Cholinergic medication for antipsychotic‐induced tardive dyskinesia

Irina Tammenmaa‐Aho; Rosie Asher; Karla Soares‐Weiser; Hanna Bergman

doi:10.1002/14651858.CD000207.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

Study flow diagram for 2015 and 2017 searches.

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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

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

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Analysis 1.1

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement (50% or more change on any validated TD scale).

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Analysis 1.2

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 2 Tardive dyskinesia: 2a. Not any improvement (as assessed by rater).

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Analysis 1.3

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 3 Tardive dyskinesia: 2b. Not any improvement (as assessed by self report).

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Analysis 1.4

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 4 Tardive dyskinesia: 3a. Average endpoint score on AIMS (low score = better).

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Study	Intervention	Mean	SD	N	Comments
deanol ‐ more than 6 weeks
Tarsy 1977	Deanol	10	5.48	4
Tarsy 1977	Placebo	10	0	1	The confidence interval of mean difference was not estimable because the placebo group only had one participant.

Analysis 1.5

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 5 Tardive dyskinesia: 3b. Average endpoint score on modified Simpson TDRS (low score = better).

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Analysis 1.6

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 6 Tardive dyskinesia: 4a. Deterioration (as assessed by rater).

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Analysis 1.7

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 7 Tardive dyskinesia: 4b. Deterioration (as assessed by self report).

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Analysis 1.8

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 8 Global outcome: Death for any reason.

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Analysis 1.9

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 9 Global outcome: Intervention not useful as assessed by Global Usefulness Rating (GUR).

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Analysis 1.10

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 10 Global state: Average endpoint score on CGI (low score = better).

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Analysis 1.11

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 11 Mental state: Deterioration.

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Analysis 1.12

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 12 Adverse effects: Any.

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Analysis 1.13

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 13 Adverse effects: Various specific.

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Analysis 1.14

Comparison 1 CHOLINERGIC DRUGS versus PLACEBO, Outcome 14 Leaving the study early.

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Analysis 2.1

Comparison 2 CHOLINERGIC DRUGS versus OTHER CHOLINERGIC DRUGS, Outcome 1 Tardive dyskinesia: 2a. Not any improvement (as assessed by rater) ‐ less than 6 weeks.

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Analysis 2.2

Comparison 2 CHOLINERGIC DRUGS versus OTHER CHOLINERGIC DRUGS, Outcome 2 Global outcome: Death for any reason ‐ less than 6 weeks.

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Analysis 2.3

Comparison 2 CHOLINERGIC DRUGS versus OTHER CHOLINERGIC DRUGS, Outcome 3 Leaving the study early ‐ less than 6 weeks.

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Table 2. Excluded studies which are relevant to other reviews

Excluded study	Comparison				Treatment category		Relevant review
					#1	#2
Nasrallah 1986	Alpha‐methyl‐p‐tyrosine (AMPT)	versus choline chloride			Amino acid	Organic salt	‐
		versus hydroxytryptophan				Amino acid (serotonin precursor)	‐
		versus valproic acid				Mood stabilisers	‐
		versus L‐DOPA				Amino acid	‐
Lieberman 1988	Benztropine versus bromocriptine				Anticholinergic	Dopamine agonist	‐
	Bromocriptine versus haloperidol				Dopamine agonist	Antipsychotic	‐
Nasrallah 1986	Choline chloride			versus L‐DOPA	Organic salt	Amino acid	‐
				versus hydroxytryptophan			‐
				versus valproic		Anticonvulsant	‐
Jus 1978	Deanol		versus lithium carbonate		Antidepressant	Organic salt	‐
			versus placebo			Placebo	‐
Chien 1978			versus sodium valproate			Anticonvulsant	‐
			versus oxpertine			Antipsychotic	‐
Nasrallah 1986	Hydroxytryptophan versus L‐DOPA				Amino acid	Amino acid	‐
	L‐DOPA versus valproic acid					Anticonvulsant	‐
Jus 1978	Lithium carbonate versus placebo				Mood stabiliser	Placebo	‐
Chien 1978	Oxypertine versus sodium valproate				Antipsychotic	Anticonvulsant	‐

Table 2. Excluded studies which are relevant to other 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.* Age: any. Sex: both. History: any. N = 300.**
Interventions	Specific cholinergic drug (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 3. Suggestions for design of future study

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Summary of findings for the main comparison. CHOLINERGIC DRUGS versus PLACEBO for antipsychotic‐induced tardive dyskinesia

CHOLINERGIC DRUGS versus PLACEBO for antipsychotic‐induced tardive dyskinesia
Patient or population: people with various psychiatric disorders (mainly schizophrenia) and antipsychotic‐induced tardive dyskinesia Settings: mostly inpatients in Australia, Canada, Germany, Japan, Switzerland and the USA. Intervention: CHOLINERGIC DRUGS (deanol, donepezil, galantamine, meclofenoxate, lecithin) versus PLACEBO
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	PLACEBO	CHOLINERGIC DRUGS
Tardive dyskinesia: No clinically important improvement follow‐up: 2 to 12 weeks	1000 per 1000	890 per 1000 (650 to 1000)	RR 0.89 (0.65 to 1.23)	27 (4 studies)	⊕⊝⊝⊝ very low^1,2	None of the subgroups that reported on this outcome (deanol, donepezil, lecithin) found a significant difference between cholinergic drug and placebo.
Tardive dyskinesia: Deterioration follow‐up: 9 days to 12 weeks	116 per 1000	129 per 1000 (64 to 260)	RR 1.11 (0.55 to 2.24)	147 (8 studies)	⊕⊕⊝⊝ low^1,3	None of the subgroups that reported on this outcome (deanol, donepezil, lecithin, meclofenoxate) found a significant difference between cholinergic drug and placebo.
Mental state: Deterioration follow‐up: 11 days to 12 weeks	56 per 1000	28 per 1000 (6 to 145)	RR 0.50 (0.10 to 2.61)	77 (5 studies)	⊕⊝⊝⊝ very low^1,2	None of the subgroups that reported on this outcome (deanol, lecithin) found a significant difference between cholinergic drug and placebo.
Adverse effects: Any adverse events follow‐up: 9 days to 8 weeks	98 per 1000	55 per 1000 (15 to 210)	RR 0.56 (0.15 to 2.14)	106 (4 studies)	⊕⊝⊝⊝ very low^1,2	None of the subgroups that reported on this outcome (donepezil, lecithin, meclofenoxate) found a significant difference between cholinergic drug and placebo.
Acceptability of treatment: Leaving the study early follow‐up: 9 days to 12 weeks	90 per 1000	98 per 1000 (50 to 188)	RR 1.09 (0.56 to 2.10)	288 (12 studies)	⊕⊝⊝⊝ very low^1,3,4	None of the subgroups that reported on this outcome (deanol, donepezil, galantamine, meclofenoxate, lecithin) found a significant difference between cholinergic drug and placebo.
Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported	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; 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 step for risk of bias: for many studies it was unclear whether randomisation procedure and allocation concealment were carried out adequately. ² Downgraded two steps for imprecision: very few events and participants, wide CIs that include both no effect and appreciable benefit for the intervention. ³ Downgraded one step for imprecision: wide CIs that include appreciable benefit for both the intervention and the control group, as well as no effect. ⁴ Downgraded one step for indirectness: leaving the study early is not a direct measure of acceptability of the intervention.

Summary of findings for the main comparison. CHOLINERGIC DRUGS versus PLACEBO for antipsychotic‐induced tardive dyskinesia

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Table 1. Other reviews in the series

Interventions	Reference
Anticholinergic medication	Soares‐Weiser 1997
Benzodiazepines	Bhoopathi 2006
Calcium channel blockers	Essali 2011
Cholinergic medication	This review
Gamma‐aminobutyric acid agonists	Alabed 2011
Miscellaneous treatments	Soares‐Weiser 2003
Neuroleptic reduction and/or cessation and neuroleptics	Soares‐Weiser 2006
Non‐neuroleptic catecholaminergic drugs	El‐Sayeh 2006
Vitamin E	Soares‐Weiser 2011

Table 1. Other reviews in the series

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Comparison 1. CHOLINERGIC DRUGS versus PLACEBO

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tardive dyskinesia: 1. No clinically important improvement (50% or more change on any validated TD scale) Show forest plot	4	27	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.65, 1.23]

1.1 deanol ‐ more than 6 weeks	2	11	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.51, 1.60]
1.2 donepezil ‐ less than 6 weeks	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.70, 1.43]
1.3 lecithin ‐ less than 6 weeks	1	6	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.31, 1.66]
2 Tardive dyskinesia: 2a. Not any improvement (as assessed by rater) Show forest plot	9	180	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.71, 1.07]

2.1 deanol ‐ less than 6 weeks	3	63	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.58, 1.18]
2.2 deanol ‐ more than 6 weeks	2	11	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.26, 2.57]
2.3 donepezil ‐ less than 6 weeks	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.72, 2.44]
2.4 lecithin ‐ less than 6 weeks	2	36	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.63, 1.21]
2.5 meclofenoxate ‐ more than 6 weeks	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.55, 1.27]
3 Tardive dyskinesia: 2b. Not any improvement (as assessed by self report) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 lecithin ‐ less than 6 weeks	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.62, 1.36]
4 Tardive dyskinesia: 3a. Average endpoint score on AIMS (low score = better) Show forest plot	7	171	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.44, 0.21]

4.1 deanol ‐ more than 6 weeks	1	6	Mean Difference (IV, Fixed, 95% CI)	1.42 [‐0.29, 3.13]
4.2 galantamine ‐ more than 6 weeks	1	35	Mean Difference (IV, Fixed, 95% CI)	1.5 [‐0.44, 3.44]
4.3 lecithin ‐ less than 6 weeks	1	6	Mean Difference (IV, Fixed, 95% CI)	‐1.07 [‐2.21, 0.07]
4.4 lecithin ‐ more than 6 weeks	1	14	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐1.04, 0.84]
4.5 meclofenoxate ‐ more than 6 weeks	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.58, 0.20]
4.6 rivastigmine ‐ less than 8 weeks	1	40	Mean Difference (IV, Fixed, 95% CI)	2.20 [‐1.16, 5.56]
4.7 donepezil ‐ less than 6 weeks	1	10	Mean Difference (IV, Fixed, 95% CI)	1.10 [‐4.22, 6.42]
5 Tardive dyskinesia: 3b. Average endpoint score on modified Simpson TDRS (low score = better) Show forest plot			Other data	No numeric data

5.1 deanol ‐ more than 6 weeks			Other data	No numeric data
6 Tardive dyskinesia: 4a. Deterioration (as assessed by rater) Show forest plot	8	147	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.55, 2.24]

6.1 deanol ‐ less than 6 weeks	2	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.48, 5.76]
6.2 deanol ‐ more than 6 weeks	2	11	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.20, 2.18]
6.3 donepezil ‐ less than 6 weeks	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.06, 7.85]
6.4 lecithin ‐ less than 6 weeks	2	36	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.16, 6.31]
6.5 meclofenoxate ‐ more than 6 weeks	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [0.18, 19.55]
7 Tardive dyskinesia: 4b. Deterioration (as assessed by self report) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 lecithin ‐ less than 6 weeks	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 68.26]
8 Global outcome: Death for any reason Show forest plot	11	278	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

8.1 deanol ‐ less than 6 weeks	4	83	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 deanol ‐ more than 6 weeks	2	11	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.3 galantamine ‐ more than 6 weeks	1	38	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.4 lecithin ‐ less than 6 weeks	3	86	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.5 meclofenoxate ‐ more than 6 weeks	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Global outcome: Intervention not useful as assessed by Global Usefulness Rating (GUR) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 meclofenoxate ‐ more than 6 weeks	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.59, 1.32]
10 Global state: Average endpoint score on CGI (low score = better) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

10.1 lecithin ‐ less than 6 weeks	1	31	Mean Difference (IV, Fixed, 95% CI)	‐0.43 [‐1.36, 0.50]
11 Mental state: Deterioration Show forest plot	5	77	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.10, 2.61]

11.1 deanol ‐ less than 6 weeks	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.02, 6.65]
11.2 deanol ‐ more than 6 weeks	2	11	Risk Ratio (M‐H, Fixed, 95% CI)	1.2 [0.08, 18.75]
11.3 lecithin ‐ less than 6 weeks	2	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.81]
12 Adverse effects: Any Show forest plot	4	106	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.15, 2.14]

12.1 donepezil ‐ less than 6 weeks ‐ any adverse events	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 lecithin ‐ more than 6 weeks ‐ any other adverse effects, undesirable body odour, sedation	2	36	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.3 meclofenoxate ‐ more than 6 weeks ‐ any adverse events	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.15, 2.14]
13 Adverse effects: Various specific Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

13.1 deanol ‐ less than 6 weeks ‐ gastric adverse effects	5	61	Risk Ratio (M‐H, Fixed, 95% CI)	9.0 [0.55, 147.95]
13.2 deanol ‐ less than 6 weeks ‐ sedation, periferal cholinergic effects, undesirable body odour	6	94	Risk Ratio (M‐H, Fixed, 95% CI)	6.83 [0.99, 47.25]
13.3 lecithin ‐ less than 6 weeks ‐ GI adverse effects	2	36	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Leaving the study early Show forest plot	12	288	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.56, 2.10]

14.1 deanol ‐ less than 6 weeks	4	83	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.02, 6.65]
14.2 deanol ‐ more than 6 weeks	2	11	Risk Ratio (M‐H, Fixed, 95% CI)	1.2 [0.08, 18.75]
14.3 donepezil ‐ less than 6 weeks	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.4 galantamine ‐ more than 6 weeks	1	38	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.96, 9.39]
14.5 lecithin ‐ less than 6 weeks	3	86	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.17, 1.45]
14.6 meclofenoxate ‐ more than 6 weeks	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. CHOLINERGIC DRUGS versus PLACEBO

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Comparison 2. CHOLINERGIC DRUGS versus OTHER CHOLINERGIC DRUGS

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Tardive dyskinesia: 2a. Not any improvement (as assessed by rater) ‐ less than 6 weeks Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 deanol 2g vs deanol 1g	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Global outcome: Death for any reason ‐ less than 6 weeks Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1 deanol 2g vs deanol 1g	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Leaving the study early ‐ less than 6 weeks Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 deanol 2g vs deanol 1g	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 2. CHOLINERGIC DRUGS versus OTHER CHOLINERGIC DRUGS

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