Anticholinergic medication for antipsychotic‐induced tardive dyskinesia

Hanna Bergman; Karla Soares‐Weiser

doi:10.1002/14651858.CD000204.pub2

Fármacos anticolinérgicos para la discinesia tardía inducida por antipsicóticos

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References

References to studies included in this review

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Soares‐Weiser K, Mobsy C, Holliday E. Anticholinergic medication for neuroleptic‐induced tardive dyskinesia. Cochrane Database of Systematic Reviews 1997, Issue 2. [DOI: 10.1002/14651858.CD000204]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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Bucci 1971

Methods	Allocation: random, further details not reported. Blindness: not reported. Duration: 40 weeks. Design: parallel. Setting: outpatients, USA.
Participants	Diagnosis: chronic schizophrenia treated with phenothiazine for several years and demonstrating obvious dyskinetic manifestations. Duration of tardive dyskinesia (TD): ≥2 years. N = 20. Sex: 16 female, 4 male. Age: range 45 to 62 years.
Interventions	1. Procyclidine (anticholinergic), 5 mg B.I.D. + chlorpromazine, 100 mg T.I.D. N = 10. 2. Isocarboxazid (MAO inhibitor), 10 mg B.I.D. + chlorpromazine, 100 mg T.I.D. N = 10. Continuous phenothiazine‐antiparkisonian treatment for at least 2 years. Other concomitant medication: not reported.
Outcomes	TD symptoms: improvement (clinical evaluation, scale not reported). Leaving the study early. Adverse events. Unable to use ‐ Mental state (data not reported for both groups).
Notes	Sponsorship source: not reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	“The patients were divided at random into groups of 10 each”, no further details reported.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not reported.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding of participants and personnel not reported.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding of outcome assessment not reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	“One male patient on chlorpromazine and isocarboxazid was discontinued after 6 weeks as he became increasingly tense, apprehensive and sleepless.”
Selective reporting (reporting bias)	High risk	Unclear if all outcomes have been reported. A protocol is not available for verification. Adverse effects reported only as those related to treatment. Mental state data not reported for group 2.
Other bias	Unclear risk	Insufficient information to make a judgement.

Greil 1984

Methods	Allocation: "randomly assigned" no further details. Blind: "double‐blind" no further details. Design: parallel group. Setting: not reported if inpatients or outpatients or both; Germany. Duration: 7 weeks.
Participants	Diagnosis: chronic schizophrenics (ICD‐9) with tardive dyskinesia based on the presence of a 'typical' bucco‐linguo‐masticatory syndrome and the absence of other adequate explanations for the movement disorder. Duration of tardive dyskinesia: ≥1 year, severity of the symptoms stable for at least one month before admission to the study. N = 10. Sex: 7 female, 3 male. Age: mean 56.6 (SD 9.2) years; range 35 to 65 years.
Interventions	1. Biperiden (same dose as before the trial) stopped after 4 weeks followed by placebo for 3 weeks. N = 4. 2. Biperiden (same dose as before the trial) stopped after 1 week followed by placebo for 6 weeks. N = 6. All stable on antipsychotics and anticholinergics for at least 5 months before entry and during the trial. Other concomitant medication: not reported.
Outcomes	Leaving the study early. Unable to use (results not reported per randomised group) ‐ TD symptoms: Abnormal Involuntary Movements Scale (AIMS). EP symptoms: Simpson‐Angus Scale. Study author was contacted for additional data but no reply was received.
Notes	Sponsorship source: not reported. Knoll AG supplied placebo. Declarations of interest: not reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomly assigned", further details not reported.
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not reported.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"double‐blind" "investigators were not informed about the study design"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of raters was not mentioned.
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Nine patients completed the trial. One patient dropped out one week after biperiden withdrawal because of severe parkinsonism; in this patient, only one rating could be carried out while on the placebo."
Selective reporting (reporting bias)	High risk	TD symptoms data were not reported per randomised group, but before biperiden removal versus after biperiden removal.
Other bias	Unclear risk	Insufficient information to make a judgement.

Characteristics of excluded studies [ordered by study ID]

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included studies
awaiting classification

Study	Reason for exclusion
Casey 1977	Allocation: not randomised, controlled clinical study.
DiMascio 1976	Allocation: randomised. Participants: no TD measure at baseline, not stable dose of antipsychotics.
Double 1993	Allocation: randomised. Participants: no TD symptoms at baseline.
Elie 1972	Allocation: randomised. Participants: people with chronic schizophrenia, no TD.
Fann 1976	Allocation: randomised. Participants: no TD symptoms at baseline.
Friis 1983	Allocation: randomised. Participants: antipsychotic‐induced akathisia, parkinsonism and hyperkinetic movements, 11/15 participants had tardive dyskinesia. Intervention: valproate vs biperiden vs placebo. Outcomes: two period crossover ‒ no data about allocation in first period. Dr Gerlach (author) contacted and replied promptly. Data were destroyed and no more information is available.
Gardos 1984	Allocation: not randomised, controlled clinical trial.
Gerlach 1976	Allocation: not randomised, controlled clinical trial.
Gerlach 1978	Allocation: not randomised ‐ randomisation was only in one arm of the study “haloperidol + biperiden for 4 weeks (phase 2 and phase 3 in randomized sequence)”; all other arms were not randomised (thioridazine for 3 months, haloperidol for 4 weeks, thioridazine for 4 weeks, clozapine for 4 weeks).
Jus 1974	Allocation: not randomised, controlled clinical trial.
Klett 1972	Allocation: randomised. Participants: no information about those with TD symptoms at baseline. Intervention: benztropine withdrawal vs maintenance. Dr Klett (author) contacted and replied promptly. Data were destroyed and no more information is available.
Konig 1996	Allocation: not randomised, controlled clinical trial.
Lejoyeux 1993	Allocation: not randomised, controlled clinical trial.
Lieberman 1988	Allocation: randomised. Participants: schizophrenia, schizoaffective disorder, major affective disorder attention deficit disorder and TD (criteria of Schooler & Kane). Intervention: physostigmine vs bromocriptine vs benztropine vs haloperidol. Outcomes: no outcome data were been provided for the first period before crossover. Study author was contacted for data; no additional information was received and as this study is over 25 years old, we excluded this trial.
Ludatscher 1989	Allocation: randomised. Participants: people with chronic schizophrenia who had symptoms of severe persistent TD and who had been treated with antipsychotic drugs. Intervention: L‐dopa 500 mg + carbidopa 50 mg/d + low dose antipsychotics (N = 35) vs placebo + anticholinergic medication + low dose antipsychotic (N = 25). Outcomes: no outcome data could be used. The study is over 25 years old and we were unable to identify contact details for the author.
NDSG 1986	Allocation: randomised crossover. Participants: psychiatric inpatients with TD. Intervention: chlorprothixene vs haloperidol vs perphenazine or haloperidol + biperiden with placebo periods in between phases. Outcomes: no outcome data has been provided for the first period before crossover. Author was contacted but did not reply. Study is over 30 years old and we excluded it.
Silver 1995	Allocation: randomised. Participants: people with schizophrenia (DSM‐III‐R), with and without TD. Interventions: biperiden vs amantadine. Outcomes: no outcome data has been provided for the first period before crossover. We were unable to find up‐to‐date contact details for the authors and, as this study is over 20 years old, we excluded this trial.
Smith 1979	Allocation: not randomised, controlled clinical trial.
Tamminga 1977	Allocation: not randomised, ABA design.
Wirshing 1989a	Allocation: not randomised, controlled clinical trial.
Wirshing 1989b	Allocation: not randomised, controlled clinical trial.
Zwanikken 1976	Allocation: not randomised, controlled clinical trial.

Characteristics of studies awaiting assessment [ordered by study ID]

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excluded studies

Zeng 1996

Methods	Allocation: randomised.
Participants	Diagnosis: schizophrenia with drug‐induced tremor. N = 68.
Interventions	1. Dexetimide. N = 36. 2. Benzhexol. N = 32.
Outcomes	Movement disorder: clinical response. Adverse events: TESS.
Notes	Language: Chinese ‒ assessed by Sai Zhao. Study authors have been contacted to find out if participants were diagnosed with tardive dyskinesia.

TESS ‒ Treatment Emergent Symptom Scale

Data and analyses

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Comparison 1. Anticholinergic medications versus other compounds

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 TD symptoms: no clinically significant improvement Show forest plot	1		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.1 Comparison 1 Anticholinergic medications versus other compounds, Outcome 1 TD symptoms: no clinically significant improvement.
1.1 procyclidine vs isocarboxazid	1	20	Risk Ratio (IV, Fixed, 95% CI)	4.2 [1.40, 12.58]
2 TD symptoms: not any improvement Show forest plot	1		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.2 Comparison 1 Anticholinergic medications versus other compounds, Outcome 2 TD symptoms: not any improvement.
2.1 procyclidine vs isocarboxazid	1	20	Risk Ratio (IV, Fixed, 95% CI)	7.0 [1.57, 31.15]
3 Adverse effects Show forest plot	1		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.3 Comparison 1 Anticholinergic medications versus other compounds, Outcome 3 Adverse effects.
3.1 procyclidine vs isocarboxazid	1	20	Risk Ratio (IV, Fixed, 95% CI)	0.33 [0.02, 7.32]
4 Leaving the study early Show forest plot	1		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.4 Comparison 1 Anticholinergic medications versus other compounds, Outcome 4 Leaving the study early.
4.1 procyclidine vs isocarboxazid	1	20	Risk Ratio (IV, Fixed, 95% CI)	0.33 [0.02, 7.32]

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Comparison 2. Continuation versus withdrawal of anticholinergic medications

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Leaving the study early Show forest plot	1		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.1 Comparison 2 Continuation versus withdrawal of anticholinergic medications, Outcome 1 Leaving the study early.
1.1 biperiden: withdrawal after 1 week vs withdrawal after 4 weeks	1	10	Risk Ratio (IV, Fixed, 95% CI)	2.14 [0.11, 42.52]

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

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Figure 3

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

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Figure 4

Study flow diagram for 2015 and 2017 searches.

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Analysis 1.1

Comparison 1 Anticholinergic medications versus other compounds, Outcome 1 TD symptoms: no clinically significant improvement.

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Analysis 1.2

Comparison 1 Anticholinergic medications versus other compounds, Outcome 2 TD symptoms: not any improvement.

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Analysis 1.3

Comparison 1 Anticholinergic medications versus other compounds, Outcome 3 Adverse effects.

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Analysis 1.4

Comparison 1 Anticholinergic medications versus other compounds, Outcome 4 Leaving the study early.

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Analysis 2.1

Comparison 2 Continuation versus withdrawal of anticholinergic medications, Outcome 1 Leaving the study early.

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Table 2. 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.* Age: any. Sex: both. History: any. N = 300.**
Interventions	1. Anticholinergic withdrawal (N = 150) versus anticholinergic continuation (N = 150). OR 2. Specific anticholinergic (N = 150) versus placebo (N = 150).
Outcomes	Tardive dyskinesia: any clinically important improvement in TD, any improvement, deterioration.* Adverse effects: no clinically significant extrapyramidal adverse effects ‒ any time period*, 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	* This could be diagnosed by clinical decision. If funds were permitting, all participants could be screened using operational criteria; otherwise a random sample should suffice. Size of study with sufficient power to highlight about a 10% difference between groups for primary outcome. * Primary 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 2. Suggestions for design of future study

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Summary of findings for the main comparison. Anticholinergic medication compared with placebo for antipsychotic‐induced tardive dyskinesia

Anticholinergic medication compared with other treatments for antipsychotic‐induced tardive dyskinesia
Patient or population: patients with antipsychotic‐induced tardive dyskinesia Settings: anywhere. Intervention: any anticholinergic Comparison: placebo
Outcomes	*Illustrative comparative risks (CI)**		Relative effect (CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	risk with placebo	risk with anticholinergic drugs
Tardive dyskinesia: not improved to a clinically important extent	see comment	see comment	not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
Tardive dyskinesia: deterioration of symptoms	see comment	see comment	not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
Mental state	see comment	see comment	not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
Adverse effect: any adverse effects follow‐up: 40 weeks	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	see comment	see comment	not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
Social confidence, social inclusion, social networks, or personalised quality of life	see comment	see comment	not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
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 CI). CI: Confidence interval; MAO: monoamine oxidase; RR: Risk Ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Downgraded one level for risk of bias: the included study did not adequately describe randomisation procedure or allocation concealment, and there was no mention of the study being blinded. ² Downgraded two levels for imprecision: very small sample size (n = 20). ³ Downgraded two levels for imprecision: very wide CI that includes appreciable benefit for both groups; very small sample size (n = 20). ⁴ 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 for the main comparison. Anticholinergic medication compared with placebo for antipsychotic‐induced tardive dyskinesia

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Summary of findings 2. Anticholinergic medication compared with other treatments for antipsychotic‐induced tardive dyskinesia

Anticholinergic medication compared with other treatments for antipsychotic‐induced tardive dyskiesia
Patient or population: chronic schizophrenia patients with antipsychotic‐induced tardive dyskinesia Settings: outpatients in the USA. Intervention: procyclidine (anticholinergic), 5 mg twice/day Comparison: isocarboxazid (MAO‐inhibitor), 10 mg twice/day
Outcomes	*Illustrative comparative risks (CI)**		Relative effect (CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	risk with MAO‐inhibitor	risk with anticholinergic drugs
Tardive dyskinesia: Not improved to a clinically important extent follow‐up: 40 weeks	200 per 1000	840 per 1000 (280 to 1000)	RR 4.20 (1.40 to 12.58)	20 (1 study)	⊕⊝⊝⊝ very low^{1 2}
Tardive dyskinesia: deterioration of symptoms	see comment	see comment	not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
Mental state	see comment	see comment	not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
Adverse effect: any adverse effects follow‐up: 40 weeks	100 per 1000	33 per 1000 (2 to 732)	RR 0.33 (0.02 to 7.32)	20 (1 study)	⊕⊝⊝⊝ very low^{1 3}
Acceptability of the treatment: leaving the study early follow‐up: 40 weeks	100 per 1000	33 per 1000 (2 to 732)	RR 0.33 (0.02 to 7.32)	20 (1 study)	⊕⊝⊝⊝ very low^{1 3 4}
Social confidence, social inclusion, social networks, or personalised quality of life	see comment	see comment	not estimable	(0 studies)	‐	None of the included studies reported on this outcome.
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 CI). CI: Confidence interval; MAO: monoamine oxidase; RR: Risk Ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Downgraded one level for risk of bias: the included study did not adequately describe randomisation procedure or allocation concealment, and there was no mention of the study being blinded. ² Downgraded two levels for imprecision: very small sample size (n = 20). ³ Downgraded two levels for imprecision: very wide CI that includes appreciable benefit for both groups; very small sample size (n = 20). ⁴ 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 2. Anticholinergic medication compared with other treatments for antipsychotic‐induced tardive dyskinesia

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Summary of findings 3. Withdrawal of anticholinergic medication compared to continuing anticholinergic medication for antipsychotic‐induced tardive dyskinesia

Withdrawal of anticholinergic medication compared to continuing anticholigergic medication for antipsychotic‐induced tardive dyskinesia
Patient or population: chronic schizophrenia patients with antipsychotic‐induced tardive dyskinesia Setting: Germany (1 study) Intervention: withdrawal of biperiden (stopping after 1 week) Comparison: continuing biperiden (stopping after 4 weeks)
Outcomes	*Anticipated absolute effects^ (CI)**		Relative effect (CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with continuation of anticholinergic drugs	Risk with withdrawal of anticholinergic drugs	Relative effect (CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Tardive dyskinesia: not improved to a clinically important extent	see comment	see comment	not estimable	0 (0 studies)	‐	None of the included studies reported on this outcome.
Tardive dyskinesia: deterioration of symptoms	see comment	see comment	not estimable	0 (0 studies)	‐	None of the included studies reported on this outcome.
Mental state	see comment	see comment	not estimable	0 (0 studies)	‐	None of the included studies reported on this outcome.
Adverse effects	see comment	see comment	not estimable	0 (0 studies)	‐	None of the included studies reported on this outcome.
Acceptability of the treatment: leaving the study early follow‐up: 7 weeks	0 per 1,000	0 per 1,000 (0 to 0)	RR 2.14 (0.11 to 42.52)	10 (1 RCT)	⊕⊝⊝⊝ very low^{1 2 3}
Social confidence, social inclusion, social networks, or personalised quality of life	see comment	see comment	not estimable	0 (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 CI). CI: Confidence interval; 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: the included study did not adequately describe randomisation procedure or allocation concealment. ² Downgraded one level for indirectness: leaving the study early can give an indication, but is not a direct measurement, of treatment acceptability. In addition, the continuation of anticholinergic medication group stopped biperiden after 4 weeks but the results were measured after 7 weeks. ³ Downgraded two levels for imprecision: very wide CI that includes appreciable benefit for both groups; very small sample size (n = 10).

Summary of findings 3. Withdrawal of anticholinergic medication compared to continuing anticholinergic medication for antipsychotic‐induced tardive dyskinesia

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Table 1. Other reviews in the series

Interventions	Reference
Anticholinergic medication	This review
Benzodiazepines	Bhoopathi 2006; update to be published
Calcium channel blockers	Essali 2011; update to be published
Cholinergic medication	Tammenmaa 2002; update to be published
Gamma‐aminobutyric acid agonists	Alabed 2011; update to be published
Miscellaneous treatments	Soares‐Weiser 2003; update to be published
Neuroleptic reduction and/or cessation and neuroleptics	Soares‐Weiser 2006; update to be published
Non‐neuroleptic catecholaminergic drugs	El‐Sayeh 2006; update to be published
Vitamin E	Soares‐Weiser 2011; update to be published

Table 1. Other reviews in the series

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Comparison 1. Anticholinergic medications versus other compounds

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

1.1 procyclidine vs isocarboxazid	1	20	Risk Ratio (IV, Fixed, 95% CI)	4.2 [1.40, 12.58]
2 TD symptoms: not any improvement Show forest plot	1		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

2.1 procyclidine vs isocarboxazid	1	20	Risk Ratio (IV, Fixed, 95% CI)	7.0 [1.57, 31.15]
3 Adverse effects Show forest plot	1		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

3.1 procyclidine vs isocarboxazid	1	20	Risk Ratio (IV, Fixed, 95% CI)	0.33 [0.02, 7.32]
4 Leaving the study early Show forest plot	1		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

4.1 procyclidine vs isocarboxazid	1	20	Risk Ratio (IV, Fixed, 95% CI)	0.33 [0.02, 7.32]

Comparison 1. Anticholinergic medications versus other compounds

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Comparison 2. Continuation versus withdrawal of anticholinergic medications

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Leaving the study early Show forest plot	1		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only

1.1 biperiden: withdrawal after 1 week vs withdrawal after 4 weeks	1	10	Risk Ratio (IV, Fixed, 95% CI)	2.14 [0.11, 42.52]

Comparison 2. Continuation versus withdrawal of anticholinergic medications

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References

References to studies included in this review

Bucci 1971 {published data only}

Greil 1984 {published data only}

References to studies excluded from this review

Casey 1977 {published data only}

DiMascio 1976 {published data only}

Double 1993 {published data only}

Elie 1972 {published data only}

Fann 1976 {published data only}

Friis 1983 {published data only}

Gardos 1984 {published data only}

Gerlach 1976 {published data only}

Gerlach 1978 {published data only}

Jus 1974 {published data only}

Klett 1972 {published data only}

Konig 1996 {published data only}

Lejoyeux 1993 {published data only}

Lieberman 1988 {published data only}

Ludatscher 1989 {published data only}

NDSG 1986 {published data only}

Silver 1995 {published data only}

Smith 1979 {published data only}

Tamminga 1977 {published data only}

Wirshing 1989a {published data only}

Wirshing 1989b {published data only}

Zwanikken 1976 {published data only}

References to studies awaiting assessment

Zeng 1996 {published data only}

Additional references

Alabed 2011

Alphs 1983

Altman 1996

APA 1992

Armitage 1991

Barnes 1993

Begg 1996

Bergen 1989

Bhoopathi 2006

Bland 1997

Boissel 1999

Casey 1994

Cavallaro 1993

Chouinard 2008

Cloud 2014

Correll 2004

Correll 2008

Deeks 2000

Divine 1992

Donner 2002

Egger 1997

El‐Sayeh 2006

Elbourne 2002

Essali 2011

Fernandez 2001

Fleiss 1984

Furukawa 2006

Glazer 1990

Glazer 2000

Gulliford 1999

Higgins 2003

Higgins 2011

Jeste 1982

Kane 1994

Kay 1986

Leon 2006

Leucht 2005a

Leucht 2005b

Lieberman 1996

Marshall 2000

Mulrow 1999

NICE 2014

Overall 1962

Pocock 1983

Schooler 1993

Schünemann 2008

Shokraneh 2017

Smith 1980