Combining subjects who dropped out for psychiatric symptoms with the

subjects who experienced at least a 15% decrease in positive affect resulted in 4 of 12 subjects in the metoclopramide versus 1 of 10 subjects in the placebo group experiencing significant affective toxicity (X 2=1.691, 1 df, P=0.193). Change in positive affect from baseline to the final week of study medication in the remaining subjects ranged from an increase Inhibitors,research,lifescience,medical of 14.7% to a decrease of 13.6% (t=0.675,16 df, P=0.509). TABLE I. Table I. The slope for changes in positive and negative affect overtime between the rnetoclopramide and placebo groups. Discussion As the goal of this investigation is to provide the most sensitive methodology for detecting affective toxicity, it is reasonable to explore both toxicity in the broader sense that may affect all subjects who are exposed to a given medication, and also whether particular patients or patient groups are vulnerable to a given medication. In order to explore the more global toxicity issues, we Inhibitors,research,lifescience,medical were able to examine the aggregate slopes representing the effect of metoclopramide. Inhibitors,research,lifescience,medical The results from this analysis demonstrate

that metoclopramide does not cause significant reproducible R406 order decrements in positive or negative affect in healthy older adults. In order to enhance the sensitivity of detecting effects for individuals, one must consider combining effects that lead to study withdrawal with significant changes in individuals who are able to tolerate study completion. In this study, the finding that 4 subjects in the metoclopramide group and 1 in the placebo group withdrew from the study due to lethargy/depressive symptoms or experienced Inhibitors,research,lifescience,medical significant affective

toxicity (33% of those on metoclopramide versus 10% on placebo), suggests that metoclopramide may cause significant affective toxicity in individual subjects. Indeed, Inhibitors,research,lifescience,medical though the small sample size of this study does not allow detection of a statistically significant effect, this difference is potentially very significant clinically. Using methods developed by Cohen, a study with 96 subjects would be predicted to reproduce this finding with a power of 80% (128 subjects for 90% power).16 In addition to the limitations apparent by the small sample size of each study group, there is the possibility that the measures employed were insensitive to measuring affective toxicity. Given that these data Electron transport chain are highly suggestive of an effect, concern for this is dampened. In addition, combining study noncompletion information with results from patients who do complete the study, but have significant effects, introduces the need to develop methods for selecting appropriate parameters for defining the effect. Clearly, the choice of at least a 15% decrement in positive affect from baseline to completion is arbitrary and will need further exploration.