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Six trials met the eligibility criteria set by the GDG, providing data on 462
participants. All studies were published in peer-reviewed journals between 1976 and
1999. In addition, four studies were excluded from the analysis; two because they
were case studies, one because of insufficient data, and one because of methodologi-
cal problems (further information about both included and excluded studies can be
found in Appendix 17).
11.3.4 Clinical evidence for psychological interventions versus
protocol-managed medication for children with ADHD
There is only sparse clinical trial evidence allowing direct comparison of the clinical
effectiveness of psychological and pharmacological interventions for ADHD. Of the
six trials that meet inclusion criteria, five are relatively small, with the medication
or psychological intervention group sizes ranging from nine to 30. The MTA study
(MTA1999) was relatively large, having 120 participants in the medication group and
119 in the psychological intervention group.
For individual outcomes, the quality of the evidence was generally moderate to
high. Overall, for children with ADHD the evidence from trials that compare stimu-
lant medication (predominantly methylphenidate) with a psychological intervention
delivered to a group not receiving medication for ADHD generally favours stimulant
medication, although where they reach statistical significance the effects are not large
(see Table 36).
For both teacher and parent ratings of core ADHD symptoms and conduct prob-
lems at the end of treatment, stimulant medication delivers better outcomes than
psychological interventions, with effect sizes in the small to moderate range. However,
the benefits of stimulant medication over psychological therapies for core ADHD
symptoms and conduct problems in general do not appear to be sustained at later
follow-up assessments (3–6 months, 7–12 months and 13–24 months after the end
of treatment). The MTA study (MTA1999) found a benefit of medication over the
complex MTA psychological intervention on the composite parent- and teacher-rated
measure of core ADHD symptoms at 10 months after the end of the intervention, but
the effect did not reach the magnitude of a small effect size.
Stimulant medication also appears to be more effective than psychological inter-
ventions at improving social skills as rated by teachers, but this effect was small at the
end of treatment, was not sustained at later follow-up assessments, and was not
reflected in parent ratings of social skills, which does not point to any benefit of stim-
ulant medication over psychological therapies at the end of treatment or any time
thereafter. For emotional state (as represented by depression, anxiety, emotional
adjustment and internalising symptoms) there was also a benefit of stimulant medica-
tion over psychological interventions at the end of treatment, but the effect size was
small and for this outcome limited to parent ratings, with no effect on teacher ratings
detected.
Combining and comparing psychological and pharmacological interventions
329
Combining and comparing psychological and pharmacological interventions
330
Stimulant medication versus
psychological intervention
Total number of studies (number 6 (462)
of participants)
Study ID BROWN1985
FIRESTONE1981
FIRESTONE1986
GITTELMAN-KLEIN1976
KLEIN1997
MTA1999
Age 5–12 years
Benefits (end of treatment)
Core ADHD symptoms at end of SMD 0.72 (1.12 to 0.32)
treatment (teacher-rated) Quality: High
K 5, N 392
Core ADHD symptoms at end of SMD 0.45 (0.66 to 0.23)
treatment (parent-rated) Quality: High
K 4, N 350
Conduct at end of treatment SMD 0.48 (0.70 to 0.25)
(teacher-rated) Quality: High
K 3, N 321
Conduct at end of treatment SMD 0.22 (0.43 to 0.01)
(parent-rated) Quality: High
K 3, N 355
Social skills at end of treatment SMD 0.33 (0.57 to 0.08)
(teacher-rated) Quality: High
K 2, N 258
Social skills at end of treatment SMD 0.08 (0.33 to 0.17)
(parent-rated) Quality: High
K 1, N 151
Emotional outcomes at end of SMD 0.14 (0.10 to 0.39)
treatment (teacher-rated) Quality: High
K 2, N 158
Table 36: Study information and evidence summary table for trials
of stimulant medication versus psychological interventions
Stimulant medication versus
psychological intervention
Emotional outcomes end of SMD 0.23 (0.45 to 0.01)
treatment (parent-rated) Quality: High
K 3, N 331
Benefits (3–6 months post treatment)
Core ADHD symptoms at 3 months SMD 0.20 (1.08 to 0.68)
post-treatment (teacher-rated) Quality: Moderate
K 1, N 20
Core ADHD symptoms at 3 months SMD 0.82 (1.74 to 0.11)
post-treatment (parent-rated) Quality: Moderate
K 1, N 20
Benefits (7–12 months post-treatment)
Core ADHD symptoms at SMD 0.53 (1.23 to 0.17)
7–9 months post-treatment Quality: Moderate
(teacher-rated) K 1, N 35
Core ADHD symptoms at 10 months SMD 0.25 (0.49 to 0.01)
post-treatment (parent- and Quality: High
teacher-rated composite score) K 1, N 267
Conduct at 7–9 months post- SMD 0.32 (1.02 to 0.38)
treatment (parent-rated) Quality: Moderate
K 1, N 34
Conduct at 10 months post- SMD 0.10 (0.34 to 0.14)
treatment (parent- and Quality: High
teacher-rated composite score) K 1, N 267
Social skills at 10 months post- SMD 0.07 (0.31 to 0.17)
treatment (parent- and Quality: High
teacher-rated composite score) K 1, N 267
Benefits (13–24 months post-treatment)
Core ADHD symptoms at SMD 0.00 (0.88 to 0.88)
19–21 months post-treatment Quality: Moderate
(teacher-rated) K 1, N 20
Core ADHD symptoms at SMD 0.58 (0.32 to 1.48)
19–21 months post-treatment Quality: Moderate
(parent-rated) K 1, N 20
Table 36: (Continued)
Continued
Combining and comparing psychological and pharmacological interventions
331
Combining and comparing psychological and pharmacological interventions
332
Stimulant medication versus
psychological intervention
Core ADHD symptoms at SMD 0.06 (0.21 to 0.09)
13–24 months post-treatment Quality: High
(parent- and teacher-rated K 1, N 242
composite score)
Conduct at 22 months post- SMD 0.00 (0.25 to 0.25)
treatment (parent- and Quality: High
teacher-rated composite score) K 1, N 243
Social skills at 22 months post- SMD 0.04 (0.29 to 0.21)
treatment (parent- and Quality: High
teacher-rated composite score) K 1, N 243
Education outcomes at end of treatment
Reading at end of treatment SMD 0.10 (0.30 to 0.09)
Quality: High
K 5, N 397
Mathematics at end of treatment SMD 0.01 (0.20 to 0.22)
Quality: High
K 4, N 358
Education outcomes at 3–6 months post-treatment
Reading at 3 months post-treatment SMD 0.11 (0.77 to 0.99)
Quality: Moderate
K 1, N 20
Mathematics at 3 months SMD 0.57 (0.32 to 1.47)
post-treatment Quality: Moderate
K 1, N 20
Education outcomes at 7–12 months post-treatment
Reading at 7–10 months SMD 0.05 (0.27 to 0.18)
post-treatment Quality: High
K 2, N 301
Education outcomes at 13–24 months post-treatment
Reading 19–22 months SMD 0.03 (0.22 to 0.27)
post-treatment Quality: High
K 2, N 260
Dichotomous outcomes
Leaving study for any reason Data not pooled
Table 36: (Continued)
The lack of evidence for the sustained superiority of medication over psychologi-
cal interventions for ADHD is, however, difficult to interpret. At longer follow-up
time points outcomes may be influenced by the treatment a child has received since
the end of the period of the experimental intervention. In particular, children who
received a psychological intervention and were not on medication for ADHD during
the period of the trial while the intervention was delivered may have subsequently
begun to receive stimulant medication for ADHD. Notably, in the MTA trial, by the
follow-up time point at 10 months after the end of the experimental intervention, 44%
of the group that only received the MTA behavioural intervention had commenced
medication. At 22 months after the end of the experimental intervention, the propor-
tion of the MTA behavioural intervention group that was using medication at high
levels was little changed at 45% (Jensen et al., 2007). In contrast 71% of MTA study
participants who were in the medication management and combined intervention
groups were using medication at high levels 22 months after the end of the experi-
mental intervention, a decrease from 91% at the end of the intervention.
11.3.5 Clinical evidence summary
While there is no evidence that psychological interventions are favoured over stimu-
lant medication for any outcome, or at any time point, it is also the case that medica-
tion does not appear to be strongly favoured over psychological interventions.
11.4 THE MTA STUDY: IMPLICATIONS FOR TREATMENT DECISIONS
11.4.1 Further considerations with respect to the treatment of
ADHD – additional evidence from the MTA study
A number of publications have reported on sub-analysis and secondary analysis of
data gathered as part of the MTA study (for example, MTA Co-operative Group,
Stimulant medication versus
psychological intervention
BROWN1985: 0% (medication)
versus 0% (psychological)
FIRESTONE1986: 0% versus 0%
MTA1999: 6% versus 2%
Non-responders at end of treatment RR 0.61 (0.50 to 0.76)
Quality: High
K 4, N 366
Non-responders at 10 months RR 0.91 (0.77 to 1.07)
post-treatment Quality: High
K 4, N 288
Table 36: (Continued)
Combining and comparing psychological and pharmacological interventions
333
2004a; Jensen et al., 2007). Only primary outcome data reported for the end of
treatment and 14 and 22 months post-treatment follow-up have been used in the
analysis of the effectiveness of interventions for ADHD, but some of the further
analysis reported by the MTA Co-operative Group may help inform choices made in
the treatment of ADHD.
Longer term impact of MTA interventions and the relation
to substance use and delinquency
The MTA study group has reported follow-up outcome data at time points beyond the
end of the MTA intervention (MTA Co-operative Group, 2004a; Jensen et al., 2007).
The initial primary outcome data was collected at the end of the MTA interventions
(14 months after interventions were commenced), with follow-up data reported to
date for 10 months after the end treatment and 22 months after the end treatment (or
24 and 36 months after the interventions were commenced). It is important to note
that after the end of the MTA interventions the participants in the trial returned to
usual care.
According to the outcome data collected 22 months after the end of the MTA
interventions, the MTA treatment allocation groups could no longer be distinguished
on any measure according to primary analysis (Jensen et al., 2007). On average MTA
participants maintained some of the gains made at the end of treatment time point on
measures of both ADHD and oppositional defiant disorder symptoms. The behavi-
oural treatment and community care groups maintained the gains they had made at
the end of treatment. In contrast the combined treatment and medication management
groups lost their end of treatment advantage over the behavioural treatment and
community care groups, although they maintained gains over baseline that approxi-
mated to the sustained gains made by the behavioural and community care groups.
These findings are, however, based on the comparison with baseline data for each
group, not on a comparison with an untreated control group, and hence it is not possi-
ble to conclude that any of the MTA interventions have long-term beneficial effects
over no treatment. Indeed, at 22 months after the end of treatment, prognostic factors
for ADHD were found to have more of an impact on outcomes than treatment group
allocation – girls and those of higher socioeconomic status fared better than boys.
Follow-up data gathered 10 months after the end of the experimental MTA inter-
ventions is in line with the data gathered at 22 months after the end of treatment
(MTA Co-operative Group, 2004a). Ten months after the end of the MTA interven-
tions, the combined treatment and medication management groups, which showed the
greatest improvement compared with baseline at the end of the intervention, show
some deterioration, whereas the behavioural treatment and community care groups
maintain gains made in comparison with baseline during the period of the trial
intervention.
Jensen and colleagues (2007) suggest that factors that may contribute to the
convergence of outcomes for the four MTA study intervention groups at longer-term
follow-up compared with outcomes at the end of treatment include: a decrease in
ADHD symptoms related to age independent of treatment; changes in the intensity of
medication use; and different degrees of starting and stopping medication in the
Combining and comparing psychological and pharmacological interventions
334
different treatment allocation groups that occurred after the end of the MTA
interventions. Other factors may also be involved. There is a degree of convergence
across the four groups in terms of their use of medication for ADHD at follow-up.
Medication use in the group allocated to behavioural treatment increased from 14%
at the end of the MTA intervention to 45% 22 months later, whereas among MTA
participants who received the medication management intervention (including the
combined treatment group) medication use decreased from 91% to 71%. In the
community care group medication use was near unchanged: 60% at end of treatment
and 62% 22 months later. Further support for the inference that changes in medica-
tion use may have mediated the convergence between outcomes across the groups at
follow-up is provided by analysis indicating that the subgroup that reported stopping
taking medication 10 months after the end of treatment showed the greatest deteriora-
tion (MTA Co-operative Group, 2004b).
Substance use at 22 months after the end of the MTA interventions was lower in
the MTA participants who received intensive behaviour therapy (members of the
combined treatment and behavioural intervention groups) compared with those who
did not (members of the medication management and community care groups)
(Molina et al., 2007). However, the data did not point to there being any associations
between treatment allocation and early substance use, growth of delinquency over
time and the level/seriousness of delinquency. Seriousness of offences was associated
with self-selected use of prescription medication, and Molina and colleagues (2007)
speculate that this could be reactive in that there may be a tendency to opt for medica-
tion in response to increased symptom severity.
The analysis by Molina and colleagues (2007) did not point to either a protective
or adverse effect of medication for ADHD (whether study allocated or self-selected
in community care participants) on the initiation of substance use in MTA partici-
pants. However, it should be noted that at the post-treatment follow-up at 22 months
the mean age of participants was still relatively young (most were between 11 and 13
years of age).
Factors associated with treatment effects according to data gathered at the end of the
MTA interventions
Analysis of the MTA data points to some impacts of socioeconomic status on treat-
ment outcomes at the end of the intervention (Rieppi et al., 2002). For children from
better educated families, combination treatment may be more effective than medica-
tion management alone for ADHD symptoms whereas for low socioeconomic status
families, combination treatment may be more effective for oppositional aggressive
symptoms.
Other analysis found that response to treatment in the MTA study did not differ
significantly by ethnicity after controlling for public assistance (Arnold et al., 2003).
However, at the end of the intervention medication doses reached a higher level for
African American children receiving medication management only compared with
the average for the group allocated to this intervention. As this was not the case for
children from ethnic minorities receiving combination treatment, Arnold and
colleagues (2003) suggest that it is possible that the behavioural intervention may
Combining and comparing psychological and pharmacological interventions
335
have neutralised adverse effects of low socioeconomic status that might otherwise
exacerbate symptoms and lead to a need for a higher medication dose. A speculative
inference from the analysis is that white middle class children without comorbid
anxiety or disruptive behaviour may not gain from adding behavioural treatment to
medication, but children of low socioeconomic status, or with comorbid anxiety and
disruptive behaviour, especially if from a minority ethnic group, may gain added
benefit from combining behavioural treatment with medication.
Another analysis looking at potential moderators of the response to treatment in
the MTA study found no moderators of response to behavioural treatment or commu-
nity care (Owens et al., 2003). However, the analysis indicated that parental depres-
sion decreased treatment effectiveness in the medication management group but not
in the behavioural treatment group. This finding led Owens and colleagues (2003) to
speculate that the parental components of the behavioural intervention may in effect
treat the parents to some degree, thus mitigating negative impacts of parental depres-
sion on the outcomes for the child. Owens and colleagues (2003) also found that a
high initial severity of ADHD symptoms decreased the treatment effects from the
medication management and combined treatment interventions, but as the analysis
used a measure of response to treatment it is possible that this may reflect the need
for those with more severe symptoms at the outset to improve more so as to be classed
as responding to treatment.
A further finding unrelated to behavioural treatment reported by Owens and
colleagues (2003), was that for those on medication management (that is, participants
receiving the medication management or combined treatment interventions), partici-
pants in the subgroup with parental depression and a higher severity of symptoms
responded better to medication if they had a higher starting IQ compared with those
in this subpopulation with lower IQ. In terms of implications for treatment, Owens
and colleagues (2003) suggest that their analysis indicates that treatment of parental
depression may be important in order to get a positive response to treatment of ADHD
using medication. They also speculate that it might be important to intervene early
with medication management or combined treatment before ADHD severity increases
and a positive response to treatment becomes less likely.
Analysis looking at outcomes at the end of treatment for subgroups with comor-
bid anxiety and disruptive behaviour (oppositional defiant disorder or conduct disor-
der) pointed to some impacts on treatment effects (Jensen et al., 2001). All MTA
interventions including community care were found to be effective in the subgroup
with ADHD and comorbid anxiety. For subgroups with ADHD only or ADHD and
disruptive behaviour (oppositional defiant disorder or conduct disorder), medication
was favoured – whether alone or in combination with behavioural treatment – but
behavioural treatment alone may be contraindicated. For the subgroup with ADHD
and both anxiety and disruptive behaviour, there was evidence of an advantage of
combined treatment, particularly with respect to overall impairment and functioning.
Earlier analysis looking at the impact of comorbidity suggested that MTA partici-
pants with comorbid disruptive behaviours (oppositional defiant disorder and conduct
disorder) did not benefit from the addition of behavioural treatment (that is, combined
treatment) over medication management alone at the end of treatment time point
Combining and comparing psychological and pharmacological interventions
336
(MTA Co-operative Group, 1999b). A further tentative inference from the data gath-
ered at the end of treatment is that the intensive MTA behavioural intervention may
have had similar effects to routine medication because the majority (66%) of the
community care group received medication for ADHD and the behavioural interven-
tion group did not differ significantly from the community care group for end of treat-
ment outcomes. It must, however, be noted that the absence of a statistical difference
between the groups does not prove that there is no difference between the effects of
the behavioural intervention and continued community care.
Secondary analysis looking at treatment response found that twice as many chil-
dren met criteria for successful treatment at the end of treatment time point in the
groups receiving medication management (medication management and combined
treatment groups) compared with the behavioural intervention and community care
groups (Swanson et al., 2001). The authors infer that if medication management was
adopted in usual care the number of cases successfully treated would effectively
double from 30% to 62%. The analysis also suggests that the addition of intensive
psychological treatment in combination with medication management would result in
12% more children being successfully treated as the response rate was 56% in the
medication management group compared with 68% in the combined treatment group
(equivalent to a 20% increase in the success rate through the addition of intensive
psychological treatment).
A further analysis of the MTA study data gathered at the end of treatment time
point indicates that the more severe subgroup meeting criteria for hyperkinetic disor-
der showed a larger decrease in symptoms with medication than with behaviour
therapy, and a larger medication advantage than those not meeting criteria for hyper-
kinetic disorder (Santosh et al., 2005). Accordingly, as they show a greater response
to medication than the less severe non-hyperkinetic disorder subgroup, Santosh and
colleagues suggest that for those with hyperkinetic disorder medication management
is favoured as a first-line treatment. As the response of the non-hyperkinetic disorder
subgroup to medication was in the same direction, albeit to a lesser degree, the data
also suggest that stimulants may be indicated for some children with ADHD who do
not meet criteria for hyperkinetic disorder.
11.5 HEALTH ECONOMICS EVIDENCE
11.5.1 Systematic literature review
The systematic literature search identified two economic studies that compared the
cost effectiveness of pharmacological, psychological and combination therapies in
children with ADHD (Lord & Paisley, 2000; Zupancic et al., 1998), plus an economic
analysis of the interventions assessed in the MTA study (Jensen et al., 2005; Foster
et al., 2007). In addition, the economic modelling undertaken to support NICE guid-
ance on the use of methylphenidate, atomoxetine and dexamfetamine in children
with ADHD incorporated a sub-analysis that compared combination therapies with
the evaluated medications (King et al., 2006). Details on the methods used for the
Combining and comparing psychological and pharmacological interventions
337
Combining and comparing psychological and pharmacological interventions
338
systematic search of the economic literature are described in Chapter 3. The
economic analysis of the MTA study is described in a separate sub-section in this
chapter. Information on the methods used and the results reported in all economic
studies included in the systematic literature review are presented in the form of
evidence tables in Appendix 14.
Lord and Paisley (2000) conducted an economic analysis to compare the cost effec-
tiveness of combination therapy, consisting of methylphenidate plus behavioural ther-
apy, with behavioural therapy alone for children with ADHD in the UK. The perspective
of the analysis was that of the NHS. The study, based on a decision-analytic model,
utilised clinical-effectiveness data from the MTA study. Resource use estimates were
based on expert opinion and reflected clinical practice in the UK. Costs consisted of
drug acquisition and pharmacotherapist costs. Costs of behavioural therapy were omit-
ted from the analysis, as these were common in the two strategies assessed. The meas-
ure of outcome was the SMD in the SNAP-IV score between the two treatment options.
The time horizon of the analysis was 14 months, the length of the MTA study.
According to the results of the analysis, the ICER of combination therapy versus behav-
ioural therapy alone was £1,596 per SMD in the SNAP-IV score (1999 prices). This
ratio ranged in sensitivity analysis from £694 to £4,545 per SMD in the SNAP-IV score.
One limitation of the analysis was the use of the change in SNAP-IV scores as the
primary outcome measure, which could not capture the HRQoL of children with
ADHD. In addition, the study utilised clinical data from the MTA study, which was
conducted in the US and examined interventions that were more intensive than typical
interventions in the UK. On the other hand, the resource use estimates by Lord and
Paisley (2000) referred to UK clinical practice, and therefore the results of the economic
analysis should be interpreted with caution.
Zupancic and colleagues (1998) assessed the cost effectiveness of methyl-
phenidate, dexamfetamine, pemoline, psychological/behavioural therapy and combi-
nation therapy (consisting of psychological/behavioural therapy and methylphenidate)
in comparison with no treatment from the perspective of a third-party payer in
Canada. Details on the methodology of the study are reported in Chapter 10. The
meta-analysis of clinical studies included in the systematic literature review indicated
that psychological/behavioural therapy, either alone or as an adjunct to pharmacolog-
ical therapy, was not effective. The economic analysis demonstrated that
methylphenidate dominated both psychological/behavioural therapy and combination
therapy. The limitations of the analysis are described in Chapter 10. Additional limi-
tations specific to the evaluation of psychological/behavioural and combination ther-
apies were: the rather poor quality and the insufficient power of clinical studies
assessing these two strategies; the assumptions regarding duration of therapy (daily
provision of drugs versus 16-hour provision of psychological/behavioural therapy),
which, according to the authors, might have biased the results against psychological/
behavioural and combination therapies; and, finally, the choice of the outcome meas-
ure, that is, the change in CTRS scores, which might have underestimated the efficacy
of psychological/behavioural therapy alone or in combination, given that this therapy
has been shown to be more effective in enhancing academic performance and improv-
ing conflicted peer relations rather than improving core ADHD symptoms.
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