The new-generation antipsychotics - Integrating the neuropathology and pharmacology of schizophrenia

Despite a well-established role for dopamine (DA) in the neuropathology of schizophrenia, and the evidence of a hyperdopaminergic state in the schizop hrenic brain, many questions still remain. Typical agents acting predominan tly on DA D-2 receptors are only partially effective. New data now indicate that the interaction between DA and the various DA receptors as well as DA interaction with other transmitter systems, are more critical in deciding the therapeutic success of an antipsychotic than actions on DA alone. These interactions are closely associated with what is being documented regardin g the neuro-anatomy, neurobiology and neuropsychology of the disorder. There have been major advances in the understanding of the neuropathology o f schizophrenia that, while not replacing the original DA hypothesis, have forced a re-evaluation of our understanding of the disorder. In this paper we present the biochemical and neuropathological basis for schizophrenia an d discuss six new atypical antipsychotics according to these theories. Drug s reviewed include clozapine, risperidone, olanzapine, ziprasidone, sertind ole and quetiapine. While not a comparative analysis of these drugs, this paper is an appraisal of how their pharmacology correlates with our present knowledge of the dis order and highlights differences among the drugs in this group. These agent s therefore possess specifically designed qualities, to varying degrees, pr omising a significant improvement over earlier agents in terms of treating positive and negative symptoms, with a minimal risk of extrapyramidal, symp toms (EPS). These qualities include an emphasis on D-2 selectivity, D-1/D-2 balance, DA/serotonin (5HT) balance, D-3/D-4 selectivity, DA/acetylcholine (Ach) balance and glutamate (Glu)/gamma-aminobutyric acid (GABA) balance. The drugs are discussed with reference to these criteria. Targeted drug design has created a goal-directed strategy with which to tre at schizophrenia. These new antipsychotics appear to have several distinct advantages over their predecessors, and should make a major contribution to the treatment of schizophrenia and the re-integration of these patients in to society.