ISSUES IN CLINICAL TRIAL DESIGNS

The introduction of the randomized, double-blind, clinical trial was one of the major advances in the development of medical science. In the arena of psychotropic drug develop-ment this approach has proven to be of enormous value in advancing a field in which laboratory tests and strictly objective methods for diagnosis and outcome assessment are not currently available. Designing trials in the treatment of schizophrenia high-lights some of these challenges. Schizophrenia is a complex illness affecting to varying degrees a range of functions, in-cluding cognition, affect, behavior, mood, and motivation. The fact that this disorder affects so many different do-mains, varying from individual to individual, and to some extent within individuals over time, makes development of pharmacologic treatments even more challenging. Although there are core features of schizophrenia that involve percep-tion (hallucinations), cognition (attention, working mem-ory, etc.), motivation (avolition), inferential reasoning (de-lusions), and affect (blunted or inappropriate), there is no pathognomonic sign or symptom of the disease. This has important implications for the diagnostic process, which is also complicated by the fact that the evaluation of some core features (e.g., hallucinations and delusions) relies solely on subjective reporting, the accuracy of which is potentially influenced by the very symptoms themselves as well as by other social situational and personality variables. In addition, the fact that such an array of domains and functions is disturbed in this illness creates a challenge for drug development. The tendency has been to conduct an array of assessments to evaluate drug effects in a number of domains concurrently, when in fact different domains may require different study designs, patient selection criteria, du-rations of treatment, etc. In the future, more attention will be given to those issues, and it is possible that multiple treatments will be studied rather with the goal of finding combinations able to improve outcome across a variety of domains. It is hoped that new treatments will be develope