Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia

Hanna Bergman; John Rathbone; Vivek Agarwal; Karla Soares‐Weiser

doi:10.1002/14651858.CD000459.pub3

Cochrane Database of Systematic Reviews

Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia

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DOI:

https://doi.org/10.1002/14651858.CD000459.pub3 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

06 febrero 2018see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Esquizofrenia

Copyright:

Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Hanna Bergman

Correspondencia a: Cochrane Response, Cochrane, London, UK

[email protected]

[email protected]
John Rathbone

Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Australia
Vivek Agarwal

General Adult Psychiatry, North Essex Partnership University NHS Foundation Trust, Colchester, UK
Karla Soares‐Weiser

Cochrane Editorial Unit, Cochrane, London, UK

Contributions of authors

HB ‐ study selection, data extraction and assimilation, GRADE and Summary of Findings tables, report writing (2017 update)

JR ‐ study selection, data extraction and assimilation, report writing (original version).

VA ‐ report writing (2017 update).

KSW ‐ protocol development, searching, study selection, data extraction and assimilation, report writing (original version and 2017 update).

Sources of support

Internal sources

Queensland Health, Australia.
CAPES ‐ Ministry of Education, Brazil.
Universidade Federal de São Paulo, Brazil.
Enhance Reviews Ltd., UK.

Logistics support for Hanna Bergman

External sources

NIHR HTA Project Grant, reference number: 14/27/02, UK.

Salary support for Hanna Bergman.
Support for patient involvement consultation.
Support for accessible, traceable data.

Declarations of interest

HB worked for Enhance Reviews Ltd. during preparation of this review and was paid for her contribution to this review. Enhance Reviews Ltd. is a private company that performs systematic reviews of literature. HB works for Cochrane Response, an evidence consultancy that takes commissions from healthcare guideline developers and policy makers.

JR is not aware of any conflicts of interest for this review.

VA has declared no known conflicts of interest for this review.

KSW is the Deputy Editor‐in‐Chief for Cochrane and Cochrane Innovations. When the NHIR HTA programme grant relevant to this review update was awarded, KSW was the Managing Director of Enhance Reviews Ltd.

One of the earlier reviewers (JJM) is a member of the following advisory boards: Janssen‐Cilag Australia, Eli Lilly Australia, Lundbeck Australia. In addition, JJM has been a co‐investigator on studies of neuroleptic medications produced by the following companies: Astra Zeneca (ICI), Janssen‐Cilag, Eli Lilly, Sandoz, and Pfizer. The same companies have provided travel and accommodation expenses for JJM to attend relevant investigator meetings and scientific symposia. No funds have been paid directly to JJM. Payments related to participation in drug trials and board attendance has been paid to a Government‐audited trust account to support schizophrenia research.

Acknowledgements

In earlier versions of this review (1998 to 2002), John McGrath was a reviewer and made a considerable contribution to the review by developing the protocol, data extracting, data assimilation, and report writing. We are grateful for his substantial input.

We are indebted to Kirsten Mason, Tracey Richardson, Geoff Davies, Carmel Meir, Leanne Roberts, Nicholas Henschke, and Loukia Spineli for assistance with this review. The following authors kindly provided additional information in order to assist this review: Dr D Bateman, Dr M Campbell, Dr S Caroff, Dr G Chouinard, Dr I Cookson, Dr J de Jesus Mari, Dr M Herz, Dr D Johnson, Dr J Kalachnik, Dr J Kane, Dr S Lal, Dr G Paulson, Dr H Spohn, Dr N Quinn, and Dr M Woerner.

We are grateful to Judy Wright (2005) and Farhad Sokraneh (2015, 2017) for the updated trial searches and to Clive Adams for his constant advice.

We thank Rosie Asher and Antonio Grande for screening literature and helping with data extraction for the 2017 update, and Ben Gray for writing the Plain language summary. We are also grateful to Dawn‐Marie Walker, Ruth Sayers, Megan Lees, and Vanessa Pinfold from McPin Foundation for organising and holding the public and patient involvement consultation with TD service users that contributed to selecting outcomes for the 'Summary of findings' tables and to guide future research. Finally, we wish to thank Sai Zhao for assessing articles in Chinese.

Version history

Published

Title

Stage

Authors

Version

2018 Feb 06

Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia

Review

Hanna Bergman, John Rathbone, Vivek Agarwal, Karla Soares‐Weiser

https://doi.org/10.1002/14651858.CD000459.pub3

2006 Jan 25

Neuroleptic reduction and/or cessation and neuroleptics as specific treatments for tardive dyskinesia

Review

Karla Soares‐Weiser, John Rathbone

https://doi.org/10.1002/14651858.CD000459.pub2

1998 Apr 27

Neuroleptic reduction and/or cessation and neuroleptics as specific treatments for tardive dyskinesia

Review

John McGrath, Karla Soares‐Weiser

https://doi.org/10.1002/14651858.CD000459

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Table 1. Other Cochrane Reviews in this series

Interventions	Current reference (updates underway)
Anticholinergic medication	Soares‐Weiser 1997; Soares 2000
Benzodiazepines	Bhoopathi 2006
Calcium channel blockers	Essali 2011
Cholinergic medication	Tammenmaa 2002
Gamma‐aminobutyric acid agonists	Alabed 2011
Miscellaneous treatments	Soares‐Weiser 2003
Neuroleptic reduction and/or cessation and neuroleptics	This review
Non‐neuroleptic catecholaminergic drugs	El‐Sayeh 2006
Vitamin E	Soares‐Weiser 2011

Differences between protocol and review

The protocol as published with this review has evolved over time. The revisions of protocol are in line with the development of Review Manager and in keeping with Cochrane guidance. We think the revisions have greatly improved and enhanced this review. We do not think, however, that it has materially affected our conduct of the review or interpretation of the results.

There was a substantial update to the protocol in the 2017 review update. The biggest changes to affect the review were to:

broaden the inclusion criteria, and add the comparison 'Specific antipsychotic versus other drug';
change the title from 'Neuroleptic reduction and/or cessation and neuroleptics as specific treatments for tardive dyskinesia' to 'Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia';
update list of outcomes following consultation with consumers; and
add 'Summary of findings' tables.

Previous methods are reproduced in Appendix 1.

Notes

Cochrane Schizophrenia Group internal peer review complete (see Group’s Module).
External peer review scheduled.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Female; Humans; Male; Middle Aged;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Message from one of the participants of the public and patient involvement consultation of service user perspectives on tardive dyskinesia research

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 4

Study flow diagram for 2015 and 2017 searches for this review

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Analysis 1.1

Comparison 1 Reduced overall dose of antipsychotic vs antipsychotic maintenance, Outcome 1 Tardive dyskinesia: no clinically important improvement (long term).

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Analysis 1.2

Comparison 1 Reduced overall dose of antipsychotic vs antipsychotic maintenance, Outcome 2 Tardive dyskinesia: no improvement (long term).

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Analysis 1.3

Comparison 1 Reduced overall dose of antipsychotic vs antipsychotic maintenance, Outcome 3 Tardive dyskinesia: deterioration (long term).

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Analysis 1.4

Comparison 1 Reduced overall dose of antipsychotic vs antipsychotic maintenance, Outcome 4 General mental state: relapse (long term).

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Analysis 1.5

Comparison 1 Reduced overall dose of antipsychotic vs antipsychotic maintenance, Outcome 5 Acceptability of the treatment: leaving the study early (long term).

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Analysis 2.1

Comparison 2 Switch to specific antipsychotic vs antipsychotic cessation, Outcome 1 Tardive dyskinesia: no clinically important improvement (medium term).

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Analysis 2.2

Comparison 2 Switch to specific antipsychotic vs antipsychotic cessation, Outcome 2 Tardive dyskinesia: average endpoint score (AIMS, high = poor) (medium term).

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Analysis 2.3

Comparison 2 Switch to specific antipsychotic vs antipsychotic cessation, Outcome 3 General mental state: average endpoint score (BPRS, high = poor) (medium term).

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Analysis 2.4

Comparison 2 Switch to specific antipsychotic vs antipsychotic cessation, Outcome 4 Acceptability of the treatment: leaving the study early (medium term).

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Analysis 2.5

Comparison 2 Switch to specific antipsychotic vs antipsychotic cessation, Outcome 5 Adverse effects: use of antiparkinsonism drugs (medium term).

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Analysis 2.6

Comparison 2 Switch to specific antipsychotic vs antipsychotic cessation, Outcome 6 Adverse effects: parkinsonism ‐ average endpoint score (ESRS) (medium term).

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Analysis 2.7

Comparison 2 Switch to specific antipsychotic vs antipsychotic cessation, Outcome 7 Adverse effects: dystonia ‐ average endpoint score (ESRS) (medium term).

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Analysis 3.1

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 1 Tardive dyskinesia: no clinically important improvement.

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Analysis 3.2

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 2 Tardive dyskinesia: not any improvement (short term).

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Analysis 3.3

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 3 Tardive dyskinesia: deterioration (short term).

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Analysis 3.4

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 4 Tardive dyskinesia: average endpoint score (various scales).

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Analysis 3.5

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 5 Tardive dyskinesia: average change score (AIMS, low = better) (medium term).

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Analysis 3.6

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 6 General mental state: deterioration.

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Analysis 3.7

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 7 General mental state: average endpoint score (PANSS‐general psychopathology, low = better) (long term).

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Analysis 3.8

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 8 General mental state: average change score (BPRS, low = better) (medium term).

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Analysis 3.9

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 9 Acceptability of the treatment: leaving the study early (short term).

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Analysis 3.10

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 10 Acceptability of the treatment: leaving the study early (medium term).

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Analysis 3.11

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 11 Acceptability of the treatment: leaving the study early (long term).

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Analysis 3.12

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 12 Adverse events: extrapyramidal symptoms (need of antiparkinsonism drugs).

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Analysis 3.13

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 13 Adverse effects: parkinsonism (SHRS) ‐ average endpoint scores (short term).

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Analysis 3.14

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 14 Adverse effects: parkinsonism (SAS, ESRS, low = better) ‐ average change score (medium term).

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Analysis 3.15

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 15 Adverse effects: dyskinesia (ESRS, low = better) ‐ average change score (medium term).

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Analysis 3.16

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 16 Adverse effects: akathisia (BAS, ESRS, low = better) ‐ average change scores (medium term).

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Analysis 3.17

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 17 Adverse effects: dystonia (ESRS, low = better) ‐ average change score (medium term).

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Analysis 3.18

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 18 Adverse effects: general adverse events (UKU, low = better) ‐ average change score (medium term).

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Analysis 3.19

Comparison 3 Switch to a specific antipsychotic vs switch to a different antipsychotic, Outcome 19 General global state: average change score (CGI) (medium term).

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Analysis 4.1

Comparison 4 Specific antipsychotic vs other drugs, Outcome 1 Tardive dyskinesias: no clinically important improvement (medium term).

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Analysis 4.2

Comparison 4 Specific antipsychotic vs other drugs, Outcome 2 Tardive dyskinesia: no improvement (medium term).

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Analysis 4.3

Comparison 4 Specific antipsychotic vs other drugs, Outcome 3 Tardive dyskinesia: deterioration (medium term).

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Analysis 4.4

Comparison 4 Specific antipsychotic vs other drugs, Outcome 4 Acceptability of the treatment: leaving the study early (medium term).

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Table 2. Excluded studies relevant to schizophrenia: comparisons for existing or potential reviews

Study ID	Participants – people with:	Intervention	Comparison for review	Cochrane Review
Cai 1988	Tardive dyskinesia	1‐stepholidine vs placebo	1‐stepholidine for schizophrenia	‐
Speller 1997	Schizophrenia	Amisulpride vs haloperidol	Amisulpride versus haloperidol for schizophrenia
Gerlach 1978	Tardive dyskinesia	Biperiden vs no treatment	Anticholinergic drugs for tardive dyskinesia
NDSG 1986		Chlorprothixene versus haloperidol vs perphenazine vs haloperidol + biperiden
Greil 1984		Biperiden vs placebo
Chouinard 1979	Schizophrenia	Ethopropazine vs benztropine	Anticholinergics for parkinsonism
Spohn 1988		Abrupt neuroleptic cessation vs neuroleptic maintenance	Antipsychotic reduction or withdrawal for schizophrenia
Spohn 1993		Abrupt neuroleptic cessation vs neuroleptic maintenance
Wistedt 1983		Fluphenazine/flupenthixol decanoate continuation vs withdrawal
Goldberg 1981		Withdrawal of fluphenazine decanoate vs continuation
Hershon 1972		Trifluoperazine withdrawal vs trifluoperazine continuation
Johnson 1987		Dose reduction vs maintenance (both arms used flupenthixol decanoate)
Kinon 2004		Olanzapine with different timings of dose‐reduction periods
Levine 1980		Fluphenazine withdrawal vs continuation
Marder 1987		Low‐ vs conventional‐dose maintenance therapy with fluphenazine decanoate
Newcomer 1992		Haloperidol dose reduction vs maintained dose
Singh 1990		Abrupt neuroleptic cessation vs neuroleptic maintenance
Zeng 1994	Tardive dyskinesia	Flunarizine vs placebo	Calcium channel blockers for neuroleptic‐induced tardive dyskinesia
Jeste 1977	Schizophrenia	Chlorpromazine schedule A vs chlorpromazine schedule B	Chlorpromazine timing of dose for schizophrenia.
NDSG 1986	Tardive dyskinesia	Chlorprothixene vs haloperidol vs perphenazine vs haloperidol + biperiden	Chlorprothixene for schizophrenia.
Andia 1998	Schizophrenia	Clozapine vs haloperidol	Clozapine versus haloperidol for schizophrenia
Gerlach 1975		Clozapine vs haloperidol	Clozapine versus haloperidol for schizophrenia
Bitter 2000		Clozapine vs olanzapine	Clozapine versus olanzapine for schizophrenia
Jean‐Noel 1999		Clozapine vs olanzapine	Clozapine versus olanzapine for schizophrenia
Caine 1979	Gilles de la Tourette's, Huntington's disease and drug‐induced atypical dyskinesia	Clozapine vs placebo	Clozapine versus placebo for schizophrenia.
Chouinard 1994	Schizophrenia	Clozapine versus risperidone	Clozapine versus risperidone for schizophrenia
Chouinard 1989		Haloperidol decanoate vs fluphenazine decanoate	Depot fluphenazine for schizophrenia
Cookson 1991		Fluphenazine decanoate vs haloperidol decanoate
Curson 1985		Fluphenazine decanoate vs placebo
McCreadie 1980		Fluphenazine decanoate vs intermittent pimozide
Odejide 1982		Fluphenazine decanoate vs vitamin B complex
Chouinard 1978		Fluphenazine ethanoate vs pipothiazine palmitate
Chouinard 1989, Cookson 1991		Haloperidol decanoate vs fluphenazine decanoate	Depot haloperidol decanoate for schizophrenia.
Chouinard 1978		Fluphenazine ethanoate vs pipothiazine palmitate	Depot pipothiazine for schizophrenia.
Burner 1989		Progabide vs placebo	GABA for schizophrenia
Bateman 1979	Tardive dyskinesia and psychiatric history	Metoclopramide (10 mg, 20 mg or 40 mg) vs haloperidol (5 mg or 10 mg)	Haloperdiol dose for schizophrenia
Tran 1997, Rosenheck 2003, Tollefson 1997	Schizophrenia	Haloperidol vs olanzapine	Haloperidol vs olanzapine for schizophrenia
NDSG 1986	Tardive dyskinesia	Chlorprothixene vs haloperidol vs perphenazine vs haloperidol + biperiden	Haloperidol vs perphenazine for schizophrenia
Kopala 2004, Wirshing 1999	Schizophrenia	Haloperidol vs risperidone	Haloperidol vs risperidone for schizophrenia
Jolley 1990		Brief intermittent antipsychotic treatment vs fluphenazine decanoate	Intermittent antipsychotic treatment for schizophrenia
McCreadie 1980		Fluphenazine decanoate vs intermittent pimozide
Newton 1989		Haloperidol with 'drug holiday' vs haloperidol
Goldberg 1981		Withdrawal of fluphenazine decanoate vs continuation
MacKay 1980		Lithium vs placebo	Lithium for schizophrenia
Borison 1987		Molidone vs haloperidol	Molidone vs haloperidol for schizophrenia
Williamson 1995		Olanzapine 1 mg vs olanzapine 10 mg versus placebo	Olanzapine dose for schizophrenia.
de Jesus Mari 2004		Olanzapine vs "conventional antipsychotic drugs"	Olanzapine for schizophrenia
Peluso 2012		First‐generation antipsychotic vs second‐generation antipsychotic	Olanzapine for schizophrenia
Kinon 2004		Olanzapine with different timings of dose reduction periods	Olanzapine reduction for schizophrenia
Peluso 2012		First‐generation antipsychotic versus second‐generation antipsychotic	Olanzapine vs other atypical antipsychotics for schizophrenia
Williamson 1995		Olanzapine 1 mg vs olanzapine 10 mg vs placebo	Olanzapine vs placebo for schizophrenia
Peluso 2012		First‐generation antipsychotic vs second‐generation antipsychotic	Perphenazine for schizophrenia
McCreadie 1980		Fluphenazine decanoate vs intermittent pimozide	Pimozide for schizophrenia
Cortese 2008		Quetiapine vs continuation of usual antipsychotic	Quetiapine vs continuation of usual antipsychotic for schizophrenia
Peluso 2012		First generation antipsychotic vs second‐generation antipsychotic	Quetiapine vs other atypical antipsychotics for schizophrenia
			Quetiapine vs typical antipsychotic medications for schizophrenia
			Risperidone vs olanzapine for schizophrenia
			Risperidone vs other atypical antipsychotics for schizophrenia
Cortese 2008		Quetiapine vs continuation of usual antipsychotic	Switching antipsychotic for schizophrenia.
Singer 1971	Tardive dyskinesia	Thiopropazate vs placebo	Thiopropazate for schizophrenia
Lal 1974	Schizophrenia	Thiopropazine vs trifluoperazine vs placebo	Thiopropazine vs placebo for schizophrenia
Lal 1974	Schizophrenia	Thiopropazine vs trifluoperazine vs placebo	Thiopropazine vs trifluoperazine for schizophrenia
Delwaide 1979	Tardive dyskinesia	Thioproperazine and tiapride vs placebo	Thioproperazine for schizophrenia
Delwaide 1979		Thioproperazine and tiapride vs placebo	Tiapride for schizophrenia
Buruma 1982		Tiapride vs placebo	Tiapride for schizophrenia
Crane 1970	Schizophrenia	Trifluoperazine high‐dose vs trifluoperazine low‐dose vs placebo	Trifluoperazine dose for schizophrenia
Crane 1970			Trifluoperazine vs placebo for schizophrenia
Lal 1974		Thiopropazine vs trifluoperazine vs placebo	Trifluoperazine vs placebo for schizophrenia
Odejide 1982		Fluphenazine decanoate vs vitamin B complex	Vitamins for schizophrenia
Peluso 2012		First‐generation antipsychotic vs second‐generation antipsychotic	Ziprasidone vs other atypical antipsychotics for schizophrenia

Table 2. Excluded studies relevant to schizophrenia: comparisons for existing or potential reviews

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Table 3. Suggestions for design of future study

Methods	Allocation: randomised, with sequence generation and concealment of allocation clearly described Blindness: double, tested Duration: 12 months beyond end of intervention at least Raters: independent
Participants	People with antipsychotic‐induced tardive dyskinesia^a Age: any Sex: both History: any N = 300^b
Interventions	1. Antipsychotic reduction/cessation (N = 150) vs antipsychotic maintenance (N = 150) OR 2. Specific antipsychotic (N = 150) vs other specific antipsychotic (N = 150)
Outcomes	Tardive dyskinesia: any clinically important improvement in tardive dyskinesia, any improvement, deterioration^c Adverse effects: no clinically significant extrapyramidal adverse effects ‐ any time period^c, use of any antiparkinsonism drugs, other important adverse events Leaving the study early Service outcomes: admitted, number of admissions, length of hospitalisation, contacts with psychiatric services Compliance with drugs Economic evaluations: cost‐effectiveness, cost‐benefit General state: relapse, frequency and intensity of minor and major exacerbations Social confidence, social inclusion, social networks, or personalised quality of life: binary measure Distress among relatives: binary measure Burden on family: binary measure
Notes	^aThis could be diagnosed by clinical decision. If funds were permitting all participants could be screened using operational criteria, otherwise a random sample should suffice. ^bSize of study with sufficient power to highlight about a 10% difference between groups for primary outcome. ^cPrimary outcome. The same applies to the measure of primary outcome as for diagnosis. Not everyone may need to have operational criteria applied if clinical impression is proved to be accurate.

Table 3. Suggestions for design of future study

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Summary of findings for the main comparison. Reduced dose of antipsychotics compared with antipsychotic maintenance for antipsychotic‐induced tardive dyskinesia

Reduced dose of antipsychotic compared with antipsychotic maintenance for antipsychotic‐induced tardive dyskinesia
Patient or population: psychiatric patients (schizophrenia or schizoaffective disorder) with antipsychotic‐induced tardive dyskinesia Setting: inpatients and outpatients in the UK (1 study) and the USA (1 study) Intervention: Reduced dose of antipsychotic Comparison: Antipsychotic maintenance
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with antipsychotic maintenance	Risk with reduced dose of antipsychotic
Tardive dyskinesia: no clinically important improvement Follow‐up: 44‐48 weeks	Study population		RR 0.42 (0.17 to 1.04)	17 (2 RCTs)	⊕⊝⊝⊝ Very low^1,2
	875 per 1000	368 per 1000 (149 to 910)
Tardive dyskinesia: deterioration of symptoms Follow‐up: 44‐48 weeks	Study population		RR 0.61 (0.11 to 3.31)	17 (2 RCTs)	⊕⊝⊝⊝ Very low^1,2
	250 per 1000	153 per 1000 (28 to 828)
General mental state: relapse Follow‐up: 44‐48 weeks	Study population		RR 3.00 (0.16 to 57.36)	8 (1 RCT)	⊕⊝⊝⊝ Very low^2,3
	0 per 1000	0 per 1000 (0 to 0)
Adverse effect: any ‐ not reported	See comment	See comment	Not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
Adverse effect: extrapyramidal symptoms ‐ not reported	See comment	See comment	Not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
Acceptability of the treatment: leaving the study early Follow‐up: 44‐48 weeks	Study population		RR 0.33 (0.06 to 1.99)	8 (1 RCT)	⊕⊝⊝⊝ Very low^2,3,4
	750 per 1000	248 per 1000 (45 to 1000)
Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported	See comment	See comment	Not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Downgraded one level for risk of bias: none of the studies adequately described allocation concealment, one study was a subsample from one site of an RCT, and one study's baseline characteristics were not balanced between study groups. ²Downgraded two levels for imprecision: 95% CI includes both no effect and appreciable benefit for antipsychotic reduced dose; very small sample size. ³Downgraded one level for risk of bias: allocation concealment was not adequately described, only a subsample from one site of an RCT qualified for inclusion. ⁴Downgraded one level for indirectness: leaving the study early can give an indication, but is not a direct measurement, of treatment acceptability.

Summary of findings for the main comparison. Reduced dose of antipsychotics compared with antipsychotic maintenance for antipsychotic‐induced tardive dyskinesia

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Summary of findings 2. Antipsychotic cessation compared with antipsychotic maintenance for antipsychotic‐induced tardive dyskinesia

Antipsychotic cessation compared with antipsychotic maintenance for antipsychotic‐induced tardive dyskinesia
Patient or population: psychiatric patients with antipsychotic‐induced tardive dyskinesia Setting: inpatients and outpatients in any country Intervention: Antipsychotic cessation Comparison: Antipsychotic maintenance
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Antipsychotic maintenance	Antipsychotic cessation
There is no evidence about the effects of withdrawal of antipsychotics compared with continuation of antipsychotics; none of the included studies evaluated this comparison.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

Summary of findings 2. Antipsychotic cessation compared with antipsychotic maintenance for antipsychotic‐induced tardive dyskinesia

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Summary of findings 3. Switch to another antipsychotic compared with antipsychotic cessation for antipsychotic‐induced tardive dyskinesia

Switch to another antipsychotic compared with antipsychotic cessation for antipsychotic‐induced tardive dyskinesia
Patient or population: psychiatric patients (schizophrenia) with antipsychotic‐induced tardive dyskinesia Setting: inpatients in Canada (1 study) and Taiwan (1 study) Intervention: Switch to another antipsychotic (risperidone, haloperidol) Comparison: Antipsychotic cessation (with placebo; from FGAs)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with antipsychotic cessation (placebo)	Risk with switch to another antipsychotic
Tardive dyskinesia: no clinically important improvement Follow‐up: 12 weeks	Study population		RR 0.45 (0.23 to 0.89)	42 (1 RCT)	⊕⊕⊝⊝ Low^1,2
	700 per 1000	315 per 1000 (161 to 623)
Tardive dyskinesia: deterioration of symptoms ‐ not reported	See comment	See comment	Not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
General mental state: average endpoint score (BPRS, high = poor) Follow‐up: 12 weeks	The mean general mental state average endpoint score (BPRS, high = poor) was 19	MD 4.30 lower (10.48 lower to 1.88 higher)	‐	42 (1 RCT)	⊕⊝⊝⊝ Very low^1,3
Adverse effect: any ‐ not reported	See comment	See comment	Not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
Adverse effects: use of antiparkinsonism drugs Follow‐up: 8‐12 weeks	Study population		RR 2.08 (0.74 to 5.86)	48 (1 RCT) ⁴	⊕⊝⊝⊝ Very low^1,3	Another study reported ESRS scale data for parkinsonism and also found little or no difference between groups (MD ‐0.4 95% CI ‐1.25 to 0.45, 42 participants).
	273 per 1000	567 per 1000 (202 to 1000)
Acceptability of the treatment: leaving the study early Follow‐up: 12 weeks	Study population		RR 0.60 (0.16 to 2.25)	50 (1 RCT)	⊕⊝⊝⊝ Very low^1,3,5
	200 per 1000	120 per 1000 (32 to 450)
Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported	See comment	See comment	Not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FGA: first‐generation antipsychotic; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹ Downgraded one level for risk of bias: generation of random sequence and allocation concealment not adequately described. ² Downgraded one level for imprecision: very small sample size. ³ Downgraded two levels for imprecision: 95% CI includes appreciable benefit for both interventions as well as no effect; very small sample size. ⁴ Two comparisons from one study. ⁵ Downgraded one level for indirectness: leaving the study early can give an indication, but is not a direct measurement, of treatment acceptability.

Summary of findings 3. Switch to another antipsychotic compared with antipsychotic cessation for antipsychotic‐induced tardive dyskinesia

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Summary of findings 4. Switch to a specific antipsychotic compared with switch to a different specific antipsychotic for antipsychotic‐induced tardive dyskinesia

Switch to specific antipsychotic compared with switch to a different specific antipsychotic for antipsychotic‐induced tardive dyskinesia
Patient or population: psychiatric patients (mainly schizophrenia) with antipsychotic‐induced tardive dyskinesia Setting: inpatients and outpatients in Canada (1 study), Denmark and Finland (1 study), South Africa (1 study), Taiwan (2 studies) and the USA (5 studies) Interventions: switch to specific antipsychotic (amisulpride, clozapine, haloperidol, molindone, olanzapine, risperidone, thiopropazate, quetiapine, ziprasidone, zuclopenthixol)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with specific antipsychotic 1	Risk with specific antipsychotic 2
Tardive dyskinesia: no clinically important improvement Follow‐up: 3‐50 weeks	Study population		‐	140 (4 RCTs)	⊕⊝⊝⊝ Very low^1,2	No meta‐analysis, studies stratified by antipsychotic. The following comparisons found no clinically important improvement: THI vs HAL, ZUC vs HAL, OLZ vs RIS, QUE vs HAL
	See comment	See comment
Tardive dyskinesia: deterioration Follow‐up: 3‐4 weeks	Study population		‐	35 (2 RCTs)	⊕⊝⊝⊝ Very low^1,2	No meta‐analysis, studies stratified by antipsychotic. The following comparisons found no difference in deterioration: THI vs HAL, ZUC vs HAL
	See comment	See comment
General mental state: deterioration Follow‐up: 3‐50 weeks	Study population		‐	120 (3 RCTs)	⊕⊝⊝⊝ Very low ^1,2	No meta‐analysis, studies stratified by antipsychotic. The following comparisons found no difference in mental state deterioration: ZUC vs HAL, OLZ vs RIS, QUE vs HAL
	See comment	See comment
Adverse events: extrapyramidal symptoms (need of antiparkinsonism drugs) Follow‐up: 8‐50 weeks	Study population		‐	53 (2 RCTs)	⊕⊕⊝⊝ Low^1,3	No meta‐analysis, studies stratified by antipsychotic. HAL more likely to need antiparkinsonism drugs than QUE (1 RCT, 45 participants, RR 0.45, 95% CI 0.21 to 0.96). No difference: RIS vs HAL
	See comment	See comment
Adverse effects: general adverse events (UKU Average change score) Follow‐up: 24 weeks	See comment	See comment	‐	80 (1 RCT)	⊕⊝⊝⊝ Very low^1,2	No meta‐analysis, 3‐arm study comparing OLZ, ASP and unspecified FGAs found no difference in general adverse events for all pairwise comparisons.
Acceptability of the treatment: leaving the study early Follow‐up: 2 weeks ‐ 18 months	Study population		‐	466 (7 RCTs)	⊕⊝⊝⊝ Very low^1,2,4	RIS more likely to leave study early than OLZ (2 RCTs, 130 participants, RR 0.73, 95% CI 0.57 to 0.95). Remaining studies no meta‐analysis, no difference (6 RCTs, 450 participants): MOL/THI/CLO/QUE vs HAL, OLZ/ASP vs unspecified FGAs, OLZ vs QUE/ZIP, QUE vs ZIP/RIS, ZIP vs RIS
	See comment	See comment
Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported	None of the included studies reported on this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ASP: amisulpride; CI: confidence interval; CLO: clozapine; FGA: first‐generation anti‐psychotic; HAL: haloperidol; MOL: molindone; OLZ: olanzapine; RCT: randomised controlled trial; RIS: risperidone; RR: risk ratio; THI: thiopropazate; QUE: quetiapine; ZIP: ziprasidone; ZUC: zuclopenthixol
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Downgraded one step for risk of bias: randomisation procedure, allocation concealment or blinding were not adequately described. ²Downgraded two steps for imprecision: small sample size, and 95% CI includes appreciable benefit for both or one of the interventions as well as no effect. ³Downgraded one step for imprecision: small sample size. ⁴Downgraded one step for indirectness: leaving the study early can give an indication, but is not a direct measurement, of treatment acceptability.

Summary of findings 4. Switch to a specific antipsychotic compared with switch to a different specific antipsychotic for antipsychotic‐induced tardive dyskinesia

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Summary of findings 5. Specific antipsychotic compared with other drugs for antipsychotic‐induced tardive dyskinesia

Specific antipsychotic compared with other drugs for antipsychotic‐induced tardive dyskinesia
Patient or population: psychiatric patients (mainly schizophrenia) with antipsychotic‐induced tardive dyskinesia Setting: inpatients in the USA (1 study) Intervention: specific antipsychotic (haloperidol) Comparison: other drugs (tetrabenazine)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with tetrabenazine	Risk with haloperidol
Tardive dyskinesia: not improved to a clinically important extent Follow‐up: 18 weeks	Study population		RR 1.07 (0.51 to 2.23)	13 (1 RCT)	⊕⊝⊝⊝ Very low^1,2
	667 per 1000	713 per 1000 (340 to 1000)
Tardive dyskinesia: deterioration of symptoms Follow‐up: 18 weeks	Study population		RR 0.86 (0.07 to 10.96)	13 (1 RCT)	⊕⊝⊝⊝ Very low^1,2
	167 per 1000	143 per 1000 (12 to 1000)
Mental state ‐ not reported	See comment	See comment	Not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
Adverse effect: any ‐ not reported	See comment	See comment	Not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
Adverse effect: extrapyramidal symptoms ‐ not reported	See comment	See comment	Not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
Acceptability of the treatment: leaving the study early Follow‐up: 18 weeks	Study population		RR 4.38 (0.25 to 76.54)	13 (1 RCT)	⊕⊝⊝⊝ Very low^1,2,3
	0 per 1000	0 per 1000 (0 to 0)
Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported	See comment	See comment	Not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹Downgraded one step for risk of bias: randomisation procedure, allocation concealment and blinding were not adequately described. ²Downgraded two steps for imprecision: small sample size, and 95% CI includes appreciable benefit for both interventions. ³Downgraded one step for indirectness: leaving the study early can give an indication, but is not a direct measurement, of treatment acceptability.

Summary of findings 5. Specific antipsychotic compared with other drugs for antipsychotic‐induced tardive dyskinesia

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Table 1. Other Cochrane Reviews in this series

Interventions	Current reference (updates underway)
Anticholinergic medication	Soares‐Weiser 1997; Soares 2000
Benzodiazepines	Bhoopathi 2006
Calcium channel blockers	Essali 2011
Cholinergic medication	Tammenmaa 2002
Gamma‐aminobutyric acid agonists	Alabed 2011
Miscellaneous treatments	Soares‐Weiser 2003
Neuroleptic reduction and/or cessation and neuroleptics	This review
Non‐neuroleptic catecholaminergic drugs	El‐Sayeh 2006
Vitamin E	Soares‐Weiser 2011

Table 1. Other Cochrane Reviews in this series

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Comparison 1. Reduced overall dose of antipsychotic vs antipsychotic maintenance

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tardive dyskinesia: no clinically important improvement (long term) Show forest plot	2	17	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.17, 1.04]

2 Tardive dyskinesia: no improvement (long term) Show forest plot	2	17	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.17, 1.04]

3 Tardive dyskinesia: deterioration (long term) Show forest plot	2	17	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.11, 3.31]

4 General mental state: relapse (long term) Show forest plot	1	8	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.16, 57.36]

5 Acceptability of the treatment: leaving the study early (long term) Show forest plot	1	8	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.06, 1.99]

Comparison 1. Reduced overall dose of antipsychotic vs antipsychotic maintenance

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Comparison 2. Switch to specific antipsychotic vs antipsychotic cessation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tardive dyskinesia: no clinically important improvement (medium term) Show forest plot	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.23, 0.89]

2 Tardive dyskinesia: average endpoint score (AIMS, high = poor) (medium term) Show forest plot	1	42	Mean Difference (IV, Fixed, 95% CI)	‐5.5 [‐8.60, ‐2.40]

3 General mental state: average endpoint score (BPRS, high = poor) (medium term) Show forest plot	1	42	Mean Difference (IV, Fixed, 95% CI)	‐4.30 [‐10.48, 1.88]

4 Acceptability of the treatment: leaving the study early (medium term) Show forest plot	1	50	Risk Ratio (IV, Fixed, 95% CI)	0.6 [0.16, 2.25]

5 Adverse effects: use of antiparkinsonism drugs (medium term) Show forest plot	1	48	Risk Ratio (IV, Fixed, 95% CI)	2.08 [0.74, 5.86]

5.1 Haloperidol	1	12	Risk Ratio (IV, Fixed, 95% CI)	2.0 [0.56, 7.09]
5.2 Risperidone	1	36	Risk Ratio (IV, Fixed, 95% CI)	2.26 [0.37, 13.60]
6 Adverse effects: parkinsonism ‐ average endpoint score (ESRS) (medium term) Show forest plot	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.40 [‐1.25, 0.45]

7 Adverse effects: dystonia ‐ average endpoint score (ESRS) (medium term) Show forest plot	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.70 [‐1.76, 0.36]

Comparison 2. Switch to specific antipsychotic vs antipsychotic cessation

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Comparison 3. Switch to a specific antipsychotic vs switch to a different antipsychotic

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tardive dyskinesia: no clinically important improvement Show forest plot	4		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

1.1 Thiopropazate vs haloperidol ‐ short term	1	20	Risk Ratio (IV, Fixed, 95% CI)	1.53 [0.58, 4.05]
1.2 Zuclopenthixol vs haloperidol ‐ short term	1	15	Risk Ratio (IV, Fixed, 95% CI)	1.0 [0.79, 1.27]
1.3 Olanzapine vs risperidone ‐ medium term	1	60	Risk Ratio (IV, Fixed, 95% CI)	1.25 [0.82, 1.90]
1.4 Quetiapine vs haloperidol ‐ medium term	1	45	Risk Ratio (IV, Fixed, 95% CI)	0.80 [0.52, 1.22]
1.5 Quetiapine vs haloperidol ‐ long term	1	45	Risk Ratio (IV, Fixed, 95% CI)	0.88 [0.64, 1.21]
2 Tardive dyskinesia: not any improvement (short term) Show forest plot	2		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

2.1 Thiopropazate vs haloperidol	1	20	Risk Ratio (IV, Fixed, 95% CI)	0.41 [0.05, 3.28]
2.2 Zuclopenthixol vs haloperidol	1	15	Risk Ratio (IV, Fixed, 95% CI)	0.88 [0.16, 4.68]
3 Tardive dyskinesia: deterioration (short term) Show forest plot	2		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

3.1 Thiopropazate vs haloperidol	1	20	Risk Ratio (IV, Fixed, 95% CI)	1.22 [0.09, 16.92]
3.2 Zuclopenthixol vs haloperidol	1	15	Risk Ratio (IV, Fixed, 95% CI)	0.88 [0.16, 4.68]
4 Tardive dyskinesia: average endpoint score (various scales) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.1 Molindone vs haloperidol, 100% masking dose (AIMS, short term)	1	18	Mean Difference (IV, Fixed, 95% CI)	1.87 [‐0.20, 3.94]
4.2 Molindone vs haloperidol, 200% masking dose (AIMS, short term)	1	18	Mean Difference (IV, Fixed, 95% CI)	3.44 [1.12, 5.76]
4.3 Zuclopenthixol vs haloperidol (SHRS, short term)	1	15	Mean Difference (IV, Fixed, 95% CI)	‐4.81 [‐12.15, 2.53]
4.4 Olanzapine vs risperidone (AIMS, medium term)	1	60	Mean Difference (IV, Fixed, 95% CI)	2.20 [‐0.53, 4.93]
5 Tardive dyskinesia: average change score (AIMS, low = better) (medium term) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.1 Olanzapine vs FGA	1	53	Mean Difference (IV, Fixed, 95% CI)	1.66 [‐0.45, 3.77]
5.2 Amisulpride vs FGA	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.82 [‐2.85, 1.21]
5.3 Olanzapine vs amisulpride	1	54	Mean Difference (IV, Fixed, 95% CI)	2.48 [0.44, 4.52]
5.4 Olanzapine vs risperidone	1	60	Mean Difference (IV, Fixed, 95% CI)	1.20 [‐2.58, 4.98]
6 General mental state: deterioration Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Zuclopenthixol vs haloperidol ‐ short term	1	15	Risk Ratio (M‐H, Fixed, 95% CI)	0.30 [0.01, 6.29]
6.2 Olanzapine vs risperidone ‐ medium term	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.15, 6.64]
6.3 Quetiapine vs haloperidol ‐ long term	1	45	Risk Ratio (M‐H, Fixed, 95% CI)	1.83 [0.62, 5.39]
7 General mental state: average endpoint score (PANSS‐general psychopathology, low = better) (long term) Show forest plot	1	45	Mean Difference (IV, Fixed, 95% CI)	‐2.20 [‐6.02, 1.62]

7.1 Quetiapine vs haloperidol	1	45	Mean Difference (IV, Fixed, 95% CI)	‐2.20 [‐6.02, 1.62]
8 General mental state: average change score (BPRS, low = better) (medium term) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

8.1 Olanzapine vs FGA	1	53	Mean Difference (IV, Fixed, 95% CI)	‐1.14 [‐4.79, 2.51]
8.2 Amisulpride vs FGA	1	53	Mean Difference (IV, Fixed, 95% CI)	‐2.46 [‐6.27, 1.35]
8.3 Olanzapine vs risperidone	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.70 [‐8.37, 4.97]
8.4 Olanzapine vs amisulpride	1	54	Mean Difference (IV, Fixed, 95% CI)	1.32 [‐1.94, 4.58]
9 Acceptability of the treatment: leaving the study early (short term) Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 Molindone vs haloperidol	1	18	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Thiopropazate vs haloperidol	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.01, 4.44]
10 Acceptability of the treatment: leaving the study early (medium term) Show forest plot	3		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

10.1 Olanzapine vs FGA	1	56	Risk Ratio (IV, Fixed, 95% CI)	1.86 [0.18, 19.38]
10.2 Amisulpride vs FGA	1	55	Risk Ratio (IV, Fixed, 95% CI)	0.96 [0.06, 14.65]
10.3 Olanzapine vs amisulpride	1	57	Risk Ratio (IV, Fixed, 95% CI)	1.93 [0.19, 20.12]
10.4 Olanzapine vs risperidone	2	170	Risk Ratio (IV, Fixed, 95% CI)	0.73 [0.57, 0.95]
10.5 Olanzapine vs quetiapine	1	116	Risk Ratio (IV, Fixed, 95% CI)	0.70 [0.54, 0.90]
10.6 Olanzapine vs ziprasidone	1	82	Risk Ratio (IV, Fixed, 95% CI)	0.77 [0.56, 1.05]
10.7 Quetiapine vs risperidone	1	118	Risk Ratio (IV, Fixed, 95% CI)	1.05 [0.88, 1.25]
10.8 Quetiapine vs ziprasidone	1	90	Risk Ratio (IV, Fixed, 95% CI)	1.10 [0.86, 1.40]
10.9 Ziprasidone vs risperidone	1	84	Risk Ratio (IV, Fixed, 95% CI)	0.95 [0.74, 1.23]
11 Acceptability of the treatment: leaving the study early (long term) Show forest plot	2		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

11.1 Clozapine vs haloperidol	1	39	Risk Ratio (IV, Fixed, 95% CI)	3.36 [0.45, 25.16]
11.2 Quetiapine vs haloperidol	1	45	Risk Ratio (IV, Fixed, 95% CI)	1.31 [0.63, 2.69]
12 Adverse events: extrapyramidal symptoms (need of antiparkinsonism drugs) Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

12.1 Risperidone vs haloperidol (medium term)	1	37	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.34, 1.35]
12.2 Quetiapine vs haloperidol (long term)	1	45	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.21, 0.96]
13 Adverse effects: parkinsonism (SHRS) ‐ average endpoint scores (short term) Show forest plot	1	15	Mean Difference (IV, Fixed, 95% CI)	‐4.81 [‐12.15, 2.53]

13.1 Zuclopenthixol vs haloperidol	1	15	Mean Difference (IV, Fixed, 95% CI)	‐4.81 [‐12.15, 2.53]
14 Adverse effects: parkinsonism (SAS, ESRS, low = better) ‐ average change score (medium term) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

14.1 Olanzapine vs FGA	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.85 [‐2.55, 0.85]
14.2 Amisulpride vs FGA	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.5 [‐2.45, 1.45]
14.3 Olanzapine vs risperidone	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.7 [‐1.33, ‐0.07]
14.4 Olanzapine vs amisulpride	1	54	Mean Difference (IV, Fixed, 95% CI)	‐0.35 [‐2.44, 1.74]
15 Adverse effects: dyskinesia (ESRS, low = better) ‐ average change score (medium term) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

15.1 Olanzapine vs risperidone	1	60	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.91, 1.51]
16 Adverse effects: akathisia (BAS, ESRS, low = better) ‐ average change scores (medium term) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

16.1 Olanzapine vs FGA	1	53	Mean Difference (IV, Fixed, 95% CI)	0.08 [‐0.30, 0.46]
16.2 Amisulpride vs FGA	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.11 [‐0.42, 0.20]
16.3 Olanzapine vs risperidone	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.8 [‐1.76, 0.16]
16.4 Olanzapine vs amisulpride	1	54	Mean Difference (IV, Fixed, 95% CI)	0.19 [‐0.12, 0.50]
17 Adverse effects: dystonia (ESRS, low = better) ‐ average change score (medium term) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

17.1 Olanzapine vs risperidone	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.7 [‐1.41, 0.01]
18 Adverse effects: general adverse events (UKU, low = better) ‐ average change score (medium term) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

18.1 Olanzapine vs FGA	1	53	Mean Difference (IV, Fixed, 95% CI)	0.08 [‐1.85, 2.01]
18.2 Amisulpride vs FGA	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.55 [‐2.33, 1.23]
18.3 Olanzapine vs amisulpride	1	54	Mean Difference (IV, Fixed, 95% CI)	0.63 [‐0.93, 2.19]
19 General global state: average change score (CGI) (medium term) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

19.1 Olanzapine vs FGA	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.07 [‐0.41, 0.27]
19.2 Amisulpride vs FGA	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.47, 0.09]
19.3 Olanzapine vs risperidone	1	60	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.61, 0.81]
19.4 Olanzapine vs amisulpride	1	54	Mean Difference (IV, Fixed, 95% CI)	0.12 [‐0.19, 0.43]

Comparison 3. Switch to a specific antipsychotic vs switch to a different antipsychotic

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Comparison 4. Specific antipsychotic vs other drugs

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tardive dyskinesias: no clinically important improvement (medium term) Show forest plot	1	13	Risk Ratio (IV, Fixed, 95% CI)	1.07 [0.51, 2.23]

1.1 Haloperidol vs tetrabenazine	1	13	Risk Ratio (IV, Fixed, 95% CI)	1.07 [0.51, 2.23]
2 Tardive dyskinesia: no improvement (medium term) Show forest plot	1	13	Risk Ratio (IV, Fixed, 95% CI)	2.57 [0.35, 18.68]

2.1 Haloperidol vs tetrabenazine	1	13	Risk Ratio (IV, Fixed, 95% CI)	2.57 [0.35, 18.68]
3 Tardive dyskinesia: deterioration (medium term) Show forest plot	1	13	Risk Ratio (IV, Fixed, 95% CI)	0.86 [0.07, 10.96]

3.1 Haloperidol vs tetrabenazine	1	13	Risk Ratio (IV, Fixed, 95% CI)	0.86 [0.07, 10.96]
4 Acceptability of the treatment: leaving the study early (medium term) Show forest plot	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	4.38 [0.25, 76.54]

4.1 Haloperidol vs tetrabenazine	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	4.38 [0.25, 76.54]

Comparison 4. Specific antipsychotic vs other drugs

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Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia

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