今日の臨床サポート

遅発性ジスキネジア

著者: 冨山誠彦 弘前大学大学院医学研究科脳神経内科学講座

監修: 高橋裕秀 昭和大学藤が丘病院 脳神経内科

著者校正/監修レビュー済:2022/07/20
参考ガイドライン:
  1. American Academy of Neurology:Evidence-based guideline: treatment of tardive syndromes. Bhidayasiri et al., Neurology 81 (2013) 463-9
  1. 日本神経精神薬理学会:統合失調症薬物治療ガイドライン(2017改訂)
患者向け説明資料
薬価収載情報:2022年5月25日 ジスバル カプセル40mg(バルベナジントシル酸塩 VMAT2阻害剤 -遅発性ジスキネジア治療剤-)

概要・推奨   

  1. 早期の遅発性ジスキネジア(TDの察知はTDを最小限に抑え、寛解をもたらす可能性を高める。
  1. TD発症の危険因子として、加齢、女性、気分障害、器質的脳疾患の合併、抗精神病薬の総投与量と治療早期の錐体外路症状の合併が挙げられる。
  1. 非定型抗精神病薬は定型抗精神病薬よりもTDの発症は少ない。
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  1. 現時点で治療効果が期待される薬剤として、クロナゼパム、銀杏葉エキス、アマンタジンやその他にビタミンE、ドネペジル、抗てんかん薬のレベチラセタムやガバペンチン、ビタミンB6、メラトニン、Ca拮抗薬などが挙げられているが、これらの有効性は確証されていない(推奨度3)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
冨山誠彦 : 未申告[2022年]
監修:高橋裕秀 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 有効性が確立された薬剤(VMAT-2阻害薬)が登場した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 遅発性ジスキネジア(tardive dyskinesia、 TD)とは、抗精神病薬に関連して、ゆっくりあるいは遅れて発症する不随意運動のことであり、原因薬剤を中止しても1カ月以上持続し、一旦発症すると難治となることが多い。ジスキネジアばかりでなく、振戦、アカシジアやジストニアを呈する症例もあり、これらを総称してtardive syndromeとも呼ばれる。
  1. tardive syndromeの内訳(参考文献:[1]
  1. 100例のtardive syndromeのタイプは、72%が口~頬~舌のジスキネジア(古典的遅発性ジスキネジア)、30%が遅発性振戦、22%が遅発性アカシジア、16%が遅発性ジストニア、4%が遅発性チック、1%が遅発性ミオクローヌスだった。35%が上記の2つ以上の遅発性不随意運動の組み合わせであった。
  1. TDの出現部位は舌口周辺が最多であり、次いで四肢、躯幹の順に認められる。まれではあるが、舌口部にジスキネジアを有する患者では食道にも併存することがある。ジスキネジアは呼吸や嚥下、会話に影響することがある(推奨度2、O)(参考文献:[2][3][4]
  1. Lauterbachは30例のTD患者において、重症度評価法の異常不随意運動評価尺度(AIMS)を用いてジスキネジアの出現部位を検討した。TDは舌に87%、口周辺に48%、下顎に38%、顔面に21%、上肢に66%、下肢に47%、頚部・躯幹に23%に認められ、舌、口周辺、下顎および顔面を合わせると96.7%に及んだ。
  1. 非定型抗精神病薬(約20%)定型抗精神病薬(約30%)よりもTDの発症は少ない[5][6]しかし非定型抗精神病薬の処方例が増加しており、TDは依然として大きなunmet needsのひとつ[7]
  1. TDは発症すると日常生活を著しく障害し、かつ難治であることは変わりない。
  1. 本症は薬物の副作用という理解だけでなく、薬物治療に伴うmovement disorderとして対処する必要がある。
  1. TD発症の危険因子として、加齢、女性、気分障害、器質的脳疾患の合併、抗精神病薬の総投与量と治療早期の錐体外路症状の合併、が挙げられている[8][9]
  1. TDを起こしやすい要因として、加齢、アルコール乱用依存歴、女性、糖尿病、てんかん、頭部外傷など器質的な脳病変の合併、治療早期の錐体外路症状の合併、また高用量長期間の抗精神病薬の服用などが挙げられている。しかし、性差、糖尿病に関しては否定的な報告もあり、一定の見解には至っていない。喫煙はTDの重症度と相関し、喫煙量が多いほどTDが重症であった(推奨度2、O)(参考文献:[3][10][11][12][13][14]
  1. さまざまな危険因子が報告されているが、そのうち年齢(加齢)は危険因子として統一した見解である。
  1. TDの発生率は若年成人では3〜5%に対し、高齢者では30%と5−6倍であり、高齢者において3年間の追跡調査ではTDの発生率は60%にまで達した。CATIE schizophrenia trialの結果では、人種差、性差、糖尿病、高血圧はTD群と非TD群で有意差を認めなかった。
  1. 従来TDは、抗精神病薬によるドパミン受容体の遮断により、線条体のドパミンD2受容体が過感受性を獲得したことに起因すると考えられてきた[15]。小胞モノアミントランスポーター8-2(VMAT-2)阻害薬の有効性はこれを支持する。定型抗精神病薬は非定型抗精神病薬に比べD2受容体に親和性が高く、解離も遅いために、遅発性ジスキネジア発現リスクが高いとされる[16]
  1. 近年では抗精神病薬による酸化ストレスがTD発症に重要であるとされている。またTD発症に遺伝的要因も関係している。
  1. TDの発症要因は、いまだ明確にされていない。(参考文献:[17][18][19]
  1. 従来よりTDは、抗精神病薬によるドパミン受容体の遮断により線条体のドパミンD2受容体が過感受性を獲得したことに起因すると考えられてきた。
病歴・診察のポイント  
  1. 特徴的症状からTDを疑う:
  1. 常同的で無目的な異常不随意運動で、TDの90%以上が舌、口周囲にみられる。顔面や舌に反復する常同的な比較的素早い動きが特徴的である。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

M Ortí-Pareja, F J Jiménez-Jiménez, A Vázquez, M J Catalán, M Zurdo, J A Burguera, P Martínez-Martín, J A Molina, Grupo Centro de Trastornos del Movimiento
Drug-induced tardive syndromes.
Parkinsonism Relat Disord. 1999 Apr;5(1-2):59-65.
Abstract/Text We reviewed the database of five Movement Disorders Units to establish drugs responsible for tardive syndromes or TS (tardive dyskinesia, dystonia, akathisia, tremor, tics or tourettism, and myoclonus). The diagnostic criteria for TS included: (1) appearance of persistent dyskinesia, dystonia, akathisia, tremor, tics or tourettism, or myoclonus, related to prolonged drug exposure, (2) exclusion of other possible causes of these movement disorders. One-hundred patients fulfilled the diagnostic criteria for TS (26 males, 74 females, mean age 69.4+/-15.8 years). TS were related to 1, 2, 3, 4 and 5 drugs in 58, 27, 9, 5 and 1 patients, respectively. The most frequently offending drugs were antipsychotic drugs, substituted benzamides, thietylperazine and calcium-channel blockers. Seventy-two patients had buccolinguomasticatory syndrome, 30 had tremor, 22 akathisia and 16 dystonia (35 patients had a combination of at least two of these TS). Forty-two patients had coexistent parkinsonism. The TS disappeared following withdrawal of the offending drug in 40 cases. Old age and being female were more frequently associated with TS, with the exception of tardive dystonia. Substituted benzamides, calcium-channel blockers and thiethylperazine (a neuroleptic used for vertigo) were a frequent cause of TS in our series.

PMID 18591121
E C Lauterbach, W G Carter, K M Rathke, B H Thomas, S D Shillcutt, R L Vogel, N C Moore, J W Mimbs, W H Nelson
Tardive dyskinesia--diagnostic issues, subsyndromes, and concurrent movement disorders: a study of state hospital inpatients referred to a movement disorder consultation service.
Schizophr Bull. 2001;27(4):601-13.
Abstract/Text Of 49 state hospital patients referred for movement disorder consultation for tardive dyskinesia (TD), 11 (23.9%) of 46 meeting inclusion criteria had movement disorders other than TD. These other disorders led to a false diagnosis of TD in 6 subjects (12.2%). Between-day dyskinesia variability affected TD ascertainment in only 3.2 percent of subjects. Prevalences of other neurological conditions in the 30 patients identified with definite TD were parkinsonism (90%), dystonia (25%), akathisia (16%), cerebellar signs (40%), dysmetria (23%), cerebellar tremor (17%), tardive dystonia (3.3%), and tardive akathisia (3.3%). Concurrence rates of parkinsonism with TD varied significantly according to which clinical signs were used to define parkinsonism. Using a rating score threshold of at least mild, rigidity occurred in 79.3 percent, bradykinesia in 55.2 percent, and resting tremor in 41.4 percent of subjects with TD; more significant rigidity occurred in 41.4 percent, bradykinesia in 31.0 percent, and resting tremor in 20.7 percent. Concurrence rates of neurological conditions with TD subsyndromes were distributed rather evenly according to condition prevalences, except for an association of cervicotruncal TD with bradykinesia (perhaps because of ventromedial striatal presynaptic and postsynaptic D2 blockade, respectively). These findings, as well as the occurrence of equal gender ratio and relative under-representation of bipolar and alcohol disorders in subjects with definite TD, are discussed.

PMID 11824487
Stanley N Caroff, Irene Hurford, Janice Lybrand, E Cabrina Campbell
Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial.
Neurol Clin. 2011 Feb;29(1):127-48, viii. doi: 10.1016/j.ncl.2010.10.002.
Abstract/Text Drug-induced movement disorders have dramatically declined with the widespread use of second-generation antipsychotics, but remain important in clinical practice and for understanding antipsychotic pharmacology. The diagnosis and management of dystonia, parkinsonism, akathisia, catatonia, neuroleptic malignant syndrome, and tardive dyskinesia are reviewed in relation to the decreased liability of the second-generation antipsychotics contrasted with evidence from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial. Data from the CATIE trial imply that advantages of second-generation antipsychotics in significantly reducing extrapyramidal side effects compared with haloperidol may be diminished when compared with modest doses of lower-potency first-generation drugs.

Published by Elsevier Inc.
PMID 21172575
J Horiguchi, T Shingu, T Hayashi, A Kagaya, S Yamawaki, Y Horikawa, Y Kitadai, M Inoue, T Nishikawa
Antipsychotic-induced life-threatening 'esophageal dyskinesia'.
Int Clin Psychopharmacol. 1999 Mar;14(2):123-7.
Abstract/Text We report two patients with lingual dyskinesia and complaints of food regurgitation following long-term antipsychotic therapy. Esophageal contrast radiography revealed dyskinetic movements extending from the pharynx to the upper portion of the esophagus. The elevation of intraesophageal pressure was confirmed by esophageal manometry. The dyskinetic movements almost disappeared along with improvement of lingual dyskinesia following the administration of sulpiride in one patient. Another patient suddenly died due to asphyxiation of foods before the beginning of treatment. We termed this life-threatening movement, 'esophageal dyskinesia'. It should be emphasized that 'esophageal dyskinesia' associated with lingual dyskinesia is a potentially fatal adverse reaction to antipsychotic therapy.

PMID 10220128
Maren Carbon, Cheng-Hsi Hsieh, John M Kane, Christoph U Correll
Tardive Dyskinesia Prevalence in the Period of Second-Generation Antipsychotic Use: A Meta-Analysis.
J Clin Psychiatry. 2017 Mar;78(3):e264-e278. doi: 10.4088/JCP.16r10832.
Abstract/Text OBJECTIVE: Comparison of tardive dyskinesia (TD) prevalence during contemporaneous treatment with first-generation antipsychotics (FGAs) and/or second-generation antipsychotics (SGAs).
DATA SOURCES: PubMed/MEDLINE/Google Scholar search (January 1, 2000-September 30, 2015) without language restriction using (tardive dyskinesia OR tardive) AND (antipsychotic*) plus specific names of SGAs.
STUDY SELECTION: Of 8,895 hits, we screened 203 full-text articles for cross-sectional, rating scale-based TD rates during SGA, FGA, or FGA+SGA treatment. Forty-one studies were used for random effects meta-analysis and meta-regression.
DATA EXTRACTION: Two authors independently extracted data on overall and antipsychotic class-wise TD rates and on TD moderators.
RESULTS: The global mean TD prevalence was 25.3% (95% CI = 22.7%-28.1%) across all 41 studies (N = 11,493, mean age = 42.8 years, male = 66.4%, schizophrenia-spectrum disorders = 77.1%). TD prevalence varied greatly: Rates were lower with current SGA treatment (20.7%; 95% CI = 16.6%-25.4%, N = 5,103) vs current FGA treatment (30.0%; 95% CI = 26.4%-33.8%, N = 5,062; Q = 9.17, P = .002). This difference remained significant after controlling for moderators: higher age (Z = 2.85, P = .004; number of studies = 39 ) and region (39 studies; Asia vs Europe, Z = 1.55, P = .12; Asia lower than United States, Z = 2.6, P = .009; Asia lower than other regions, Z = 2.42, P = .015). Additional moderators of TD prevalence included longer illness duration (R² = 0.15; P = .03; 21 studies) and frequency of parkinsonism (R² = 0.23, P = .017; number of studies = 19). Particularly low TD prevalence (7.2%; number of studies = 4) was found in the treatment arms with FGA-naive subjects relative to SGA-treated cohorts with likely prior FGA exposure (23.4%; P < .001; 28 studies). Lower TD prevalence of SGA relative to FGA was also confirmed in the subgroup of studies reporting on ≥ 2 antipsychotic classes/combinations; this was found for both SGAs vs FGAs (risk ratio = 0.80; 95% CI = 0.67-0.95, Z = -2.55, P = .011) and FGA + SGA vs FGAs (risk ratio = 0.80, 95% CI = 0.71-0.90, Z = -3.56, P < .001). Reports on TD severity, provided by 10 studies, were of insufficient quality for meta-analysis.
CONCLUSIONS: Rating scale-based TD remains highly prevalent, with higher rates during FGA than during SGA treatment. However, TD severity was insufficiently reported to allow for interpretation of the clinical impact of identified TD cases with SGAs and FGAs. Reasons for high geographical variation warrant future research.

© Copyright 2017 Physicians Postgraduate Press, Inc.
PMID 28146614
Maren Carbon, John M Kane, Stefan Leucht, Christoph U Correll
Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis.
World Psychiatry. 2018 Oct;17(3):330-340. doi: 10.1002/wps.20579.
Abstract/Text Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second-generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first-generation antipsychotics, FGAs). As some reports questioned this notion, we meta-analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head-to-head RCTs, including 32 FGA and 86 SGA arms, were meta-analyzed, yielding 32 FGA-SGA pairs and 35 SGA-SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3-7.8%) vs. 2.6% (95% CI: 2.0-3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39-0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28-0.45, p<0.0001, number-needed-to-treat, NNT=20). Meta-regression showed no FGA dose effect on FGA-SGA comparisons (Z=-1.03, p=0.30). FGA-SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non-clozapine SGAs in exploratory pairwise comparisons. SGA-SGA comparisons confirmed the olanzapine advantage vs. non-clozapine SGAs (RaR=0.66, 95% CI: 0.49-0.88, p=0.006, k=17, NNT=100). This meta-analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.

© 2018 World Psychiatric Association.
PMID 30192088
Leslie J Cloud, Deepti Zutshi, Stewart A Factor
Tardive dyskinesia: therapeutic options for an increasingly common disorder.
Neurotherapeutics. 2014 Jan;11(1):166-76. doi: 10.1007/s13311-013-0222-5.
Abstract/Text Tardive dyskinesia (TD) is a serious, often disabling, movement disorder that is caused by medications that block dopamine receptors (i.e., neuroleptics, anti-emetics). There is currently no standard treatment approach for physicians confronted with such patients. This may be the result of notions that TD is disappearing because of the switch to second-generation antipsychotic agents and that it is largely reversible. In this article we demonstrate that second-generation antipsychotics do, indeed, cause TD and, in fact, the frequency is likely higher than expected because of growing off-label uses and a tripling of prescriptions written in the last 10 years. In addition, studies demonstrate that TD actually remits in only a minority of patients when these drugs are withdrawn. Furthermore, neuroleptic agents are often utilized to treat TD, despite prolonged exposure being a risk factor for irreversibility. The outcome of these trends is a growing population afflicted with TD. We review non-neuroleptic agents that have shown positive results in small, early-phase, blinded trials, including tetrabenazine, amantadine, levetiracetam, piracetam, clonazepam, propranolol, vitamin B6, and Ginkgo biloba. Other options, such as botulinum toxin and deep brain stimulation, will also be discussed, and a suggested treatment algorithm is provided. While these agents are reasonable treatment options at this time there is a need, with a concerted effort between neurology and psychiatry, for full-scale drug development, including multicenter, randomized, blinded trials to confirm the effectiveness of the agents that were positive in phase 2 trials and the development of newer ones.

PMID 24310603
K D Sethi
Movement disorders induced by dopamine blocking agents.
Semin Neurol. 2001;21(1):59-68.
Abstract/Text Movement disorders are frequently due to dopamine blocking agents (DBAs) prescribed for psychiatric illnesses. DBAs are sometimes also prescribed inappropriately for other maladies. These drugs can cause a wide variety of involuntary movements, sometimes in combination. When these appear in the setting of psychiatric illnesses, the association is easy to recognize but the treatment remains a difficult problem. However, in other situations the diagnosis may be missed for extended periods of time, resulting in unnecessary diagnostic work-up and inappropriate therapy. The diagnosis depends on a compulsive drug history not only from the patient but also from patient's family, primary physician, and the pharmacist. The treatment options include removal of the offending agent or substitution with an atypical neuroleptic. Symptomatic treatments are varied and have an inconsistent effect on the movement disorders. Prevention remains the most important strategy.

PMID 11346026
Karla Soares-Weiser, Hubert H Fernandez
Tardive dyskinesia.
Semin Neurol. 2007 Apr;27(2):159-69. doi: 10.1055/s-2007-971169.
Abstract/Text This article provides up-to-date information regarding clinical manifestations, pathophysiology, and evidence-based treatment for tardive dyskinesia (TD). We conducted a comprehensive literature search, including sources such as the Cochrane Library, EMBASE, and Medline; and we manually searched bibliographic references. We also contacted the authors of each included trial. All randomized clinical trials that compared different types of active interventions with placebo or no intervention in patients with neuroleptic-induced TD were included in our data. Two reviewers independently applied the selection criteria to all identified references, appraised the methodological quality of each trial, and extracted the relevant data. Relative risks and 95% confidence intervals were estimated using the fixed effect model. More than 500 randomized trials evaluating over 90 different interventions to treat TD were identified. From those, 45 trials were included in the current reviews. None of the trials pooled on these reviews found a definitive therapy for TD. Clinicians faced with conditions such as TD should carefully weigh the risks and benefits involved with any given intervention.

PMID 17390261
Daniel Tarsy, Codrin Lungu, Ross J Baldessarini
Epidemiology of tardive dyskinesia before and during the era of modern antipsychotic drugs.
Handb Clin Neurol. 2011;100:601-16. doi: 10.1016/B978-0-444-52014-2.00043-4.
Abstract/Text Late or tardive dyskinesias/dystonias (TD), contrary to expectation, have not disappeared with the use of expensive, modern antipsychotic drugs (APDs). Risk appears to be substantially lower than with older neuroleptics, and there is sparing of most acute movement disorders traditionally associated with APD treatment. However, risks of TD with modern APDs have been reduced much less than expected, by perhaps two- to threefold or even less, with substantial risks in the elderly. Major challenges in assessing prevalence or, preferably, incidence of TD arise from prolonged and erratic past exposure to various APDs, relatively recent use of modern APDs, and the occurrence of spontaneous movement disorders (about 5% and more in the elderly). TD risks associated with modern APDs may be similar to some older neuroleptics, especially those of low-moderate potency. Risperidone (and its active metabolite paliperidone), at high doses, may carry unusually high TD risk, whereas TD risk is low with clozapine, and perhaps quetiapine and aripiprazole. Optimistic expectations for the efficacy and neurological safety of modern APDs have encouraged their wide use in many conditions, sometimes off-label or in combinations, with little research support, increasing the chance of a higher prevalence of TD, especially at older ages. Measures to limit TD risk include: (1) critical, objective indications for APD use; (2) long-term use only for compelling or research-supported indications, primarily chronic psychotic illness that worsens when APD is slowly discontinued; (3) avoiding off-label indications; (4) using alternative treatments when APD treatment is elective, or early dyskinesia is identified; (5) using low but effective doses of single APDs, especially in the elderly; and (6) regular and specific examination for early TD.

Copyright © 2011 Elsevier B.V. All rights reserved.
PMID 21496610
Del D Miller, Joseph P McEvoy, Sonia M Davis, Stanley N Caroff, Bruce L Saltz, Miranda H Chakos, Marvin S Swartz, Richard S E Keefe, Robert A Rosenheck, T Scott Stroup, Jeffrey A Lieberman
Clinical correlates of tardive dyskinesia in schizophrenia: baseline data from the CATIE schizophrenia trial.
Schizophr Res. 2005 Dec 1;80(1):33-43. doi: 10.1016/j.schres.2005.07.034. Epub 2005 Sep 19.
Abstract/Text OBJECTIVE: To examine the clinical characteristics of individuals with schizophrenia that develop tardive dyskinesia (TD) associated with antipsychotic treatment.
METHODS: Baseline data on 1460 patients with schizophrenia were collected as part of the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study. Subjects who met Schooler-Kane criteria for probable TD were compared to those without TD. Multiple regression analyses were used to examine the relationship between TD and clinical variables.
RESULTS: 212 subjects met the Schooler-Kane criteria for probable TD and 1098 had no history or current evidence of TD. Subjects with TD were older, had a longer duration of receiving antipsychotic medication, and were more likely to have been receiving a conventional antipsychotic and an anticholinergic agent. After controlling for important baseline covariates, diabetes mellitus (DM) and hypertension did not predict TD, whereas substance abuse significantly predicted TD. Differences in cognitive functioning were not significantly different after controlling for baseline covariates. The TD subjects also had higher ratings of psychopathology, EPSE, and akathisia.
CONCLUSION: Our results confirm the established relationships between the presence of TD and age, duration of treatment with antipsychotics, treatment with a conventional antipsychotic, treatment with anticholinergics, the presence of EPS and akathisia, and substance abuse. Subjects with TD had higher ratings of psychopathology as measured by the PANSS. We found no support for DM or hypertension increasing the risk of TD, or for TD being associated with cognitive impairment.

PMID 16171976
A Diehl, I Reinhard, A Schmitt, K Mann, W F Gattaz
Does the degree of smoking effect the severity of tardive dyskinesia? A longitudinal clinical trial.
Eur Psychiatry. 2009 Jan;24(1):33-40. doi: 10.1016/j.eurpsy.2008.07.007. Epub 2008 Sep 6.
Abstract/Text BACKGROUND: Tardive dyskinesia (TD) is a movement disorder observed after chronic neuroleptic treatment. Smoking is presumed to increase the prevalence of TD. The question of a cause-effect-relationship between smoking and TD, however, remains to be answered. Purpose of this study was to examine the correlation between the degree of smoking and the severity of TD with respect to differences caused by medication.
METHOD: We examined 60 patients suffering from schizophrenia and TD. We compared a clozapine-treated group with a group treated with typical neuroleptics. Movement disorders were assessed using the Abnormal-Involuntary-Movement-Scale and the technical device digital image processing, providing rater independent information on perioral movements.
RESULTS: We found a strong correlation (.80CONCLUSION: Concerning a possible cause-effect-relationship between smoking and TD, smoking is more of a general health hazard than neuroleptic exposure in terms of TD.

PMID 18774276
Perminder Sachdev
Early extrapyramidal side-effects as risk factors for later tardive dyskinesia: a prospective study.
Aust N Z J Psychiatry. 2004 Jun;38(6):445-9. doi: 10.1080/j.1440-1614.2004.01382.x.
Abstract/Text OBJECTIVE: To determine whether acute neuroleptic-induced parkinsonism and akathisia were risk factors for the later development of tardive dyskinesia (TD) in patients on typical neuroleptics.
METHOD: Of 100 subjects examined for parkinsonism and akathisia after the initiation of typical neuroleptic medication, 78 were followed up for TD after a mean 41.2 months.
RESULTS: Nine (11.5%) subjects were diagnosed with TD, predominantly manifesting as oro-facial dyskinesia. They had greater severity of parkinsonism and akathisia at baseline, and a larger neuroleptic load, than those who did not develop TD. On regression analyses, parkinsonism at baseline was a significant predictor of later TD. Examined independently of parkinsonism, akathisia severity at 2 weeks was also a significant predictor of later TD.
CONCLUSIONS: Acute drug-induced parkinsonism and akathisia are both predictors of TD, with parkinsonism having greater predictive value. Acute and tardive extrapyramidal syndromes may share vulnerability factors.

PMID 15209837
L Ganzini, R T Heintz, W F Hoffman, D E Casey
The prevalence of tardive dyskinesia in neuroleptic-treated diabetics. A controlled study.
Arch Gen Psychiatry. 1991 Mar;48(3):259-63.
Abstract/Text In a controlled study, we compared the prevalence of tardive dyskinesia in 38 neuroleptic-treated diabetics with the prevalence of tardive dyskinesia in a group of 38 nondiabetic neuroleptic-treated controls, matched for age, sex, psychiatric diagnosis, and dose and duration of neuroleptic treatment. Members of each group were evaluated for movement disorders by a rater who used standard rating scales and was "blind" to all diagnoses and treatments. Neuroleptic-treated diabetics had a significantly higher prevalence and severity of tardive dyskinesia. There were no differences between groups on other possible risk factors for tardive dyskinesia, including parkinsonism, anticholinergic drug treatment, or cognitive function. These data suggest that diabetes mellitus should be examined further as a risk factor for tardive dyskinesia.

PMID 1671743
Stephen M Stahl
Neuronal traffic signals in tardive dyskinesia: not enough "stop" in the motor striatum.
CNS Spectr. 2017 Dec;22(6):427-434. doi: 10.1017/S109285291700061X.
Abstract/Text Tardive dyskinesia is a disturbance in the balance between dopamine receptor stimulation and dopamine receptor blockade in the motor striatum, with hypothetically too much stimulation of supersensitive D2 receptors, resulting in "don't stop" signaling to motor output.

PMID 29205123
Stewart A Factor, Pierre R Burkhard, Stanley Caroff, Joseph H Friedman, Connie Marras, Michele Tinazzi, Cynthia L Comella
Recent developments in drug-induced movement disorders: a mixed picture.
Lancet Neurol. 2019 Sep;18(9):880-890. doi: 10.1016/S1474-4422(19)30152-8. Epub 2019 Jul 3.
Abstract/Text A large and ever-growing number of medications can induce various movement disorders. Drug-induced movement disorders are disabling but are often under-recognised and inappropriately managed. In particular, second generation antipsychotics, like first generation agents, are associated with potentially debilitating side-effects, most notably tardive syndromes and parkinsonism, as well as potentially fatal acute syndromes. Appropriate, evidence-based management is essential as these drugs are being prescribed to a growing population vulnerable to these side-effects, including children and elderly people. Prevention of the development of drug-induced movement disorders is an important consideration when prescribing medications that can induce movement disorders. Recent developments in diagnosis, such as the use of dopamine transporter imaging for drug-induced parkinsonism, and treatment, with the approval of valbenazine and deutetrabenazine, the first drugs indicated for tardive syndromes, have improved outcomes for many patients with drug-induced movement disorders. Future research should focus on development of safer antipsychotics and specific therapies for the different tardive syndromes and the treatment of drug-induced parkinsonism.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 31279747
Shrinivas K Kulkarni, Pattipati S Naidu
Pathophysiology and drug therapy of tardive dyskinesia: current concepts and future perspectives.
Drugs Today (Barc). 2003 Jan;39(1):19-49.
Abstract/Text Nearly 1% of the world population suffers from schizophrenia, and neuroleptics are the major class of drugs used to treat this disorder. Neuroleptics are associated with wide variety of extrapyramidal side effects, such as akathesia, dystonia, neuroleptic malignant syndrome, Parkinson-ism and tardive dyskinesia. Despite the awareness that neuroleptics could cause extrapyramidal side effects, these drugs remain the most effective means of treating schizophrenia and Tourette's syndrome, as well as for the management of behavioral disorders in developmentally disabled individuals. Tardive dyskinesia is a complex hyperkinetic syndrome consisting of choriform, athetoid or rhythmically abnormal involuntary movements. Estimates of the prevalence rate of tardive dyskinesia in patients receiving neuroleptics range from 0.5-70%, with an average prevalence rate of 24%. Despite much research, the pathogenesis of tardive dyskinesia remains elusive. So far, various neurochemical hypotheses have been proposed for the development of tardive dyskinesia. These include dopaminergic hypersensitivity, disturbed balance between dopamine and cholinergic systems, dysfunctions of striatonigral GABAergic neurons and excitotoxicity. Similarly, different suppressive agents have been tried with limited success. Recently, the role of oxidative stress and structural abnormality in the pathophysiology of tardive dyskinesia has gained much impetus. Induction of free radicals by neuroleptic drugs leading to the oxidative stress and resultant structural abnormality could be the key factor in the pathogenesis of tardive dyskinesia. This hypothesis has been supported by numerous reports that chronic neuroleptic treatment increases free radical production and causes structural damage. More recently, the genetic vulnerability for the predisposition for the development of tardive dyskinesia, i.e., pharmacogenetic aspect of tardive dyskinesia, is also gaining impetus as a research area, and is discussed in detail in this article.

(c) Prous Science 2003. All rights reserved.
PMID 12669107
James B Lohr, Ronald Kuczenski, Alexander B Niculescu
Oxidative mechanisms and tardive dyskinesia.
CNS Drugs. 2003;17(1):47-62.
Abstract/Text Tardive dyskinesia has been and continues to be a significant problem associated with long-term antipsychotic use, but its pathophysiology remains unclear. In the last 10 years, preclinical studies of the administration of antipsychotics to animals, as well as clinical studies of oxidative processes in patients given antipsychotic medications, with and without tardive dyskinesia, have continued to support the possibility that neurotoxic free radical production may be an important consequence of antipsychotic treatment, and that such production may relate to the development of dyskinetic phenomena. In line with this hypothesis, evidence has accumulated for the efficacy of antioxidants, primarily vitamin E (alpha-tocopherol), in the treatment and prevention of tardive dyskinesia. Early studies suggested a modest effect of vitamin E treatment on existing tardive dyskinesia, but later studies did not demonstrate a significant effect. Because evidence has continued to accumulate for increased oxidative damage from antipsychotic medications, but less so for the effectiveness of vitamin E, especially in cases of long-standing tardive dyskinesia, alternative antioxidant approaches to the condition may be warranted. These approaches may include the use of antioxidants as a preventive measure for tardive dyskinesia or the use of other antioxidants or neuroprotective drugs, such as melatonin, for established tardive dyskinesia.

PMID 12467492
Todd Lencz, Anil K Malhotra
Pharmacogenetics of antipsychotic-induced side effects.
Dialogues Clin Neurosci. 2009;11(4):405-15.
Abstract/Text Currently available antipsychotic drugs (APDs) carry significant though highly variable, liability to neurologic and metabolic side effects. Pharmacogenetics approaches offer the possibility of identifying patient-specific biomarkers for predicting risk of these side effects. To date, a few single nucleotide polymorphisms (SNPs) in a handful of genes have received convergent support across multiple studies. The primary focus has been on SNPs in dopamine and serotonin receptor genes: persuasive meta-analytic evidence exists for an effect of the dopamine D2 and D3 receptor genes (DRD2 and DRD3) in risk for tardive dyskinesia (TD) and for an effect of variation at the 5-HT2C receptor gene (HTR2C) for liability to APD-induced weight gain. However, effect sizes appear to be modest, and pharmacoeconomic considerations have not been sufficiently studied, thereby limiting clinical applicability at this time. Effects of these genes and others on risk for TD, extrapyramidal side effects, hyperprolactinemia, and weight gain are reviewed in this article.

PMID 20135898
Maju Mathews, Sylvia Gratz, Babatunde Adetunji, Vinu George, Manu Mathews, Biju Basil
Antipsychotic-induced movement disorders: evaluation and treatment.
Psychiatry (Edgmont). 2005 Mar;2(3):36-41.
Abstract/Text
PMID 21179628
Roongroj Bhidayasiri, Suthida Boonyawairoj
Spectrum of tardive syndromes: clinical recognition and management.
Postgrad Med J. 2011 Feb;87(1024):132-41. doi: 10.1136/pgmj.2010.103234. Epub 2010 Dec 3.
Abstract/Text Tardive syndrome (TS) refers to a group of delayed onset disorders characterised by abnormal movements and caused by dopamine receptor blocking agents (DRBAs). Classical tardive dyskinesia is a specific type of oro-buccal-lingual dyskinesia. However, TS may exist in other forms--for example, stereotypy, dystonia, and akathisia--and frequently occur in combination. The onset typically is insidious and after reaching its maximum severity it often stabilises. Frequently reported risk factors are age, dose and duration of neuroleptic exposure, the use of conventional DRBAs, and co-existing mood disorders. This review highlights the broad spectrum of TS, not limited to classical tardive dyskinesia, as well as the clues for its recognition. Despite challenges in the treatment of TS, dictated by the different phenomenology, severity of TS and the need for ongoing neuroleptic treatment, the authors provide evidence based recommendations for patient management, which is not restricted to only withdrawal of the offending neuroleptics or the selection of an alternative medication, such as clozapine. In a minority of cases with significant functional disability, symptomatic or suppressive treatments should be considered. Recently, there has been a resurgence of stereotactic pallidal surgery for the treatment of TS. Although the efficacy of both pallidotomy and pallidal deep brain stimulation in dystonia has been encouraging, the evidence is still limited.

PMID 21131613
Pratibha G Aia, Gonzalo J Revuelta, Leslie J Cloud, Stewart A Factor
Tardive dyskinesia.
Curr Treat Options Neurol. 2011 Jun;13(3):231-41. doi: 10.1007/s11940-011-0117-x.
Abstract/Text OPINION STATEMENT: Tardive dyskinesia (TD) is iatrogenic (drug-induced); hence the best strategy is prevention. Try to limit exposure to any dopamine receptor blocking agents (DRBAs) if possible. These agents may be unavoidable in some psychiatric conditions such as schizophrenia, but alternative therapies can be used in many situations, such as in the treatment of depression, anxiety, gastrointestinal conditions, and other neurologic conditions, including migraines and sleep disorders. When DRBAs are necessary, physicians should prescribe the smallest possible dose and try to taper and stop the drug at the earliest signs of TD. Abrupt cessation should be avoided, as this can worsen symptoms of TD. Always discuss and document the possibility of TD as an adverse effect when starting patients on DRBAs. If TD is mild and tolerable, the withdrawal of the offending agent is possible, and exposure to DRBAs was short, physicians should consider avoiding treatment and waiting for spontaneous recovery. When treatment is necessary, tetrabenazine (TBZ) is considered a potential first-line agent and is known to be one of the most effective drugs in treating TD, but it is expensive and adverse effects such as depression, akathisia and parkinsonism frequently occur. Therefore, second-line agents with better tolerability profiles are often tried first in practice. These include amantadine, benzodiazepines, beta-blockers, and levetiracetam. When using TBZ, adverse effects should be aggressively monitored. (Depression often can be managed with antidepressants, for instance). In patients with psychosis, withdrawal of the antipsychotic may not be possible. Switching to clozapine or quetiapine is one option to minimize TD. When these agents are contraindicated and the patient must continue using other atypical antipsychotic drugs, try to add dopamine-depleting agents such as TBZ or reserpine, but watch for the development of parkinsonism. When the symptoms are focal, such as tongue protrusion or blepharospasm, botulinum toxin injections can be very effective if spontaneous recovery does not occur. As a last resort, when disabling, life-threatening symptoms of TD persist despite all of the above-mentioned methods, some advocate resuming treatment with the DRBA to suppress symptoms of TD. This has the potential to worsen TD in the long run.

PMID 21365202
Roongroj Bhidayasiri, Stanley Fahn, William J Weiner, Gary S Gronseth, Kelly L Sullivan, Theresa A Zesiewicz, American Academy of Neurology
Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology.
Neurology. 2013 Jul 30;81(5):463-9. doi: 10.1212/WNL.0b013e31829d86b6.
Abstract/Text OBJECTIVE: To make evidence-based recommendations regarding management of tardive syndromes (TDS), including tardive dyskinesias (TDD), by addressing 5 questions: 1) Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TDS treatment? 2) Does switching from typical to atypical DRBAs reduce TDS symptoms? 3) What is the efficacy of pharmacologic agents in treating TDS? 4) Do patients with TDS benefit from chemodenervation with botulinum toxin? 5) Do patients with TDS benefit from surgical therapy?
METHODS: PsycINFO, Ovid MEDLINE, EMBASE, Web of Science, and Cochrane were searched (1966-2011). Articles were classified according to a 4-tiered evidence-rating scheme; recommendations were tied to the evidence.
RESULTS AND RECOMMENDATIONS: Clonazepam probably improves TDD and ginkgo biloba probably improves TDS (both Level B); both should be considered as treatment. Risperidone may improve TDS but cannot be recommended as treatment because neuroleptics may cause TDS despite masking symptoms. Amantadine and tetrabenazine might be considered as TDS treatment (Level C). Diltiazem should not be considered as TDD treatment (Level B); galantamine and eicosapentaenoic acid may not be considered as treatment (Level C). Data are insufficient to support or refute use of acetazolamide, bromocriptine, thiamine, baclofen, vitamin E, vitamin B6, selegiline, clozapine, olanzapine, melatonin, nifedipine, fluperlapine, sulpiride, flupenthixol, thiopropazate, haloperidol, levetiracetam, quetiapine, ziprasidone, sertindole, aripiprazole, buspirone, yi-gan san, biperiden discontinuation, botulinum toxin type A, electroconvulsive therapy, α-methyldopa, reserpine, and pallidal deep brain stimulation as TDS treatments (Level U). Data are insufficient to support or refute TDS treatment by withdrawing causative agents or switching from typical to atypical DRBA (Level U).

PMID 23897874
Roongroj Bhidayasiri, Onanong Jitkritsadakul, Joseph H Friedman, Stanley Fahn
Updating the recommendations for treatment of tardive syndromes: A systematic review of new evidence and practical treatment algorithm.
J Neurol Sci. 2018 Jun 15;389:67-75. doi: 10.1016/j.jns.2018.02.010. Epub 2018 Feb 5.
Abstract/Text BACKGROUND: Management of tardive syndromes (TS) is challenging, with only a few evidence-based therapeutic algorithms reported in the American Academy of Neurology (AAN) guideline in 2013.
OBJECTIVE: To update the evidence-based recommendations and provide a practical treatment algorithm for management of TS by addressing 5 questions: 1) Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TS treatment? 2) Does switching from typical to atypical DRBAs reduce TS symptoms? 3) What is the efficacy of pharmacologic agents in treating TS? 4) Do patients with TS benefit from chemodenervation with botulinum toxin? 5) Do patients with TS benefit from surgical therapy?
METHODS: Systematic reviews were conducted by searching PsycINFO, Ovid MEDLINE, PubMed, EMBASE, Web of Science and Cochrane for articles published between 2012 and 2017 to identify new evidence published after the 2013 AAN guidelines. Articles were classified according to an AAN 4-tiered evidence-rating scheme. To the extent possible, for each study we attempted to categorize results based on the description of the population enrolled (tardive dyskinesia [TD], tardive dystonia, tardive tremor, etc.). Recommendations were based on the evidence.
RESULTS AND RECOMMENDATIONS: New evidence was combined with the existing guideline evidence to inform our recommendations. Deutetrabenazine and valbenazine are established as effective treatments of TD (Level A) and must be recommended as treatment. Clonazepam and Ginkgo biloba probably improve TD (Level B) and should be considered as treatment. Amantadine and tetrabenazine might be considered as TD treatment (Level C). Pallidal deep brain stimulation possibly improves TD and might be considered as a treatment for intractable TD (Level C). There is insufficient evidence to support or refute TS treatment by withdrawing causative agents or switching from typical to atypical DRBA (Level U).

Copyright © 2018 Elsevier B.V. All rights reserved.
PMID 29454493
Hélène Pouclet-Courtemanche, Tiphaine Rouaud, Stephane Thobois, Jean-Michel Nguyen, Christine Brefel-Courbon, Isabelle Chereau, Emmanuel Cuny, Philippe Derost, Alexandre Eusebio, Dominique Guehl, Chloé Laurencin, Patrick Mertens, Fabienne Ory-Magne, Sylvie Raoul, Jean Regis, Miguel Ulla, Tatiana Witjas, Pierre Burbaud, Olivier Rascol, Philippe Damier
Long-term efficacy and tolerability of bilateral pallidal stimulation to treat tardive dyskinesia.
Neurology. 2016 Feb 16;86(7):651-9. doi: 10.1212/WNL.0000000000002370. Epub 2016 Jan 20.
Abstract/Text OBJECTIVE: To confirm the efficacy and safety of deep brain stimulation (DBS) of the internal part of the globus pallidus in improving severe tardive dyskinesia (TD).
METHODS: Nineteen patients with severe pharmacoresistant TD were included. All were assessed at baseline and at 3, 6 (main outcome measure), and 12 months, and in the long term (6-11 years) for 14 patients, after bilateral pallidal DBS, using motor scales (Extrapyramidal Symptoms Rating Scale [ESRS], Abnormal Involuntary Movement Scale [AIMS]), cognitive scales, and a psychiatric assessment. At 6 months, a double-blind ESRS evaluation was performed in the stimulation "on" and stimulation "off" conditions.
RESULTS: At 6 months, all patients had a decrease of more than 40% on the ESRS. The efficacy of the procedure was confirmed by a double-blind evaluation. This improvement was maintained at 12 months (ESRS: decrease of 58% [21%-81%];
AIMS: decrease of 50% [7%-77%]) and in the long term (ESRS: decrease of 60% [22%-90%];
AIMS: decrease of 63% [14%-94%], n = 14). All the subscores of the ESRS (parkinsonism, dystonia, and chorea) and of the AIMS (facial, oral, extremities, and trunk movements) improved. Despite psychiatric comorbidities at baseline, cognitive and psychiatric tolerability of the procedure was excellent. No cognitive decline was observed and mood was improved in most of the patients.
CONCLUSIONS: Pallidal DBS procedure should be considered as a therapeutic option in disabling TD refractory to medical treatment.
CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with severe pharmacoresistant TD with implanted pallidal leads, the stimulation "on" condition significantly improved ESRS scores compared to the stimulation "off" condition.

© 2016 American Academy of Neurology.
PMID 26791148
A M Elkashef, R J Wyatt
Tardive dyskinesia: possible involvement of free radicals and treatment with vitamin E.
Schizophr Bull. 1999;25(4):731-40. doi: 10.1093/oxfordjournals.schbul.a033414.
Abstract/Text A decade ago a hypothesis introduced to explain tardive dyskinesia (TD) implicated free radicals generated secondary to neuroleptic treatment. Since then many preclinical and clinical studies have investigated this possibility. These studies suggest that free radicals are probably involved in the pathogenesis of TD and that vitamin E could be efficacious in its treatment.

PMID 10667743
Samer Alabed, Youssef Latifeh, Husam Aldeen Mohammad, Abdullah Rifai
Gamma-aminobutyric acid agonists for neuroleptic-induced tardive dyskinesia.
Cochrane Database Syst Rev. 2011 Apr 13;(4):CD000203. doi: 10.1002/14651858.CD000203.pub3. Epub 2011 Apr 13.
Abstract/Text BACKGROUND: Chronic antipsychotic drug treatment may cause tardive dyskinesia (TD), a long-term movement disorder. Gamma-aminobutyric acid (GABA) agonist drugs, which have intense sedative properties and may exacerbate psychotic symptoms, have been used to treat TD.
OBJECTIVES: To determine the clinical effects of GABA agonist drugs (baclofen, gamma-vinyl-GABA, gamma-acetylenic-GABA, progabide, muscimol, sodium valproate and tetrahydroisoxazolopyridine (THIP) for people with schizophrenia or other chronic mental illnesses who also developed neuroleptic-induced tardive dyskinesia.
SEARCH STRATEGY: We updated the previous Cochrane review by searching the Cochrane Schizophrenia Group Register (June 2010).
SELECTION CRITERIA: We included reports if they were controlled trials dealing with people with neuroleptic-induced TD and schizophrenia or other chronic mental illness who had been randomly allocated to either non-benzodiazepine GABA agonist drugs with placebo or no intervention.
DATA COLLECTION AND ANALYSIS: Working independently, we selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate we calculated risk ratios (RR) and their 95% confidence intervals (CI) with the number needed to treat (NNT). For continuous data we calculated mean differences (MD).
MAIN RESULTS: We identified eight small poorly reported studies for inclusion. For the outcome of 'no clinically important improvement in tardive dyskinesia' GABA agonist drugs were not clearly better than placebo (n = 108, 3 RCTs, RR 0.83 CI 0.6 to 1.1). Deterioration in mental state was more likely to occur in people receiving GABA medication (n = 95, 4 RCTs, RR 2.47 CI 1.1 to 5.4), but this effect was influenced by the decision to assign a negative outcome to those who left early before the end of the study. A greater proportion of people allocated GABA medication may fail to complete the trial compared with those allocated placebo (20% versus 9%), but this difference was not statistically significant (n = 136, 5 RCTs, RR 1.99 CI 0.8 to 4.7). There is a suggestion of an increase in ataxia (loss of power of muscular coordination) for both baclofen and sodium valproate (n = 95, 2 RCTs, RR 3.26 CI 0.4 to 30.2), and in sedation (n = 113, 3 RCTs, RR 2.12 CI 0.8 to 5.4) compared with placebo, but this was not significant. Withdrawal of tetrahydroisoxazolopyridine (THIP) may cause seizures.
AUTHORS' CONCLUSIONS: Evidence of the effects of baclofen, progabide, sodium valproate, or THIP for people with antipsychotic-induced TD is inconclusive and unconvincing. Any possible benefits are likely to be outweighed by the adverse effects associated with their use.

PMID 21491376
Irina A Tammenmaa, Eila Sailas, John J McGrath, Karla Soares-Weiser, Kristian Wahlbeck
Systematic review of cholinergic drugs for neuroleptic-induced tardive dyskinesia: a meta-analysis of randomized controlled trials.
Prog Neuropsychopharmacol Biol Psychiatry. 2004 Nov;28(7):1099-107. doi: 10.1016/j.pnpbp.2004.05.045.
Abstract/Text The authors evaluated the efficacy of cholinergic drugs in the treatment of neuroleptic-induced tardive dyskinesia (TD) by a systematic review of the literature on the following agents: choline, lecithin, physostigmine, tacrine, 7-methoxyacridine, ipidacrine, galantamine, donepezil, rivastigmine, eptastigmine, metrifonate, arecoline, RS 86, xanomeline, cevimeline, deanol, and meclofenoxate. All relevant randomized controlled trials, without any language or year limitations, were obtained from the Cochrane Schizophrenia Group's Register of Trials. Trials were classified according to their methodological quality. For binary and continuous data, relative risks (RR) and weighted or standardized mean differences (SMD) were calculated, respectively. Eleven trials with a total of 261 randomized patients were included in the meta-analysis. Cholinergic drugs showed a minor trend for improvement of tardive dyskinesia symptoms, but results were not statistically significant (RR 0.84, 95% confidence interval (CI) 0.68 to 1.04, p=0.11). Despite an extensive search of the literature, eligible data for the meta-analysis were few and no results reached statistical significance. In conclusion, we found no evidence to support administration of the old cholinergic agents lecithin, deanol, and meclofenoxate to patients with tardive dyskinesia. In addition, two trials were found on novel cholinergic Alzheimer drugs in tardive dyskinesia, one of which was ongoing. Further investigation of the clinical effects of novel cholinergic agents in tardive dyskinesia is warranted.

PMID 15610922
Maria Carolina Hardoy, Mauro Giovanni Carta, Bernardo Carpiniello, Carlo Cianchetti, Socrate Congia, Immacolata D'Errico, Guido Emanuelli, Franco Garonna, Maria Julieta Hardoy, Marcello Nardini
Gabapentin in antipsychotic-induced tardive dyskinesia: results of 1-year follow-up.
J Affect Disord. 2003 Jul;75(2):125-30. doi: 10.1016/s0165-0327(02)00043-5.
Abstract/Text BACKGROUND: In a previous study, improvement of antipsychotic-induced blefarospasm and involuntary oral-mandibulo movements were observed with the use of the anticonvulsant drug gabapentin among affectively ill patients who had been exposed to maintenance neuroleptics. The results reported in the present paper represent the sequel to the previous study.
METHODS: The purported efficacy of gabapentin in the treatment of tardive dyskinesia has been assessed in an open design 1-year follow-up study, in which 30 schizoaffective, bipolar I and schizophrenic patients from seven Italian centres were evaluated by means of AIMS. The results showed a statistically significant time-related decrease in AIMS scores. The mean percentage of improvement at AIMS was 47.5+/-18.2%. An improvement of more than 35% after 1 year in 76% of the subjects who completed the trial (n=25) and in 63.3% of the entire sample admitted to the study was revealed.
LIMITATION: Open trial.
CONCLUSION: The introduction of new antipsychotic drugs has probably already limited the problems related to tardive dyskinesia. However, this type of side-effect is also observed during the course of treatment with atypical neuroleptics albeit with a lesser frequency. The fact that gabapentin treatment may have further improved clinical conditions of patients in whom therapeutic protocols had already been modified, appears to suggest exertion of a possible synergic action by the new neuroleptics on tardive dyskinesia.

PMID 12798252
Joseph Bergman, Tzvi Dwolatzky, Izidor Brettholz, Vladimir Lerner
Beneficial effect of donepezil in the treatment of elderly patients with tardive movement disorders.
J Clin Psychiatry. 2005 Jan;66(1):107-10.
Abstract/Text BACKGROUND: Tardive dyskinesia and other delayed-onset abnormal involuntary movement disorders may occur as a result of the use of psychotropic drugs. A distinction is usually made between classic tardive dyskinesia (TD) (orobuccal-lingual-facial) and tardive dystonia, tardive tremor (TT), tardive akathisia, and other related syndromes. In spite of the development of atypical antipsychotics with fewer side effects, tardive movement disorders nevertheless continue to present a significant clinical and therapeutic challenge. Several reports have suggested that donepezil may be helpful in the treatment of TD.
METHOD: A preliminary study was conducted of 7 patients (5 women and 2 men) enrolled over a period of 6 months who had been experiencing TT for a period of at least 1 year. The ages of the patients ranged from 64 to 79 years, and all patients were on stable antipsychotic therapy. Donepezil was added to their usual treatment for 8 weeks. The severity of patients' extrapyramidal symptoms was assessed using the tremor subscale of the Simpson-Angus Scale (SAS) and self-rated with a modification of the Clinical Global Impressions scale, the Subjective Clinical Improvement Impression scale. The clinical response was evaluated by comparing the rating scores at baseline prior to donepezil treatment and every 2 weeks thereafter.
RESULTS: The addition of donepezil (up to 10 mg/day) was associated with a clinically significant improvement (from 37.5% to 63.6%) on the SAS tremor subscale following 4 weeks of therapy. Only 1 patient discontinued follow-up due to side effects.
CONCLUSION: The results suggest that donepezil may be effective in the treatment of TT, and this finding should be evaluated further by a randomized controlled study.

PMID 15669896
Scott W Woods, John R Saksa, C Bruce Baker, Shuki J Cohen, Cenk Tek
Effects of levetiracetam on tardive dyskinesia: a randomized, double-blind, placebo-controlled study.
J Clin Psychiatry. 2008 Apr;69(4):546-54.
Abstract/Text OBJECTIVE: The goal of this study was to evaluate the efficacy and safety of levetiracetam versus placebo for tardive dyskinesia (TD).
METHOD: This double-blind, placebo-controlled, randomized study was conducted at the Connecticut Mental Health Center between September 2004 and April 2006. Antipsychotic-treated patients meeting Glazer-Morgenstern criteria for TD were assigned at random to receive levetiracetam 500 mg/day to 3000 mg/day or placebo for 12 weeks. After completion of 12 weeks, patients were permitted to receive open-label levetiracetam for a further 12 weeks. The principal efficacy outcome measure was improvement in the Abnormal Involuntary Movement Scale (AIMS) total score. Safety was assessed with an adverse event scale, psychiatric symptom rating scales, weight, and hematologic tests.
RESULTS: A total of 50 patients were randomly assigned to treatment. AIMS total scores were moderate in severity at baseline. Mixed regression models revealed that AIMS total scores declined 43.5% from baseline in the levetiracetam group compared to 18.7% for placebo (p = .022). Patients continuing levetiracetam in the open-label phase continued to improve, and patients crossed over to open-label levetiracetam improved to a similar degree as those initially assigned. Levetiracetam was well tolerated.
CONCLUSION: Levetiracetam appeared effective for TD in this study. The mechanisms of its therapeutic effect are unclear but may involve reducing neuronal hypersynchrony in basal ganglia. Future studies should attempt to replicate the current results.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00291213.

PMID 18312060
Vladimir Lerner, Chanoch Miodownik, Alexander Kaptsan, Yuly Bersudsky, Igor Libov, Ben-Ami Sela, Eliezer Witztum
Vitamin B6 treatment for tardive dyskinesia: a randomized, double-blind, placebo-controlled, crossover study.
J Clin Psychiatry. 2007 Nov;68(11):1648-54.
Abstract/Text BACKGROUND: Tardive dyskinesia (TD) is a significant clinical problem. Vitamin B(6) is a potent antioxidant and takes part in almost all of the possible mechanisms that are suggested as being associated with appearance of TD. The aims of this study were (1) to reexamine the efficacy and safety of higher doses of vitamin B(6) versus placebo in a greater sample of patients for a longer time and (2) to evaluate the carryover effect of vitamin B(6).
METHOD: A 26-week, double-blind, placebo-controlled trial was conducted in a university-based research clinic from August 2002 to January 2005 on 50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD. In a double-blind crossover paradigm, all study subjects were randomly assigned to start treatment with either vitamin B(6) (daily dose of 1200 mg) or placebo. After 12 weeks of treatment and then a 2-week washout, subjects were crossed over to receive the other treatment for 12 weeks. The primary outcome measure was the change from baseline in Extra-pyramidal Symptom Rating Scale (ESRS) scores.
RESULTS: The mean decrease in ESRS clinical global impression scores from baseline to endpoint was 2.4 points in patients treated with vitamin B(6) and 0.2 points in patients treated with placebo (p < .0001). The mean decrease in the parkinsonism subscale score was 18.5 points and 1.4 points, respectively (p < .00001), and the mean decrease in the dyskinesia subscale score was 5.2 points and -0.8 points, respectively (p < .0001).
CONCLUSION: Vitamin B(6) appears to be effective in reducing symptoms of TD. The specific mechanisms by which vitamin B(6) attenuates symptoms of TD are not clear.

PMID 18052557
A Rapaport, M Sadeh, D Stein, J Levine, P Sirota, T Mosheva, S Stir, A Elitzur, I Reznik, D Geva, J M Rabey
Botulinum toxin for the treatment of oro-facial-lingual-masticatory tardive dyskinesia.
Mov Disord. 2000 Mar;15(2):352-5. doi: 10.1002/1531-8257(200003)15:2<352::aid-mds1030>3.0.co;2-x.
Abstract/Text
PMID 10752596
Ahmed Saeed Yahya, Shakil Khawaja
Electroconvulsive Therapy as a Treatment for Tardive Dyskinesia.
Prim Care Companion CNS Disord. 2021 May 6;23(3). doi: 10.4088/PCC.20r02775. Epub 2021 May 6.
Abstract/Text OBJECTIVE: To review the published literature over the last 10 years for the use of electroconvulsive therapy (ECT) in tardive dyskinesia (TD), focusing on the efficacy of this treatment.
DATA SOURCES: A comprehensive evidence search of the published literature in the last 10 years (2010-2020) was conducted using the search terms electroconvulsive therapy, electroshock therapy, ECT, tardive dyskinesia, and tardive dystonia. The review was limited to articles published in the English language. MEDLINE, Embase, PubMed, PsycInfo, Cochrane Library, Google Scholar, and the NICE (National Institute for Health and Care Excellence) guidelines were also searched.
STUDY SELECTION: Twenty-three case studies published within the last 10 years were retrieved. The search revealed 5 articles of potential relevance.
DATA EXTRACTION: The articles were analyzed by both authors to obtain clinical information relevant to meeting the objectives of the review.
DATA SYNTHESIS: The efficacy in using ECT for TD is derived only from case series and case reports. There were no controlled trials, and the evidence collated was limited and of low quality.
CONCLUSIONS: The review indicates that ECT could be considered as a treatment for TD. However, this treatment may only be considered when patients present with a coexistent refractory mood or affective disorder. Further clinical trials are needed to improve understanding regarding the efficacy, tolerability, and safety of using ECT in this patient group.

© Copyright 2021 Physicians Postgraduate Press, Inc.
PMID 34000170

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