Does Study Design Influence Outcome?

Background: Clinicians and researchers synthesize data from randomized controlled trials (RCTs) of antidepressants to make conclusions about the efficacy of medications for depression. All treatments include nonspecific factors in addition to the specific effects of drugs, and study design may influence patient outcomes via nonspecific fac tors. This study investigated whether placebo control and treatment duration affect the outcome in antidepressant RCTs. Methods: Medline and the Cochrane Database were searched to identify RCTs of antidepressants for major depression approved by the Food and Drug Administration. Included studies enrolled outpatient participants aged 18–65, lasted 6–12 weeks, compared an antidepressant to placebo or another antidepressant and were published in English after 1985. Excluded trials enrolled inpatients, pregnant women and subjects with psychosis or mania. Mixed-effects logistic regression models including study type (placebo-controlled or comparator) and study duration (6, 8 or 12 weeks) as fixed effects determined whether these factors affected response and remission rates. Results: In the 90 trials analyzed, the odds of depression response (OR = 1.79, 95% CI = 1.45–2.17, p ! 0.001) and remission (OR 1.53, 95% CI = 1.11–2.11, p ! 0.001) were significantly higher in comparator relative to placebo-controlled trials. Trials lasting 8 (OR = 1.37, CI = 1.14– 1.64, p = 0.001) and 12 (OR = 1.52, CI = 1.12–2.07, p = 0.008) Received: March 27, 2008 Accepted: April 3, 2008 Published online: March 24, 2009 Bret R. Rutherford 1051 Riverside Drive, Box 98 New York, NY 10032 (USA) Tel. +1 212 543 5746, Fax +1 212 543 6100 E-Mail [email protected] © 2009 S. Karger AG, Basel Accessible online at: www.karger.com/pps Study Design and Outcome in Antidepressant Trials Psychother Psychosom 2009;78:172–181 173 medication response rates are greater at the trial endpoint compared to 8 weeks [3] , but similar response rates have been observed across trials of 6, 8 and 12 weeks duration [4, 5] . These discrepant results suggest that study design may affect treatment outcome, and they leave unclear which analyses constitute the best evidence to answer specific clinical questions. Few previous investigators have directly addressed the questions of whether or how study design impacts treatment response [6] . In one of the few available reports, higher antidepressant response rates were found in placebo-controlled relative to comparator trials (58.1 and 50.6%, respectively) [7] . However, this analysis included unipolar as well as bipolar depression and examined RCTs dating to 1959, when methodological problems plagued many trials. Subsequent investigators found an average medication response rate of 49% in placebo-controlled versus 59% in comparator trials for late-life depression [4] . However, they did not conduct a formal literature search, provide inclusion and exclusion criteria for the studies they examined or test whether the observed difference was statistically significant. Sneed et al. [8] recently examined antidepressant response rates in 9 placebo-controlled and 7 comparator trials for late-life depression. A 46% response rate to medication was found in placebo-controlled trials compared to 63% in comparator trials. The odds of medication response in comparator trials were nearly 2 times the odds in placebo-controlled trials (OR = 1.78, 95% CI = 1.10– 2.90, p ! 0.001). This study used rigorous trial selection criteria and statistical methods but was limited to subjects 1 60 years old, leaving unclear whether these results can be generalized to all adults. To further explore the influence of RCT design on antidepressant treatment outcome, response and remission rates to antidepressant medications were compared across placebo-controlled and comparator trials enrolling outpatient participants aged 18–65. Analyses of antidepressant response and remission rates in trials of 6, 8 and 12 weeks duration were also performed. Response and remission were chosen as outcomes because they provide clinically meaningful measures denoting the significant decrease or absence of depressive symptoms and reduction in the risk of depression recurrence and adverse medical outcomes [9–11] . The primary hypotheses were that response and remission rates to medications in comparator trials would be significantly higher than those observed in placebo-controlled studies and that response and remission rates to medication in 6-, 8and 12-weekduration trials would not be significantly different. Method Identification of Studies A Medline search was conducted to identify RCTs contrasting antidepressants with placebo or active comparator in adults with depression. The index terms ‘depression – drug therapy’, ‘depressive disorder – drug therapy’, and ‘antidepressant agents’, in addition to the class and individual generic name of all antidepressants were combined using the ‘or’ operator. This returned 19,338 results, which were limited to (1) English language articles; (2) publication year from 1985 to 2006; (3) age group 6 18 (to be inclusive), and (4) publication types including clinical trials, controlled clinical trials, meta-analysis, multicenter study, RCT or review, which yielded 2,821 journal articles. The year 1985 was chosen to select trials utilizing more rigorous methods. The first author (B.R.R.) conducted a review of these titles to rule out those which were not clinical trials of antidepressants for depression, resulting in 564 titles. Three judges (B.R.R., J.R.S. and S.P.R.) reviewed the 564 titles, sequentially proceeding from article title to abstract and finally full paper text, to determine whether they met inclusion or exclusion criteria ( fig. 1 ). These evaluations were pooled, and any differences between judges were resolved by discussion. To further ensure all relevant papers were reviewed, the references of all meta-analyses and review articles published since 2000 among the 2,821 journal articles were searched for pertinent references. In addition, the Cochrane Database of Systematic Reviews was electronically searched using the topics depression, anxiety and neurosis. This yielded 24 protocols and completed reviews, each of whose references was reviewed to ensure they were among the reviewed trials. Criteria for Including Studies The inclusion criteria stipulated that articles report RCTs of an antidepressant medication for major depressive disorder in outpatient subjects aged 18–65 approved by the Food and Drug Administration (FDA). While meta-analyses were reviewed to identify studies, only data from individual RCTs were included in the analysis. Further criteria required trials to last between 6 and 12 weeks (inclusive), have comparison groups of placebo or another FDA-approved antidepressant medication, be written in English, published in 1985 or later and have response or remission rates specified using a standardized outcome measurement [e.g., Hamilton Rating Scale for Depression (HRSD) [12] , Beck Depression Inventory [13] , Montgomery-Asberg Depression Rating Scale (MADRS) [14] , Clinical Global Impression (CGI) [15] ]. Trials were excluded for enrolling inpatients, pregnant women, subjects who were psychotic or those defined to have treatment-resistant depression. Also excluded were antidepressant augmentation studies and trials requiring as inclusion criteria a specific subtype of major depression, a specific medical illness, or an axis I disorder other than depression. Data Extraction Publication information (year of publication, funding source, type of study, number of groups), demographic characteristics of the included subjects (sample size, age, gender, race, clinical characteristics), details of the treatment condition (medication name, mean dose) and outcome data (preand posttreatment means, standard deviations, response and remission rates) were extracted