (the not
medicated subgroup) also showed a similar increase in
relative size across this time frame. To support the
hypothesis of growth rebound, the growth rates of the
stimulant-treated groups would have to exceed that of
the stimulant-untreated clinical control group, which
did not occur in this study. We did not include a
J. AM. ACAD. CH ILD ADOLESC. PSYCHIAT RY, 46:8, AUGUST 2007

randomized withdrawal of medication, which would
have provided a test of the growth rebound hypothesis
(greater than normal growth velocity for a time after
medication is stopped) that was suggested by Safer et al.
(1975).
Similarly, our findings do not support the hypothesis
of delayed maturation in children with ADHD. At
entry into the MTA, the height and weight of
stimulant-naı̈ve 7.0- to 9.9-year-old children were
greater than expected (rather than smaller as would be
predicted by delayed maturation). For those left
untreated with stimulant medication, the growth rate
over the next 3 years was greater as opposed to less than
that of the LNCG (the classmate control group) or the
population norms. This is an important new finding
from the MTA, suggesting a disorder-related acceler-
ated rather than delayed maturation.
Basic science research collaborators with expertise
in the neurotransmitter dopamine in multiple
pathways at multiple levels of analysis (Bosse et al.,
1997; Posner and Raichle, 1994; Volkow et al.,
2002) suggested how the mechanism of action of
stimulant medications may affect growth. Studies
using positron emission tomography show that
clinical doses of methylphenidate in adults (Volkow
et al., 2002) and adolescents (Neto et al., 2002)
increased (rather than decreased, as proposed by
some theories) extrasynaptic levels of dopamine in
the striatum due to potent blockade of dopamine
transporters, but with a time course that minimized
the reinforcing (euphoric) effects accompanying
intravenous doses (Volkow et al., 1999). Studies of
mice (Bosse et al., 1997) that lack the dopamine
transporter show that high levels of dopamine occur
in the hypothalamus as well as the striatum. The
excess dopamine is dispersed by blood flow, reaches
the pituitary, and retards growth in these animals.
Caron (2004) summarized this converging informa-
tion from basic science studies and speculated that a
common synaptic mechanism (dopamine transporter
blockade and increased dopamine levels) in different
brain regions (hypothalamus and striatum) may
mediate side effects (reduction in growth rate) as
well as efficacy (symptom reduction).
Limitations
The most important limitation of this study is the
lack of random assignment to the subgroups that were
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 46:8, AUGUST 2007
Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
EFFECTS OF STIMULANT MEDICATION ON GROWTH
evaluated here. Instead, these naturalistic subgroups
were formed partially by the assignment to the initial
treatment conditions provided in the MTA protocol
with (MedMgt and Comb) and without (Beh)
stimulant medication, and then by choices over time
to start, stop, or continue the use of stimulant
medication. These decisions depended on the assigned
treatment group. Unless the assignment to a condition
that included medication was refused, the only way to
be in the Bnever medicated[ group was to enter
stimulant naı̈ve and be assigned to Beh or be in the
minority of CC children who were not medicated.
Thus, the never-medicated group was determined more
by original randomization than the other three
naturalistic groups, which were compatible with assign-
ment to any of the four groups (Comb, MedMgt, CC,
even Beh if nonprotocol medication was taken before
14 months). Self-selection for the never medicated
group was passive, amounting to not starting medica-
tion, whereas for the other three groups, self-selection
would require taking action by continuing, starting, or
stopping medication. Furthermore, the self-selection to
stay not medicated was based largely on satisfactory
results with the assigned behavioral treatment, whereas
decisions to continue or start medication were not
necessarily based on satisfaction with treatment results.
At 14 months 26% of Beh subjects had found it
necessary to add nonprotocol medication because Beh
alone was not sufficient treatment, and more than half
of those had taken medication 950% of the time from
baseline. These subjects were counted in a medicated
group for purpose of the analyses presented here, which
may have weeded out the worst treatment responders
and more serious cases from the never-medicated
group. Thus, it is possible that the never-medicated
group was pared down to good responders and the
medicated groups enriched with poor Beh responders.
These limitations of the naturalistic medication groups
must be kept in mind when attempting to interpret
Figure 1c, which suggests lack of effectiveness for
stimulant medication at the 36-month assessment in
the presence of lingering but significant stimulant-
related reduction in growth rate.
Another serious limitation is the length of the follow-
up reported here, which covered only 3 years after the
initiation of treatment in the MTA protocol. Because
the participants in the study entered between the ages
of 7 and 9 years, they were between the ages of 10 to
1023
SWANSON ET AL.
12 years when the 36-month assessments were
performed. Subsequent reports of the continued
follow-up of the MTA sample will provide assessment
after puberty, in adolescence, and eventually in
adulthood. These assessments will allow evaluation of
the impact of childhood treatment on ultimate size,
which is not addressed in this report.
A third major limitation of this study is that only one
stimulant medication (methylphenidate) and one
formulation (immediate release) of stimulant medica-
tion were systematically evaluated. The MTA imple-
mented state-of-the-art treatment in the early 1990s
and used an immediate-release formulation of methyl-
phenidate (Ritalin, which then was prescribed for most
cases when stimulant medication was used to treat
children with ADHD (Arnold et al., 1997; Greenhill
et al., 2001; MTA Cooperative Group, 2004b).
However, in 1998, 4 years after the initiation of
the MTA, another stimulant, the 75:25 ratio of
D,L - amphetamine (once used for weight control
[Obetrol]) was renamed Adderall and was evaluated
for the treatment of ADHD. Adderall was shown to be
effective in a double-blind study (Swanson et al., 1998)
and soon after became widely used in clinical practice.
Because Adderall was not available when the MTA was
initiated, its effect was not evaluated and thus could not
be reported here. Also, after 2000, controlled-release for-
mulations of both methylphenidate (Concerta: Swanson
et al., 1999, 2000, 2003; Wolraich et al., 2001; Metadate
CD: Greenhill et al., 2002; Swanson et al., 2004; Wigal
et al., 2003; Ritalin LA: Biederman et al., 2003) and
amphetamine (Adderall SR; Greenhill et al., 2001;
McCracken et al., 2003) were developed and became
widely used in clinical practice, rapidly replacing the
prescription of multiple daily doses of immediate-
release stimulant medications for the treatment of
ADHD. Because these controlled-release formulations
were not available or used when the MTA was initiated
or during the initial two follow-up phases, they were
not evaluated and could not be reported here. Thus, the
findings here strictly apply to the immediate-release
formulation of methylphenidate.
A fourth limitation was the definition of medication
use based on information from the SCA-PI. Two
different definitions of medication use have been
considered for the MTA analyses of efficacy (i.e., within
30 days before an assessment and 50% of the days since
the previous assessment), and consistency of these
1024
Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
classifications by medication have been considered as
well, as in the naturalistic subgroups described here and
in previous publications on the findings of the MTA
follow-up. Also, other definitions are possible and some
have been considered here (i.e., total exposure in terms
of milligrams consumed or days treated), but the specific
contributions of dose or consistency of medication use
have not been adequately evaluated.
A fifth limitation was the lack of evaluation of
planned medication holidays on the weekends or
during the summer, as some guidelines have proposed.
For example, the use of summer (or periodic) holidays,
which represent relatively long intervals of nontreat-
ment interspersed within blocks of medication use in
clinical practice, has been proposed as a strategy to
mitigate stimulant-related reductions in growth rates
(Safer et al., 1975), but this was not evaluated in the
present analyses. In two recent studies (Pliszka et al.,
2006; Spencer et al., 2006) in which drug holidays were
allowed but were not systematically varied, stimulant-
related reductions in growth rates were not documen-
ted. This and other unspecified factors still must be
considered to understand the effects of stimulant
medication on growth rates.
Clinical Implications
The practice parameter of the American Academy of
Child and Adolescent Psychiatry (2002) regarding the
use of stimulant medication (presently under revision)
suggests that height and weight be measured before
initiating treatment (p 28S), and for the management
of possible treatment-related side effects recommends
the regular assessment of weight (but not height) as a
Bclinical guideline[ but not as a Bminimal standard[
(p 29S). During the first two stages of treatment to
titrate dose and select among alternative stimulants,
weekly to monthly monitoring of both height and
weight is suggested (Table 2, p 38S), but recommenda-
tions for long-term monitoring are not explicitly
provided. In the section on Bcomplications and side
effects[ (p 44S), the prevailing view is stated, indicating
that the literature supports short-term decrements in
rate of weight acquisition but not height acquisition,
and no long-term effect on ultimate height.
The findings reported here from the prospective
MTA follow-up suggest that short-term (up to 2 years)
effects on height as well as weight may occur when
J. AM. ACAD. CH ILD ADOLESC. PSYCHIAT RY, 46:8, AUGUST 2007

initiating treatment in stimulant-naı̈ve school-age
children with ADHD Combined type. This conclusion
is based on two opposing patterns of growth in the
MTA: greater than expected annual growth rates in the
subgroup of ADHD children who were not treated with
stimulant medication and smaller than expected annual
growth rates in the subgroup of ADHD children who
were continuously treated. This difference in annual
growth rates may be present for up to 3 years of
treatment and accumulate to result in a difference of
about 2.0 cm in height and about 2.0 kg in weight.
The finding of a reduction in growth rate in height that
extends up to 3 years is consistent with two recent
retrospective reviews of clinical charts (Lisska and
Rivkees, 2003; Poulton and Cowell, 2003), but not
with two others (Pliszka et al., 2006; Spencer et al.,
2006). Despite this inconsistency across chart-review
studies, the finding from the prospective study of school-
age children reported here as well as in a prospective study
of preschool children (Swanson et al., 2006) may provide
enough evidence to consider revision of clinical practice
parameters to acknowledge the possibility of stimulant-
related slowing in the usual developmental gains in height
as well as weight during the course of treatment of
prepubertal children with ADHD.
The Multimodal Treatment Study of Children with ADHD (MTA)
was a National Institute of Mental health (NIMH) cooperative
agreement randomized clinical trial involving six clinical sites.
Collaborators from the National Institute of Mental Health: Peter S.
Jensen, M.D. (currently at Columbia University, New York), L.
Eugene Arnold, M.D., M.Ed. (currently at Ohio State University),
Joanne B. Severe, M.S. (Clinical Trials Operations and Biostatistics
Unit, Division of Services and Intervention Research), Benedetto
Vitiello, M.D. (Child and Adolescent Treatment and Preventive
Interventions Research Branch), Kimberly Hoagwood, Ph.D.
(currently at Columbia University); previous contributors from
NIMH to the early phase: John Richters, Ph.D. (currently at
National Institute of Nursing Research); Donald Vereen, M.D.
(currently at National Institute on Drug Abuse). Clinical sites and
principal investigators and co-investigators are University of
California, Berkeley/San Francisco: Stephen P. Hinshaw, Ph.D.
(Berkeley), Glen R. Elliott, M.D., Ph.D. (San Francisco); Duke
University: C. Keith Conners, Ph.D., Karen C. Wells, Ph.D., John
March, M.D., M.P.H., Jeffrey Epstein, Ph.D.; University of
California, Irvine/Los Angeles: James Swanson, Ph.D. (Irvine),
Dennis P. Cantwell, M.D. (deceased, Los Angeles), Timothy Wigal,
Ph.D. (Irvine), Annamarie Stehli, M.P.H. (Irvine); Long Island
Jewish Medical Center/Montreal Children_s Hospital: Howard B.
Abikoff, Ph.D. (currently at New York University School of
Medicine), Lily Hechtman, M.D. (McGill University, Montreal);
New York State Psychiatric Institute/Columbia University/Mount
Sinai Medical Center: Laurence L. Greenhill, M.D. (Columbia
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 46:8, AUGUST 2007
Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
EFFECTS OF STIMULANT MEDICATION ON GROWTH
University), Jeffrey H. Newcorn, M.D. (Mount Sinai School of
Medicine), Mark Davies (New York State Psychiatric Institute);
University of Pittsburgh: William E. Pelham, Ph.D. (currently at
State University of New York, Buffalo), Betsy Hoza, Ph.D.
(currently at University of Vermont, Burlington), Brooke Molina,
Ph.D. Original statistical and trial design consultant: Helena C.
Kraemer, Ph.D. (Stanford University). Follow-up phase statistical
collaborators: Robert D. Gibbons, Ph.D. (University of Illinois,
Chicago), Sue Marcus, Ph.D. (Mount Sinai School of Medicine),
Kwan Hur, Ph.D. (University of Illinois, Chicago). Collaborator
from the Office of Special Education Programs/U.S. Department of
Education: Thomas Hanley, Ed.D. Collaborator from Office
of Juvenile Justice and Delinquency Prevention/Department of
Justice: Karen Stern, Ph.D. Non-MTA collaborators were Marc
Caron, Ph.D. (Duke University), and Nora D. Volkow (National
Institute of Drug Abuse and Brookhaven National Laboratory).
Disclosure: During the course of the MTA, since 1992: Dr. Swanson has
received research support from Alza, Richwood, Shire, Celgene,
Novartis, Celltech, Gliatech, Cephalon, Watson, CIBA, Janssen, and
McNeil; has been on the advisory board of Alza, Richwood, Shire,
Celgene, Novartis, Celltech, UCB, Gliatech, Cephalon, McNeil, and
Eli Lilly; has been on the speakers_ bureaus of Alza, Shire, Novartis,
Celltech, UCB, Cephalon, CIBA, Janssen, and McNeil; and has
consulted to Alza, Richwood, Shire, Celgene, Novartis, Celltech, UCB,
Gliatech, Cephalon, Watson, CIBA, Janssen, McNeil, and Eli Lilly.
Dr. Elliott has received research funding from Cephalon, McNeil,
Shire, Sigma Tau, and Novartis; has consulted to Cephalon and
McNeil; and has been on the speakers_ bureaus of Janssen, Eli Lilly, and
McNeil. Dr. Greenhill has received research funding or has been on the
speakers_ bureaus of Eli Lilly, Alza, Shire, Cephalon, McNeil, Celltech,
Novartis, Sanofi Aventis, Otsuka, and Janssen. Dr. Wigal has received
research funding from Eli Lilly, Shire, Novartis, and McNeil, and has
been on the speakers_ bureaus of McNeil and Shire. Dr. Arnold has
received research funding from Celgene, Shire, Noven, Eli Lilly,
Targacept, Sigma Tau, and Novartis; has consulted to Shire, Noven,
Sigma Tau, Ross, and Organon; and has been on the speakers_ bureaus
of Abbott, Shire, McNeil, and Novartis. Dr. Vitiello has consulted to
Richwood Pharmaceuticals. Dr. Hechtman has received research
funding from the National Institute of Mental Health, Eli Lilly,
GlaxoSmithKline, Janssen-Ortho, Purdue Pharma, and Shire; has been
on the speakers_ bureaus of the National Institute of Mental Health, Eli
Lilly, Janssen-Ortho, and Shire; and has been on the advisory boards of
Eli Lilly, Janssen-Ortho, Purdue Pharma, and Shire. Dr. Epstein has
received research funding from McNeil, Shire, Eli Lilly, and Novartis;
has been on the advisory board of Shire; and has been on the speakers_
bureaus of Shire and McNeil. Dr. Pelham has received research funding
from Alza, Shire, Noven, Eli Lilly, and Cephalon; has served on
advisory boards or has consulted to Alza/McNeil Richwood/Shire,
Noven, Eli Lilly, Cephalon, Novartis, Celgene, and Abbott; and has
been on the speakers_ bureaus of Shire, and McNeil. Dr. Abikoff has
received research funding from McNeil, Shire, Eli Lilly, and Bristol-
Myers Squibb; has consulted to McNeil, Shire, Eli Lilly, Pfizer,
Celltech, Cephalon, and Novartis; and has been on the speakers_
bureaus of McNeil, Shire, and Celltech. Dr. Newcorn has received
research funding from or has been on the speakers_ bureaus of Eli Lilly,
Alza, Shire, Celgene, McNeil, Celltech/UCB, Novartis, Sanofi Aventis,
Janssen, and Bristol-Myers Squibb. Dr. Hinshaw has consulted to
Noven and Sigma Tau and has been on the speakers_ bureau of McNeil.
Dr. Hoza has received research funding from MediaBalance, Inc., and
has received support for educational conferences from Abbott
1025
SWANSON ET AL.
Laboratories. Dr. Jensen has received research funding from McNeil
and unrestricted grants from Pfizer; has consulted to Best Practice, Inc.,
Shire, Janssen, Novartis, and UCB; and has been on the speakers_
bureaus of Janssen-Ortho, Alza, McNeil, UCB, CME Outfitters, and
the Neuroscience Education Institute. Dr. March has been a consultant
or scientific advisor to or received research funding from Eli Lilly,
Pfizer, Wyeth, Jazz, MedAvante, Shire, Cephalon, Organon, McNeil,
and AstraZeneca; serves on a DSMB for Organon, Johnson & Johnson,
and AstraZeneca; and holds stock in MedAvante. Dr. Conners has
received research funding from Celgene, Shire, Noven, Eli Lilly,
Targacept, and Novartis; has consulted to Celgene, Shire, Novartis,
Alza, and Noven; is on the Eli Lilly Advisory Committee, and has been
on the speakers_ bureaus of Shire, McNeil, and Novartis. Dr. Caron has
received research funding from and has consulted to Lundbeck, has been
on the Scientific Advisory Board of Acadia Pharmaceutical, and has
had an unrestricted grant from Bristol-Myers Squibb. Dr. Volkow has
received research funding from GlaxoSmithKline. The other authors
have no financial relationships to disclose.
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