Donepezil for mild cognitive impairment

Jacqueline Birks; Leon Flicker

doi:10.1002/14651858.CD006104

Donepezilo para el deterioro cognitivo leve

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Referencias

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Salloway S, Ferris S, Kluger A, Goldman R, Griesing T, Kumar D, Richardson S, for the Donepezil '401' Study Group. Efficacy of donepezil in mild cognitive impairment. Neurology 2004;63:651‐657.

Chen X, Magnotta VA, Duff K, Boles Ponto LL, Schultz SK. Donepezil effects on cerebral blood function in older adults with mild cognitive deficits. Journal of Neuropsychiatry and Clinical Neurosciences 2006;18(2):178‐185.

Galasko DR, Gauthier S, Bennett D, Sano M, Kaye J, Marson D, Peterson R. Impairment of activities of daily living in patients with amnestic mild cognitive impairment in an ADCS randomized clinical trial. 57th Annual meeting of the American Academy of Neurology, Miami Beach, April 2005. 2005.

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Petersen R, Grundman M, Thomas R, Thal L. Donepezil and vitamin E as treatments for mild cognitive impairment. Neurobiology of Aging 2004;25(S2):20.

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Ozenli Y, Yagci D, Karaca S. Efficacy of donepezil on cognitive functions in mild cognitive impairment. Klinik Psikofarmakoloji Bulteni 2007;17(2):62‐67.

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Pelton GH, Harper OL, Tabert MH, Sackeim HA, Scarmeas N, Roose SP, Devenand DP. Randomized double‐blind placebo‐controlled donepezil augmentation in antidepressant‐treated elderly patients with depression and cognitive impairment: a pilot study. International Journal of Geriatric Psychiatry 2008;23(7):670‐676.

Rozzini L, Costardi D, Chilovi BV, Franzoni S, Trabucchi M, Padovani A. Efficacy of cognitive rehabilitation in patients with mild cognitive impairment treated with cholinesterase inhibitors. International Journal of Geriatric Psychiatry 2007;22(4):356‐360.

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Boustani M. Donepezil in the Prevention of Post‐Operative Cognitive Decline. ClinicalTrials.gov2005.

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Murthy A. Protocol E2020‐A001‐412: A One Year, Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Evaluation of the Efficacy and Safety of Donepezil Hydrochloride in Subjects with Mild Cognitive Impairment (MCI). http://www.clinicaltrials.gov/ct/show/NCT001000222005.

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Schultz SK. Cognitive enhancers explored with PET imaging. Clinical Trials.gov2002:1‐3.

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Referencias adicionales

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Birks J, Flicker L. Donepezil for mild cognitive impairment. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD006104]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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401

Methods	24‐week, randomized, double‐blind, parallel‐group, placebo‐controlled study
Participants	Country: USA 22 centres 269 participants, aged 55‐90 years, mean age 72.4(8.0) 155 men and 114 women. Mean MMSE=27.5 Selection criteria: memory complaint, MMSE 24‐30, CDR=0.5, ADL normal, HAM‐D <=12, modified Hachinski <=4 Exclusion criteria: diagnosis of possible or probable AD
Interventions	1. donepezil (10 mg/day) 2. placebo
Outcomes	NYU paragraph test delayed recall ADCS CGIC CGIC‐MCI ADAS‐Cog WMS‐R digit span backwards symbol digit modalities test NYU paragraph test immediate recall neuropsychological battery
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Chen 2006

Methods	6 month, randomized, double‐blind, parallel‐group, placebo‐controlled study
Participants	Country: USA 15 participants, mean age 71 5 men and 10 women. Mean MMSE=29.7 Selection criteria: objective memory complaint on at least one scale (Mattis, DRS, WAIS or Brief Visuospatial) Exclusion criteria: major neurological, metabolic or psychiatric illness
Interventions	1. donepezil (10 mg/day) 2. placebo
Outcomes	MMSE, Hopkins Verbal Learning Test revised
Notes	The main objective was to study cerebral blood flow using MRI and PET scans.

Thal 1999

Methods	3‐year, randomized, double‐blind, parallel‐group, placebo‐controlled study
Participants	Country: USA 69 centres 769 participants, aged 55‐90 years, mean age 72.9(7.3) Mean MMSE=27.3 417 men and 352 women. Selection criteria: amnestic mild cognitive impairment of a degenerative nature (insidious onset and gradual progression), a Logical memory delayed‐recall score approximately 1.5 to 2 s.d.s below an education adjusted norm, CDR=0.5, MMSE 24‐30
Interventions	1. donepezil (10 mg/day) 2. vitamin E (2000 IU/day) 3. placebo
Outcomes	time to development of possible or probable AD MMSE ADAS‐Cog CDR CDR‐sum of boxes ADCS GDS neuropsychological battery
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Ozenli 2007	Treatment not blinded.
Pelton 2008	Patients presented with depression and cognitive impairment. All patients receiving sertraline
Rozzini 2007	Retrospective comparison, treatment not blinded

Characteristics of ongoing studies [ordered by study ID]

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Boustani 2005

Trial name or title	NCT00182845
Methods
Participants	age >65 years baseline MCI (MMSE<28) normal ADL undergoing elective hip or knee replacement
Interventions	1. donepezil 2. placebo
Outcomes	post‐operative cognitive decline delirium status (CAM) MMSE length of stay in hospital
Starting date	feb 2005
Contact information	Stephanie Munger [email protected]
Notes	sponsored by Pfizer

Murthy 2005

Trial name or title	NCT00100022 E2020‐A001‐412
Methods
Participants	age 45‐90 memory complaint no diagnosis of AD
Interventions	1. donepezil 2. placebo
Outcomes	Cognitive function behavioural , global outcomes neuroimaging
Starting date	dec 2003
Contact information	[email protected] [email protected]
Notes	sponsored by Pfizer and Eisai

Schultz 2002

Trial name or title	NCT00042172
Methods
Participants	MCI, but normal ADL
Interventions	first 6 months 1. donepezil 2. placebo second 6 months 1. donepezil+Ginkgo biloba 2. donepezil
Outcomes	PET scan to assess brain activity during memory tasks
Starting date	june 2002
Contact information	University of Iowa Departatment of Psychiatry, Iowa City, Iowa 52242
Notes	sponsored by NIMH

Data and analyses

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Comparison 1. donepezil (10mg/day) vs placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cognitive function (change from baseline at 24 weeks) ITT‐LOCF Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.1 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 1 Cognitive function (change from baseline at 24 weeks) ITT‐LOCF.
1.1 ADAS‐Cog 13 item	1	262	Mean Difference (IV, Fixed, 95% CI)	1.90 [0.51, 3.29]
1.2 NYU Paragraph Test Delayed Recall	1	262	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.41, 1.01]
1.3 NYU Paragraph Test Immediate Recall	1	262	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐0.11, 1.31]
1.4 WMS (Wechsler) Digit Span Backwards	1	262	Mean Difference (IV, Fixed, 95% CI)	0.5 [‐0.05, 1.05]
1.5 Symbol Digit Modalities	1	262	Mean Difference (IV, Fixed, 95% CI)	1.7 [‐0.11, 3.51]
2 Total number of withdrawals at 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	2.37 [1.33, 4.22]
Open in figure viewer Analysis 1.2 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 2 Total number of withdrawals at 24 weeks.
3 Total number of withdrawals due to adverse event at 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	3.54 [1.65, 7.60]
Open in figure viewer Analysis 1.3 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 3 Total number of withdrawals due to adverse event at 24 weeks.
4 Total number of patients who suffered at least one adverse event by 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	2.52 [1.34, 4.76]
Open in figure viewer Analysis 1.4 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 4 Total number of patients who suffered at least one adverse event by 24 weeks.
5 Total number of patients who suffered at least one adverse event of diarrhoea by 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	4.71 [2.23, 9.97]
Open in figure viewer Analysis 1.5 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 5 Total number of patients who suffered at least one adverse event of diarrhoea by 24 weeks.
6 Total number of patients who suffered at least one adverse event of nausea by 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	2.52 [1.10, 5.75]
Open in figure viewer Analysis 1.6 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 6 Total number of patients who suffered at least one adverse event of nausea by 24 weeks.
7 Total number of patients who suffered at least one adverse event of vomiting by 24 weeks Show forest plot	1	270	Peto Odds Ratio (Peto, Fixed, 95% CI)	8.30 [2.61, 26.37]
Open in figure viewer Analysis 1.7 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 7 Total number of patients who suffered at least one adverse event of vomiting by 24 weeks.
8 Total number of patients who suffered at least one adverse event of leg cramps by 24 weeks Show forest plot	1	270	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.63 [1.58, 13.55]
Open in figure viewer Analysis 1.8 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 8 Total number of patients who suffered at least one adverse event of leg cramps by 24 weeks.
9 Total number of patients who suffered at least one adverse event of abnormal dreams by 24 weeks Show forest plot	1	270	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.31 [2.61, 10.79]
Open in figure viewer Analysis 1.9 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 9 Total number of patients who suffered at least one adverse event of abnormal dreams by 24 weeks.
10 Total number of patients who suffered at least one adverse event of depression by 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	6.43 [0.76, 54.11]
Open in figure viewer Analysis 1.10 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 10 Total number of patients who suffered at least one adverse event of depression by 24 weeks.
11 Total number of patients who suffered at least one adverse event of insomnia by 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	2.18 [0.85, 5.60]
Open in figure viewer Analysis 1.11 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 11 Total number of patients who suffered at least one adverse event of insomnia by 24 weeks.
12 Number who progress to AD or another dementia after 1 year of treatment Show forest plot	1	512	Odds Ratio (M‐H, Fixed, 95% CI)	0.39 [0.21, 0.72]
Open in figure viewer Analysis 1.12 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 12 Number who progress to AD or another dementia after 1 year of treatment.
13 Number who progress to AD or another dementia after 3 years of treatment Show forest plot	1	512	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.57, 1.25]
Open in figure viewer Analysis 1.13 Comparison 1 donepezil (10mg/day) vs placebo, Outcome 13 Number who progress to AD or another dementia after 3 years of treatment.

Analysis 1.1

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 1 Cognitive function (change from baseline at 24 weeks) ITT‐LOCF.

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Analysis 1.2

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 2 Total number of withdrawals at 24 weeks.

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Analysis 1.3

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 3 Total number of withdrawals due to adverse event at 24 weeks.

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Analysis 1.4

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 4 Total number of patients who suffered at least one adverse event by 24 weeks.

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Analysis 1.5

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 5 Total number of patients who suffered at least one adverse event of diarrhoea by 24 weeks.

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Analysis 1.6

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 6 Total number of patients who suffered at least one adverse event of nausea by 24 weeks.

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Analysis 1.7

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 7 Total number of patients who suffered at least one adverse event of vomiting by 24 weeks.

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Analysis 1.8

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 8 Total number of patients who suffered at least one adverse event of leg cramps by 24 weeks.

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Analysis 1.9

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 9 Total number of patients who suffered at least one adverse event of abnormal dreams by 24 weeks.

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Analysis 1.10

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 10 Total number of patients who suffered at least one adverse event of depression by 24 weeks.

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Analysis 1.11

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 11 Total number of patients who suffered at least one adverse event of insomnia by 24 weeks.

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Analysis 1.12

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 12 Number who progress to AD or another dementia after 1 year of treatment.

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Analysis 1.13

Comparison 1 donepezil (10mg/day) vs placebo, Outcome 13 Number who progress to AD or another dementia after 3 years of treatment.

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Comparison 1. donepezil (10mg/day) vs placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cognitive function (change from baseline at 24 weeks) ITT‐LOCF Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 ADAS‐Cog 13 item	1	262	Mean Difference (IV, Fixed, 95% CI)	1.90 [0.51, 3.29]
1.2 NYU Paragraph Test Delayed Recall	1	262	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.41, 1.01]
1.3 NYU Paragraph Test Immediate Recall	1	262	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐0.11, 1.31]
1.4 WMS (Wechsler) Digit Span Backwards	1	262	Mean Difference (IV, Fixed, 95% CI)	0.5 [‐0.05, 1.05]
1.5 Symbol Digit Modalities	1	262	Mean Difference (IV, Fixed, 95% CI)	1.7 [‐0.11, 3.51]
2 Total number of withdrawals at 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	2.37 [1.33, 4.22]

3 Total number of withdrawals due to adverse event at 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	3.54 [1.65, 7.60]

4 Total number of patients who suffered at least one adverse event by 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	2.52 [1.34, 4.76]

5 Total number of patients who suffered at least one adverse event of diarrhoea by 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	4.71 [2.23, 9.97]

6 Total number of patients who suffered at least one adverse event of nausea by 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	2.52 [1.10, 5.75]

7 Total number of patients who suffered at least one adverse event of vomiting by 24 weeks Show forest plot	1	270	Peto Odds Ratio (Peto, Fixed, 95% CI)	8.30 [2.61, 26.37]

8 Total number of patients who suffered at least one adverse event of leg cramps by 24 weeks Show forest plot	1	270	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.63 [1.58, 13.55]

9 Total number of patients who suffered at least one adverse event of abnormal dreams by 24 weeks Show forest plot	1	270	Peto Odds Ratio (Peto, Fixed, 95% CI)	5.31 [2.61, 10.79]

10 Total number of patients who suffered at least one adverse event of depression by 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	6.43 [0.76, 54.11]

11 Total number of patients who suffered at least one adverse event of insomnia by 24 weeks Show forest plot	1	270	Odds Ratio (M‐H, Fixed, 95% CI)	2.18 [0.85, 5.60]

12 Number who progress to AD or another dementia after 1 year of treatment Show forest plot	1	512	Odds Ratio (M‐H, Fixed, 95% CI)	0.39 [0.21, 0.72]

13 Number who progress to AD or another dementia after 3 years of treatment Show forest plot	1	512	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.57, 1.25]

Comparison 1. donepezil (10mg/day) vs placebo

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Referencias

Referencias de los estudios incluidos en esta revisión

401 {published data only}

Chen 2006 {published data only}

Thal 1999 {published data only}

Referencias de los estudios excluidos de esta revisión

Ozenli 2007 {published data only}

Pelton 2008 {published data only}

Rozzini 2007 {published data only}

Referencias de los estudios en curso

Boustani 2005 {published data only}

Murthy 2005 {published data only}

Schultz 2002 {published data only}

Referencias adicionales

Berg 1988

Birks 2006 b

Bruscoli 2004

Folstein 1975

Gauthier 2005

Kluger 1999

Lezak 1995

McKhann 1984

Mohs 1997

Petersen 2001

Schneider 1997

Schulz 1995

Smith 1982

Referencias de otras versiones publicadas de esta revisión

Birks 2006 a

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Data and analyses

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