New dopaminergic and non-dopaminergic theories in schizophrenia and their therapeutic impact.

Abstract

The dopamine (DA) hypothesis of schizophrenia, postulating that schizophrenia is characterized by increased dopamine function, has been the most influential theory on the pathogenesis of schizophrenia. It has recently been revised based on the appreciation that the core symptoms of schizophrenia may not be the positive (psychotic) symptoms, but rather the negative symptoms and the cognitive deficits found in schizophrenic patients. This revision has prompted the hypothesis that schizophrenia is characterized by both decreased prefrontal dopamine activity (causing deficit symptoms) and increased dopamine activity in mesolimbic dopamine neurons (causing positive symptoms). Notwithstanding this revision of a role for dopamine in schizophrenia, it has become increasingly evident that dysfunction of other monoaminergic systems may be as important in contributing to the pathophysiology of schizophrenia. Specifically, the putative role of serotonin (5-hydroxytryptamine, 5-HT) in schizophrenia is gaining considerable attention. Several observations, such as the ability of the 5-HT antagonist, ritanserin, to alleviate schizophrenic symptoms and, when added to haloperidol (Haldol®), to decrease its extrapyramidal side-effects (EPS), have stimulated studies into a role of 5-HT in schizophrenia. The finding that clozapine (Leponex®), clinically superior to conventional neuroleptics, is a weak DA2 antagonist but a potent 5-HT1c and 5-HT2 antagonist has further stimulated 5-HT-related research in schizophrenia.