Chapter 1 Antipsychotic Agents

Abstract

Publisher Summary The organic pathology underlying chronic schizophrenia, which remains a devastating mental disorder, has emerged as a major topic of discussion. It presents an extremely difficult challenge for the discovery of safe and effective therapeutics. Recent studies, employing positron emission tomography have provided clear evidence of dopamine (DA) receptor proliferation in untreated schizophrenics. This finding may be an important underpinning for the DA hypothesis of schizophrenia, especially in light of the fact that DA antagonists are still the only established pharmacotherapy for psychosis. Nevertheless, anti-psychotic medications leave much to be desired, in terms of both efficacy and side effect profile. Consequently, the search continues for DA antagonists with improved therapeutic ratios as well as novel agents that can attenuate dopaminergic neurotransmission without direct interaction at DA receptors. Neuroleptic drugs are effective against the florid symptoms of psychosis. The benzamide neuroleptics form a distinct class of drugs on the basis of two attributes— that is, structural commonality and selectivity for D 2 DA receptors. Substituted benzamides have exhibited varying propensities to induce extrapyramidal side effects (EPS). Such drugs, for example, metoclopramide, resembles with classical neuroleptics with regard to EPS liability, while remoxipride also being similar in efficacy to classical agents but causes less severe EPS. It is recently observed to be a very selective, low potency D 2 blocker in vitro . Remoxipride preferentially inhibits the binding of [ 3 H]spiperone to DA receptors in limbic regions(rat brain). Striatal DA receptors are blocked only to the extent of 60%, even at very high drug doses. Raclopride possesses very high affinity for D 2 receptors in vitro and binds preferentially to the striatum in the rat in vivo . While neuroleptic drugs are effective against the florid symptoms of psychosis, negative symptoms of schizophrenia, such as social withdrawal and cognitive decline, remain uncontrolled.