Neuroleptic drugs are crucial elements in the treatment of schizophrenia and other psychoses. Unfortunately, they have several undesirable acute and chronic side effects which limit their effectiveness. Drug-induced parkinsonism (DIP) and tardive dyskinesia (TD) are common extrapyramidal syndromes (EPS) encountered in chronically neuroleptic treated populations. Both syndromes occur with greater frequency in older persons and may reach prevalances of 50% in this high risk group. Measures of brain dysfunction (""""""""organicity"""""""") have been investigated both as risk factors for and correlates of TD and, to a much lesser extent, DIP. There is some evidence of a relationship between cognitive dysfunction and TD, although the data are neither consistent nor conclusive. Other measures of brain structure and function have been even less informative about cerebral correlates of EPS. Neuroleptic and antiparkinson drug treatment may obscure the relationship of TD to other measures of brain function. Usually, neuroleptics suppress TD while antiparkinson agents enhance it. Opposite effects occur for DIP. The effects of concurrent drug treatment on apparent EPS-brain relationships is unknown. The proposed studies will examine the effects of neuroleptic and anticholinergic drug withdrawal on TD, DIP, and measures of brain structure and function. One-hundred-sixty chronic schizophrenics over age 45 will be randomly assigned to equal sized groups who will subsequently be withdrawn from 1) neuroleptics, 2) anticholinergics, 3) both, or 4) neither (control). A baseline CT scan of the brain will be obtained. Neuropsychological function, positive and negative symptoms of schizophrenia, and severity of TD and DIP will be assessed both at baseline and after three weeks drug free. Analysis of group differences before and after withdrawal will provide information critical to the understanding of how current treatment influences the apparent relationship between TD, DIP, and other indicators of brain function. Important issues include: 1) Nature and extent of neuroleptic and anticholinergic influence on the expression of TD and DIP; 2) Nature of specific neuropsychological deficits associated with the movement disorders; 3) Influence of brain atrophy on TD and DIP and its interaction with drug treatment; and 4) Influence of medication or the association of specific patterns of psychiatric symptoms with EPS.
