Does Inclusion of a Placebo Arm Influence Response to Active Antidepressant Treatment in Randomized Controlled Trials? Results From Pooled and Meta-Analyses
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Searches of MEDLINE, PsycINFO, and pharmaceutical Web sites for published trials or trials conducted but unpublished between January 1996 and October 2007.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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ABSTRACT: Although newer interview methods such as Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale (SIGMA; MADRS) with audiotaping and Rater Applied Performance Scale (RAPS) appraisal have been introduced to improve reliability of ratings in antidepressant clinical trials, there is limited evidence that these methods actually improve trial outcome. The objective of this study uis to evaluate outcome in four similarly designed trials of two recently approved antidepressants: two trials randomly used taped SIGMA interviews with RAPS appraisal and two trials used traditional semi-structured MADRS interviews. We reviewed data from patients who were screened (N = 243) and randomized (N = 148), evaluating the magnitude of change with placebo and antidepressants on mean total MADRS score. Depressed patients assigned to placebo in trials using taped SIGMA interviews with RAPS appraisal had a significantly larger MADRS change score (M = -11.5 ± 12.7) compared to patients assigned to placebo in trials using traditional semi-structured interviews (-5.4 ± 8.9; F(df = 1.57) = 5.58, p = 0.022). The error variance was also significantly larger in the placebo arm of trials using SIGMA interviews (F = 5.43, p = 0.023). Depressed patients assigned to antidepressants had similar outcome in all of the four trials. The recently suggested modifications in obtaining clinical data in antidepressant trials such as taped SIGMA interviews with RAPS rating appraisals may in fact result in a higher magnitude of placebo response and a lower magnitude of antidepressant-placebo differences compared to the traditional methods of collecting clinical data. These results were unexpected and indicate the necessity to test new methods prospectively, no matter how intuitively sensible they seem, prior to their implementation.Psychopharmacology 04/2014; 231(22). DOI:10.1007/s00213-014-3584-4 · 3.99 Impact Factor
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ABSTRACT: To study the impact of negative expectation related to receiving a placebo (the "lessebo effect") on efficacy outcome measures of symptomatic treatments in Parkinson disease (PD). We conducted meta-analyses of double-blind randomized controlled trials (RCTs) of dopamine agonists in PD and compared the pooled mean score change of the motor section of the Unified Parkinson's Disease Rating Scale (mUPDRS) across active treatment arms according to the presence of a placebo arm or the probability of placebo assignment (0%, <50%, and 50%) of the original RCT. A mixed-effects model was used. Heterogeneity was assessed by subgroup analyses and meta-regression modeling. A total of 28 study arms were extracted from active-controlled trials (3,277 patients) and 42 from placebo-controlled trials (4,554 patients). The overall difference between groups in the pooled mean score change in the mUPDRS was 1.6 units (95% confidence interval [CI] 0.2, 3.0; p = 0.023), in favor of the active-controlled group. In subgroup analyses, this difference was of higher magnitude in the early PD group without motor fluctuations (3.3 mUPDRS units, 95% CI 1.1, 5.4; p = 0.003) and for study duration ≤12 weeks (4.1 mUPDRS units, 95% CI 1.0, 7.2; p = 0.009). There was no between-group difference using probability of placebo assignment as criterion. This study shows that the use of a placebo can be associated with a clinically significant reduction in the magnitude of change of the mUPDRS after an active treatment in RCTs for PD. These new findings have potential implications in the development of new treatments and appraisal of current treatment options for PD and possibly for other neurologic disorders.Neurology 03/2014; 82(16). DOI:10.1212/WNL.0000000000000340 · 8.30 Impact Factor
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ABSTRACT: Objective: Major depressive disorder is often chronic, with relapse and recurrence common. Levomilnacipran extended-release is a potent and selective serotonin and reuptake inhibitor approved in the United States for treatment of major depressive disorder in adults. The objective of this study (NCT01085812) was to evaluate the efficacy, safety, and tolerability of levomilnacipran extended-release in the prevention of relapse in patients with major depressive disorder. Design: A 24-week Phase III randomized, double-blind, controlled trial comparing levomilnacipran extended-release 40-120mg/day with placebo for relapse prevention in patients with major depressive disorder who had responded to 12-week, open-label treatment with levomilnacipran extended-release. Statistical power was calculated on the assumption that 38 percent of placebo and 20 percent of levomilnacipran extended-release patients would relapse. Setting: Thirty-six outpatient study centers throughout the United States and Canada. Participants: Of 348 patients who met randomization criteria and entered double-blind treatment, three discontinued prior to treatment, 112 were randomized to placebo, and 233 to levomilnacipran extended-release. Measurements: Primary outcome: Time to relapse was analyzed using the Cox proportional hazard-regression model with treatment group and baseline Montgomery-Åsberg Depression Rating Scale score as explanatory variables. Safety was also evaluated. Results: Time to relapse was longer for levomilnacipran extended-release versus placebo (hazard ratio [95% confidence interval] = 0.68 [0.40][1.17]), but the treatment difference was not statistically significant (P=0.165). A relatively low percentage of patients from either group relapsed (placebo=20.5%, levomilnacipran extended-release=13.9%). Conclusion: This study did not detect between-treatment group differences, potentially due to lower than expected relapse rates in the placebo group. Levomilnacipran extended-release was generally well tolerated.Innovations in Clinical Neuroscience 01/2014; 11(1-2):10-22.