Neurobiological background for the development of new drugs in schizophrenia

Psychopharmacology of schizophrenia has remained static for many years because the mechanisms explored have been basically monoaminergics, primarily focused toward the modification of dopaminergic function and, later on, serotonergic. In fact, most of the antipsychotics introduced in clinical practice in the last years have been antagonists or selective agonists of these receptors (D(2)/5-HT(2)). The exploration of other receptor pathways, and in particular those additionally involved in the action of the paradigmatic "atypical" antipsychotic clozapine (ie, cholinergic and noradrenergic), has not been very significant. Besides, research in the antipsychotics field has developed also by exploring pathways that are beyond the spectrum of clozapine. Among the most promising mechanisms are those based on the glutamatergic hypothesis of schizophrenia (agonists at the glycine-binding modulatory site of the N-methyl-D-aspartate receptor, glycine transporter inhibitors, modulators of the AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid] receptor and selective agonists of the metabotropic receptor Glu(2)). Other less classic pathways are also under study and have led to some agents that are found in very early stages of development such as those acting on sigma receptors, cholecystokinin antagonists, neurotensin agonists, neurokinin receptor antagonists, GABAergic (+-aminobutyric acid [GABA]) enhancers, and cannabinoid(gamma-aminobutiric) receptor modulators.