Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics, part 2: illustrating their mechanism of action.

BRAINSTORMS is a monthly section of The Journal of Clinical Psychiatry aimed at providing updates of novel concepts emerging from the neurosciences that have relevance to the practicing psychiatrist. From the Neuroscience Education Institute in Carlsbad, Calif., and the Department of Psychiatry at the University of California San Diego. Reprint requests to: Stephen M. Stahl, M.D., Ph.D., Editor, BRAINSTORMS, Neuroscience Education Institute, 5857 Owens Street, Ste. 102, Carlsbad, CA 92009. new class of antipsychotics, called dopamine system stabilizers (DSSs) (Figures 1 and 2A), is in research and development and could become the next generation of treatment for schizophrenia and psychotic illnesses. On the one hand, DSSs reduce dopaminergic neurotransmission when dopamine is excessive in the limbic system (Figure 2B); on the other hand, these agents maintain or enhance dopaminergic neurotransmission so that it is in the normal range in motor areas of the brain (the nigrostriatal system) (Figure 2C). DSSs thus reduce the hyperactivity of dopamine neurons that mediate psychosis and at the same time restore dopamine activity in the cortical regions that mediate negative and cognitive symptoms as well as the brain areas that regulate motor movements and prolactin. These new therapeutic agents are sometimes called “Goldilocks” antipsychotics because they find a desirable position between too much and too little dopamine receptor stimulation, much like Goldilocks found a soup that was neither too hot or too cold (Figure 2D). If the result is “just right,” antipsychotic actions are accompanied by a decrease in negative and cognitive symptoms without the production of motor side effects or prolactin elevation. Figure 1. Effects of Dopamine and Antipsychotics on Receptor Output