Treatment of Tardive Dyskinesia With Galantamine: A Randomized Controlled Crossover Trial

Stanley N. Caroff, M.D.; Patricia Walker, B.A.; E. Cabrina Campbell, M.D.; Alan Lorry, R.Ph.; Christopher Petro, B.S.; Kevin Lynch, Ph.D.; and Robert Gallop, Ph.D.

Objective: Recent evidence suggests that tardive 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.

Method: 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.

Results: 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.

Conclusions: 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.

Clinical Trials Registration: ClinicalTrials.gov identifier NCT00164242. 

(J Clin Psychiatry 2007;68:410-415)

Received April 4, 2006; accepted July 3, 2006. From the Department of Veterans Affairs Medical Center (Drs. Caroff and Campbell, Ms. Walker, and Mr. Lorry) and the Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia (Drs. Caroff, Campbell, and Lynch and Mr. Petro) and the Department of Mathematics and Applied Statistics, West Chester University, West Chester, Pa. (Dr. Gallop).

Supported by a grant from Ortho-McNeil Neurologics, Inc.

Dr. Caroff has received grant/research support from Pfizer and Ortho-McNeil. Ms. Walker has received grant/research support from Ortho-McNeil. Drs. Campbell, Lynch, and Gallop and Messrs. Lorry and Petro report no additional financial or other relationships relevant to the subject of this article.

Corresponding author and reprints: Stanley N. Caroff, M.D., VA Medical Center-116A, University Ave., Philadelphia, PA 19104(e-mail: stanley.caroff@va.gov).