Concern about disappointing results from recent multicenter trials of new antidepressants prompted several ACNP workshops on "improving the technology of clinical trials." The workshops focused on technical problems, such as patient screening, reliability of clinical ratings, and the role of the placebo control. They aimed to determine how to 27 , NO . 3 ducing adverse events, and lessening the complexity of dosing regimens. In addition, attention is currently focused on accelerating the onset of drug action to generate more rapidly acting antidepressants. Unfortunately, recently conducted multi-center clinical trials of some of these agents encountered serious technical problems and did not produce the results anticipated from preclinical studies. Although this may be partly due to limitations in extrapolating pre-clinical data to patients, it may also be that there are significant constraints in the current clinical trials model that make it difficult to demonstrate efficacy.The current clinical trials model is now 30 years old. The essential principles of randomization, double blind evaluation, and a placebo control remain sound. But other important aspects of the research design and the methodology are no longer sufficient or well suited to the testing of these new drugs. In effect, such deficiencies in current trial methodologies make it increasingly difficult to demonstrate antidepressant efficacy of these new drugs.One important reason the current model has proved inadequate is that it was initially applied to hospitalized depressed patients. Today new drugs are tested almost exclusively on outpatient samples, many of whom are symptomatic volunteers, responding to advertisements. Depressed outpatients have milder depressive symptomatology than the predominantly inpatient samples used to test the first established drugs. Patients with milder severity provide a narrower range of possible change, and produce a greater number of placebo responders (Fisher et al. 1965;Bowden et al. 2000;Khan et al. 2002).As a consequence of the smaller difference between active treatment and placebo treatment, larger patient samples and/or more sensitive clinical methods are needed to detect differences between drug and placebo. The most commonly utilized scales, the Hamilton Depression Rating Scale (HDRS) (Hamilton 1960) and the Clinical Global Impression Scale (CGI) (Guy 1976), were designed to measure changes in overall severity of the disorder. These scales are not sufficiently sensitive to assess the specific behavioral changes brought about by the newer drugs (Montgomery and Asberg 1979). Further, intensive evaluation of symptomatology and behavioral change are carried out infrequently with outpatients, making evaluation of rapidity of response problematic. Consequently, it appears important to improve the technology applied to assessing the specific actions, onset, and efficacy of the newer drugs.Acknowledging the increased complexity of the goals of clinical trials and the need to improve trial procedures, the desi...