Anticholinergic medication for antipsychotic‐induced tardive dyskinesia

Hanna Bergman; Karla Soares‐Weiser

doi:10.1002/14651858.CD000204.pub2

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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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