A European perspective on tardive dyskinesia.

Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by the use of dopamine receptor-blocking agents (DRBAs), a category of medications that includes first- and second-generation antipsychotics (APs) and agents such as metoclopramide that are used for the treatment of nausea and gastrointestinal dysmotility. While TD can affect people of all ages, older age is associated with increased risk of TD and also with the emergence of TD occurring after shorter treatment durations and lower dosages of DRBAs. TD is characterized by involuntary movements that include the face, limbs, and trunk, and is associated with increased comorbidities, social stigmatization, and impaired physical and mental health. Once present, TD tends to persist despite AP dose adjustment or discontinuation. Even with the use of US Food and Drug Administration (FDA)-approved medications for TD, symptoms may persist. Because the leading hypothesis for the pathophysiology of TD has been dysregulation of dopamine transmission due to treatment with DRBAs, APs that avoid postsynaptic dopamine receptor blockade may provide an alternative therapeutic approach for patients who require an AP. In this review, we discuss the risks, burdens, prevention, and management of TD, with a focus on older people.

Tardive Dyskinesia: Assessing and Treating a Debilitating Side Effect of Prolonged Antipsychotic Exposure

Tardive dyskinesia is an involuntary athetoid or choreiform movement lasting a minimum of a few weeks. It is associated with the use of neuroleptic medication for at least three months and persists beyond four to eight weeks. Tardive dyskinesia usually occurs as a result of the long-term use of dopamine receptor-blocking agents, mainly first-generation antipsychotics or a high-dose, second-generation antipsychotic.We present a case of a 28-year-old female with osteogenesis imperfecta presented later with major depressive disorder with psychotic features. She was given a low-dose second-generation antipsychotic, namely, risperidone (2 mg) for psychosis for a cumulative duration of three months. As a result, she developed extrapyramidal symptoms in the form of akathisia, axial dystonia, involuntary movement of the right hand, and smacking movement of the lips. Symptoms persisted for more than eight weeks despite discontinuing risperidone and switching to quetiapine. After the exclusion of other differential diagnoses, she was labeled as a case of tardive dyskinesia. More studies are needed to assess whether undiscovered contributing factors to tardive dyskinesia exist and to understand how second-generation antipsychotics (SGAs) contribute to the development of tardive dyskinesia.

Treatment of Tardive Dyskinesia

What CATIE Found: Results From the Schizophrenia Trial

Tardive dyskinesia (TD) is a potentially irreversible movement disorder induced by dopamine receptor-blocking agents, including antipsychotics. Despite progress in antipsychotic medications, TD remains widely prevalent even in the era of second-generation antipsychotics. Early detection is critical for preventing irreversible damage and minimizing the disorder's impact on patients' daily lives. Risk factors for TD include advanced age, female sex, medical comorbidities, and prolonged use of dopamine receptor-blocking agents (DRBAs). Effective screening for TD should incorporate evidence-based screening techniques such as the Abnormal Involuntary Movement Scale (AIMS) and informal methods to capture a comprehensive view of TD's severity and impact. Combining these approaches allows for a thorough assessment of both healthcare practitioner-perceived severity and patient-reported effects on daily life. Modern treatment options, including vesicular monoamine transporter 2 (VMAT2) inhibitors like valbenazine and deutetrabenazine, have demonstrated significant efficacy and safety in clinical trials. Approved by the FDA in 2017, these medications enable continued psychiatric care while managing TD symptoms. Long-term studies support their sustained efficacy and safety, underscoring the importance of individualized, evidence-based treatment plans to improve patient outcomes.

Tardive Dyskinesia Induced by a Switch From Haloperidol Depot to Paliperidone Palmitate

Tardive dyskinesia is a drug-induced involuntary movement related to long-term use of dopamine receptor-blocking agents. If there is no improvement upon discontinuation or change in the causative drug, treatment needs to be initiated. The most effective drug is the vesicular monoamine transporter 2 selective inhibitor. Other drugs, such as clonazepam, amantadine, yokukansan, and Ginkgo biloba extract, may be effective in some patients. Botulinum toxin treatment and deep brain stimulation are potential treatment options for patients with tardive dyskinesia that is refractory to the aforementioned agents. Optimal treatment should be selected while monitoring for mental illnesses.

Gastroparesis is a debilitating disorder with limited treatment options, and metoclopramide remains the only FDA-approved pharmacologic therapy. Concerns about metoclopramide-induced tardive dyskinesia (TD) are based on older studies with inconsistent incidence estimates (1%-15%). A reassessment of metoclopramide's TD risk is needed. A retrospective cohort study using the MarketScan Research database analyzed TD incidence in adults (2011-2020) with at least 12 months of medical and pharmacy benefits. TD rates were compared among metoclopramide-treated gastroparesis patients, those untreated, and the general population. Poisson regression models adjusted for person-years (p-yrs) at risk. The incidence of TD among metoclopramide-treated gastroparesis patients was 159.4 per 100,000 p-yrs (0.37%), notably lower than guideline estimates (1%-15%). Comparatively, TD incidence was 121.3 (0.26%) in untreated gastroparesis patients, 51.4 (0.12%) among all metoclopramide users, and 7.6 (0.02%) in the general population. Higher TD rates were observed in older adults (≥ 65 years), females, and in patients with prolonged metoclopramide use, diabetes, psychiatric conditions, Parkinson's disease, or concurrent use of dopamine receptor-blocking agents. Adjusted analyses found no significant independent association between metoclopramide use and increased TD risk in gastroparesis patients. TD incidence is uncommon with metoclopramide use and lower than previously estimated in gastroparesis patients. These findings suggest metoclopramide may be a viable treatment option and warrant a reassessment of its risk-benefit profile in gastroparesis management.

The nosology of tardive syndromes

Back to table of contents Previous article Next article Letters to the EditorFull AccessComment on “Tardive Dyskinesia Circa 2006”ROBERT A. ROSENHECK M.D.,ROBERT A. ROSENHECK M.D.Search for more papers by this author,Published Online:1 Jan 2007https://doi.org/10.1176/ajp.2007.164.1.170AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Risk assessment of tardive dyskinesia might be further strengthened by considering its severity and impact on quality of life. Descriptive data from two clinical trials (1 , 2) are used to illustrate the relationship of Quality of Life Interview ratings and tardive dyskinesia levels documented by combined average scores on the three global ratings of the Abnormal Involuntary Movement Scale. Using 1,275 ratings from 423 refractory schizophrenia patients (1) and observations when no tardive dyskinesia was present as a reference point (mean Quality of Life Interview score=43.3 [SD=17.1]), mild tardive dyskinesia was associated with a 3.6-point lower (–8%) mean Quality of Life Interview rating, and moderate tardive dyskinesia was associated with a 6.9-point lower (–16%) mean Quality of Life Interview rating. After multivariate adjustment for differences in concurrent symptoms (total Positive and Negative Syndrome Scale scores), differences in adjusted means reversed direction. Adverse effects of tardive dyskinesia on ratings of quality of life were thus not independent of the effect of symptom severity in this cohort. Data from another trial (2) included 826 observations from 309 patients with schizophrenia. As compared with observations when no tardive dyskinesia was present (mean Quality of Life Interview score=47.2 [SD=16.7]), mild tardive dyskinesia was associated with a 4.0-point lower (–8%) average Quality of Life Interview rating, and moderate tardive dyskinesia was associated with a 2.2-point (–4.5%) lower rating. After adjusting for symptoms of schizophrenia and other neurological side effects, these differences were reduced only slightly to 3.6- and 1.8-point lower ratings (–7.4% and –3.6%, respectively). These data show average net reduction of quality of life associated with mild or moderate tardive dyskinesia ranging from 0% (based on the risk-adjusted analyses in the first cohort) to –16% (without adjustment). John M. Kane, M.D., (3) suggests a 3%–5% annual incidence of tardive dyskinesia in patients with first generation antipsychotics and 1% with newer medications. The attributable risk of tardive dyskinesia because of first generation antipsychotics would thus be 2%–4% per year. Multiplying the attributable risk by the reductions in quality of life estimated above, one can calculate average annual tardive dyskinesia-related reductions in quality of life attributable to first generation antipsychotics. This risk would be estimated to range from 0% (based on the risk-adjusted analysis of the first cohort) to a maximum of –0.64% (i.e., 0.04 attributable risk of tardive dyskinesia multiplied by –16% reduction in Quality of Life Interview scores). These analyses are limited, however, by the absence of data on severe tardive dyskinesia. An upper bound estimate of the average risk of decline in Quality of Life Interview scores because of mild or moderate tardive dyskinesia with first generation antipsychotics may thus be less than 1%. Clinical decision making must be based on individual patient circumstances and preferences, rather than on average risk calculations. However, side effect risks are central to antipsychotic treatment decisions, and it may be informative to use quantitative methods to evaluate their net effects on measures of well-being.West Haven, Conn.

Back to table of contents Previous article Next article Letters to the EditorFull AccessComment on “Tardive Dyskinesia Circa 2006”ROBERT A. ROSENHECK M.D.,ROBERT A. ROSENHECK M.D.Search for more papers by this author,Published Online:1 Jan 2007https://doi.org/10.1176/ajp.2007.164.1.170AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Risk assessment of tardive dyskinesia might be further strengthened by considering its severity and impact on quality of life. Descriptive data from two clinical trials (1 , 2) are used to illustrate the relationship of Quality of Life Interview ratings and tardive dyskinesia levels documented by combined average scores on the three global ratings of the Abnormal Involuntary Movement Scale. Using 1,275 ratings from 423 refractory schizophrenia patients (1) and observations when no tardive dyskinesia was present as a reference point (mean Quality of Life Interview score=43.3 [SD=17.1]), mild tardive dyskinesia was associated with a 3.6-point lower (–8%) mean Quality of Life Interview rating, and moderate tardive dyskinesia was associated with a 6.9-point lower (–16%) mean Quality of Life Interview rating. After multivariate adjustment for differences in concurrent symptoms (total Positive and Negative Syndrome Scale scores), differences in adjusted means reversed direction. Adverse effects of tardive dyskinesia on ratings of quality of life were thus not independent of the effect of symptom severity in this cohort. Data from another trial (2) included 826 observations from 309 patients with schizophrenia. As compared with observations when no tardive dyskinesia was present (mean Quality of Life Interview score=47.2 [SD=16.7]), mild tardive dyskinesia was associated with a 4.0-point lower (–8%) average Quality of Life Interview rating, and moderate tardive dyskinesia was associated with a 2.2-point (–4.5%) lower rating. After adjusting for symptoms of schizophrenia and other neurological side effects, these differences were reduced only slightly to 3.6- and 1.8-point lower ratings (–7.4% and –3.6%, respectively). These data show average net reduction of quality of life associated with mild or moderate tardive dyskinesia ranging from 0% (based on the risk-adjusted analyses in the first cohort) to –16% (without adjustment). John M. Kane, M.D., (3) suggests a 3%–5% annual incidence of tardive dyskinesia in patients with first generation antipsychotics and 1% with newer medications. The attributable risk of tardive dyskinesia because of first generation antipsychotics would thus be 2%–4% per year. Multiplying the attributable risk by the reductions in quality of life estimated above, one can calculate average annual tardive dyskinesia-related reductions in quality of life attributable to first generation antipsychotics. This risk would be estimated to range from 0% (based on the risk-adjusted analysis of the first cohort) to a maximum of –0.64% (i.e., 0.04 attributable risk of tardive dyskinesia multiplied by –16% reduction in Quality of Life Interview scores). These analyses are limited, however, by the absence of data on severe tardive dyskinesia. An upper bound estimate of the average risk of decline in Quality of Life Interview scores because of mild or moderate tardive dyskinesia with first generation antipsychotics may thus be less than 1%. Clinical decision making must be based on individual patient circumstances and preferences, rather than on average risk calculations. However, side effect risks are central to antipsychotic treatment decisions, and it may be informative to use quantitative methods to evaluate their net effects on measures of well-being.West Haven, Conn.

BackgroundAntipsychotics can potentially induce various involuntary movement, such as extrapyramidal symptoms (EPS) and tardive dyskinesia (TD)1. The specific risk associated with different classes of antipsychotics in causing these side effects in the Japanese population remains unclear.Aims & ObjectivesThe aim of this study is to investigate the risk of developing EPS and TD in relation to antipsychotics compared to other medications as well as to assess the variation in risk across different classes of antipsychotics.MethodWe conducted an analysis of the cases of EPS and TD reported in the Japanese Adverse Drug Event Report (JADER) database, published by PMDA, covering the period from April 2011 to March 2021. The reported cases encompassed a range of conditions, including akathisia, dystonia, dyskinesia, tremor, parkinsonism, dysarthria, rigidity, and hypersalivation. To identify potential signals, we calculated the reporting odds ratio (ROR) to compare 1) antipsychotics to other medications, 2) first- generation antipsychotics (FGAs) to second generation antipsychotics (SGAs), and sub-classes within SGA. Furthermore, we calculated the adjusted ROR, accounting for factors such as age, reported year, sex, and concomitant medication use, such as anticholinergic agents, and lithium.ResultsThe aggregate number of reported cases of EPS associated with antipsychotics was 3256 cases (including FGA: 398 cases, SGA; 2858 cases). TD cases associated with antipsychotics were 349 (FGA: 76 cases; SGA: 273 cases). Meanwhile, there were 3335 cases of EPS and 433 cases of TD associated with other medications. In comparison with other medications, the adjusted ROR and corresponding 95%CI indicates that antipsychotics were associated with a higher risk for akathisia (1.77 [1.51-2.08]), dyskinesia (2.89 [2.46-3.40]), parkinsonism (2.28 [2.05-2.53]), and hypersalivation (2.53 [2.17-2.96]). When comparing across different classes of antipsychotics, the adjusted ROR for FGAs compared to SGAs showed a higher risk for akathisia (1.61 [1.07-2.43]), dystonia (2.72 [2.17-3.41]), dyskinesia (4.50 [3.56-5.69]), and TD (2.41 [1.73- 3.35]), while SGAs were associated with a higher risk for parkinsonism (1.45 [1.11-1.88]) and hypersalivation (1.91 [1.26-2.89]) compared to FGAs.LimitationJADER is relying on reports not only from physicians, but also from other healthcare professionals, caregivers, and family members. The accuracy of EPS and TD diagnosis reported by non-physicians source may be constrained. Moreover, the information regarding the severity of symptoms and treatment outcomes is restricted in this database. Finally, the actual incidence of TD and EPS in patients exposed to antipsychotics and other medications cannot be estimated based on this dataset.Discussion & ConclusionThe ROR analysis using JADER could identify signals of antipsychotic-induced EPS and TD cases in Japan. Meanwhile, there were variations in the risk of EPS and TD across different types of antipsychotics.Notably, the EPS and TD risks were observed in both FGAs and SGAs.

Tardive dyskinesia (TD) is a movement disorder that presents with abnormal, involuntary, and irregular choreoathetoid movements involving mouth, tongue, face, trunk, or extremities after prolonged use of dopamine receptor-blocking agents. Currently, there is still a lack of effective treatment for it. Here, we report a female patient with paranoid schizophrenia, who has had persistent TD for 8 years. After electroconvulsive therapy (ECT) was performed, both of her psychotic symptoms and dyskinetic movements were improved. The efficacy and potential clinical variables of ECT in the treatment of TD were reviewed.

Back to table of contents Previous article Next article Letters to the EditorFull AccessAtypical Antipsychotics, Tardive Dyskinesia, and D 2 ReceptorsHARPREET S. DUGGAL M.D.,DATTATREYA NAMDEORAO MENDHEKAR M.D.,HARPREET S. DUGGAL M.D.Search for more papers by this author,DATTATREYA NAMDEORAO MENDHEKAR M.D.Search for more papers by this author,Published Online:1 Aug 2006https://doi.org/10.1176/ajp.2006.163.8.1449bAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Atypical antipsychotics are associated with lower incidence of tardive dyskinesia (1) . However, individual atypical antipsychotics may vary in their propensity to cause tardive dyskinesia, which may be, in part, because of differences in D 2 receptor affinity (2) . We describe the case of a patient who initially developed tardive dyskinesia while taking haloperidol. The tardive dyskinesia remitted when haloperidol was substituted with clozapine but recurred when olanzapine was added to clozapine. “Mr. A,” a 53-year-old man who was diagnosed with chronic schizophrenia, had been treated with various typical antipsychotic drugs such as haloperidol, trifluoperazine, and chlorpromazine. Three years prior, while taking haloperidol (up to 30 mg/day) for 4 months, he developed tardive dyskinesia (his chief symptom being a pin-rolling movement of the fingers). Haloperidol was subsequently discontinued, and clozapine was started and increased to 400 mg/day over a 6 week-period, with complete remission of tardive dyskinesia. Three years later, while on the same dose of clozapine, the patient experienced a relapse of psychotic symptoms. Because of significant sialorrhea that limited further dose increases of clozapine, olanzapine (10 mg/day) was added. Six weeks after adding olanzapine to clozapine, Mr. A developed truncal tardive dyskinesia, manifested by repetitive rhythmic and involuntary pelvic thrusting. His score on the Abnormal Involuntary Movement Scale was 12. Olanzapine was discontinued immediately, and sequential trials with propranolol, tetrabenazine, and quetiapine (up to 200 mg/day) did not result in any improvement in the patient’s symptoms of tardive dyskinesia. However, his involuntary movements disappeared 6 months after their onset, following resumption of monotherapy with clozapine (400 mg/day). Because of an upregulation of D 2 receptors induced by a blockade by antipsychotics, dopaminergic hypersensitivity remains the most accepted hypothesis of tardive dyskinesia (3) . Olanzapine has a higher affinity and striatal occupancy rate for D 2 receptors than clozapine, thus leading to greater upregulation and hypersensitivity of these receptors (4) . One study showed that olanzapine induced similar degrees of D 2 receptor upregulation as haloperidol (5) . This finding concurs with the observation in our patient, who developed tardive dyskinesia while taking haloperidol and again while taking olanzapine, but not while on clozapine. In a similar case, a patient developed tardive dyskinesia while taking olanzapine, which ameliorated with quetiapine but recurred on augmentation with risperidone, another atypical agent with a potent D 2 blockade (2) . In that particular case and in the case described here, tardive dyskinesia recurred more rapidly after re-exposure to a potent atypical D 2 antagonist. (2) . Thus, we encourage more research to determine the exact role of D 2 receptors in reversible tardive dyskinesia because of potent atypical antipsychotics and the rapid recurrence symptoms with these agents in patients with prior histories of tardive dyskinesia. Tecumseh, Mich.Delhi, India