Tardive Dyskinesia: Clues to the Diagnosis and Treatment

DECEMBER 08, 2007
Javaid Rashid, MD and Fred Rosner, MD, FACP

Tardive dyskinesia is a common problem associated with the long-term use of potent antipsychotic drugs. It has become less common with the increased use of the newer atypical antipsychotic medications. The condition is manifested by abnormal orofacial, extremity, and sometimes trunk movements. Decades after it was first identified, our understanding of the pathophysiology of tardive dyskinesia remains incomplete, and currently no definitive treatment is available. Encouraging advances in recent years point to promising new treatment options. This article discusses factors that may predispose to tardive dyskinesia as well as the latest developments in treatment.

Javaid Rashid, MD
Resident
Department of Psychiatry
Elmhurst Hospital Center
Fred Rosner, MD, FACP
Professor of Medicine
Teaching Attending Physician
Department of Medicine
Mount Sinai School of Medicine
New York, NY

PRACTICE POINTS

  • TD is associated with the long-term use of dopamine-receptor-blocking agents.
  • Atypical antipsychotics are less likely to result in this condition.
  • The characteristic clinical signs include abnormal involuntary choreiform movements, most often of the tongue, face, and neck muscles.
  • Prescribe neuroleptic medications in the smallest therapeutic doses for the shortest possible time.

Tardive dyskinesia (TD) is a well-recognized complication of conventional antipsychotic drugs, such as fluphenazine (Prolixin), haloperidol (Haldol), thiothixene (Navane), trifluoperazine HCl, chlorpromazine HCl (Thorazine), or thioridazine HCl.1 It has become less common since the advent of the newer atypical antipsychotics. Some age-groups and patients with certain general medical, psychiatric, or neurologic conditions are at increased risk for the development of TD.

TD is an extrapyramidal syndrome that occurs after the prolonged use of antipsychotic drugs. It is characterized by involuntary choreiform (ticlike) movements, often with an athetotic or dystonic component. Classically, the tongue, face, and neck muscles are involved, but the extremity muscles and the muscles controlling body posture and breathing can also be affected.2 In theory, the disorder can progress to the point that the patient cannot swallow or chew effectively, with the resultant morbidity. But such a dire outcome is now rare, with the more widespread use of atypical antipsychotics.

Illustrative Case

A46-year-old Hispanic man is brought to the emergency department by emergency medical services. He is unemployed and is living with his mother. The patient has had many psychiatric admissions since he was diagnosed with schizophrenia at the age of 18 years, most recently about 6 months ago. One month after discharge from the hospital, he stopped taking his medications and started to decompensate. On the day of his current admission, he had an argument with his mother, claiming she was stealing his money and trying to poison his food. That afternoon, he barricaded himself and his mother in their home, tried to pull her hair, and shouted at the neighbor to stop watching them through his window. The neighbor called 911, and the patient was brought to the emergency department.

The patient has had multiple psychiatric admissions beginning at age 18 years. Five years ago he was in a long-term psychiatric care facility for 8 months. At that time he had tried to slash his wrists in a suicidal gesture. He has taken many antipsychotic medications, including haloperidol, risperidone (Risperdal), and olanzapine (Zyprexa), and combinations of these at times. He said that the haloperidol he has been taking for about 30 years has helped him the most. He stopped taking the medications whenever he felt better because he thought there was nothing wrong with him.

In the psychiatric emergency room, he had to be physically restrained. He was administered intramuscular ziprasidone (Geodon) and lorazepam (Ativan) and was started on oral olanzapine, 10 mg twice daily.

Mental status examination showed he was disheveled, malodorous, and appeared older than his age. He was frowning, puckering and smacking his lips, and was noncooperative. He had psychomotor agitation and was irritable and loud. His affect was constricted; he was tangential and had persecutory delusions. He denied any perceptual problems or suicidal or homicidal thoughts. His cognition was intact.

The patient was admitted to the hospital, and on hospital day 5 he was evaluated for TD. The results of his Abnormal Involuntary Movement Scale (AIMS) examination suggested the diagnosis of TD. Although there are no universally accepted guidelines for interpreting AIMS, a high total score can be used to complement clinical judgment. Thus, the score of 7 in our patient supported the clinical diagnosis of TD.

Prevalence

The annual risk of TD is 5% during the first few years of neuroleptic use, but the cumulative rate with continuing use for more than 5 years increases to more than 20%.3 A recent study of 99 patients with schizophrenia who were taking neuroleptic medications found that approximately 32% had drug-induced TD.4 Incidence varies by age. In one study among 102 children and adolescents taking typical neuroleptics and/or atypical antipsychotics, fewer than 6% had probable TD.5 In contrast, in a study of 261 patients aged 55 years and older (mean age, 76.9 years), cumulative incidence of TD was 25% after 1 year of antipsychotic treatment, 34% after 2 years, and 53% after 3 years.6 The incidence of TD is generally lower in all age-groups, including the elderly, with the newer atypical antipsychotics. For example, in a study of 330 elderly patients with dementia, the 1-year cumulative incidence of persistent TD in the 255 patients without dyskinesia at baseline was only 2.6% with risperidone (Risperdal) at a dose of 0.75 to 1.5 mg/day.7 Higher rates in blacks and lower rates in Chinese and other Asian groups have been reported,8 but the basis for this ethnic disparity is unclear. Some evidence suggests that mentally retarded individuals taking neuroleptics have a higher incidence of TD.9

Pathophysiology

There are gaps in our understanding of the pathophysiology and etiology of TD. Of the various mechanisms explored, dopamine receptor hypersensitivity, gamma-amino butyric acid (GABA) insufficiency, and free radical formation from catecholamine metabolism are the 3 most widely accepted.

Dopamine receptor hypersensitivity

This hypothesis is based on the pharmacologic interplay between antipsychotic medications and dopamine receptors, which are thought to become highly sensitive over time because of chronic blockade.10 Support for this concept comes from rodent models showing increases in reversible behavioral responses to dopamine agonists after dopamine antagonist treatment at 2 to 3 days, several weeks, and 1 year.10 These responses disappear within a few days to weeks after medication discontinuation. Primate studies also support the dopamine hypersensitivity model.

The GABA insufficiency hypothesis

Reduced GABA activity in the nigrostriatal pathway that controls motor function has been supported as an underlying mechanism in studies showing alterations in GABA function with chronic neuroleptic use in rodents, possibly because of a decrease in the number of GABA terminals.10 An exciting feature of this model is a reduction in glutamic acid decarboxylase, a rate-limiting enzyme in GABA synthesis, and the simultaneous occurrence of dyskinesia in rats given neuroleptics.11 Thus TD may be associated with a reduction in glutamic acid decarboxylase in the substantia nigra, the globus pallidus, and the subthalamic nuclei.11 Clinically, reduced glutamic acid decarboxylase has been observed in a small percentage of patients with neuroleptic-induced TD.12 In humans, this reduction occurs only in the medial globus pallidus, not in the substantia nigra or subthalamic nuclei.

Catecholamine metabolism, free radical formation

This hypothesis describes the development of TD as a response to structural changes at the cellular level caused by neurotoxicity. It focuses on free radical formation from catecholamine metabolism, which may cause cellular changes in neurons.10 One study showed that compared with persons without TD, patients with TD had significantly higher concentrations of N-acetylaspartate, N-acetyl-aspartylglutamate, and aspartate in their cerebrospinal fluid (CSF), suggesting that elevated levels of oxidative stress and glutamatergic neurotransmissions may play a role in the pathophysiology.13 Neuroleptics increase catecholamine turnover, which causes higher production of free radicals in the basal ganglia, a catecholamine-rich structure. Brain cells are at risk of dying because of injury to their membrane resulting from the increased oxidative metabolism in the basal ganglia. This has led to an exploration of the use of vitamin E in TD, but studies have produced mixed results.14,15

The role of iron in TD

Iron catalyzes the formation of free radicals, particularly in the basal ganglia, where iron and dopamine levels are high.16 Serum iron indices may not be an accurate representation of brain iron levels because of the protective effect of an intact bloodbrain barrier. Antipsychotics may be able to mobilize the peripheral iron stores to the brain or decrease iron turnover in the brain without any significant changes in serum iron.17

Other hypotheses

Other mechanisms have been proposed, which include the noradrenergic system as a possible contributor to TD,10 as well as metabolic causes.

Risk Factors

TD is associated with prolonged exposure to dopamine-receptor-blocking agents, most frequently antipsychotics. It can also occur with the antidepressant amoxapine, the antiemetic agents metoclopramide (Reglan) and prochlorperazine (Compazine), and other drugs with dopamine-receptor-blocking properties.

The most important risk factors for the development of TD include age, gender, genetics, and psychiatric and general medical disorders, such as depression, diabetes, or head trauma (Table 1). In general, TD occurs earlier in women than in men.

Signs and Symptoms

Facial and oral movements are the most common presenting signs. Early signs of TD include subtle movements of the surface or body of the tongue, increased eye blinking, and chorea of the fingers or toes. There may be involuntary movements of the forehead, eyebrows, periorbital area, and cheeks, as well as involuntary frowning, blinking, smiling, and grimacing. Also typical are involuntary puckering, pouting, and smacking of the lips. Involuntary biting, clenching, chewing, mouth opening, and lateral movements of the jaw may also occur, along with protrusion, tremor, and choreoathetoid movements (ie, rolling, wormlike movement of the tongue without displacement from the mouth).

Movements of the arms, wrists, hands, and fingers in a choreiform or athetoid manner may also occur. Occasional involuntary movements of the knees, ankles, and toes, as well as inversion or eversion of the foot are possible. Abnormal movements of the neck and shoulders and hip rocking and twisting are other components of TD. Diurnal variability in the frequency and severity of signs and symptoms is common.

The History

Signs and symptoms may develop during prolonged exposure to a neuroleptic medication or within 4 weeks of withdrawal from an oral neuroleptic, or within 8 weeks of withdrawal from a depot neuroleptic medication. This usually involves a history of at least 3 months of neuroleptic medication use (or 1 month in individuals >60 years old). All dyskinesia in an individual taking a neuroleptic medication is not necessarily neuroleptic-induced TD. Other neurologic causes, such as Huntington's disease, Sydenham's chorea, or spontaneous dyskinesia, must be excluded, along with hyperthyroidism, Wilson's disease, and other general medical diseases. Exposure to medications such as levodopa (Larodopa) or bromocriptine mesylate (Parlodel) must also be ruled out.

Prevention of TD

Because of the relatively poor understanding of the pathophysiology, no effective treatment for TD is currently available. The best approach to management remains prevention, including restricting the use of antipsychotic medications to established indications and alternative treatments when possible. When neuroleptic medications are appropriate, they should be prescribed in the smallest therapeutic doses for the shortest possible time. Atypical antipsychotics should be considered as first-line therapy. Patients taking antipsychotic medications should be reevaluated every 3 to 4 months to determine their ongoing need for such medications and identify early features of TD.

Medical Treatment

No single treatment is effective for all patients with TD; a number of medications have been tried with varying degrees of success (Table 2). Catecholamine-depleting agents, such as oxypertine (not available in the United States) or tetrabenazine (orphan drug status in the United States), have been shown to be superior to placebo.18,19 However, the efficacy of oxypertine decreases over time, and side effects, such as aggression, agitation, restlessness, or increased extrapyramidal symptoms limit its use.18 Tetrabenazine, in a dosage range of 25 to 150 mg/day, has shown promising results in some patients.19 The most recent study of tetrabenazine in 118 patients with TD and other movement disorders showed that it was moderately effective at a median dosage of 75 mg/day.19

Gabaminergic drugs, such as sodium valproate (Depakote), clonazepam (Klonopin), diazepam (Valium), baclofen (Lioresal), or progabide (not available in the United States) have all been used for TD with varying degree of success.20 Sodium valproate and baclofen have been found to be superior to placebo.20 Patients taking sodium valproate experienced more side effects but this did not reach statistical significance. Baclofen was associated with ataxia, dizziness, and decreased muscle tone in at least 1 out of 6 patients in one study.21

The antiadrenergic drugs alpha-methyldopa, reserpine, propranolol HCl (Inderal), and clonidine HCl (Catapres) have also been studied. Alphamethyldopa and reserpine have been shown to be better than placebo but are associated with hypotension and depression.20

Antipsychotic medications could be the most effective short-term treatment to suppress the manifestations of TD caused by the long-term use of any potent antipsychotic agent, but this approach usually requires increasing doses. Improvements eventually disappear, and symptoms may become further aggravated. A 50% reduction in dyskinetic movement has been documented in most patients by 18 months after discontinuing antipsychotic agents.22

Fat-soluble vitamin E in daily dosages up to 1600 IU may have some therapeutic benefit, usually in patients who have had TD for less than 5 years.23,24 Arecent study of 41 inpatients with TD showed that 12 weeks of treatment with vitamin E, 1200 IU/day, significantly improved AIMS scores compared with placebo (56% vs 4%, respectively).15 Vitamin E may protect neurons from the damaging effects of free radicals, but its therapeutic effect decreases over time. It has been proposed that vitamin B6, much like vitamin E, acts as an antioxidant and free radical scavenger. Preliminary reports suggest that vitamin B6 may ameliorate the symptoms of TD. In one open-label study, when 4 weeks of vitamin B6, 100 mg/day, was added to regular medications, 4 of 5 patients with TD had more than 30% improvement on measures of involuntary movement (including AIMS), and 3 patients had clinically significant improvement on the Brief Psychiatric Rating Scale.25 No side effects were reported.

In a 3-week trial, branched-chain amino acids with a ratio of valine to isoleucine to leucine of 3:3:4 decreased CSF phenylalanine and tyrosine levels and symptoms in men with TD by up to 60% compared with placebo.26 Symptoms improved as soon as 1 week after treatment started, but the longer-term sustained effect of branched-chain amino acids is unknown. Their efficacy in women has yet to be tested.

Anticholinergic medications in high dosages benefit some patients but may also worsen some forms of TD.

For severe and refractory TD, one of the most promising treatments is clozapine. Arecent open-label study of clozapine (mean dosage, 428 mg/d) in 7 patients with severe TD showed that mean Extrapyramidal Rating Scale scores decreased 83% after 3 years and 88% after 5 years.27 This drug should, however, be reserved for severe TD in patients who do not respond to other agents.28 Another recent study of 40 patients with severe TD found that risperidone (mean dosage, 3.6 mg/d) resulted in significant improvements in AIMS scores at week 8, with benefits persisting for the duration of the 48-week trial.29

Posteroventral pallidotomy, a surgical technique that is effective treatment for both akinetic and hyperkinetic motor symptoms in Parkinson's disease, has shown efficacy in preliminary case reports of patients with severe refractory TD, but additional studies are needed.

Amantadine HCl (Symmetrel), diltiazem HCl (Cardizem), bromocriptine, lithium (Eskalith, Lithobid), insulin, levodopa, and tiapride (not available in the United States) have been used for TD with variable results. The tendency toward spontaneous remission in TD offers some hope, especially in young patients.

Potential Therapies

Estrogen modulates dopamine-mediated behaviors and protects against oxidative stress-induced cell damage caused by long-term exposure to antipsychotic medications.30 Its multimodal central nervous system activity may prove useful for the amelioration or prevention of the features of TD. A placebo-controlled, randomized trial is needed in postmenopausal women with TD.

Clinically significant improvement as assessed by AIMS has been seen with melatonin therapy compared with placebo,31 but there is a paucity of data on melatonin use. Melatonin is a dietary supplement that is minimally regulated by the Food and Drug Administration, so issues such as contamination, adulteration, or substitution are a concern, in addition to possible side effects.

Conclusion

Decades after TD was first identified, our understanding of its pathophysiology remains inadequate. The elderly and patients with certain general medical, psychiatric, and neurologic conditions are at increased risk for the development of TD. Currently, there is no definitive treatment. In recent years, several novel treatments have shown promising results. In the future, vitamin B6, branched-chain amino acids, and melatonin may play a role in the treatment of TD.

Acknowledgments

The authors are indebted to Bogdan P. Sasaran, MD, attending psychiatrist, Mount Sinai Services, Elmhurst Hospital Center, New York City, for his input and support, and to Sheryl L. Ramer, library information systems coordinator, Elmhurst Hospital Center, for her help in providing some of the references.

SELF-ASSESSMENT TEST

1. All these statements about TD are true, except:

  1. The etiology in unknown
  2. The pathophysiology is unknown
  3. It is associated with prolonged exposure to dopamine-receptor blockers
  4. It has not been associated with antiemetic agents

2. Which of these agents is least likely to cause TD?

  1. Haloperidol
  2. Chlorpromazine
  3. Clozapine
  4. Thiothixene

3. Which of these patients is a lowest risk of drug-induced TD?

  1. Adolescent girl
  2. Elderly man
  3. Elderly woman
  4. A30-year-old man with mental retardation

4. All these are features of TD, except:

  1. Involuntary facial movements
  2. Increased eye blinking
  3. Involuntary verbal utterances
  4. Foot eversion

5. Which of these statements about the treatment of TD is NOT true?

  1. Antipsychotic agents usually work only in the short-term
  2. Vitamin E has not shown consistent benefit
  3. Clozapine is ineffective for severe TD
  4. Posteroventral pallidotomy is an experimental treatment

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2. Schwartz M, Silver H, Tal I, et al. Tardive dyskinesia in northern Israel: preliminary study. Eur Neurol. 1993;33:264-266.

3. Kane JM, Jeste DV, Barnes TRE, et al. Tardive Dyskinesia: A Task Force Report of the American Psychiatric Association. Washington, DC: American Psychiatric Association; 1992.

4. Janno S, Holi M, Tuisku K, et al. Prevalence of neuroleptic-induced movement disorders in chronic schizophrenia inpatients. Am J Psychiatry. 2004;161:160-163.

5. Connor DF, Fletcher KE, Wood JS. Neuroleptic-related dyskinesias in children and adolescents. J Clin Psychiatry. 2001;62:967-974.

6.Woerner MG, Alvir JM, Saltz BL, et al. Prospective study of tardive dyskinesia in the elderly: rates and risk factors. Am J Psychiatry. 1998;155:1521-1528.

7. Jeste DV, Okamoto A, Napolitano J, et al. Low incidence of persistent tardive dyskinesia in elderly patients with dementia treated with risperidone. Am J Psychiatry. 2000;157:1150-1155.

8. Pandurangi AK, Aderibigbe YA. Tardive dyskinesia in non-western countries: a review. Eur Arch Psychiatry Clin Neurosci. 1995;246:47-52.

9. Sachdev P. Drug-induced movement disorders in institutionalised adults with mental retardation: clinical characteristics and risk factors. Aust N Z J Psychiatry. 1992;26:242-248.

10. Casey DE. Tardive dyskinesia: pathophysiology. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995:1497-1502.

11. Delfs JM, Ellison GD, Mercugliano M, et al. Expression of glutamic acid decarboxylase mRNA in striatum and pallidum in an animal model of tardive dyskinesia. Exp Neurol. 1995;133:175-188.

12. Andersson U, Haggstrom JE, Levin ED, et al. Reduced glutamate decarboxylase activity in the subthalamic nucleus in patients with tardive dyskinesia. Mov Disord. 1989;4:37-46.

13. Tsai G, Goff DC, Chang RW, et al. Markers of glutamatergic neurotransmission and oxidative stress associated with tardive dyskinesia. Am J Psychiatry. 1998;155:1207-1213.

14. Adler LA, Rotrosen J, Edson R, et al, for the Veterans Affairs Cooperative Study #394 Study Group. Vitamin E treatment for tardive dyskinesia. Arch Gen Psychiatry. 1999;56:836-841.

15. Zhang XY, Zhou DF, Cao LY, et al. The effect of vitamin E treatment on tardive dyskinesia and blood superoxide dismutase: a double-blind placebo-controlled trial. J Clin Psychopharmacol. 2004;24:83-86.

16. Chong SA, Mythily RG. Tardive dyskinesia and iron status [letter]. J Clin Psychopharmacol. 2004;24:235-236.

17.Wirshing DA, Bartzokis G, Pierre JM, et al. Tardive dyskinesia and serum iron indices. Biol Psychiatry. 1998;44:493-498.

18. Soni SD, Freeman HL, Bamrah JS, et al. Oxypertine in tardive dyskinesia: a long-term controlled study. Acta Psychiatr Scand. 1986;74:446-450.

19. Paleacu D, Giladi N, Moore O, et al. Tetrabenazine treatment in movement disorders. Clin Neuropharmacol. 2004;27:230-233.

20. Soares KV, McGrath JJ. The treatment of tardive dyskinesia?a systematic review and meta-analysis. Schizophr Res. 1999;39:1-16.

21. Adler LA, Peselow E, Rotrosen J, et al. Vitamin E treatment of tardive dyskinesia. Am J Psychiatry. 1993;150:1405-1407.

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

23. Lohr JB, Caligiuri MP. A double-blind placebo-controlled study of vitamin E treatment of tardive dyskinesia. J Clin Psychiatry. 1996;57:167-173.

24. Egan MF, Hyde TM, Albers GW, et al. Treatment of tardive dyskinesia with vitamin E. Am J Psychiatry. 1992;149:773-777.

25. Lerner V, Kaptsan A, Miodownik C, et al. Vitamin B6 in treatment of tardive dyskinesia: a preliminary case series study. Clin Neuropharmacol. 1999;22:241-243.

26. Richardson MA, Bevans ML, Read LL, et al. Efficacy of branchedchain amino acids in the treatment of tardive dyskinesia in men. Am J Psychiatry. 2003;160:1117-1124.

27. Louza MR, Bassitt DP. Maintenance treatment of severe tardive dyskinesia with clozapine: 5 years'follow-up. J Clin Psychopharmacol. 2005;25:180-182.

28. Lieberman JA, Saltz BL, Johns CA, et al. The effects of clozapine on tardive dyskinesia. Br J Psychiatry. 1991;158:503-510.

29. Bai YM, Yu SC, Chen JY, et al. Risperidone for pre-existing severe tardive dyskinesia: a 48-week prospective follow-up study. Int Clin Psychopharmacol. 2005;20:79-85.

30. Turrone P, Seeman MV, Silvestri S. Estrogen receptor activation and tardive dyskinesia. Can J Psychiatry. 2000;45:288-290.

31. Nelson LA, McGuire JM, Hausafus SN. Melatonin for the treatment of tardive dyskinesia. Ann Pharmacother. 2003;37:1128-1131.

Answers: 1. D; 2. C; 3. A; 4. C; 5. C




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