1892_ADHD_steele 12/1/06 2:22 PM Page 1892

Clinical Therapeutics/Volume 28, Number 11, 2006

Remission Versus Response as the Goal of Therapy in ADHD:

A New Standard for the Field?
Margaret Steele, MD, FRCPC, MEd1; Peter S. Jensen, MD2;
and Declan M.P. Quinn, MB, FRCPC3
1Departments of Psychiatry, Pediatrics, and Family Medicine, Schulich School of Medicine and Dentistry,
University of Western Ontario, London, Ontario, Canada; 2Center for the Advancement of Children’s
Mental Health, Columbia University/NY State Psychiatric Institute, New York, New York; and
3Department of Psychiatry, Child & Youth Division, University of Saskatchewan College of Medicine,

Saskatoon, Saskatchewan, Canada

ABSTRACT of ≤1 on most standardized questionnaires. For the

6
Background: Attention-deficit/hyperactivity disor- medications examined (OROS methylphenidate,
der (ADHD) has a substantial negative impact; how-
0
immediate-release methylphenidate, atomoxetine, and
0
ever, within long-term follow-up studies, a proportion
2
mixed amphetamine salts), response rates were com-
,
of patients do very well, both symptomatically and
c
parable at ~70% to 75%; however, remission rates
In
l
functionally, suggesting that the lower the symptom were higher with OROS methylphenidate compared
,
burden, the greater the functional improvements.
a
i a
with either immediate-release methylphenidate or ato-

di
c
c
Studies in major depressive disorder have identified a moxetine (remission rates with amphetamines were
relationship between symptomatic remission and
restoration of normal functioning.
a e r Me
not found). Benefits, including decreased illness bur-
den as well as improved psychosocial and academic

rp
t m n
Objective: The purpose of this article was to propose

m o
functioning, were associated with treatment versus no

e i
a definition of remission in ADHD, review remission treatment and were greater with medication that of-

Ex C o u t
c
rates in clinical trials for commonly used medications, fered higher remission rates.

© r rib
and explore the relationship between symptomatic re- Conclusions: The literature provided evidence that

t o
mission and optimal functioning. greater symptom improvements are associated with

ig t f
h
s t
Methods: Remission and response rates for medica-
r i
greater functional improvements, emphasizing that re-

No D
tions were obtained through MEDLINE searches of mission of ADHD as defined should be the goal of
p y
English-language citations (1999–2005) and meeting therapy. Treatment ought to include the early use of

Co
abstracts (2003–2005) using the terms amphetamine,
atomoxetine, methylphenidate, ADHD, efficacy, effec-
tiveness, and controlled trial, as well as hand searches
of efficacy studies. Evidence from randomized con-
trolled trials, as well as effectiveness studies, where the
proportions of patients achieving predefined cutoff
points for remission or response are reported, was
reviewed. Because higher remission rates were identi-
fied with the oral, osmotic, controlled-release system
(OROS) of methylphenidate, a relationship between
symptomatic response/remission and optimal function-
ing was explored further.
Results: Remission in ADHD should be defined as
a loss of diagnostic status, minimal or no symptoms,
and optimal functioning when individuals are being
treated with or without medication. Symptomatic re-
mission can be operationalized as a mean total score
strategies with the greatest chance of achieving remis-
sion. Future clinical research should use remission as
the primary outcome. (Clin Ther. 2006;28:1892–1908)
Copyright © 2006 Excerpta Medica, Inc.
Key words: remission, response, attention-deficit/
hyperactivity disorder, amphetamine, methylphenidate,
atomoxetine, oral, osmotic, controlled-release system.
INTRODUCTION
Attention-deficit/hyperactivity disorder (ADHD) is a
prevalent chronic health condition affecting school-aged
Accepted for publication April 18, 2006.
doi:10.1016/j.clinthera.2006.11.006
0149-2918/06/$19.00
Printed in the USA. Reproduction in whole or part is not permitted.
Copyright © 2006 Excerpta Medica, Inc.

1892 Volume 28 Number 11

1892_ADHD_steele 12/1/06 2:22 PM Page 1893
children and adolescents.1 The reported prevalence of
ADHD in children 6 to 12 years of age ranges from 4%
to 12% depending on the setting, gender, and diagnos-
tic criteria used.2,3 Surveys based on the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV) criteria report cumulative prevalence rates of
6.8% to 7.5% among children aged up to 19 years.4,5
ADHD is diagnosed more often in boys than in girls,
with the male to female ratio in prevalence estimated at
~3:1 to 9:1.3,6,7 ADHD is often complicated by comor-
bid oppositional defiant disorder (ODD) or conduct dis-
order (CD) in 25% to 50%, anxiety disorders in 25%
to 35%, mood disorders in 20%, and specific develop-
mental disorders in 20%.8–11 The presence of comorbid
ODD or CD in patients with ADHD has been associat-
ed with a poorer prognosis.12–15
Several long-term studies (4–15 years) have fol-
lowed up pediatric patients with ADHD into adoles-
cence and adulthood.16–25 These studies found that
for many patients, ADHD is a lifelong disorder, with
long-term impact on academic achievement, social
Repeat a grade
Failure to graduate HS
Involved in teen pregnancy
‡
STD
Substance abuse
Illness and accidents
At-fault car accident
Arrested
Incarcerated
Fired from job
0 10
Figure 1. Functional impairments in patients with attention-deficit/hyperactivity disorder (ADHD) compared with
those without ADHD.16–18,20,21,23–25 HS = high school; STD = sexually transmitted disease. *P ≤ 0.01;
†P ≤ 0.001; ‡P ≤ 0.006.
November 2006
M. Steele et al.
functioning, self-esteem, and employment stability
(Figure 1). Up to 3 times more patients with ADHD
have to repeat a grade (30% vs 11%; P < 0.01),16 or
fail to complete high school (31% vs 10%; P <
0.01),17 compared with individuals without ADHD.
Teenagers with ADHD are likely to become sexually
active earlier than their peers (15.5 vs 16.3 years; P =
0.044), are less likely to use contraception (75% vs
90%; P = 0.046), and are at higher risk of being in-
volved in a teenage pregnancy (38% vs 4%; P <
0.001) or contracting a sexually transmitted disease
(17% vs 4%; P = 0.006).18 Patients with ADHD have
higher rates of antisocial personality (21% vs 4%; P <
0.01),19 are more likely to have been arrested (46% vs
11%; P < 0.001) and incarcerated (22% vs 1%; P <
0.001),20 have higher rates of substance abuse disor-
ders (52% vs 27%; P ≤ 0.01),21 have significantly
compromised occupational functioning, with lower
occupational rank (4.6 vs 3.9; P = 0.01)22 and higher
risk of being fired (53% vs 31%; P < 0.006),23 as well
as increased rates of illness and accidents (46% vs
ADHD
* Normal
*
†
*
†
†
†
‡
20 30 40 50 60
Subjects (%)
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Clinical Therapeutics
15%; P < 0.001)24 during adolescence or adulthood
compared with control groups. Individuals with ADHD
have more driving-related negative outcomes, includ-
ing traffic citations (4.4 vs 1.1; P < 0.021), especially
for speeding (1.5 vs 0.4; P = 0.01), and are involved
in more at-fault motor vehicle crashes (49% vs 11%;
P < 0.001)25 than control patients. A significant finan-
cial burden is associated with ADHD, in terms of both
direct patient costs ($1574 vs $541) and indirect costs
to family members ($2728 vs $1440) (1998 annual
costs [US $], significant at 95% CI).26
Overall, the long-term outcomes of ADHD appear
to be problematic for many patients. However, within
long-term follow-up studies, a proportion of patients
do very well, both symptomatically (15%–33% had
few or no symptoms12,16,17) and functionally (20%).27
It appears that the lower the symptom burden, the
greater the functional improvements.28–37 It has been
suggested that with appropriate management, patients
with ADHD can become virtually asymptomatic,
achieving remission of ADHD.38
The most recent algorithm for pharmacotherapeu-
tic therapy of ADHD from the Texas Children’s Medi-
cation Algorithm Project (CMAP) recommends the
use of stimulants as first- and second-line options
(Figure 2).39 Either methylphenidate or amphetamine
monotherapy are recommended first, and if the child
fails to respond—or experiences adverse effects that
make the long-term use of such treatment inappropri-
ate—then monotherapy with the alternative stimulant
should be tried. A recently presented update to the
Texas CMAP has suggested that because stimulants
are more effective, atomoxetine should be reserved for
use after 2 different stimulants have been tried, replac-
ing pemoline in the algorithm.40
Remission should be the goal of therapy in ADHD,
and management of ADHD should consider those
medication strategies with the greatest chances of
achieving remission. The purpose of this article was to
propose a definition of remission in ADHD, review re-
mission rates in clinical trials for commonly used medi-
cations, and explore the relationship between symp-
tomatic remission and optimal functioning.
MATERIALS AND METHODS
A MEDLINE search of English-language citations
(1999–2005) and meeting abstracts (2003–2005) using
the terms amphetamine, atomoxetine, methylphenidate,
ADHD, efficacy, effectiveness, and controlled trial, as
1894
well as hand searches of efficacy studies for data re-
ported in the form of remission or response rates, were
conducted. Meeting abstracts were incorporated be-
cause they provide new research data, but they have
not yet been published in peer-reviewed journals.
Evidence from randomized controlled trials, as well
as effectiveness studies, where the proportions of pa-
tients achieving predefined cutoff points for remission
or response are reported, was reviewed. Because high-
er remission rates were identified with the oral, os-
motic, controlled-release system (OROS) of methyl-
phenidate, a relationship between symptomatic response/
remission and optimal functioning was explored further.
RESULTS
Definition of Remission Versus Response as
the Goal of Therapy in ADHD
Concept of Remission in Psychiatry
The concepts of response and remission in psychia-
try were first proposed for major depressive disorder
(MDD) by researchers at the University of Pittsburgh
(Pittsburgh, Pennsylvania) in the early 1990s.41,42 Al-
though a variety of terms were proposed, 2 of the most
important were response and remission. In essence,
response was defined as an improvement in symptoms
as a result of treatment,41 which in MDD is usually
operationalized as a 25% to 50% improvement in
symptom scores; more than minimal symptoms usual-
ly remain. Generally, patients who respond to therapy
no longer fully meet the DSM-IV criteria for the dis-
order. However, since this definition does not consid-
er the initial severity of illness, “responders” can
include patients who continue to have active illness.
Consequently, remission was defined as sufficient im-
provement such that the patient no longer has syn-
dromal criteria for the disorder and is virtually asymp-
tomatic; this is usually operationalized in MDD as a
symptom score of ≤7 on the Hamilton Depression
Rating Scale.41 Remission of an extended duration
(>2–6 months), without relapse, was termed recov-
ery.41 Subsequent treatment trials have demonstrated
that there are significant benefits associated with
achieving remission. Not only is there the expected re-
duction in acute symptom burden, but remission is
also associated with decreased relapse rates, com-
pared with not achieving remission (76% vs 25%; P <
0.001; n = 60),43 restoration of social functioning (so-
cial adjustment scale [SAS], self-report, 1.71 vs 2.14
and 2.44, P ≤ 0.5; n = 635) and occupational func-
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M. Steele et al.

Diagnostic assessment and family

Stage 0 consultation regarding treatment
alternatives

Nonmedication
treatment alternatives
Any stage(s) can be skipped
depending on the clinical assessment

Stage 1 Monotherapy:
methylphenidate, amphetamine

Response
Continuation
Partial response
or nonresponse

Stage 2 Monotherapy:
stimulant not used in stage 1

Response
Continuation
Partial response
or nonresponse

Stage 3 Monotherapy alternative class:

pemoline*

Response
Continuation
Partial response
or nonresponse

Stage 4 Bupropion, imipramine, or

nortriptyline

Response
Continuation
Partial response
or nonresponse

Stage 5 Antidepressant not used

in stage 4

Response
Continuation
Partial response
or nonresponse

Stage 6 ␣-Agonists†

Maintenance

Figure 2. Texas Children’s Medication Algorithm Project: Algorithm for the pharmacotherapeutic treatment of
attention-deficit/hyperactivity disorder without comorbid psychiatric disorders. *Plus liver function
monitoring and substance abuse history. †Cardiovascular side effects. Reprinted with permission from
Pliszka SR, Greenhill LL, Crismon ML, et al. The Texas Children’s Medication Algorithm Project: Report
of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/
Hyperactivity Disorder. Part I. Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry.
2000;39:908–919.39

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Clinical Therapeutics

tioning (SAS work composite, 1.45 vs 1.82 and 2.21,
P ≤ 0.5; n = 635),44 and potentially lower health care
costs (1996 US $1813 vs $2477 and $5264, P = 0.06;
n = 290).45 Additional review articles offer a more
complete discussion of remission in MDD.46–49
Concept of Remission in ADHD
The concepts of response and remission are impor-
tant to both investigational and clinical treatment of
ADHD. Standardized criteria, such as measures of
severity of ADHD symptoms, allow for comparisons
of treatment efficacy and correlation of symptom im-
provements to short- and long-term functional im-
provements. Remission is particularly important in
ADHD since the illness occurs during the early years,
usually before the age of 7 years, and thus may disrupt
subsequent education, career, and social develop-
ment.16–25 Therefore, as the goal of therapy, remission
of ADHD should be more than the relief of symp-
toms; it should also include optimal functioning in
emotional, behavioral, academic, and social realms.
Remission in ADHD should be defined as loss of di-
agnostic status based on standardized measures of
ADHD, minimal or no symptoms, and optimal func-
tioning when individuals are being treated with or
without medication. There is evidence in ADHD re-
search that decreasing symptom burden is associated
with increasing functional restoration, and it is possi-
ble that the longer the duration of remission the
greater the functional recovery will be.34–37
Remission as Defined in ADHD Studies
Various definitions of remission of ADHD as used
in clinical trials are shown in Table I.34,38,50–56 Swanson
et al proposed a definition of remission in ADHD in
an analysis of data from the National Institute of
Mental Health collaborative, multisite Multimodal
Treatment Study of Children with ADHD (MTA).28,38
Using a standardized symptom scale (Swanson, Nolan
and Pelham, Version IV [SNAP-IV]), a cutoff score
was defined, such that there was a loss of diagnostic
status, and scores were in the range of a matched con-
trol population without ADHD. In essence, the pa-
tient no longer has ADHD. Many symptom scales are
available, but regardless of which scale is used, it is
important to set a cutoff score to ensure that patients
are achieving symptomatic remission. Most scales are
based on the 18 symptoms of the DSM-IV diagnostic
criteria, which address attention, hyperactivity, and
impulsivity.7 Symptoms are usually ranked on a scale
ranging from “not at all” to “very much,” and as-
signed a numerical value. The scores are totaled and
divided by the number of questions (items) to deter-
mine a mean score for an individual.

Table I. Definitions of remission of attention-deficit/hyperactivity disorder (ADHD) used in clinical trials.

Scale Description Remission

SNAP-IV-18 Swanson, Nolan and Pelham, Version IV50 Mean score of ≤1, not at all or
First 18 items on a 90-item scale assessing inattention just a little ill38 or ≤1 on each
and hyperactivity item34
Items are rated from 0 = not at all to 3 = very much
ADHD-RS-IV ADHD Rating Scale, Version IV51 Score of ≤18, never, rarely,
18 Items assessing inattention and hyperactivity or sometimes ill52
Items are rated from 0 = not at all to 3 = very much
CGI-S Clinical Global Impressions–Severity scale53 Score of ≤2, not at all or
Single-item assessment of severity of ADHD symptoms minimally ill52,54,55
Severity of impairment is rated from 1 = not at all ill to
7 = maximal, profound impairment
CPRS-R I/O Conners’ Parent Rating Scale–Revised, Inattention/
Overactivity subscale56 Mean score of ≤5, not true at
5 Items assessing inattention/overactivity all/never or just a little true/
Items are rated from 0 = not at all true/never to 3 = occasionally
very much true/very often

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In clinical trials to date, a response to therapy has
usually been defined as a 25% to 30% improvement
in symptom scores.54,55,57–59 Using only a percentage
reduction in symptoms does not take into considera-
tion the initial severity of the illness, and as a result,
“responders” may include individuals who continue
to be highly symptomatic. Similarly, on the Clinical
Global Impressions–Improvement scale, response is
generally defined as “much” or “very much improved,”
but again this does not account for baseline illness
severity.52,58,60,61
The most common definitions of symptomatic
remission that have been used in recent clinical trials
assessing treatment options (Table I) have been the
SNAP-IV, the ADHD Rating Scale, Version IV
(ADHD-RS-IV), and the Clinical Global Impressions–
Severity (CGI-S) scale.28,34,38,52,54,55 One recent study
defined remission as ≥50% improvement on the
Conners’ Parent Rating Scale–Revised, Inattention/
Overactivity subscale; using the mean baseline score
of 10.5, that would equate to a mean cutoff score of
≤5.57 All of these definitions have in common achiev-
ing a cutoff score such that the patient no longer ful-
fills DSM-IV criteria for ADHD and the patient is not
at all or minimally ill. Because all of these tools use a
scale of 0 to 3, with the exception of the CGI-S (which
uses a scale of 1–7), the definitions of remission can be
extrapolated to a standardized definition of ≤1 on any
scale simply by dividing the total score by the number
of items in the questionnaire.
Validity of Remission Definitions
Although additional studies are needed, the appro-
priateness of the cutoff scores outlined in Table I was
evaluated using data from the MTA study.28,38 Remis-
sion was defined as a mean score of ≤1 on the first
18 items of the SNAP-IV, which equates to a low
symptom severity (not at all or just a little ill). Patients
achieving this score no longer meet the DSM-IV crite-
ria for ADHD, which state that symptoms must be
sufficiently severe to be maladaptive.7 In addition, this
standard was achieved by 88% of comparable chil-
dren without ADHD.38
Further evidence that the cutoff values for these
scales are comparable is seen in a study by Stein et al,52
in which remission was measured using both a score of
≤18 on the ADHD-RS-IV and a score of ≤2 on the
CGI-S. Remission rates—defined as ADHD-RS-IV ≤18
and CGI-S ≤2—were 14% and 7% in the placebo
November 2006
M. Steele et al.
group, 32% and 25% in the 18-mg OROS methyl-
phenidate group, 40% and 45% in the 36-mg OROS
methylphenidate group, and 66% and 52% in the
54-mg OROS methylphenidate group, respectively
(P < 0.05 for dose response) (Figure 3).52
Thus, remission, defined as minimal or no symp-
toms, appears to equate to the average optimally func-
tioning child without ADHD, which may be true
regardless of the scoring tool used, at least among
those tools reviewed here. However, preliminary data
remain to be confirmed.
Efficacy of Treatments in Achieving Response
and Remission in ADHD
In randomized controlled clinical trials, response to
therapy has been defined as a 25% to 30% improve-
ment in symptoms or a global rating of “much” or
“very much” improved.52,54,55,57–61 About 65% to
75% of patients will respond, with response rates
being generally similar among the various treatments
at clinically effective doses: OROS methylphenidate
QD, 65% to 84%52,57,60,62; immediate-release (IR)
methylphenidate BID or TID, 61% to 73%57,62,63; IR
dextroamphetamine or mixed amphetamine salts BID,
54% to 75%58,61,63,64; and atomoxetine QD or BID,
37% to 70%54,55,59 – 61,65 (Table II). However, the goal
of therapy should be remission, defined as minimal
symptoms. Remission rates reported with methyl-
phenidate treatment have been higher than those with
the nonstimulant atomoxetine. In separate, random-
ized clinical trials, remission rates at clinically effec-
tive doses have been 40% to 66% with OROS
methylphenidate QD52,57 and 38% to 56% with IR
methylphenidate TID,28,38,57 compared with 27% to
29% with atomoxetine QD54,55 (Table II).
Behavioral therapy can boost remission rates when
used in conjunction with pharmacotherapy. For exam-
ple, in the MTA study, the remission rate was 56%
with IR methylphenidate TID and was increased to
68% when behavioral therapy was added to the medi-
cation regimen.38
Effectiveness of Treatments in Achieving
Response and Remission in ADHD
Effectiveness studies have also examined the poten-
tial for treatment to achieve remission in the “real
world.” In clinical practice, other issues such as com-
pliance and management follow-up influence the ef-
fectiveness of treatment for ADHD. For example, in
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Clinical Therapeutics
100
80
Remission Rate (%)
60
40
32
25
20
0
OROS MPH 18 mg
Figure 3. Remission rates with the oral, osmotic, controlled-release system of methylphenidate (OROS MPH) as
determined by using scores of ≤2 on the Clinical Global Impressions–Severity (CGI-S) scale and ≤18 on
the ADHD Rating Scale, Version IV (ADHD-RS-IV). P < 0.05 for dose response. Data from Stein et al.52
the MTA study, remission rates were 56% in the medi-
cal management group (IR methylphenidate TID) com-
pared with 25% in the community care group (67%
received ADHD medication, primarily IR methyl-
phenidate BID).38,66 Community care participants did
not receive study treatments but were provided a re-
port of their initial study assessments, along with a list
of community mental health resources. Patients re-
ceived higher doses of medication and closer follow-
up from their physicians in the medication arm of the
trial.38,67
In the multicenter Canadian study of OROS methyl-
phenidate (CONCAN-1), 145 children with a baseline
CGI-S score of ≥4 were randomized to “usual care”
open-label treatment with OROS methylphenidate or IR
methylphenidate over a period of 8 weeks (Table II).34
Remission rates were significantly higher with OROS
methylphenidate compared with IR methylphenidate
(44% and 16%, respectively; P < 0.001) (Figure 4).
This may be attributable, in part, to the fact that pa-
tients in the OROS methylphenidate group received
more methylphenidate. Mean daily doses were higher
(37.8 vs 33.2 mg) and compliance was better (mean
number of missed doses, 1.9 vs 10.4; P < 0.001) with
1898
CGI-S, ≤2
ADHD-RS-IV, ≤18
66
52
45
40
14
7
OROS MPH 36 mg OROS MPH 54 mg Placebo
the OROS formulation compared with the IR formu-
lation of methylphenidate. However, in a subanalysis
of patients receiving IR methylphenidate BID or TID,
both IR subgroups continued to show significantly
lower rates (P < 0.001) of remission compared with
those receiving OROS methylphenidate (Figure 4).34
In CONCAN-2, patients in CONCAN-1 from ei-
ther treatment group continued on OROS methyl-
phenidate.68,69 Follow-up data found that benefits were
maintained at 6 months among patients who had re-
ceived OROS methylphenidate throughout the trial.68
Patients in the IR methylphenidate group who were
switched to the OROS formulation improved (23%)
but did not achieve the same remission rates (P = 0.01)
seen in the group that had been on OROS methyl-
phenidate since the beginning of the trial (49%)
(Figure 4). This finding suggests that strategies with
the highest chances of remission should be used early
to maximize the benefits of therapy. Although addi-
tional research is needed, it appears possible that suc-
cess in achieving early remission might explain why
some patients do well in long-term follow-up studies,
while for others ADHD appears to be a life-long dis-
order.16,17,20,22,70–75
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M. Steele et al.

Table II. Response and remission rates with pharmacotherapy for attention-deficit/hyperactivity disorder from
clinical trials.*

Study, Design, Drug/Mean

Baseline Test Scores Daily Dose Response Rates Remission Rates
Stein et al, 200352; CGI-S ≤3 ADHD RS-IV ≤18 CGI-S ≤2
crossover, 1 wk, PBO 14% 14% 7%
N = 32 OROS MPH, 18 mg 44% 32% 25%
ADHD-RS-IV, OROS MPH, 36 mg 65% 40% 45%
t score, 72.5–75.7; OROS MPH, 54 mg 72% 66% 2%
CGI-S, 4.4 (P < 0.05 for dose response)
Greenhill et al, 200457; IOWA C ≥30% IOWA C ≥50% IOWA C ≥70%
RCT, 4 wks, PBO 21.4% 11.9% 3.6%
N = 282 OROS MPH, 18 mg 40.0% 26.7% 6.7%
IOWA I/O, 10.47 OROS MPH, 36–54 mg 83.6% 62.3%† 29.5%
IR MPH, NR 60.9% 37.5%†‡ 12.2%
(P < 0.001)
Pelham et al, 200162; Parent GAE
RCT, 1 wk, PBO 4.4% NR
N = 70 OROS MPH, 35 mg 66.2%
IOWA I/O, 10.42 IR MPH, 29 mg 64.7%
(P < 0.001)
Kemner et al, 200560; CGI-I ≤2
randomized, open-label, OROS MPH 32.7 mg 68.6% NR
3 wks, N = 651 ATX 1.08 mg/kg 52.8%
ADHD-RS-IV, 39.3 (P < 0.001)
Steele et al, 200634; NR SNAP-IV-18 ≤1 on each item
randomized, open-label, OROS MPH, 37.8 mg 44%
8 wks, N = 143 IR MPH, 33.2 mg 16%
SNAP-IV-26, 51 (P < 0.001)
Swanson et al, NR SNAP-IV mean ≤1
200128,38; 14 mos, N = 579 IR MPH, 37.7 mg 56%
IOWA C mean, 2.29 Community care 25%
(P < 0.05)
Efron et al, 199763; PGPQ, global
crossover, 2 wks, DEX, 0.15 mg/kg 69% NR
N = 125 IR MPH, 0.3 mg/kg 73%
CPRS-R t score, 73.5
Ahmann et al, 200164;
crossover, 2 wks, PBO Multiple criteria‡ NR
N = 154 MAS, 0.15–0.3 mg/kg 54.0%
CPRS-48 Hyper, 75.6 (P < 0.001)
Spencer et al, 200158; CGI-I ≤2 ADHD-RS-IV ≥30%
crossover, 7 wks, PBO 3.7% 7% NR
N = 27, adults MAS, 54 mg 66.7% 70%
Baseline NR (P < 0.001)
(continued)

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Table II. (Continued)

Study, Design, Drug/Mean

Baseline Test Scores Daily Dose Response Rates Remission Rate

Wigal et al, 200561; CGI-I ≤2

RCT, 3 wks, MAS, 10–30 mg 74.5% NR
N = 215 ATX, 0.5–1.2 mg/kg 36.5%
Baseline NR (P < 0.001)

Spencer et al, 200259; ADHD-RS-IV ≥25%

RCT, 12 wks, PBO 25% NR
N = 147, stimulant naive ATX, ≤2 mg/kg 64%
ADHD-RS-IV, 41.3; IR MPH, ≤1.5 mg/kg NR
CGI-S, 4.9 (P = 0.003)

Spencer et al, 200259; ADHD-RS-IV ≥25%

RCT, 12 wks, PBO 40% NR
N = 144, prior stimulant use ATX, ≤2 mg/kg 59%
ADHD-RS-IV, 37.7; MPH, ≤1.5 mg/kg NR
CGI-S, 4.9 (P = 0.001)

Michelson et al, 200254; ADHD-RS-IV ≥25% CGI-S ≤2

RCT, 6 wks, PBO 31.3% 9.6%
N = 171 ATX, 1–1.5 mg/kg 59.5% 28.6%
ADHD-RS-IV, 37.1 (P < 0.001) (P = 0.003)

Kelsey et al, 200455; ADHD-RS(P) ≥25% CGI-S ≤2

RCT, 8 wks, PBO 33.3% 5.0%
N = 197 ATX, 1.3 mg/kg 62.7% 27.0%
ADHD-RS-IV, 42.2 (P < 0.001) (P < 0.001)

Weiss et al, 200565; ADHD-RS(T) ≥20%

RCT, 7 wks, PBO 43.1% NR
N = 153 ATX, 1.2–1.8 mg/kg 69.0%
CGI-S, 4.9 (P = 0.003)

ADHD-RS-IV = ADHD Rating Scale, Version IV; CGI-S = Clinical Global Impressions–Severity scale (1 = no symptoms, 2 = mini-
mal symptoms); PBO = placebo; OROS MPH = oral, osmotic, controlled-release system of methylphenidate; RCT = ran-
domized controlled trial; IOWA I/O = Iowa Conners’ Inattention/Overactivity subscale; IR MPH = immediate-release
methylphenidate; NR = not reported; IOWA C = Iowa Conners’ Rating Scale; GAE = global assessment of efficacy response
(was good or excellent on a scale of poor, fair, good, or excellent); ATX = atomoxetine; CGI-I = Clinical Global
Impressions–Improvement scale (1 = very much improved, 2 = much improved); SNAP-IV-26 = first 26 items on the Swanson,
Nolan and Pelham, Version IV scale; SNAP-IV-18 = first 18 items on the Swanson, Nolan and Pelham, Version IV scale; CPRS-R
= Conners’ Parent Rating Scale, Revised; DEX = dextroamphetamine; PGPQ = Parent Global Perception Questionnaire (re-
sponse was better or much better on a 5-point scale of much better, better, same, worse, or much worse); CPRS-48 Hyper =
Hyperactivity Index of the Conners’ Parent Rating Scale–48; MAS = mixed amphetamine salts; ADHD-RS(P) = ADHD Rating
Scale (Parent); ADHD-RS(T) = ADHD Rating Scale (Teacher).
*P values are versus PBO unless otherwise specified.
†P < 0.001
‡ The criteria that defined a positive response to MAS relative to PBO (with each patient serving as his or her own control) in-

cluded an indication of response by at least 1 of 2 parent measures of children’s behavior or at least 2 of 5 teacher measures
of children’s behavior. The MAS efficacy rate was determined based on parent criteria alone, teacher criteria alone, and by a
more stringent definition of response that required concurrence between parent and teacher criteria.

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M. Steele et al.

60 8-Week Trial 6-Month Trial

49†
50
44*

40
Patients (%)

30
24 23
20
16

10
4

0
OROS MPH IR MPH All IR MPH TID IR MPH BID OROS MPH IR MPH/
(n = 72) (n = 73) (n = 43) (n = 27) (n = 54) OROS MPH
(n = 55)

Figure 4. Remission rates in the 8-week CONCAN-1 study reflecting clinical practice. Patients were randomized
to either an oral, osmotic, controlled-release system of methylphenidate (OROS MPH) or to immediate-
release methylphenidate (IR MPH). In a subanalysis of patients receiving IR MPH TID or BID, both
groups continued to show significantly (P < 0.001) lower rates of remission versus the OROS MPH
group. In the 6-month CONCAN-2 study, patients from either treatment group of CONCAN-1 contin-
ued with OROS MPH treatment.34,68 *P < 0.001 versus IR MPH all, P ≤ 0.05 versus IR MPH TID, P <
0.001 versus IR MPH BID; †P = 0.01 versus IR MPH/OROS MPH.

As mentioned earlier, the presence of comorbid ODD
or CD in patients with ADHD has been associated with
a poorer prognosis.12–15 Methylphenidate has also been
shown to improve symptoms of ODD.38,62,76–78 In the
subanalysis of CONCAN-1, almost 50% of patients
had a history of or current ODD.79 Analysis of remis-
sion of ODD symptoms (defined as a score of ≤1 on
ODD subitems of the SNAP-IV) revealed significantly
higher remission rates with OROS methylphenidate
compared with IR methylphenidate (58% and 35%,
respectively; P = 0.004).
The Relationship Between Remission and
Optimal Functioning
Remission as the goal of therapy for ADHD is
more than just relieving symptoms; it is also impor-
tant to optimize functioning. Various studies have
assessed improvements in functional outcomes in
ADHD (Table III).28–35,65,80 Some data suggest that
better symptom control leads to better outcomes, and
those treatment strategies that provide greater rates of
remission offer greater improvements in functional
outcomes as well.28–37 Compared with baseline,
methylphenidate therapy has been associated with im-
proved functional outcomes in both emotional and
academic areas.28–31 For example, in the Comparison
of Methylphenidate in an Analog Classroom Setting
study,29 treatment with OROS methylphenidate was
associated with an increased number (P < 0.016) of cor-
rectly answered math problems (Table III, Figure 5).
Similarly, in the MTA study,28 well-titrated medi-
cation strategies that resulted in remission also
achieved better outcomes in terms of teacher-rated so-
cial skills, compared with community care strategies
(defined earlier) (Table III). These benefits appear to
be sustained over the longer term; in a study of up to
2 years of stimulant treatment, improvements were
noted in reading (total score, 634 vs 572; P < 0.001)
and math (application scores, 636 vs 576; P < 0.001)
with IR methylphenidate compared with baseline.30
Interestingly, in a recent study with atomoxetine in
which the remission rate (teacher-rated CGI-S score, ≤2)

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Clinical Therapeutics

Table III. Improvements in functional outcomes.

Drug/Mean
Study, Design Daily Dose* Results
MTA study, 199928; COMB, MPH, 31.2 mg COMB > CC for parent–child relations, P = 0.003;
randomized, parallel design, MED, MPH, 37.7 mg social skills, P = 0.001; academic reading (scores,
14 mos, N = 579 BEH 99.4 vs 95.4), P < 0.001
CC, MPH, 22.6 mg

Swanson et al OROS MPH, 18–54 mg More correctly answered math problems with
(COMACS study), 200429; PBO OROS MPH vs PBO, ES = 0.28–0.54 (P < 0.016)
crossover, 1 wk, N = 184

Hechtman et al, 200430; IR MPH Improvements in reading (total score, 634 vs 572;
randomized, open-label, IR MPH + MPT P < 0.001) and math (application scores, 636 vs
2 y, N = 103 IR MPH + ACT 576; P < 0.001) with IR MPH over 2 years
compared with baseline

Swanson et al, 200331; MPH TID, 15–45 mg Academic improvement in speed and accuracy for
crossover, N = 32 MPH ascending, 15–45 mg MPH TID (ES, 0.9 and 0.7) and MPH ascending
PBO (ES, 0.9 and 0.9) vs PBO (P < 0.001)

Biederman, 200332; Medicated Decreased rate of substance use with treatment

longitudinal follow-up, Unmedicated (25% vs 75%; OR, 0.15; 95% CI, 0.04–0.6)
N = 260

Wilens et al, 200333; Medicated Decreased rate of substance use with treatment
meta-analysis, 6 studies, Unmedicated (1.9-fold reduction; 95% CI, 1.1–3.6)
N = 1034

Steele et al (CONCAN-1 study), OROS MPH, 37.8 mg Improvements in measures of social play (–17.9 vs
200634; randomized, open-label, IR MPH, 33.2 mg –7.5; P = 0.03) and parental stress (–14.0 vs –6.1;
8 wks, N = 143 P = 0.008) with OROS MPH vs IR MPH

Lage and Hwang, 200435;
cohort study, N = 1775
OROS MPH Decreased rate of accident or injury (OR, 0.58;
IR MPH 95% CI, 0.35–0.95), significantly fewer emergency
department visits (0.59 fewer; P < 0.001) and GP
visits (1.39 fewer; P < 0.001) per patient over 1 year
with OROS MPH versus IR MPH

Weiss et al, 200565; ATX, 1.2–1.8 mg/kg No significant improvement in academic scores
RCT, 7 wks, N = 153 PBO (APRS total, 4.8 vs 2.2; P = 0.106)

Cox et al, 200580; OROS MPH, 72 mg Superior overall driving performance with OROS
crossover, 5–10 days, N = 34 se-AMP ER, 30 mg MPH vs PBO (P = 0.005)
PBO

MTA = Multimodal Treatment Study of Children with ADHD; COMB = combined treatment; MPH = methylphenidate; MED =
medication management; BEH = behavioral treatment; CC = community care; COMACS = Comparison of Methylphenidate in
an Analog Classroom Setting study; OROS MPH = oral, osmotic, controlled-release system of methylphenidate; PBO = place-
bo; ES = effect size; IR MPH = immediate-release methylphenidate; MPT = multimodal psychosocial treatment; ACT = attention
control treatment; OR = odds ratio; GP = general practitioner; RCT = randomized controlled trial; ATX = atomoxetine; APRS =
Academic Performance Rating Scale; se-AMP ER = extended-release single-entity amphetamine.
*Some studies did not report the mean daily dose.

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M. Steele et al.

OROS MPH
100 Placebo
PERMP/Mean No. Answered Correctly

90

80

70

60

50
0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
Hour Postdose

Figure 5. Improvements in academic outcomes as shown by an increased number of correctly answered math
problems. A 10-minute, written math test provided an objective measure from its Permanent Product
Measure of Performance (PERMP), defined as the number of problems answered correctly. The oral, os-
motic, controlled-release system of methylphenidate (OROS MPH) was statistically significantly better
than placebo at all time points (P < 0.016). Reprinted with permission from Swanson et al.29

was only 21%, no improvement in the Academic
Performance Rating Scale (total, 4.8 vs 2.2; P = 0.106)
was seen.65
In both efficacy and effectiveness studies, OROS
methylphenidate has resulted in significant remission
rates compared with the IR formulation (Table II)34,57;
also, in another analysis, it has been associated with
better functional outcomes (Table III).34,35 In the
CONCAN-1 study of 145 children randomized to
open-label treatment, OROS methylphenidate was as-
sociated with 2 times greater improvement in mea-
sures of social play (–17.9 vs –7.5; P = 0.03) com-
pared with IR methylphenidate.34 In addition,
parental stress (–14 vs –6.1; P = 0.008) was signifi-
cantly reduced with the OROS formulation versus the
IR formulation of methylphenidate.
A recent survey of 1431 children treated with OROS
methylphenidate and 344 treated with IR methyl-
phenidate found that those receiving the OROS for-
mulation were 42% less likely to experience an acci-
dent or injury (odds ratio, 0.58; 95% CI, 0.35–0.95).35
OROS methylphenidate was associated with fewer
emergency department (0.59 fewer; P < 0.001) and
general practitioner (1.39 fewer; P < 0.001) visits
per patient over 1 year compared with IR methyl-
phenidate. In another critical area of functioning, the
number of driving errors was significantly reduced
(P = 0.005) with OROS methylphenidate compared
with IR methylphenidate.80
As yet, it is not clear whether the possible better re-
mission rates achieved with longer-acting prepara-
tions are the result of the easier demands of QD
preparations (thereby delivering more consistent, ap-
propriate, and efficacious treatment) or whether they
might occur through effects on other symptoms and
functional domains not yet fully understood.
Achieving Remission in Clinical Practice
To maximize the chance of achieving symptomatic
remission and optimal functioning with methylpheni-
date in clinical practice, it is important to use ade-
quate doses. In the MTA study, the mean daily dose of
IR methylphenidate was 22.6 mg in the community
care population (25% remission rate), while it was
37.7 mg in the medication arm (56% remission rate).38,66
In the medication arm, 28.8% of children were as-

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Clinical Therapeutics
signed to low doses (≤15 mg/d), 32.8% to moder-
ate doses (16–34 mg/d), and 38.4% to high doses
(≥35 mg/d).
Data from the study by Stein et al52 of OROS
methylphenidate also support the importance of ade-
quate doses in achieving optimal outcomes. Remission
rates were increased with higher doses of OROS
methylphenidate (P < 0.05): 40% to 66% with 36
and 54 mg/d versus 25% to 32% with 18 mg/d and
7% to 14% with placebo (Figure 3). Dose conversion
for the IR and OROS formulations of methylphenidate
are as follows: 5 mg TID = 18 mg; 10 mg TID = 36 mg;
and 15 mg TID = 54 mg.29
For most children, careful initial titration can yield
a stimulant dose in the general range of the effective
maintenance dose, but it does not prevent the need for
subsequent maintenance adjustments. For example, in
the MTA study,28 of the 230 children for whom the
first months of titration identified an optimal medica-
tion dose, only 17% remained on the initial dose
throughout the ensuing 13 months. In fact, a mean of
2.8 pharmacologic changes per child were required
over the study, with the mean time to first dose change
being 4.7 months, even after initial titration where
multiple doses were compared. Thus, for optimal
pharmacologic treatment of ADHD to achieve and
maintain remission, both careful initial titration and
ongoing medication management are needed.
Unfortunately, follow-up intervals of ≥6 months
are all too common in clinical practice.28 It is thus not
surprising that the 24-month follow-up of the MTA
study showed that on return of patients to standard
community care, their subsequent treatment was char-
acterized by few follow-up visits (only twice/year vs
once monthly during the active period of the study)
and static medication doses, resulting in a substantial
proportion of patients showing symptomatic relapse
and loss of remission.81,82
DISCUSSION AND CONCLUSIONS
Remission in ADHD should be defined as a loss of di-
agnostic status, minimal or no symptoms, and optimal
functioning when individuals are being treated with
or without medication. Symptomatic remission can be
operationalized in ADHD as a mean total score of ≤1
on most standardized questionnaires by dividing the
total score by the number of items in the question-
naire. This cutoff score was found in the MTA study
to be in the range of a matched control population
1904
without ADHD,38 but validation studies are needed.
Using only a percentage reduction in symptoms or
response does not take into consideration the initial
severity of the illness; as a result, “responders” may
include individuals who continue to be highly sympto-
matic. Future clinical research should use remission as
the primary outcome.
Because there is evidence that greater symptom im-
provements are associated with greater functional im-
provements, the definition of remission should include
loss of diagnostic status and optimal functioning.28–37
After reviewing the literature, it appears that when ade-
quate doses of methylphenidate are used, the individu-
al achieves better success with respect to resolution of
ADHD symptoms as well as functioning.38,52,66 Studies
in which sustained-release formulations of stimulant
medications are used, such as OROS methylphenidate,
have been associated with higher ADHD symptom
resolution rates compared with IR formulations,34 as
well as improved functioning as noted by decreased
accidents and injuries,35 decreased emergency depart-
ment and general practitioner visits,35 and improved
functional recovery in psychosocial areas34 and driv-
ing performance.36,37 Based on the literature, there-
fore, it appears that remission as defined here is
achievable and should be a goal of treatment. How-
ever, further research needs to be completed.
ACKNOWLEDGMENTS
The authors received an honorarium and/or had ex-
penses paid by Janssen-Ortho, Inc. (Toronto, Ontario,
Canada) to attend a roundtable working discussion in
anticipation of the manuscript being prepared.
The authors would like to thank Pauline Lavigne,
MSc (CMED, Toronto, Ontario, Canada), for her assis-
tance in the manuscript preparation.
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Clinical Therapeutics

treatment strategies for attention-

deficit/hyperactivity disorder. Pediatrics.
2004;113:754–761.

Address correspondence to: Margaret Steele, MD, FRCPC, MEd, London

Health Sciences Center–South Street Campus, 346 South Street, Room
102D, London, Ontario, N6A 4G5, Canada. E-mail: margaret.steele@
lhsc.on.ca

1908 Volume 28 Number 11