Objective: Treatment of dyskinetic disorders, in general, and of tardive dyskinesia (TD), in particular, is difficult. The opiate peptide enkephalin coexits with gamma aminobutyric acid in the projection neurons of striatum forming the "indirect" pathway. Several lines of preclinical evidence implicate this enkephalin-comediated pathway in the pathophysiology and therapeutics of dyskinesia. However, previous studies, most using relatively low doses of opioid antagonists, showed mixed results. The goal of the current study was to test whether moderately high doses of naltrexone, alone or in combination with a subtherapeutic dose of a gamma aminobutyric acid agonist, improve TD.
Methods: In 2 double-blind, placebo-controlled, randomized, crossover trials, effects of naltrexone alone (n = 9) and in combination with clonazepam (n = 14) were tested on TD. In both trials, patients' antipsychotic medication and dose remained unchanged through the trial. Naltrexone dose was increased over a period of 3 weeks to 200 mg/d and maintained at that dose for another week. In the second study, patients were first stabilized on low dose (0.25 to 0.5 mg) of clonazepam for 4 weeks or longer. In addition to the TD scores, saccadic peak velocity and latency, as measures of vigilance, and antisaccade error rate were obtained during the fourth week of placebo and naltrexone in a subgroup of patients.
Results: There were no significant effects of naltrexone alone on TD (mean +/- SD decrease in TD score = 0.1 +/- 4.8), psychosis scores, or eye movement measures. Low dose of clonazepam had no effect on TD. However, addition of naltrexone significantly improved TD (mean, SD decrease in TD score 4.0 +/- 3.6). There was no clinical or laboratory evidence of increased sedation during treatment with naltrexone compared to placebo. There were no significant effects on the antisaccade error rate or psychosis scores.
Conclusion: These findings suggest effectiveness of a strategy of combining a GABA(gamma aminobutyric acid)mimetic drug with an enkephalin antagonist to treat dyskinesia.
Copyright 2004 Lippincott Williams and Wilkins