Abstract
Objective
Tardive syndrome (TS) is an umbrella term used to describe a group of abnormal movement disorders caused by chronic exposure to dopamine receptor blocking agents. Few follow-up studies have been performed on the outcome of TS in patients using antipsychotics. The purpose of our study was to investigate the prevalence, incidence, remission rate, and factors associated with remission in patients using antipsychotics.
Methods
This retrospective cohort study consisted of 123 patients who received continuous treatment of antipsychotics in a medical center in Taiwan, from April 1, 2011 to May 31, 2021. We assessed the demographic and clinical characteristics, prevalence, incidence, remission rate, and factors associated with remission in patients using antipsychotics. TS remission was defined as a Visual Analogue Scale score ≤ 3.
Results
Of the 92 patients who completed the 10-year follow-up, 39 (42.4%) were found to have at least one episode of TS, with tardive dyskinesia (TD) being the most prevalent subtype (51.3%). With regard to concurrent physical illness, a history of extrapyramidal symptoms were significant risk factors for TS. During the 10-year follow-up period, the remission rate of TS was 74.3%. The use of antioxidants including vitamin B6 and piracetam was related to the remission of TS. Patients with tardive dystonia had a higher remission rate (87.5%) compared to TD (70%).
Conclusion
Our study suggests that TS may be a treatable condition, and the key to a better outcome is early detection and prompt intervention, including closely monitoring antipsychotics-related TS symptoms and using antioxidants.
Keywords: Antipsychotic agents, Tardive syndromes, Outcome, Longitudinal studies
INTRODUCTION
Tardive syndrome (TS) is an umbrella term used to describe a group of abnormal movement disorders caused by chronic exposure to dopamine receptor blocking agents (DRBA) [1] and was first defined as representing chronic and persistent neuroleptic-induced movement disorders in 1995 [2]. This condition is a challenge for both patients and clinicians due to its potentially permanent and debilitating course [3,4]. However, the prevalence and incidence remain difficult to estimate due to underdiagnosis and fluctuating symptom severity [5]. Of the 123 subjects included in one of our previous study, 35 patients (28.5%) were found to have at least one episode of TS [6].
The subtypes of TS include tardive dyskinesia (TD), tardive dystonia, tardive akathisia, tardive tremor, tardive myoclonus, tardive parkinsonism, tardive tics, and tardive sensory syndrome (tardive pain) [1,7]. TD, the most widely studied phenomenology of TS, manifests with classical oro-buccal-lingual dyskinesia and choreic movements and is believed to have the highest prevalence among TS [8]. In a 2017 meta-analysis of 41 studies with patients taking antipsychotics, the global mean of TD prevalence was 25.3% [9]. In our 2014 study, the prevalence of subtypes of TS was as follows: TD, 21.1%; tardive dystonia, 12.5%; tardive tremor, 2.4%; and tardive akathisia, 2.4% [6]. The TD prevalence of our 2014 study was similar to that of the 2017 meta-analysis study.
There were studies about the risk factor of TD, and TD is used to describe the choreic-athetoid syndrome as well as all TS. The most common risk factors of TD are older age, female gender, white or African descent, history of extrapyramidal symptoms (EPS), first generation antipsychotic (FGA) users, and presence of a major affective disorder [1,5]. Genes that are associated with the target receptor and metabolism of DRBA are also possible factors for TD, such as the cytochrome P450 gene, Dopa-mine D2 and D3 receptor genes, vesicular monoamine transporter 2 gene, and heparan sulfate proteoglycan 2 gene [10]. As for the relationship between TD and antipsychotic usage dose, results were inconsistent potentially due to the plateau effect [9] and possibly because higher doses of antipsychotic use are a risk factor of EPS.
Few follow-up studies have been carried out on TD or tardive dystonia. For example, in a prospective study of 99 of 182 patients available for reassessment after a 3- year-follow-up, the point prevalence of oro-facial dyskinesia increased from 39% to 47% [11]. In a 10-year follow-up study in Hungary, 66 out of 122 patients with TD received 5- and 10-year follow-up assessments, and the overall prevalence of TD changed little over time, with 30.2% at baseline, 36.5% at 5 years, and 31.7% at 10 years [12]. Another 10-year follow-up study of 10 patients with TD receiving FGA treatment showed an equal likelihood for improvement as for deterioration, while progressive worsening to severe forms of TD was not observed [13]. Based on the aforementioned follow-up studies, TD prevalence may change overtime with range from 30.2% to 47%, and outcomes were not consistent. There-fore, the outcomes of antipsychotic-induced TD need further follow-up study.
As for tardive dystonia, in a population-based nine-year follow-up study of 194 psychiatric patients on a Caribbean Island, 26 patients had tardive dystonia at baseline, and 64% recovered, 20% persisted, and 16% experienced an intermittent course. Of the 27 incident cases, 80% recovered, 8% persisted, and12% were intermittent [14]. Further follow-up large-scale studies on the outcome of tardive dystonia are warranted.
Treatment of TS include detection of possible causative agents with immediate discontinuation or reduction. Phar-macologic treatments with dopamine depleting agents, such as tetrabenazine, have been considered effective for treating TS [15], and benzodiazepine, particularly clonazepam, may be useful in the treatment of TD [16]. A 12-week, double-blind, randomized, crossover trial of 19 patients with TD showed a 37.1% reduction in the Mary-land Psychiatric Research Center movement disorders scale under treatment with clonazepam [17]. Other pharmacologic treatments included such antioxidants as vitamin E, vitamin B6, piracetam, and Ginkgo biloba [18-20]. A possible treatment effect of vitamin B6 was noted in a randomized, double-blind, placebo-controlled trial, show-ing that 1,200 mg per day of vitamin B6 may reduce scores on the Extrapyramidal Symptom Rating Scale (ESRS) to the extent of 2.4 units, compared to 0.2 units in the placebo group [18]. However, the overall treatment effect of antioxidants remains controversial due to the inconsistent results of current studies.
Non-pharmacologic treatments of TS include injection of botulinum toxin, electroconvulsive therapy (ECT), and deep brain stimulation (DBS). Case series have shown that botulinum toxin may also play a role in the treatment of tardive dyskinesia and tardive dystonia [11,21]. Some case reports have revealed the possible treatment effect of ECT [22,23], which also improved patients’ psychosis or mood. In the treatment of refractory TS with severe disability, DBS may be considered [24].
To the best of our knowledge, most of the studies about the outcome of antipsychotic-induced TS were cross-sectional studies. Further follow-up studies on this issue are warranted. The aims of our study are as follows: 1) To detect the prevalence, incidence, and remission rate of antipsychotic-induced TS; 2) To investigate the prevalence of various subtypes of antipsychotics-induced TS; 3) To research the clinical risk factors for this syndrome; and 4) To evaluate the treatment response of antioxidants and ECT to TS.
METHODS
Subject Recruitment and Assessment
This study was conducted as a retrospective cohort study and was approved by the Kaohsiung Chang Gung Memorial Hospital review board (202100879B0). Study subjects were consecutively recruited throughout the 10- year review of patient medical charts at a staff psychiatrist’s outpatient clinic at a medical center in southern Taiwan, based on the same subjects of our 2014 study, a retrospective epidemiological study about the prevalence of TS [6]. Any patient who received antipsychotics, but no other agents capable of causing involuntary movements, for at least 6 months was considered. Age and sex were not limited. We excluded patients who concomitantly used other medications that may have caused involuntary movements, such as reserpine, tetrabenazine, methyldopa, lithium, calcium channel blockers, antiemetic agents, antihistamines, central nervous system stimulants, and dopamine agonists.
Demographic characteristics including sex, age, education, marital status, and employment were obtained via chart review. Physical illnesses, history of EPS, mood disorders, and substance abuse were also reviewed. We closely examined their medical histories for antioxidant treatment and ECT. Assessment of TS was performed using Fahn and Jankovic’s criteria: 1) presenting as a late-onset and sometimes persistent abnormal involuntary movement, 2) caused by exposure to a dopamine receptor blocking agent within 6 months of the onset of symptoms, and 3) persisting for more than 1 month after stopping the offending drugs [25]. In the outpatient clinic setting, once we found that a subject had a possible TS diagnosis, we referred the patient to a collaborative neurologist (Y.Y.C.), who was an expert in movement disorders, to make a final confirmation of the TS diagnosis based on the clinical information, laboratory data, and image study including computed tomography of brain and 99mTc-TRODAT-1 SPECT of probable cases.
Subject Assessment and Treatment
Every subject included underwent a psychiatric diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition [26]. Diagnosis of TS was based on the criteria proposed by Fahn and Jankovic and the ESRS criteria of Chouinard and Margoles [27]. EPS was defined as reversible parkinsonism, acute dystonia, or akathisia based on clinical assessment. The severity of TS was further assessed by the staff psychiatrist using the Extrapyramidal Symptom Rating Scale (ESRS) [27], which can be broadly applied to drug-induced movement disorders and showed high concordance with Abnormal Involuntary Movement Scale [28]. Each TS patient’s score of ESRS were assessed by the same experienced staff psychiatrist twice (Yu Lee), in 2011 and 2021 respectively. The diagnosis of EPS was based on the clinical assessment and chart comments by the same psy-chiatrist. The severity of TS was also assessed by the visual analogue scale (VAS) to evaluate the condition in a clinical setting. A VAS is typically a straight line, with both ends anchored with two extreme boundaries of the sensation, feeling, or response to be measured (VAS: range, 0 = “no discomfort” to 10 = “worst discomfort you can imagine”). It has previously been used in a study that evaluated quality of life in patients with schizophrenia [29]. Accord-ing to our clinical experience, the level of VAS and severity of TS symptoms may be relevant. Most of the patients with severe symptoms of TS show great distress while those with mild symptoms are less bothered by the condition.
Once we diagnosed the TS subjects in the outpatient clinic, we promptly changed the offending antipsychotics and/or added antioxidants (e.g., piracetam or vitamin B6) to decrease TS symptoms. Under the aforementioned management, we closely monitored the symptoms of TS from 2011−2021, and TS remission was defined as a VAS score of 3 or smaller [30,31].
Statistical Analysis
The data are presented as means (standard deviation) and analyzed using IBM SPSS Statistics 25.0 for Windows (IBM Co.). Descriptive statistics (χ2 and ttest) was first used to test the difference in demographic characteristics, psychiatric diagnoses, physical illness history, history of EPS, and cumulative length of antipsychotics exposure, between subjects with and without TS. We adopted forward logistic regression to examine the possible risk factors for TS. Statistical significance was set at 2-tailed p < 0.05.
RESULTS
Initially, 123 subjects were included based on our 2014 study. Following the chart review, 31 of the subjects were excluded due to loss of follow-up. Therefore, this study consisted of 92 subjects who completed the 10-year follow-up period. Around two-thirds of the subjects were females and unmarried (65.2% and 68.5%), with a level of education lower than college and unemployed status (67.4% and 65.2%). The most prevalent psychiatric diagnosis of the subjects was schizophrenia (95.7%), followed by delusional disorder (2.2%) (Table 1). Among the 92 patients in our cohort study (Fig. 1), 12 of them had TS, and 80 patients did not have TS (Non-TS) in 2011. In the 12 patients with TS in 2011, eight patients had remitted TS, and four patients had non-remitted TS in 2021. As for the 80 patients without TS in 2011, 27 of them had new-onset TS, representing an incidence of 33.8%. Twenty-one of them showed remitted TS, while six of them showed non-remitted TS in 2021. The prevalence of TD was 21.7% (n = 20); tardive dystonia, 17.4% (n = 16); tardive tremor, 12.0% (n = 11); tardive akathisia, 1.1% (n = 1); and tardive parkinsonism, 1.1% (n = 1). None of the patients showed tardive myoclonus, tardive tics, or tardive sensory syndrome. Fifty-three patients remained TS-free during the 10-year follow-up. In total, 39 (42.4%) patients suffered from TS (10 males and 29 females) at some point during the 10-year follow-up. Among all the 92 patients, only four of them took two types of antipsychotics (Supplementary Table 1; available online). Among the 39 patients who experienced TS, the antipsychotics in use included sulpiride, risperidone, quetiapine, clozapine, amisulpride, aripiprazole, olanzapine, ziprasidone, and paliperidone (Table 2).
Table 1.
Demographic and clinical characteristics of patients with and without tardive syndrome
| Characteristic | TS (n = 39) | Non-TS (n = 53) | Total (n = 92) | χ2/ ttest | pvalue |
|---|---|---|---|---|---|
| Sex | 0.06 | 0.80 | |||
| Male | 13 (33.3) | 19 (35.8) | 32 (34.8) | ||
| Female | 26 (66.7) | 34 (64.2) | 60 (65.2) | ||
| Age (yr) | 54.2 (13.4) | 52.7 (10.28) | 53.4 (11.6) | 0.59 | 0.56 |
| Education (yr) | 11.21 (4.69) | 11.96 (3.84) | 11.54 (4.21) | −0.85 | 0.40 |
| Education | 2.60 | 0.27 | |||
| Under elementary school | 8 (20.5) | 5 (9.4) | 13 (14.1) | ||
| High school | 18 (46.2) | 31 (58.5) | 49 (53.3) | ||
| College and above | 13 (33.3) | 17 (32.1) | 30 (32.6) | ||
| Marital status | 0.60 | 0.44 | |||
| Unmarried | 25 (64.1) | 38 (71.7) | 63 (68.5) | ||
| Married | 14 (35.9) | 15 (28.3) | 29 (31.5) | ||
| Unemployment | 27 (69.2) | 33 (62.3) | 60 (65.2) | 0.48 | 0.49 |
| Psychiatric diagnosis | 4.19 | 0.24 | |||
| Delusional disorder | 0 | 2 (3.8) | 2 (2.2) | ||
| Organic delusional disorder | 1 (2.6) | 0 | 1 (1.1) | ||
| Schizoaffective disorder | 1 (2.6) | 0 | 1 (1.1) | ||
| Schizophrenia | 37 (94.9) | 51 (96.2) | 88 (95.7) | ||
| Mood disorder history | 16 (41.0) | 15 (28.3) | 31 (33.7) | 1.63 | 0.20 |
| Substance abuse | 2 (5.1) | 6 (11.3) | 8 (8.7) | 1.09 | 0.30 |
| Antioxidants | 21 (53.8) | 1 (1.9) | 22 (23.9) | 33.3 | < 0.001 |
| Physical illness | 37 (94.9) | 41 (77.4) | 78 (84.8) | 5.34 | 0.02 |
| Diabetes | 8 (20.5) | 4 (7.5) | 12 (13.0) | 3.33 | 0.07 |
| Hypertension | 10 (25.6) | 10 (18.9) | 20 (21.7) | 0.61 | 0.44 |
| Hyperlipidemia | 12 (30.8) | 10 (18.9) | 22 (23.9) | 1.75 | 0.19 |
| Hepatitis | 10 (25.6) | 5 (9.4) | 15 (16.3) | 4.33 | 0.04 |
| Electroconvulsive therapy | 10 (25.6) | 4 (7.5) | 14 (15.2) | 5.70 | 0.02 |
| Family history of schizophrenia | 5 (12.8) | 5 (9.4) | 10 (10.9) | 0.27 | 0.61 |
| Family historyof mood disorder | 2 (5.1) | 3 (5.7) | 5 (5.4) | 0.01 | 0.91 |
| History of EPS | 37 (94.9) | 24 (45.3) | 61 (66.3) | 24.73 | < 0.001 |
| Duration of psychiatric disorders (mo) | 293.5 (111.0) | 282.9 (78.3) | 287.4 (93.2) | 0.51 | 0.61 |
| Duration of antipsychotic use (mo) | 268.6 (89.5) | 264.5 (66.5) | 266.3 (76.7) | 0.24 | 0.81 |
| Antipsychotics | 3.21 | 0.07 | |||
| First generation | 1 (2.6) | 7 (13.2) | 8 (8.7) | ||
| Second generation | 38 (97.4) | 46 (86.8) | 84 (91.3) | ||
| Chlorpromazine equivalent doses of antipsychotics | 293.2 (33.3−1,293.8) | 224.3 (18.8−1,250.0) | 253.4 (18.8−1,293.8) | 1.37 | 0.17 |
Values are presented as number (%), mean (standard deviation), or median (range).
TS, tardive syndrome; EPS, extrapyramidal symptoms.
Fig. 1.
Flowchart of TS among pa-tients with using antipsychotics.
TS, tardive syndrome; Non-TS, no tardive syndrome; R-TS, remitted tardive syndrome; NR-TS, non-remitted tardive syndrome.
Table 2.
Tardive syndrome induced by different antipsychotics
| Antipsychotic drugs | Non-remitted tardive syndrome (n = 10) | Remitted tardive syndrome (n = 29) |
|---|---|---|
| First-generation antipsychotics (%) | ||
| Sulpiride | 0 | 1 (100.0) |
| Second-generation antipsychotics (%) | ||
| Olanzapine | 4 (50.0) | 4 (50.0) |
| Clozapine | 3 (27.3) | 8 (72.7) |
| Amisulpride | 1 (33.3) | 2 (66.7) |
| Aripiprazole | 1 (20.0) | 4 (80.0) |
| Paliperidone | 1 (50.0) | 1 (50.0) |
| Zotepine | 1 (50.0) | 1 (50.0) |
| Risperidone | 0 | 4 (100.0) |
| Quetiapine | 0 | 6 (100.0) |
Values are presented as number (%).
When examining the demographic data, none of the variables reached statistical significance as associated factors of TS (Table 1). In other possible associated factors for TS, the use of antioxidants (p < 0.001), history of EPS (p < 0.001), physical illness (p = 0.02), and ECT (p = 0.02) were found to have a significant association with TS. Among all items of physical illness, hepatitis had the strongest association with TS. The physical illnesses of our patients included stroke, diabetes mellitus, hepatitis, chronic pain, cancer, and other chronic illnesses, such as hypertension, hyperthyroidism, renal stone, gastric ulcer, hyperlipidemia, benign tumor (ovarian tumor, uterine myoma), and heart disease. The TS patients also demonstrate a trend of a higher prevalence of diabetes than Non-TS patients (20.5% vs. 5.7%) (p = 0.07).
When the significant associated factors above were analyzed relative to TS using the stepwise forward model of logistic regression, physical illness (odds ratio [OR]: 6.53; 95% confidence interval [CI]: 1.15−37.16; p < 0.05) and history of EPS (OR: 24.06; 95% CI: 4.92−117.78; p < 0.05) were found to be significant risk factors (Table 3).
Table 3.
Risk factors for tardive syndrome: logistic regression analysis
| Item | β | SE (β) | Wald | OR | 95% CI | pvalue |
|---|---|---|---|---|---|---|
| Physical illness | 1.88 | 0.89 | 4.47 | 6.53 | 1.148−37.162 | 0.034 |
| History of EPS | 3.18 | 0.81 | 15.41 | 24.06 | 4.916−117.775 | < 0.001 |
| Electroconvulsive therapy | 1.64 | 0.84 | 3.82 | 5.17 | 0.996−26.846 | 0.051 |
Values are presented as numbers and odds ratio (95% confidence interval).
OR, odds ratio; CI, confidence interval; EPS, Extrapyramidal symptoms.
We further classified the 39 patients with TS into remitted (n = 29, 74.4%) and non-remitted TS (n = 10, 25.6%). The remission rate was 74.4%. The mean (standard deviation) ESRS score of non-remitted TS was 8.20 ± 3.05. The VAS of remitted and non-remitted TS were 1.59 and 5.10, respectively. When examining the demographic and clinical characteristics of patients with non-remitted or remitted TS, the use of antioxidants (p = 0.02) and duration of antipsychotic (p = 0.02) use reached statistical signifi-cance. We observed no differences in terms of history of EPS (p = 0.39), physical illness (p = 0.39), or ECT (p = 0.23) (Table 4).
Table 4.
Demographic and clinical characteristics of patients with non-remitted tardive syndrome and remitted tardive syndrome
| Characteristic | Non-remitted TS (n = 10) | Remitted TS (n = 29) | Total (n = 39) | χ2/ttest | pvalue |
|---|---|---|---|---|---|
| Sex | 0.07 | 0.80 | |||
| Male | 3 (30.0) | 10 (34.5) | 13 (33.3) | ||
| Female | 7 (70.0) | 19 (65.5) | 26 (66.7) | ||
| Age (yr) | 57.6 (11.5) | 53.0 (13.9) | 54.2 (13.4) | 0.94 | 0.35 |
| Education (yr) | 9.9 (4.7) | 11.7 (4.7) | 11.21 (4.7) | −1.02 | 0.31 |
| Education | 3.32 | 0.19 | |||
| Under elementary school | 4 (40.0) | 4 (13.8) | 8 (20.5) | ||
| High school | 4 (40.0) | 14 (48.3) | 18 (46.2) | ||
| College and above | 2 (20.0) | 11 (37.9) | 13 (33.3) | ||
| Marital status | 0.20 | 0.65 | |||
| Unmarried | 7 (70.0) | 18 (62.1) | 25 (64.1) | ||
| Married | 3 (30.0) | 11 (37.9) | 14 (35.9) | ||
| Unemployment | 9 (90.0) | 18 (62.1) | 27 (69.2) | 2.72 | 0.10 |
| Psychiatric diagnosis | 3.28 | 0.19 | |||
| Organic delusional disorder | 0 | 1 (3.4) | 1 (2.6) | ||
| Schizoaffective disorder | 1 (10.0) | 0 | 1 (2.6) | ||
| Schizophrenia | 9 (90.0) | 28 (96.6) | 37 (94.9) | ||
| Mood disorder history | 5 (50.0) | 11 (37.9) | 16 (41.0) | 0.45 | 0.50 |
| Substance abuse | 0 | 2 (6.9) | 2 (5.1) | 0.73 | 0.39 |
| Antioxidants | 9 (90.0) | 12 (41.4) | 21 (53.8) | 7.07 | 0.008 |
| Vitamin B6 | 9 (90.0) | 9 (31.0) | 18 (46.2) | 10.40 | 0.001 |
| Piracetam | 8 (80.0) | 5 (17.2) | 13 (33.3) | 13.18 | < 0.001 |
| Vitamin B6 and Piracetam | 8 (80.0) | 2 (6.9) | 10 (25.6) | 20.84 | < 0.001 |
| Physical illness | 10 (100) | 27 (93.1) | 37 (94.9) | 0.73 | 0.39 |
| Diabetes | 3 (30.0) | 5 (17.2) | 8 (20.5) | 0.74 | 0.39 |
| Hypertension | 2 (20.0) | 8 (27.6) | 10 (25.6) | 0.22 | 0.64 |
| Hyperlipidemia | 4 (40.0) | 8 (27.6) | 12 (30.8) | 0.54 | 0.46 |
| Hepatitis | 1 (10.0) | 9 (31.0) | 10 (25.6) | 1.73 | 0.19 |
| Electroconvulsive therapy | 4 (40.0) | 6 (20.7) | 10 (25.6) | 1.45 | 0.23 |
| Family historyof schizophrenia | 1 (20.0) | 4 (13.8) | 5 (12.8) | 0.10 | 0.76 |
| Family history of mood disorder | 1 (10.0) | 1 (3.4) | 2 (5.1) | 0.66 | 0.42 |
| History of EPS | 10 (100.0) | 27 (93.1) | 37 (94.9) | 0.73 | 0.39 |
| Duration of psychiatric disorders (mo) | 338.4 (91.9) | 278.7 (114.2) | 293.5 (111.0) | 1.51 | 0.14 |
| Duration of antipsychotic use (mo) | 316.8 (87.9) | 252.0 (85.3) | 268.6 (89.5) | 2.06 | 0.047 |
| Antipsychotics | 0.35 | 0.55 | |||
| First generation | 0 | 1 (3.4) | 1 (2.6) | ||
| Second generation | 10 (100.0) | 28 (96.6) | 38 (97.4) | ||
| Antipsychotics changed | 2 (20.0) | 14 (48.3) | 16 (41.0) | 2.46 | 0.12 |
| Chlorpromazine equivalent doses of antipsychotics | 292.7 (50.0−800.0) | 293.4 (33.3−1,293.8) | 293.2 (33.3−1,293.8) | −0.01 | 1.00 |
Values are presented as number (%), mean (standard deviation), or median (range).
TS, tardive syndrome; EPS, extrapyramidal symptoms.
We also analyzed the factors associated with remitted TS, using the stepwise forward model of logistic regres-sion. Antioxidants (OR: 0.01; 95% CI: 0.000−0.273; p = 0.007), duration of antipsychotic use (OR: 0.98; 95% CI: 0.969−0.998; p = 0.023), and change of antipsychotic (OR: 28.16; 95% CI: 1.341−591.169; p = 0.032) were all significant associated factors (Table 5).
Table 5.
Factors associated to remitted tardive syndrome: Logistic regression analysis
| Item | β | SE (β) | Wald | OR | 95% CI | pvalue |
|---|---|---|---|---|---|---|
| Antioxidants | −4.70 | 1.74 | 7.33 | 0.01 | 0.000−0.273 | 0.007 |
| Duration of antipsychotic use | −0.02 | 0.01 | 5.20 | 0.98 | 0.969−0.998 | 0.023 |
| Antipsychotics changed | 3.34 | 1.55 | 4.62 | 28.16 | 1.341−591.169 | 0.032 |
Values are presented as numbers and odds ratio (95% confidence interval).
OR, odds ratio; CI, confidence interval.
DISCUSSION
Prevalence
In our 10-year-follow-up study, we evaluated 92 patients who used antipsychotics. The overall prevalence of TS was 42.4%, and the prevalence of TD was 21.7%. Most available studies address the prevalence of TD instead of TS. In a 2017 meta-analysis including 41 studies from 2000 to 2015, the global mean of TD prevalence during treatment with FGAs and/or second generation antipsychotics was 25.3% [32], which is similar to the results of our study. The overall prevalence of TD is estimated to be around 30% among outpatients treated with antipsychotics, ranging from 20% to 50% [9], another finding consistent with our results. A 2014 study of 584 male inpatients with schizophrenia in China revealed an overall TD prevalence of 44.5% [33], which was higher than in our study. Prevalence of TD varies substantially between studies, and several reasons could be causing these differences. First of all, the definition of TD may differ from study to study, with some of them labeling all other subtypes, such as tardive dystonia or tardive tremor, as TD, while others specifically focused on classical TD. Second, the severity and clinical course of TD may fluctuate due to the masking of symptoms by medications, such as the hypokinetic effect of antipsychotics [34] or the muscle relaxant properties of BZDs [16]. Third, due to the outbreak of COVID-19, the wearing of masks may have increased the difficulty in detecting TS due to covering the face [35]. Fourth, the differences of possible risk factors of TS, such as age, sex, race, history of EPS [2], and duration treatment among study samples may cause inconsistencies in the results.
The prevalence of tardive dystonia also varied among different studies. In a 1996 study of 194 people in the Dutch Antilles, the prevalence of tardive dystonia was 13.4% [36], similar to that of our study (17.4%). In a 2017 longitudinal study of 1,120 patients with non-affective psychosis, the prevalence of tardive dystonia was 1.5% [37], which is much lower than that of our study. Possible explanations for this difference are the older mean age of our study group (53.4 vs. 27) and the inclusion of patients with mild symptoms of tardive dystonia [14,36]. Tardive tremor is a rare subtype of TS, with few cases reports elicited in prior studies [38]. The increasing prevalence from 2.4% to 12% according to our previous and present study showed that tardive tremor may be underdiagnosed/under-recognized in other studies [6]. Additional studies are needed to test this hypothesis.
Incidence
The 10-year incidence of TS in our study was 33.8%, with the 10-year incidence of TD and tardive dystonia being 12.5% and 15%, respectively. Few studies have specifically addressed the incidence of TS, with most of them focusing on TD. In a 3-year follow-up study with 182 patients, the incidence of TD was 37% [11]. In another nine-year follow-up study of 194 psychiatric patients, the cumulative nine-year incidence of tardive dystonia was 16.1% [14]. The results of TS incidence are inconsistent among different studies, but the incidence rates of TS, TD, and tardive dystonia in our study were relatively lower than in others. We suggest that early detection and intervention of TS-like symptoms, such as EPS, may partially explain our lower incidence of TS compared to other studies.
Remission Rate
In our study, the remission rate of subtypes of TS were high, with TD, 70%; tardive dystonia, 87.5%; tardive tremor, 63.6%; and tardive parkinsonism, 100%. Com-pared with our previous study [6], the growing number of remission rates in patients with TD and tardive dystonia during the 10-year follow-up period revealed the possible reversibility of TS. In a retrospective cohort of 108 TS patients, only 13% of the patients experienced reversibility of TS [4]. The aforementioned study demonstrated a low remission rate for TS in both psychiatric and non-psychiatric patients, which differed from our results that showed a high remission rate of 74.3% in patients with TS. A possible explanation of the high remission rate in our study may be the regular screening of TS symptoms by asking patients during each visit to the out-patient clinic. Doing so may help with the early detection of TS, with a higher chance of finding cases with mild symptoms. Further-more, early intervention in these patients may lead to a higher chance of remission. This correlation of higher case-finding and better remission rate is also seen in the series of studies by van Harten et al. [14,36].
According to a 2001 study of patients with schizophrenia, TD improved and parkinsonism worsened in patients who continued to receive neuroleptic drugs over a 14-year period [39]. However, we did not trace the severity of EPS such as parkinsonism or akathisia during the 10-year follow-up. Further studies are needed to evaluate the possibility of TD improvement at the expense of worsening of parkinsonism.
Another possible explanation of high remission rate may be the treatment role of antioxidants, especially vitamin B6 and piracetam. In our study, once TS is noted, we immediately treated patients with antioxidants, especially in patients with severe TS. This may explain why more patients with non-remitted TS received the treatment of antioxidants than remitted TS patients (Table 4). A randomized, double-blind, placebo-controlled study of treatment with vitamin B6 in 50 TD patients showed that a daily dose of 1,200 mg of vitamin B6 decreased ESRS to the extent of 5.2 points [18]. A similar study of the treatment with piracetam in 40 patients of TD revealed a mean decrease of ESRS of 3.0 points with the daily dose of 1,200 mg of piracetam [40]. Piracetam has been shown to have effects on neurotransmission, neuroprotection, and neuroplasticity [41]. The specific mechanism by which piracetam may have the efficacy on treating TS is not clear, and further studies for evaluation are needed. According to the results of our study and other trials, the treatment role of antioxidants in patients with TS may be promising. Further large-scale studies are needed to confirm this treatment effect.
Risk Factors
Regarding the clinical risk factors for TS, history of EPS (p < 0.001) and physical illness (p = 0.02) both had a significant association with TS, which is consistent with our previous study [6]. This result implicated that both history of EPS and physical illness are true risks that contribute to the development of TS [7,9]. Moreover, hepatitis and then diabetes mellitus were observed to have the strongest associations with TS among all items of physical illness. Recent animal studies of the beneficial treatment effect of isoflavones [34,42] in oral dyskinesia revealed the possible pathophysiology of TS in inflammation, which may offer us a way of interpreting how physical illnesses with relatively inflammatory states may be related to a higher risk of TS. However, in a 2018 study of 170 patients with bipolar disorder, the levels of inflammatory markers including interleukin-6 and high sensitivity C-reactive protein did not differ between patients with and without tardive dyskinesia [43]. More human studies will be required to clarify the relation of TS and inflammation.
ECT may be related with TS (p = 0.02), with more patients with TS receiving ECT compared with patients without TS. Patients in our study received ECT due to severe TS or psychosis and were more likely to receive a higher dose of antipsychotics or have a longer treatment course, which made them more susceptible to TS. However, it did not reach a significant difference in the logistic regression analysis, which may have been due to only a few patients receiving ECT in our study (n = 14). A 2014 Japanese study of 18 patients with tardive involuntary movement disorders showed a response rate of 39% of ECT [44]. Several case reports also showed that ECT improved not only TS but also symptoms of depression [22,45,46]. ECT can be considered in patients with severe TS, but studies with larger scales will be needed to verify this indication.
Few studies have addressed the associated factors of remitted TS, and the results of those have been inconsistent. Factors such as younger age at onset, shorter duration of therapy, and faster withdrawal appeared to improve outcomes of TS in some studies [47]. In a 2018 Cochrane Review of 13 randomized controlled trials involving 771 subjects [48], none of the interventions, including discontinuation, switching, or lowering the dose of antipsychotics, showed benefit to the outcome of TS. In our results, duration of antipsychotic use and change of antipsychotic showed a possible relationship with remitted TS. We suggested that the shorter duration of antipsychotic use and the prompt change of antipsychotic are associated factors of remitted TS. As for the use of antioxidants as a negative associate of remitted TS, possible explanations are rigorous clinical management for patients with non-remitted TS condition and limited case numbers. Additional studies are needed to test this finding.
Strengths and Limitations
This retrospective cohort study is the first to focus on the prevalence, incidence, and remission rate of patients with antipsychotic-induced TS. However, our study also has some limitations. First, the follow-up rate of this study is around 75%, with 31 out of 123 patients being lost to follow-up. The missing data may influence the accuracy, but this still remains the largest study about the follow-up of TS in patients with continuous treatment of antipsy-chotics. Second, there were different diagnostic criteria for TS, which may cause variation when comparing our study with others. Third, the severity of TD determines the quality of life, and patients with moderate to severe TD symptoms are often bothered [49]. However, patients with dyskinesias of the choreo-athethoid type, including TD, often do not perceive their movements even when others perceive them as moderate. The assessment of patients by using VAS was subjective, and whether VAS represented the severity of TD symptoms remains uncertain. Fourth, most of the patients with TS in our study were being treated with SGA, so we were not able to clarify the risk between SGA and FGA use. Fifth, both the duration of the illness and the duration of the treatment were reviewed by history taking and medical charts, and recall bias may be noted especially in patients with longer illness duration. Sixth, we did not exclude patients being treated with clonazepam or other BZDs, which may become a confounding factor when evaluating the treatment response of antioxidants or ECT. Finally, we chose only vitamin B6 and piracetam to treat our patient with TS due to the concern of accessibility and tolerance. The treatment role of other antioxidants such as vitamin E was not assessed.
In conclusion, our study suggested that TS may be a treatable condition, despite recurrence being noted. Re-gular screening of TS symptoms by the physician’s examination and the patients’ report may be helpful for the early detection of TS. The use of antioxidants, such as vitamin B6 and piracetam, may warrant more studies to support their role in the treatment of TS. Close monitoring of antipsychotics-related TS symptoms should be continued even after remission to prevent the possibility of recurrence.
Funding Statement
Funding None.
Footnotes
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Conceptualization: Yu Lee, Yung-Yee Chang, Pao-Yen Lin. Data curation: Yu Lee, Yung-Yee Chang, Pao-Yen Lin. Formal analysis: Pei-Chien Chou, Liang-Jen Wang. Methodology: Yu Lee, Pei-Chien Chou, Liang-Jen Wang. Project administration: Yu Lee, Yung-Yee Chang, Pao-Yen Lin. Writing−original draft: Pei-Chien Chou. Writing−review & editing: Yu Lee, Liang-Jen Wang
References
- 1.Truong DD, Frei K. Setting the record straight: The nosology of tardive syndromes. Parkinsonism Relat Disord. 2019;59:146–150. doi: 10.1016/j.parkreldis.2018.11.025. [DOI] [PubMed] [Google Scholar]
- 2.Jankovic J. Tardive syndromes and other drug-induced movement disorders. Clin Neuropharmacol. 1995;18:197–214. doi: 10.1097/00002826-199506000-00001. [DOI] [PubMed] [Google Scholar]
- 3.Sienaert P, van Harten P, Rhebergen D. The psychopharmacology of catatonia, neuroleptic malignant syndrome, akathisia, tardive dyskinesia, and dystonia. Handb Clin Neurol. 2019;165:415–428. doi: 10.1016/B978-0-444-64012-3.00025-3. [DOI] [PubMed] [Google Scholar]
- 4.Zutshi D, Cloud LJ, Factor SA. Tardive syndromes are rarely reversible after discontinuing dopamine receptor blocking agents: Experience from a university-based movement disorder clinic. Tremor Other Hyperkinet Mov (N Y) 2014;4:266. doi: 10.5334/tohm.199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Tarsy D, Baldessarini RJ. Epidemiology of tardive dyskinesia: Is risk declining with modern antipsychotics? Mov Disord. 2006;21:589–598. doi: 10.1002/mds.20823. [DOI] [PubMed] [Google Scholar]
- 6.Lee MJ, Lin PY, Chang YY, Chong MY, Lee Y. Antipsychotics- induced tardive syndrome: A retrospective epidemiological study. Clin Neuropharmacol. 2014;37:111–115. doi: 10.1097/WNF.0000000000000040. [DOI] [PubMed] [Google Scholar]
- 7.Chen CY, Chiang HL, Fuh JL. Tardive syndrome: An update and mini-review from the perspective of phenomenology. J Chin Med Assoc. 2020;83:1059–1065. doi: 10.1097/JCMA.0000000000000435. [DOI] [PubMed] [Google Scholar]
- 8.Solmi M, Pigato G, Kane JM, Correll CU. Clinical risk factors for the development of tardive dyskinesia. J Neurol Sci. 2018;389:21–27. doi: 10.1016/j.jns.2018.02.012. [DOI] [PubMed] [Google Scholar]
- 9.Aquino CC, Lang AE. Tardive dyskinesia syndromes: Current concepts. Parkinsonism Relat Disord. 2014;20 Suppl 1:S113–S117. doi: 10.1016/S1353-8020(13)70028-2. [DOI] [PubMed] [Google Scholar]
- 10.Frei K. Tardive dyskinesia: Who gets it and why. Parkinsonism Relat Disord. 2019;59:151–154. doi: 10.1016/j.parkreldis.2018.11.017. [DOI] [PubMed] [Google Scholar]
- 11.Barnes TR, Kidger T, Gore SM. Tardive dyskinesia: A 3-year follow-up study. Psychol Med. 1983;13:71–81. doi: 10.1017/S003329170005008X. [DOI] [PubMed] [Google Scholar]
- 12.Gardos G, Casey DE, Cole JO, Perenyi A, Kocsis E, Arato M, et al. Ten-year outcome of tardive dyskinesia. Am J Psychiatry. 1994;151:836–841. doi: 10.1176/ajp.151.6.836. [DOI] [PubMed] [Google Scholar]
- 13.Rittmannsberger H. Ten year outcome of tardive dyskinesia during continuous treatment with first generation antipsycho-tics. Psychiatr Danub. 2008;20:461–465. [PubMed] [Google Scholar]
- 14.van Harten PN, Matroos GE, Van Os J. The course of tardive dystonia in Afro Caribbean patients, a population-based study: The Curacao extrapyramidal syndromes study: VII. Schizophr Res. 2008;98:79–83. doi: 10.1016/j.schres.2007.09.010. [DOI] [PubMed] [Google Scholar]
- 15.Niemann N, Jankovic J. Treatment of tardive dyskinesia: A general overview with focus on the vesicular monoamine transporter 2 inhibitors. Drugs. 2018;78:525–541. doi: 10.1007/s40265-018-0874-x. Erratum in: Drugs 2018;78:609. [DOI] [PubMed] [Google Scholar]
- 16.Bashir HH, Jankovic J. Treatment of tardive dyskinesia. Neurol Clin. 2020;38:379–396. doi: 10.1016/j.ncl.2020.01.004. [DOI] [PubMed] [Google Scholar]
- 17.Thaker GK, Nguyen JA, Strauss ME, Jacobson R, Kaup BA, Tamminga CA. Clonazepam treatment of tardive dyskinesia: A practical GABAmimetic strategy. Am J Psychiatry. 1990;147:445–451. doi: 10.1176/ajp.147.4.445. [DOI] [PubMed] [Google Scholar]
- 18.Lerner V, Miodownik C, Kaptsan A, Bersudsky Y, Libov I, Sela BA, et al. Vitamin B6 treatment for tardive dyskinesia: A ran-domized, double-blind, placebo-controlled, crossover study. J Clin Psychiatry. 2007;68:1648–1654. doi: 10.4088/JCP.v68n1103. [DOI] [PubMed] [Google Scholar]
- 19.Lohr JB, Caligiuri MP. A double-blind placebo-controlled study of vitamin E treatment of tardive dyskinesia. J Clin Psychiatry. 1996;57:167–173. [PubMed] [Google Scholar]
- 20.Zheng W, Xiang YQ, Ng CH, Ungvari GS, Chiu HF, Xiang YT. Extract of Ginkgo biloba for tardive dyskinesia: Meta-analysis of randomized controlled trials. Pharmacopsychiatry. 2016;49:107–111. doi: 10.1055/s-0042-102884. [DOI] [PubMed] [Google Scholar]
- 21.Rapaport A, Sadeh M, Stein D, Levine J, Sirota P, Mosheva T, et al. Botulinum toxin for the treatment of oro-facial-lingual-masticatory tardive dyskinesia. Mov Disord. 2000;15:352–355. doi: 10.1002/1531-8257(200003)15:2<352::AID-MDS1030>3.0.CO;2-X. [DOI] [PubMed] [Google Scholar]
- 22.Yeh JY, Chiu NM, Chang YY, Lin PY, Lee Y. Successful electroconvulsive therapy for a 74-year-old female with major depressive disorder and tardive tremor: A case report and literature review. Clin Psychopharmacol Neurosci. 2020;18:331–336. doi: 10.9758/cpn.2020.18.2.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Yahya AS, Khawaja S. Electroconvulsive therapy as a treatment for tardive dyskinesia. Prim Care Companion CNS Disord. 2021;23:20r02775. doi: 10.4088/PCC.20r02775. [DOI] [PubMed] [Google Scholar]
- 24.Macerollo A, Deuschl G. Deep brain stimulation for tardive syndromes: Systematic review and meta-analysis. J Neurol Sci. 2018;389:55–60. doi: 10.1016/j.jns.2018.02.013. [DOI] [PubMed] [Google Scholar]
- 25.Jankovic J, Hallett M, Okun MS, Comella C, Fahn S. Principles and practice of movement disorders E-book. Elsevier Health Sciences; Philadelphia: 2021. [DOI] [Google Scholar]
- 26.American Psychiatric Association, author. Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association; Washington, D.C.: 2013. [DOI] [Google Scholar]
- 27.Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS) Schizophr Res. 2005;76:247–265. doi: 10.1016/j.schres.2006.03.043. Erratum in: Schizophr Res 2006;85:305. [DOI] [PubMed] [Google Scholar]
- 28.Gharabawi GM, Bossie CA, Lasser RA, Turkoz I, Rodriguez S, Chouinard G. Abnormal Involuntary Movement Scale (AIMS) and Extrapyramidal Symptom Rating Scale (ESRS): Cross-scale comparison in assessing tardive dyskinesia. Schizophr Res. 2005;77:119–128. doi: 10.1016/j.schres.2005.03.008. [DOI] [PubMed] [Google Scholar]
- 29.Caroff SN, Yeomans K, Lenderking WR, Cutler AJ, Tanner CM, Shalhoub H, et al. RE-KINECT: A prospective study of the presence and healthcare burden of tardive dyskinesia in clinical practice settings. J Clin Psychopharmacol. 2020;40:259–268. doi: 10.1097/JCP.0000000000001201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Pérez V, Martínez-Navarro R, Pérez-Aranda A, Martínez-Sadurní L, Arranz-Estévez FJ, Colom F, et al. A multicenter, observa-tional study of pain and functional impairment in individuals with major depressive disorder in partial remission: The DESIRE study. J Affect Disord. 2021;281:657–660. doi: 10.1016/j.jad.2020.11.095. [DOI] [PubMed] [Google Scholar]
- 31.Correll DJ. The measurement of pain: Objectifying the subjective. In: Waldman SD, editor. Pain management. Elsevier Inc.; Philadelphia: 2007. pp. 197–211. [DOI] [Google Scholar]
- 32.Carbon M, Hsieh CH, Kane JM, Correll CU. Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: A meta-analysis. J Clin Psychiatry. 2017;78:e264–e278. doi: 10.4088/JCP.16r10832. [DOI] [PubMed] [Google Scholar]
- 33.Ye M, Tang W, Liu L, Zhang F, Liu J, Chen Y, et al. Prevalence of tardive dyskinesia in chronic male inpatients with schizophrenia on long-term clozapine versus typical antipsychotics. Int Clin Psychopharmacol. 2014;29:318–321. doi: 10.1097/YIC.0000000000000041. [DOI] [PubMed] [Google Scholar]
- 34.Mezzomo NF, da Silva Schmitz I, de Lima VB, Dorneles GP, Schaffer LF, Boeck CR, et al. Reversal of haloperidol-induced orofacial dyskinesia and neuroinflammation by isoflavones. Mol Biol Rep. 2022;49:1917–1923. doi: 10.1007/s11033-021-07003-7. [DOI] [PubMed] [Google Scholar]
- 35.Laboe C, Jain A, Cardiel Sam H. Masked tardive dyskinesia in the coronavirus disease 2019 era. Cureus. 2021;13:e16999. doi: 10.7759/cureus.16999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.van Harten PN, Matroos GE, Hoek HW, Kahn RS. The prevalence of tardive dystonia, tardive dyskinesia, parkinsonism and akathisia The Curaçao Extrapyramidal Syndromes Study: I. Schizophr Res. 1996;19:195–203. doi: 10.1016/0920-9964(95)00096-8. [DOI] [PubMed] [Google Scholar]
- 37.Mentzel TQ, Lieverse R, Bloemen O, Viechtbauer W, van Harten PN. High incidence and prevalence of drug-related movement disorders in young patients with psychotic dis-orders. J Clin Psychopharmacol. 2017;37:231–238. doi: 10.1097/JCP.0000000000000666. [DOI] [PubMed] [Google Scholar]
- 38.Kashyap S, Ceponiene R, Savla P, Bernstein J, Ghanchi H, Ananda A. Resolution of tardive tremor after bilateral subthalamic nucleus deep brain stimulation placement. Surg Neurol Int. 2020;11:444. doi: 10.25259/SNI_723_2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Fernandez HH, Krupp B, Friedman JH. The course of tardive dyskinesia and parkinsonism in psychiatric inpatients: 14-year follow-up. Neurology. 2001;56:805–807. doi: 10.1212/WNL.56.6.805. [DOI] [PubMed] [Google Scholar]
- 40.Libov I, Miodownik C, Bersudsky Y, Dwolatzky T, Lerner V. Efficacy of piracetam in the treatment of tardive dyskinesia in schizophrenic patients: A randomized, double-blind, placebo-controlled crossover study. J Clin Psychiatry. 2007;68:1031–1037. doi: 10.4088/JCP.v68n0709. [DOI] [PubMed] [Google Scholar]
- 41.Winblad B. Piracetam: A review of pharmacological properties and clinical uses. CNS Drug Rev. 2005;11:169–182. doi: 10.1111/j.1527-3458.2005.tb00268.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Wang MH, Yang CC, Tseng HC, Fang CH, Lin YW, Soung HS. Naringin ameliorates haloperidol-induced neurotoxicity and orofacial dyskinesia in a rat model of human tardive dyskinesia. Neurotox Res. 2021;39:774–786. doi: 10.1007/s12640-021-00333-1. [DOI] [PubMed] [Google Scholar]
- 43.Rajan TM, Bharadwaj B, Rajkumar RP, Adole PS. Frequency and correlates of tardive dyskinesia in Indian patients with type I bipolar disorder. Asian J Psychiatr. 2018;32:92–98. doi: 10.1016/j.ajp.2017.12.001. [DOI] [PubMed] [Google Scholar]
- 44.Yasui-Furukori N, Kikuchi A, Katagai H, Kaneko S. The effects of electroconvulsive therapy on tardive dystonia or dyskinesia induced by psychotropic medication: A retrospective study. Neuropsychiatr Dis Treat. 2014;10:1209–1212. doi: 10.2147/NDT.S62490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Emmanuel T. Remission of treatment-resistant depression with tardive akathisia with electroconvulsive therapy. BMJ Case Rep. 2019;12:e229714. doi: 10.1136/bcr-2019-229714. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Peng LY, Lee Y, Lin PY. Electroconvulsive therapy for a patient with persistent tardive dyskinesia: A case report and literature review. J ECT. 2013;29:e52–e54. doi: 10.1097/YCT.0b013e31829e0aea. [DOI] [PubMed] [Google Scholar]
- 47.Friedman JH. Tardive syndromes. Continuum (Minneap Minn) 2019;25:1081–1098. doi: 10.1212/CON.0000000000000754. [DOI] [PubMed] [Google Scholar]
- 48.Bergman H, Rathbone J, Agarwal V, Soares-Weiser K. Anti-psychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia. Cochrane Database Syst Rev. 2018;2:CD000459. doi: 10.1002/14651858.CD000459.pub3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Vijayakumar D, Jankovic J. Drug-induced dyskinesia, part 2: Treatment of tardive dyskinesia. Drugs. 2016;76:779–787. doi: 10.1007/s40265-016-0568-1. [DOI] [PubMed] [Google Scholar]
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