Research design features and patient characteristics associated with outcome of antidepressant clinical trials

Duke University, Durham, North Carolina, United States
American Journal of Psychiatry (Impact Factor: 12.3). 11/2004; 161(11):2045-9. DOI: 10.1176/appi.ajp.161.11.2045
Source: PubMed


The authors examined which, if any, research design features and patient characteristics would significantly differ between successful and unsuccessful antidepressant trials.
Clinical trial data were reviewed for nine antidepressants approved by the Food and Drug Administration between 1985 and 2000. From the antidepressant research programs on these medications, 52 clinical trials were included in the study. The authors evaluated trial design features, patient characteristics, and difference in response between placebo and antidepressant.
Nine trial design features and patient characteristics were present in the research programs for all nine of the antidepressants. The severity of depressive symptoms before patient randomization, the dosing schedule (flexible versus fixed), the number of treatment arms, and the percentage of female patients were significantly associated with the difference in response to antidepressant and placebo. The duration of the antidepressant trial, number of patients per treatment arm, number of sites, and mean age of the patients were similar in successful trials (with a greater antidepressant-placebo difference) and less successful trials (with a smaller antidepressant-placebo difference).
These findings may help in the design of future antidepressant trials.

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    • "The double-blind trials in these analyses ranged from 8 to 12 weeks; it is possible that longer trials are associated with a larger drug-placebo difference because the drug has more time to exert its effects in longer trials. Although previous studies [7], [38] have not found a significant relationship between duration of treatment and antidepressant efficacy in the treatment of depression, no previous analyses have examined this moderator variable for antidepressant efficacy in the treatment of anxiety. 4) Publication status. "
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    ABSTRACT: Background Previous meta-analyses of published and unpublished trials indicate that antidepressants provide modest benefits compared to placebo in the treatment of depression; some have argued that these benefits are not clinically significant. However, these meta-analyses were based only on trials submitted for the initial FDA approval of the medication and were limited to those aimed at treating depression. Here, for the first time, we assess the efficacy of a selective serotonin reuptake inhibitor (SSRI) in the treatment of both anxiety and depression, using a complete data set of all published and unpublished trials sponsored by the manufacturer. Methods and Findings GlaxoSmithKline has been required to post the results for all sponsored clinical trials online, providing an opportunity to assess the efficacy of an SSRI (paroxetine) with a complete data set of all trials conducted. We examined the data from all placebo-controlled, double-blind trials of paroxetine that included change scores on the Hamilton Rating Scale for Anxiety (HRSA) and/or the Hamilton Rating Scale for Depression (HRSD). For the treatment of anxiety (k = 12), the efficacy difference between paroxetine and placebo was modest (d = 0.27), and independent of baseline severity of anxiety. Overall change in placebo-treated individuals replicated 79% of the magnitude of paroxetine response. Efficacy was superior for the treatment of panic disorder (d = 0.36) than for generalized anxiety disorder (d = 0.20). Published trials showed significantly larger drug-placebo differences than unpublished trials (d’s = 0.32 and 0.17, respectively). In depression trials (k = 27), the benefit of paroxetine over placebo was consistent with previous meta-analyses of antidepressant efficacy (d = 0.32). Conclusions The available empirical evidence indicates that paroxetine provides only a modest advantage over placebo in treatment of anxiety and depression. Treatment implications are discussed.
    PLoS ONE 08/2014; 9(8). DOI:10.1371/journal.pone.0106337 · 3.23 Impact Factor
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    • "Placebo dropout and antidepressant efficacy 5 guided by findings in previous reports (Walsh et al., 2002; Khan et al., 2004, 2010; Undurraga and Baldessarini, 2012). Outcome was based on standardized mean difference (SMD) in improvements of depression ratings in antidepressant vs. placebo arms in peer-reviewed, randomized , placebo-controlled antidepressant trials reported over the past three decades. "
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    ABSTRACT: Drug-placebo differences (effect-sizes) in controlled trials of antidepressants for major depressive episodes have declined for several decades, in association with selectively increasing clinical improvement associated with placebo-treatment. As these trends require adequate explanation, we tested the hypothesis that decreasing trial-dropout rates may be an important contributor. We gathered reports of peer-reviewed, placebo-controlled trials of antidepressants (1980-2011) by computerized literature searching, and applied meta-analysis, meta-regression and multiple linear regression methods to evaluate associations of dropout rates and other factors of interest, to reporting year and reported efficacy [standardized mean drug-placebo difference (SMD) as Hedges' g-statistic]. In 56 trials meeting inclusion and exclusion criteria, we confirmed significant overall efficacy of antidepressants but declining drug-placebo contrasts over the past three decades. Among other changes, there was a corresponding increase in placebo-associated improvement with a decline in placebo-dropout rate, mainly for lack of efficacy. These effects were found only when last-observation-carried-forward (LOCF) analyses were used. Other trial-design and subject factors, including drug-responses and drug-dropout rates, were much less associated with efficacy. We propose that declining placebo-dropout rates ascribed to inefficacy combined with use of LOCF analyses led to increasing improvement in placebo-arms that contributed to declining antidepressant-placebo contrasts in controlled treatment trials since the 1980s.
    The International Journal of Neuropsychopharmacology 03/2014; 17(08):1-10. DOI:10.1017/S1461145714000224 · 4.01 Impact Factor
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    • "However, the CHMP is of the opinion that this argument is based on the doubtful assumption that the placebo effect and the pharmacological effect are additive. Furthermore, some of the placebo effects are probably due to study-specific procedures such as increased attention or the therapeutic impact of weekly rating sessions, and study design (such as inclusion and exclusion criteria, outpatients, assessment scales, study duration etc.) that are not present or issues in normal clinical practice (Walsh et al., 2002; Khan et al., 2004, 2007). Hence, the 16% difference observed in placebo-controlled studies is considered to be the lower limit of the pharmacological effect that would be expected in clinical practice (Melander et al., 2008). "
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    ABSTRACT: Recent publications have raised questions over the efficacy and clinically relevant effects of antidepressants that have been approved for the treatment of major depression. In this context, the European Commission requested that the European Medicines Agency (EMEA) and its scientific committee (CHMP) issue an opinion on these data under Article 5(3) of Regulation (EC) No 726/2004. Results from a recent meta-analysis [Kirsch, I., Deacon, B.J. et al., (2008) Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 5(2), e45.] have questioned the clinical relevance of the use of some antidepressants in treating major depression. This analysis focused only on statistically significant mean differences versus placebo in changes in a rating scale (such as the Hamilton Depression Rating Scale). This, however, would not be an adequate basis for the evaluation of clinical relevance and, from a regulatory perspective, would not be sufficient to grant an antidepressant the approval needed to allow it onto the market. Improvements that are both statistically significant (based on improvements in validated rating scales between baseline and study end) and clinically relevant (based on responder rates) need to be shown in short-term studies. In addition, these short-term results need to be confirmed in a randomised withdrawal study to demonstrate the maintenance of an antidepressant's effects. The CHMP concluded that the approval of antidepressants for the treatment of patients with major depression is based on data that provide robust and sufficient evidence of clinically meaningful benefits for patients with major depression. Therefore, the CHMP is of the opinion that, as no public health concerns have been identified, no regulatory action is necessary on the basis of Kirsch et al.'s findings.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 06/2009; 19(5):305-8. DOI:10.1016/j.euroneuro.2009.01.012 · 4.37 Impact Factor
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