At the time of our previous submission, GABA agonists were of only questionable interest in the treatment of tardive dyskinesia (TD). Subsequently, our own data and those from several other investigators have reported potent GABA-agonist efficacy in reducing symptoms of TD. Current evidence appears to suggest their use as a practical treatment. But, many unanswered questions remain, particularly related to practical application like GABA-agonist toxicity, age effect, interaction with concurrent neuroleptic treatment, and potential tolerance. The role of GABA systems in TD may also be of pathophysiologic, not just therapeutic interest, based on our finding of a GABA reduction in the spinal fluid of drug-free schizophrenics with TD compared to a matched group without TD. This has allowed us to raise the GABA deficit hypothesis of TD: all neuroleptic treated patients develop dopamine (DA)-receptor supersensitivity in striatum but only those who develop tardive dyskinesia evidence GABA system hypofunction in basal ganglia. This hypothesis is supported by results from animal model studies of TD and is consistent with known GABA-mediated neuronal pathways in brain. To pursue this hypothesis further and clarify the treatment implications, we have planned three experiments. First, we will test the efficacy of progabide (SL-76002), a direct acting GABA agonist, in dyskinetic schizophrenics some of whom are concurrently treated with neuroleptic drugs and other of whom are neuroleptic-free. The treatment will be extended over twelve weeks in a placebo-controlled, parallel-groups design to observe for any tolerance to the drug effect. Second, we will examine levels of CSF GABA and the response of CSF GABA concentrations to predicted symptom reduction in TD induced by our non-GABAmimetic treatment strategies. Our assumption is that low CSF GABA is a trait characteristic of TD and that the GABA will """"""""normalize"""""""" to the non-TD schizophrenic range as the dyskinetic symptoms diminish. Third, we will test the potential of progabide to block some of those neuroleptic-induced changes in striatum and substantia nigra which we and others have linked to the clinical manifestations of tardive dyskinesia. Based on the suggestive data from animal models of TD, we will test the action of progabide in blocking neuroleptic-induced alterations in dopaminergic and GABAergic systems and in glucose metabolism in the basal ganglia.
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