Regression to the Mean: Implications for Clinical Trials of Psychotropic Agents in Dementia

Abstract

Effective drug development depends on understanding and optimizing results from controlled clinical trials. A recent double-blind, randomized, controlled trial of the treatment of agitation in patients with Alzheimer's disease (AD) found no difference among the four arms of the study: haloperidol, trazodone, behavioral therapy, placebo. The current analysis was undertaken to further investigate the issues bearing on this outcome and to identify better means of detecting psychotropic effects in trials involving patients with AD.This was post hoc analysis of a clinical trial data set. Patients in the placebo group were divided into responders (25% reduction in symptoms), worseners (25% worsening in baseline agitation scores), and those without a change in symptoms.Analysis of the trial outcomes demonstrated that the reduction observed in the placebo group was of the same magnitude as predicted by regression to the mean. Patients exhibiting greater improvement had more severe baseline behavioral disturbances. The relatively modest severity of agitation and the low medication doses achieved in the study may have further contributed to the failure to distinguish among treatment groups.Research design adjustments such as collection of both screening and baseline measures to determine eligibility may limit the effects of regression to the mean on trial outcomes and reduce this challenge to clinical trials. REGRESSION TO THE MEAN: IMPLICATIONS FOR CLINICAL TRIALS OF PSYCHOTROPIC AGENTS IN DEMENTIARandomized controlled trials (RCT) are necessary to establish the efficacy of potentially useful pharmacologic agents. In the past ten years, RCT have been employed in assessing In clinical trials addressing neuropsychiatric symptoms in AD, robust changes have been observed in patients in the placebo group [2,3]. In contrast to other disorders where such responses have been intensively studied, there have been no previous investigations of the placebo-group changes in RCTs involving patients with AD. True placebo effects, regression to the mean, and treatment benefit from participating in a clinical trial may all contribute to placebo group responses. A recent randomized clinical trial 5 found no difference between placebo, pharmacotherapy, and behavioral therapy in the treatment of agitation in AD; all groups improved. This trial is of particular importance since it is the only multicenter trial conducted comparing pharmacologic and nonpharmacologic instruments in AD. To investigate the observations made in this trial, we conducted a post hoc analysis of the response in the placebo group. We investigated patient characteristics (dementia severity, dementia duration and characteristics of the behavioral abnormalities), caregiver characteristics (gender, age, education), and trial characteristics (site and time of entry of the patient into the trial) to identify potential predictors of the response observed in the placebo group. We also assessed the timing of the response in the different trial groups and examined the p...

Different ways to estimate treatment effects in randomised controlled trials

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Effect of a Serotonin Reuptake Inhibitor on Irritability, Apathy, and Psychotic Symptoms in Patients With Alzheimer's Disease

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Management of behavioral problems in Alzheimer's disease

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