Tardive dyskinesia (TD) is a troublesome and often incapacitating movement disorder that develops in 3-5% of patients per year who are treated with typical neuroleptics over the first five years, and 68% after 20 to 25 years of exposure.(1) This problem is one of the principle reasons for the effort to develop the new generation of "atypical" antipsychotic compounds. The early data indicate that the new antipsychotics, used over the long term, prevent most cases of TD.(2) However for existing cases of TD, especially those that are moderate or greater in severity, the clinical challenge is considerable. For a long time, no treatment strategy was reliably successful, though switching to atypicals was usually recommended (assuming the patient could not be withdrawn from antipsychotics).(2a)

For patients who develop TD which persists after stopping the antipsychotic or switching to a new generation medication, unfortunately, there are no clearly effective treatments. There is some literature on four options, some of them relatively benign in terms of toxicity, that may be worth trying: Vitamin E, Vitamin B6, melatonin, and donepezil (or possibly other cholinomimetic agents).

Vitamin E is an antioxidant. 9 of 11 pilot studies suggested a positive effect, typically at doses of 600 IU bid (started at 300 qd and increased by 300 per week to 1200). In all, 28% of patients improved.(3) But then, a randomized multicenter placebo controlled study in 158 patients failed to show efficacy.(4) Nevertheless, given the lack of options, some clinicians still use Vitamin E and report success.

Vitamin B6 (pyridoxine) was used in 5 studies, the most recent a double-blind placebo controlled crossover study in 15 patients.(5) Dose was 400 mg/d, achieved by starting with 50 mg bid and increasing by 50 bid weekly for 4 weeks. There were no adverse effects. The mechanism might relate to antioxidant/free radical scavenging effects, or to reduction of dopamine. There was no change on placebo and 38-69% reduction in movement scores on Vitamin B6. This look promising but larger and longer-term studies are needed.

Melatonin at a dose of 10 mg per day was tried for 6 weeks in 22 patients.(6) AIMS scores, which started at a baseline of about 10, were reduced by about 2.5. A commentary by another author questioned if this was clinically significant.(7) Melatonin is a strong antioxidant and may modulate dopamine release. No adverse events were reported.

Donepezil (Aricept) was tried, open-label, for 8 weeks in ten male patients with schizophrenia or schizoaffective disorder.(9) The theory is that there may be a deficiency in acetylcholine underlying the psychopathology of TD, and this could be corrected by increasing acetylcholine effect through a cholinesterase inhibitor (of the type now being used in Alzheimer's disease). Patients received 5 or 10 mg per day. 9 of 10 patients responded. AIMS scores decreased from a mean of 12-13 to 5-7 (multiple observations). This was significant at the p = .0009 level, and there was no relationship with duration of TD, duration of antipsychotic treatment, or age of the patient. The results could have been confounded by the discontinuation of anticholinergic drugs prior to starting the donepezil. Placebo-controlled study is needed before this use of donepezil can be strongly recommended.

It has been proposed that prophylactic useof an antioxidant might be a more successful strategy against TD if the patient needs to be on a typical neuroleptic.(8) However, there is no data that supports this proposition at this time.

(1)Glazer WM, Morgenstern H, Doucett JT. Predicting the long term risk of TD in outpatients maintained on neuroleptic medications. J Clin Psychiatry 1993;54:133-139

(2)Glazer WM. Expected incidence of TD with atypical antipsychotics. J Clin Psychiatry 2000;619suppl 4):21-26

(2a)Egan MF, Apud J, Wyatt RJ. Treatment of tardive dyskinesia. Schizophrenia Bull 1997;23(4):583-609.

(3)Barak Y, Swartz M, Shamir E, et al. Vitamin E in the treatment of TD: a statistical meta-analysis. Ann Clin Psychiatry 1998;10:101-105

(4)Adler LA, Rotrosen, J, Edson R, et al. including the VA Cooperative Study 394 Group. Vitamin E treatment for tardive dyskinesia. Arch Gen Psychiatry 1999;56:836-841

(5)Lerner V, Miodownik C, Kaptsan A, et al. Vitamin B6 in the treatment of TD: a double-blind, placebo-controlled, crossover study. Am J Psychiatry 2001;158(9):1511-1514

(6)Shamir E, Barak Y, Shalman I, et al. Melatonin treatment for TD: a double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry 2001;58(11):1049-1052

(7)Glazer WM, Goff D. Commentary: Should sisyphus have taken melatonin? Arch Gen Psychiatry 2001;58(11):1054-55

(8)Tsai G, Goff D, Chang R, et al. Markers of glutamatergic neurotransmission and oxidative stress associated with tardive dyskinesia. Am J Psychiatry 1998;9:1207-1213.

(9)Caroff SN, Campbell EC, Havey J, et al. Treatment of tardive dyskinesia with donepezil: a pilot study. J Clin Psychiatry 2001;62:772-775.