Review Paper

Attention-Deficit Hyperactivity Disorder: Critical

Appraisal of Extended Treatment Studies
Russell Schachar, MD, FRCPC1, Alejandro R Jadad, MD, DPhil2 , Mary Gauld, BA3,
Michael Boyle, PhD4, Lynda Booker, BA5, Anne Snider, MEd5, Marie Kim, MD, FRCPC6,
Charles Cunningham, PhD7

We undertook a systematic review of the literature on the long-term treatment of attention-

deficit hyperactivity disorder (ADHD). We used systematic strategies to identify random-
ized treatment studies in which treatment was administered for 12 weeks or more. We in-
cluded 14 studies involving 1379 subjects. Because of the limited number of high-quality
studies and the heterogeneity of outcome measures, we did not perform metaanalysis. We
rated 5 studies as adequate for methodological quality. Five studies followed children for
more than 26 weeks. Pharmacologic interventions were studied more frequently than non-
pharmacologic ones. Six studies permitted evaluation of the effects of combined drug and
behavioural intervention. Twenty-five different outcomes were measured using 26 different
tests. Stimulant medication appears to reduce ADHD (7 studies), dysfunctional social be-
haviour (6 studies), and internalizing symptoms (2 studies). Available studies provide little
evidence for improved academic performance with stimulants (3 studies). Medications
other than stimulants have not been studied extensively (3 studies). Only 1 study showed
that combination therapy adds to the effects of medication. Rigorous treatment research
among representative samples of ADHD individuals is needed.
(Can J Psychiatry 2002;47:337–348)

Clinical Implications
• Systematic reviews are important tools for decision makers but the methodological rigour of
randomized controlled trials (RCTs) of long-term attention-deficit hyperactivity disorder
(ADHD) treatment is low.
• These studies do not clarify the effect of treatment on important outcomes.
• Combined pharmacologic and nonpharmacologic interventions yield the best outcomes.

Limitations
• The effects of nonpharmacologic treatment and drugs other than stimulants are little studied.
• Systematic review of available studies is limited by the wide array of outcomes, designs, diag-
nostic measures, and other critical study elements.
• RCTs may not be the best design to evaluate the effectiveness of long-term therapy.

Key Words: attention-deficit hyperactivity disorder, ADHD, systematic review, treatment,

stimulants, behavioural therapy
ttention-deficit hyperactivity disorder (ADHD) (1) is a
A common psychiatric disorder occurring in approxi-
mately 5% of school-aged children, adolescents, and adults
(1,2). It is a frequent reason for referral to mental health serv-
ices (3). ADHD is first evident in the preschool years (4) and
persists in as many as 70% of individuals throughout child-
hood and adolescence and into adulthood (5,6). Affected indi-
viduals are at risk for oppositional defiant disorder (ODD),
conduct disorder (CD), depression, anxiety, and learning dis-
ability (LD) (7). They are also at risk for the development of
delinquency or criminality, and for school suspension, aca-
demic underachievement, low self-esteem, and substance
abuse (8). Treatments must be of sufficient intensity to have
an immediate impact on the core ADHD symptoms, and they

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The Canadian Journal of Psychiatry—Review Paper
Acronyms and Abbreviations Used in This Paper
AC: attention control
AD: anxiety disorder
ADD: attention deficit disorder (DSM-I–III)
ADHD: attention-deficit hyperactivity disorder
(DSM-III-R–IV)
Afric-Amer: African American heritage
Beh: behavioural interventions
CBT: cognitive-behavioural therapy
CC: assessment and referral to care in the community
CD: conduct disorder
Clin: clinician
Comb: combined medication management and
behavioural interventions
Comm: community
CPRS: Conners’ Parent Rating Scale
CT: child training
DD: depressive disorder
DEX: dextroamphetamine
HoIP: hospital inpatient
must be of adequate duration and intensity to alter adverse
outcomes, many of which do not develop for several years.
In 1997, the Agency for Healthcare Research and Quality
charged the McMaster Evidence-based Practice Centre with
the conduct of a comprehensive, systematic review of the lit-
erature on ADHD treatment . Our first objective was to con-
duct a formal critical appraisal of existing systematic reviews
and metaanalyses. In addition to other issues, we wished to de-
termine whether existing reviews had adequately evaluated
the evidence on the effectiveness of extended treatment for
ADHD. The main conclusion from the appraisal of published
reviews (9) was that most existing systematic reviews and
metaanalyses had extensive flaws due to poor description of
the methods used to identify, select, assess, and synthesize in-
formation. Of the 13 reviews (3,10–21), only 2 (10,13) had
minimal flaws, but these reviews were narrowly focused on
treatment effects as measured on the Continuous Performance
Task (13) or on school-based interventions (10). Only 1 re-
view (15) specifically evaluated evidence for long-term
ADHD treatment, but that study had significant methodologi-
cal limitations. Consequently, the evidence for the effective-
ness of long-term pharmacologic and nonpharmacologic
interventions for ADHD was not addressed by previously
published reviews.
This article systematically appraises the methods and results
of published studies in which ADHD treatment persisted for
more than 12 weeks (Table 1, 22–35). Although ADHD treat-
ment typically continues for many years (36), we identified
those studies in which treatment persisted for a minimum of
12 weeks under randomized conditions. This criterion was ar-
bitrary but ensured that the review would identify the longest
studies from which to draw preliminary conclusions. This
338
HoOP: hospital outpatient
LD: learning disorder
MedMgt : medication management
MHOP: mental health clinic outpatient
MPH or MPH-reg: methylphenidate
MPH-SR: sustained release methylphenidate
MRIQ: mental retardation or low IQ
MTA: Multimodal Treatment Study of Children with ADHD
NM: none mentioned
NP: none present
NR: not reported
NS: not significant
ODD: oppositional defiant disorder
RCT: randomized controlled trial
SD: standard deviation
ST: supportive therapy
Teach : teacher
THIOR : thioridazine
Tourette : Tourette syndrome
distinction does not, of course, imply that 3 months of treat-
ment defines optimal extended therapy. The entire report is
available at (http://www.ahcpr.gov:80/clinic/index.html#evi-
dence). We focused on evidence provided by randomized
controlled trials (RCTs) because they are the simplest and
most powerful research designs in which to evaluate the effi-
cacy and effectiveness of interventions.
Methods
Selection of Studies
Inclusion and Exclusion Criteria. We regarded as potentially
eligible full reports published in peer-reviewed journals, in
any language, that focused on the treatment of ADHD in hu-
mans. We selected any reported RCT in which treatment per-
sisted for a minimum of 12 weeks un der randomized
conditions. Where studies included subjects with conditions
other than ADHD, they were selected only if they provided
separate analyses for patients with ADHD.
Search Strategy. Potentially eligible studies were identified
through a systematic search of Medline (from 1966), CI-
NAHL (from 1982), HEALTHStar (from 1975), Psycinfo
(from 1984), and EMBASE (from January 1, 1984, to Novem-
ber 30, 1997). (The search strategy may be obtained from the
principal author.) We also searched the Cochrane Library (is-
sue 4, 1997). Finally, we searched the reference lists of any
eligible article from these sources, as well as files of research
team members and partner organizations.
Data Extraction
We developed and tested data extraction forms for this project
(http://hiru.mcmaster.ca/ADHD/forms). Two reviewers inde-
pendently extracted data from each full report. Differences
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The Canadian Journal of Psychiatry—Review Paper

were resolved by consensus and by referring to

the information in the original report. Any differ-
ences that the 2 reviewers could not resolve were
resolved by a third reviewer. The original reports
were not masked because masking is time-
consuming and does not have an important im-
pact on the results of systematic reviews (37).
Data were extracted on each of the treatment
arms, outcomes, and tests used in each study. In-
formation on outcomes was extracted regardless
of the instrument or test used within each study.
Only information gathered during the subjects’
participation in the randomized groups was ex-
tracted: no data gathered after discontinuation of
therapy were sought.
The outcomes of interest, selected a priori by the
panel of experts (led by the AAP Task Force),
were as follows:
Behaviour Symptoms: observed core symptoms
of inattention, hyperactivity, and impulsivity,
and the results of a laboratory test of attention.
Academic Performance: results of achievement
tests and grades, as well as verbal, reading,
mathematics, and spelling skills.
Social Behaviour, Conduct, and Oppositional
Disturbance: diagnosis of ODD or CD, degree of
aggressiveness and social competence.
Internalizing Symptoms: depression, anxiety,
crying, sadness, global mood, and level of emo-
tional well-being and self-esteem.

Assessment of Study Quality

We assessed the methodological quality of the
studies in several ways.
Quality Assessment Scale. The methodological
quality scale (38) produces a minimum score of 0
points and a maximum score of 5 points. This
scale assesses whether the study includes a de-
scription of appropriate methods to generate the
randomization sequence (2 points), double blind-
ing (2 points), and a detailed account of with-
drawals and dropouts (1 point). The higher the
score, the better the methodological quality of the
RCT. Studies with a score of less than or equal to
2 points have been shown to exaggerate esti-
mates of intervention effects by more than 30%,
on average (39). Blinding helps prevent ascer-
tainment bias and protects the randomization se-
quence after allocation, but cannot always be

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 Attention-Deficit Hyperactivity Disorder: Critical Appraisal of Extended Treatment Studies
implemented, as was the case for most trials in this review
(40). Even when a trial was not double-blind, a study could
still be awarded 3 points if it included a description of ran-
domization and adherence.
Concealment. We determined whether the allocation of indi-
viduals to the different study groups had been concealed until
after their consent was obtained. Studies in which allocation
was unclear or inadequately concealed have been shown to
exaggerate estimates of intervention effects, by more than
35%, on average (39,40). Allocation concealment prevents
selection bias, protects the randomization sequence before the
interventions are given to study participants, and can always
be implemented.
Relation with Industry. We also sought information on any as-
sociation between the investigators and the pharmaceutical or
a related industry. It has been shown that reports of trials spon-
sored by pharmaceutical companies are more likely to favour
the experimental intervention than are trials not sponsored by
pharmaceutical companies (41,42).
Presence of Clinically Relevant Elements. By summing the
presence of 20 elements in these published studies (see Table
2a,b), we derived a secondary measure of methodological
quality. We included counts of these elements to help readers
decide whether study results may be generalized to particular
samples and settings. We identified these as clinically impor-
tant elements by consensus; however, the specific impact of
these characteristics on validity has not been supported by re-
search evidence. Because no evidence exists on the relative
weights of each element, the count of each should not be re-
garded as a quality score.
The following is a brief description of these elements and their
possible theoretical effects on the validity and applicability of
research on the treatment of ADHD.
Sampling Issues. The number of eligible patients constitutes
the sampling frame of subjects available for study. If more
subjects than needed are eligible, probability sampling should
be used to identify study participants, so that the study find-
ings can be generalized to a defined group. The investigator
should also report on the response to enlistment, including
both the number of subjects who decline and those who agree
to participate. The ratio of these 2 groups is a good indicator of
the level of acceptability associated with the treatment op-
tions. In studies where a high percentage of subjects decline, it
is possible that treatment is only applicable to a very small
group of patients with distinctive features.
Number of Patients Randomized and Analyzed. The proper
denominator for evaluating treatment effectiveness is the
number of patients randomized. Subject withdrawals and
losses to follow-up often lead to fewer subjects for analysis.
The magnitude and distribution of these losses across
W Can J Psychiatry, Vol 47, No 4, May 2002
treatment groups will have important implications for under-
standing treatment acceptability and effectiveness. Without
this information, study results cannot be interpreted.
Patient Characteristics. Intervention outcomes may vary as a
function of age, sex, intellectual abilities, and family charac-
teristics. In addition, findings in a specific ethnic group may
not apply to others.
Treatment Setting. The treatment setting provides the context
for an investigation. Many features are embedded in context
(for example, the investigators’ professional affiliations and
the facility’s reputation, acceptability, and accessibility).
These may affect both the characteristics of the subjects
within a study catchment area and the acceptability and effec-
tiveness of treatment.
Inclusion and Exclusion Criteria. These criteria define the
“target population,” or the subjects for whom the study results
are intended to apply. In the absence of these criteria, it is very
difficult, if not impossible, to assess the limits of generaliz-
ability for a particular study.
Identification of the Primary Outcome. If the primary out-
come is not specified a priori (or at all) and all outcomes are
treated alike, authors are at increased risk of highlighting
those with the most striking results. In addition, the more out-
comes analyzed, the greater the risk of finding false-positive,
statistically significant results, merely by chance. Identifying
the primary outcome is also an essential step to estimating the
study’s power to detect true-negative results.
Diagnosis-Related Issues. Diagnostic criteria for ADHD have
evolved over time. Various diagnostic models may well de -
fine samples that differ in natural history, severity, comorbid-
ity, ADHD subtype, and response to treatment (43).
Comorbid Conditions. Information on the presence of comor-
bid disorders is important to judge the generalizability of re-
sults to a particular clinical setting. In addition, comorbid
disorders may be associated with different responses to treat-
ment or different levels of treatment adherence.
Individual(s) Who Made the Diagnosis. In general, infor-
mants show low agreement on the presence of the core ADHD
symptoms. Current diagnostic models require evidence that
symptoms are pervasive. Relying on a single informant may
generate biased study samples that differ in severity or comor-
bidity from those generated by other informants. For example,
teacher-rated ADHD is more strongly associated with aca-
demic achievement than is parent-rated ADHD (44).
Sample Origin. Subjects for treatment studies may come from
clinic (inpatient and outpatient) or nonclinic populations, or
both. The sample’s origin is likely to have a strong bearing on
the severity and complexity of the cases being treated, and on
their prognosis.
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Treatment Fidelity and Monitoring. Fidelity reflects the ex -
tent to which treatment is delivered correctly. Fidelity also en-
sures that interventions which are not part of the treatment
protocol are not administered inadvertently. It can be en-
hanced in several ways, including training professionals who
administer treatment, conducting treatment according to
treatment manuals, self-monitoring of treatment administra-
tion, and conducting independent adherence checks. Studies
that monitor and report fidelity allow readers to determine
whether potentially effective treatments were fairly tested.
Further, the treatment manuals developed to support clinical
trials can help to disseminate effective treatments to commu-
nity practitioners.
Treatment Compliance. Compliance reflects the extent to
which patients correctly carry out treatment plans. Compli-
ance might require the timely administration of correct doses
of medication, the completion of parent-training homework
proj ects, or the con sis tent ap pli ca tion of class room
behaviour-management strategies.
Availability of Baseline Test Scores in the Report. Baseline
test scores permit researchers to identify atypical samples (for
example, those characterized by severity or comorbidity) and
to evaluate the comparability of the subjects in various study
groups at the outset.
Estimation of Effect Size
We assessed the feasibility and validity of conducting a
metaanalysis of these treatment outcome data. For a given
treatment, we identified few studies of sufficient methodo-
logical quality that employed a similar outcome measure.
Moreover, based on the means and standard deviations, out-
come scores were not often normally distributed, and we had
no access to individual patient data. Many studies had few
subjects. Under these circumstances, metaanalysis can result
in erroneous conclusions.
For descriptive purposes only, we calculated the size of medi-
cation treatment effects in 2 cases (core ADHD behaviour and
reading) where there was some consistency in the outcome
meas ure (Con ners’ Rating Scale and the Wide Range
Achievement Test [WRAT] reading). It should be noted that
these studies used many different versions of the Conners’
scale. Effect size was calculated using the following formula:
placebo mean at baseline – active mean at end of study
Effect size =
placebo standard deviation at baseline
Results
Literature Search Yield
Electronic databases searches, reference list reviews, and re-
ferrals from experts yielded 2402 citations. Of 521 potentially
342
eligible articles (based on the citation information) we ob-
tained hard copies of 519 (2 are unobtainable due to incorrect
indexing). Of these, 429 described comparative studies, while
90 described noncomparative studies. Of the 429 comparative
studies, 293 were RCTs, and 136 were non-RCTs. Of these,
we identified 14 RCTs that met criteria for long-term treat-
ment studies (22–35). Studies using the same subjects were
combined and considered as a single data set (45).
General Characteristics
The total number of subjects in these studies was 1379, of
which 579 (42%) were from a single study (the MTA study
[33]) (Table 1). Four studies included 10 subjects or fewer per
treatment arm. Five studies involved treatment of 26 weeks or
longer, of which 3 involved treatment of 52 weeks or longer.
The most frequently evaluated medication was methylpheni-
date (MPH, 9 studies) followed by dextroamphetamine
(DEX, 3 studies), lithium (1 study), imipramine (1 study), and
thioridazine (1 study). Eight studies evaluated nonpharma-
cologic interventions and combined interventions: child ther-
apy of various types (3 studies), cognitive-behavioural
therapy (2 studies), combined psychosocial treatments (1
study), supportive therapy (1 study), parent training (1 study),
and EEG biofeedback (1 study). Six studies permitted a com-
parison of the effects of combined pharmacologic and behav-
ioural intervention. Twenty-five different outcomes were
measured in the 14 studies (Table 1). The most frequently
measured outcomes were the core and global symptoms of in-
attention, hyperactivity, and impulsivity (11 studies), fol-
lowed by social behaviour (9 studies), academic attainment (8
studies), and internalizing symptoms (5 studies). Twenty-six
different tests were used to measure the outcomes. Conners’
Rating Scale (7 studies) was the most frequently used test, but
the version of the questionnaire varied across studies. Only 6
studies used both parents and teachers as informants to assess
outcome. Few studies included direct observations of child
behaviour as outcome measures. Seven studies were funded
by industry.
The main reasons for suboptimal quality scores were as fol-
lows: the method of randomization was not described (13
studies); there was no report of double blinding (3 studies),
methods to achieve double blinding were not described (9 tri-
als), and withdrawals and dropouts were poorly described (9
trials). Twelve trials did not mention concealment of alloca-
tion to study groups. In the MTA study, primary outcome
measures (parent and teacher behavioural ratings) were not
blind to the treatment group.
Only the MTA study included information on all 20 clinically
relevant elements selected a priori for extraction from the arti-
cles. One-half the studies did not describe the number of eligi-
ble subjects, and less than one-quarter of the trials mentioned
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 Attention-Deficit Hyperactivity Disorder: Critical Appraisal of Extended Treatment Studies
ethnicity of participants. Three of the studies did not report or
were vague about inclusion criteria, and 5 trials did not report
the exclusion criteria. The primary outcome of interest to the
researchers was not specified in 13 of the 14 studies. No study
involved preschool children or adults. Family characteristics
were not mentioned in 8 studies. Treatment fidelity was not
described in 4 studies, and compliance was not measured in 6
studies.
Effect on ADHD Behaviour
Seven of the 11 studies reported treatment effects on behav-
iour (core or global symptoms). Stimulant medication (MPH
or DEX) was superior to placebo in 4 studies and not superior
to placebo in 2 studies. MPH was superior to thioridazine in 1
study and equivalent to imipramine in 1 study. Four studies
permitted comparison of MPH and a nonpharmacologic inter-
vention, or of MPH and combined pharmacologic and behav-
ioural therapy. The MTA study reported that medication
management was equivalent to combined medication and be-
havioural intervention; both were superior to behaviour ther-
apy alone or to assessment and referral to care in the
community. No treatment effect was noted on directly ob-
served behaviour . In each of the 5 studies for which we calcu-
lated effect size, the effect size of active MPH was greater than
that of the control condition. Typically, the effect size for
MPH was 50% to 100% greater than that of the control treat-
ment (data available at http://hiru.mcmaster.ca/ADHD/ef-
fects). Biofeedback was superior to no treatment in 1 study,
and cognitive-behavioural therapy was superior to supportive
therapy in 1 study.
Effect on Academic Performance
Three of 7 studies that assessed academic outcomes reported a
treatment effect. Based on an unspecified teacher report of
arithmetic, but not on a teacher report of reading, Gittleman-
Klein and others (29) reported that MPH with or without thio-
ridazine resulted in greater improvement than thioridazine
alone. Linden and others (32) reported that a group treated
with EEG biofeedback showed significantly greater improve-
ment on an intelligence test than did a wait-list control group.
The MTA study reported the superiority of combined treat-
ment over community care and the behaviour treatment strate-
gies. However, combined treatment was not superior to
medication management, nor did medication management,
community care, and behaviour treatments differ in their im-
pact on academic outcomes. The MTA study found no differ-
ential effect of treatments for arithmetic and spelling. The
effect sizes observed for reading test scores with MPH treat-
ment were not large (in the range of 0.1 SD) and were not
greater than effect sizes observed for placebo treatment (0.1
SD).
W Can J Psychiatry, Vol 47, No 4, May 2002
Effect on Social Behaviour
Of the 9 studies that assessed the effect of treatment on con-
duct and oppositional and social behaviour, all but 3 showed a
treatment effect. In each case, the beneficial effects could be
attributed to either MPH or DEX, rather than to the addition of
other treatments such as parent training, thioridazine, or be-
haviour therapy. The MTA study included 7 measures of so-
cial behaviour and interaction. Outcomes were not identical
for all measures. In general, medication management was
equivalent to combined therapy, and both were superior to be-
haviour treatment alone and to community care. Combined
therapy, but not medication management, was superior to be-
haviour treatment or community care on oppositional or ag -
gres sive symp toms, teacher- rated so cial skills, and
parent-child relationships.
Effect on Internalizing Behaviour
Of the 5 studies that examined internalizing symptoms, one
study in di cated an im prove ment in self- esteem with
cognitive-behavioural therapy. For internalizing symptoms,
the MTA study found that combined treatment had an advan-
tage over medication management and that both combined
therapy and medication management had an advantage over
behaviour therapy. This additional benefit of combined treat-
ment was found only in parent-rated anxiety and was not con-
firmed by either teacher report or child self-report of anxiety
symptoms. Children with ADHD and comorbid anxiety im-
proved more with behaviour treatment than with community
care, despite the fact that two-thirds of community care sub-
jects received medication.
Discussion
The impetus for our review was the need for quality informa-
tion upon which to develop practice parameters for treating
ADHD. ADHD treatment is controversial, primarily because
of the rapidly increasing frequency of the diagnosis and the
prevalence of stimulant drug use. Over the last decade, the
number of prescriptions for medication to treat children with
ADHD has increased fourfold; in the US, it rose from 2 mil-
lion in 1990 to 5 million in 1994 (46). Although the prevalence
of stimulant use may be lower than in the US, Canada and
Australia have seen similar increases in drug use (47). Most of
these prescriptions are for stimulants, in particular MPH
(46,48,49). This steady rise in medication rates is attributable,
for the most part, to increased prescriptions for school-age
children (47). An additional impetus for a review of extended
treatment was the increasing duration of treatment for individ-
ual patients. Treatment duration may be increasing because of
recognized risks for the persistence of ADHD and the devel-
opment of additional disorders in adolescence and adulthood
(for example, 8).
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Table 2a Studies evaluating long-term therapy: characteristics checked

Author Subjects Subjects Subjects Ethnic groups Treatment Inclusion Exclusion Primary Age Sex
eligible randomized analyzed considered setting criteria criteria outcome (years)
(n) (n) (n) reported reported stated
Brown 1985 NR 30 30 No MHOP Yes Yes No 5–12 M
(22) Home
Brown 1986 NR 40 35 No MHOP No No No 5–12 M
(23) 13–18 F
Brown 1988 NR 71 NR No HoOP Yes Yes No 5–12 M
(24) Home 13–18 F
Conrad 262 81 68 No MHOP Yes No No 5–12 NR
1971 (25) Home
Fehlings 1991 NR 26 25 No HoOP Yes Yes No 5–12 M
(26) 13–18
Firestone 1986 134 NR 73 No HoOP Yes Yes No 5–12 M
(27) F
Gillberg 1997 72 62 32 No MHOP Yes Yes No 5–12 M
(28) F
Gittelman-Klein 166 166 155 White MHOP Yes No No 5–12 M
1976 (29) Afric-Amer Home F
Greenhill 1973 NR 9 9 White HoOP Yes No No 5–12 M
(30) HoIP 13–18 F
Home
School
Kupietz 1988 58 58 47 No MHOP Yes Yes No 5–12 M
(31) 13–18 F
Linden 1996 NR 18 18 No MHOP No Yes No 5–12 NR
(32) 13–18
MTA Coop 609 579 559 White Home Yes Yes Yes 5–12 M
Group 1999 Afric-Amer School F
(33) Hispanic Comm
Quinn 1975 NR 75 36 No Comm No No No NR M
(34)
Schachar 1997 105 91 66 No HoOP Yes Yes No 5–12 M
(35) F
See abbreviation list

Systematic reviews are important tools for decision makers.
Given the variety of available treatments, the heterogeneity of
subjects with ADHD, and the difficulties and costs of con-
ducting extended-treatment studies, metaanalysis and sys-
tematic review of available studies can play an important role
in clinical decision making and in health care planning. A sys-
tematic review includes strategies to minimize bias and to
maximize precision. It incorporates an explicit and detailed
description of how the review was conducted, such that any
interested reader will be able to replicate it (50). Systematic
reviews must weigh the apparent outcomes of various treat-
ments in relation to the methodological rigour of the available
research. Standards of quality in research and in its reporting
are constantly rising. The rigour of the studies included in this
report was assessed using current parameters. Early research
that may be found liable to bias today could have been re-
garded as state-of-the-art at the time it was conducted or
published.
We limited this review to RCTs and excluded other poten-
tially valuable study designs, such as case-control, cohort
studies, case series, and single-case designs. The RCT is the
simplest and most powerful research design for evaluating the
efficacy and effectiveness of interventions. Consequently,
few studies of behavioural intervention qualified for the re-
view. Recent reviews of behavioural therapy’s effectiveness
indicate that most studies involve single-case designs and that
behavioural interventions may play a role in the treatment of
ADHD (51). Reviews of single-case studies following the
same strict methodology that we applied in this study would
complement our review. In addition, we did not attempt to
identify unpublished studies. Analysis of unpublished studies
may reveal a negative publication bias.
This evaluation of existing RCTs led us to conclude that
metaanalysis would be inappropriate to summarize the evi-
dence. The main reasons for this decision were the substantial
heterogeneity of the published studies (for example, in

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Table 2b Studies evaluating long-term therapy: characteristics checked

Author IQ considered Diagnosis Comorbid Comorbid Diagnosis Sample Family Fidelity, Treatment Baseline Total
in subject model considered in by origin charac- treatment compliance test scores
selection used population teristics monitoring
Brown 1985 Yes ADD Yes NP Clin PCOP No Yes No Yes 15
(22) NM Parent School
Teach
Brown 1986 Yes ADD Yes CD Clin PCOP No Yes Yes Yes 14
(23) NM School
Brown 1988 Yes ADD Yes NP Clin NR Yes Yes Yes Yes 15
(24) NM Parent
Teach
Conrad Yes TeachDx No NM Teach School Yes Yes Yes No 12
1971 (25) NM
Fehlings Yes ADHD Yes NP Clin PCOP No Yes Yes Yes 16
1991 (26) ≥ 85 School
Firestone Yes ADD Yes CD Clin MHOP Yes Yes No Yes 16
1986 (27) ≥ 85 PCOP
Gillberg 1997 Yes ADHD Yes ODD Clin MHOP No No No Yes 15
(28) ≥ 50 CD, AD
Tourette
MRIQ
Autism
Gittelman-Kle Yes ADD Yes NP Clin MHOP Yes No No Yes 16
in 1976 (29) ≥ 85 Parent PCOP
Home
School
Greenhill Yes NR Yes NP NR NR Yes Yes No No 12
1973 (30) NM
Kupietz 1988 Yes ADD Yes NP Clin HoOP No No Yes Yes 16
(31) ≥ 80 Teach Comm
School
Linden 1996 Yes ADHD Yes ODD Clin Comm No Yes Yes Yes 14
(32) NM LD
MTA Coop Yes ADHD Yes ODD,CD Clin MHOP Yes Yes Yes Yes 20
Group 1999 > 80 Tourette, Parent Comm
(33) DD,AD School
Quinn 1975 NR NR Yes NP NR NR No No No Yes 7
(34)
Schachar Yes ADHD Yes ODD Clin HoOP No Yes Yes Yes 17
1997 (35) ≥ 80 CD,AD
See abbreviation list

therapies evaluated, in patient populations, and in treatment
duration), a wide range of outcome measures, the lack of stud-
ies with high-quality methodology, and the incompleteness of
data reporting. Using metaanalysis to synthesize this type of
data has been associated with a greater chance of obtaining an
imprecise and potentially misleading result (52). Therefore,
this report is a systematic, qualitative review of the existing
evidence that emphasizes the implications for clinical practice
and the directions that future researchers could take to fill ex-
isting knowledge gaps.
Our first conclusion is that there is a relative lack of methodol-
ogically sound research upon which to base clinical and policy
decisions. The main reasons for the studies’ low scores for
methodological quality were lack of description of the method
of randomization, lack of description of methods to achieve
double blinding, and poor description of withdrawals and
dropouts. Double blinding is difficult to achieve in treatment
studies that involve nonpharmacologic therapies. Yet, even if
double blinding were excluded as a criterion, the methodo-
logical quality of existing research would still be low. It has

W Can J Psychiatry, Vol 47, No 4, May 2002 345

The Canadian Journal of Psychiatry—Review Paper
been shown consistently that trials with low ratings of meth-
odological quality are more likely to exaggerate treatment ef-
fects (53–55).
In addition to low overall methodological quality, most stud-
ies had one or more factors that limited their external validity
or generalizability. Typically, these studies were character-
ized by small sample size, absence of research on female, pre-
school, adolescent, and adult subjects, and brief duration of
treatment, compared with the typical duration of ADHD treat-
ment (36). We found few studies on nonpharmacologic thera-
pies, inadequate description of interventions, failure to
describe the number of eligible subjects, inadequate descrip-
tion of ethnicity, and unclear description of inclusion and ex-
clusion criteria. Most studies did not specify a primary
outcome measure. Treatment compliance was rarely reported.
Consequently, it is difficult to generalize from available re-
search to the treatment of specific clinic groups.
The recently completed MTA study (33) has almost doubled
the number of subjects included in this body of research.
Moreover, the methodological quality of this study was high.
This study is the only one to date that enrolled enough subjects
to permit analysis of the effect of treatment on specific sub-
groups. Yet, despite the contribution of this single study, the
total number of individuals treated across all studies is ex-
tremely small, compared with the considerable number of
children currently receiving various therapies for ADHD and
compared with the number of subjects included in treatment
outcome studies of other conditions. Moreover, a single study
cannot satisfactorily address the impact of selection bias and
treatment methods on the generalizability of the results
(55,56).
Available studies generally lack evidence pertaining to sev -
eral important aspects of long-term outcome. We continue to
lack evidence on medication’s role in reducing the overall risk
of developing substance use disorders, improving occupa-
tional outcomes, enhancing peer relationships and self-
esteem, and reducing the impairment and cost associated with
ADHD. These studies also lack information on why many
children discontinue medication. There is little information on
situation-specific outcome measures (for example, outcomes
measured at home and at school), and adverse effects are re-
ported infrequently (adverse effects will be reported in a sepa-
rate publication).
Most studies have evaluated MPH. Based on the limited avail-
able research, neither thioridazine nor lithium appear to be ef-
fective alternatives to stimulants. One study found no
difference between MPH and imipramine (34). There have
been no studies of extended treatment with pemoline (recently
withdrawn from the market), specific serontonin reuptake in-
hibitors, or clonidine.
346
There has been little research on nonpharmacologic therapies.
One study found evidence for the efficacy of EEG biofeed-
back (32), and one for cognitive-behavioural therapy (26).
These studies had few subjects, and the results require replica-
tion. The MTA study did not support the efficacy of behav-
ioural therapy as a monotherapy. The single exception was
that children with ADHD and anxiety fared better with rigor-
ously applied behavioural intervention than with typical
community- based treat ment, even though it in volved
medication.
We know little about the potential for psychosocial and be-
havioural treatment combined with medication to increase the
treatment impact, reduce the dosage of medication required,
enhance the persistence of effects upon medication with-
drawal, or improve satisfaction with and adherence to treat-
ment. The MTA study provided some evidence for the
superiority of combined medication and behavioural strate-
gies over medication alone. Moreover, mediator and modera-
tor analyses indicated clinically relevant person-by-treatment
interactions. Combined medication and behavioural interven-
tions yielded better outcomes among poor participants and
achieved equivalent effects with lower dosages of medication.
Moreover, satisfaction was greater with combined treatment.
These intriguing findings require replication and extension.
There also appears to be improvement in conduct and opposi-
tional and social behaviour, as well as improvement in social
competence ratings. Despite improvement, behaviour is not
normalized with medication in all cases (31,33).
Attaining and maintaining optimal dosages appears to be im-
portant for achieving therapeutic benefit (31,33). For exam-
ple, the MTA study found that children treated in the
medication management arm fared better than those treated
with medication in the community control arm. This differ-
ence may result from the rigorous algorithms used to optimize
medication treatment or the supportive counselling that oc-
curred during medication visits, or both. It could also be a re-
sult of dif fer ences in pre scribed medi ca tion dos ages.
Medication benefit is limited in duration because of the short
half-life of stimulants, which are the primary medications
used to treat ADHD. It may be necessary to administer a third
dose toward the end of the day to ensure the generalization of
medication effects to the home setting. Benefits dissipate rap-
idly, even following prolonged therapy (23,35).
Evidence from short-term studies of medication (57–59) as in-
dicated improved academic productivity. These short-term
gains lead to an expectation that, over time, longer-term treat-
ment might result in substantially improved academic
achievement. However, little evidence indicates that stimu-
lants improve academic attainment, even after as long as 1
year of treatment.
W Can J Psychiatry, Vol 47, No 4, May 2002
 Attention-Deficit Hyperactivity Disorder: Critical Appraisal of Extended Treatment Studies
The lack of RCTs of extended ADHD treatment reflects, in
part, the difficulty of executing this type of study with high
methodological rigour. Given the solid evidence for the
short-term benefit of stimulant treatment, it may no longer be
possible to justify administration of placebo for more than
brief periods. Long-term studies must deal with substantial
treatment dropout or contend with the possibility that their
samples do not represent children with ADHD in the general
population. RCTs over extended time periods are associated
with considerable rates of crossover, treatment “contamina-
tion,” and study attrition. Nonadherence to treatment, reasons
for nonadherence, and crossover to alternative treatment will
be important treatment endpoints. Continuous monitoring of
benefits and adverse effects will be required to capture the rea-
sons for treatment discontinuation. The main challenge for fu-
ture research will be to design long-term studies that can
reduce these methodological impediments. Cohort observa-
tional studies could be used to follow large numbers of treated
and untreated patients to examine treatment risks and benefits
and to develop models to account for adherence and improve-
ment. Patient preference trials in which participants choose
their treatment or allow themselves to be randomized to treat-
ment may provide partial solutions (60).
Acknowledgements
The authors thank the members of the American Academy of Pediat-
rics Subcommittee on ADHD, Dr Deborah Zarin, Ms Carmela Vidic,
Dr George DuPaul, Dr William Pelham, and Dr James Swanson for
information that was otherwise unavailable to us, and Dr David At-
kins, for his valuable input. This research was performed by the
McMaster Evidence-based Practice Center under contract to the
Agency for Health Care Policy and Research (AHCPR), AHCPR
Contract #290-97-0017.
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1
Staff Psychiatrist and Senior Scientist, Department of Psychiatry, University
of Toronto, Division of Child and Adolescent Psychiatry; Brain and Behav-
iour Program, Research Institute, The Hospital for Sick Children, Toronto,
Ontario.
2
Director, McMaster University Evidence-based Practice Centre, Health In-
formation Research Unit, Hamilton, Ontario. .
3
Research Assistant, Department of Clinical Epidemiology and Biostatistics,
McMaster University, Hamilton, Ontario.
4
Senior Scientist, Department of Psychiatry and Behavioural Neurosciences,
McMaster University, Hamilton, Ontario.
5
Research Assistant, McMaster University Evidence-based Practice Centre,
Health Information Research Unit, Hamilton, Ontario; Planning and Admin-
istration, Cancer Care Ontario.
6
Department of Pediatrics, McMaster University, Hamilton Health Sciences
Corporation, Hamilton, Ontario.
7
Clinical Psychologist, Children’s Hospital, Hamilton Health Sciences, Ham-
ilton, Ontario.
Address for correspondence: Dr R Schachar, Division of Child and Adoles-
cent Psychiatry, The Hospital for Sick Children, 555 University Avenue, To-
ronto, ON M5G 1X8
e-mail:russell.schachar@sickkids.on.ca

Résumé : Trouble d’hyperactivité avec déficit de l’attention : évaluation critique

des études sur le traitement de longue durée

Nous avons procédé à une revue systématique de la documentation sur le traitement de longue durée
du trouble d’hyperactivité avec déficit de l’attention (THADA). Nous avons utilisé des stratégies
systématiques pour repérer les études aléatoires sur le traitement administré pendant 12 semaines ou
plus. Nous avons inclus 14 études auxquelles participaient 1 379 sujets. En raison du nombre limité
d’études de grande qualité et de l’hétérogénéité des mesures de résultats, nous n’avons pas effectué de
méta-analyse. Nous avons jugé 5 études adéquates quant à leur qualité méthodologique. Cinq études
suivaient des enfants pendant plus de 26 semaines. Les interventions pharmacologiques faisaient plus
fréquemment l’objet d’études que les non pharmacologiques. Six études ont permis l’évaluation des
effets de la combinaison des médicaments avec une intervention comportementale. Vingt-cinq résul-
tats différents étaient mesurés à l’aide de 26 tests différents. Les stimulants semblent réduire le
THADA (7 études), le comportement social dysfonctionnel (6 études) et les symptômes d’internalisa-
tion (2 études). Les études disponibles offrent peu de preuves de l’amélioration du rendement scolaire
par les stimulants (3 études). Les médicaments autres que les stimulants n’ont pas été étudiés à fond
(3 études). Une seule étude indiquait que la thérapie combinée ajoute aux effets des médicaments.
Une recherche rigoureuse sur le traitement auprès d’échantillons représentatifs de personnes souffrant
du THADA est nécessaire.

348
W Can J Psychiatry, Vol 47, No 4, May 2002