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Fluoxetine plus cognitive behavioural therapy improves symptoms of major depressive disorder in adolescentsMarch J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: treatment for adolescents with depression study (TADS) randomized controlled trial. JAMA 2004;292:807–20.
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Q Does fluoxetine plus cognitive behavioural therapy improve symptoms of depression in adolescents with major p = 0.4). Fluoxetine plus CBT significantly improved response ratecompared with placebo or CBT alone (p = 0.001), but not compared Design: Randomised controlled trial.
with fluoxetine alone (p = 0.11). Fluoxetine plus CBT produced thegreatest reduction in suicidal thoughts (p = 0.02).
CONCLUSIONSFluoxetine in combination with CBT is more effective than fluoxetinealone or CBT alone for improving symptoms of depression in Blinding: Single blind (assessors blinded to treatment).
adolescents with major depressive disorder.
Fluoxetine alone and placebo alone were given double blind, whereasCBT plus fluoxetine and CBT alone were given unblinded.
Setting: Thirteen academic and community clinics, USA; spring2000 to summer 2003.
Patients: 439 adolescents with major depressive disorder (aged12–17 years). Exclusions: non-English speaking; IQ ,80; highrisk of suicide; taking antidepressants or psychotropic drugs; The Treatment for Adolescents with Depression Study (TADS) is notable for its rigorous design and timely clinical findings. Although diagnosis of bipolar, pervasive developmental or thought acutely suicidal adolescents were necessarily excluded from the disorder; substance abuse; pregnant or refused to take birth study, self harm, suicide attempts, and suicidal ideation were carefully control; or receiving psychotherapy.
monitored as they should be in clinical and research settings alike.
Furthermore, the controversial use of placebo in depressed adolescents, Intervention: Fluoxetine (10–40 mg/day) plus cognitive coupled with careful monitoring, did not contribute to problems with behavioural therapy (CBT); fluoxetine alone; CBT alone; or safety or attrition and in fact resulted in some symptomatic benefit.
placebo. Participants receiving CBT took part in 15 one hour Moreover, including a placebo group increased hypothesised group sessions with a therapist. Sessions included: psychoeducation differences, therefore reducing required sample size, and consequently, about depression, goal setting, mood monitoring cognitive the (potential) number of non-responders.1 restructuring, social problem solving, and increasing pleasurable Consider the timely nature of these results. In 2003 the UK’s Drug activities (week 1–6); tailored sessions to improve social skills(week 7–12). Parents also received two psychoeducation sessions Licensing Authority Committee on Safety of Medicines warned, ‘‘There is no, or insufficient, evidence from clinical trials that benefits outweigh therisks of side effects for sertraline (Lustral), citalopram (Cipramil), Outcomes: Improvement in symptoms of depression (Children’s escitalopram (Cipralex) and fluvoxamine (Faverin). Fluoxetine, or Depression Rating Scale-Revised, Clinical Global Impressions Prozac, appears to have a positive balance of risks and benefits…’’2 improvement score), and reduction in suicidal thoughts (Suicidal The US Food and Drug Administration (FDA) subsequently conducted an Ideation Questionnaire-Junior High School Version).
extensive review of all recent paediatric antidepressant RCTs involving over 4000 children.3 4 There were no fatalities in these trials. Moststriking, however, only three of 15 RCTs for MDD showed efficacy onthe primary outcome.3 In fact, fluoxetine, which has a paediatricindication for depression, was the only antidepressant with more thanone positive paediatric RCT supporting its use.5 6 Although suicidality (ideation or attempts) was uncommon in these trials, the risk:benefit ratio At 12 weeks, fluoxetine plus CBT significantly improved symptoms of was disturbing. The FDA concluded that, although suicidality was rare, depression compared with placebo in adolescents with major the risk was significantly higher in children receiving antidepressants depressive disorder (p = 0.001; see http://www.ebmentalhealth.com/ relative to placebo.4 As a result, a black box warning regarding clinical supplemental for table). Fluoxetine plus CBT was more effective at worsening and suicide risk is now required on all antidepressants sold in reducing symptoms of depression than fluoxetine alone or CBT alone the US,7 and the FDA has issued proposed guidance about using (fluoxetine plus CBT v fluoxetine, p = 0.02; fluoxetine plus CBT v antidepressants in children and teenagers.
CBT, p = 0.001). There was no significant difference in reduction of This study is further evidence of the efficacy of fluoxetine for depressive symptoms between fluoxetine alone or CBT alone adolescents with depression, particularly when used in combination with compared with placebo (fluoxetine v placebo, p = 0.1; CBT v placebo, CBT. It provides an important empirical basis for clinical decision makingand is exemplary for the design of paediatric psychopharmacology RCTs.
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Professor of Biostatistics in Psychiatry and Professor of Public Health, For correspondence: John S March MD MPH, Department of Psychiatry, Weill Medical College of Cornell University, NY, USA Duke University Medical Center, 718 Rutherford Street, Box 3527, Durham, Please visit http://www.ebmentalhealth.com/supplemental for reference Sources of funding: National Institute of Mental Health, USA.
Fluoxetine plus cognitive behavioural therapy
improves symptoms of major depressive
disorder in adolescents
Evid Based Mental Health 2005 8: 10doi: 10.1136/ebmh.8.1.10 Updated information and services can be found at: Data Supplement
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