Vol 4 n° 4 - Drug Development
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he therapies for psychiatric disease have not been revolutionized in the last 10 years and no major new  anxiolytics  or  antidepressants  have  appeared (although some interesting compounds are in develop- ment).The second generation of antipsychotics certainly allows better therapy, particularly in terms of cognitive aspects, but trade off improved tolerance, in terms of extrapyramidal side effects, for metabolic side effects (particularly weight gain) and, in some instances, car- diovascular issues. Although there have never been as many recognized potential targets for drug therapy in psychiatric disease as at present, there has been no major progress in terms of marketed  agents  revolutionizing  therapy. The  partial cloning of the human genome now allows us to define the total number of receptors in the human genome (for example, about 48 nuclear receptors, about 750 receptors coupled to G proteins). This is a definitive statement defining the future, and perhaps eventually the limits, of drug discovery. One of us (M. Spedding) is chairman of the  Nomenclature  Committee  for  the  International Union of Pharmacology (NC-IUPHAR), which has the mission of classifying these receptors. The sequences of the receptors coupled to G proteins (GPCRs) have now been defined, and the olfactory receptors and pseudo- genes  separated,  leaving  several  hundred  known  or orphan receptors that may be drug targets. However, screening for agonists and antagonists, and then proceed- ing to clinical trials to test whether a certain hypothesis works, is one of the most expensive experiments known to man! Furthermore, the main reason for the failure of new drugs when they get into clinical trials is not phar- macokinetics or toxic side effects, but lack of efficacy (Figure 1). This  lack  of  efficacy  means  that  either  the  original hypothesis of why the drug should work in man was wrong or—and this is more likely—that the tests per- C l i n i c a l   r e s e a r c h 3 3 6 New directions for drug discovery in psychiatric disease Michael Spedding, PhD; Claude Sebban, MD; Laurent Perret, MD Keywords: schizophrenia; EEG; drug discovery; clozapine; phencyclidine Author affiliations: Institut de Recherches Internationales Servier, Neuilly-sur- Seine, France (Michael Spedding, Laurent Perret); Laboratoire de Biologie du Vieillissement, Hôpital Charles Foix, Ivry-sur-Seine, France (Claude Sebban) Address for correspondence: Prof Michael Spedding, Institut de Recherches Internationales Servier, 29-31, rue du Pont, 92578 Neuilly-sur-Seine Cedex, France (e-mail: michael.spedding@fr.netgrs.com) T Although many new potential drug targets have been dis- covered subsequent to the cloning of the human genome and the discovery of most of the relevant receptors, the role of these receptors in psychiatric disease is still not clear. We argue that research into the disease process leading to new animal models that can be transposed to man is critical to drug discovery, and present an example of an animal model for schizophrenia using electroen- cephalography. Dialogues Clin Neurosci. 2002;4:336-341.