Treatment of tardive dyskinesia with galantamine: a randomized controlled crossover trial. Deanol acetamidobenzoate treatment in choreiform movement disorders. A double blind trial of sulpiride in Huntington's disease and tardive dyskinesia. Clozapine in tardive dyskinesia: observations from human and animal model studies. Failure of lithium treatment in established tardive dyskinesia. Effect of baclofen on tardive dyskinesia.
Recent evidence suggests that tar-dive dyskinesia may result from antipsychotic-induced damage to striatal cholinergic neurons. To test whether cholinesterase inhibitors compensate for diminished cholinergic activity, we conducted a 30-week randomized, double-blind, placebo-controlled crossover trial of galantamine in patients with tardive dyskinesia.
                Patients with tardive dyskinesia were recruited between June 2001 and June 2004. After a 2-week baseline period, 35 male schizophrenia patients, on stable doses of antipsychotics, were randomly assigned to receive galantamine (8-24 mg) or placebo for two 12-week phases separated by a 4-week washout period. Patients were evaluated every 2 weeks for changes in extrapyramidal symptoms and before and after each treatment for effects on psychiatric symptoms and cognition.
                Galantamine reduced mean total Abnormal Involuntary Movement Scale (AIMS) scores more than placebo, but this difference was not statistically significant (p = .08). However, patients initially randomly assigned to galantamine showed a reversal of AIMS scores after switching to placebo. Simpson-Angus Scale ratings of parkinsonism were significantly higher with galantamine than placebo (p = .0005) and correlated with age. There were no significant differences between groups in akathisia, cognition, or psychiatric symptoms. More patients dropped out while receiving galantamine, but this outcome did not significantly influence the results.
                In contrast to previous reports, reductions in tardive dyskinesia associated with galantamine were not statistically significant compared with placebo in this trial. However, galantamine was associated with a modest rebound in dyskinesia scores after discontinuation and clinically minor but statistically higher ratings of parkinsonism. These findings support the need for further investigations of cholinergic mechanisms underlying tardive dyskinesia and extrapyramidal effects of cholinesterase inhibitors when used in combination with antipsychotics in susceptible patients.
                ClinicalTrials.gov identifier NCT00164242. Deanol acetamidobenzoate was administered in double-blind, crossover fashion with placebo to five patients with tardive dyskinesia, three patients with Huntington's chorea, and one patient with posthemiplegic chorea. No significant effect on dyskinesia was observed. Preliminary administration of physostigmine salicylate to patients with tardive dyskinesia had a variable effect, while benztropine mesylate produced no change. Since the status of deanol as an effective precursor of acetylcholine is uncertain, further trials with putative cholinergic agents remain warranted in choreiform syndromes. Eleven patients with Huntington's disease and nine patients with tardive dyskinesia participated in a randomised double-blind crossover trial of sulpiride (as sole antidopaminergic therapy) versus placebo. Although functional improvement was not seen in Huntington's disease patients, sulpiride reduced movement count and total dyskinesia score in both conditions. Sulpiride differs pharmacologically in several respects from conventional neuroleptics, and has not been convincingly shown to cause tardive dyskinesia. Among currently available treatments, it may therefore be considered a drug of choice for treatment of tardive dyskinesia. Clozapine has long been considered a useful treatment in patients who have schizophrenia with the neuroleptic-induced delayed-onset side effect tardive dyskinesia. We present data in support of the clinical impression using both an animal model of the disorder and dyskinetic patients themselves. Clozapine produces a lower rate of oral dyskinesia in laboratory rats after 6 months of chronic treatment than does haloperidol (8.6 +/- 1.3 vs. 13.6 +/- 1.4 vacuous chewing movements every 5 minutes, respectively), suggesting a lower propensity to cause tardive dyskinesia. In the human, when clozapine was compared with haloperidol in the treatment of patients with tardive dyskinesia, clozapine produced significantly greater benefit for motor symptoms after 12 months of treatment than did haloperidol (p < .001). Moreover, the dyskinesia rebound, which occurred equally in both drug groups at the beginning of the study, was sustained in the haloperidol group but lost in the clozapine-treated patients. These data suggest that dyskinetic patients lose their symptoms of tardive dyskinesia, along with dopaminergic hypersensitivity, with long-term clozapine treatment. Eleven patients with tardive dyskinesia were treated with lithium carbonate in a placebo-controlled double-blind crossover study. No significant effect of lithium on either tardive dyskinesia or blood prolactin concentrations was demonstrated, but 5 patients developed pseudo-Parkinsonian features. Eighteen chronic psychiatric patients with neuroleptic-induced tardive dyskinesia of 1/2-9 years duration participated in a double-blind crossover study on the effect and side effects of baclofen and placebo in the treatment of tardive dyskinesia. Each treatment phase lasted 3 weeks. Evaluation of the results included an assessment of video-tape recording. Baclofen (20-120 mg daily) reduced the hyperkinesias (median score from 5 to 3, P less than 0.05) and increased the parkinsonism (median score from 5 to 7, P less than 0.01). The effect on the oral movement pattern of tardive dyskinesia was characterized by a reduced frequency, an unchanged or slightly reduced amplitude, and an increased duration of each separate mouth opening and tongue protrusion, a response pattern very similar to the response pattern of alpha-methyl-p-tyrosine, an inhibitor of the catecholamine synthesis. Sediation, muscular weakness, and confusion were observed in 50% of the patients. These side effects, appearing mainly in elderly patients, sometimes set in before the anti-hyperkinetic effect, thus limiting the practical usefulness of baclofen in the treatment of tardive dyskinesia.
Tardive dyskinesia remains a major public health problem. The clinical effects of older cholinergic drugs are unclear, as too few, too small studies leave many questions unanswered. Cholinergic drugs should remain of interest to researchers and currently have little place in routine clinical work. However, with the advent of new cholinergic agents now used for treating Alzheimer's disease, scope exists for more informative trials. If these new cholinergic agents are to be investigated for treating people with tardive dyskinesia, their effects should be demonstrated in well-designed, conducted and reported randomised trials.