Article

Does Inclusion of a Placebo Arm Influence Response to Active Antidepressant Treatment in Randomized Controlled Trials? Results From Pooled and Meta-Analyses

Department of Psychiatry, University of Toronto, Ontario, Canada.
The Journal of Clinical Psychiatry (Impact Factor: 5.14). 03/2010; 71(3):270-9. DOI: 10.4088/JCP.08r04516blu
Source: PubMed

ABSTRACT To determine if the inclusion of a placebo arm and/or the number of active comparators in antidepressant trials influences the response rates of the active medication and/or placebo.
Searches of MEDLINE, PsycINFO, and pharmaceutical Web sites for published trials or trials conducted but unpublished between January 1996 and October 2007.
2,275 citations were reviewed, 285 studies were retrieved, and 90 were included in the analysis. Trials reporting response and/or remission rates in adult subjects treated with an antidepressant monotherapy for unipolar major depression were included.
The primary investigator recorded the number of responders and/or remitters in the intent-to-treat population of each study arm or computed these numbers using the quoted rates.
Poisson regression analyses demonstrated that mean response rate for the active medication was higher in studies comparing 2 or more active medications without a placebo arm than in studies comparing 2 or more active medications with a placebo arm (65.4% vs 57.7%, P < .0001) or in studies comparing only 1 active medication with placebo (65.4% vs 51.7%, P = .0005). Mean response rate for placebo was significantly lower in studies comparing 1 rather than 2 or more active medications (34.3% vs 44.6%, P = .003). Mean remission rates followed a similar pattern. Meta-analysis confirmed results from the pooled analysis.
These data suggest that antidepressant response rates in randomized control trials may be influenced by the presence of a placebo arm and by the number of treatment arms and that placebo response rates may be influenced by the number of active treatment arms in a study.

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    • "Observations in clinical trials confirm that the possibility of receiving a placebo decreases the overall efficacy of the drug. Trials with active comparators reveal higher efficacy for a drug than trials with placebo arms [8] [16] [35] [37], and it can be hypothesized that this is due to different expectations generated by these study designs . Second, many drugs induce minor bodily sensations immediately after administration that could induce greater nonspecific effects. "
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    • "Greater severity and longer duration of illness have been associated with greater drug–placebo separation in some (Fournier et al, 2010; Kirsch et al, 2008; Khan et al, 1991; Kobak et al, 2009), but not all (Khan et al, 2007) studies. Among trial design factors, greater placebo effects have been associated with greater number of treatment arms (Sinyor et al, 2010), more frequent trial visits (Posternak and Zimmerman 2007), and flexible rather than fixed dosing (Khan et al, 2007). "
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    • "Indeed, inadequate concealment of allocation sequences and inadequate blinding have been shown to increase estimates of treatment effects [19], [20]. Regardless of the success of blinding, patients' beliefs about the likelihood of placebo allocation are associated with the magnitude of placebo response [21]–[24]. Furthermore, merely obtaining informed consent has been shown to alter the magnitude of placebo effects [25] and target treatment effects [26]. There is also preliminary evidence that informing participants that placebos elicit side-effects reduces patient-reports of side-effects [27], and the same adverse events are reported in placebo arms as in the corresponding treatment arm of trials in migraine [28] and depression [29]. "
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