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Many double-blind, placebo-controlled, antidepressant clinical trials conducted in patients with major depressive disorder (MDD) fail to separate the candidate drug from placebo.  Multiple factors can affect trial outcomes including the patient’s expectations and motivation, the clinician’s ratings competency and reliability, and the design of the trial itself. Two factors affecting treatment outcome associated with trial design are 1) the reliability of the baseline measure, and 2) an early, indiscriminate symptomatic response following randomization that can occur regardless of treatment assignment. 

The motivation to participate in the trial itself can influence the baseline measurement as well as the early symptomatic response that follows the baseline.  An unreliable baseline measure will affect all subsequent symptomatic assessments during the clinical trial and may affect the interpretation of results.

The baseline measure is usually the primary contingency variable used to evaluate treatment outcome in clinical trials and is typically a single point in time measurement obtained sometime on the baseline day.  It is well known that the symptoms of MDD naturally fluctuate during the day (diurnal variation) and from day to day as well.  Consequently, it is unrealistic to presume that a single point in time measurement can accurately and reliably capture the true symptom severity of all MDD patients at baseline. 

Several MDD trials have revealed an early symptomatic response that occurs shortly after randomization regardless of treatment assignment.  It has been shown that the early symptomatic response may be sustained throughout the trial, includes patients assigned to placebo, and may impede signal detection at the end of the study. 

This review explores the importance of baseline reliability and the influence of early symptomatic response in some clinical trials of MDD patients and considers an alternative assessment method (ecological momentary assessment) as an innovative strategy to improve the reliability of the baseline measurement.