Tardive dyskinesia (TD) is an involuntary hyperkinetic disorder likely to affect a large number of mentally ill persons requiring neuroleptic treatment. This project focuses on developing a pharmacologic approach to ameliorate symptoms of the syndrome. The etiology of TD has been attributed to traditional neuroleptic drug use and its pathophysiology to a neuroleptic-induced dopamine receptor supersensitivity. Clinically, the syndrome is hyperdopaminergic. Despite focused research, no effective treatment of the disorder has been identified. Pharmacologic manipulation of the GABA system has long been suggested for the treatment of hyperdopaminergic disorders on a theoretical basis; however, the pharmacologic tools necessary for clinical application have only recently become available. We propose to test the GABAmimetic treatment of TD by enhancing GABA-mediated neural transmission using three different pharmacologic strategies: 1) Increasing brain GABA levels by blocking GABA-Transaminase (GABA-T), the degratory enzyme for GABA, using the irreversible inhibitor, gamma-vinyl GABA; 2) directly stimulating GABA receptors using the direct acting GABA agonist, THIP; and 3) selectively enhancing the antidyskinetic effect of muscimol in tardive dyskinesia with benzodiazapine potentiation. Schizophrenic patients with TD will be selected to participate in the project. Studies will be carried out in a double-blind, placebo-controlled design. Patients will be rated at baseline on movement disorder and mental status scales. Ratings and video tapings done twice weekly throughout drug and placebo courses will document the drug effect. Biochemical tests done on regularly collected samples of plasma and cerebrospinal fluid will be used to measure GABA levels and quantities of the anterior pituitary hormones affected by GABA, namely, growth hormone and prolactin. Previous studies with muscimol and preliminary observations with gamma-vinyl GABA suggest that these compounds will have an antidyskinetic action. This proposal will test a GABA-mimetic strategy as a treatment approach for TD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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University of Maryland Baltimore
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