Unexpected effects of methylphenidate in attention-deficit/hyperactivity disorder reflect decreases in core/secondary symptoms and physical complaints common to all children.

Abstract

Abstract Hypotheses concerning unexpected, psychostimulant-related effects reported in previous studies were examined by separating behavioral/physical complaints highly specific to methylphenidate (MPH) from those that (a) may mimic core/secondary symptoms of the disorder, or (b) are commonly reported by unmedicated children in the general population. Sixty-five children with attention-deficit/hyperactivity disorder (ADHD) participated in a double-blind, placebo-controlled, within-subject (crossover) experimental design and received a placebo and four MPH doses in counterbalanced order following baseline assessment. Behavioral and physical complaints were significantly higher under baseline relative to placebo and the four immediate-release MPH conditions (5 mg, 10 mg, 15 mg, and 20 mg) across three symptom categories: ADHD core/secondary symptoms; symptoms commonly reported in the general population, including unmedicated children with ADHD; and symptoms highly specific to MPH. No significant differences were found among active drug conditions. Past unexpected findings of psychostimulant effects in ADHD may be due to the inclusion of scale items that reflect core/secondary features of ADHD and normally occurring behavioral/physical complaints in children.

Full text

Page 1

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY
Volume 18, Number 3, 2008
© Mary Ann Liebert, Inc.
Pp. 237–247
DOI: 10.1089/cap.2007.0140
Unexpected Effects of Methylphenidate in Attention-
Deficit/Hyperactivity Disorder Reflect Decreases in
Core/Secondary Symptoms and Physical Complaints
Common to All Children
Mark D. Rapport, Ph.D., Michael J. Kofler, M.S., Maria M. Coiro, Ph.D., Joseph S. Raiker, B.S.,
Dustin E. Sarver, B.A., and R. Matt Alderson, M.S.
Abstract
Hypotheses concerning unexpected, psychostimulant-related effects reported in previous studies were exam-
ined by separating behavioral/physical complaints highly specific to methylphenidate (MPH) from those that
(a) may mimic core/secondary symptoms of the disorder, or (b) are commonly reported by unmedicated chil-
dren in the general population. Sixty-five children with attention-deficit/hyperactivity disorder (ADHD) par-
ticipated in a double-blind, placebo-controlled, within-subject (crossover) experimental design and received a
placebo and four MPH doses in counterbalanced order following baseline assessment. Behavioral and physi-
cal complaints were significantly higher under baseline relative to placebo and the four immediate-release MPH
conditions (5 mg, 10 mg, 15 mg, and 20 mg) across three symptom categories: ADHD core/secondary symp-
toms; symptoms commonly reported in the general population, including unmedicated children with ADHD;
and symptoms highly specific to MPH. No significant differences were found among active drug conditions.
Past unexpected findings of psychostimulant effects in ADHD may be due to the inclusion of scale items that
reflect core/secondary features of ADHD and normally occurring behavioral/physical complaints in children.
237
A
development whose behavioral and cognitive consequences
pervade multiple areas of functioning. Core features of the
disorder involve difficulties with attention, impulsiveness,
and hyperactivity (APA 2000) and are hypothesized to affect
behavioral and cognitive functioning to the extent that the
latter are dependent upon the former for successful execu-
tion (Rapport et al. 2001). Treatment of ADHD traditionally
involves using behavior or pharmacological therapy alone
or in combination (for reviews, see Chronis et al. 2004; Con-
ners et al. 2001; Jensen 1999).
Pharmacological interventions (and particularly the psy-
chostimulants), however, are generally considered more cost
effective and have the added benefit of affecting both be-
havioral and cognitive domains throughout the day without
the specific programming and oversight required by behav-
ior therapy (DuPaul and Eckert 1997; Gittelman-Klein and
Klein 1976; MTA Cooperative Group 1999). Methylphenidate
(MPH) is by far the most commonly prescribed pharmaco-
TTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD) is a
complex and chronic disorder of brain, behavior, and
logical treatment for ADHD (Faraone et al. 2002; Grcevich et
al. 2001; Jensen 1999; Swanson and Volkow 2002), and its
reputation is well deserved based on traditional benchmarks,
including breadth of effectiveness and overall response rate
among affected individuals (Barkley, 2006; Denney and Rap-
port 2001; Rapport et al. 1994). As with all therapies, how-
ever, treatment emergent symptoms can and do occur.
Side effects associated with psychostimulant treatment are
well documented in the literature and fall primarily into one
of three categories: cardiovascular effects (i.e., heart rate,
blood pressure), physical effects (i.e., weight and growth),
and physical and behavioral complaints. Recent reviews in-
dicate that cardiovascular and physical effects associated
with psychostimulant therapy are usually transient, dose de-
pendent, readily resolved by discontinuing therapy, and fail
to remain significant in long-term follow-up studies (Rap-
port and Moffitt 2002). Psychostimulant-related physical and
behavioral complaints, on the other hand, have received re-
newed interest secondary to the unexpected effects reported
in recent, well-controlled studies. For example, parents
Department of Psychology, University of Central Florida, Orlando, Florida

Page 2

report that their children experience fewer behavioral (Gor-
man et al. 2006) and physical complaints such as day-
dreaming, irritability, anxiety, staring, and nail biting under
MPH relative to placebo or baseline (Ahman et al. 1993; Fin-
dling et al. 2001; Greenhill et al. 2001b; Short et al. 2004).
Teachers also report more severe physical and behavioral
complaints for children under placebo relative to low MPH
doses (Barkley et al. 1990; DuPaul et al. 1996; Fischer and
Newby 1991).
Two hypotheses have been proposed to account for the
unexpected findings: (1) Adult raters (parents, teachers) con-
fuse some symptoms of ADHD (e.g., daydreaming and star-
ing) with drug-related side effects (Fine and Johnson 1993;
Firestone et al., 1998); and (2) ratings under no medication
conditions (i.e., baseline, placebo) reflect normal levels of
physical and behavioral complaints for boys in general, in-
cluding unmedicated children with ADHD, that may occur
less frequently as a function of treatment (Rapport et al.
2002). Both hypotheses are possible because of the nonspe-
cific nature of side effect rating scales. Most scales are de-
signed to assess a wide range of possible symptoms rather
than emergent symptoms associated with a specific phar-
macological regimen.
The rater confusion hypothesis can be addressed by ex-
amining the type of physical and behavioral complaints re-
ported under no-drug conditions, and changes from this
state that occur under placebo and active drug conditions
(Barkley et al. 1990; Greenhill et al. 2001). Results indicating
treatment-related decreases in only complaints that mimic
core/secondary features of ADHD (e.g., inattentiveness, dif-
ficulty concentrating, staring, daydreaming), coupled with
no change or a worsening of complaints not typically asso-
ciated with the disorder (e.g., cardiovascular, gastrointesti-
nal, and pseudoneurological symptoms), would lend em-
pirical support to the rater confusion hypothesis. The
pre-existing/normal level complaints hypothesis, on the
other hand, can be examined by juxtaposing the psycho-
stimulant emergent symptom literature with extant litera-
ture concerning the prevalence of physical and behavioral
complaints in samples of non-referred and clinically diag-
nosed children.
The occurrence of physical and behavioral complaints in
community samples of non-referred children and adoles-
cents is well documented. For example, nearly half of the
540 children and adolescents in a community sample at-
tending third through twelfth grade reported at least one
physical symptom during the preceding two weeks (Gar-
ber et al. 1991), with the highest frequency of complaints
involving headaches (25%), low energy (23%), sore muscles
(21%), and abdominal discomfort (17%). Literature reviews
confirm that headaches represent the most commonly re-
ported painful physical or behavioral symptom, and occur
at least weekly in 10% to 30% of children in community
samples (Campo and Fritsch 1994). Epidemiological stud-
ies corroborate these findings, wherein 50% to 80% of chil-
dren report some type of headache within the past year
(Barea et al. 1996), and upwards to 15% experience head-
aches of a migrainous nature (Abu-Arefeh and Russell
1996). Recurrent abdominal pain is also common (10% to
25% of school-age children and adolescents), and nearly
15% of children complain of daily fatigue (Apley 1975; Gar-
ber et al. 1991; Linna et al. 1991). Other physical and be-
havioral complaints commonly reported by children in-
clude musculoskeletal pain, back pain, and dizziness
(Campo and Fritsch 1994).
Physical and behavioral complaints in children are not
limited to Western culture (cf. Belmaker et al. 1985), and
extant evidence suggests that the frequency and type of
physical and behavioral complaints vary with age and gen-
der (Last 1991). For example, recurrent abdominal pain ap-
pears to be more common in early childhood, whereas
headaches, limb pain, and polysymptomatic complaints in
general increase with age (Achenbach 1989). Psychiatric
disability confers additional risk for physical and behav-
ioral complaints. Twenty percent to 69% of children and
adolescents with at least one psychiatric diagnosis experi-
ence physical and behavioral complaints (Egger et al. 1999;
Masi et al. 2000; Taylor et al. 1996), particularly children
with anxiety and mood disorders (Carlson and Kashani
1998; Pine 2002). Children with externalizing disorders are
also at greater risk than non-psychiatric controls for phys-
ical and behavioral complaints. Boys with conduct disor-
der report twice as many headaches as boys without the
disorder, and unmedicated children with ADHD complain
more frequently of stomachaches (Egger et al. 1999), poly-
dipsia, and polyuria (Mitchell et al. 1987) relative to non-
psychiatrically-disabled children.
Collectively, the physical and behavioral complaint liter-
ature indicates that moderate to elevated complaints of head-
aches, low energy, sore muscles, abdominal discomfort, daily
fatigue, musculoskeletal pain, back pain, and dizziness are
common among children, and that a diagnosis of ADHD con-
fers additive risk for stomachaches, polydipsia, and polyuria.
These findings suggest that a substantial number of physi-
cal and behavioral complaints attributed to medication in
past studies may have been confounded with high base rate
occurrences of these behaviors in children with ADHD. This
hypothesis can be examined by comparing base rate occur-
rences of the above physical and behavioral complaints re-
ported in the literature with those reported under placebo
and active medication conditions, as previously suggested
by Barkley and colleagues (1990) and more recently by
Greenhill and colleagues (2001a). A stable or decreasing fre-
quency of complaints under placebo and active medication
conditions relative to baseline levels would support the pre-
existing/normal level complaints hypothesis.
Other types of emergent symptoms specific to MPH ther-
apy (e.g., cardiovascular symptoms, upset stomach, reduced
appetite)—other than those commonly reported by children
or potentially confused with core and secondary symptoms
of ADHD—may worsen as a function of increasing MPH
dose. These can be extracted from side effect rating scales
and examined separately to determine whether changes in
frequency occur as a function of expectancy (placebo) or ac-
tive drug over and above base rate levels (i.e., true emergent
symptoms).
The present study examined rival hypotheses that may ac-
count for past reports of unexpected reductions in physical
and behavioral complaints in children with ADHD receiv-
ing psychostimulant therapy. Adverse events endorsed by
parents and children under baseline, placebo, and four MPH
conditions (5 mg, 10 mg, 15 mg, 20 mg) were allocated to
one of three categories using the empirically-driven rational
approach described below—behavioral/physical complaints
RAPPORT ET AL. 238

Page 3

that (1) may mimic core/secondary features of ADHD; (2)
are commonly reported by children in the general popula-
tion, including unmedicated children with ADHD; or (3) are
commonly associated with psychostimulant treatment (i.e.,
true emergent symptoms)—then subjected to analysis.
Method
Participants
Sixty-five children (58 boys, 7 girls) referred by commu-
nity psychiatrists, pediatricians, and school personnel met
the following inclusion criteria and participated in the study:
(a) diagnosis of ADHD based on parent clinical interview us-
ing the Schedule for Affective Disorders and Schizophrenia
for School-Age Children (K-SADS; Kaufman et al. 1997); (b)
problems in at least 50% of the situations on Barkley’s (2006)
Home Situations Questionnaire; (c) a maternal rating at least
two standard deviations above the mean on the Werry-
Weiss-Peters Activity Scale (Routh et al. 1974); (d) a teacher
rating of at least two standard deviations above the mean on
the Abbreviated Conners’ Teacher Rating Scale (ACTRS;
Conners et al. 1998); (e) absence of conduct disorder; and (f)
absence of gross neurological, sensory, or motor impairment
as determined by pediatric examination. The University In-
ternal Review Board approved the study, parents provided
informed consent, and children provided assent to partici-
pate in the study. Children were from 6 to 11 years of age
(M ? 8.56, SD ? 1.25) and fell within the average range of
intelligence (M ? 102.8, SD ? 10.0) based on the Peabody
Picture Vocabulary Test (Dunn and Dunn 1997). They were
all Caucasian and from families of low to middle socioeco-
nomic status (Hollingshead 1975). Eight had experienced
brief trials of stimulant therapy within the previous 4 years.
None were prescribed psychostimulants immediately prior
to beginning the current study.
Several children showed symptoms of—but did not meet
formal criteria for—mood, anxiety, oppositional defiant dis-
order, and conduct disorders. Increasing the heterogeneity
of ADHD samples by including children comorbid for other
disorders would impair interpretation of research findings
as argued elsewhere (e.g., Vaessen and Van der Meere 1990).
All selected children met criteria for ADHD-Combined Type
and were attending general education elementary school
classrooms, although several received concurrent special ed-
ucation services.
Experimental design and procedures
A double-blind, placebo-controlled, within-subject (cross-
over) experimental design was used. Children with ADHD
received a placebo and each of four active immediate-release
MPH doses following baseline assessment. Order of dose ad-
ministration was counterbalanced and determined by ran-
dom assignment such that an equal number of children re-
ceived each dose during a given week of the study. MPH
was prescribed by each child’s physician in the following
doses: placebo, 5 mg (range ? .10 to 0.26 mg/kg), 10 mg
(range ? 0.20 to 0.52 mg/kg), 15 mg (range ? 0.29 to 0.79
mg/kg) and 20 mg (range ? 0.39 to 1.1 mg/kg). Fixed doses
were used to reflect typical pediatric practice because re-
sponse to MPH is independent of body mass (Rapport and
Denney 1997; Swanson et al. 1991). MPH and placebo doses
were packaged in colored gelatin capsules by the clinic’s
pharmacist to avoid detection of dose and taste. Capsules
were sealed in individual, daily envelopes to help control for
accurate administration.
After baseline data collection (first week), parents were
given one week of medication in predated envelopes at a sin-
gle dose level (i.e., placebo, 5 mg, 10 mg, 15 mg, or 20 mg).
Single morning doses (as opposed to twice per day) were ad-
ministered to maintain experimental control, as it was not
possible to ensure that medication would be appropriately
administered at school at an established time during the day.
This procedure continued until each child received every
dose for 6 consecutive days. All weekly dose changes oc-
curred on Sundays (i.e., no capsules were administered on
Saturdays) to allow for “washout” and to control for possi-
ble rebound/carryover effects. Parents were instructed to
give their child a capsule each morning, 30 minutes before
breakfast. Both used and unused envelopes were returned
on a weekly basis to assess medication compliance. Medica-
tion was properly administered nearly 100% of the time.
Behavioral and physical complaint items were adapted
from the National Institute of Mental Health Subject’s Treat-
ment Emergent Symptoms Scale (STESS; Guy 1976). The
STESS was initially devised for adult raters and consists of
questions concerning the occurrence and severity of a broad
range of possible physical and behavioral complaints and
emergent symptoms associated with pharmacotherapy. A
child version was created using the same items, but re-
worded to ask children (1) whether they had experienced a
particular problem within the past three days, and (2) if so,
the degree of severity using the original version’s 4-point re-
sponse format (“not at all,” “just a little,” “pretty much,”
“very much”). Additional details of the development of the
child version are reported in Rapport et al. (2002). The re-
vised child version has been shown to be sensitive to med-
ication status and dosage changes (Rapport et al. 2002).
Parents were asked to respond to each item during each
weekly visit throughout the study. Children were adminis-
tered the items during each weekly visit by trained gradu-
ate research assistants who read each item aloud to the child
and recorded their verbal response. Parents and children
were asked about the presence and severity of each symp-
tom during the preceding three days. Graduate assistants
were blind to children’s medication status. Completed ques-
tionnaires reflected physical and behavioral complaints ex-
perienced by children within the past three days and asso-
ciated with a single experimental condition (baseline,
placebo, or one of the four MPH conditions).
Items were judged to fall into one of three categories us-
ing an empirically-driven rational approach (Clark and Wat-
son 1995). Four independent judges reviewed the empirical
literature described above and determined whether each
item reflected behavioral/physical complaints that (1) may
mimic core and secondary features of ADHD (Ahman et al.
1993; Barkley et al. 1990; Beidel et al. 1991; APA 2000); (2)
are common to pediatric age children (Belmaker et al. 1985;
Campo and Fritsch 1994; Garber et al. 1991), including un-
medicated children with ADHD (Egger et al. 1999; Mitchell
et al. 1987); or (3) do not fit into the preceding categories and
are associated with psychostimulant treatment (e.g., nau-
sea/upset stomach, dry mouth, decreased appetite). Intra-
class correlation and Fleiss’ kappa were computed to test the
ADHD PHYSICAL/BEHAVIORAL COMPLAINTS 239

Page 4

reliability of the revised scale categories (Nunnally and Bern-
stein 1994). Intraclass correlation was computed using the
Shrout and Fleiss (1979; Case 2) method to determine the
generalizability of the four judges’ item categorization to the
larger population of potential judges (i.e., others that have
reviewed the treatment emergent and physical complaints
literatures), ICC(2, 4) ? .95, p ? .0005. Fleiss’ kappa for more
than two raters (Siegel and Castellan 1988) was computed
using SPSS syntax (King 2004), and provided further evi-
dence of reliability, ? ? .86. Individual disagreements were
discussed and resolved based on empirical literature. Items
judged to belong to each category are shown in Tables 1
and 2.
Results
All tests were two-tailed with alpha level set at .05. A
three-tier data analytic strategy was used to examine the
study’s two primary hypotheses: (Tier I) that adult raters
confuse some features of ADHD with drug-related side ef-
fects; and (Tier II) that baseline/placebo measures reflect
normal levels of physical and behavioral complaints for boys
in general including unmedicated children with ADHD. Tier
III analyzed endorsement of remaining emergent symptoms
associated with psychostimulants to determine whether pre-
viously reported unexpected effects remain evident after re-
moving ADHD-like and common behavior and physical
complaints. Mean severity and percentage of parents and
children endorsing each symptom are shown in Tables 1
and 2.
Tier I analysis: Rater confusion hypothesis
Parental report of physical and behavioral complaints that
may mimic core/secondary features of ADHD were ana-
lyzed using a repeated measures ANOVA (conditions: base-
line, placebo, 5 mg, 10 mg, 15 mg, 20 mg). The analysis ex-
amines the hypothesis that adult raters confuse ADHD
core/secondary features as MPH side effects. The main ef-
fect for drug condition was significant, F (5, 640) ? 16.34, p ?
.001. Tukey post hoc analysis revealed that parent endorse-
ment of physical and behavioral complaints that mimic
core/secondary ADHD features under baseline were signif-
icantly higher than complaints endorsed under placebo and
all active medication conditions (all p ? .05). Additionally,
behavioral complaints were significantly higher in the
placebo condition relative to the four MPH conditions (all
p ? .05). No significant differences emerged among the four
MPH doses (see Fig. 1).
Analysis of trend was performed to examine the shape of
the relationship between parent ratings of physical/behav-
ioral complaints and MPH dose. Parent endorsements under
baseline and active medication conditions were examined in
the initial analysis (i.e., the placebo condition was excluded).
The ensuing analysis was conducted using placebo and ac-
tive drug conditions with baseline excluded.1The propor-
tion of treatment variance (R2trend) was computed for each
significant trend to determine the relative contribution of
each trend component (e.g., linear, cubic, quadratic) when
more than one component reached statistical significance
(Keppel 1991).
Trend analysis of parent endorsement of physical and be-
havioral complaints excluding the placebo condition (i.e.,
baseline, 5 mg, 10 mg, 15 mg, 20 mg) revealed significant lin-
ear F (4, 256) ? 37.83, p ? .001, quadratic F (4, 256) ? 20.77,
p ? .001, and cubic F (4, 256) ? 9.31, p ? .001 trends. The lin-
ear trend accounted for the greatest proportion of variance
(15%), whereas 6% and 3% of unique variance was accounted
for by the two higher-order trends, respectively. This find-
ing indicates that parental report of physical and behavioral
complaints that mimic core/secondary features of the dis-
order evince a moderately abrupt decrease between baseline
and MPH 5-mg, with minimal variation in frequency under
higher dose conditions (see Fig. 1). Only the linear trend was
significant for the placebo-active drug trend analysis F (4,
256) ? 12.35, p ? .001, and the small proportion of variance
accounted for by the model (5%) indicates that the primary
change in complaint frequency results from changes between
baseline and active drug conditions.
Collectively, the preceding analyses indicate a significant
reduction in parental report of physical and behavioral com-
plaints that mimic core/secondary ADHD features under
placebo relative to baseline, and under active MPH condi-
tions relative to both baseline and placebo, with no signifi-
cant variation in complaint frequency among active drug
conditions. These findings are consistent with the hypothe-
sis that adult raters confuse some features of ADHD with
drug-related side effects.
Tier II analysis: Preexisting/normal level hypothesis
Parent and child reports of physical and behavioral com-
plaints common to pediatric age children were analyzed us-
ing a 2 (child and parent raters) ? 6 (conditions: baseline,
placebo, 5 mg, 10 mg, 15 mg, 20 mg) mixed-model ANOVA
to examine the preexisting/normal level hypothesis. This hy-
pothesis posits that the base rate of physical and behavioral
complaints commonly reported by children (including un-
medicated children with ADHD) must be accounted for by
examining baseline frequencies to separate them from actual
treatment emergent symptoms associated with MPH.
The main effect for drug condition was significant, F (5,
640) ? 4.42, p ? .001. Examination of Fig. 2 suggests that the
significant decrease in endorsements from baseline to
placebo (p ? .05) and all active MPH conditions (all p-val-
ues ? .05) is related primarily to decreased child endorse-
ments. However, neither the main effect for rater, F (1, 128) ?
2.84, ns, nor the rater by drug condition interaction, F (5,
640) ? 2.22, ns, was significant.
Tier III analysis: Side effects commonly attributed to
psychostimulant treatment
Parent and child reports of physical and behavioral com-
plaints commonly attributed to psychostimulant therapy
(true emergent symptoms) were analyzed using a 2 (child
and parents raters) ? 6 (conditions: baseline, placebo, 5 mg,
10 mg, 15 mg, 20 mg) Mixed-model ANOVA. The rater by
drug interaction, F (5, 640) ? 2.94, p ? .05, and main effect
for drug were significant, F (5, 640) ? 10.66, p ? .001. There
was no significant main effect for rater, F (1, 128) ? .099, ns.
Tukey post hoc analysis indicated that children endorsed
RAPPORT ET AL. 240
1A basic assumption of trend analysis is that “levels” of experi-
mental conditions be of similar magnitude, which precludes simul-
taneous use of baseline and placebo in the same analysis.

Page 5

TABLE 1.
MEAN SEVERITY AND PERCENTAGE OF PARTICIPANTS ENDORSING EACH BEHAVIORAL AND PHYSICAL SYMPTOM UNDER BASELINE, PLACEBO,
AND ACTIVE METHYLPHENIDATE CONDITIONS—CHILD RATINGS
Behavioral/Physical Complaints1
Baseline
Placebo
5 mg
10 mg
15 mg
20 mg
Core/secondary symptoms of ADHD
Difficulty sitting still
.47(25%)
.16(6.6%)
.15(8.2%)
.21(9.5%)
.20(7.8%)
.06(3.2%)
Difficulty sleeping
.86(39.1%)
.24(12.9%)
.25(14.1%)
.27(14.1%)
.33(14.1%)
.24(9.7%)
Decreased sleep
.26(18.5%)
.21(9.7%)
.34(12.5%)
.22(10.9%)
.11(4.7%)
.13(6.7%)
Crying
.17(7.7%)
.16(6.5%)
.05(1.5%)
.08(3.2%)
.08(3.1%)
.00(0.0%)
Difficulty with attention
.41(15.9%)
.25(11.5%)
.10(4.8%)
.16(6.3%)
.09(6.3%)
.02(1.7%)
More talkative
.98(44.4%)
.37(15%)
.44(18%)
.41(17.5%)
.27(12.7%)
.36(13.1%)
Difficulty with sports
.25(10.8%)
.08(3.3%)
.05(1.6%)
.03(1.6%)
.05(1.6%)
.03(1.6%)
Difficulty with parent relationships
.13(9.4%)
.21(11.1%)
.09(6.2%)
.13(6.3%)
.03(3.1%)
.03(3.3%)
Difficulty with peer relationships
.53(25%)
.24(12.7%)
.18(8.1%)
.16(6.3%)
.21(8.2%)
.13(6.5%)
Anger
.54(24.6%)
.13(6.5%)
.08(3.1%)
.17(6.3%)
.20(11.1%)
.10(4.8%)
Complaints common to all children
Stomach aches
.46(33.8%)
.21(11.3%)
.23(13.8%)
.25(14.1%)
.25(15.9%)
.25(12.7%)
Cramps
.31(20%)
.18(9.8%)
.18(6.5%)
.13(6.3%)
.16(9.7%)
.23(9.7%)
Headaches
.50(23.4%)
.18(9.7%)
.18(9.2%)
.38(18.8%)
.25(14.1%)
.21(11.1%)
Dizziness
.23(13.8%)
.11(6.6%)
.02(1.6%)
.08(4.7%)
.02(1.6%)
.16(9.7%)
Tiredness/fatigue
.60(32.3%)
.37(16.1%)
.33(17.2%)
.38(15.6%)
.36(18.8%)
.18(11.5%)
Muscle aches
.34(25%)
.09(6.3%)
.06(4.6%)
.06(3.1%)
.09(6.2%)
.12(6.2%)
Emergent symptoms
Less eating
.23(20%)
.20(10%)
.11(4.8%)
.30(10.9%)
.16(6.3%)
.14(7.9%)
More drinking
1.22(53.1%)
.32(11.7%)
.21(9.7%)
.27(9.4%)
.32(12.7%)
.26(11.3%)
Dry mouth
.59(35.9%)
.37(14.5%)
.31(13.8%)
.20(10.9%)
.27(14.1%)
.21(11.5%)
More bowel movements
.09(6.3%)
.12(6.7%)
.11(4.7%)
.17(6.3%)
.05(1.6%)
.03(3.3%)
Fewer bowel movements
.36(21.9%)
.31(13.1%)
.20(7.8%)
.17(7.9%)
.19(7.8%)
.12(5.0%)
Harder bowel movements
.05(4.9%)
.11(4.8%)
.11(4.8%)
.05(1.6%)
.00(0.0%)
.02(1.7%)
Softer bowel movements
.40(21.7%)
.24(12.9%)
.11(4.8%)
.36(12.5%)
.19(6.3%)
.15(6.8%)
Sick to stomach
.36(25%)
.21(11.3%)
.18(9.2%)
.27(14.1%)
.25(12.7%)
.23(9.7%)
Throw up
.19(14.3%)
.10(4.8%)
.02(1.6%)
.08(3.1%)
.13(6.3%)
.03(3.2%)
More bedwetting
.11(4.7%)
.11(4.8%)
.08(3.1%)
.11(4.7%)
.11(4.7%)
.06(3.2%)
Polyurea
.25(12.3%)
.11(6.6%)
.09(4.7%)
.11(4.7%)
.00(0.0%)
.07(3.3%)
Decreased urine
.31(23.1%)
.23(8.2%)
.15(7.7%)
.19(6.3%)
.16(7.9%)
.13(6.6%)
Painful urination
.08(4.6%)
.10(6.5%)
.00(0.0%)
.06(3.2%)
.06(3.1%)
.00(0.0%)
Skin itching
.41(28.1%)
.25(9.8%)
.20(7.8%)
.28(12.5%)
.19(12.5%)
.18(6.5%)
Rash
.12(9.2%)
.11(5.0%)
.11(6.3%)
.11(6.3%)
.10(6.5%)
.06(3.2%)
Difficulty with harder words
.22(11.1%)
.13(8.2%)
.00(0.0%)
.00(0.0%)
.05(1.6%)
.00(0.0%)
More shaky
.17(9.4%)
.11(4.9%)
.06(3.1%)
.16(6.3%)
.02(1.6%)
.13(8.3%)
Harder to do things with hands
.08(7.7%)
.16(8.1%)
.11(4.9%)
.09(4.7%)
.05(1.6%)
.07(6.6%)
More bad dreams
.22(10.8%)
.10(4.8%)
.15(6.2%)
.06(3.1%)
.05(1.6%)
.11(4.8%)
More energy
1.24(55.6%)
1.18(48.4%)
.82(36.1%)
.76(27.4%)
.78(32.8%)
.89(32.8%)
Unhappy
.20(10.8%)
.06(3.2%)
.16(6.3%)
.10(4.8%)
.05(1.6%)
.00(0.0%)
Feeling “worse”
.04(3.8%)
.06(3.2%)
.14(7.9%)
.08(4.8%)
.02(1.6%)
.03(3.2%)
Note: Values in each column reflect symptom mean severity score. Values in parentheses reflect percentage of participants endorsing symptom
1Moderate increases in parent or child ratings of select emergent symptoms were reported for some children under the two highest doses (15 mg and 20 mg): feeling sick to stomach, n ? 11; itchy skin,
n ? 10; dry mouth, n ? 9; and reduced appetite, n ? 6).
ADHD, attention-deficit/hyperactivity disorder.

Page 6

TABLE 2.
MEAN SEVERITY AND PERCENTAGE OF PARTICIPANTS ENDORSING EACH BEHAVIORAL AND PHYSICAL SYMPTOM UNDER BASELINE, PLACEBO,
AND ACTIVE METHYLPHENIDATE CONDITIONS—PARENT RATINGS
Behavioral/Physical Complaints1
Baseline
Placebo
5 mg
10 mg
15 mg
20 mg
Core/secondary symptoms of ADHD
Clumsiness
.21(15%)
.15(11.3%)
.00(0.0%)
.03(3.3%)
.13(7.9%)
.00(0.0%)
Difficulty sleeping
.08(4.7%)
.13(11.3%)
.06(6.2%)
.27(20.6%)
.10(10.2%)
.13(8.3%)
Decreased sleep
.17(14.1%)
.14(11.1%)
.08(7.7%)
.16(14.8%)
.13(11.5%)
.15(15.3%)
Crying
.46(34.9%)
.26(19.4%)
.28(23.1%)
.32(21.7%)
.35(23.8%)
.28(21.7%)
Daydreaming
.23(19.4%)
.11(9.8%)
.09(9.4%)
.02(1.7%)
.07(5.0%)
.11(6.6%)
Difficulty with attention
.87(46.8%)
.83(45.0%)
.42(29.2%)
.31(21.3%)
.23(14.8%)
.24(13.6%)
More talkative
.63(36.5%)
.60(38.7%)
.43(29.2%)
.58(33.3%)
.48(30.6%)
.37(27.1%)
Difficulty with sports
.25(12.3%)
.17(7.8%)
.05(4.9%)
.00(0.0%)
.08(4.8%)
.05(3.2%)
Difficulty with parent relationships
.91(56.3%)
.67(43.8%)
.53(40%)
.45(32.3%)
.43(25.4%)
.48(33.9%)
Difficulty with peer relationships
1.12(61.5%)
.70(42.2%)
.49(34.4%)
.48(33.9%)
.44(25.4%)
.40(29%)
Anger
1.29(69.2%)
.69(48.4%)
.60(41.9%)
.47(38.7%)
.54(33.3%)
.47(29%)
Complaints common to all children
Stomach aches
.33(26.6%)
.27(18.8%)
.20(18.8%)
.30(25.4%)
.22(17.5%)
.32(27.4%)
Cramps
.05(4.8%)
.08(4.8%)
.12(9.2%)
.05(4.8%)
.02(1.6%)
.08(4.8%)
Headaches
.39(37.5%)
.19(18.8%)
.25(20%)
.24(17.5%)
.17(14.1%)
.19(14.5%)
Dizziness
.00(0.0%)
.05(3.2%)
.00(0.0%)
.03(3.2%)
.03(1.6%)
.11(8.1%)
Tiredness/fatigue
.15(10.8%)
.05(4.8%)
.20(18.8%)
.16(16.1%)
.20(15%)
.21(17.7%)
Muscle aches
.09(7.8%)
.06(3.1%)
.05(4.8%)
.03(3.2%)
.00(0.0%)
.15(8.1%)
Emergent symptoms
Less eating
.12(10.8%)
.17(15.9%)
.25(20%)
.30(22.2%)
.37(23.8%)
.38(27%)
More drinking
.14(10.8%)
.13(9.5%)
.22(15.6%)
.15(11.5%)
.27(22.2%)
.16(11.5%)
Dry mouth
.05(4.9%)
.10(9.8%)
.15(11.7%)
.08(6.5%)
.10(6.8%)
.13(10%)
Constipation
.05(4.7%)
.02(1.6%)
.00(0.0%)
.03(3.2%)
.03(3.2%)
.00(0.0%)
Diarrhea
.09(9.4%)
.11(7.9%)
.11(7.9%)
.16(11.3%)
.10(4.8%)
.08(6.3%)
Nausea
.03(1.6%)
.08(6.3%)
.05(4.6%)
.06(4.8%)
.08(6.3%)
.16(11.3%)
Bedwetting
.17(10.8%)
.11(7.9%)
.00(0.0%)
.10(4.8%)
.11(7.8%)
.05(3.2%)
Polyurea
.08(6.3%)
.00(0.0%)
.10(7.9%)
.07(5%)
.08(4.9%)
.08(6.6%)
Decreased urine
.02(1.6%)
.00(0.0%)
.00(0.0%)
.05(3.3%)
.00(0.0%)
.00(0.0%)
Painful urination
.00(0.0%)
.02(1.6%)
.00(0.0%)
.00(0.0%)
.02(1.6%)
.02(1.6%)
Skin itching
.09(6.3%)
.19(14.3%)
.09(7.7%)
.10(9.7%)
.16(14.1%)
.15(14.5%)
Rash
.03(3.1%)
.05(3.1%)
.06(6.2%)
.03(3.2%)
.13(9.4%)
.10(8.1%)
Light sensitivity
.05(4.8%)
.06(6.5%)
.05(4.9%)
.07(4.9%)
.05(4.9%)
.05(3.5%)
Difficulty with balance
.18(11.5%)
.08(6.5%)
.03(3.2%)
.03(3.3%)
.06(3.2%)
.02(1.7%)
Difficulty with speech
.09(6.3%)
.08(6.3%)
.05(4.7%)
.02(1.6%)
.06(3.2%)
.03(3.3%)
Shaky hands
.03(3.1%)
.03(3.3%)
.00(0.0%)
.02(1.7%)
.05(3.2%)
.05(3.3%)
More bad dreams
.02(1.6%)
.05(4.9%)
.05(3.2%)
.05(4.9%)
.03(3.2%)
.07(4.9%)
Difficult to please
.58(35.4%)
.48(38.1%)
.34(29.2%)
.37(24.2%)
.27(21%)
.18(16.4%)
More serious
.26(25.8%)
.30(25%)
.39(37.5%)
.38(28.6%)
.48(34.4%)
.48(33.9%)
Silliness
.73(50.8%)
.48(32.8%)
.31(24.6%)
.49(33.3%)
.39(29.7%)
.30(27.9%)
More energy
.69(36.9%)
.60(39.7%)
.35(24.6%)
.50(30.6%)
.29(20.6%)
.26(16.4%)
Less Energy
.02(1.6%)
.06(4.8%)
.22(15.4%)
.18(13.1%)
.22(14.3%)
.26(21%)
More withdrawn
.06(6.2%)
.05(4.8%)
.06(6.2%)
.03(3.3%)
.15(9.7%)
.16(11.3%)
Unhappy
.41(32.8%)
.24(17.5%)
.16(15.6%)
.18(12.9%)
.21(14.3%)
.16(16.1%)
Happiness
.52(31.3%)
.44(26.2%)
.37(26.2%)
.47(32.2%)
.44(31.7%)
.33(23.3%)
More repetitive behaviors
.44(25.8%)
.23(17.7%)
.09(6.3%)
.18(16.4%)
.08(8.1%)
.17(8.3%)
More self-harm behaviors
.03(1.5%)
.00(0.0%)
.00(0.0%)
.00(0.0%)
.03(1.6%)
.00(0.0%)
Feeling “worse”
.44(20.6%)
.58(33.9%)
.25(20.6%)
.23(16.4%)
.22(13.3%)
.16(10.5%)
Note: Values in each column reflect symptom mean severity score. Values in parentheses reflect percentage of participants endorsing symptom
1Moderate increases in parent or child ratings of select emergent symptoms were reported for some children under the two highest doses (15 mg and 20 mg): feeling sick to stomach, n ? 11; itchy skin,
n ? 10; dry mouth, n ? 9; and reduced appetite, n ? 6).
ADHD, attention-deficit/hyperactivity disorder.

Page 7

significantly more physical and behavioral complaints com-
monly attributed to psychostimulants under baseline rela-
tive to placebo and all four active MPH conditions (all p ?
.05), and under placebo relative to 5 mg, 15 mg, and 20 mg
conditions (all p ? .05). No significant differences emerged
among the active MPH conditions (see Fig. 3). Parent en-
dorsements showed a similar pattern of results—signifi-
cantly more physical and behavioral complaints were re-
ported under baseline relative to 5 mg and 20 mg MPH (both
p ? .05). No other contrasts were significant.
Collectively, these results indicate that the significant in-
teraction effect was due to initially higher child relative to
adult complaint endorsements under baseline, coupled with
lower complaint frequency under the MPH conditions.
Trend analysis reveals that child ratings are best character-
ized by a linear decrease in physical and behavioral com-
plaints, with the largest decrease occurring between baseline
and active medication conditions. Parent ratings are best
characterized by a cubic decrease in complaints that accounts
for less than 2% of change—indicating minimal change
across the experimental conditions.
Group-level analysis was supplemented by examination
of individual child rating scale results, and revealed moder-
ate increases in select emergent symptoms for some children
(e.g., feeling sick to stomach, n ? 11; itchy skin, n ? 10; dry
mouth, n ? 9; and reduced appetite, n ? 6) under the two
highest doses (15 mg and 20 mg).
Discussion
The present study examined competing hypotheses re-
garding past reports of unexpected reductions in physical
and behavioral complaints associated with MPH therapy for
children with ADHD. Symptoms on the child version of the
STESS side effect rating scale (Rapport et al. 2002) were sep-
arated into specific categories using an empirically-driven
rational approach to investigate predictions that some phys-
ical and behavioral complaints represent ADHD primary/
secondary features, some reflect non-medication-related
complaints reported by children in general, and others are
true emergent symptoms specific to psychostimulant treat-
ment.
Child endorsements of both common physical complaints
and true emergent symptoms showed significant reductions
from baseline to active immediate-release MPH conditions,
and were of a sufficient magnitude to be considered clini-
cally meaningful (range ? 27% to 62% reduction). Significant
reductions in symptom endorsements were also observed
between placebo and active MPH conditions for parent rat-
ings that reflect ADHD core/secondary features (e.g., sitting
still, difficult peer relationships), and for child symptom rat-
ings specific to MPH treatment (e.g., stomachaches, reduced
appetite). These changes were smaller in magnitude than
those observed for the baseline-MPH contrasts, and suggest
that part of the observed effect is associated with expectancy,
“cry for help,” regression to the mean, or other factors re-
lated to placebo phenomena. No significant differences
emerged among the four active MPH doses for child and
parent endorsements across the three categories.
Our results are consistent with those reported in past stud-
ies that included baseline measures of psychostimulant ef-
fects. For example, Ahman and colleagues (1993) reported
reduced frequencies in four behavioral symptoms assessed
by the Stimulant Drug Side Effects Rating Scale (Barkley
2006) under their high dose MPH condition (dose range ?
.3 mg/kg to .6 mg/kg). Efron and colleagues (1997) reported
ADHD PHYSICAL/BEHAVIORAL COMPLAINTS 243
FIG. 1.
toms endorsed by parents that may reflect core or secondary
features of attention-deficit/hyperactivity disorder under
baseline, placebo, and active methylphenidate (MPH) con-
ditions.
Mean number of physical and behavioral symp-
FIG. 2.
ments of physical and behavioral complaints commonly re-
ported by children (including those with attention-
deficit/hyperactivity disorder) in the general population.
MPH ? methylphenidate; BL ? baseline; PL ? placebo.
Mean severity ratings of parent and child endorse-

Page 8

similar results—a decrease in frequency and severity of side
effects relative to baseline when comparing MPH to dexam-
phetamine at .3 mg/kg and .15 mg/kg, respectively. Placebo-
controlled dose-response investigations without baseline
measures report similar findings (e.g., Firestone et al. 1998;
Fischer and Newby 1991; Short et al. 2004). Collectively, these
findings suggest that several items included on emergent rat-
ing scales likely reflect phenotypical, behavioral features of
ADHD rather than true emergent symptoms related to MPH
therapy. Parent and teacher ratings of these scale items have
previously been attributed to rater confusion. However, an
equally plausible explanation is that raters are accurately re-
flecting observed behavior changes in children consistent
with the vast literature on psychostimulant response, and in-
vestigators have misinterpreted these ratings by relying on
total rather than item or factor scale scores. This explanation
also holds for scales developed specifically to monitor emer-
gent symptoms associated with psychostimulant therapy,
such as the Stimulant Drug Side Effects Rating Scale (Barkley
2006), which contains multiple items that mirror core and
secondary features of ADHD (e.g., trouble sleeping, prone-
ness to crying, daydreams).
Children’s complaints of physical discomfort on a weekly
and reoccurring basis are well documented in the literature
(Egger et al. 1999; DuPaul et al. 1996; Mitchell et al. 1987).
Our results corroborate extant research in demonstrating
that children with ADHD share this propensity for experi-
encing weekly discomfort such as headaches, feeling tired,
muscle aches, stomachaches, and occasional dizziness under
no-medication conditions. The results provide a compelling
rationale for recognizing that children, like adults, regularly
experience physical discomfort that must be recognized and
accounted for prior to initiating a medication trial. An un-
expected result, however, was the significant decrease in
these complaints under placebo and MPH conditions rela-
tive to baseline by child endorsements. Mean child complaint
severity decreased between 44% and 56% from baseline to
active MPH conditions. A proportion of this change appears
to be related to expectancy effects associated with placebo
phenomena in child ratings (i.e., changes from baseline to
placebo for child ratings was 52%). These effects are tradi-
tionally attributed to a person’s belief in a treatment’s po-
tential efficacy, but may also be mediated by changes in emo-
tional state, perception, and behavioral improvement
(Stewart-Williams 2004).
Placebo effects, however, only partially account for the sig-
nificant reductions in complaints from baseline to MPH. A
halo effect may explain the similar magnitude reductions
from placebo to active medication conditions across all three
symptom categories. In other words, active medication re-
duces impairing symptoms (reflected in the Tier I analyses),
which may result in parents viewing their children as health-
ier in general (as reflected in the Tiers II and III analyses).
The reduction in children’s endorsements may also reflect
improvement in associated areas of daily functioning, such
as improved attention, academic performance, and class-
room conduct associated with both placebo and active med-
ication conditions (e.g., DuPaul and Rapport 1993; MTA Co-
operative Group 1999; Pelham et al. 1990). This potential halo
effect merits consideration and requires a carefully designed
protocol to determine whether improved behavioral and/or
academic functioning serve as significant mediators for chil-
dren’s emergent symptoms (Greenhill et al. 2001b).
Similar results were found when examining child en-
dorsement of symptoms highly specific to psychostimulant
medication. Children endorsed a significantly higher sever-
ity of complaints for this category under baseline relative to
placebo (a 34% decrease) and all four active MPH conditions
(decreases between 43% and 59%); and under placebo rela-
tive to 5mg (25% decrease), 15-mg (31% decrease), and 20-
mg (38% decrease) conditions. Parent endorsements showed
fewer significant contrasts, with higher severity of physical
and behavioral complaints reported under baseline relative
to 5mg (28% decrease) and 20mg (27% decrease) MPH con-
ditions only. Idiographic examination revealed moderate in-
creases for some children in nausea (n ? 11), itchy skin (n ?
10), dry mouth (n ? 9), and reduced appetite (n ? 6) under
the two highest doses (15mg and 20 mg).
Limitations
Although all three classes of potential emergent symptoms
showed significant decreases from baseline, several caveats
merit consideration. Increased frequency and/or severity of
emergent symptoms reported by or observed in children re-
ceiving psychostimulant therapy are probable to the extent
that dosing regimens differ from the parameters reported
herein, particularly in those symptoms highly specific to
MPH. That is, children receiving multiple doses per day, sin-
gle doses exceeding 20 mg, different MPH formulations, and
MPH over a longer duration of time are likely to experience
a higher frequency and/or severity of emergent symptoms
(Gadow and Sverd 2006). The immediate-release MPH for-
mulary is currently used less frequently than newer formu-
lations, and the generalizability of the present findings to
long-duration, sustained-release, and other variants is
unknown. Preschool children with ADHD (Connor 2002;
RAPPORT ET AL.244
FIG. 3.
toms endorsed by parents and children that are commonly
attributed to methylphenidate (MPH) therapy (true side ef-
fects).
Mean number of physical and behavioral symp-

Page 9

Kollins 2004), and those whose presentation includes other
clinical features such as developmental delays (Aman et al.
1991; Handen et al. 1992), may also experience a higher fre-
quency and/or severity of psychostimulant-related emer-
gent symptoms. Because baseline assessments necessarily
preceded placebo and active medication conditions, and no
age-matched control group was included, the influence of
halo, order, or regression to the mean effects on the signifi-
cant decreases in symptom severity between baseline and
placebo cannot be entirely eliminated. However, the pattern
of symptom reductions from the counterbalanced placebo to
active medication conditions was similar to the pattern
shown from baseline (albeit smaller magnitude). Carryover
effects are unlikely due to counterbalancing and the inclu-
sion of a “washout” day between all conditions. In addition,
four days elapsed between the administration of the pre-
ceding week’s final dosage and symptom ratings for the cur-
rent dosage. A final caveat involves the applicability of
group-level results for titrating and monitoring psychostim-
ulant regimens for individual children. Generalization can
never be assumed, and is always limited by the highly idio-
syncratic treatment response observed within and across be-
havioral, cognitive, and emergent symptom domains in chil-
dren with ADHD (Rapport and Kelly 1991).
Conclusions
Collectively, our findings point to a clear need to develop
psychometrically sound treatment emergent symptom rat-
ing scales for purposes of monitoring physical and behav-
ioral complaints in children treated with psychostimulants
(Greenhill et al. 2001b). Special care is warranted in word-
ing scale items to ensure that their content differentiates be-
tween emergent symptoms and core/secondary symptoms
of the disorder. This can be accomplished through extensive
item refinement and submitting items to expert judges for
review (see Clark and Watson 1995). The development of a
separate factor scale that contains typical daily complaints
endorsed by children based on extant research may also be
desirable. Separating these complaints from drug-related
emergent symptoms affords practitioners improved ability
to assess the extent of a child’s usual complaint frequency
and severity, and to determine whether it changes with treat-
ment as evidenced herein. Including items that help differ-
entiate improved attention from staring or constricted at-
tention are also desirable. Finally, the administration of
treatment emergent scales prior to initiating therapy must be
considered a de rigueur component of clinical management
for establishing a true baseline of child complaints (Barkley
et al. 1990; Greenhill et al. 2001a).
Disclosures
Drs. Rapport and Coiro and Mr. Kofler, Mr. Raiker, Mr.
Alderson, and Mr. Sarver have no financial, corporate, or
commercial relationships to disclose.
References
Abu-Arefeh I, Russell G: Recurrent limb pain in school. Arch
Dis Child 74:336–339, 1996.
Achenbach TM: Empirically based assessment of child and ado-
lescent disorders: Implications for diagnosis, classification,
epidemiology, and longitudinal research. In: Children at Risk:
Assessment, Longitudinal Research, and Intervention. Edited
by Brambring M, Losel F. Oxford, England, Walter De
Gruyter, 1989, pp 24–45.
Ahman PA, Waltonen SJ, Olson KA, Theye FW, Van Erem AJ,
LaPlant, RJ: Placebo controlled evaluation of Ritalin side ef-
fects. Pediatrics 91:1101–1106, 1993.
Aman MG, Marks RE, Tubott SH, Wilsher CP, Merry SN: Clin-
ical effects of methylphenidate and thioridazine in intellectu-
ally subaverage children. J Am Acad Child Adolesc Psychia-
try 30:246–256, 1991.
American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders (4thed.). Washington, DC, Amer-
ican Psychiatric Association, 2000.
Apley J: The child with Abdominal Pains (2nded.). London,
Blackwell, 1975.
Barea LM, Tannhauser M, Rotta NT: An epidemiologic study of
headache among children and adolescents of southern Brazil.
Cephalalgia 16:545–550, 1996.
Barkley RA, McMurray MB, Edelbrock CS, Robbins K: Side ef-
fects of methylphenidate in children with attention deficit hy-
peractivity disorder: A systematic, placebo-controlled evalu-
ation. Pediatrics 86:184–192, 1990.
Barkley RA: Attention Deficit Hyperactivity Disorder: A Hand-
book for Diagnosis and Treatment (3rd edition). New York,
Guildford Press, 2006.
Beidel DC, Christ MA, Long PJ: Somatic complaints in anxious
children. J Abnorm Child Psychol 19:659–670, 1991.
Belmaker E, Espinoza R, Pogrund R: Use of medical services by
adolescents with non-specific somatic symptoms. Int J Ado-
lesc Med Health 1:150–156, 1985.
Campo JV, Fritsch SL: Somatization in children and adolescents.
J Am Acad Child Adolesc Psychiatry 33:1223–1235, 1994.
Carlson GA, Kashani JH: Phenomenology of major depression
from childhood through adulthood: Analysis of three studies.
Am J Psychiatry 145:1222–1225, 1988.
Chronis, AM, Chacko, A, Fabiano, GA, Wymbs, BT, & Pelham,
WE: Enhancements to the behavioral parent training para-
digm for families of children with ADHD: Review and future
directions. Clin Child Fam Psychol Rev 7: 1–27, 2004.
Clark LA, Watson D: Constructing validity: Basic issues in ob-
jective scale development. Psychol Assess 7:309–319, 1995.
Connor DF: Controlled trial of methylphenidate in preschool
children with minimal brain dysfunction. Int J Ment Health,
4:61–74, 2002
Conners CK, Epstein JN, March JS: Multimodal treatment of
ADHD in the MTA: An alternative outcome analysis. J Am
Acad Child Adolesc Psychiatry 40:159–167, 2001.
Conners CK, Sitarenios G, Parker JDA, & Epstein JN: Revision
and restandardization of the Conners Teacher Rating Scale
(CTRS-R): Factor structure, reliability, and criterion validity.
J Abnorm Child Psychol 26: 279–291, 1998.
Denney CB, Rapport MD: Cognitive pharmacology of stimulants
in children with ADHD. In: Stimulant Drugs and ADHD: Ba-
sic and Clinical Neuroscience. Edited by Solanto MV, Amsten
AFT. New York, Oxford University Press, 2001, pp 283–302.
Dunn LM, Dunn LM: Peabody Picture Vocabulary Test-Third
Edition. Circle Press, Minn.: American Guidance Service, 1997.
DuPaul GJ, Rapport MD: Does methylphenidate normalize the
classroom performance of children with attention deficit dis-
order? J Am Acad Child Adolesc Psychiatry 32:190–198, 1993.
DuPaul GJ, Anastopoulos AD, Kwasnick D, Barkley RA, Mc-
Murray MB: Methylphenidate effects on children with atten-
tion deficit hyperactivity disorder: Self-report symptoms, side
effects and self-esteem. J Atten Disord 1:3–15, 1996.
ADHD PHYSICAL/BEHAVIORAL COMPLAINTS 245

Page 10

DuPaul GJ, Eckert TL: Interventions for students with Attention-
Deficit/Hyperactivity Disorder: One size does not fit all.
School Psych Rev 26:369–381, 1997.
Efron D, Jarman F, Barker M: Side effects of methylphenidate
and dexamphetamine in children with attention deficit hy-
peractivity disorder: A double-blind, crossover trial. Pedi-
atrics 100:662–666, 1997.
Egger H, Costello EJ, Angold A: Headaches and psychopathol-
ogy in children and adolescents. J Am Acad Child Adolesc
Psychiatry 37:951–958, 1999.
Faraone SV, Biederman J, Roe C: Comparative efficacy of adder-
all and methylphenidate in attention-deficit/hyperactivity
disorder: A meta-analysis. J Clin Psychopharmacol 22:468–
473, 2002.
Findling RL, Short EJ, Manos MJ: Developmental aspects of psy-
chostimulant treatment in children and adolescents with at-
tention-deficit/hyperactivity disorder. J Am Acad Child
Adoelsc Psychiatry 40:1441–1447, 2001.
Fine S, Johnston C: Drug and placebo side effects in
methylphenidate-placebo trial for attention deficit hyperac-
tivity disorder. Child Psychiatry Hum Dev 24: 25–30, 1993.
Firestone P, Musten LM, Pisterman S, Mercer J, Bennett S: Short-
term side effects of stimulant medication are increased in
preschool children with attention deficit hyperactivity disor-
der: A double-blind placebo-controlled study. J Child Adolesc
Psychopharmacol 8:13–25, 1998.
Fischer M, Newby RF: Assessment of stimulant response in
ADHD children using a refined multimethod clinical proto-
col. J Clin Child Adolesc Psychol 20:232–244, 1991.
Gadow J, Sverd J: Attention Deficit Hyperactivity Disorder,
Chronic Tic Disorder, and Methylphenidate. In: Advances in
Neurology: Tourette Syndrome Vol. 99. Edited by Walkup J,
Mink J, Hollenbeck P. Philadelphia, Lippincott, 2006, pp
197–207.
Garber J, Walker L, Zeman J: Somatization symptoms in a com-
munity sample of children and adolescents: Further valida-
tion of the Children’s Somatization Inventory. Psychol Assess
3:588–595, 1991.
Gittelman-Klein R, Klein DF: Methylphenidate effects in learn-
ing disabilities: Psychometric changes. Arch Gen Psychiatry,
33:655–664, 1976.
Gorman EB, Klorman R, Thatcher JE, Borgstedt AD: Effects of
methylphenidate on subtypes of attention-deficit/hyperactiv-
ity disorder. J Am Acad Child Adolesc Psychiatry 45:808–816,
2006.
Grcevich S, Rowane WA, Marcellino B, Sullivan-Hurst S: Ret-
rospective comparison of Adderall and methylphenidate in
the treatment of attention-deficit/hyperactivity disorder. J
Child Adolesc Psychopharmacol, 11:35–41, 2001.
Greenhill L, Swanson JM, Vitiello B, Davies M, Clevenger W,
Wu M, Arnold LE, Abikoff HB, Bukstein OG, Conners CK, El-
liott GR, Hechtman L, Hinshaw SP, Hoza B, Jensen PS, Krae-
mer HC, March JS, Newcorn JH, Severe JB, Wells K, Wigal T:
Impairment and deportment
methylphenidate doses in children with ADHD: The MTA
titration trial. J Am Acad Child Adolesc Psychiatry,
40:180–187, 2001a.
Greenhill LL, Vitiello B, Abikoff H, Levine J, March JS, Riddle
MA, Capasso L, Cooper T, Davies M Fisher P, Findling RL,
Fried J, Labellarte M, McCracken J, McMahon DJ, Robinson J,
Skrobala AM, Scahill L, Walkup J, Zito J: Improving the meth-
ods for evaluating the safety of psychotropic medications in
children and adolescents. Current Therapeutic Res 62:873–884,
2001b.
responses to different
Guy W: ECDEU Assessment Manual for Psychopharmacology
(revised). Rockville, Maryland, Department of Health, Edu-
cation and Human Welfare Publication No. (ADM) 76–338,
1976.
Handen BL, Breaux AM, Janosky J, McAuliffe S, Feldman H,
Gosling H: Effects and noneffects of methylphenidate in chil-
dren with mental retardation and ADHD. J Am Acad Child
Adolesc Psychiatry 31:455–461, 1992.
Hollingshead AB: Four Factor Index of Social Status. New Haven
(Connecticut), Yale University, 1975.
Jensen PS: Fact versus fancy concerning the multimodal treat-
ment study for attention-deficit hyperactivity disorder. Can J
Psychiatry 44:975–980, 1999.
Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P,
Williamson D, Ryan N: Schedule for Affective Disorders and
Schizophrenia for School-Age Children-Present and Lifetime
Version (K-SADS-PL): Initial reliability and validity data. J
Am Acad Child Adolesc Psychiatry 36:980-988, 1997.
Keppel G: Design and Analysis: A Researcher’s Handbook
(3rded.). Upper Saddle River (New Jersey), Prentice Hall,
1991.
King JE: Software solutions for obtaining kappa-type statistic for
use with multiple raters. Dallas (Texas), Southwest Educa-
tional Research Association Annual Meeting, 2004.
Kollins SH, the PATS Study Group: Preschool ADHD Treatment
Study. Phoenix (Arizona), National Institute of Mental Health,
New Clinical Drug Evaluation Unit (NCDEU) Annual Meet-
ing, 2004.
Last C: Somatic complaints in anxiety disordered children. J
Anxiety Disord 5:125–138, 1991.
Linna S, Moilanen I, Keistinen H, Ernvall ML: Prevalence of psy-
chosomatic symptoms in children. Psychother Psychosom
56:85–87, 1991.
Masi G, Favilla L, Millepiedi S, Mucci M: Somatic symptoms in
children and adolescents referred for emotional and behav-
ioral disorders. Psychiatry 63:140–149, 2000.
Mitchell EA, Aman MG, Turbott SH, Manku M: Clinical char-
acteristics and serum essential fatty acid levels in hyperactive
children. Clin Pediatr (Phila) 26:406–411, 1987.
Multimodal Treatment Study of Children with ADHD Cooper-
ative Group: Moderators and mediators of treatment response
for children with attention-deficit/hyperactivity disorder: The
Multimodal treatment study of children with attention-
deficit/hyperactivity disorder. Arch Gen Psychiatry 56:1088–
1096, 1999.
Nunnally JC, Bernstein IH: Psychometric Theory (3rded.). New
York, McGraw-Hill, 1994.
Pelham WE, McBurnett K, Harper GW, Milich R, Murphy DA,
Clinton J, Thiele C: Methylphenidate and baseball playing in
ADHD children: Who’s on first? J Consult Clin Psychol
58:130–133, 1990.
Pine DS: Treating children and adolescents with selective sero-
tonin reuptake inhibitors: How long is appropriate? J Child
Adolesc Psychopharmacol 2:189–203, 2002.
Rapport MD, Kelley KL: Psychostimulant effects on learning and
cognitive function: Findings and implications for children
with attention deficit hyperactivity disorder. Clin Psychol Rev
11:61–92, 1991.
Rapport MD, Denney C, DuPaul GJ, Gardner MJ: Attention
deficit disorder and methylphenidate: Normalization rates,
clinical effectiveness, and response prediction in 76 children.
J Am Acad Child Adolesc Psychiatry 33:882–893, 1994.
Rapport MD, Denny C: Titrating methylphenidate in children
with attention-deficit/hyperactivity disorder: Is body mass
RAPPORT ET AL. 246

Page 11

predictive of clinical response? J Am Acad Child Adolesc Psy-
chiatry 36:523–530, 1997.
Rapport MD, Chung K-M, Shore G, Issacs P: A conceptual model
of child psychopathology: Implications for understanding at-
tention deficit hyperactivity disorder. J Clin Child Adolesc
Psychol 30:48–58, 2001.
Rapport MD, Moffitt C: Attention-deficit/hyperactivity disor-
der and methylphenidate: A review of height/weight, car-
diovascular, somatic complaint side effects. Clin Psychol Rev
22:1107–1131, 2002.
Rapport MD, Moffit C, Randall R: Attention-deficit/hyperac-
tivity disorder and methylphenidate: A dose response analy-
sis and parent-child comparisons of somatic complaints. J At-
ten Disord 6:15–24, 2002.
Routh DK, Schroeder CS, O’Tauma L: Development of activity
level in children. Dev Psychol 10:163–168, 1974.
Short EJ, Manos MJ, Findling RL, Schubel EA: A prospective
study of stimulant response in preschool children: Insights
from ROC analyses. J Am Acad Child Adolesc Psychiatry
43:251–259, 2004.
Shrout PE, Fleiss JL: Intraclass correlations: Uses in assessing
rater reliability. Psychol Bull 2: 420–428, 1979.
Siegel S, Castellan NJ: Nonparametric Statistics for the Behav-
ioural Sciences (2nd ed.). New York, McGraw-Hill, 1988.
Stewart-Williams S: The placebo puzzle: Putting together the
pieces. Health Psychol 23:198–206, 2004.
Swanson JM, Cantwell D, Lerner M, McBurnett K, Hanna G: Ef-
fects of stimulant medication on learning in children with
ADHD. J Learn Disabil 24:219–230, 1991.
Swanson JM, Volkow ND: Pharmacokinetic and pharmacody-
namic properties of stimulants: Implications for the design of
new treatment for ADHD. Behav Brain Res 130:73–78, 2002.
Taylor DC, Szatmari P, Boyle MH, Offord DR: Somatization and
the vocabulary of everyday bodily experiences and concerns:
A community study of adolescents. J Am Acad Child Adolesc
Psychiatry 35:491–499, 1996.
Vaessen W, & Van der Meere JJ: Issues in the selection of hy-
peractive/ADD(H) children for experimental clinical studies.
In Developmental Biopsychology: Experimental and Obser-
vational Studies in Groups “at Risk”. Edited by A. F. Kalver-
boer. Ann Arbor: University of Michigan Press, 1990, pp.
21–37.
Address reprint requests to:
Mark D. Rapport, Ph.D.
Department of Psychology
4000 Central Florida Blvd.
Orlando, Fl 32816
E-mail: mrapport@mail.ucf.edu
ADHD PHYSICAL/BEHAVIORAL COMPLAINTS247