Sequential Treatment of Pediatric MDD to Increase Remission and Prevent Relapse

Major depressive disorder (MDD) is a serious psychiatric disorder that affects approximately
1 out of every 12 to 15 children and adolescents. Depression can cause problems with school,
family, and friends, and if left untreated, these difficulties can persist into adulthood.
Treatments using antidepressants and forms of psychotherapy have been shown to be effective
in reducing symptoms of depression. However, many youth experience a return of depressive
symptoms within 1 to 2 years of remission. Recent studies have shown that adding cognitive
behavioral therapy (CBT), a form of psychotherapy that focuses on behavioral modification,
to initial antidepressant treatment may increase remission and reduce relapse rates. This
study will compare the effectiveness of fluoxetine alone versus fluoxetine plus added CBT in
increasing recovery and preventing relapse in youth with MDD.

Participation in this study will last 78 weeks. Potential participants will undergo initial
screening, which will include interviews and questionnaires about mood, behavior, and
medical history; vital sign measurements; a meeting with a psychiatrist; and lab draws
and/or urine drug or pregnancy tests if indicated by the psychiatrist. All eligible
participants will then begin 6 weeks of treatment with fluoxetine. During this 6-week
period, participants will attend weekly study visits, which will include vital sign
measurements, questionnaires on symptoms and mood, and medication dosage adjustments. At
Week 6, participants will be evaluated by an independent evaluator who will determine
whether their depression has significantly improved. Participants who have not improved with
fluoxetine will end their study participation and will be provided with recommendations for
other treatment options.

All participants who have shown significant improvement will continue to receive fluoxetine
for another 24 weeks, for a total of 30 weeks of treatment. Half of these participants will
be randomly assigned to additionally receive CBT for the remaining 24 weeks. All
participants will attend study visits that will occur every other week for 3 months and then
monthly for 3 months. These visits will last 20 to 30 minutes and will include vital sign
measurements and questions about mood and behavior. Participants receiving CBT will also
attend 10 to 12 CBT sessions, which will last 50 minutes each and will occur weekly for the
first 4 weeks, every other week for 1.5 months, and monthly for the last 3 months. The CBT
sessions will involve both individual child and parent-child sessions, which will focus on
modifying depressive thoughts, feelings, and behaviors. Participants will undergo repeat
evaluations with the independent evaluator at Weeks 12, 18, 24, 30, 52, and 78.

Inclusion Criteria:

- Primary diagnosis of nonpsychotic MDD (single or recurrent) for at least 4 weeks
before study entry

- In good general medical health

- Normal intelligence

Exclusion Criteria:

- Lifetime history of any psychotic disorder, including psychotic depression

- Lifetime history of bipolar I and II disorders

- Alcohol or substance dependence within the 6 months before study entry

- Anorexia nervosa or bulimia within the 6 months before study entry

- Pregnant or breastfeeding females, or sexually active females not using medically
acceptable means of birth control (e.g., IUD, birth control pills, barrier devices)

- Chronic medical illness (medically unstable and requires regular medication that may
interfere with treatment interventions)

- Concurrent medication(s) with psychotropic effects (e.g., anticonvulsants, steroids,
etc.) other than stable ADHD medication

- First degree relatives with bipolar I disorder

- Severe suicidal ideation or previous history of serious suicide attempt within this
episode

- Prior failure to respond to an adequate treatment with fluoxetine (defined as at
least 40 mg/day for 4 weeks)

- Non-English speaking