Preclinical Research After the identification of the schizophrenia as an illness over a century ago, treatment of affected individuals included unspecific, mostly very robust methods including deep insulin coma and lobectomy/leucotomy. The first relatively specific treatment of schizophrenia started about 60 years ago with the antipsychotic chlorpromazine. All currently approved antipsychotic drugs block dopamine receptors, indicating that manipulation of dopaminergic function is fundamental to a therapeutic response in psychosis. Despite refinements in their mechanism of action, the therapeutic effects of subsequent generations of antipsychotics are insufficient in claiming superiority over the first generation, with the possible exception of clozapine. Dopamine receptor blockade is necessary but not always sufficient for antipsychotic response and improvements have been reported with molecules acting on other receptors (glutamate, glycine, cannabidiol, estrogen), intracellular signaling proteins, or products of identified risk genes. Here, we review the current status of drugs under investigation. In addition, we emphasize that the development of the novel compounds to target the underlying cognitive dysfunction and negative symptom dimension of full blown schizophrenia, or attenuated psychosis syndrome and specific endophenotypes related to the increased risk of psychosis in the general population, alongside efforts to deconstruct the concept of schizophrenia(s), represent the best way to meet patient needs for better therapies and more favorable outcomes. Drug Dev Res 77 : 357-367, 2016. © 2016 Wiley Periodicals, Inc.
Keywords: NMDR; antipsychotic; clinical trial; dopamine; drug discovery.
© 2016 Wiley Periodicals, Inc.