Context Initial treatment of major depressive disorder in adolescents may include
cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor
(SSRI). However, little is known about their relative or combined effectiveness.
Objective To evaluate the effectiveness of 4 treatments among adolescents with
major depressive disorder.
Design, Setting, and Participants Randomized controlled trial of a volunteer sample of 439 patients between
the ages of 12 to 17 years with a primary Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of
major depressive disorder. The trial was conducted at 13 US academic and community
clinics between spring 2000 and summer 2003.
Interventions Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone,
(3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10
to 40 mg/d). Placebo and fluoxetine alone were administered double-blind;
CBT alone and CBT with fluoxetine were administered unblinded.
Main Outcome Measures Children's Depression Rating Scale-Revised total score and, for responder
analysis, a (dichotomized) Clinical Global Impressions improvement score.
Results Compared with placebo, the combination of fluoxetine with CBT was statistically
significant (P = .001) on the Children's Depression
Rating Scale-Revised. Compared with fluoxetine alone (P = .02) and CBT alone (P = .01), treatment
of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment
to CBT alone (P = .01). Rates of response for fluoxetine
with CBT were 71.0% (95% confidence interval [CI], 62%-80%); fluoxetine alone,
60.6% (95% CI, 51%-70%); CBT alone, 43.2% (95% CI, 34%-52%); and placebo,
34.8% (95% CI, 26%-44%). On the Clinical Global Impressions improvement responder
analysis, the 2 fluoxetine-containing conditions were statistically superior
to CBT and to placebo. Clinically significant suicidal thinking, which was
present in 29% of the sample at baseline, improved significantly in all 4
treatment groups. Fluoxetine with CBT showed the greatest reduction (P = .02). Seven (1.6%) of 439 patients attempted suicide;
there were no completed suicides.
Conclusion The combination of fluoxetine with CBT offered the most favorable tradeoff
between benefit and risk for adolescents with major depressive disorder.
Major depressive disorder (MDD) in adolescence is common—the point
prevalence is 1 in 20—and is associated with significant morbidity and
family burden.1,2 Depression also
is an important contributor to adolescent suicidal behavior and to completed
suicide,3,4 which is the third
leading cause of death among adolescents.5 Furthermore,
depression in adolescence is a major risk factor for MDD, suicide, and long-term
psychosocial impairment in adulthood.6 Thus,
improvements in the treatment of MDD among adolescents should positively affect
public health.
When the Treatment for Adolescents With Depression Study (TADS) was
designed in 1998, empirical literature supported cognitive-behavioral therapy
(CBT) as a treatment for MDD in youth,7 with
both behavioral8 and cognitive9 approaches
well represented.10 In contrast, Emslie et
al's11 randomized controlled trial comparing
fluoxetine with placebo, along with the lack of favorable efficacy data for
the tricyclic antidepressants,12 formed the
sole empirical basis for the TADS pharmacotherapy condition. Although the
fluoxetine results were subsequently replicated,13 which
lead to approval from the Food and Drug Administration of fluoxetine for MDD
in youth—the only medication so recognized—meta-analyses of antidepressant
trials for MDD in children and adolescents tell a mixed story regarding benefits
and risks of medication management.14,15 Given
that antidepressants are widely used as first-line treatments for depressed
youth,16 it seemed critical then (and even
more so now) that rapid replication of the efficacy studies of CBT and fluoxetine
be performed in an effectiveness sample of depressed adolescents.
Response rates for CBT and medication in previous studies are approximately
60%, leaving substantial room for improvement in treatment outcomes. In adults,
the combination of CBT with medication may lead to greater improvement in
depression than monotherapy with either treatment.17-19 Although
combined treatment is frequently recommended by experts, especially for more
severely ill patients,20,21 the
relative efficacy of CBT and medication, alone and in combination, for depressed
adolescents is unknown. It also is not clear which patients might benefit
most from combined treatment.
TADS is a multicenter, randomized, clinical trial designed to evaluate
the effectiveness of treatments for adolescents with MDD.22 Stage
1 compares randomly assigned groups receiving 12-week treatment with (1) fluoxetine
alone, (2) CBT alone, (3) fluoxetine with CBT, or (4) placebo. Placebo and
fluoxetine alone were administered double-blind, while CBT alone and fluoxetine
with CBT were administered unblinded. Blinding for the primary dependent measures
was maintained by means of an independent evaluator.
The specific aims of the study, the design, and the rationale for choices
made, the required sample size calculations, and the methods used are detailed
elsewhere.22 The demographic and clinical characteristics
of the sample and the external validity relative to epidemiological and treatment-seeking
samples have also been published.23 The intent-to-treat
effectiveness and safety outcomes for stage 1 of TADS are presented herein.
A volunteer sample of 439 patients with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition24(DSM-IV), diagnosis of MDD
entered the study between spring 2000 and summer 2003. Patients were recruited
without regard to sex, race, or ethnicity from (1) clinics; (2) paid and public
service advertisements in newspapers and on the radio and TV; (3) primary
care physicians; (4) other mental health clinicians; and (5) schools and juvenile
justice facilities at 13 academic and community clinics. All patients and
at least one of their parents provided written informed consent. The Duke
University Medical Center (Durham, NC) and the institutional review boards
at each site approved and monitored the protocol; TADS was monitored quarterly
by the data safety and monitoring board of the National Institute of Mental
Health (Bethesda, Md).
Inclusion criterion were age of 12 to 17 years (inclusive); ability
to receive care as an outpatient; a DSM-IV diagnosis
of MDD at consent and again at baseline; a Children's Depression Rating Scale-Revised25 (CDRS-R) total score of 45 or higher at baseline;
a full-scale IQ of 80 or higher; and not taking antidepressant(s) prior to
consent. Depressive mood had to have been present in at least 2 of 3 contexts
(home, school, among peers) for at least 6 weeks prior to consent. Concurrent
stable psychostimulant treatment (eg, methylphenidate or mixed amphetamine
salts) for attention-deficit/hyperactivity disorder was permitted.
Exclusion criterion were current or past diagnosis of bipolar disorder,
severe conduct disorder, current substance abuse or dependence, pervasive
developmental disorder(s), thought disorder, concurrent treatment with psychotropic
medication or psychotherapy outside the study, 2 failed selective serotonin
reuptake inhibitor (SSRI) trials, a poor response to clinical treatment containing
CBT for depression, intolerance to fluoxetine, confounding medical condition,
non-English speaking patient or parent, and/or pregnancy or refusal to use
birth control. No patients were asked or required to discontinue other forms
of psychiatric treatment to enter the study.
Patients were excluded for dangerousness to self or others if they had
been hospitalized for dangerousness within 3 months of consent or were deemed
by a cross-site panel to be "high risk" because of a suicide attempt requiring
medical attention within 6 months, clear intent or an active plan to commit
suicide, or suicidal ideation with a disorganized family unable to guarantee
adequate safety monitoring.
Randomization and Blinding
Eligible patients were randomly assigned to fluoxetine alone, CBT alone,
fluoxetine with CBT, or placebo using a computerized stratified randomization,
a 1:1:1:1 treatment allocation ratio, permuted blocking (first block size
= 4, with subsequent random block sizes of 4 and 8) within each stratum, and
site and sex as stratification variables. Except in emergencies, participants
and clinicians remained blind in the fluoxetine alone and placebo treatment
groups. Patients and clinicians were aware that participants in the fluoxetine
with CBT group received active medicine and that participants in the CBT alone
group did not receive medication. As is necessary in efficacy studies comparing
psychosocial and pharmacological interventions, masking was maintained for
the primary dependent measures by means of independent evaluators blind to
treatment assignment. Except at assessments, independent evaluators were physically
isolated from patients, data, and treating clinicians. Specific instructions
were provided to the parents, participants, and the independent evaluator
not to disclose treatment assignment.
Treatments were designed to meet best practice standards and were performed
according to instruction manuals to allow ready dissemination (if warranted)
in clinical practice at the conclusion of the trial.22
Patients had only one pharmacotherapist throughout the study. In addition
to monitoring clinical status and medication effects during six 20- to 30-minute
medication visits spread across 12 weeks of treatment, the pharmacotherapist
offered general encouragement about the effectiveness of pharmacotherapy for
MDD. Using a flexible dosing schedule dependent on pharmacotherapist-assigned
Clinical Global Impressions26 (CGI) severity
score and the ascertainment of clinically significant adverse events, doses
of placebo and fluoxetine began at a starting dose of 10 mg/d, which was then
increased to 20 mg/d at week 1 and, if necessary, to a maximum of 40 mg/d
by week 8.
In TADS, CBT is a skills-oriented treatment based on the assumption
that depression is either caused by or maintained by depressive thought patterns
and a lack of active, positively reinforcing behavioral patterns; treatment
included 15 sessions, which lasted between 50 and 60 minutes, over the first
12 weeks.27,28 In this context,
the approach taken for CBT required skill-building and optional or modular
sessions, which allowed flexible tailoring of the treatment to the adolescent's
needs in a developmentally sensitive fashion and integrated parent and family
sessions with individual sessions. The required aspects of treatment (weeks
1-6 or longer if necessary) included psychoeducation about depression and
its causes, goal-setting with the adolescent, mood monitoring, increasing
pleasant activities, social problem-solving, and cognitive restructuring.
Subsequently, modules chosen jointly by the therapist and adolescent during
weeks 7 through 12 addressed relevant social skill deficits of the adolescent,
such as problems in social engagement, communication, negotiation, compromise,
or assertion. Two parent-only sessions provided psychoeducation about depression
and, depending on need, 1 to 3 conjoint parent and adolescent sessions focused
on addressing parent and adolescent concerns.
Treatment combining fluoxetine with CBT contained all of the components
from both the medication alone and CBT alone groups. To allow limited integration
between CBT and medication management, CBT was functionally independent of
medication management (ie, no decisions regarding the CBT protocol depended
on decisions about medication management). Second, the protocols for administering
medication and CBT were functionally independent for all medication increases
other than those depending on the presence of partial response. Third, when
partial response was present, the pharmacotherapist in consultation with the
CBT therapist evaluated compliance with CBT, the overall change trajectory,
and the adverse event profile when considering whether to adjust the dose
of fluoxetine.
Diagnostic and Outcome Measures
The diagnosis of MDD and associated comorbidities at baseline were established
using the Schedule for Affective Disorders and Schizophrenia for School-Age
Children-Present and Lifetime Version,29 which
was administered by the same independent evaluator who rated the primary dependent
measures.
Two primary outcome measures were chosen a priori: the scalar CDRS-R
total score, which is based on a synthesis of information collected from interviewing
both the adolescent and the parent,25 and an
end-of-treatment CGI improvement score26 (defined
as much improved or very much improved). Both outcome measures were assessed
by the independent evaluator at baseline, week 6, and week 12. Data is also
presented herein from the Reynolds Adolescent Depression Scale (RADS),30 which is an adolescent self-report measure of depression
that was included because of the prominent place accorded adolescent self-report
in the CBT literature.7 The Suicidal Ideation
Questionnaire-Junior High School Version (SIQ-Jr),31 which
is a self-reported measure of suicidal ideation, also was included to clarify
the ratio of benefit to harm. Psychometric properties and intercorrelations
for all measures are presented elsewhere.23
Independent evaluators were clinicians with either master or doctorate
degrees, with experience administering research-related structured clinical
interviews with depressed patients or adolescent psychiatric patients or,
in most cases, both. Quality assurance procedures and reliability of the baseline
assessments are documented elsewhere.22,23 For
the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present
and Lifetime Version diagnostic criteria of the DSM-IV for
MDD, 94.1% of the reviewed interviews met the criterion of at least 80% agreement
between the 2 raters. The intraclass correlation coefficient for the total
number of MDD symptoms present was 0.80. The intraclass correlation coefficient
for the 14-item CDRS-R total score at baseline was 0.95, suggesting excellent
interrater reliability for both measures. The intraclass correlation coefficient
for the 14-item CDRS-R total score during stage 1 of treatment was 0.95, again
suggesting excellent interrater reliability on the primary dependent measure.
To ensure patient safety, evaluate the tolerability of treatment, and
to minimize the potential for cross-site differences in protocol delivery,
integrated procedures were used for adverse event monitoring and adjunctive
services and attrition prevention.22 An adverse event was defined as any unfavorable medical change
occurring postrandomization that was accompanied by functional or clinical
impairment. An adverse event may or may not be related to or caused by the
study drug or CBT treatment. A functional threshold on adverse event reporting
was imposed, specifying that an adverse event must (1) cause clinically significant
interference with functioning, (2) require medical attention, or (3) be associated
with any impairment in functioning and cause the patient to take a concomitant
medication. A harm-related adverse event was defined
as involving harm to self, which can include a nonsuicidal event, such as
cutting for relief of dysphoric affects, worsening of suicidal ideation without
self-harm, or a suicide attempt of any lethality; or harm to others, which
includes aggressive or violent ideation or action against another person or
property. A suicide-related adverse event requires
that the patient exhibit either worsening suicidal ideation or make a suicide
attempt, or both. Harmful behaviors without suicidal ideation or intent, such
as some instances of cutting, are not included in the definition of a suicide-related
adverse event. Reporting of an adverse event does not include preexisting
conditions or illnesses that do not worsen in severity or increase in frequency
during the study period.
Sample Size and Power Estimates
The primary end point used in the sample size estimate was treatment
response rate, which was defined as a CGI improvement score of 1 (very much
improved) or 2 (much improved), assigned by the independent evaluator. Using
a χ2 statistic, power estimates for detecting differences in
treatment response in the 4 groups were then computed using the following
assumptions: (1) Ha:P(fluoxetine) = .60, P(CBT)= .60, P(fluoxetine with CBT) = .80, and P(placebo) = .40; (2) no adjustment for loss to follow-up; (3) no adjustment for
multiple comparisons; and (4) α level of .05 for a 2-tailed test. Under
these assumptions, 108 patients per treatment group (N = 432) were needed
to achieve 80% or greater power to detect a difference of .20 in response
rates between any 2 treatment groups.
Data entry and verification, data transfer, confidentiality and security,
back-up and storage, and data analyses were conducted under the direction
of the principal investigator and the principal statistician. All effectiveness
and safety analyses were conducted using an intent-to-treat principle in which
the analysis included all randomized patients in the treatment groups to which
they were randomly assigned, regardless of their protocol adherence, actual
treatment received, and/or subsequent withdrawal from treatment, assessments,
or deviations from protocol.32
Statistical analyses on the primary outcome measure using CDRS-R scores
were conducted using a linear random coefficient regression model.33-35 Consistent with an
intent-to-treat approach, random regression permits estimation of changes
in continuous repeated measures in the presence of missing data on both a
population and participant-specific level without necessitating last observation
carried forward or exclusion of participants with missing data.33-35 Specifically,
the impact of treatment on outcome was modeled as a linear function of fixed
effects for treatment, time (defined as the natural log of days since baseline
+ 1), and treatment-by-time interaction and random effects for participant
and clinical site, including all 2- and 3-way interactions in the initial
model. Clinical site and its interaction effects were fitted in the model
as random effects. Although site was retained in the model, the site interaction
terms were omitted because they accounted for a minimal amount of the overall
variance and their omission did not alter the outcome.35 Under
the assumption of random intercepts and slopes for each patient, the overall
and treatment group-specific rate of change for the 4 treatment groups for
the primary CDRS-R outcome were examined. Pairwise comparisons on treatment
slopes (linear trends with time) were then conducted. Supplemental between-treatment
contrast analyses also were conducted on the adjusted week 12 means. Identical
analyses were performed on secondary measures assessing self-reported adolescent
depression (RADS) and suicidal ideation (SIQ-Jr).
Responder rates based on the dichotomized end-of-treatment CGI improvement
score for each treatment group were compared using a logistic regression model
for the last available assessment point (last observation carried forward)
with site as a covariate. The Wald χ2 test results and adjusted
odds ratios (ORs) derived from the regression analysis provided pairwise comparisons
of the treatment effects. Generalized linear models and tests for differences
in proportions (χ2 and Fisher exact tests) were performed to
evaluate differences across treatment groups at baseline. The rate of harm-
and suicide-related adverse events in each treatment group were compared using χ2 and Fisher exact tests, with ORs calculated to provide an indicator
of relative risk of active treatment to the placebo or a control condition.
For hypotheses stipulated in the statistical plan for the 2 primary
outcomes, the nominal significance level was set a priori at a 2-tailed type
I error rate of .05 for the omnibus tests designed to compare all 4 treatment
groups. If the treatment or treatment-by-time interaction term was significant,
then pairwise comparisons were conducted using a closed test procedure with
an α level of .05 for each test. In the event of a nonsignificant omnibus
result, a sequential rejective approach was planned to safeguard against type
I error.36 Because adverse events were rare
and the study was not powered for their detection, the sequential rejective
method was not applied to adverse event reporting.
To evaluate the clinical significance of the impact of treatment on
outcome, effect sizes (Hedge g) were calculated as ME − MC/SDpooled, where ME represents the adjusted mean
of experimental treatment, MCrepresents the adjusted mean of the
comparison treatment, and SDpooled represents pooling of the SDs
from within both groups.37 The number needed to treat was defined as the number of patients who need
to be treated to bring about one additional good outcome and was calculated
according to methods outlined by Sackett et al.38
Analyses were conducted using SAS statistical software (version 8.2,
SAS Institute Inc, Cary, NC) with PROC MIXED used for the random regression
analyses.39
A total of 2804 patients were screened by telephone (Figure 1). Of these, 1088 signed consent for evaluation of inclusion
and exclusion criteria and 439 were randomized to treatment and baseline assessment.
Of those randomized, 56% learned of the study via an advertisement; the remainder
were recruited via clinical or self-referral. The most frequent reasons for
exclusion were prohibited psychotropic medication use (8.8%), did not meet
criteria for MDD (17.5%), MDD not stable and pervasive (11.7%), or missed
more than 25% of school days in previous 2 months (13.2%). Of those excluded,
1.6% had not improved with clinical treatment during a previous fluoxetine
trial or were intolerant to fluoxetine; 1.1% had not improved with clinical
treatment during 2 previous SSRI trials; and 0.8% had not improved with clinical
treatment during of a CBT trial.
Of the 439 analyzable patients, 411 (94%) of the sample had at least
1 postbaseline CDRS-R data point. Forty-eight patients (10.9%) withdrew consent
prior to week 12. Another 42 patients (9.6%) were terminated prematurely by
the TADS team because they required an out-of-protocol treatment in place
of or in addition to study treatment. Thus, 359 patients (82%) remained and
351 (80%) were assessed in their assigned treatment group at week 12. Treatment
assignment did not influence the probability of dropping out (P = .18) or premature termination (P = .50).
Of the possible 15 sessions, the mean (median) number of completed CBT
sessions was 11 (12) in both the in the CBT alone group and the CBT with fluoxetine
group. The mean (SD) highest dose of fluoxetine was 28.4 (8.6) mg/d in the
fluoxetine with CBT group; 33.3 (10.8) mg/d for the fluoxetine alone group;
and 34.1 (9.5) mg/d for the placebo group.
Demographic and Clinical Characteristics
Participants resemble adolescents with MDD seen in general clinical
practice (Table 1). The mean (SD)
age was 14.6 (1.5) years; 45.6% of the sample was male; 73.8% was white; 12.5%
was black; and 8.9% was Hispanic (includes black and white Hispanics). Race
and ethnicity were self-classified. With a range of mild (CDRS-R total score
of 45) to severe depression (CDRS-R total score of 98), the mean (SD) CDRS-R
raw score at entry was 60 (10.4), which translates to a normed t score (standardized to a mean [SD] of 50 [10]) of 76 (6.43), indicating
moderate to moderately severe MDD. This level of depression is consistent
with a mean (SD) CGI severity score of 4.77 (0.83) and a CGAS score of 49.6
(7.5). Eighty-six percent of patients experienced only 1 episode of depression,
with a median (range) duration of 40.0 (3-572) weeks. More than half the sample
(52.1%) was comorbid for at least 1 other psychiatric disorder. Sixty (13.67%)
of 439 patients met DSM-IV criteria for ADHD and,
of these, 21 (4.8%) took an approved psychostimulant. The modal family income
was between $50 000 and $74 000, with a range of less than $5000
to more than $200 000. Forty-one percent lived in a single-parent home;
27% had been suspended or expelled from school. No statistically significant
differences between the 4 treatment groups on any baseline characteristic
were noted.
Table 2 presents the intent-to-treat
CDRS-R adjusted mean (SD) total scores by treatment group; CDRS-R adjusted
mean scores for site are depicted graphically in Figure 2A. Random regression analyses on longitudinal CDRS-R score
identified a statistically significant linear trend with time (F1,382= 1066; P = .001) and a time-by-treatment interaction
(F3,381= 9.08; P = .001). Planned contrasts
on the CDRS-R slope coefficients across 12 weeks of treatment produced a statistically
significant ordering of outcomes. Specifically, fluoxetine with CBT (P = .001) was statistically significant compared with placebo,
whereas treatment with fluoxetine alone (P = .10)
and CBT alone (P = .40) were not. Fluoxetine with
CBT was superior to fluoxetine alone (P = .02) and
to CBT alone (P = .001). Despite failure to separate
from placebo, fluoxetine alone also was superior to CBT alone (P = .01). Supportive contrasts performed on the week 12 adjusted means
yielded a slightly different result. Specifically, fluoxetine with CBT (P = .001) and fluoxetine alone (P =
.002) proved superior to placebo whereas CBT alone did not (P = .97). Fluoxetine with CBT was superior to CBT alone (P = .001), but not to fluoxetine alone (P =
.13), whereas fluoxetine alone proved superior to CBT alone (P = .001).
With a positive response defined as a CGI improvement score of 1 (very
much improved) or 2 (much improved), rates of response adjusted for clinical
site were 71.0% (95% CI 62%-80%) for fluoxetine with CBT; 60.6% (95% CI, 51%-70%)
for fluoxetine alone; 43.2% (95% CI, 34%-52%) for CBT alone; and 34.8% (95%
CI, 26%-44%) for placebo. When clinical site and treatment were entered in
the logistic regression model, the effect of the clinical site was nonsignificant
(Wald χ2 = .14; P = .71), whereas
treatment was statistically significant (Wald χ2 = 33.9; P = .001). Planned pairwise contrasts indicated that fluoxetine
with CBT (P = .001) and fluoxetine alone (P = .001) were superior to placebo whereas CBT alone was not (P = .20). Fluoxetine with CBT and fluoxetine alone did
not differ statistically (P = .11). Both fluoxetine
with CBT (P = .001) and fluoxetine alone (P = .01) proved superior to CBT alone.
The adjusted mean (SD) total scores on the RADS for the intent-to-treat
sample broken out by treatment group are presented in Table 2 and depicted graphically in Figure 2B. Random regression analyses on longitudinal RADS total
score identified a statistically significant linear trend with time (F1,380= 471.41; P = .001) and a time-by-treatment
interaction (F3,380= 10.32; P = .001).
Planned contrasts on the RADS slope coefficients produced a statistically
significant ordering of outcomes that was identical to that found on the CDRS-R.
Specifically, fluoxetine with CBT (P = .001) proved
statistically superior to placebo whereas fluoxetine alone (P = .34) and CBT alone (P = .21) did not.
Fluoxetine with CBT was superior to fluoxetine alone (P = .002) and to CBT alone (P = .001). Despite
failure to separate from placebo, fluoxetine alone also was superior to CBT
alone (P = .03). Supportive contrasts performed on
the week 12 adjusted means also followed the pattern established on the CDRS-R.
Specifically, fluoxetine with CBT (P = .001) and
fluoxetine alone (P = .003) proved superior to placebo
whereas CBT alone did not (P = .94). Fluoxetine with
CBT was superior to CBT alone (P = .001), but not
to fluoxetine alone (P = .11), whereas fluoxetine
alone again proved superior to CBT alone (P = .003).
The clinical significance (magnitude) of the impact of treatment on
outcome was evaluated by calculating effect sizes (Hedge g) and the number needed to treat relative to placebo. The effect size
on the CDRS-R was 0.98 for fluoxetine with CBT, 0.68 for fluoxetine alone,
and −0.03 for CBT alone. Effect sizes derived from the OR for the dichotomized
CGI improvement were 0.84 for fluoxetine with CBT, 0.58 for fluoxetine alone,
and 0.20 for CBT alone. The number needed to treat for the dichotomized CGI
improvement was 3 (95% CI, 2-4) for fluoxetine with CBT, 4 (95% CI, 3-8) for
fluoxetine alone, and 12 (95% CI, 5-23) for CBT alone. Taken together, these
scalar and categorical indicators of clinical magnitude indicate that combination
of fluoxetine with CBT is better than fluoxetine alone, which is better than
CBT alone, which is equal to placebo.
Despite the exclusion for high-risk suicidality, a substantial minority
of patients endorsed at least some suicidal ideation at baseline. For CDRS-R
suicide item No. 13, 27% of patients were defined as having at least minimal
suicidal ideation (score of ≥2), with 2% endorsing severe ideation (score
of ≥6). On the SIQ-Jr, 29% of patients attained a score of 31 or higher,
which indicates a level of suicidality requiring prompt clinical attention.
By the end of 12 weeks of treatment, the percentage of patients showing an
elevated CDRS-R item No. 13 or a SIQ-Jr score had decreased to 9.4% and 10.3%,
respectively.
The adjusted mean (SD) total scores on the SIQ-Jr for the intent-to-treat
sample are presented in Table 2 and
depicted graphically in Figure 2C.
Random regression analyses on longitudinal SIQ-Jr total score identified a
statistically significant linear trend with time (F3,419= 131.34; P = .001) and a time-by-treatment interaction (F3,409= 3.59; P = .01). Planned contrasts on the
SIQ-Jr slope coefficients across 12 weeks of treatment produced a statistically
significant ordering of outcomes different in direction from those identified
on the CDRS-R and RADS. Specifically, fluoxetine with CBT (P = .02) proved statistically superior to placebo whereas fluoxetine
(P = .36) alone and CBT alone (P = .76) did not. Fluoxetine with CBT was superior to fluoxetine alone
(P = .002) and to CBT alone (P = .05) while fluoxetine alone was not significantly different from
CBT alone (P = .22). Consistent with substantial
improvement across all 4 treatment groups, none of the post-hoc week 12 contrasts
was statistically significant. Effect sizes (Hedge g)
on the week 12 SIQ-Jr adjusted means were 0.28 for fluoxetine with CBT, 0.33
for CBT alone, and 0.05 for fluoxetine alone, implying a discrete albeit small
protective effect for CBT on suicidal ideation.
Harm-Related Adverse Events
Counts, rates, and ORs (95% CI relative to placebo) for harm- and suicide-related
adverse events are presented by treatment group in Table 3. Thirty-three (7.5%) of 439 patients experienced a harm-related
adverse event. Of these, 23 (69.7%) met the Food and Drug Administrations's
definition for a serious adverse event. Twenty-four (5.5%) of 439 patients
experienced a suicide-related adverse event. Rates of harm-related adverse
events by treatment group were fluoxetine alone (11.9%), fluoxetine with CBT
(8.4%), CBT alone (4.5%), and placebo (5.4%). For harm-related adverse events,
an omnibus χ2 test for differences across the 4 treatment groups
was not statistically significant (P = .15). Inspection
of the ORs indicated little or no increased risk (defined as OR ≤2) in
the CBT alone group and intermediate risk for the fluoxetine and CBT combined
group, suggesting a protective effect for CBT. However, the ORs (95% CIs)
indicated a statistically significant elevated risk for harm-related adverse
events only in SSRI-treated participants (fluoxetine alone and fluoxetine
with CBT pooled) in contrast to non-SSRI treated patients (CBT only and placebo
pooled) (OR, 2.19; 95% CI, 1.03-4.62). While the pattern is the same, none
of the ORs for suicide-related events were statistically significant. Seven
patients—too small a number (1.6% of the total sample) for statistical
comparison—attempted suicide: 4 were assigned to fluoxetine with CBT,
2 to fluoxetine alone, and 1 to CBT alone. There were no completed suicides.
Psychiatric Adverse Events
Table 4 presents absolute
rates for psychiatric-related adverse events, which reflect the broad construct
of emotional and behavioral disinhibition. As expected, these adverse events
were more common in patients receiving fluoxetine with CBT (16/107; 15%) and
fluoxetine alone (23/109; 21%) compared with CBT alone (1/111; 1%) or placebo
(11/112; 9.8%). Because overlapping adverse events can occur within the same
patient, Table 4 also presents
the total number of patients experiencing a psychiatric adverse event. Using
the latter figure, the OR for active treatment vs placebo was 1.45 (95% CI,
0.58-3.58; 11.2%) for fluoxetine combined with CBT; 2.57 (95% CI, 1.11, 5.94;
18.5%) for fluoxetine alone; and 0.1 (95% CI, 0.01-0.84; 0.9%) for CBT alone.
Thus, treatment with fluoxetine alone shows a statistically significant elevated
risk for psychiatric adverse events; fluoxetine combined with CBT shows an
intermediate risk between fluoxetine alone and CBT alone. Only 2 events met
reporting requirements for a serious adverse event: worsening depression (fluoxetine)
and mania (placebo). All patients with reported adverse events responded to
dose reduction, treatment modification, addition of an out-of-protocol treatment,
or treatment discontinuation.
Rates of nonpsychiatric adverse events that occurred in at least 2%
of patients and at least twice as often in one of the active treatment groups
as in the placebo group appear in Table
5. Again, with the caveat that the rate of functionally impairing
adverse events was low, they were more common in fluoxetine-treated patients.
Headache was the only adverse event that occurred in at least 10% of patients
in any single treatment group, but with little difference between fluoxetine
combined with CBT (5.6%), fluoxetine alone (12%), and placebo (9%); no patients
assigned to CBT alone reported headache or any other nonpsychiatric adverse
event. As expected, gastrointestinal tract problems, sedation, and insomnia
were the other most common complaints.
Focused on the initial treatment of MDD in adolescents, TADS was designed
to answer clinically important questions concerning the benefit(s) of fluoxetine
with CBT relative to medication management with fluoxetine alone or to CBT
alone and the benefit(s) of CBT alone and fluoxetine alone relative to placebo.
The effectiveness outcomes were clear and the clinical implications straightforward.
The combination of fluoxetine with CBT produced the greatest improvement in
symptoms of MDD. Fluoxetine alone was effective, but not as effective as fluoxetine
with CBT. Treatment of CBT alone was less effective than fluoxetine alone
and not significantly more effective than placebo. With respect to risk, suicidality
decreased substantially with treatment. Improvement in suicidality was greatest
for patients receiving fluoxetine with CBT and least for fluoxetine alone.
While fluoxetine did not appear to increase suicidal ideation, harm-related
adverse events may occur more frequently in fluoxetine-treated patients and
CBT may protect against these events. Taking risks and benefits into account,
the combination of fluoxetine with CBT appears superior as a short-term treatment
for MDD in adolescents.
Patients exhibited the full range of mild-to-severe MDD, with a mean
illness severity on the CDRS-R indicating moderate-to-moderately severe MDD.
Given the tendency of industry-funded registration trials to exclude comorbid
patients, it is especially noteworthy that more than 50% of the sample exhibited
1 or more comorbid disorders. Thus, while participants likely were more psychiatrically
disturbed than participants in previous studies of medication and CBT monotherapy,
TADS succeeded in recruiting a sample that includes the full range of treatment-seeking
patients with MDD.23 Accordingly, we conclude
that the results of the study should be broadly applicable to youth with MDD
seen in clinical practice.23
Treatment With Fluoxetine Alone
The response rates for fluoxetine monotherapy in TADS were consistent
with those seen previously in pediatric fluoxetine trials. In the first placebo-controlled
trial that demonstrated significantly positive effects of an antidepressant
over placebo, the response rate for the fluoxetine group was 56% based on
a CGI improvement score of 1 or 2.11 In a multisite
replication, fluoxetine had a 52% response rate based on a CGI improvement
score of 1 or 2.40 Thus, we conclude that the
TADS response rate of 60.6% effectively replicates previous research demonstrating
that fluoxetine monotherapy is an effective treatment for MDD in adolescents.
The 43% response rate for CBT alone in TADS is surprising given previous
research showing that approximately 60% of depressed adolescents responded
positively to CBT.7,10 This lower
absolute rate of response could be due to differences in the version of CBT
and/or sample composition. Albeit modified for dissemination across multiple
sites, the CBT used in TADS was based on models previously shown to be efficacious.8,9,41 Although unlikely,
it is possible that these modifications inadvertently weakened the intervention.
Regarding sample composition, patients receiving CBT alone appear to have
had more severe and chronic depression and higher rates of comorbidity than
participants in previous CBT trials and thus may have faired more poorly with
treatment. With respect to comparative effectiveness, it is important to note
that this is the first adolescent depression study in which any psychotherapy
has been compared with clinical management with either active medication or
pill placebo. While it was not hypothesized that CBT monotherapy would fail
to separate from pill placebo or prove inferior to fluoxetine monotherapy,
CBT did show the specific effect of decreasing suicidality in both the CBT
alone group and the CBT combined with fluoxetine group. Subsequent analyses
regarding expectancy, treatment fidelity, mediational processes, and compliance
with treatment should further explicate the pattern of findings. Finally,
in all but one of the adult trials,42 the comparative
strength of CBT has been greater in the follow-up phase than during acute
treatment. Examination of postacute treatment response and durability will
be critical to a more nuanced understanding of the short- and long-term impact
of CBT in this patient population.
Treatment With CBT Combined With Fluoxetine
The effectiveness of combined CBT and fluoxetine for treating clinically
depressed youth has not been examined previously in a randomized controlled
trial. As has generally been the case in studies of depressed adults,18,19 CBT incrementally enhanced clinical
management with fluoxetine leading to the highest response rate among all
treatments. However, because the CBT plus placebo condition was not included
in the design (it was deemed both too expensive and too artificial to have
clinical relevance) it is not possible to determine whether this combined
effect is additive (more is better) or synergistic (the 2 treatments enhance
each other). Conversely, the divergent response patterns for depression and
suicidality for participants who received fluoxetine with CBT suggests that
the combination may exert a complimentary effect (targeting different domains)
that enhances the overall outcome.
Placebo response rates in TADS (34%) were consistent with the placebo
rates in the 2 fluoxetine trials11,40 (33%
and 37%, respectively, based on CGI improvement score).11,13 In
the 2 earlier fluoxetine studies, the placebo response rates were lower than
placebo response rates seen in other pediatric antidepressant trials. Because
the response to active drug was comparable, it was the placebo response rate
that generally determined the effect sizes and, hence, whether a trial was
positive or negative.14
Why was there a low placebo response rate in TADS? From the point of
view of experimental design, TADS was designed to minimize the placebo response
rate. The inclusion criteria explicitly required stable depressed mood for
at least 6 weeks in at least 2 of 3 contexts (home, school, among peers),
making placebo-responsive mood fluctuations less likely. In addition, the
primary outcome measures were rated by an independent evaluator blind to treatment
assignment and to treatment course. Using an independent evaluator may have
introduced a bias for interpreting improvement as being related to assignment
to an active treatment.43 Additionally, in
contrast to other trials that included many small clincal sites with little
research experience, all 3 fluoxetine studies used fewer clinical sites and
the investigators were predominantly from clinical institutions with experience
conducting treatment outcome studies with depressed adolescents.
The appropriateness of using a placebo group in randomized controlled
trials with adolescent participants remains a subject of debate.44 In
this trial, symptomatic improvement, direct benefit from careful monitoring,
high patient retention rate, and low adverse event rate all indicate that
including a placebo group did not acutely place patients at unacceptable risk.
Inclusion of a placebo group proved critical to documenting the effectiveness
and safety outcomes reported herein. Thus, TADS supports the overall conclusion
of a recent American Academy of Child and Adolescent Psychiatry report that
including a placebo group in randomized controlled trials in pediatric psychopharmacology
can be ethical and essential to the scientific aims of the study.45
Approximately 500 000 adolescents in the United States attempt
suicide each year; almost 2000, one half of whom suffer from major depression,
die as a result.3-5 While
the rate of suicide attempts or completed suicide in (treated or untreated)
adolescents with MDD is unknown, given the overall improvement in depression
and suicidality in TADS it is likely that the rate of harm-related adverse
events seen throughout the trial is below what might be expected in an untreated
sample of depressed youth.
The separate question of whether SSRI medication is associated with
an increased risk of developing suicidal ideation or facilitating suicidal
behavior has been under intense scrutiny for years. Initial reports of adult
patients developing intense suicidal ideation concurrent with fluoxetine treatment46 led to investigations of clinical trial databases
to assess the possibility of a causal connection.47,48 In
general, investigations with adult patients have failed to provide support
for a specific causal association between antidepressant treatment and increased
risk of suicidal ideation or behavior. Recently, controversy arose over similar
issues among pediatric patients.15 In June
2003, regulatory agencies in the United States and the United Kingdom issued
safety warnings concerning the use of paroxetine in children and adolescents
due to at least 1 study identifying increased risk of developing significant
suicidality associated with paroxetine treatment. Further examination of this
concern in a wide variety of second-generation antidepressants led the regulatory
agency of the British Medicines and Healthcare to contraindicate all drugs
in this class (except fluoxetine) for use in pediatric patients with MDD due
to an unfavorable risk to benefit ratio.49 The
US Food and Drug Administration is continuing to study this issue and has
made no definitive statements about risk enhancement specifically in pediatric
patients. However, it has requested that stronger warnings be given to prescribing
physicians about the need for close monitoring of all patients with second-generation
antidepressants for worsening of depression or the development of acute suicidal
thinking or behavior.50
Data from our study suggest a more complicated risk analysis. It is
important to note at the outset that there were no deaths during the first
12 weeks of the study (and none to date of which we are aware for any of the
enrolled participants). The number of actual suicide attempts was too small
to analyze statistically, and their lethality was low to moderate. The impact
of treatment with fluoxetine on reduction of suicidal ideation was identical
to that of placebo, suggesting that fluoxetine on average does not increase
suicidal ideation. On the other hand, as expected in this population, suicidal
crises and nonsuicidal self-harming behaviors were not uncommon and, with
the caveat that the numbers were so small as to make statistical comparisons
suspect,51 seemed possibly to be associated
with fluoxetine treatment. When considered in light of the SIQ-Jr results,
which showed no exacerbation of suicidal ideation in fluoxetine-treated compared
with placebo-treated patients, this finding may indicate that self-harm is
not driven solely or even primarily by suicidal ideation. Recent research
in this area suggests that the movement from ideation to attempt is facilitated
by stressful psychosocial events, substance abuse, agitation, irritability,
or disinhibition.4,52 TADS findings
are consistent with work suggesting that CBT has a specific beneficial effect
on suicidal ideation53 and, importantly, that
CBT combined with fluoxetine may confer a protective effect not only against
suicidal ideation, but also on harm-related behaviors.
Given the clear superiority of fluoxetine combined with CBT in reducing
depression and suicidal ideation, the excess of suicide attempts in the fluoxetine
with CBT group is perplexing. Reflecting a trend (P =
.06) toward higher SIQ-Jr scores in the fluoxetine with CBT group, all but
1 of the 7 participants who attempted suicide met SIQ-Jr criteria for clinically
significant suicidal ideation at baseline, suggesting that this finding might
be related to an imbalance across treatment groups in risk for suicide at
baseline. Of note, the TADS fluoxetine and placebo data will be included in
the Food and Drug Administration reanalysis of suicide risk, which because
of greater power associated with a much larger sample size should allow for
stronger conclusions using a covariate-adjusted statistical model.
The imposition of a functional impairment threshold presumably exerted
a downward effect on the rates of adverse events. Nevertheless, with few patients
ceasing treatment due to adverse events, treatment in TADS appeared to be
reasonably well tolerated. As expected, gastrointestinal tract adverse events,
sedation, and insomnia were more often reported in fluoxetine-treated patients.
Mania/hypomania, irritability, agitation/restlessness, and anxiety, although
more common in fluoxetine-treated patients, were rare and patients generally
responded well to dose reduction or drug discontinuation. Mania was associated
with a harm-related adverse event in only 1 of the 33 harm-related adverse
events. Incident narratives indicate that irritability, agitation/restlessness,
and anxiety were not commonly reported in association with harm-related adverse
events, suggesting that other factors, such as substance use and psychosocial
stressors, may be more important in mediating the risk of harm-related adverse
events.
The limitations of this study are inherent to the research questions,
design, and methods that were selected. In the process of selecting the design,
we discarded several alternatives, including a balanced fully factorial design,
which was deemed better suited to a strict efficacy trial; a fifth placebo
plus CBT group, which was not elected because of concerns about ecological
validity and cost; psychosocial alternatives to a pill placebo group, such
as educational support, which if credible are active and if truly inactive
lack credibility; and a community-based treatment as a usual comparison group,
which was discarded because of concerns about cross-site variability in quality
of and access to treatment. In the end, there was unanimous agreement among
the study investigators and the TADS Scientific Advisory Board that the final
design represented the best compromise between scientific rigor and credibility,
ethical considerations, stakeholder concerns, feasibility of implementation,
and cost.
Three specific limitations merit comment. First, the patient's knowledge
of the treatment he/she received varied across the 4 groups and across the
2 treatment modalities. Psychotherapeutic interventions cannot be masked at
the participant level for experimental purposes, and the provision of CBT
was not masked in any treatment group. Regarding pharmacotherapy, provision
of fluoxetine was masked in 2 of the 4 groups. Blinding patients in the placebo
and fluoxetine alone groups but not in the CBT alone group (participants knew
they would not be receiving fluoxetine) and the fluoxetine combined with CBT
group (participants knew that they would be receiving fluoxetine) may have
interacted with expectancy effects regarding improvement and acceptability
of treatment assignment. Second, contact time with the treatment clinicians
and expectancy effects were not equated across treatment conditions, so the
"active ingredient" in improvement cannot be specified. Third, patients deemed
at high risk for suicidal behavior because of recent attempts or pervasive
suicidal thoughts were excluded from this outpatient study. Given potentiation
of suicidality among patients with substance abuse, exclusion for primary
substance abuse or substance dependence also likely reduced the risk for self-harm
among TADS patients. Methods for ascertaining suicidality, while more intensive
than typical for industry trials, were less than ideal for a trial in which
suicide is a primary end point. Specifically, suicide per se is too rare an
event to be a primary end point in a 3-month effectiveness trial targeting
MDD, and even suicide attempts are too rare to offer adequate statistical
power in the TADS framework.
TADS is based on a best practice model that connects disorder (MDD),
empirically supported treatment components (fluoxetine and CBT), and outcome
(reduced MDD and collateral symptoms), which should make the treatment procedures
widely applicable in a variety of mental health settings. In this context,
the remarkably strong and consistent findings reported herein lead us to make
the following recommendations for health care decision makers at all levels.
First, given the high prevalence, morbidity, and significant mortality associated
with MDD, the identification of depressed adolescents and provision of evidence-based
treatment should be mandatory in health care systems. Second, despite calls
to restrict access to medications, medical management of MDD with fluoxetine,
including careful monitoring for adverse events, should be made widely available,
not discouraged. Third, given incremental improvement in outcome when CBT
is combined with medication and, as importantly, increased protection from
suicidality, CBT also should be readily available as part of comprehensive
treatment for depressed adolescents.
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