Schizophrenia: genesis, receptorology and current therapeutics

Schizophrenia is a debilitating mental disease affecting approximately 1% of the population worldwide. Since the discovery of the first modern treatment for schizophrenia, chlorpromazine, in 1952 there have been many new structures investigated, only a small fraction of which have resulted in clinically useful drugs. Of these, haloperidol may be regarded as the drug for first line treatment. Since then, clozapine has emerged as the benchmark therapeutic ameliorating positive and negative symptoms and devoid of movement disorders, with its greatest feature being improvement of treatment-resistant patients. However, a major, potential lethal side-effect of clozapine is the induction of agranulocytosis, a blood disorder with unknown mechanism that results in lowered white-blood cell counts and consequent susceptibility to infections. In the 50 years of antipsychotic drug development, several novel theories have evolved that focus on receptor sub-types (serotonin 5-HTsub>2A, dopamine D(2) and D(4)) and the degree to which they need to be selectively attenuated by the drugs. Also of significance is the location of these receptors in the brain in relation to the disease state, the myriad of side-effects associated with antipsychotics and physicochemical properties of antipsychotic molecules relative to models of the drugs and the GPCR receptors involved. The techniques for investigation have shown increasing sophistication and refinement over this period, involving cloned receptors and PET scanning for determination of receptor location, density and binding, and rate constants at receptors. Knowledge of receptor structure, although in its infancy since no membrane bound CNS-receptor has yet been crystallized, is likely to benefit substantially with advances in computer-aided modelling. Overall, these new techniques have resulted in a number of novel antipsychotics such as risperidone, sertindole, olanzapine, seroquel, zotepine and ziprasidone, whose design, synthesis and testing has benefited enormously from the accumulated knowledge base of the past 50 years. In this review, we will provide a comprehensive update of the theories of action and clinical profiles of the latest drugs listed. The following appraisal of the literature will provide the practising medicinal chemist interested in this critical area of research with sufficient insight and understanding, to embark on productive investigations into the design and development of new therapeutic agents devoid of clinically limiting side-effects.