Antipsychotic (neuroleptic) drug-induced neurological dysfunctions in the motor system are substantial limitations of therapy. These motor disorders include acute dystonic reactions and drug-induced parkinsonism. They occur at the initiation of neuroleptic treatment and may continue in many patients throughout the course of treatment. The underlying pharmacological basis of these disorders is poorly understood. A recently developed drug, Clozapine, appears to have very few of these neurological side effects yet maintains good clinical antipsychotic efficacy. Therefore, it is important to study Clozapine and other potentially new antipsychotic drugs to identify the possible mechanism of action that will lead to reduced neurological side effects. To better understand this issue, we have studied 31 Cebus monkeys in short-term trials lasting a few days to a few months. Drugs which affect the receptor subtypes of dopamine D1 and D2 and serotonin 5HT1A and 5HT2 have been studied. All these drugs produce typical signs of dystonia and parkinsonism, with the exception of Clozapine and 5HT1A agonists. These findings suggest that the mechanism of Clozapine is as yet unknown. Combinations of receptor antagonists of dopamine and serotonin subtypes have not yet identified a clear line of drug development to pursue for creating new antipsychotic drugs that free of neurological side effects. FUNDING NIH MH36657 PUBLICATIONS Casey DE. Effects of clozapine (Clozaril) therapy in schizophrenic individuals at risk for tardive dyskinesia. J Clin Psychiatry 59(Suppl 3):31-37, 1998. Casey DE, Garver DC, Lasagna L, Marder SR, Masand PS, Miller D, Pickar D, Tandon R. Clinical trial evaluations and outcome measures in psychiatry. J Clin Psychiatry 59(Suppl 12):1-52, 1998.