ObjectiveTo assess the scientific and ethical basis for clinical innovation in psychopharmacology.MethodsWe conducted a literature review, utilizing MEDLINE search and bibliographic cross-referencing, and historical evidence regarding the discovery and development of new medications in psychiatry. Clinical innovation was defined as use of treatments in a clinical setting which have not been well-proven in a research setting.ResultsEmpirical data regarding the impact of clinical innovation in psychopharmacology are lacking. A conceptual and historical assessment of this topic highlights the ethical and scientific importance (...) of clinical innovation. Ethically, it touches a borderline that, in our judgment, is not adequately framed in contemporary mainstream bioethics. Currently, research is viewed as not at all benefiting the patients who participate in it, while clinical care is viewed as being solely for the benefit of patients. Clinical innovation straddles these two worlds, uncomfortably at times. While many argue that clinical innovation should either be avoided or folded into research projects, we argue that clinical innovation is necessary for progress in psychopharmacology research, and that it can prosper best when guided by the following ethical principles: 1.) The treatment should be based on a viable hypothesis. 2.) Whenever possible, one's clinical observations should be reported so they can be evaluated by the scientific community. 3.) One should be willing to report unexpected observations of drug effects. 4.) A high standard of informed consent should be maintained. Again, this proposal goes against the standard view among bioethicists that research and clinical care are categorically opposed activities, as made clear by the either-or dichotomy of the Belmont Report on bioethics. This approach has so polarized our profession into clinicians versus researchers, that many clinicians will not apply new knowledge produced by clinical research until it eventually gets incorporated into formal treatment guidelines, while researchers have little to guide them as to what kind of new knowledge it is most important to provide.SummaryClinical innovation brings out the ambiguities in our current ethical conceptions of research versus clinical care. Yet, historically, clinical innovation has been an important contributor to progress in psychopharmacology. We argue that clinical innovation should not be discouraged, but rather it should occur under certain ethical conditions."Almost everyone can and should do research...because almost everyone has a unique observational opportunity at some time in his life which he has an obligation to record....If one considers the fundamental operations or methods of research, one immediately realizes that most people do research at some time or another, except that they do not call their activity by that name. There are seven operations....In simple language they are counting, sorting, measuring, comparing, nature-study, guess testing, and reappraisal....Guess testing is of course what most people think of when the word research is mentioned; except that it is bad manners to call a guess a guess. It should be called an hypothesis. Let us make one plea. Guessing becomes merely a game unless it is done in the context of a plan for action. It is a waste of time elaborating untestable hypotheses [1]."John Cade. (shrink)