Haloperidol for agitation in dementia

Edmund Lonergan; Jay Luxenberg; John M Colford; Jacqueline Birks

doi:10.1002/14651858.CD002852

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Analysis 1.1

Comparison 1 Haloperidol vs placebo, Outcome 1 Behavioural symptoms (change from baseline) ITT.

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Analysis 1.2

Comparison 1 Haloperidol vs placebo, Outcome 2 Agitation (change from baseline ) ITT.

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Analysis 1.3

Comparison 1 Haloperidol vs placebo, Outcome 3 Aggression (change from baseline ) ITT.

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Analysis 1.4

Comparison 1 Haloperidol vs placebo, Outcome 4 CGIC (improvement ) ITT.

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Analysis 1.5

Comparison 1 Haloperidol vs placebo, Outcome 5 Caregiver burden (change from baseline ) ITT.

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Analysis 1.6

Comparison 1 Haloperidol vs placebo, Outcome 6 Activities of daily living (change from baseline ) ITT.

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Analysis 1.7

Comparison 1 Haloperidol vs placebo, Outcome 7 dropouts by endpoint.

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Analysis 1.8

Comparison 1 Haloperidol vs placebo, Outcome 8 dropouts due to adverse events.

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Analysis 1.9

Comparison 1 Haloperidol vs placebo, Outcome 9 Number suffering at least one adverse event by endpoint.

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Analysis 1.10

Comparison 1 Haloperidol vs placebo, Outcome 10 Number suffering an adverse event (broken down by type) by endpoint.

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Table 1. Baseline Characteristics

Name	Country	Population	Mean Age	% Female	Intervention	Diagnosis	Mean MMSE
Allain 2000	France, Holland, Germany	Institutionalized; Alzheimer's dementia; vascular demetnia; various dementias	79.6	64.0%	Triapride (N=102); haloperidol (N=101); placebo (N=103); haloperidol dose 2mg ‐ 6mg per day, po; 3wk course.	Dementia: DSM IIIR criteria for mild or moderate dementia;; Agitation: MOSES subscale score (irritability/aggressiveness)between 16 and 30; Global: CGI;
Auchus 2000	United States	Outpatients; Alzheimer's dementia	75.6	66.6%	Fluoxetine (N=5); haloperidol (N=5); placebo (N=5); 3 wk course; haloperidol dose 3mg day po.	Dementia: NINCDS‐ADRDA criteria for probable or possible AD; Agitation: CMAI (short form) score of 25 or more; BEHAVED‐AD	15.2 (4.6)
DeDyn 1999	Belgium, Canada, Denmark, United Kingdom, Republic of Ireland, The Netherlands, Sweden, Switzerland	Institutionalized; Alzheimer's dementia; vascular dementia; various dementias.	81.5	56..3%	Risperidone (N=115); haloperidol (N=115); placebo (N=114); end point 30% reduction in mean BEHAVED‐AD score from baseline or after 12 wks; haloperidol dose 0.25mg ‐ 4mg per day po, mean dose 1.2mg per day.	Dementia: DSM IV criteria for Alzheimer's dementia, vascular dementia, or mixed dementia; Agitation: CMAI; BEHAVED‐AD	8.4
Devanand 1998	United States	Outpatients; Alzheimer's dementia	72.1	64.8%	Haloperidol 0.5mg ‐ 0.75mg per day po (N=20); haloperidol 2mg ‐ 3mg per day po (N=20); placebo (N=20); 6 wk course	Dementia: DSM IIIR criteria for dementia and the NICDS and ADRDA criteria for probable Alzheimer's Disease; Agitation: SADS‐PD criteria for the presence of a hallucination or delusion; as well as a BPRS score of 4 (moderate severity) on the hallucinatory behaviour or unusual thought content item, or a total score of 6 or more on these two items; the criterion for disruptive behaviour was 4 or more on the scale for physical aggression or psychomotor agitation on the Behavior Syncromes Scale for Dementia (DSSD).	19.4 (11.6)
Teri 2000	United States	Outpatients; Alzheimer's dementia	75.3	62.8%	Haloperidol 0.5mg ‐ 3.0 mg per day po (N=34); placebo (N=36); 16 wk course	Dementia: NINCDS‐ADRDA criteria for probable or possible AD; Agitation: Agitated Behavior Inventory for Dementia ABID), at least two episodes per week for two weeks prior to entering the study; ADCS‐CGIC; BRSD; CMAI; ABID	13.0 (7.5)

Table 1. Baseline Characteristics

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Table 2. Outcomes, Instruments, and Studies

Outcomes	Instruments	Studies
Agitation	Multidimensional Observational Scale for Elderly Subjects (MOSES), irritability, aggressiveness subscale	Allain 2000
	Cohen‐Mansfield Agitation Inventory (CMAI)	Auchus 1997
	CMAI	DeDyn 1999
	Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE‐AD)	Auchus 1997
	BEHAVE‐AD	DeDyn 1999
	Brief Psychiatric Rating Scale (BPRS), hallucinatory behavior or unusual content item	Devanand 1998
	Schedule for Affective Disorders and Schizophrenia (SADS), psychiatric disorganization item subset	Devanand 1998
Global Impression	Clinical Global Impression Scale (CGI)	Allain 2000
Side Effects	UKU Side Effecft Rating Scale (UKU)	Allain 2000
	Neurologic Events	Allain 2000
	Number of Adverse Symptoms	Auchus 1997
	Extrapyramidal Symptom Rating Scale (ESRS)	DeDyn 1999
	Treatment Emergent Symptoms (TES)	Devanand 1998
	Targeting Abnormal Kinetic Effects (TAKE)	Devanand 1998
	Rockland Tardive Dyskenisia Scale (ROCKLAND)	Devanand 1998
Cognition/Function	MiniMental State Examination (MMSE)	Allain 2000
	MMSE	Devanand 1998
Agitation	Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCS‐CGIC); Consortium to Establish a Registry for Alzheimer's Disease Behavioral Rating Scale for Dementia (CERAD‐BRSD); CMAI; Agitated Behavior Inventory for Dementia (ABID)	Teri 2000
Global Impression	ADCS‐CGIC	Teri 2000
Side Effects	Side Effects Check list	Teri 2000
Cognition/Function	MMSE; Physical Self‐Maintenance (PMS); Instrumental Activities of Daily LIving (IADL)	Teri 2000

Table 2. Outcomes, Instruments, and Studies

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Comparison 1. Haloperidol vs placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Behavioural symptoms (change from baseline) ITT Show forest plot	4	369	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.40, 0.01]

1.1 Fixed dose 3mg/day, endpoint 6 weeks	1	10	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.46 [‐1.73, 0.80]
1.2 Mean dose 1.7 mg/day, endpoint 6 weeks	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.11 [‐0.65, 0.43]
1.3 Mean dose 1.2 mg/day, endpoint 12 weeks	1	229	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.26 [‐0.52, 0.00]
1.4 Mean dose 1.8 mg/day, endpoint 16 weeks	1	70	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.00 [‐0.47, 0.47]
2 Agitation (change from baseline ) ITT Show forest plot	4	369	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.33, 0.08]

2.1 Fixed dose 3mg/day, endpoint 6 weeks	1	10	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.09 [‐1.33, 1.16]
2.2 Mean dose 1.7 mg/day, endpoint 6 weeks	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.15 [‐0.69, 0.39]
2.3 Mean dose 1.2 mg/day, endpoint 12 weeks	1	229	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.14 [‐0.40, 0.12]
2.4 Mean dose 1.8 mg/day, endpoint 16 weeks	1	70	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.53, 0.41]
3 Aggression (change from baseline ) ITT Show forest plot	3	489	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.31 [‐0.49, ‐0.13]

3.1 Mean dose 3.53 mg/day, endpoint 3 weeks	1	200	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.39 [‐0.67, ‐0.11]
3.2 Mean dose 1.7 mg/day, endpoint 6 weeks	1	60	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.14 [‐0.68, 0.40]
3.3 Mean dose 1.2 mg/day, endpoint 12 weeks	1	229	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.29 [‐0.55, ‐0.03]
4 CGIC (improvement ) ITT Show forest plot	2	274	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.50 [0.88, 2.55]

4.1 Mean dose 3.53 mg/day, endpoint 3 weeks	1	204	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.70 [0.91, 3.18]
4.2 Mean dose 1.8 mg/day, endpoint 16 weeks	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.09 [0.40, 2.96]
5 Caregiver burden (change from baseline ) ITT Show forest plot	1	70	Mean Difference (IV, Fixed, 95% CI)	0.81 [‐0.89, 2.51]

5.1 Mean dose 1.8 mg/day, endpoint 16 weeks	1	70	Mean Difference (IV, Fixed, 95% CI)	0.81 [‐0.89, 2.51]
6 Activities of daily living (change from baseline ) ITT Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1 Physical activities of daily living, mean dose 1.8 mg/day, endpoint 16 weeks	1	70	Mean Difference (IV, Fixed, 95% CI)	1.19 [‐0.38, 2.76]
6.2 Instrumental activities of daily living, mean dose 1.8 mg/day, endpoint 16 weeks	1	70	Mean Difference (IV, Fixed, 95% CI)	0.91 [‐0.59, 2.41]
7 dropouts by endpoint Show forest plot	5	573	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.00 [0.68, 1.46]

7.1 Mean dose 3.53 mg/day, endpoint 3 weeks	1	204	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.42 [0.70, 2.89]
7.2 Mean dose 1.7 mg/day, endpoint 6 weeks	1	60	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.19 [0.03, 1.14]
7.3 Fixed dose 3mg/day, endpoint 6 weeks	1	10	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.36 [0.18, 30.67]
7.4 Mean dose 1.2 mg/day, endpoint 12 weeks	1	229	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.78 [0.45, 1.35]
7.5 Mean dose 1.8 mg/day, endpoint 16 weeks	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.58 [0.60, 4.17]
8 dropouts due to adverse events Show forest plot	2	274	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.52 [1.22, 5.21]

8.1 Mean dose 3.53 mg/day, endpoint 3 weeks	1	204	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.99 [1.26, 7.10]
8.2 Mean dose 1.8 mg/day, endpoint 16 weeks	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.69 [0.45, 6.40]
9 Number suffering at least one adverse event by endpoint Show forest plot	2	433	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.53 [1.00, 2.35]

9.1 Mean dose 3.53 mg/day, endpoint 3 weeks	1	204	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.57 [0.86, 2.88]
9.2 Mean dose 1.2 mg/day, endpoint 12 weeks	1	229	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.49 [0.81, 2.74]
10 Number suffering an adverse event (broken down by type) by endpoint Show forest plot	3		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

10.1 Extrapyramidal symptom (mean dose 3.5mg/day, endpoint 3 weeks)	1	204	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.34 [1.25, 4.38]
10.2 Endocrine symptom (mean dose 3.5mg/day, endpoint 3 weeks)	1	204	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.75 [0.25, 2.22]
10.3 Somnolence (Mean dose 1.2mg/day, endpoint 12 weeks)	1	229	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.20 [1.78, 9.91]
10.4 Drooling (mean dose 1.8 mg/day, endpoint 16 weeks)	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	8.08 [0.49, 131.94]
10.5 Parkinsonian gait (mean dose 1.8 mg/day, endpoint 16 weeks)	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.68 [0.71, 10.14]
10.6 Dry mouth (mean dose 1.8 mg/day, endpoint 16 weeks)	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.17 [0.68, 6.95]
10.7 Dizziness (mean dose 1.8 mg/day, endpoint 16 weeks)	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.69 [0.11, 4.23]
10.8 Akathesia (mean dose 1.8 mg/day, endpoint 16 weeks)	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.07 [0.25, 4.60]
10.9 Rigidity (mean dose 1.8 mg/day, endpoint 16 weeks)	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.81 [0.93, 8.50]
10.10 Dyskinesia (mean dose 1.8 mg/day, endpoint 16 weeks)	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.42 [0.09, 1.96]
10.11 Drowsiness (mean dose 1.8 mg/day, endpoint 16 weeks)	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.48 [0.80, 7.71]
10.12 Bradykinesia (mean dose 1.8 mg/day, endpoint 16 weeks)	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.95 [0.67, 5.65]
10.13 Tremor (mean dose 1.8 mg/day, endpoint 16 weeks)	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.17 [0.68, 6.95]
10.14 Fatigue (mean dose 1.8 mg/day, endpoint 16 weeks)	1	70	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.39 [2.04, 14.22]

Comparison 1. Haloperidol vs placebo

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