[40 years of neuroleptic drugs]

Since the Delay, Deniker and Harl's initial report, the story of neuroleptics comprises three distinct periods. Firstly the discovery of several drugs and of their clinical effects occurred and was followed only a posteriori by definition. In 1963, Carlsson supported a hyper-dopaminergic theory of psychoses. A second period began with many biochemical hypotheses concerning schizophrenia (serotoninergic, noradrenergic, glutamatergic hypothesis...). These hypothesis should be considered as "not proven" but their presence means that schizophrenia is most probably a multi-neurotransmitter-system disease and that several critical issues remain to be clarified concerning the dopamine hypothesis of schizophrenia. During these years (1960-1980) almost all "available compounds" have been marketed. In the eighties a third period seems to begin. The notions of refractory schizophrenia and of atypical neuroleptics have been described. An "atypical" neuroleptic is an effective antipsychotic drug without inducing concomitant extrapyramidal side effects. The concept of atypicity has become a new vista for research of new antipsychotic drugs. The notions of partial dopaminergic agonism, antagonism of D4 receptor, selective 5HT2 antagonism must be viewed as a source of future research and therapeutic improvement.