Limbic-prefrontal connectivity and clozapine.

The mechanisms of the antipsychotic efficacy and side effect profile of clozapine are incompletely understood. In vivo pharmacologic studies suggest that while clozapine does produce D2 receptor blockade, its unusual clinical profile may relate to activity at other receptor sites and to anatomical areas outside the striatum. Rodent studies indicate that acute administration of clinical doses of antipsychotic drugs, including clozapine, induces Fos (the protein product of the immediate early gene, c-fos) in the nucleus accumbens. However, unlike typical antipsychotic drugs, clozapine does not induce Fos in the dorsal striatum and does induce Fos in medial portions of the prefrontal cortex. Clozapine seems to produce a unique signature effect on long-term neuronal metabolism in its induction of Fos in the shell of the nucleus accumbens and in the medial prefrontal cortex. Future in vivo studies of cerebral blood flow and glucose metabolism in human patients may help to elucidate the specificity and reproducibility of the effects of clozapine in the ventral striatum and prefrontal cortex.