SURVEY ON THE PHARMACODYNAMICS OF THE NEW ANTIPSYCHOTIC RISPERIDONE

This review reports on the pharmacodynamics of the new antipsychotic risperidone. The primary action of risperidone is serotonin 5-HT2 receptor blockade as shown by displacement of radioligand binding (K-i: 0.16 nM), activity on isolated tissues (EC(50): 0.5 nM), and antagonism of peripherally (ED(50): 0.0011 mg/kg) and centrally (ED(50): 0.014 mg/kg) acting 5-HT2 receptor agonists in rats. Risperidone is at least as potent as the specific 5-HT2 receptor antagonist ritanserin in these tests. Risperidone is also a potent dopamine D, receptor antagonist as indicated by displacement of radioligand binding (K-i: 1.4 nM), activity in isolated striatal slices (IC50: 0.89 nM), and antagonism of peripherally (ED(50): 0.0057 mg/kg in dogs) and centrally acting D-2 receptor agonists (ED(50): 0.056-0.15 mg/kg in rats). Risperidone shows all effects common to D-2 antagonists, including enhancement of prolactin release. However, some central effects such as catalepsy and blockade of motor activity occur at high doses only. Risperidone is 4-10 times less potent than haloperidol as a central D-2 antagonist in rats and it differs from haloperidol by the following characteristics: predominant 5-HT2 antagonism; LSD antagonism; effects on sleep; smooth dose-response curves for D-2 antagonism; synergism of combined 5-HT2/D-2 antagonism; pronounced effects on amphetamine-induced oxygen consumption; increased social interaction; and pronounced effects on dopamine (DA) turnover. Risperidone displays similar activity at pre- and postsynaptic D-2 receptors and at D-2 receptors from various rat brain regions. The binding affinity for D-4 and D-3 receptors is 5 and 9 times weaker, respectively, than for D-2 receptors; interaction with D-1 receptors occurs only at very high concentrations. The pharmacological profile of risperidone includes interaction with histamine H-1 and alpha-adrenergic receptors but the compound is devoid of significant interaction with cholinergic and a variety of other types of receptors. Risperidone has excellent oral activity, a rapid onset, and a 24-h duration of action. Its major metabolite, 9-hydroxyrisperidone, closely mimics risperidone in pharmacodynamics. Risperidone can be characterized as a potent D-2 antagonist with predominant 5HT(2) antagonistic activity and optimal pharmacokinetic properties.