Unanswered questions in schizophrenia clinical trials.

The treatment of schizophrenia remains an enormous challenge. Patients with this illness present with a wide variety of signs and symptoms. Response to treatment and illness course vary considerably. At the same time, we do not have the benefit of established neuropathological, neurophysiological, or neurochemicalmeasures to inform phenotypic classification, and as a result we rely on the clinical evaluation of an array of signs and reports of subjective experience in order to establish diagnoses. The care and thoroughness with which the differential diagnostic process is carried out varies enormously from one clinical setting to another and from clinical practice to clinical research. In addition, mental health care is fragmented, and records are often poor or not readily obtainable and as a result gathering an accurate history of previous symptoms, course, treatments utilized, and response (either therapeutic or adverse) can be very difficult. Patients are not generally in a position to provide the desired historical details. It is in this context that clinicians make day-to-day decisions as to how to treat their patients. Clinicians will rely on a number of sources of information in developing a treatment plan but will also be influenced by a variety of other factors. It is difficult to rank order these influences; however, personal training and experience, the influence of current colleagues and ‘‘institutional traditions,’’ pharmaceutical detailing and marketing, lectures and continuing medical education activities, journal articles (ranging from reports of individual trials to reviews and meta-analyses) published guidelines, algorithms or expert consensus reports, cost, access, patient preference, and perceived ‘‘hassles’’ are the most salient. It is with this background that we wish to review the role of the clinical trial in providing appropriate influence in this process. The clinical trial is a mainstay of evidenced-based medicine. In psychiatry, we should be particularly sensitive to the need for appropriate strategies to eliminate, or reduce to the extent possible, subjectivity and bias. It is only after well-controlled studies are conducted that we can draw meaningful conclusions about a treatment’s effects. Though unreplicated trials, uncontrolled systematic descriptions, case reports, etc. can be critical in the process of developing new knowledge, the randomized clinical trial provides the most important evidence and remains the gold standard. It is also true that no single trial, no matter how large, can address themultiple questions that might be relevant in a complex disease like schizophrenia. In addition, small trials might have insufficient statistical power to allow firm conclusions, but meta-analysis has become an increasingly valuable (though not without its own pitfalls) strategy to combine results from all available trials to provide further critical knowledge on treatment effects and characteristics (see Adams, this issue). In order to discuss the unanswered questions in schizophrenia, it is important to recognize different possibilities as to why questions are unanswered. First, it is possible that a relevant trial was never done. Second, (although less likely now) such a trial was done, but never reported or reported in a foreign language and not widely disseminated. Third, a trial was done, but inconclusive or unreplicated. Fourth, the trial though conducted and published was methodologically flawed, inadequately or inappropriately analyzed and/or reported, not readily generalizable, etc. Another factor is the sponsor and purpose for which trials are conducted. The overwhelming majority of clinical trials in schizophrenia are sponsored by the pharmaceutical industry. Many of these trials are designed for regulatory purposes, in other words as part of the clinical drug development process required for regulatory approval to market the compound. This is a daunting task in and of itself, but a process that has specific goals and parameters. It is not required by regulatory agencies or necessarily appropriate that everything a clinician might possibly want to know about a drug or drugs will be available prior to marketing. A number of industry-sponsored studies are also conducted postmarketing, but these tend to have a focus and a rationale which might be oriented toward expanding indications, continued To whom correspondence should be addressed; tel: 718 470-8141, fax: 718 343-7739, e-mail: [email protected]. Schizophrenia Bulletin vol. 34 no. 2 pp. 302–309, 2008 doi:10.1093/schbul/sbm143 Advance Access publication on January 16, 2008