The neurochemistry of schizophrenia

For more than 30 years much of the focus of neurochemical research in schizophrenia has been on the dopamine hypothesis, although serotonin systems may also be dysfunctional. Certainly, the primary action of antipsychotic drugs is to diminish dopamine D2 receptor-mediated neurotransmission. Although there is little indication of primary disturbances in dopamine (or serotonin) neurotransmission in the schizophrenia, recent functional neuro-imaging studies have demonstrated an increase in stimulated release of dopamine in the brain of patients with schizophrenia. It seems likely that this neurochemical correlate of positive symptoms might be secondary to disturbances in other neurotransmitter systems. Evidence from in vivo imaging and post-mortem studies of the brain in schizophrenia, as well as from experimental models, points to deficits of γ-aminobutyric acid (GABA)-containing neurons, and dysfunction of glutamate-containing neurons, in the cortex and elsewhere. Such regionally specific neuronal abnormalities probably underlie negative features and cognitive deficits, as well as contributing to a disinhibition of subcortical dopamine. Experimental models suggest that GABAergic deficits, perhaps of developmental origin, could result in progressive damage to other neuronal systems. Several of the recently identified genetic risk factors for schizophrenia also influence neurotransmitter and synaptic function, with some convergence on glutamate. This is providing new targets for antipsychotic drug treatment.