Pathophysiology of schizophrenia and the role of newer antipsychotics.

Schizophrenia is an illness with numerous neurobiologic features. It is hypothesized that patients may have a relative deficit of dopamine neurotransmission in the nigrostriatal and mesocortical tracts of the brain, as contrasted with an excess of dopamine neurotransmission in the mesolimbic area. The dopamine deficit may be related to the negative symptoms (blunted affect, anhedonia, asociality, inability to initiate and carry out complex tasks to completion) of schizophrenia, whereas the dopamine excess may be responsible for the positive symptoms (hallucinations, delusions, and thought disorder). Compared with healthy subjects, schizophrenic patients may also have increased levels of serotonin and decreased levels of norepinephrine in the brain. Conventional antipsychotic drugs nonselectively block dopamine D2 receptors throughout the central nervous system. This may help reduce positive symptoms, but has little or no effect on negative symptoms. Newer agents have more anatomically selective activity with respect to dopaminergic systems but are more complex with respect to their actions in other neurochemical systems, such as serotonin and norepinephrine, which presumably contributes to their apparent greater therapeutic efficacy.