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Deconstructing Pediatric Depression Trials: An Analysis of the Effects of Expectancy and Therapeutic Contact

https://doi.org/10.1016/j.jaac.2011.04.004Get rights and content

Objective

This study investigated how study type, mean patient age, and amount of contact with research staff affected response rates to medication and placebo in acute antidepressant trials for pediatric depression.

Method

Data were extracted from nine open, four active comparator, and 18 placebo-controlled studies of antidepressants for children and adolescents with depressive disorders. A multilevel meta-analysis examined how study characteristics affected response rates to antidepressants and placebo.

Results

The primary finding was a main effect of study type across patient age and contact amount, such that the odds of medication response were greater in open versus placebo-controlled studies (odds ratio 1.87, 95% confidence interval 1.17–2.99, p = .012) and comparator studies (odds ratio 2.01, 95% confidence interval 1.16–3.48, p = .015) but were not significantly different between comparator and placebo-controlled studies. No significant main effects of patient age or amount of contact with research staff were found for analyses of response rates to medication and placebo. Response to placebo in placebo-controlled trials did significantly increase with the amount of therapeutic contact in older patients (age by contact; odds ratio 1.08, 95% confidence interval 1.01–1.15, p = .038).

Conclusions

Although patient expectancy strongly influences response rates to medication and placebo in depressed adults, it appears to be less important in the treatment of children and adolescents with depression. Attempts to limit placebo response and improve the efficiency of antidepressant trials for pediatric depression should focus on other causes of placebo response apart from expectancy.

Section snippets

Search Strategy and Selection Criteria

A Medline search was conducted to identify clinical studies of antidepressants in children and adolescents with depressive disorders. The search strategy comprising depression or depressive disorder or major depressive disorder or dysthymia and antidepressant or the class and individual generic name of all antidepressants approved by the Food and Drug Administration returned 55,353 results (Figure 1). These results were limited to English-language articles, age group 18 years or younger, and

Characteristics of Included Studies and Participants

Nine open studies, 18 placebo-controlled trials, and four comparator trials met the study's inclusion and exclusion criteria (Table 1).25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 As presented in Table 2, these included nine medication monotherapy conditions enrolling 228 participants in the open studies, five medication monotherapy conditions enrolling 325 participants in the comparator studies, and 19 medication

Discussion

This meta-analysis examined 31 studies of antidepressant medication for depressive disorders in children and adolescents across open, placebo-controlled, and active comparator study designs. Consistent with the study hypotheses, open studies of antidepressant medications were associated with a significantly higher medication response rate compared with placebo-controlled and comparator RCTs. Contrary to the hypotheses, response rates to antidepressant medication did not differ significantly

References (65)

  • G.J. Emslie et al.

    Paroxetine treatment in children and adolescents with major depressive disorder: a randomized, multicenter, double-blind, placebo-controlled trial

    J Am Acad Child Adolesc Psychiatry

    (2006)
  • G.J. Emslie et al.

    Escitalopram in the treatment of adolescent depression: a randomized placebo-controlled multisite trial

    J Am Acad Child Adolesc Psychiatry

    (2009)
  • B. Geller et al.

    Pharmacokinetically designed double-blind placebo-controlled study of nortriptyline in 6- to 12-year-olds with major depressive disorder

    J Am Acad Child Adolesc Psychiatry

    (1992)
  • M.B. Keller et al.

    Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial

    J Am Acad Child Psychiatry

    (2001)
  • S. Kutcher et al.

    Response to desipramine treatment in adolescent depression: a fixed-dose, placebo-controlled trial

    J Am Acad Child Adolesc Psychiatry

    (1994)
  • C.H. Kye et al.

    A randomized, controlled trial of amitriptyline in the acute treatment of adolescent major depression

    J Am Acad Child Adolesc Psychiatry

    (1996)
  • K.D. Wagner et al.

    A double-blind, randomized, placebo-controlled trial of escitalopram in the treatment of pediatric depression

    J Am Acad Child Adolesc Psychiatry

    (2006)
  • R. DiGiuseppe et al.

    Developing the therapeutic alliance in child-adolescent psychotherapy

    Appl Prev Psychol

    (1996)
  • R. Tao et al.

    Early prediction of acute antidepressant treatment response and remission in pediatric major depressive disorder

    J Am Acad Child Adolesc Psychiatry

    (2009)
  • R.A. Kowatch et al.

    Prediction of response to fluoxetine and placebo in children and adolescents with major depression: a hypothesis generating study

    J Affect Disord

    (1999)
  • J. Curry et al.

    Predictors and moderators of acute outcome in the Treatment for Adolescents with Depression Study (TADS)

    J Am Acad Child Adolesc Psychiatry

    (2006)
  • A. Angold et al.

    Comorbidity

    J Child Psychol Psychiatry

    (1999)
  • G.J. Emslie

    Understanding placebo response in pediatric depression trials

    Am J Psychiatry

    (2009)
  • D. Cohen et al.

    Are child and adolescent responses to placebo higher in major depression than in anxiety disorders?A systematic review of placebo-controlled trials

    PLOS One

    (2008)
  • J.A. Bridge et al.

    Placebo response in randomized controlled trials of antidepressants for pediatric major depressive disorder

    Am J Psychiatry

    (2009)
  • B.R. Rutherford et al.

    Expectancy effects in the treatment of depression: a review of experimental methodology, effects on patient outcome, and neural mechanisms

    Curr Rev Psychiatry

    (2010)
  • B.R. Rutherford et al.

    Does study design affect outcome?The effects of placebo control and treatment duration in antidepressant trials

    Psychother Psychosom

    (2009)
  • B.R. Rutherford et al.

    Antidepressant study design affects patient expectancy: a pilot study

    Psychol Med

    (2010)
  • B. Meyer et al.

    Treatment expectancies, patient alliance, and outcome: further analyses from the National Institute of Mental Health Treatment of Depression Collaborative Research Program

    J Consult Clin Psychol

    (2002)
  • H.V. Krell et al.

    Subject expectations of treatment effectiveness and outcome of treatment with an experimental antidepressant

    J Clin Psychiatry

    (2004)
  • M. Fava et al.

    The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach

    Psychother Psychosom

    (2003)
  • E.O. Poznanski et al.

    A depression rating scale for children

    Pediatrics

    (1979)
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    This work was supported by National Institute of Mental Health grants K23 MH085236 (B.R.R.), K23 MH075006 (J.R.S.), R21 MH087774 (J.R.S.), MH36197 (B.S.P.), and K02-74677 (B.S.P.), a Hope for Depression Research Foundation grant (B.R.R.), and a National Alliance for Research on Schizophrenia and Depression Young Investigator Award (B.R.R.).

    Disclosure: Dr. Roose has served on a Data and Safety Monitoring Board for Medtronics, Inc. Drs. Rutherford, Sneed, Rindskopf, and Peterson and Ms. Tandler report no biomedical financial interests or potential conflicts of interest.

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