The Treatment for Adolescents With Depression Study

Article
The Treatment for Adolescents With Depression Study
(TADS): Outcomes Over 1 Year of Naturalistic Follow-Up
Treatment for Adolescents With
Depression Study (TADS) Team
Objective: The Treatment for Adolescents With Depression Study (TADS) evaluates the effectiveness of fluoxetine, cognitive-behavioral therapy (CBT), and their
combination in adolescents with major
depressive disorder. The authors report
effectiveness outcomes across a 1-year
naturalistic follow-up period.
Method: The randomized, controlled
trial was conducted in 13 academic and
community sites in the United States.
Stages I, II, and III consisted of 12, 6, and
18 weeks of acute, consolidation, and
continuation treatment, respectively. Following discontinuation of TADS treatments at the end of stage III, stage IV consisted of 1 year of naturalistic follow-up.
The participants were 327 subjects between the ages of 12 and 17 with a primary DSM-IV diagnosis of major depressive disorder. No TADS treatment was
provided during the follow-up period;
treatment was available in the community. The primary dependent measures,
rated by an independent evaluator blind
to treatment status, were the total score
on the Children’s Depression Rating
Scale—Revised and the rate of response,
defined as a rating of much or very much
improved on the Clinical Global Impressions improvement measure.
Results: Sixty-six percent of the eligible
subjects participated in at least one stage
IV assessment. The benefits seen at the
end of active treatment (week 36) persisted during follow-up on all measures of
depression and suicidality.
Conclusions: In contrast to earlier reports on short-term treatments, in which
worsening after treatment is the rule, the
longer treatment in the TADS was associated with persistent benefits over 1 year
of naturalistic follow-up.
(Am J Psychiatry 2009; 166:1141–1149)
M
ajor depressive disorder, which has a point prevalence of 5% in adolescents, is associated with significant
morbidity and family burden (1). It also is a major contributor to suicidal behavior and completed suicide (2).
Hence, improvements in the treatment of major depressive disorder in adolescents should be of significant public
health value. To this end, the National Institute of Mental
Health in 1999 funded the Treatment for Adolescents With
Depression Study (TADS) (3). TADS is a randomized, controlled trial that is intended to evaluate the effectiveness of
three active treatments for adolescents with major depression: clinical management with fluoxetine, cognitive-behavioral therapy (CBT), their combination (fluoxetine plus
CBT), and, acutely only, clinical management with pill
placebo as a control condition.
Previous publications from the TADS described the study
aims, rationale, and design (3), characteristics of the study
group (4), and the results of acute (5) and long-term (6) randomized treatment. To briefly summarize, CBT alone was
less effective than combined treatment or fluoxetine and
not significantly more effective than placebo at week 12 (5).
Secondary analyses at 12 weeks (7) also showed superiority
for combined treatment with respect to speed of response
(8), quality of life and functioning (9), remission (10), and
overall safety (11). CBT “caught up” with fluoxetine at week
Am J Psychiatry 166:10, October 2009
18, and combined treatment reached maximum medical
benefit at that point, several months earlier than fluoxetine
or CBT, with all treatments converging on an approximately
80% response rate by week 36 (6). In a recent paper from the
TADS, Rohde and colleagues found that the majority of adolescents who had not achieved sustained response during
acute treatment did achieve that level of improvement during continuation and maintenance therapies, with CBT and
combined treatment showing greater persistence of sustained response than fluoxetine (12).
In epidemiological studies, most children and adolescents who experience an episode of depression typically
recover within 1 to 2 years from baseline (13, 14), and approximately one-half of those who recover subsequently
relapse (15). In the TADS study group, the mean episode
duration at intake was greater than 1 year, and more than
one-half had received previous treatment within the current episode, suggesting that in the absence of evidencebased treatment, depression persists (4). Likewise, in follow-ups of psychotherapy (16) or pharmacotherapy (17)
randomized, controlled trials, 25% to 50% of treated subjects experience a relapse within 6 months to 2 years after
treatment. In one study showing an advantage for CBT over
other psychosocial treatments (18), there were no differences in clinical outcomes, including relapse, at 2-year folajp.psychiatryonline.org
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TADS FOLLOW-UP
low-up (16). Thirty percent of the subjects had a recurrence
of depression, and 21% were depressed during at least 80%
of the follow-up period. In the only trial of maintenance
psychotherapy in depressed teens of which we are aware,
CBT booster sessions did not reduce the rate of recurrence
but did appear to accelerate recovery among participants
who were still depressed at the end of the acute phase (19).
In a recent study, Emslie and colleagues, using a placebocontrolled discontinuation design, found a higher rate of
relapse (69%) in those who discontinued fluoxetine after 12
weeks of treatment compared to those who continued to
take fluoxetine for an additional 6 months (42%) (20).
Taken together, these findings strongly suggest that in the
absence of evidence-based treatment or with only shortterm treatment, depression is a waxing and waning illness
and that new intervention strategies are required to promote long-term reductions in depressive symptoms (21).
To this end, TADS was designed to test the hypothesis
that longer-term treatment would improve outcomes and
promote stability of remission. We now report effectiveness outcomes for subjects assigned initially to combined
treatment, fluoxetine only, and CBT only across 1 year
(TADS stage IV) of naturalistic follow-up in which TADS
treatments were stopped and treatment was available
openly in the community. For ethical and feasibility reasons, the subjects assigned to placebo were treated openly
after week 12, and the placebo group was not included in
these analyses by design.
Method
The randomized, controlled trial was conducted in 13 academic and community sites in the United States. Stages I, II, and
III consisted of 12, 6, and 18 weeks of acute, consolidation, and
continuation treatment, respectively. Following discontinuation
of TADS treatments at the end of stage III, stage IV consisted of 1
year of naturalistic follow-up. The methods for the TADS have
been extensively documented in previous publications (3–6, 22–
29), and only the aspects of the study that are directly relevant to
the stage IV analyses will be presented here.
End of Stage III
Immediately before the week 36 visit, which constituted the
end of active treatment and the beginning of stage IV, the site
team reviewed each subject’s clinical status and assigned an endof-treatment score on the severity measure of the Clinical Global
Impression (CGI) (30) and recommended additional treatment as
follows.
Level 1. Participants with a summary CGI severity score of 1 or 2
(normal or borderline ill) and who were otherwise well, i.e., did
not need treatment for other disorders or problems, received a
recommendation to discontinue all treatment unless 1) in the
opinion of the site team, continued treatment was indicated, for
example, because of a history of relapse, or 2) there was a strong
subject or family preference for continuing treatment.
Level 2. Those with a CGI severity rating of 3 (mildly ill) or who
required other treatments were given a recommendation (as appropriate clinically) to continue TADS-like treatment(s) and to
add other treatments if necessary.
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Level 3. Those with a CGI severity score of 4 or worse (moderately ill or worse) received whatever recommendation the treating site deemed clinically and ethically appropriate.
With respect to clinical referrals, each site used a standardized
resource list of referrals that included psychologists, social workers, and psychiatrists who in the opinion of the referring site were
committed to evidence-based mental health care.
Stage IV Procedure
In stage IV, subjects were assessed by their independent evaluator, blind to treatment condition, with an abbreviated battery at
3 and 9 months and with a complete battery at 6 months and at
the end of 1 year. A debriefing session was held at the end of each
assessment and up to two “adjunctive services and attrition prevention” sessions (31) were provided. In addition, subjects were
told that if their depressive symptoms worsened between assessment visits, they should call their primary clinician to schedule an
additional visit (within 3 days) for assessment. If the subject appeared to the clinician to be relapsing, a visit with the independent evaluator was scheduled and the subject was referred for
open community treatment according to previously established
referral procedures.
TADS employed two primary outcome measures: 1) the scalar
Children’s Depression Rating Scale—Revised total score (32) and
2) responder status, which was defined as being rated much improved or very much improved on the CGI improvement scale
(30). In addition to responder status, we examined remission status by using a cutoff score of 28 or less on the Children’s Depression Rating Scale (10, 33). Data from the adolescent self-report,
the Reynolds Adolescent Depression Scale (34), were included because of the prominent place accorded adolescent self-report in
the CBT literature. To ascertain suicidal ideation, we employed a
“flag” score of 31 or greater on the Suicidal Ideation Questionnaire—Junior High School Version (35), which denotes suicidal
ideation of sufficient severity to warrant prompt clinical evaluation. Psychometric properties and intercorrelations for all measures were acceptable (4). Since the subjects were not receiving
study treatment and were not seen except for scheduled assessment visits, we did not assess (and do not report) the incidence of
new suicidal events or other serious adverse events during stage
IV follow-up.
The participants and at least one parent provided informed
consent or assent. Institutional review boards at each site approved and monitored the protocol. Safety monitoring was done
quarterly by a National Institute of Mental Health data safety and
monitoring board.
Stage IV Statistical Analysis Plan
The primary effectiveness and safety analyses were conducted
by using an intention-to-treat principle, by which the analysis included all subjects randomly assigned to the three active treatments (combined treatment, fluoxetine, and CBT) regardless of
adherence to study treatment or procedures. Longitudinal analyses of the primary and secondary scalar outcome measures were
conducted by using quadratic random coefficients regression
models designed to assess individual subject trajectories from
baseline to the end of stage IV. Specifically, the impact of treatment on outcome was modeled as a function of fixed effects for
treatment, natural log of time, and clinical site (and their two-way
and three-way interaction terms) as well as the random effects for
subject and subject-by-time interactions. Site was retained, but
its interactions were omitted from the final model owing to statistical nonsignificance.
To test for treatment differences in remission rates over time
and to generate estimated probabilities of remission in the three
treatment arms from week 6 to the end of stage IV, we used a generalized linear mixed model for binary outcomes, applying the
Am J Psychiatry 166:10, October 2009
TADS TEAM
generalized estimating equation method. This model included
treatment, time, treatment-by-time interaction, and site. Baseline
response scores were not included because all subjects met the
criteria for DSM-IV major depressive disorder before treatment
initiation. For the dichotomized outcome of response based on
CGI-rated improvement, a logistic regression model applying a
last-observation-carried-forward imputation method and controlling for site was conducted to examine the effects of randomized treatment on response at the end of stage IV. Although a longitudinal analysis employing a generalized estimating equation
approach was preferred, such a model was not possible owing to
the high treatment response rate in all three treatment arms by
month 6 of the stage IV follow-up period.
For hypotheses stipulated in the statistical plan, the nominal
significance level was set a priori at a two-tailed type I error rate of
0.05 for the omnibus tests designed to compare all three treatment arms. If the treatment or a treatment-by-time (linear or
quadratic) interaction term was significant, then pairwise comparisons were conducted by means of a closed test procedure
with an alpha of 0.05 for each test. In the event of a nonsignificant
omnibus result, a sequential rejective approach was planned to
safeguard the type II error rate. Analyses were conducted by using
SAS 8.2 software (SAS Institute, Cary, N.C.), with PROC MIXED
employed for the random regressions on the scalar outcomes,
PROC GENMOD for applying the generalized estimating equation method to the remission outcome, and PROC LOGISTIC for
the CGI improvement outcome.
Results
Subject Characteristics
The full TADS study group (N=439) has been extensively
described and compared to both clinical and epidemiological samples (4). The participants ranged in age from 12 to
17 years and had a primary DSM-IV diagnosis of major depressive disorder. The baseline clinical and demographic
characteristics of the 327 adolescents assigned to an active
treatment arm (fluoxetine, CBT, or combined treatment)
are as follows. The mean age was 14.6 years (SD=1.5), 45.0%
were male, 74.0% were Caucasian, 11.3% were African
American, and 9.8% were Hispanic. Depression ranged
from mild to severe depression. The total raw scores on the
Children’s Depression Rating Scale ranged from 45 to 98,
and the mean score at entry was 60.8 (SD=10.3), which
translates to a T score of 75.7 (SD=6.5), which is above the
98th percentile on the Children’s Depression Rating Scale.
Among the 234 adolescents who completed a week 36 assessment (the entry point into stage IV), there were no statistically significant between-treatment differences in
demographic variables, family income, functioning, or
pattern of comorbidity, with three exceptions. Before treatment, more subjects receiving fluoxetine (four of 73, or
5.5%) than combined treatment (one of 78, or 1.3%) or CBT
(none of 76, or 0.0%) had a score on the Suicidal Ideation
Questionnaire above 31, indicating clinically significant
suicidality (Fisher’s exact test, overall p=0.05). There was
also a higher rate of current disruptive behavior disorder
for those receiving combined treatment (12 of 81, or 14.8%)
than for the fluoxetine group (four of 73, or 5.5%) or the
CBT group (three of 76, or 3.9%) (Fisher’s exact test, overall
Am J Psychiatry 166:10, October 2009
p=0.04). In addition, there was a higher rate of current anxiety disorder for CBT (eight of 76, or 10.5%) relative to combined treatment (two of 81, or 2.5%) or fluoxetine (one of
73, or 1.4%) (Fisher’s exact test, overall p=0.03).
Subject Disposition
A total of 2,804 subjects were screened by phone (gate
A). Of these, 1,088 signed consent for evaluation of inclusion and exclusion criteria (gate B) and 439 completed the
baseline assessment and were subsequently randomly assigned to treatment (gate C). This report concerns only the
327 subjects randomly assigned to active treatment conditions: combined treatment (N=107), fluoxetine (N=109),
and CBT (N=111). Of these 327 subjects, 234 (71.6%) remained in the study at week 36. Of these, 178 (54.4%) completed stage III in the treatment condition to which they
had been randomly assigned. Sixty-six percent of the eligible subjects (N=215) participated in at least one stage IV
assessment. During stage IV, 49 (45.8%) of the 107 in combined treatment, 46 (42.2%) of the 109 receiving fluoxetine, and 53 (47.7%) of the 111 in the CBT group completed
all four stage IV assessments. The proportions were somewhat higher for those who completed an assessment at
month 12: 65 (60.7%) of the 107 in combined treatment, 56
(51.4%) of the 109 receiving fluoxetine, and 67 (60.4%) of
the 111 CBT subjects. During stage IV, 215 (65.7%) of the
327 families provided information on mental health services. Data collapsed across stage IV indicated that 2.8% of
the subjects received inpatient mental health care, 34.0%
received outpatient mental health care, 34.0% received
services from a nonphysician mental health provider, and
17.2% received services from a physician mental health
provider. There were no differences between treatment
groups in the type of services received in stage IV.
Benefits
Table 1 presents the adjusted mean scores on the Children’s Depression Rating Scale, Reynolds Adolescent Depression Scale, and Suicidal Ideation Questionnaire, as
well as the response and remission rates by the stage IV assessment point for each treatment and the total group.
Figure 1 illustrates the trajectory of scores on the Children’s Depression Rating Scale for the three active treatments across stages I–IV. Figure 2 illustrates comparable
trajectories for the Reynolds Adolescent Depression Scale
and Suicidal Ideation Questionnaire, as well as the response and remission measures for the three active treatments across stage IV. When presented in either tabled or
graphical format, in all cases the data show that improvement in the group average scores continued on a positive
trajectory during stage IV follow-up.
The random regression analyses on the Children’s Depression Rating Scale total scores across the entire study
identified a statistically significant linear time effect (F=
202.07, df=1, 292, p<0.001), time-by-treatment interaction
(F=12.13, df=2, 292, p<0.001), and quadratic time-by-treatajp.psychiatryonline.org
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TABLE 1. Descriptive Statistics for Outcome Measures During Naturalistic Follow-Up for 327 Adolescents With Major Depressive Disorder Treated With Fluoxetine, Cognitive-Behavioral Therapy (CBT), or a Combination
Outcome Measure and Treatment
Arm
Total score on Children’s Depression Rating Scale—Revisedb
Combined treatment
Fluoxetine
CBT
Total
Total score on Reynolds Adolescent
Depression Scalec
Combined treatment
Fluoxetine
CBT
Total
Total score on Suicidal Ideation
Questionnaire—Junior High
School Versionc
Combined treatment
Fluoxetine
CBT
Total
Response (CGI improvement rating
of much or very much improved)d
Combined treatment
Fluoxetine
CBT
Total
Remission (score ≤28 on Children's
Depression Rating Scale—Revised)e
Combined treatment
Fluoxetine
CBT
Total
N
End of Study Treatment
(stage III week 36)
Meana
SD
Naturalistic Follow-Up (stage IV)
Month 3
Meana
SD
Month 6
Meana
SD
Month 9
Meana
SD
Month 12
Meana
SD
107
109
111
327
29.2
30.4
32.0
30.6
7.1
6.6
7.7
7.2
28.3
29.0
29.9
29.1
6.8
6.4
7.4
6.9
27.6
27.9
28.3
27.9
6.5
6.2
7.2
6.6
27.0
27.1
26.9
27.0
6.3
6.1
7.1
6.5
26.6
26.4
25.7
26.2
6.2
6.1
7.1
6.5
107
109
111
327
53.8
56.5
58.2
56.2
12.1
11.9
12.6
12.3
53.1
55.7
56.2
55.0
12.1
11.9
12.6
12.3
52.6
55.0
54.6
54.1
12.1
12.0
12.7
12.3
52.2
54.5
53.2
53.3
12.1
12.2
12.9
12.4
51.9
54.1
52.0
52.7
12.2
12.4
13.1
12.6
107
109
111
327
10.2
12.1
9.5
10.6
%
8.8
11.1
9.1
9.8
9.9
11.5
9.0
10.1
%
8.4
10.8
8.7
9.4
9.6
11.1
8.7
9.8
%
8.1
10.6
8.4
9.1
9.4
10.8
8.4
9.5
%
8.0
10.4
8.2
9.0
9.3
10.5
8.2
9.3
%
7.8
10.4
8.1
8.9
107
109
111
327
81
72
69
74
79
74
69
74
81
73
72
75
83
74
68
75
82
75
70
76
107
109
111
327
59
54
64
59
65
66
62
64
74
57
69
67
64
61
63
63
68
67
69
68
a Derived from the random coefficients regression model with adjustments for fixed and random effects.
b Completed by the blinded clinical evaluator.
c Completed by the youth.
d CGI ratings provided by the blinded clinical evaluator. Response rates were calculated by applying the last
observation carried forward
as an imputation method, with adjustments for fixed and random effects.
e Based on the predicted probabilities derived from the generalized estimating equation with adjustments for fixed and random effects.
ment interaction (F=11.72, df=1, 264, p<0.001). The effect
of site was significant (F=2.46, df=12, 311, p=0.005).
Planned contrasts at week 36 and at stage IV months 3, 6,
9, and 12 identified superiority for combined treatment
relative to CBT at week 36 (F=5.08, df=1, 267, p=0.03); all of
the stage IV contrasts were nonsignificant.
by-time interaction (χ2=30.67, df=16, p=0.02) were statistically significant; the effect of site also was significant (χ2=
25.09, df=9, p=0.003). All but one of the planned stage IV
contrasts were nonsignificant; combined treatment was
superior to fluoxetine at month 6 (χ2=4.15, df=1, p=0.05).
With a positive response defined as a CGI improvement
score of 1 (very much improved) or 2 (much improved), logistic regression using the last observation carried forward
indicated that the effect of treatment on the response rate
at stage IV month 12 was not statistically significant (χ2=
4.20, df=2, p=0.13), nor was site (χ2=9.70, df=9, p=0.38).
The adjusted rates of response at month 12 were 82.2% for
combined treatment, 75.2% for fluoxetine, and 70.3% for
CBT. Planned contrasts at month 12 identified no significant differences among the treatment groups.
Random regression analyses of the Reynolds Adolescent
Depression Scale total score across time identified a statistically significant linear time effect (F=75.87, df=1, 286,
p<0.001), time-by-treatment interaction (F=13.34, df=2,
286, p<0.001), and quadratic time-by-treatment interaction (F=11.60, df=2, 261, p<0.001). The effect of site was
significant (F=2.62, df=12, 314, p=0.002). Planned contrasts at weeks 36 and stage IV months 3, 6, 9, and 12 identified superiority for combined treatment relative to CBT
at week 36 (F=5.22, df=1, 282, p=0.03); all other stage IV
contrasts were nonsignificant.
When a cutoff score of 28 or less on the Children’s Depression Rating Scale was used to define remission, generalized estimating equation analyses indicated that the effect of time (χ2=123.25, df=8, p<0.001) and the treatment-
Random regression analyses of the Suicidal Ideation
Questionnaire total score across time identified a statistically significant linear time effect (F=49.53, df=1, 273,
p<0.001), quadratic time effect (F=4.53, df=1, 228, p<0.04),
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Am J Psychiatry 166:10, October 2009
TADS TEAM
FIGURE 1. Depression Scores From Baseline to End of Naturalistic Follow-Up for 327 Adolescents With Major Depressive
Disorder Treated With Fluoxetine, Cognitive-Behavioral Therapy (CBT), or a Combination
Adjusted Predicted Mean Score
on Children’s Depression Rating
Scale—Revised
(intention-to-treat analysis) a
65
Combination treatment
Fluoxetine
55
CBT
45
35
25
Baseline
6
12
18
24
30
36
3
Week of Study
Treatment
a
6
9
12
Month of Naturalistic
Follow-Up
Derived from the random coefficients regression model with adjustments for fixed and random effects.
and time-by-treatment interaction (F=3.93, df=2, 273,
p<0.03). The effect of site was nonsignificant. Planned
contrasts at weeks 36 and stage IV months 3, 6, 9, and 12
were nonsignificant.
Loss of Benefits
To evaluate the extent to which subjects deteriorated
during stage IV, we examined worsening on the CGI severity
scale, Suicidal Ideation Questionnaire, and remission measure. According to the CGI severity rating at week 36, 81.7%
of the study group were minimally impaired (CGI score ≤3).
During stage IV, 13.1% deteriorated to mildly to extremely
impaired (score=4–7): 15.1% in combined treatment, 9.9%
in the fluoxetine group, and 14.5% in the CBT group. There
were no statistically significant differences across the three
treatment groups. According to the suicidality flag, defined
as a total score of 31 or greater on the Suicidal Ideation
Questionnaire, 91.1% of the sample did not report clinically
significant suicidality at week 36. During stage IV, 6.4% developed clinically significant suicidality: 5.9% of those in
combined treatment, 7.6% in the fluoxetine group, and
6.4% in the CBT group. There were no statistically significant differences across the three treatment groups. Using a
score of 28 or less on the Children’s Depression Rating Scale
as the remission threshold, we found that 59.9% of the subjects were in remission at week 36. During stage IV, 32.8% of
those in combined treatment, 28.6% of the fluoxetine
group, and 30.4% of the CBT group lost remission status at
some point. There were no statistically significant differences across the three treatment groups.
Discussion
Relative to our previous reports for short-term treatment (week 12) (5) and longer-term treatment (week 36)
Am J Psychiatry 166:10, October 2009
(6), the new data from stage IV on benefits and harms over
1 year of naturalistic follow-up provide important new information. First, the stage IV analyses replicate previous
findings showing that combined treatment reaches maximum medical benefit earlier (week 18) than fluoxetine
and CBT (weeks 30 and 36, respectively) and that 9 months
of treatment is superior to 12 weeks irrespective of treatment modality. Second, in contrast to previous reports on
epidemiological and treatment samples showing high
rates of clinical deterioration after short-term treatment,
longer-term treatment results in sustained, clinically
meaningful improvement even when active treatment is
discontinued. Granting that loss of benefit as we define it
represents very mild deterioration, 6% to 33% of the TADS
patients, depending on the measure chosen, worsened
following the cessation of TADS treatment. While this is
smaller than the 69% relapse rate identified in a recently
completed study using placebo during withdrawal of fluoxetine (20), it remains substantial and indicates a need
for further improvements in long-term treatment of major
depressive disorder in youth. Third, although rarely statistically significant, combined treatment generally maintained numerical superiority relative to CBT and fluoxetine on many if not all stage IV endpoints. Thus, the stage
IV results are in line with earlier reports from the TADS
showing a meaningful advantage for combined treatment
over both monotherapies.
Limitations
Despite the inevitable methodological concerns that
arise in effectiveness research (for a thorough discussion,
see reference 7), TADS is generally thought to represent the
state of the art in comparative treatment trials for this patient population (36–39). Nevertheless, interpretation of
the stage IV results is compromised by three primary limiajp.psychiatryonline.org
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Adjusted Mean Total Score on Reynolds
Adolescent Depression Scalea
FIGURE 2. Self-Report Depression Scores, Suicidal Ideation Scores, and Rates of Response and Remission During Naturalistic Follow-Up for 327 Adolescents With Major Depressive Disorder Treated With Fluoxetine, Cognitive-Behavioral Therapy
(CBT), or a Combination
85
Fluoxetine
75
CBT
65
55
45
Month 3
Month 6
Month 9
10
Month 12
Naturalistic Follow-Up
End of
Study
Treatment
(Week 36)
Month 3
End of
Study
Treatment
(Week 36)
Month 3
Month 6
Month 9
Month 12
Naturalistic Follow-Up
100
Adjusted Rate of Remission
Based on Children’s Depression
Rating Scale—Revised (%)c
100
90
80
70
60
50
40
30
20
10
0
20
0
End of
Study
Treatment
(Week 36)
Adjusted Rate of Response Based on
CGI Improvement Rating (%)b
Adjusted Mean Total Score on
Suicidal Ideation Questionnaire—
Junior High School Versiona
30
Combination treatment
90
80
70
60
50
40
30
20
10
End of
Study
Treatment
(Week 36)
Month 3
Month 6
Month 9
Month 12
Naturalistic Follow-Up
0
Month 6
Month 9
Month 12
Naturalistic Follow-Up
a Derived from the random coefficients regression model with adjustments for fixed and random effects.
b Rating of much improved or very much improved. Response rates were calculated by applying the last observation
c
carried forward as an imputation method, with adjustments for fixed and random effects.
Score of 28 or less. Remission rates were based on the predicted probabilities derived from the generalized estimating equation with adjustments for fixed and random effects.
tations: 1) substantial missing data in stage IV, 2) the lack of
untreated and actively treated comparison groups, and 3)
lack of detail regarding service utilization in stage IV.
While the analyses using only the subjects who actually
entered stage IV and had at least one stage IV data point
(unadjusted scores; data not shown) provided results identical to those in the intent-to-treat analyses (adjusted predicted scores), indicating that the findings are not driven
by the analytic model, the main limitation of the present
report is the extent of missing data in stage IV, since it is
possible that greater subject retention would have contributed to lower stability in maintenance of response.
Without an untreated (or a placebo-treated) comparison group, it is impossible to know for certain that the
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TADS treatments benefited subjects beyond the simple
passage of time (6, 7). However, we know from a recently
completed trial of acute treatment discontinuation (20)
that patients relapse more commonly if medication is discontinued early. In the TADS, subjects treated acutely with
placebo were treated openly after 12 weeks, depending on
clinical status, and by the end of 36 weeks had reached a
clinical status equivalent to that of patients assigned to active treatment (40). We also know (data not shown) that
placebo-treated subjects continued to do well in stage IV.
Taken together, these findings imply that for the average
patient, 6 to 9 months of active treatment is sufficient to
maintain benefits once treatment is discontinued. To definitively establish the necessary duration of treatment, a
Am J Psychiatry 166:10, October 2009
TADS TEAM
randomized maintenance therapy clinical trial will be
necessary.
Likewise, without an actively treated comparison group
(e.g., a randomized discontinuation design in which subjects were randomly assigned to continue or to discontinue
treatment), it is impossible to state with confidence that
persistent benefit is identical to maximum benefit. Given
that relatively few TADS subjects received mental health
treatment during stage IV, continued maintenance treatment might have improved outcomes for the subjects who
deteriorated, especially the 3% who needed hospitalization.
Finally, collection of data on services utilization in stage
IV suffered from a much higher percentage of missing data
than in stages I–III. For example, while we obtained data of
reasonable quality on provider type, data on the type of
treatment were mostly missing at some sites, making it
impossible to predict treatment course by treatment type
or exposure without the application of extensive and potentially questionable data imputation methods.
Conclusion and Clinical Implications
With publication of the findings from acute treatment
(stage I), long-term treatment (stages I–III), and now the
naturalistic 1-year follow-up (stage IV), the central findings
from the TADS are as follows: 1) combined treatment
meaningfully accelerates recovery from depression relative
to CBT and fluoxetine, 2) longer-term treatment results in
improved outcomes relative to short-term treatment, 3)
longer-term treatment may decrease the chances of relapse
or recurrence when treatment is discontinued, and 4) adding CBT to fluoxetine minimizes persistent suicidal ideation
and treatment-emergent suicidal events associated with
medication monotherapy. While not definitive in all respects, the TADS adds important new information to the
existing literature and, along with the Adolescent Depression and Psychotherapy Trial (ADAPT) (41) and Treatment
of Resistant Depression in Adolescents (TORDIA) study
(42), begins to provide an evidence-based platform for establishing treatment guidelines for adolescent depression.
From the outset, TADS treatments were designed according to “best practice” standards and were manualized
to allow ready dissemination (if warranted) into clinical
practice at the conclusion of the trial (3). Given the fact that
combined treatment is more cost-effective than fluoxetine
alone, in part because of the higher suicidality-driven
health care costs associated with medication monotherapy
(43), there are substantial public health and health economic benefits that would accrue from providing evidence-based combined treatment to moderately to severely ill depressed teens. As the TADS comes to an end, we
believe that it is now time for the TADS to inform programs
of research focused on disseminating evidence-based care
and on quality improvement initiatives in practice settings.
Received Nov. 3, 2008; revision received May 7, 2009; accepted
June 1, 2009 (doi: 10.1176/appi.ajp.2009.08111620). Members of
the Treatment for Adolescents With Depression Study (TADS) Team
Am J Psychiatry 166:10, October 2009
are the authors of this report. TADS is coordinated by the Department of Psychiatry and Behavioral Sciences and the Duke Clinical Research Institute at Duke University Medical Center in collaboration
with NIMH, Rockville, Md. Address correspondence and reprint requests to Dr. March, Division of Neurosciences Medicine, Duke Clinical Research Institute, Rm. 0311, 2400 Pratt St., Duke University Medical Center, Durham, NC 27705; john.march@duke.edu (e-mail).
The members of the TADS Team are as follows. The Coordinating
Center principal collaborators are John March, Susan Silva, John
Curry, Karen Wells, John Fairbank, Barbara Burns, and Marisa Domino. The NIMH principal collaborators are Benedetto Vitiello and
Joanne Severe. The principal investigators and co-investigators from
the clinical sites are as follows: Carolinas Medical Center: Charles Casat, Karyn Riedal, Marguerita Goldman; Case Western Reserve University: Norah Feeny, Robert Findling, Sheridan Stull, Susan Baab;
Children’s Hospital of Philadelphia: Elizabeth B. Weller, Michele Robins, Ronald A. Weller, Naushad Jessani; Columbia University: Bruce
Waslick (now at Baystate Health/Tufts University), Michael Sweeney,
Randi Dublin, Johns Hopkins University: John Walkup, Golda Ginsburg, Elizabeth Kastelic, Hyung Koo; University of Nebraska: Christopher Kratochvil, Diane May, Randy LaGrone, Brigette Vaughan; New
York University: Anne Marie Albano (now at Columbia University),
Glenn S. Hirsch, Elizabeth Podniesinki, Angela Chu; University of Chicago/Northwestern University: Mark Reinecke, Bennett Leventhal,
Gregory Rogers, Rachel Jacobs; Cincinnati Children’s Hospital Medical
Center: Sanjeev Pathak, Jennifer Wells, Sarah A. Lavanier, Arman
Danielyan; University of Oregon: Paul Rohde, Anne Simons, James
Grimm, Stephenie Frank; University of Texas Southwestern Medical
Center: Graham Emslie, Beth Kennard, Carroll Hughes, Taryn L.
Mayes; and Wayne State University: David Rosenberg, Nili Benazon,
Michael Butkus, Marla Bartoi. The TADS protocol and all of the TADS
manuals are available on the Internet at https://trialweb.dcri.duke.edu/tads/index.html. The TADS de-identified data set
is available through the NIMH limited access data set mechanism:
http://www.nimh.nih.gov/health/trials/datasets/nimh-proceduresfor-requesting-data-sets.shtml.
Dr. March owns stock in MedAvante; is a consultant and/or scientific advisor for Lilly, Pfizer, and Wyeth; receives research support (including medication) from Lilly and Pfizer; serves on a data safety
monitoring board for Johnson & Johnson; and receives royalty payments from Guilford Press, MultiHealth Systems, and Oxford University Press. Dr. Silva serves on a data safety and monitoring board for
Pfizer. Dr. Karen Wells receives consulting fees through the REACH Institute and from the State of New York. Dr. Findling receives or has received research support from, acted as a consultant to, and/or served
on speakers bureaus for Abbott, Addrenex, AstraZeneca, Biovail, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Johnson & Johnson,
KemPharm, Lilly, Lundbeck, Neuropharm, Novartis, Organon, Otsuka, Pfizer, Sanofi-Aventis, Sepracore, Shire, Solvay, Supernus, Validus, and Wyeth. Dr. Elizabeth Weller receives royalties from American
Psychiatric Press. Dr. Ronald Weller receives royalties from American
Psychiatric Press. Dr. Waslick receives research support from GlaxoSmithKline and Somerset. Dr. Walkup reports receiving support in
the form of free medication and/or placebo from Abbott, Lilly, and
Pfizer; he receives honoraria from the Tourette Syndrome Association. Dr. Kratochvil receives research support from NIMH (grant
5K23-MH-06612701A1); receives additional grant support (including
medication) from Abbott, Lilly, and Somerset; is a consultant for Abbott, Lilly, and Pfizer; and is a member of the REACH Institute Primary Pediatric Psychopharmacology Steering Committee. Dr. Leventhal receives research support from Bristol-Myers Squibb, Lilly, and
Pfizer; he receives speaking fees from Lilly. Dr. Pathak is employed by
AstraZeneca. Dr. Emslie receives research funding from NIMH, Biobehavioral Diagnostics, Forest, Shire, and Somerset; he is a consultant
for Biobehavioral Diagnostics, Forest, Lilly, Pfizer, Shire, Validus, and
Wyeth. Dr. Hughes is a consultant for Biobehavioral Diagnostics. Dr.
Rosenberg serves on the speakers bureau for Jazz Pharmaceuticals
and is a consultant for Gerson Lehman Group. The other authors report no competing interests.
TADS is supported by contract 98-DS-0008 from NIMH to Duke University Medical Center (principal investigator: John S. March, M.D.,
M.P.H.). NIMH program staff participated in designing and implementing the TADS, analyzing the data, and authoring this manuscript. Eli Lilly and Company provided fluoxetine and matching pla-
ajp.psychiatryonline.org
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TADS FOLLOW-UP
cebo under an independent educational grant to Duke University
but otherwise had no role in the design or implementation of the
study, data analysis, or writing of this manuscript.
The authors thank the TADS scientific advisers (Susan Essock, Ph.D.;
Barbara Geller, M.D.; Joel Greenhouse, Ph.D.; Robert Johnson, M.D.;
James Leckman, M.D.; Lydia Lewis; Sue M. Marcus, Ph.D.; Kevin Stark,
Ph.D.) for their contributions to the design and methods of the study;
David Brent, M.D., and Greg Clarke, Ph.D., for their consultation regarding CBT; and the members of the NIMH Data and Safety Monitoring Board for monitoring the progress of the study.
The opinions and assertions contained in this report are the private
views of the authors and are not to be construed as official or as reflecting the views of NIMH, NIH, or the Department of Health and Human Services.
Clinical Trial Registry: www.clinicaltrials.gov NCT00006286.
12.
13.
14.
15.
References
1. Essau C, Dobson K: Epidemiology of depressive disorders, in
Depressive Disorders in Children and Adolescents: Epidemiology, Course and Treatment. Edited by Essau C, Petermann F.
Northvale, NJ, Jason Aronson, 1999, pp 69–103
2. Gould MS, King R, Greenwald S, Fisher P, Schwab-Stone M,
Kramer R, Flisher AJ, Goodman S, Canino G, Shaffer D: Psychopathology associated with suicidal ideation and attempts
among children and adolescents. J Am Acad Child Adolesc Psychiatry 1998; 37:915–923
3. Treatment for Adolescents With Depression Study Team: Treatment for Adolescents With Depression Study (TADS): rationale,
design, and methods. J Am Acad Child Adolesc Psychiatry
2003; 42:531–542
4. Treatment for Adolescents With Depression Study Team: The
Treatment for Adolescents With Depression Study (TADS): demographic and clinical characteristics. J Am Acad Child Adolesc
Psychiatry 2005; 44:28–40
5. Treatment for Adolescents With Depression Study Team: Fluoxetine, cognitive-behavioral therapy, and their combination for
adolescents with depression: Treatment for Adolescents With
Depression Study (TADS) randomized controlled trial. JAMA
2004; 292:807–820
6. Treatment for Adolescents With Depression Study Team: The
Treatment for Adolescents With Depression Study (TADS): longterm effectiveness and safety outcomes. Arch Gen Psychiatry
2007; 64:1132–1143
7. March J, Silva S, Vitiello B: The Treatment for Adolescents With
Depression Study (TADS): methods and message at 12 weeks. J
Am Acad Child Adolesc Psychiatry 2006; 45:1393–1403
8. Kratochvil C, Emslie G, Silva S, McNulty S, Walkup J, Curry J, Reinecke M, Vitiello B, Rohde P, Feeny N, Casat C, Pathak S, Weller
E, May D, Mayes T, Robins M, March J, TADS Team: Acute time
to response in the Treatment for Adolescents With Depression
Study (TADS). J Am Acad Child Adolesc Psychiatry 2006; 45:
1412–1418
9. Vitiello B, Rohde P, Silva S, Wells K, Casat C, Waslick B, Simons
A, Reinecke M, Weller E, Kratochvil C, Walkup J, Pathak S, Robins M, March J, TADS Team: Functioning and quality of life in
the Treatment for Adolescents With Depression Study (TADS). J
Am Acad Child Adolesc Psychiatry 2006; 45:1419–1426
10. Kennard B, Silva S, Vitiello B, Curry J, Kratochvil C, Simons A,
Hughes J, Feeny N, Weller E, Sweeney M, Reinecke M, Pathak S,
Ginsburg G, Emslie G, March J, TADS Team: Remission and residual symptoms after short-term treatment in the Treatment
of Adolescents With Depression Study (TADS). J Am Acad Child
Adolesc Psychiatry 2006; 45:1404–1411
11. Emslie G, Kratochvil C, Vitiello B, Silva S, Mayes T, McNulty S,
Weller E, Waslick B, Casat C, Walkup J, Pathak S, Rohde P, Posner K, March J, Columbia Suicidality Classification Group, TADS
Team: Treatment for Adolescents With Depression Study
1148
ajp.psychiatryonline.org
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
(TADS): safety results. J Am Acad Child Adolesc Psychiatry 2006;
45:1440–1455
Rohde P, Silva SG, Tonev ST, Kennard BD, Vitiello B, Kratochvil
CJ, Reinecke MA, Curry JF, Simons AD, March JS: Achievement
and maintenance of sustained response during the Treatment
for Adolescents With Depression Study continuation and maintenance therapy. Arch Gen Psychiatry 2008; 65:447–455
Kovacs M, Feinberg T, Crouse N: Depressive disorders in childhood: long term characteristics and recovery. Arch Gen Psychiatry 1984; 41:229–237
McCauley E, Myers K, Mitchell J, Calderon R, Schloredt K, Treder
R: Depression in young people: initial presentation and clinical
course. J Am Acad Child Adolesc Psychiatry 1993; 32:714–722
Lewinsohn P, Clarke G, Seeley J, Rohde P: Major depression in
community adolescents: age at onset, episode duration, and
time to recurrence. J Am Acad Child Adolesc Psychiatry 1994;
33:809–818
Birmaher B, Brent DA, Kolko D, Baugher M, Bridge J, Holder D,
Iyengar S, Ulloa RE: Clinical outcome after short-term psychotherapy for adolescents with major depressive disorder. Arch
Gen Psychiatry 2000; 57:29–36
Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Carmody T,
Mayes TL: Fluoxetine in child and adolescent depression: acute
and maintenance treatment. Depress Anxiety 1998; 7:32–39
Brent DA, Kolko DJ, Birmaher B, Baugher M, Bridge J: A clinical
trial for adolescent depression: predictors of additional treatment in the acute and follow-up phases of the trial. J Am Acad
Child Adolesc Psychiatry 1999; 38:263–270
Clarke GN, Rohde P, Lewinsohn PM, Hops H, Seeley JR: Cognitive-behavioral treatment of adolescent depression: efficacy of
acute group treatment and booster sessions. J Am Acad Child
Adolesc Psychiatry 1999; 38:272–279
Emslie GJ, Kennard BD, Mayes TL, Nightingale-Teresi J, Carmody
T, Hughes CW, Rush AJ, Tao R, Rintelmann JW: Fluoxetine versus
placebo in preventing relapse of major depression in children
and adolescents. Am J Psychiatry 2008; 165:459–467
Emslie GJ: Improving outcome in pediatric depression (editorial). Am J Psychiatry 2008; 165:1–3
Curry JF, Wells KC: Striving for effectiveness in the treatment of
adolescent depression: cognitive behavior therapy for multisite community intervention. Cogn Behav Pract 2005; 12:177–
185
Ginsburg GS, Albano AM, Findling RL, Kratochvil C, Walkup J:
Integrating cognitive behavioral therapy and pharmacotherapy in the treatment of adolescent depression. Cogn Behav
Pract 2005; 12:252–262
Kennard BD, Ginsburg GS, Feeny NC, Sweeney M, Zagurski R:
Implementation challenges to TADS cognitive-behavioral therapy. Cogn Behav Pract 2005; 12:230–239
Kratochvil CJ, Simons A, Vitiello B, Walkup J, Emslie G, Rosenberg D, March JS: A multisite psychotherapy and medication
trial for depressed adolescents: background and benefits. Cogn
Behav Pract 2005; 12:159–165
Rogers GM, Reinecke MA, Curry JF: Case formulation in TADS
CBT. Cogn Behav Pract 2005; 12:198–208
Rohde P, Feeny NC, Robins M: Characteristics and components
of the TADS CBT approach. Cogn Behav Pract 2005; 12:186–
197
Simons AD, Rohde P, Kennard BD, Robins M: Relapse and recurrence prevention in the Treatment for Adolescents With Depression Study. Cogn Behav Pract 2005; 12:240–251
Sweeney M, Robins M, Ruberu M, Jones J: African-American
and Latino families in TADS: recruitment and treatment considerations. Cogn Behav Pract 2005; 12:221–229
Guy W (ed): ECDEU Assessment Manual for Psychopharmacology: Publication ADM 76-338. Washington, DC, US Department
of Health, Education, and Welfare, 1976, pp 218–222
Am J Psychiatry 166:10, October 2009
TADS TEAM
31. May DE, Kratochvil CJ, Puumala SE, Silva SG, Rezac AJ, Hallin MJ,
Reinecke MA, Vitiello B, Weller EB, Pathak S, Simons AD, March
JS: A manual-based intervention to address clinical crises and
retain patients in the Treatment of Adolescents With Depression Study (TADS). J Am Acad Child Adolesc Psychiatry 2007; 46:
573–581
32. Poznanski E, Mokros H: Children’s Depression Rating Scale, Revised (CDRS-R). Los Angeles, Western Psychological Services,
1995
33. Kennard BD, Emslie GJ, Mayes TL, Hughes JL: Relapse and recurrence in pediatric depression. Child Adolesc Psychiatr Clin N
Am 2006; 15:1057–1079, xi
34. Reynolds WM: Professional Manual for the Reynolds Adolescent Depression Scale. Odessa, Fla, Psychological Assessment
Resources, 1987
35. Reynolds WM: Professional Manual for the Suicidal Ideation
Questionnaire. Odessa, Fla, Psychological Assessment Resources, 1987
36. Apter A, Kronenberg S, Brent D: Turning darkness into light: a
new landmark study on the treatment of adolescent depression: comments on the TADS study. Eur Child Adolesc Psychiatry 2005; 14:113–116
37. Brent DA: Glad for what TADS adds, but many TADS grads still
sad. J Am Acad Child Adolesc Psychiatry 2006; 45:1461–1464
38. Jensen PS: NIMH’s TADS: more than just a tad of progress? Cogn
Behav Pract 2005; 12:156–158
Am J Psychiatry 166:10, October 2009
39. Jensen PS: After TADS, can we measure up, catch up, and ante
up? J Am Acad Child Adolesc Psychiatry 2006; 45:1456–1460
40. Kennard BD, Silva SG, Mayes TL, Rohde P, Hughes JL, Vitiello B,
Kratochvil CJ, Curry JF, Emslie GJ, Reinecke MA, March JS: Assessment of safety and long-term outcomes of initial treatment
with placebo in TADS. Am J Psychiatry 2009; 166:337–344
41. Goodyer IM, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford
S, Breen S, Ford C, Barrett B, Leech A, Rothwell J, White L, Harrington R: A randomised controlled trial of cognitive behaviour
therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors: the ADAPT trial. Health
Technol Assess 2008; 12:1–80
42. Brent D, Emslie G, Clarke G, Wagner KD, Asarnow JR, Keller M,
Vitiello B, Ritz L, Iyengar S, Abebe K, Birmaher B, Ryan N, Kennard B, Hughes C, DeBar L, McCracken J, Strober M, Suddath R,
Spirito A, Leonard H, Melhem N, Porta G, Onorato M, Zelazny J:
Switching to another SSRI or to venlafaxine with or without
cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. JAMA
2008; 299:901–913
43. Domino ME, Foster EM, Vitiello B, Kratochvil CJ, Burns BJ, Silva
SG, Reinecke MA, March JS: Relative cost-effectiveness of treatments for adolescent depression: 36-week results from the
TADS randomized trial. J Am Acad Child Adolesc Psychiatry
2009; 48:711–720
ajp.psychiatryonline.org
1149