Comparative Efficacy of Cognitive

Behavioral Therapy, Fluoxetine, and

Their Combination in Depressed
Adolescents: Initial Lessons from the
Treatment for Adolescents with
Depression Study
Sanjeev Pathak, MD*, Christopher J. Kratochvil, MD, Gregory M. Rogers, PhD,
Susan Silva, PhD, Benedetto Vitiello, MD, Elizabeth B. Weller, MD, and
John S. March, MD

Address
*University of Cincinnati College of Medicine, Children's Hospital
Medical Center, MLC # D-3014, 3333 Burnet Avenue, Cincinnati, OH
45229, USA.
E-mail: sanjeev.pathak@cchmc.org
Current Psychiatry Reports 2005, 7:429434
Current Science Inc. ISSN 1548-3584
Copyright 2005 by Current Science Inc.

Adolescents with major depressive disorder (MDD),

their families and clinicians experience significant challenges when weighing the potential risks versus benefits
of available choices in the treatment of MDD. Although
MDD is highly prevalent in adolescents and is associated
with marked suffering, impairment and risk of suicide,
the scientific data regarding the safety and efficacy of
treatments for pediatric depression are limited. Controlled clinical trials have provided support for the use
of psychotherapy and fluoxetine for the treatment of
pediatric depression, but until recently no information on
the comparative efficacy of these recommended interventions alone or in combination was available. The Treatment for Adolescents with Depression Study provides a
very important therapeutic advance in the field by convincingly showing that combination treatment with cognitive behavioral therapy and fluoxetine has the best benefit
to risk ratio for adolescents with moderate to severe
depression, and is superior to monotherapy. Moreover,
the study results confirm that fluoxetine alone is effective
in the treatment of depressed adolescents.

Introduction
The practice parameters for the assessment and treatment
of children and adolescents with depressive disorders,
developed under the aegis of the American Academy
of Child and Adolescent Psychiatry recommend using
psychotherapy as the first-line intervention [1]. These
parameters also recommend the use of selective serotonin
reuptake inhibitors (SSRIs) as first-line pharmacotherapy
in severe symptoms that prevent effective psychotherapy
and as second-line intervention if psychotherapy fails [1].
These parameters were published in 1998 and were based
largely on clinical practice standards because there was no
information available regarding the comparative efficacy
of SSRIs, psychotherapy, or their combination at that time.
The Treatment for Adolescents with Depression Study
(TADS) provides us with data from the only comparative
trial of empirically supported interventions, namely cognitive behavioral therapy (CBT), fluoxetine, and their
combination in the treatment of adolescents diagnosed
with major depressive disorder (MDD). This large, multisite clinical trial funded by the National Institute of Mental Health has provided clinically relevant data, which will
guide future treatment for adolescents with MDD in the
future. In this article, we discuss the results from TADS and
their implications against the backdrop of the recent
United States Food and Drug Administration (FDA) mandated black-box warning on antidepressants [2].
This discussion is important because MDD is a leading
cause of disability, morbidity and mortality in adolescents
and often leads to long-term psychosocial impairment in
adulthood [35]. Depression also is the most important
risk factor for suicide, which is the third leading cause of
death in adolescents [4,5]. A better understanding of the

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comparative effectiveness of available interventions may

provide much-needed guidance for clinicians treating this
serious disorder.

Rationale and Study Design for the Treatment

for Adolescents with Depression Study
The Treatment for Adolescents with Depression Study was
conceptualized and designed in the context of a literature
that contained empirical support, albeit limited, for CBT
and fluoxetine monotherapy in the treatment of pediatric
MDD [68]. However, the literature on these treatments
left many unanswered questions. All CBT trials until TADS
had enrolled patients with mild to moderate MDD [9,10].
Would the favorable results from these trials be generalizable to more severely depressed adolescents with comorbidities? Would the empirically supported psychotherapies
developed in academic settings be effective when disseminated to community settings? Additionally, the pharmacotherapy literature had a history of failed studies when
treating children and adolescents with depression, and
the limited literature on maintenance therapy showed a
high relapse rate with fluoxetine. Although two positive
placebo-controlled trials with fluoxetine had resulted in
FDA approval for fluoxetine in pediatric depression, there
also were concerns about development of suicidality with
antidepressants [2,7,11]. On September 14, 2004, a joint
advisory committee for the FDA voted in favor of a black
box warning indicating that antidepressants could increase
suicidality in children and adolescents. The black box
warning states that antidepressants increase the risk of
suicidal thinking and behavior (suicidality) in short-term
trials in children and adolescents with MDD and other psychiatric disorders. The data reviewed by the FDA contained
the pooled analyses of 24 short-term (4 to 16 weeks)
placebo-controlled trials of nine antidepressant drugs
(SSRIs and others) in approximately 4400 children and
adolescents with MDD, attention deficit hyperactivity disorder (ADHD) and anxiety disorders. This analysis, which
included the TADS placebo and fluoxetine conditions,
revealed a greater risk of suicidal thinking or behavior
(suicidality) when the data were combined for acute
studies of antidepressants. The average risk of such events
with antidepressants was 4%, twice the placebo risk of 2%.
No suicides occurred in these trials. Given the suggestion
of increased suicidality with antidepressants, the discussion of effectiveness and safety of available interventions in
pediatric MDD had gained urgency.
With the prior studies in mind, TADS was designed as a
multicenter, randomized, masked clinical trial to evaluate
the effectiveness of CBT, fluoxetine, and their combination
for MDD in adolescents [12]. TADS was divided into four
stages. Stage I compared four randomly assigned treatment
groups: fluoxetine, CBT, their combination, and pill
placebo. Participants were randomly assigned to one of the
four treatments for 12 weeks in a 1:1:1:1 ratio. Fluoxetine

and placebo (pills only) were administered in a doubleblind fashion, whereas CBT and combination were administered un-blinded because double-blinding for psychosocial interventions is impossible. Objectivity in the
primary dependent measures was maintained by using an
independent evaluator who was blinded to treatment
assignments. For patients in the pills only conditions,
the blind was broken at the end of stage I. Stage II lasted
6 weeks and provided full responders with maintenance
treatment, and partial responders with an additional 6
weeks of intensive weekly CBT or higher-dose fluoxetine
(or both in the case of combination) to answer the question of whether additional intensive treatment in partial
responders would be beneficial. For nonresponders, treatment was discontinued after stage I, and patients were
referred for clinical management outside of TADS. Stage III
lasted 18 weeks and evaluated the long-term maintenance
of treatment gains, and was followed by stage IV, which
provided 1 year of assessment only, with treatment provided as needed by clinicians in the community. Effectiveness results from stage I are the focus of this article.
A volunteer sample of 439 patients with a primary
Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition (DSM-IV) diagnosis of MDD were enrolled between
the spring of 2000 and the summer of 2003. Patients were
recruited at 13 academic or community clinics, with Duke
Clinical Research Institute as the coordinating center.
Inclusion criteria were age of 12 to 17 years (inclusive),
o u t p a t i e n t s t a t u s, D S M - I V d i a g n o s i s o f M D D a t
consent and again at baseline on Schedule for Affective
Disorders and Schizophrenia for School-Age ChildrenPresent and Lifetime Version [13], a Childrens Depression
Rating Scale-Revised (CDRS-R) total score greater than
45 at baseline, full scale intelligence quotient greater than
80, and antidepressant-free status immediately prior to
consent. Depressive mood had to have been present in
at least two of three contexts (home, school, peers) for at
least 6 weeks before consent. Because ADHD frequently is
comorbid, concurrent stable psychostimulant treatment
(eg, methylphenidate or mixed amphetamine salts) for
ADHD was permitted.
Exclusion criteria included diagnoses of severe
conduct disorder, current substance abuse or dependence,
pervasive developmental disorder(s), or thought disorder;
concurrent treatment with psychotropic medication or psychotherapy outside of the study; two previous failed SSRI
trials or a failed trial of CBT for depression; intolerance to
fluoxetine; confounding medical condition; non-English
speaking patient and/or parent; and pregnancy or refusal
to use an acceptable method of birth control. No patients
were asked or required to discontinue other forms of psychiatric treatment to enter the study. Because the teens had
the potential to be randomized to placebo, subjects were
excluded if they were considered to be at a high risk of
danger to self or others (if they had been hospitalized
for dangerousness within 3 months of consent or were

Treatment of Depressed Adolescents Pathak et al.

deemed by a cross-site panel to be high risk as indicated

by a suicide attempt requiring medical attention within 6
months, clear suicidal intent or an active plan, or suicidal
ideation with a disorganized family unable to guarantee
adequate safety monitoring).
The study used manuals specifically developed for
TADS to promote uniformity of care for the CBT and fluoxetine treatments. Pharmacotherapy visits (six to 12) lasted
20 to 30 minutes and were spread over 12 weeks of stage I.
TADS used a flexible dosing schedule, beginning at a starting dosage of 10 mg per day, which then was increased to
20 mg at 1 week. As clinically indicated, the pharmacotherapist increased the dosage, based on Clinical Global
Impressions-Improvement (CGI-I) score [14] and the presence of clinically significant adverse events, to a maximum
of 40 mg per day by week 8 in stage I.
The Treatment for Adolescents with Depression Study
CBT included 15 sessions over the first 12 weeks of treatment. The CBT, as delivered in TADS, required the subjects
to build skills to address depression-sustaining behaviors
and cognitions. It included optional sessions, providing
for flexible tailoring of the treatment to the adolescents
needs in a developmentally sensitive fashion. Moreover,
there was integration of parent and family sessions with
individual CBT. The initial treatment visits included
psychoeducation about depression and its causes, focused
on increasing pleasant activities and the development of
social problem-solving skills and cognitive restructuring.
Subsequently, during weeks 7 through 12, the therapist
and adolescent could choose sessions to address relevant
social skill deficits of the individual teenager, such as
problems in social engagement, communication, negotiation, compromise, or assertion. There were two parentonly sessions that provided psychoeducation. The therapist
addressed parent-adolescent relationship concerns in one
to three joint parent and teen sessions. Combination treatment consisted of all the components from the
medication-only and CBT-only arms. Although the treatments were provided independently, in the event of partial
response to combination therapy, the pharmacotherapist
made dosing decisions in consultation with the CBT
therapist based on compliance with CBT, the overall
change trajectory, clinical global severity score and tolerability of fluoxetine.
There were two primary outcome measures assessed
by the independent evaluator at baseline, week 6, and
week 12: 1) CDRS-R total score based on information
from the adolescent and the parent [15]; and 2) responder
status (defined as much improved or very much improved)
on the 12-week CGI-Improvement scale [14]. Two secondary outcome measures also were of significant interest
[16]. The first was the Reynolds Adolescent Depression
Scale (RADS), an adolescent self-report measure that was
included because self-report measures such as RADS are
commonly used in CBT research [6]. The second measure
was the Suicidal Ideation QuestionnaireJunior High

431

School Version (SIQ-Jr), which was included to help clarify

the risk-benefit ratio [16]. Raters at the coordinating
center maintained quality assurance by randomly reviewing audiotaped assessments for 20% of the sample. For the
K-SADS diagnostic criteria of DSM-IV MDD, CDRS-R total
scores, and CGI scores there was excellent interrater reliability among the independent evaluators and the coordinating centers quality assurance raters [16].
The Treatment for Adolescents with Depression
Study defined an adverse event as any unfavorable medical
change occurring after randomization that was accompanied by functional or clinical impairment. This definition,
requiring interference with functioning or the patient seeking medical attention, imposed a higher threshold for
adverse event reporting than seen in usual clinical trials. In
TADS, a harm-related adverse event was defined as an
event involving harm to self (such as worsening of suicidal
ideation, suicide attempt, self harm such as self mutilation)
or harm to others (aggressive or violent ideation or action
against another person or property). A suicide-related
adverse event was defined as an event involving worsening
of suicidal ideation, a suicide attempt, or both. Harmful
behaviors without suicidal ideation or intent (such as seen
in self-cutting without suicidal intent) were not included
under suicide-related adverse events.
All primary effectiveness and safety analyses were done
using an intention-to-treat approach [17]. Statistical
analyses on the primary scalar outcome measure (CDRS-R)
and secondary outcome measure RADS were done using a
linear random coefficients regression model [1820].
Comparison of responder rates on the dichotomized endof-treatment CGI-I score were done using a logistic
regression using the last observation carried forward
approach with site as a covariate. Harm- and suiciderelated adverse events in each treatment arm were compared using chi-squared test and Fishers exact test, and
odds ratios were calculated to provide a relative risk of
active treatment to placebo. The detailed statistical plan is
discussed elsewhere [12,16,21].

Demographic and Clinical Characteristics of

Enrolled Subjects
Two thousand eight hundred and four patients were
screened by phone. Of these, 1088 signed consent for
evaluation of inclusion and exclusion criteria, and 439
were randomized. The most frequent reasons for exclusion
in a descending order were: subject did not meet criteria
for MDD, MDD was not stable and pervasive, subject was
taking a prohibited psychotropic medication, or subject
had missed more than 25% of school days in the previous
2 months. Of the 439 randomized subjects, 411 (94%) had
at least one postbaseline assessment. Three hundred and
fifty-nine subjects (82%) remained, and 351 (80%) were
assessed in their assigned arm at week 12. There was no
difference in dropping out or premature termination in the

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four treatment arms. Premature terminators were defined

as subjects who still were active in the study, but the randomized treatment had been discontinued or modified by
the study clinician for ethical reasons, such as adding one
of the other treatments or an out-of-protocol treatment.
Dropouts were defined as subjects who were no longer
active in the study and were not being evaluated.
The TADS sample of 439 patients resembled adolescents with MDD seen in general clinical practice and
adolescents in the US population [21]. For instance, the
gender ratio in the TADS sample closely resembled that
found in two national samples of treated depressed adolescents (Medical Expenditure Panel Survey and the
National Ambulatory Medical Care Survey [21]). Moreover, the percentages of minorities (African American
and Hispanics) in the TADS sample were significantly
higher than in other treatment studies, and were slightly
lower but closer to the US population. The average
household income in the TADS sample also was approximately equal to that in US population data [21]. These
data suggest that the TADS results would likely be generalizable to patients seen in a clinic setting. The mean
(SD) age was 14.6 (1.5) years; 45.6% of the sample was
male; 73.8% were Caucasian, 12.5 % African-American,
and 8.9% Hispanic. CDRS-R scores at baseline in the
TADS sample indicated on average moderate to severe
MDD. In comparison, previous clinical trials, particularly those involving CBT, had enrolled patients in the
mild to moderate range. Most TADS patients (86%) had
only one episode of depression, with a mean (SD) duration of 71.6 (82.4) weeks. Most subjects (52.1%) were
comorbid for at least one other psychiatric disorder. The
most common comorbid diagnoses were generalized
anxiety disorder (15.3%), ADHD (13.7%), oppositional
defiant disorder (13.2%), social phobia (10.7%), and
dysthymia (10.5%). Of those patients diagnosed with
ADHD, 21 (4.8%) took an approved psychostimulant
during stage I. There were no statistically significant differences between the four treatment groups on the
above-mentioned baseline characteristics.

Acute Treatment Results

After 12 weeks of treatment, intent-to-treat contrasts on the
CDRS-R slope coefficients (indexing rate of improvement)
showed that combination treatment was statistically superior to placebo (P = 0.001), whereas monotherapy with fluoxetine (P = 0.1) or CBT (P = 0.40) were not. Combination
was also superior to fluoxetine (P = 0.02) and CBT (P =
0.001). Comparisons of the week 12 adjusted means
(indexing improvement at the end of acute treatment)
showed that both combination (P = 0.001) and fluoxetine
(P = 0.002) were superior to placebo, whereas CBT was not
(P = 0.97). Response rates calculated based on a dichotomous CGI-I rating of response (much improved or very

much improved) showed that 71% of subjects in the combination group, 61% in the fluoxetine alone group, 43% in
the CBT alone group, and 35% in the placebo group
had responded at 12 weeks. Pairwise contrasts on CGI-I
showed that combination (P = 0.001) and fluoxetine
(P = 0.001) were statistically superior to placebo, whereas
combination and fluoxetine did not differ from each
other (P = 0.11). Contrasts on the RADS slope and 12-week
comparison produced statistical results that were identical
to the results seen on the CDRS-R. Effect sizes (Hedges g)
for combination, fluoxetine, and CBT on the CDRS-R
were 0.98, 0.68 and -0.03, respectively. Effect sizes derived
from the odds ratio for combination, fluoxetine, and
CBT on the dichotomized CGI-I were 0.84, 0.58, and
0.20, respectively.
A substantial portion (29%) of TADS patients
endorsed at least some suicidal ideation at baseline, based
on the SIQ-Jr. By the end of 12 weeks of treatment,
the proportion of patients showing an elevated SIQ-Jr
score had fallen to 10.3% and had declined in all treatment groups. On the SIQ-Jr slope, combination was statistically superior to placebo (P = 0.02), fluoxetine
(P = 0.002), and CBT (P = 0.05). Given substantial
improvement in suicidal ideation, none of the week 12
contrasts proved statistically significant.
Thirty-three (7.5%) subjects experienced a harmrelated adverse event. As TADS excluded subjects with
high-risk of danger to self or others, this number may
represent an underestimation of the overall risk of dangerousness in adolescents with MDD. Twenty-three
(5.2%) met the FDA definition for a serious adverse
event. All but one involved harm to self. Twenty-four
(5.5%) patients experienced a suicide-related adverse
event. Harm-related adverse events occurred at the rate of
11.9% with fluoxetine, 8.4% with combination, 4.5%
with CBT, and 5.4% with placebo. Seven patients made a
suicide attempt and there were no completed suicides.
This number is too small and prohibits statistical analysis. Harm-related adverse events indicated an increased
risk (OR = 2.19; 95% CI, 1.034.62) for patients receiving
fluoxetine compared with those who were not. There
seemed to be a protective influence of CBT against harmrelated adverse effects because the odds ratio was higher
for fluoxetine alone (OR = 2.39; CI, 0.87, 6.54) compared
with fluoxetine plus CBT (OR = 1.62; CI, 0.56, 4.72).
Functionally impairing adverse events were few, but
were more common in fluoxetine-treated patients and
included headache, gastrointestinal problems, sedation,
and insomnia.
Perhaps because the mean highest daily dose of fluoxetine in the combination group (28.4 mg; SD = 8.6) was
less than that in the fluoxetine arm (33.3 mg; SD = 10.8)
and improvement in depression was greater, adverse events
overall were slightly less common in combined treatment
than fluoxetine alone.

Treatment of Depressed Adolescents Pathak et al.

Conclusions
The 12-week TADS effectiveness article is just the beginning of a series of articles that will describe the results
in further fine-grained detail [16]. Soon to follow are
articles on the moderators and mediators of depression
and other outcomes, such as function, remission rates,
safety, compliance with treatment, cost, and many additional secondary analyses. Additionally, data has been
collected on 9 months of treatment and an additional 12
months of follow-up. Although these works are pending,
the message from the acute treatment phase of TADS is
clear and emphatic.
First, the most important message from TADS is that
empirically tested and effective interventions for adolescents with MDD are available. Fluoxetine alone and fluoxetine combined with CBT were effective. Given the serious
nature of MDD with high morbidity, mortality, and poor
long-term outcome, increased availability of these interventions should be encouraged. Furthermore, dissemination of TADS results can help educate clinicians, increase
awareness, and improve acceptability of treatments for
MDD for adolescents and their families.
The second message from TADS is that combination
treatment with fluoxetine and CBT is the best treatment,
especially if suicidality is present at the start of treatment.
As stated above, combination treatment was superior to
placebo and CBT monotherapy on all five outcome measures used in stage I (CDRS-R slope contrasts, 12-week
CDRS scores, 12-week CGI-I scores, RADS slope contrasts,
12-week RADS scores). Combined treatment was superior
to fluoxetine on two measures (CDRS-R slope contrasts,
RADS slope contrasts). Additionally, fluoxetine in combination with CBT showed a larger effect size than either
monotherapy. Importantly, combination treatment had a
superior safety profile than fluoxetine alone, and was better
than either monotherapy on the SIQ-Jr slope contrasts.
The significant reduction in suicidal ideation in subjects on
the combination of fluoxetine and CBT is reassuring for
clinicians treating adolescents with MDD.
Third, fluoxetine alone is effective, but it is not as
effective as combination treatment. Fluoxetine alone was
superior to placebo on three measures (12-week CDRS-R
contrast, 12-week CGI-I scores, and 12-week RADS
outcome) and to CBT alone on all five measures (CDRS-R
slope contrasts, 12-week CDRS scores, CGI-I scores, RADS
slope contrasts, 12 week RADS scores). Moreover, analyses
of harm-related adverse events with fluoxetine seem
consistent with the FDA analysis of dangerousness with
antidepressants [2].
Fourth, the placebo arm was essential in showing the
effectiveness and safety of various treatment arms and
thereby added to the scientific value of this experiment.
The low rates of adverse events, dropouts, and premature
termination in the placebo arm is not only reassuring to
clinical investigators, but also bolsters the position that a

433

placebo arm in pediatric psychiatry trials can be ethical

and necessary [22].
Lastly, these results are broadly applicable to the population of adolescents with MDD seen in a clinical setting.
TADS enrolled subjects with a full range from mild to severe
MDD, with average illness severity in the moderate to moderately severe range. Moreover, as opposed to industryfunded trials, many comorbidities were permitted. Therefore, most patients had comorbid disorders, as is usually
seen in a clinical population.
Multiple analyses suggest that combination treatment
with fluoxetine and CBT is the superior intervention. Future
secondary analyses will bolster this position. Therefore,
TADS convincingly shows that good data trumps beliefs,
ideologies, propaganda, and polemics. It encourages and
sets the stage for future research in pediatric psychiatry.

References and Recommended Reading

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Of importance
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