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Searches of MEDLINE, PsycINFO, and pharmaceutical Web sites for published trials or trials conducted but unpublished between January 1996 and October 2007.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.

  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The knowledge of having only a 50% chance of receiving an active drug can result in reduced efficacy in blinded randomized clinical trials (RCTs) compared to clinical practice (reduced external validity). Moreover, minor onset sensations associated with the drug (but not with an inert placebo) can further challenge the attribution of group differences to drug-specific efficacy (internal validity). We used a randomized experimental study with inert placebos (inert substance) vs active placebos (inducing minor sensations), and different instructions about group allocation (probability of receiving drug: 0%, 50%, 100%). One hundred forty-four healthy volunteers were informed that a new application method for a well-known painkiller would be tested. Pain thresholds were assessed before and after receiving nasal spray. Half of the nasal sprays were inert placebos (sesame oil), while the other half were active placebos inducing prickling nasal sensations (sesame oil with 0.014% capsaicin). The major outcome was pain threshold after placebo application. A substantial expectation effect was found for the inert placebo condition, with participants who believed they had received an active drug reporting the highest pain thresholds. Active placebos show substantial differences to passive placebos in the 50% chance group. Therefore, patient expectations are significantly different in placebo-controlled clinical trials (50% chance) vs clinical practice (100% chance). Moreover, minor drug onset sensations can challenge internal validity. Effect sizes for these mechanisms are medium, and can substantially compete with specific drug effects. For clinical trials, new study designs are needed that better control for these effects.
    Pain 10/2012; 153(12). DOI:10.1016/j.pain.2012.09.007 · 5.84 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Variability in placebo response greatly complicates the design, conduct, and interpretation of clinical trials of antidepressant medications. To identify factors that impact detection of antidepressant-placebo differences, we conducted a meta-analysis of all relevant phase II-IV clinical trials for major depressive disorder conducted by the manufacturer of venlafaxine and desvenlafaxine completed by March 2011. We examined 15 factors potentially relevant to trial outcomes, using the standardized mean difference on the Hamilton Rating Scale for Depression (HAM-D(17)) score as the primary outcome. Thirty trials comprising 8933 patients were included. In univariate analyses, antidepressant efficacy (ie, drug vs placebo difference) was predicted most strongly (β=3.74, p=0.0002) by the proportion of patients in the trial enrolled from academic sites. Other factors predicting larger drug-placebo differences included lower participant completion rate, fewer post-baseline study visits, earlier year of study, and study drug (venlafaxine>desvenlafaxine). In multivariate meta-regression modeling, only the proportion of patients from academic sites maintained statistical significance as a predictor of drug-placebo separation for both HAM-D(17) continuous score change (β=2.24, p=0.034) and response rate (β=2.26, p=0.035). Including a higher proportion of academic sites may increase the ability to detect differences between active drug and placebo in clinical trials of major depressive disorder.Neuropsychopharmacology advance online publication, 22 August 2012; doi:10.1038/npp.2012.153.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2012; 37(13). DOI:10.1038/npp.2012.153 · 7.83 Impact Factor
  • Source
    • "Similarly, it has been suggested that large placebo effects are observed in trials because high randomisation ratios create raised expectations of benefit (e.g. 16:1 against the placebo in migraine, Diener et al., 2006; more than 1:1 against the placebo in depression, Papakostas & Fava, 2009; Sinyor et al., 2010). Therefore, increasing patients' expectations of benefit from a trial by encouraging positive conceptualisations of placebo would probably increase the size of the placebo effect. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Placebos are an essential tool in randomised clinical trials, where they are used to control for bias and contextual healing effects. Placebos and their effects are also studied from multiple diverse perspectives, but the perspectives of placebo recipients are seldom considered. Research shows that people form cognitive and affective representations of active treatments such as medicines, and that they use these representations to guide their behaviour; it seems reasonable to suggest that people might also think about and develop representations of placebos. We adopted a qualitative approach to examine in detail how participants in one RCT, conducted in the USA, conceptualised placebos. 12 people were interviewed 3 times each, at the start, middle, and end of a trial of placebo effects and acupuncture for Irritable Bowel Syndrome (IBS). The interview data were analysed inductively and we identified four ways in which the participants conceptualised placebos: placebos are necessary for research; placebo effects are fake; placebo acupuncture is not real acupuncture; placebos have real effects mediated by psychological mechanisms. Participants' conceptualisations of placebos were dynamic and situated in a broader psychological and socio-cultural context. Seeing placebo effects as legitimate seemed to be facilitated by having more holistic models of healing, viewing IBS as psychological, and seeing treatment as multifactorial. However, some participants maintained a negative view of placebo effects (e.g. as illusions) that was apparently inconsistent with their other beliefs (e.g. in mind-body healing mechanisms). This may indicate a dominance of negative discourses around placebos at a socio-cultural level. Negative views of placebos are inconsistent with evidence that placebo treatments can have positive effects on symptoms. RCT participants should be informed about potential benefits of placebo treatments to avoid misunderstandings and unease. Future work should improve methods of providing participants with full accurate information about placebos and their effects.
    Social Science [?] Medicine 03/2012; 74(5):767-74. DOI:10.1016/j.socscimed.2011.11.020 · 2.56 Impact Factor
Show more