This Editorial was written in response to:&nbsp;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. 2014; 4. doi:10.7916/D8MS3R8CErratum published July 27, 2015</p

Angel Vinuela

Un J. Kang

Tremor and Other Hyperkinetic Movements

PubMed

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Reversibility of Tardive Dyskinesia Syndrome

This Editorial was written in response to: 

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. 2014; 4. 10.7916/D8MS3R8C

Vinuela, Angel

Kang, Un

Columbia University Academic Commons

In Response To:Zutshi D, Cloud LJ, Factor SA. Dopamine receptor blocking agents: Experience from a university-based movement disorder clinic. Tremor Other Hyperkinet Mov.2014; 4. doi: 10.7916/D8MS3R8CEditorialsReversibility of Tardive Dyskinesia SyndromeAngel Vinuela & Un Jung Kang*Division of Movement Disorders, Department of Neurology, Columbia University Medical Center, New York, NY, USAKeywords: Tardive dyskinesia, antipsychotics, neuroleptics, remissionCitation: Vinuela A, Kang UJ. Reversibility of tardive dyskinesia syndrome. Tremor Other Hyperkinet Mov. 2014; 4. doi: 10.7916/D86Q1VXZ* To whom correspondence should be addressed. E-mail: Ujk2101@columbia.eduEditor: Elan D. Louis, Columbia University, USAReceived: October 30, 2014 Accepted: November 5, 2014 Published: November 27, 2014Copyright: ’ 2014 Vinuela et al. This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommercial–No Derivatives License, whichpermits the user to copy, distribute, and transmit the work provided that the original author(s) and source are credited; that no commercial use is made of the work; and that the work is notaltered or transformed.Funding: None.Financial disclosures: None.Conflict of interest: The authors report no conflict of interest.Tardive syndromes (TS) constitute a group of abnormal involuntarymovements and sensory symptoms caused by exposure to dopaminereceptor-blocking agents (DRBAs). The term tardive reflects theclassical thought that these symptoms occur after long-term exposureto the DRBA, but it is recognized that TS may appear as early as daysafter receiving the first few doses of a DRBA.1Historically, the main source of TS was the use of first-generationneuroleptics in the treatment of psychosis. Development of the second-generation ‘‘atypical’’ antipsychotics led to the initial expectation of areduction in frequency of TS, but whether prevalence of TS from theatypical antipsychotics is lower than the classic antipsychotics remainscontroversial. This false sense of safety may have contributed to anincreased number of prescriptions for DRBAs in the past 10 years foroff-label use as mood stabilizers, anti-anxiety agents, and treatmentsfor agitation in dementia, as well as the use of prokinetic drugs such asmetoclopramide.2 TS have not disappeared with the introduction ofatypical antipsychotics.A distinct feature of the syndrome is the persistence of the abnormalmovements despite discontinuation of the offending drugs, unlike mostof the other drug-induced side effects, which reverse upon disconti-nuation of the drug. Available long-term studies of the natural courseof TS provide a wide range of remission rates (0–73%), but most reportremission rates below 25%.1,3–8 The main limitation of most of thesestudies has been that patients continued treatment with DRBAsbecause of their underling psychiatric disease, or as a symptomatictreatment for their TS. In this context, an accurate analysis ofevolution of TS is difficult. The continued use of DRBAs can suppressinvoluntary movements and mask the diagnosis. Fernandez et al.8showed a high correlation between an unexpectedly high remissionrate of TS (62%) and an increase in parkinsonism in a group ofpatients who are using DRBAs in the long term. This suggests that TSmay have been suppressed by DRBAs that produced parkinsonism.Similarly, Kane et al.9 showed re-emergence of dyskinesia in 34% ofpatients after withdrawal of neuroleptic treatment.In the recent article by Zutshi et al.12, the authors report aretrospective analysis of 106 patients with TS in which DRBAs werediscontinued. The majority of these patients (94%) were treated fornon-psychotic disorders, and the DRBAs used were mostly gastro-intestinal drugs (41.7%) and atypical antipsychotics (36.1%). Patientswere followed for approximately 3 years. Unexpectedly, even afterdiscontinuation of the causing agents, the rate of spontaneousremission was only 2%, and the overall remission using specifictreatments was 13%. Unfortunately, probably due to the low remissionrates, the study did not identify any significant predictor of remission inthe patients, their diagnoses, or in the DRBA used. This paper is one ofvery few reporting remission rates of TS after complete withdrawal ofDRBAs, and probably the only study in which the majority of subjectstook these medications for non-psychotic disorders.Freely available onlineTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.orgThe Center for Digital Research and ScholarshipColumbia University Libraries/Information Services1As the authors acknowledge, limitations of this study are theretrospective nature, the selection bias inherent in a MovementDisorders Center with a tendency to see the most refractory patients,and a substantial proportion (13%) of the patients lost to follow-up(arguably those with milder dyskinesias). These factors may have led toan underestimation of the remission rate of TS. Nonetheless, theremission rate reported by the authors is strikingly similar to low ratesnoted by previous studies from decades ago, before the introduction ofatypical antipsychotic drugs.1,4,7The pathophysiology of TS is not completely understood and therehave been various proposed mechanisms, including upregulation andsensitization of post-synaptic D2 receptors in striatal neurons,increased glutamatergic excitotoxicity, oxidative stress, dopamineterminal loss, and maladaptive plasticity.10,11 Notably, it is not knownhow the changes in synaptic transmission produced by a receptorantagonist can lead to such persistent changes underlying TS.On a more positive note, the authors report a general tendency forimprovement of TS in most of the patients. Nonetheless, their findingstresses the need for further larger prospective studies in patients inwhom DRBAs can be withdrawn and for a better understanding of thepathophysiology of TS, which defies our knowledge of the pharma-cological effects of neurotransmitter receptor blockers. Importantly,the authors’ study and previous studies demonstrating low remissionrates of TS call for a judicious clinical practice that emphasizesprevention as the best treatment modality at this point.References1. Kang UJ, Burke RE, Fahn S. Natural history and treatment of tardive dystonia.Mov Disord 1986;1:193–208, doi: http://dx.doi.org/10.1002/mds.870010305.2. Olfson M, Blanco C, Liu SM, Wang S, Correll CU. National trends in theoffice based treatment of children, adolescents, and adults with antipsychotics.Arch Gen Psychiatry 2012;69:1247–1256, doi: http://dx.doi.org/10.1001/archgenpsychiatry.2012.647.3. Gardos G, Cole JO, Rapkin RM, et al. Anticholinergic challenge andneuroleptic withdrawal. Changes in dyskinesia and symptom measures. Arch GenPsychiatry 1984;41:1030–1035, doi: http://dx.doi.org/10.1001/archpsyc.1983.01790220020003.4. Casey DE. Tardive dyskinesia: Reversible and irreversible. PsychopharmacolSuppl 1985;2:88–97, doi: http://dx.doi.org/10.1007/978-3-642-70140-5_11.5. Yagi G, Itoh H. Follow-up study of 11 patients with potentially reversibletardive dyskinesia. Am J Psychiatry 1987;144:1496–1498.6. Bergen JA, Eyland EA, Campbell JA, et al. The course of tardivedyskinesia in patients on long-term neuroleptics. Br J Psychiatry 1989;154:523–528, doi: http://dx.doi.org/10.1192/bjp.154.4.523.7. Glazer WM, Morgenstern H, Schooler N, Berkman CS, Moore DC.Predictors of improvement in tardive dyskinesia following discontinuation ofneuroleptic medication. Br J Psychiatry 1990;157:585–592, doi: http://dx.doi.org/10.1192/bjp.157.4.585.8. Fernandez HH, Krupp B, Friedman JH. The course of tardive dyskinesiaand parkinsonism in psychiatric inpatients: 14-year follow-up. Neurology 2001;56:805–807, doi: http://dx.doi.org/10.1212/WNL.56.6.805.9. Kane JM, Woerner M, Lieberman J. Tardive dyskinesia: Prevalence,incidence, and risk factors. J Clin Psychopharmacol 1988;8:52S–56S, doi: http://dx.doi.org/10.1097/00004714-198808001-00010.10. Seeman P, Tinazzi M. Loss of dopamine neuron terminals inantipsychotic-treated schizophrenia; relation to tardive dyskinesia. ProgNeuropsychopharmacol Biol Psychiatry 2013;44:178–183, doi: http://dx.doi.org/10.1016/j.pnpbp.2013.02.011.11. Teo JT, Edwards MJ, Bhatia K. Tardive dyskinesia is caused bymaladaptive synaptic plasticity: A hypothesis. Mov Disord 2012;12:1205–1215,doi: http://dx.doi.org/10.1002/mds.25107.12. Zutshi D, Cloud LJ, Factor SA. Tardive Syndromes are RarelyReversible after Discontinuing Dopamine Receptor Blocking Agents:Experience from a University-based Movement Disorder Clinic. TremorOther Hyperkinet Mov (N Y) 2014;4:266.Vinuela A, Kang UJ Tardive Dyskinesia SyndromeTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.orgThe Center for Digital Research and ScholarshipColumbia University Libraries/Information Services2

Reversibility of Tardive Dyskinesia Syndrome

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