Comparing onset of antidepressant action using a repeated measures approach and a traditional assessment schedule

• Published in: Statistics in medicine Vol. 25; no. 14; pp. 2384 - 2397
• Main Authors: Mallinckrodt, Craig H., Detke, Michael J., Kaiser, Christopher J., Watkin, John G., Molenberghs, Geert, Carroll, Raymond J.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 30.07.2006; Wiley Subscription Services, Inc
• Subjects: antidepressant; Antidepressants; Antidepressive Agents - pharmacology; Clinical trials; Comparative studies; Computer Simulation; generalized linear mixed-effects models; Humans; Linear Models; Medical treatment; Survival Analysis
• ISSN: 0277-6715; 1097-0258
• DOI: 10.1002/sim.2309

Background: It has been recommended that onset of antidepressant action be assessed using survival analyses with assessments taken at least twice per week. However, such an assessment schedule is problematic to implement. The present study assessed the feasibility of comparing onset of action between treatments using a categorical repeated measures approach with a traditional assessment schedule. Method: Four scenarios representative of antidepressant clinical trials were created by varying mean improvements over time. Two assessment schedules were compared within the simulated 8‐week studies: (i) ‘frequent’ assessment—16 postbaseline visits (twice‐weekly for 8 weeks); (ii) ‘traditional’ assessment—5 postbaseline visits (Weeks 1, 2, 4, 6, and 8). Onset was defined as a 20 per cent improvement from baseline, and had to be sustained at all subsequent assessments. Differences between treatments were analysed with a survival analysis (KM = Kaplan–Meier product limit method) and a categorical mixed‐effects model repeated measures analysis (MMRM‐CAT). Results: More frequent assessments resulted in small reductions in empirical standard errors compared with traditional assessments for both analytic methods. More frequent assessments altered estimates of treatment group differences in KM such that power was increased when the difference between treatments was increasing over time, but power decreased when the treatment difference decreased over time. More frequent assessments had a minimal effect on estimates of treatment group differences in MMRM‐CAT. The MMRM‐CAT analysis of data from a traditional assessment schedule provided adequate control of type I error, and had power comparable to or greater than that with KM analyses of data from either a frequent or a traditional assessment schedule. Conclusion: In the scenarios tested in this study it was reasonable to assess treatment group differences in onset of action with MMRM‐CAT and a traditional assessment schedule. Additional research is needed to assess whether these findings hold in data with drop‐out and across definitions of onset. Copyright © 2005 John Wiley & Sons, Ltd.