Authors of TADS study reply to letter raising concerns
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《英国医生杂志》
EDITOR—We thank Jureidini et al for their interest in the treatment for adolescents with depression study (TADS) study1 but find their critique to lack accuracy, methodological sophistication, scientific rigour, and credibility.
TADS does not consist of "two separate randomised studies." Patients were consecutively randomised to one of the four TADS treatments using a computerised, stratified randomisation algorithm.2 3 Because comparative treatment trials that include both medication and psychotherapy conditions can double blind the conditions treated with medication only, but not those treated with psychotherapy, TADS employed an independent evaluator blind to treatment assignment, while placebo served as a credible, trial wide control.2 These are design choices, not design flaws.2 3
Jureidini et al confuse statistical significance with the magnitude of clinical effect. In TADS, combined treatment with fluoxetine and cognitive behaviour therapy proved superior to placebo and to cognitive behaviour therapy on five of five measures. Fluoxetine alone proved superior to placebo on three of five measures and to cognitive behaviour therapy on five of five measures. Effect sizes and numbers needed to treat, on the primary scalar and categorical dependent measures, indicated that the two fluoxetine conditions showed a moderate to large effect relative to placebo whereas cognitive behaviour therapy did not. The benefits of including fluoxetine (we make no claims about other antidepressants) are therefore readily apparent and clinically meaningful.
With respect to adverse events, Jureidini et al misrepresent the TADS findings. We worked closely with JAMA to document that patients' attrition did not differ by treatment assignment and primarily reflected lack of benefit rather than adverse events; present fully intention to treat analyses of adverse events, which were mild to moderate in severity; point out that adverse events were more common in participants treated with fluoxetine; and highlight data on harm showing a slightly increased risk in patients treated with fluoxetine, which may be minimised by concomitant cognitive behaviour therapy (see table).
Balance of benefits and risks, for fluoxetine and combined treatment compared with placebo4
People who would deny moderately to severely ill teenagers with major depressive disorder access to fluoxetine (preferably fluoxetine and cognitive behaviour therapy) should ask themselves: "What is the risk of overstating the case for harm due to fluoxetine?"
John S March, chief, Child and Adolescent Psychiatry Program for Child Affective and Anxiety Disorders
Duke University Child and Family Study Center, 718 Rutherford Street, Room 132, DUMC 3527, Durham, NC 27710, USA jsmarch@acpub.duke.edu
for the TADS Group
References
Jureidini J, Tonkin A, Mansfield PR. TADS study raises concerns. BMJ 2004;329: 1343-4. (4 December.)
TADS. Treatment for adolescents with depression study (TADS): rationale, design, and methods. J Am Acad Child Adolesc Psychiatry 2003;42(5): 531-42.
TADS. 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.
March J. Treatment for adolescents with depression study: stage I ITT outcomes.. Food and Drug Administration Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory Committee, 2004. www.fda.gov/ohrms/dockets/ac/04/slides/2004-4065S1_04_FDA-March.ppt (accessed 24 Feb 2005).
TADS does not consist of "two separate randomised studies." Patients were consecutively randomised to one of the four TADS treatments using a computerised, stratified randomisation algorithm.2 3 Because comparative treatment trials that include both medication and psychotherapy conditions can double blind the conditions treated with medication only, but not those treated with psychotherapy, TADS employed an independent evaluator blind to treatment assignment, while placebo served as a credible, trial wide control.2 These are design choices, not design flaws.2 3
Jureidini et al confuse statistical significance with the magnitude of clinical effect. In TADS, combined treatment with fluoxetine and cognitive behaviour therapy proved superior to placebo and to cognitive behaviour therapy on five of five measures. Fluoxetine alone proved superior to placebo on three of five measures and to cognitive behaviour therapy on five of five measures. Effect sizes and numbers needed to treat, on the primary scalar and categorical dependent measures, indicated that the two fluoxetine conditions showed a moderate to large effect relative to placebo whereas cognitive behaviour therapy did not. The benefits of including fluoxetine (we make no claims about other antidepressants) are therefore readily apparent and clinically meaningful.
With respect to adverse events, Jureidini et al misrepresent the TADS findings. We worked closely with JAMA to document that patients' attrition did not differ by treatment assignment and primarily reflected lack of benefit rather than adverse events; present fully intention to treat analyses of adverse events, which were mild to moderate in severity; point out that adverse events were more common in participants treated with fluoxetine; and highlight data on harm showing a slightly increased risk in patients treated with fluoxetine, which may be minimised by concomitant cognitive behaviour therapy (see table).
Balance of benefits and risks, for fluoxetine and combined treatment compared with placebo4
People who would deny moderately to severely ill teenagers with major depressive disorder access to fluoxetine (preferably fluoxetine and cognitive behaviour therapy) should ask themselves: "What is the risk of overstating the case for harm due to fluoxetine?"
John S March, chief, Child and Adolescent Psychiatry Program for Child Affective and Anxiety Disorders
Duke University Child and Family Study Center, 718 Rutherford Street, Room 132, DUMC 3527, Durham, NC 27710, USA jsmarch@acpub.duke.edu
for the TADS Group
References
Jureidini J, Tonkin A, Mansfield PR. TADS study raises concerns. BMJ 2004;329: 1343-4. (4 December.)
TADS. Treatment for adolescents with depression study (TADS): rationale, design, and methods. J Am Acad Child Adolesc Psychiatry 2003;42(5): 531-42.
TADS. 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.
March J. Treatment for adolescents with depression study: stage I ITT outcomes.. Food and Drug Administration Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory Committee, 2004. www.fda.gov/ohrms/dockets/ac/04/slides/2004-4065S1_04_FDA-March.ppt (accessed 24 Feb 2005).