Review Paper

Tardive Dyskinesia in the Era of Typical and Atypical Antipsychotics. Part 1: Pathophysiology and Mechanisms of Induction

Howard C Margolese, MD, CM, MSc, FRCPC¹, Guy Chouinard, MD, MSc, FRCPC², Theodore T Kolivakis, MD, CM, FRCPC³, Linda Beauclair, MD, FRCPC⁴, Robert Miller, PhD⁵

Objective: Tardive dyskinesia (TD) is the principal adverse effect of long-term treatment with conventional antipsychotic agents. Several mechanisms may exist for this phenomenon. Mechanisms for the lower incidence of TD with atypical antipsychotics also remain to be fully understood. We undertook to explore and better understand these mechanisms. Method: We conducted a comprehensive review of TD pathophysiology literature from January 1, 1965, to January 31, 2004, using the terms tardive dyskinesia, neuroleptics, antipsychotics, pathophysiology, and mechanisms. Additional articles were obtained by searching the bibliographies of relevant references. Articles were considered if they contributed to the current understanding of the pathophysiology of TD. Results: Current TD vulnerability models include genetic vulnerability, disease-related vulnerability, and decreased functional reserve. Mechanisms of TD induction include prolonged blockade of postsynaptic dopamine receptors, postsynaptic dopamine hypersensitivity, damage to striatal GABA interneurons, and damage of striatal cholinergic interneurons. Atypical antipsychotics may cause less TD because they have less impact on the basal ganglia and are less likely to cause postsynaptic dopamine hypersensitivity. Conclusion: Although the ultimate model for TD is not yet understood, it is plausible that several of these vulnerabilities and mechanisms act together to produce TD. The lower incidence of TD with atypical antipsychotics has helped to elucidate the mechanisms of TD. (Can J Psychiatry 2005; 50:541–547) Click here for author affiliations.  Click here for information on funding and support. Clinical Implications Mechanisms of TD induction include prolonged blockade of postsynaptic dopamine receptors, postsynaptic dopamine hypersensitivity, damage to striatal GABA interneurons, and damage of striatal cholinergic interneurons. Atypical antipsychotics may cause less TD because they have less impact on the basal ganglia and are less likely to cause postsynaptic dopamine hypersensitivity. Limitations The ultimate model for TD is not yet understood, and as a result, it remains a complex disorder. Key Words: antipsychotics, extrapyramidal symptoms, psychosis, schizophrenia, tardive dyskinesia Résumé : La dyskinésie tardive à l’ère des antipsychotiques typiques et atypiques. 1re partie : la pathophysiologie et les mécanismes d’induction

For many years, conventional antipsychotics were the standard treatment for schizophrenia, but use of these agents was often associated with the development of acute movement disorders, including parkinsonism, akathisia, and dystonia with short-term exposure and TD generally after long-term use (1). Since TD can lead to unintelligible speech (2), respiratory distress with diaphragmatic involvement, and falls, it is often associated with shame, guilt, anger, and depression. In patients whose psychosis is well controlled, TD can limit reintegration into society or the workforce (3,4). Because atypical antipsychotics have a lower propensity to cause TD, TD is less actively researched since the introduction of atypical antipsychotics; thus most of the articles included in this review date from prior to 2000. Atypical antipsychotics are, however, not benign and may lead to metabolic side effects in some patients (5). Nonetheless, atypical antipsychotics allow for effective control of schizophrenia symptoms with a lower incidence of TD.

Clinical Manifestations

TD is characterized by involuntary, repetitive, purposeless movements that vary in localization and form and occur in 8 main areas: tongue, jaw, lips, face, trunk, upper extremities, lower extremities, and respiratory system (6,7). The progression of TD varies, and although it may be persistent, the course of the disease often waxes and wanes with mild-to-moderate symptoms and thereafter has a range of mild-to-severe symptoms with possible periods of spontaneous remission (7,8).

Diagnosis

The diagnosis of TD is one of exclusion through an assessment of symptoms, clinical course, and diagnostic studies (9). TD must be differentiated from other neurologic disorders with similar manifestations, including Tourette syndrome, chronic motor tic disorder, Huntington’s chorea, Sydenham’s chorea, Wilson’s disease, Meige’s syndrome (for example, cranial dystonia), and the spontaneous movements in the elderly referred to as oral lingual dyskinesias and senile chorea (10).

TD is strongly associated with a history of conventional antipsychotic use and usually occurs after several years of treatment; however, TD can also occur after short-term exposure to conventional antipsychotic drugs. In fact, persistent TD can occur in patients treated with conventional antipsychotics, even at low dosages, for as few as 2 months (11,12).

Pathophysiology

The pathophysiology of TD is complex and remains to be fully elucidated (13). Multiple models have been proposed to assimilate the disparate research findings and properly evaluate the impact of atypical antipsychotics on TD.

One example that attempts to unify the wide range of clinical findings with TD is the stress–diathesis model. The stressor is the type, dosage, and duration of antipsychotic (or other medication) used; the diathesis is any condition that increases susceptibility to developing a movement disorder, including underlying motor abnormalities inherent in schizophrenia, genetic predisposition for movement disorders in general, or brain degeneration (such as the aging process) (14–16).

This paper is particularly focused on the stress component of this equation, but the diathesis merits a closer look. How can we reconcile the fact that certain patients do not develop TD despite many years of treatment with conventional antipsychotics, while others develop TD after brief exposure to low dosages of atypical antipsychotics? In this section, we discuss the factors that work synergistically to produce TD in a vulnerable subpopulation of patients with schizophrenia.

Disease-Related Vulnerability

SD is defined as abnormal involuntary movements in patients who have never been exposed to antipsychotics. Crane assessed 150 chronic male patients in Turkish mental hospitals (17), most of whom had schizophrenia, before antipsychotics were widely used. None of the patients had abnormal involuntary movements that were compatible with TD. However, Chatterjee and others found a high prevalence of EPS (16.9%) among antipsychotic-naive patients with schizophrenia (related to negative symptoms and poorer outcome) (18). The same researchers found that a poor response to treatment of a first episode of psychosis is an important factor in the development of TD (19). The authors proposed that there may be a disease-related vulnerability to TD revealed with antipsychotic exposure. Ismail and others examined younger patients with schizophrenia and some of their unaffected siblings and found that TD-like dyskinesia was present in 28.5% of siblings (20). This finding led the authors to conclude that TD-like dyskinesia may have neurodevelopmental antecedents. Anatomical and imaging studies to localize the relevant regions of the brain have been revealing. McCreadie and colleagues studied chronically ill patients who had schizophrenia and no previous exposure to antipsychotics and found that a significant portion had dyskinesia associated with enlargement of the left lentiform nucleus (21). The authors proposed that patients with dyskinesia and striatal pathology who have never been treated with antipsychotics may represent a subgroup of patients with schizophrenia.

PET and single-photon emission computed tomographic studies involving schizophrenia patients with no previous exposure to antipsychotic medication demonstrate elevated synthesis of dopamine in the striatum (22,23)—although Dao-Castellana and others report negative findings (23)—increased amphetamine-induced dopamine release (24–26), and increased baseline occupancy of dopamine D2 receptors (27). This line of evidence argues for a dysfunction in striatal dopaminergic transmission that precedes exposure to antipsychotics and is likely associated with the schizophrenia illness process per se or to psychosis in general (28). In this latest study, which used a standardized rating scale (the ESRS, 29), no TD was observed in drug-naive schizophrenia patients (28).

Genetic Vulnerability

Genetic vulnerability to dyskinetic movement disorders is distributed in the general population; therefore, conceivably, even a low dosage of an antipsychotic may lead patients at high genetic risk to express the dyskinesia phenotype. The search for genetic markers that predict such risk continues (30,31).

Decreased Functional Reserve

In addition to schizophrenia, other processes (for example, aging and head trauma) acting on the central nervous system increase the risk for TD. Generally speaking, these processes decrease the functional reserve of the systems involved in motor control; relatively small insults may therefore have a substantial impact. Hence, elderly patients are particularly vulnerable to the adverse effects of conventional antipsychotics (32,33).

Mechanisms of Antipsychotic Induction of TD

Many mechanisms have been proposed to explain how antipsychotics induce TD. The most prominent theory implicates postsynaptic dopamine receptor hypersensitivity. This model predicts that long-standing blockade of dopamine in the nigrostriatal pathway receptors leads to possibly permanent receptor hypersensitivity (Table 1) (34–47).

Damage to striatal GABA-containing neurons has also been cited in the pathophysiology of TD, as revealed in reports that show decreased activity of glutamic acid decarboxylase in the substantia nigra, globus pallidus, and subthalamic nucleus in monkeys and rats with antipsychotic-induced oral movements and a decreased number of striatal neurons in rats after long-term antipsychotic treatment (Table 1) (41). Such findings are consistent with the degeneration of striatopallidal and striatonigral GABA-aminergic pathways that occur in response to antipsychotic therapy; however, human studies using GABA agonists have shown only minimal effects (42,43).

Miller and Chouinardproposed that TD occurs in response to the damage or degeneration of striatal cholinergic interneurons (44) (Table 1). The most direct evidence for these proposals can come only from pathologic studies of postmortem brains in appropriate clinical groups. Thus far, no published studies address these issues in a specific way. However, Holt and colleagues showed a loss of cholinergic interneurons in striata obtained from patients with schizophrenia (48). Most of the brains in this study were obtained from patients extensively treated with antipsychotics before death. Although no clinical data are available in this study indicating whether these patients displayed symptoms of TD or antipsychotic-resistant psychosis, the observed cholinergic cell loss might have given rise to one of these syndromes commonly associated with schizophrenia, rather than with psychosis or schizophrenia itself (28).

Several studies in animals have reported that cholinergic cells (or the marker enzyme choline acetyl transferase) in the striatum are lost or reduced in amount after prolonged regimes of haloperidol and fluphenazine (49,50). Recently, Grimm and others showed that prolonged haloperidol treatment in rats led to cholinergic cell loss in the specific areas of the striatum related to oral movements (51). This result may provide an animal model to explain why TD in humans is most commonly a motor disorder of orofacial musculature.

Proton magnetic resonance spectroscopy provides supporting evidence for the cholinergic hypothesis. This method allows quantification of choline, the precursor of acetylcholine, in specific brain structures. Choline reuptake leads to the accumulation of choline in cholinergic neurons before its conversion to the transmitter; an excess of choline in brain tissue will signify a loss of cholinergic neurons. Using this method, investigators have shown that, in schizophrenia, choline levels in the basal ganglia are greater than normal (52). Ando and others produced further results with this method (53), implying that choline levels in the lenticular nucleus are higher in schizophrenia patients with TD than in those without the syndrome.

Apart from such methods for assessing cholinergic processes in the striatum, clinical trials with cholinergic agents in patients with TD could provide indirect evidence related to the cholinergic hypothesis (44). Caroff and colleagues showed that the anticholinesterase donepezil was effective against the symptoms of TD (54,55). Since choline, the precursor of acetylcholine, was not effective, Caroff and others regarded their evidence as support for the hypothesis of Miller and Chouinard. However, a recent metaanalysis concluded that trials of cholinergic agents in the treatment of TD conducted to date have insufficient statistical power to reach a firm conclusion about the drugs’ effectiveness (56). This area of research may be clarified when cholinergic agents effective against specific muscarinic receptors are tested in patients with TD.

Atypical Antipsychotics and TD

Although receptor-binding profiles vary among atypical antipsychotics, they all antagonize dopamine and serotonin receptors to some degree. Whether other receptor binding is involved in either TD onset or TD amelioration is not known. It is clear, however, that atypical antipsychotics are associated with the least risk of causing structural damage and provoking persistent, dynamic alterations in neurotransmitter systems involved in motor control. Atypical antipsychotics, in general, act on the mesolimbic (A10) rather than on the nigrostriatal (A9) dopamine pathways (likely mediated by 5-HT₂ antagonism) and modulate dopaminergic transmission through loose binding at the D₂ receptor. For a more thorough review regarding mechanism of action of antipsychotics, several excellent articles exist in the literature (36,45). Atypical agents that bind loosely to D₂ receptors and block 5-HT₂ receptors will likely be associated with the lowest incidence of TD and may even demonstrate a protective effect in patients at increased risk for spontaneous dyskinesia (caused by genetic, neurodevelopmental, or age-related factors), a beneficial effect in patients with established TD and altered neurotransmitter systems (such as dopaminergic hypersensitivity), and a temporary masking of damage caused by conventional antipsychotics. This could also partly be due to spontaneous remission of TD from conventional antipsychotic withdrawal; it is difficult to determine the exact effect without placebo-controlled trials.

Clozapine, quetiapine, ziprasidone, olanzapine, and risperidone (< 6 mg daily) exert a favourable effect on TD by several possible mechanisms (57–60). It is likely that these mechanisms (such as suppression, spontaneous improvement, and direct effect on pathophysiology) act together at different periods during treatment and to differing degrees along with other yet unrecognized mechanisms. Of these mechanisms, support for direct effect against the pathophysiology of TD, possibly by decreasing dopamine receptor sensitivity, is found, because the decrease in TD over time is dosage-dependent (57,59). The theory that this is due to dosage-dependent suppression similar to that associated with conventional antipsychotics (58) is not supported, because some TD symptoms are stable or remain at a low level over time when treated with atypical antipsychotics. In addition, PET data show weak D₂ binding (for clozapine) in the nigrostriatal tract, not strong D₂ binding, as predicted by this theory (37,60).

The structural brain abnormalities seen in patients with schizophrenia and TD are poorly understood at this time (61); whereas some abnormalities are reversible, there appears to be a threshold beyond which they may be persistent, even if current management strategies are undertaken (62). The multiple receptor antagonist atypical antipsychotics seem to exert neuroprotective therapeutic effects that permit them to have superior therapeutic activity for many of our patients. Cloning of human receptors has permitted a better understanding of the mechanism of action of antipsychotics and has helped to define atypicality. The D₂ blocking effect does not permit a differentiation between antipsychotics, rather, blockade of other receptors helps to define atypicality (63). Atypicality is defined by 2 properties shared by all atypical antipsychotics: neuroprotective effects on cortical toxicity and extrapyramidal toxicity caused by classical antipsychotics and multiple receptor antagonism (64–66).

Atypical antipsychotics exert therapeutic effects by simultaneously acting at levels considered efficacious in humans on more than 10 receptors that are now directly or indirectly implicated in schizophrenia (67). There are numerous studies in both humans and animals that demonstrate neuroprotective effects of atypical antipsychotics (68–74). From this perspective, the most studied medications are clozapine, risperidone, and olanzapine. Three studies review the results obtained to date in patients with schizophrenia (68–72). Frazier and colleagues revealed that caudate volume increased after exposure to typical antipsychotics in childhood-onset schizophrenia patients (68). After 2 years of treatment with clozapine, caudate volume, which was larger on the first scan, had diminished to reveal no difference between subjects and control subjects on the second scan. Lang and colleagues failed to demonstrate a difference in first-episode schizophrenia patients among volumes of the lenticular, caudate, and front wall of the amygdala (basal ganglia), compared with healthy control subjects (69). In chronically treated patients, caudate, putamen, and globus-pallidus volumes were significantly larger than in first-episode patients and control subjects. In first-episode schizophrenia patients treated with risperidone, lenticular, caudate, and front wall of the amygdala (that is, basal ganglia) volumes were unchanged after one year of treatment (69). In the study by Gur and colleagues, no difference in subcortical volume was observed between patients treated for the first time with an antipsychotic and healthy control subjects, except on thalamus volume (70). In these same patients, changes in volumes did not correlate with the intensity of negative symptoms, whereas an augmentation in thalamus and putamen volume correlated with the intensity of positive symptoms. In this same study (70), larger putamen and pallidum volumes were observed among patients previously treated with antipsychotics, compared with healthy control subjects and first-episode patients. Among previously treated patients, high-dose classical antipsychotics led to increased caudate, putamen, and thalamus volumes, whereas high-dosage atypical antipsychotics led only to increased thalamus volume (70).

Two other MRI studies conducted among schizophrenia patients confirmed that typical antipsychotics increase basal ganglia volume, whereas atypical antipsychotics have the opposite effect (71,72). We have already described 2 postmortem studies (44) that demonstrated a glial cell reaction and loss of the largest striatal neurons (probably cholinergic neurons) among schizophrenia patients chronically treated with classical antipsychotics and, more frequently, among those with TD. These studies can help explain increased caudate volume caused by classical antipsychotics seen among approximately 10% of the patients in these MRI studies.

Conclusion

TD remains a complex disorder because its mechanism is not yet fully understood. Current TD vulnerability models, which are not mutually exclusive but rather complementary, include genetic vulnerability, disease-related vulnerability, and decreased functional reserve. Mechanisms of TD induction by typical antipsychotics include prolonged blockade of postsynaptic dopamine receptors, postsynaptic dopamine hypersensitivity, damage to striatal GABA neurons, and damage to striatal cholinergic neurons. Although one unifying theory may ultimately be discovered, current understanding suggests that several of these mechanisms may coexist to produce TD or that different mechanisms may predominate in different patients or patient populations. Atypical antipsychotics may be associated with a lower risk of TD by decreasing striatal dopamine receptor sensitivity, either indirectly through serotonin or directly by looser binding to the D₂ receptor. Further, compared with typical antipsychotics, atypicals are less likely to cause changes in basal ganglia volume; thus, they are less likely to damage cells directly involved in the pathophysiology of TD. Understanding of the pathophysiology of TD has made significant advances with our understanding of atypical antipsychotic mechanisms of action and our exploration of their lower propensity to cause TD. However, the full elucidation of the mechanisms of TD remains to be discovered.

Funding and Support

Howard C Margolese is a paid speaker for Eli-Lilly, Astra Zeneca, and Janssen. He is a consultant for Janssen and Biovail. Guy Chouinard receives research support from Janssen and Pfizer and is a consultant for Pfizer, Janssen, Neuro 3 D, Solvay, and Organon. He is a paid speaker for Eli Lilly. Theodore T Kolivakis is a consultant for Janssen Ortho, Oryx Pharmaceuticals, Biovail, Eli Lilly, and Astra Zeneca. He has received speaker honoraria from Oryx Pharmaceuticals, Eli Lilly, and Wyeth. He was supported by a Fellowship from the Canadian Society for Clinical Pharmacology and by a grant from McGill Friends for Research. Linda Beauclair receives research support from Janssen, Pfizer, and Organon. Robert Miller receives conference planning support from Eli Lilly (New Zealand).

References

1. Jeste DV, Rockwell E, Harris MJ, Lohr JB, Lacro J. Conventional vs. newer antipsychotics in elderly patients. Am J Geriatr Psychiatry 1999;7:70–6.

2. Laporta M, Archambault D, Ross-Chouinard A, Chouinard G. Articulatory impairment associated with tardive dyskinesia. J Nerv Ment Dis 1990;178:660–2.

3. Margolese HC, Chouinard G, Walters-Larach V, Beauclair L. Relationship between antipsychotic-induced akathisia and tardive dyskinesia and suicidality in schizophrenia: impact of clozapine and olanzapine. Acta Psychiatrica Belgica 2001;101:128–44.

4. Kane JM. Prospective study of tardive dyskinesia in the elderly. Presented at American Psychiatric Association Annual Meeting; 1999; Washington (DC).

5. Abidi S, Bhaskara SM. From chlorpromazine to clozapine—antipsychotic adverse effects and the clinician’s dilemma. Can J Psychiatry 2003;48:749–55.

6. Freedman DX. Neurological syndromes associated with antipsychotic drug use. A special report. Arch Gen Psychiatry 1973;28:463–7.

7. Chouinard G, Annable L, Ross-Chouinard A, Mercier P. A 5-year prospective longitudinal study of tardive dyskinesia: factors predicting appearance of new cases. J Clin Psychopharmacol 1988;8:21S–26S.

8. Gardos G, Casey DE, Cole JO, Perenyi A, Kocsis E, Arato M, and others. Ten-year outcome of tardive dyskinesia. Am J Psychiatry 1994;151:836–41.

9. Schooler NR, Kane JM. Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 1982;39:486–7.

10. Owens DG, Johnstone EC, Frith CD. Spontaneous involuntary disorders of movement: their prevalence, severity, and distribution in chronic schizophrenics with and without treatment with neuroleptics. Arch Gen Psychiatry 1982;39:452–61.

11. Chouinard G, Jones BD, Annable L, Ross-Chouinard A. Sex differences and tardive dyskineasia. Am J Psychiatry 1980;137:507.

12. Chouinard G, Boisvert D, Bradwejn J. Tardive dyskinesia in a nonpsychiatric patient due to short-term use of a neuroleptic/anticholinergic combination drug. CMAJ 1982;126:821–2.

13. Casey DE. Tardive dyskinesia: pathophysiology and animal models. J Clin Psychiatry 2000;61(Suppl 4):5–9.

14. Yassa R, Nair NP, Iskander H, Schwartz G. Factors in the development of severe forms of tardive dyskinesia. Am J Psychiatry 1990;147:1156–63.

15. Yassa R, Jeste DV. Gender differences in tardive dyskinesia: a critical review of the literature. Schizophr Bull 1992;18:701–15.

16. Waddington JL. Tardive dyskinesia in schizophrenia and other disorders: association with aging, cognitive dysfunction, and structural brain pathology in relation to neuroleptic exposure. Human Psychopharmacology 1987;2:11–22.

17. Crane GE. Persistent dyskinesia. Br J Psychiatry 1973;122:395–405.

18. Chatterjee A, Chakos M, Koreen A, Geisler S, Sheitman B, Woerner M, and others. Prevalence and clinical correlates of extrapyramidal signs and spontaneous dyskinesia in never-medicated schizophrenic patients. Am J Psychiatry 1995;152:1724–9.

19. Chakos MH, Alvir JM, Woerner MG, Koreen A, Geisler S, Mayerhoff D, and others. Incidence and correlates of tardive dyskinesia in first episode of schizophrenia. Arch Gen Psychiatry 1996;53:313–9.

20. Ismail B, Cantor-Graae E, McNeil TF. Neurodevelopmental origins of tardivelike dyskinesia in schizophrenia patients and their siblings. Schizophr Bull 2001;27:629–41.

21. McCreadie RG, Thara R, Padmavati R, Srinivasan TN, Jaipurkar SD. Structural brain differences between never-treated patients with schizophrenia, with and without dyskinesia, and normal control subjects: a magnetic resonance imaging study. Arch Gen Psychiatry 2002;59:332–6.

22. Lindstrom LH, Gefvert O, Hagberg G, Lundberg T, Bergstrom M, Hartvig P, and others. Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(beta-11C) DOPA and PET. Biol Psychiatry 1999;46:681–8.

23. Dao-Castellana MH, Paillere-Martinot ML, Hantraye P, Attar-Levy D, Remy P, Crouzel C, and others. Presynaptic dopaminergic function in the striatum of schizophrenic patients. Schizophr Res 1997;23:167–74.

24. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J, and others. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 1996;93:9235–40.

25. Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, and others. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 1997;94:2569–74.

26. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, and others. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998;155:761–7.

27. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, and others. Increased baseline occupancy of D₂ receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 2000;97:8104–9.

28. Reith J, Benkelfat C, Sherwin A, Yasuhara Y, Kuwabara H, Andermann F, and others. Elevated dopa decarboxylase activity in living brain of patients with psychosis. Proc Natl Acad Sci USA 1994;91:11651–4.

29. Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophr Res 2005;76:247–65.

30. Segman RH, Heresco-Levy U, Yakir A, Goltser T, Strous R, Greenberg DA, and others. Interactive effect of cytochrome P450 17alpha-hydroxylase and dopamine D3 receptor gene polymorphisms on abnormal involuntary movements in chronic schizophrenia. Biol Psychiatry 2002;51:261–3.

31. Tan EC, Chong SA, Mahendran R, Dong F, Tan CH. Susceptibility to neuroleptic-induced tardive dyskinesia and the T102C polymorphism in the serotonin type 2A receptor. Biol Psychiatry 2001;50:144–7.

32. Caligiuri MR, Jeste DV, Lacro JP. Antipsychotic-Induced movement disorders in the elderly: epidemiology and treatment recommendations. Drugs Aging 2000;17:363–84.

33. Woerner MG, Alvir JM, Saltz BL, Lieberman JA, Kane JM. Prospective study of tardive dyskinesia in the elderly: rates and risk factors. Am J Psychiatry 1998;155:1521–8.

34. Klawans HL, Jr., Rubovits R. An experimental model of tardive dyskinesia. J Neural Transm 1972;33:235–46.

35. Tarsy D, Baldessarini RJ. Pharmacologically induced behavioural supersensitivity to apomorphine. Nat New Biol 1973;245:262–3.

36. Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 2001;158:360–9.

37. Kapur S, Roy P, Daskalakis J, Remington G, Zipursky R. Increased dopamine d(2) receptor occupancy and elevated prolactin level associated with addition of haloperidol to clozapine. Am J Psychiatry 2001;158:311–4.

38. Diederich NJ, Goetz CG. Drug-induced movement disorders. Neurol Clin 1998;16:125–39.

39. McGrath JJ, Soares KV. Neuroleptic reduction and/or cessation and neuroleptics as specific treatments for tardive dyskinesia. Cochrane Database Syst Rev 2000;(2):CD000459.

40. Silvestri S, Seeman MV, Negrete JC, Houle S, Shammi CM, Remington GJ, and others. Increased dopamine D₂ receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study. Psychopharmacology (Berl) 2000;152:174–80.

41. Delfs JM, Ciaramitaro VM, Soghomonian JJ, Chesselet MF. Unilateral nigrostriatal lesions induce a bilateral increase in glutamate decarboxylase messenger RNA in the reticular thalamic nucleus. Neuroscience 1996;71:383–95.

42. McGrath JJ, Soares KV. Benzodiazepines for neuroleptic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2000;(2):CD000205. Review.

43. Soares KV, McGrath JJ, Deeks JJ. Gamma-aminobutyric acid agonists for neuroleptic-induced tardive dyskinesia. Cochrane Database Syst Rev 2001;(2):CD000203.

44. Miller R, Chouinard G. Loss of striatal cholinergic neurons as a basis for tardive and L-dopa-induced dyskinesias, neuroleptic-induced supersensitivity psychosis and refractory schizophrenia. Biol Psychiatry 1993;34:713–38.

45. Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry 2002;47:27–38.

46. Andreassen OA, Jorgensen HA. Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia? Prog Neurobiol 2000;61:525–41.

47. Kane JM, Woerner M, Lieberman J. Epidemiological aspects of tardive dyskinesia. Encephale 1988;14:191–4.

48. Holt DJ, Herman MM, Hyde TM, Kleinman JE, Sinton CM, German DC, and others. Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia. Neuroscience 1999;94:21–31.

49. Mahadik SP, Laev H, Korenovsky A, Karpiak SE. Haloperidol alters rat CNS cholinergic system: enzymatic and morphological analyses. Biol Psychiatry 1988;24:199–217.

50. Jeste DV, Lohr JB, Manley M. Study of neuropathologic changes in the striatum following 4, 8 and 12 months of treatment with fluphenazine in rats. Psychopharmacology (Berl) 1992;106:154–60.

51. Grimm JW, Chapman MA, Zahm DS, See RE. Decreased choline acetyltransferase immunoreactivity in discrete striatal subregions following chronic haloperidol in rats. Synapse 2001;39:51–7.

52. Shioiri T, Hamakawa H, Kato T, Murashita J, Fujii K, Inubushi T, and others. Proton magnetic resonance spectroscopy of the basal ganglia in patients with schizophrenia: a preliminary report. Schizophr Res 1996;22:19–26.

53. Ando K, Takei N, Matsumoto H, Iyo M, Isoda H, Mori N. Neural damage in the lenticular nucleus linked with tardive dyskinesia in schizophrenia: a preliminary study using proton magnetic resonance spectroscopy. Schizophr Res 2002;57:273–9.

54. Caroff SN, Campbell EC, Havey J, Sullivan KA, Mann SC, Gallop R. Treatment of tardive dyskinesia with donepezil: a pilot study. J Clin Psychiatry 2001;62:772–5.

55. Caroff SN, Campbell EC, Havey JC, Sullivan KA, Katz IR, Mann SC. Treatment of tardive dyskinesia with donepezil. J Clin Psychiatry 2001;62:128–9.

56. Tammenmaa IA, McGrath JJ, Sailas E, Soares-Weiser K. Cholinergic medication for neuroleptic-induced tardive dyskinesia. (Cochrane Review). Cochrane Database Syst Rev 2002;(3):CD000207.

57. Lieberman JA, Saltz BL, Johns CA, Pollack S, Borenstein M, Kane J. The effects of clozapine on tardive dyskinesia. Br J Psychiatry 1991;158:503–10.

58. Factor SA, Friedman JH. The emerging role of clozapine in the treatment of movement disorders. Mov Disord 1997;12:483–96.

59. Cole JO, Gardos G, Deal T. Drug trials in persistent tardive dyskinesia. In: Fann WE, Smith RC, Davis JM, editors. Tardive dyskinesia: research and treatment. New York: SP Medical and Scientific Books; 1980.

60. Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT₂ and D₂ receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 1999;156:286–93.

61. Chakos MH, Shirakawa O, Lieberman J, Lee H, Bilder R, Tamminga CA. Striatal enlargement in rats chronically treated with neuroleptic. Biol Psychiatry 1998;44:675–84.

62. Scheepers FE, de Wied CC, Hulshoff Pol HE, van de FW, van der Linden JA, Kahn RS. The effect of clozapine on caudate nucleus volume in schizophrenic patients previously treated with typical antipsychotics. Neuropsychopharmacology 2001;24:47–54.

63. Gilliland SL, Alper RH. Characterization of dopaminergic compounds at hD2short, hD4.2 and hD4.7 receptors in agonist-stimulated [35S]GTPgammaS binding assays. Naunyn Schmiedebergs Arch Pharmacol 2000;361:498–504.

64. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, and others. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl) 1996;124:57–73.

65. Loetscher E, Kalkman HO. A comparison of the potencies of iloperidone and other antipsychotics in blocking alpha-2c-adrenoceptors. Int J Neuropsychopharmacol. Abstracts from the XXIInd CINP. Congress No P.01.164; 2000.

66. Bymaster FP, Tran P, Breier A. The multi-acting receptor-targeted antipsychotic (MARTA) concept of the therapeutic action of olanzapine. Zyprexa Investigator-Initiated Trial Program (Poster session 1, No 26); 2001.

67. Subramanian N, Kalkman HO. Receptor affinity of two human metabolites of iloperidone: novel mechanisms for psychotropic neuromodulation. Int J Neuropsychopharmacol Abstracts from the XXIInd CINP. Congress No P.01.163; 2000.

68. Frazier JA, Giedd JN, Kaysen D, Albus K, Hamburger S, Alaghband-Rad J, and others. Childhood-onset schizophrenia: brain MRI rescan after 2 years of clozapine maintenance treatment. Am J Psychiatry 1996;153:564–6.

69. Lang DJ, Kopala LC, Vandorpe RA, Rui Q, Smith GN, Goghari VM, and others. An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone. Am J Psychiatry 2001;158:625–31.

70. Gur RE, Maany V, Mozley PD, Swanson C, Bilker W, Gur RC. Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. Am J Psychiatry 1998;155:1711–7.

71. Chakos MH, Lieberman JA, Alvir J, Bilder R, Ashtari M. Caudate nuclei volumes in schizophrenic patients treated with typical antipsychotics or clozapine. Lancet 1995;345:456–7.

72. Corson PW, Nopoulos P, Miller DD, Arndt S, Andreasen NC. Change in basal ganglia volume over 2 years in patients with schizophrenia: typical versus atypical neuroleptics. Am J Psychiatry 1999;156:1200–4.

73. Andersson C, Lawler C, Mailman R, Lieberman J. Long-term administration of typical and atypical andtipsychotic drugs in rats. Zyprexa Investigator-Initiated Trial Program (Poster Session 1, No 2); 2001.

74. Mahadik SP, Evans DR. Pretreatment or posttreatment with olanzapine on haloperidol treatment-associated cholinergic dysfunction in rats. Zyprexa Investigator-Initiated Trial Program (Poster Session 1, No 24); 2001.

Author(s)

Manuscript received July 2004, revised, and accepted January 2005.

1. Assistant Professor, Department of Psychiatry, McGill University, Montreal, Quebec; Assistant Director, Clinical Psychopharmacology Unit, Consultation Service, McGill University Health Centre, Montreal, Quebec; Head, START Day Hospital Program, McGill University Health Centre, Montreal, Quebec; Assistant Program Director, RCPSC-accredited Residency Program in Clinical Pharmacology, McGill University, Montreal Quebec.

2. Professor, Department of Psychiatry, McGill University and Université de Montréal, Montreal, Quebec; Senior Researcher, Centre de recherche Fernand Séguin, Hôpital Louis-H Lafontaine, Montreal, Quebec; Head, Clinical Psychopharmacology Unit, McGill University Health Centre, Montreal, Quebec.

3. Assistant Professor, Department of Psychiatry, McGill University, Montreal, Quebec; Assistant Professor, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec.

4. Assistant Professor, Department of Psychiatry, McGill University, Montreal, Quebec; Associate Director, Clinical Psychopharmacology Unit, McGill University Health Centre, Montreal, Quebec; Associate Director, Special Follow-Up Clinic, Allan Memorial Institute, McGill University, Montreal, Quebec; Program Coordinator and Supervisor of Residents, RCPSC-accredited Residency Program in Clinical Pharmacology, McGill University, Montreal, Quebec.

5. Research Scientist, Otago Centre for Theoretical Studies in Psychiatry and Neuroscience, University of Otago, Dunedin, New Zealand; Honorary Fellow, Department of Anatomy and Structural Biology, University of Otago, Dunedin, New Zealand.

Address for correspondence: Dr HC Margolese, Clinical Psychopharmacology Unit, Allan Memorial Institute, 1025 Pine Avenue West, Montreal, QC H3A 1A1

e-mail: psychopharm.unit@mcgill.ca

1 | 2