Tardive Dyskinesia (TD) is a difficult side-effect which incudes abnormal tongue, limb, and trunk movement.  It is very hard to treat, although switching anti-cholinergic anti-Parkinsonian agents to amantidine has been found useful.  Also, if the patient is on a traditional anti-psychotic, switching to an atypical anti-psychotic often helps.  Vitamin E has been widely used and some research suggested it might be mildly effective.  However, recent studies suggest that vitamin E may increase mortality rates.  Other natural remedies include melatonin, B-6, CoQ10 and quercetin.  They may have some value although none have not been adequately studied.  My favorite is melatonin, although more research is definitely needed.  The main advantage to atypical anti-psychotics is their lower rate of tardive dyskinesia.

Tardive Dyskinesia Much Less with Atypicals But Still Very Uncommon with Traditionals: In the 3-year European Schizophrenia Outpatient Health Outcomes (SOHO) study, second-generation antipsychotics conferred a lower risk for tardive dyskinesia at 6 months than first-generation antipsychotics (0.9% vs. 3.8%, odds ratio [OR] = 0.29).Also, patients with tardive dyskinesia at baseline who were receiving second-generation antipsychotics were less likely than patients receiving first-generation antipsychotics to have tardive dyskinesia symptoms at 6 months (43.6% vs. 60.8%, OR = 0.50). Effects of Antipsychotic Treatment on Tardive Dyskinesia: A 6-Month Evaluation of Patients From the European Schizophrenia Outpatient Health Outcomes (SOHO) Study. Tenback DE, et al. Eli Lilly, Maastricht University, Institute of Psychiatry, London, U.K. J Clin Psychiatry. 2005 Sep;66(9):1130-1133

Biology

DRD3 Polymorphism A Risk Factor: A study of 115 Chinese schizophrenic patients found that those with the polymorphism had higher AIMS tardive dyskinesia scores. The replicates another study. Association between the Ser9Gly polymorphism of the dopamine D3 receptor gene and tardive dyskinesia in Chinese schizophrenic patients. Liao DL, Yeh YC, Chen HM, Chen H, Hong CJ, Tsai SJ. Neuropsychobiology. 2001;44(2):95-8. Two other studies have been unable to replicate the finding. J Neural Transm. 2001;108(6):671-7

Extra-Pyramidal Symptoms A Risk Factor: Baseline and 3-, 6-, and 12-month data on 9,298 patients found that initial extrapyramidal symptoms predicted later tardive dyskinesia (80% increased risk). About half of patients who developed tardive dyskinesia had earlier extrapyramidal symptoms. Although the association of tardive dyskinesia and extrapyramidal symptoms is significant, extrapyramidal symptoms do not robustly identify individuals at high risk. Drug regimens and disease processes that increase extrapyramidal symptoms are likely to result in increased risk of tardive dyskinesia. Evidence That Early Extrapyramidal Symptoms Predict Later Tardive Dyskinesia: A Prospective Analysis of 10,000 Patients in the European Schizophrenia Outpatient Health Outcomes (SOHO) Study. Tenback DE, et al. Maastricht University, the Netherlands. . Am J Psychiatry 2006 Aug;163(8):1438-40.

Ferritin Increased in Some TD Patients: Serum iron indices (ferritin, iron, and total iron binding capacity) and fluphenazine levels were measured in a group of 30 male schizophrenic patients chronically treated with fluphenazine decanoate. A significant positive correlation was observed between AIMS scores and serum ferritin. This relationship remained significant after controlling for age and plasma fluphenazine levels. No significant correlations were observed between serum iron or total iron binding capacity and choreoathetoid movement ratings. Tardive dyskinesia and serum iron indices. Wirshing DA, Bartzokis G, Pierre JM, Wirshing WC, Sun A, Tishler TA, Marder SR. West Los Angeles VA. Biol Psychiatry. 1998 Sep 15;44(6):493-8

Higher N-acetylaspartate, N-acetylaspartylglutamate in CSF: Signs of oxidative stress and glutamatergic neurotransmission are found in tardive dyskinesia. Am J Psychiatry 9/98;155:1207

Three Times Higher TD in Patients with Over 2 Interruptions in Anti-Psychotics: Cumulative dose of anti-psychotics and cumulative dose of anti-cholinergics made no difference, but # of interruptions was very important. Van Harten, Netherlands, APA 5/30/98 APA

3-5 Times Higher in Elderly: TD rates higher despite lower doses and shorter duration. Occurred in 23% of 261 patients in 8 years of follow-up. Higher with a history of major affective disorder, ECT, EPS early in treatment, higher dose, and total amount of anti-psychotic given. Less with AD or other organic disorders. Am J Psychiatry 98;155:1521

Much Less TD with Olanzepine than Haldol: The relative risk of tardive dyskinesia for the overall follow up period for haloperidol (n = 522) v. olanzapine (n = 1192) was 2.66 (95% CI = 1.50-4.70). Based on data following the initial six weeks of observation (during which patients underwent medication change and AIMS assessments as frequently as every three days), the one-year risk was 0.52% with olanzapine (n = 513) and 7.45% with haloperidol (n = 114). The relative risk throughout this follow-up period was 11.37 (95% CI = 2.21-58.60). Br J Psychiatry 1999 Jan;174:23-30

Less TD with Risperidone than Haldol: 9 month of treatment found tardive dyskinesia 3.4 times more common with haloperidol in a matched study of 128 patients. Jeste, San Diego VA, APA 5/30/98

Siblings of Dyskinesia Patients Have More Dyskinesia: Siblings of people with schizophrenia and dyskinesia, compared with siblings of people without dyskinesia, had a higher total AIMS score and more had mild dyskinetic movements in at least one area (5/15 v. 3/34, P=0.04). There were no between-group differences in parkinsonism. UK. Spontaneous dyskinesia in first-degree relatives of chronically ill, never-treated people with schizophrenia. McCreadie RG, Thara R, Srinivasan TN, Padmavathi R. Br J Psychiatry. 2003 Jul;183:45-9

TD Higher with EPS and Akathesia: Baseline data on 1460 patients with schizophrenia as part of the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study found 212 with probable TD. These were older, had a longer duration of receiving antipsychotic medication, and were more likely to have been receiving a conventional antipsychotic and an anticholinergic agent. Diabetes mellitus (DM) and hypertension did not predict TD, whereas substance abuse did. TD subjects also had higher ratings of psychopathology, EPSE, and akathisia. Clinical correlates of tardive dyskinesia in schizophrenia: Baseline data from the CATIE schizophrenia trial. Miller DD, et al. University of Iowa. Schizophr Res. 2005 Sep 17

Treatment

Meta-Analysis Says Vitamin E and Valproate: From 296 controlled clinical trials, data were extracted from 47 trials. For most interventions, we could identify no RCT-derived evidence of efficacy. A meta-analysis showed that baclofen, deanol and diazepam were no more effective than a placebo. Single RCTs demonstrated a lack of evidence of any effect for bromocriptine, ceruletide, clonidine, estrogen, gamma linolenic acid, hydergine, lecithin, lithium, progabide, seligiline and tetrahydroisoxazolopyridinol. The meta-analysis found that five interventions were effective: L-dopa, oxypertine, sodium valproate, tiapride and vitamin E; neuroleptic reduction was marginally significant. Schizophr Res 1999 Aug 23;39(1):1-16; discussion 17-8

Amantidine Helps in DB: 18 week crossover study. Expert Opin Pharmacother 2001 Apr;2(4):667-80; Same result in a hopefully different DB 18 week crossover study. A controlled trial of amantadine hydrochloride and neuroleptics in the treatment of tardive dyskinesia. Angus S, Sugars J, Boltezar R, Koskewich S, Schneider NM. J Clin Psychopharmacol 1997 Apr;17(2):88-91

Anticholinergic Discontinuation Helps: 10 with TD withdrawn on placebo study. Slight increase in Parkinsonian but improvement in TD. W Greil, Br J Psychiatry 9/84 145:304-10

Amantadine for EPS: Anticholinergics may induce TD. In a DB study of benztropine (Cogentin) vs. amantidine 100 TID in 42 high dose haloperidol-treated schizophrenic patient no difference was found with both helpful in relieving EPS. P Konig, Austria, Neuropsycholgiol ’96;33:80-4. Same results in J Clin Psychitry 4/95;56:167-70

B-6 Helped Tardive Dyskinesia: B6 incr cerebral serotonin function and melatonin production in animals. Four case report of improved TD and neuroleptic parkinsonism as well as psychotic symptoms after Rx with pyridoxine. Case of 22yo presented where Rx with 20 mg/d successful added to haldol with drastic reduction abn movements after 5 days. Vladimir Lerner, Isreal, J Clin Psychiatry 11/98 59:623-4.; DB 4 week crossover study 15 patients. B6 patients better by 3^rd week. Am J Psychiatry 2001 Sep;158(9):1511-4

Baclofen No Benefit: 31DB baclofen 30-90/d. Initial improvement then worsening. WM Glazer, Psychopharm (Berl) 85;87:480-3

Carbidopa/levodopa-Some Better Some Worse: DB 15 pt 20 wk. 5 better, 4 worse. J Clin Psychopharm 8/88, Med Coll of PA

Ceruletide Effective: Qwk IM 0.8 microg/kg suppressed TD in DB placebo study of 8 wk. Slow but long-lasting benefit. S-E mild nausea and GI. T Kojima, Nihon U Tokyo Psychiatry Res 2/92 43:129-36. Same Prog Neuropsychopharm Biol Psychiatry ’88;12:533-9

Choline No Benefit: CDP-Choline 500 mg BID 2-8 wk DB without benefit. Compr Psychiatry 1/89, Gelenberg, Mass Gen.

Clonazepam Helped: DB 21 pt. Some benefit. Am J Psychiatry 2/81 138:189-93 Bobruff

Clonidine May Help: DB 0.4mg/d 8 wk. Possible benefit. J Browne J Clin Psychopharm 4/86 6:88-92. Did help in DB of 10 pt crossover. Tripodianakis, Pharmacopsychiatry 9/86;19:365-7

Dextromethorphan Helps L-dopa dyskinesias: a NMDA antagonist. 6 pt DB crossover with placebo had over 50% improvement. Neurol 7/98 51:203-6. Similar study in Mov Disord 5/98 13:414-7

Donezepil (Aricept) Might Help Tardive Dyskinesia: In a very poor quality 8-week open-label trial of 10 schizophrenic patients with TD, donepezil 5-10 mg/d was associated with  AIMS scores decreasing (p = .0009), with no changes in other measures. Nine patients showed improvement which was greatest in orofacial and upper extremity movements. No significant interactions were noted between the total AIMS scores and age (p > .29), duration of TD (p > .38), or duration of antipsychotic treatment (p > .14). Treatment of tardive dyskinesia with donepezil: a pilot study. Caroff SN, Campbell EC, Havey J, Sullivan KA, Mann SC, Gallop R. University of Pennsylvania. J Clin Psychiatry. 2001 Oct;62(10):772-5

Essential Fatty Acids: Little benefit although helped the schizophrenia. DB supplementation. Vaddadi, Psychiatry Res. ’89;27:313-23

Estrogen May Help: DB 10 post-menopausal women with TD after 3 week 38% improvement with estrogen and 9% with placebo. WM Glazer, Psychoneuroendo ’85;10:345-50

Ferritin Serum Levels Correlate with TD: with TD in 30 schiz on fluphenazine decanoate. Anti-psychotics increase iron uptake in the brain. High serum ferritin a risk factor for TD. LA VA, Tardive dyskinesia and serum iron indices. Wirshing DA, Bartzokis G, Pierre JM, Wirshing WC, Sun A, Tishler TA, Marder SR. Biol Psychiatry 9/98 44:493-8

Fish Oil May Help: membrane phospholipid metabolism is abnormal in schizophrenic patients. Marked depletion of essential fatty acids, particularly arachidonic acid and docosahexanoic acid, in red blood cell membranes from schizophrenic patients. Similar abnormalities are present in first degree relatives of schizophrenic patients. Changes in diet, which modify membrane levels of fatty acids, can have significant effects upon symptoms of schizophrenia and tardive dyskinesia (TD). We have found that schizophrenic patients who eat more (n-3) fatty acids in their normal diet have less severe symptoms. In a pilot study of (n-3) fatty acid supplementation we observed significant improvement in both schizophrenic symptoms and tardive dyskinesia over a 6 week period. Prostaglandins Leukot Essent Fatty Acids 1996 Aug;55(1-2):71-5

GLA No Help in Two DB: Vaddadi K. Dyskinesias and their treatment with essential fatty acids: a review. Prostaglandins Leukot Essent Fatty Acids. 1996;55:89–94.

Insulin Low Dose Helps: 20 schizophrenics in a DB placebo study were given 10 units insulin SC QD x 15 days, then daily every others weeks for 90 days. Sharp decrease in TD after 7 days which persisted. J Mouret, Lyon, Eur Neurol ’91;31:199-203.

Levetiracetam (Keppra) for Tardive Dyskinesia Case Report: A 60 yo woman on fluoxetine and bupropion for depression had begun abnormal hand, tongue, and mouth movements with an AIMS score of 35 one month after stopping chronic lithium therapy. Vitamin E had no apparent benefit. While on clonidine 0.3 mg/d, her AIMS decreased to 14, but she developed symptomatic low blood pressure. On 500 mg/d levetiracetam, for three weeks, her score dropped to 3. The dyskinesia recurred when levetiracetam was stopped and disappeared completely on 1000 mg/d. Univ. Pittsburgh. McGavin C, John V, Musser W: Levetiracetam as a treatment for tardive dyskinesia: a case report. Neurol 2003;61:419-420.

Melatonin Helps in DB; Link to Pineal Gland Calcification: In a DB PC crossover study of 22 patients with TD given melatonin 10 mg/day for 6 weeks, there was a decreased AIMS score of 2.45 points vs. 0.77 with placebo. Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Shamir E, Barak Y, et al. Israel. Arch Gen Psychiatry 2001 Nov;58(11):1049-52.  No benefit was found for 2 mg/day for 4 weeks on 19 patients in an earlier study by the same research team. J Clin Psychiatry. 2000 Aug;61(8):556-8. Melatonin is a very inexpensive and reasonably effective over-the-counter natural sleep remedy increasingly used by the lay public but ignored by treating physicians. Bipolars are more susceptible to TD side-effects and have been reported to have a much higher risk of pineal gland calcification than average.  Melatonin is produced in the pineal gland. Int J Neurosci. 1990 Oct;54(3-4):307-13; It helped reserpine-induced chewing movements in rats. Brain Res. 2001 Jun 15;904(1):149-52. Chronically hospitalized schizophrenic and bipolar patients are more likely to have calcified pineal glands (18% vs. 1%). Int J Neurosci. 1990 Aug;53(2-4):223-9. Schizophrenic patients with calcifications are more likely to have tardive dyskinesia. Int J Neurosci. 1990 Aug;53(2-4):217-22.  Melatonin also reduced age-related orofacial movements in rats. Psychopharmacology (Berl). 2002 Jun;161(4):340-7. 

Melatonin May Help as Anti-Oxidant: Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats, referred to as vacuous chewing movements (VCMs). VCMs in rats are widely accepted as an animal model of TD. Rats chronically treated with haloperidol develop VCMs and tongue protrusions. Melatonin dose-dependently (1, 2, and 5 mg/kg) reversed the haloperidol-induced VCM and tongue protrusions frequencies. The haloperidol treatment induced lipid peroxidation and decreased the forebrain glutathione (GSH) levels in the rats. Haldol also decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD), and catalase. Coadministration of melatonin (1, 2, and 5 mg/kg) along with haloperidol significantly reduced the lipid peroxidation and restored the decreased GSH levels by chronic haloperidol treatment, and significantly reversed the haloperidol-induced decrease in forebrain SOD and catalase levels. However, a lower dose of melatonin (1 mg/kg) failed to reverse chronic haloperidol-induced decreases in forebrain GSH, SOD, and catalase levels. Possible mechanism of action in melatonin attenuation of haloperidol-induced orofacial dyskinesia. Naidu PS, et al. Panjab University, Chandigarh, India. Pharmacol Biochem Behav. 2003 Feb;74(3):641-8.

Omega-3 Fatty Acid No Benefit: In a 12-week, DB PC study of ethyl-EPA 2g/day versus placebo as supplemental medication, in 84 patients with schizophrenia or schizoaffective disorder, with established TD, response rates (>/=30% improvement in TD symptoms) also did not differ significantly between EPA-treated subjects (45%) and placebo-treated subjects (32%) (p=0.6). The effects of eicosapentaenoic acid in tardive dyskinesia: A randomized, placebo-controlled trial. Emsley R, et al. University of Stellenbosch, South Africa. Schiz Res 2006 Apr 21.

Oxidative Stress Higher with Traditional Anti-Psychotics: Neurotoxicity of first-generation antipsychotics (FGAs) may be involved in lipid peroxidation, which is the pathogenesis of extrapyramidal symptoms, including tardive dyskinesia (TD). Blood samples at day 0, 7, and 21 drawn from patients taking antipsychotics were analyzed for malondialdehyde (MDA) in plasma, a marker of lipid peroxidation, by high-performance liquid chromatography. Most MDA levels were within normal range. Malondialdehyde levels in patients receiving clozapine (p = 0.002), quetiapine (p = 0.003), amisulpride (p = 0.008), and risperidone (p = 0.008) were significantly lower than within the first generation antipsychotic group. Oxidative stress during treatment with first- and second-generation antipsychotics. Kropps S, et al. Medizinische Hochschule Hannover, Germany. J Neuropsychiatry Clin Neurosci. 2005 Spring;17(2):227-31

Propranolol Might Help: A DB PC study found no short-term benefit but the author claims two out of four patients responded to long-term treatment.  This claim appears to be speculative. J Clin Psychiatry 8/82

Quercetin Helped Tardive Dyskinesia in Rats: Chronic neuroleptics leads to abnormal orofacial movements described as vacuous chewing movements (VCMs) in rats, which is widely accepted as an animal model of tardive dyskinesia. Oxidative stress and the products of lipid peroxidation are implicated in the pathophysiology of various neurological disorders including tardive dyskinesia. Haloperidol (1.0 mg kg(-1) for 21 days) treatment induced vacuous chewing movements and tongue protrusions in rats. Co-administration of quercetin (a bioflavonoid present in onions, apples, tea, and other plant sources) dose dependently (25-100 mg kg(-1)) reduced haloperidol-induced vacuous chewing movements and tongue protrusions. Haloperidol treatment induces lipid peroxidation and decreases the glutathione (GSH) levels in the forebrains of rats. The antioxidant defense enzymes, superoxide dismutase (SOD) and catalase were also decreased. Co-administration of quercetin (25-100 mg kg(-1)) significantly reduced the lipid peroxidation and restored the decreased glutathione and reversed the decrease in forebrain SOD and catalase levels. Panjab Univ. Quercetin, a bioflavonoid, attenuates haloperidol-induced orofacial dyskinesia. Naidu PS, Singh A, Kulkarni SK. Neuropharmacology. 2003 Jun;44(8):1100-6. Quercetin levels in human diets in amounts of 7-50 mg/d are below the levels used in this study.  However, Quercetin is available in 250 mg capsules for 10-15 cents each and has been used at 1000 mg/d in humans for chronic prostatitis and interstitial cystitis.  These are levels similar to the rat study.  Quercetin in human diets has tended to be associated with beneficial health effects.

Reserpine and Alpha-methyldopa Helped: DB of 3 Reserpine 0.75-1.5mg/d, methyldopa 750-1500 mg/d. both showed some benefit. CC Huang, Psychopharm (Berl) 81;73:359-62

Selegiline Worse Than Placebo: In a DB PC study of 33 patients for 6 weeks, the MAO inhibitor selegiline did poorly for patients suffering from TD. Lindemann Center, Biol Psychiatry 5/93 33:700-6

Tetrabenazine Helps TD: Using a medicine not available in US but long used for movement disorders abroad, 20 patients were treated in an open trial for severe TD. Using tetrabenazine 25 mg/day increased to a maximum of 150 mg and averaging 57 mg/day. All improved by an average of 54%. One stopped due to sedation. Ondo, Baylor, Am J Psychiatry 99;156:1279. Ed: Open trials are notoriously unreliable and shouldn't even be published.

Tiapride No Benefit: In a DB PC crossover study of 21 patients, 600 mg/d of tiapride for 12 week provided no lasting benefit. W Greil, Neuropsychobiol 85;14:17-22

Tyrodep Drink to Help Side-Effects: A new drink, high in amino acids, has been developed by Guy Goodwin of Oxford University, funded by the Wellcome Mental Health Trust.  It is said to help control levels of the chemicals in the brain which are thought to underlie the illness and thus help to alleviate side effects associated with the medication. The BBC News story was 6/24/04, but the product is still unavailable. As of 1/18/05, I was unable to locate any research on the value, composition, or cost of the drink. http://www.innovations-report.com/html/reports/medicine_health/report-30127.html

Vitamin E Didn't Prevent Tardive Dyskinesia in Large, Long-Term Study: While short-term studies have found vitamin E beneficial, a 2-year DB PC study of 158 patients with tardive dyskinesia found no benefit from d-vitamin E 1600 IU/day.  Vitamin E treatment for tardive dyskinesia. Veterans Affairs Cooperative Study #394 Study Group. Adler LA, Rotrosen J, Edson R, Lavori P, Lohr J, Hitzemann R, Raisch D, Caligiuri M, Tracy K. New York Department of Veterans Affairs. Arch Gen Psychiatry. 1999 Sep;56(9):836-41

Vitamin E Said to Help: In a meta-analysis of 12 DB studies of 223 patients receiving 400-1600 IU/d, researchers found a 28% improvement with the vitamin. Y Barak, Israel, Ann Clin Psychiatry 9/98 10:101-5

Vitamin E Helped in Small DB: 41 Chinese schizophrenics with tardive dyskinesia treated for 12 weeks with 1200 IU vitamin E or placebo found 45% decrease in TD with vitamin E vs. 4% with placebo. Superoxide dismutase also decreased. Beijing Univ. The effect of vitamin e treatment on tardive dyskinesia and blood superoxide dismutase: a double-blind placebo-controlled trial. Zhang XY, Zhou DF, Cao LY, Xu CQ, Chen da C, Wu GY. J Clin Psychopharmacol. 2004 Feb; 24(1): 83-6

Vitamin E May Slow: A meta-analysis of 10 DB studies concludes that small trials with uncertain quality of randomization indicate that vitamin E protects against deterioration of TD but there is no evidence that vitamin E improves the symptoms of TD. Israel. Cochrane Database Syst Rev 2001;(4):CD000209

Vitamin E 600 IU May Help Prevent EPS: DB 39 schiz 2 weeks found less neuroleptic induced parkinsonism although p<.08. Eur Neuropsychopharmacol 1999 Dec;9(6):475-7. The effect of vitamin E addition to acute neuroleptic treatment on the emergence of extrapyramidal side effects in schizophrenic patients: an open label study. Dorfman-Etrog P, Hermesh H, Prilipko L, Weizman A, Munitz H.

Vitamin E 1600 IU No Benefit in Short DB: In a small 40-patient study of elderly schizophrenics with 5 year histories of TD were treated in a DB PC 8-week trial of vitamin E although they received the top dose only 5 weeks. Well tolerated but no significant difference although the authors still favor Vitamin E. Dorevitch A et al, Treatment of long-term tardive dyskinesia with vitamin E. Biol Psyc 98;41:114-6, Israel

Vitamin E 1600 IU Said Helps TD: Controlled but no blind study of 20 patients said benefit of 600IU faded and required increase to 1600IU/d, but sustained benefit at that level. Int Clin Psychopharmacol 1998 Jul;13(4):147-55. Vitamin E in the treatment of tardive dyskinesia: a preliminary study over 7 months at different doses. Sajjad SH.

Vitamin E 1600 IU Helped TD Long-Term: 36 week DB 40 patient. Biol Psychiatry 1998 Jun 15;43(12):868-72. Long-term treatment effects of vitamin E for tardive dyskinesia. Adler LA, Edson R, Lavori P, Peselow E, Duncan E, Rosenthal M, Rotrosen J.; Same outcome in DB 35 pt 9 week study at 1600 IU. J Clin Psychiatry 1996 Apr;57(4):167-73; Same with 28 patient. Am J Psychiatry 1993 Sep;150(9):1405-7