Evolution of Psychopharmacology Trial Design and Analysis: Six Decades in the Making

Objective: The evolution of trial design and analysis during the lifespan of psychopharmacology is examined.

Background: The clinical trial methodology used to evaluate psychopharmacologic agents has evolved considerably over the past 6 decades. The first and most productive decade was characterized by case series, each with a small number of patients. These trials used nonstandardized clinical observation as outcomes and seldom had a comparison group. The crossover design became widely used to examine acute psychiatric treatments in the 1950s and 1960s. Although this strategy provided comparison data, it introduced problems in study implementation and interpretation. In 1962, the US Food and Drug Administration began to require "substantial evidence of effectiveness from adequate and well-controlled studies." Subsequent decades saw remarkable advances in clinical trial design, assessment, and statistical analyses. Standardized instruments were developed and parallel groups, double-blinding, and placebo controls became the benchmark. Sample sizes increased and data analytic procedures were developed that could accommodate the problems of attrition. Randomized withdrawal designs were introduced in the 1970s to examine maintenance therapies. Ethical principles for research became codified in the United States at that time. A wave of regulatory approvals of novel antipsychotics, antidepressants, and anticonvulsants came in the 1980s and 1990s, each based on data from randomized double-blind, parallel-group, placebo-controlled clinical trials. These trial designs often involved fixed-dose comparisons based, in part, on a greater appreciation that much of the benefit and harm in psychopharmacology was dose related.

Conclusions: Despite the progress in randomized controlled trial (RCT) design, the discovery of new mechanisms of action and blockbuster interventions has slowed during the past decade.

J Clin Psychiatry 2011;72(3):331-340

Submitted: October 28, 2010; accepted December 9, 2010

(doi:10.4088/JCP.10r06669).

Corresponding author: Andrew C. Leon, PhD, Weill Cornell Medical College, Department of Psychiatry, Box 140, 525 East 68th St, New York, NY 10065 (acleon@med.cornell.edu).