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Comparison 1 Divalproex vs placebo, Outcome 1 Brief Psychiatric rating scale Total score. Change from baseline at 6 weeks (ITT).
Figures and Tables -
Analysis 1.1

Comparison 1 Divalproex vs placebo, Outcome 1 Brief Psychiatric rating scale Total score. Change from baseline at 6 weeks (ITT).

Comparison 1 Divalproex vs placebo, Outcome 2 BPRS agitation factor. Change from baseline at 6 weeks (ITT).
Figures and Tables -
Analysis 1.2

Comparison 1 Divalproex vs placebo, Outcome 2 BPRS agitation factor. Change from baseline at 6 weeks (ITT).

Comparison 1 Divalproex vs placebo, Outcome 3 BPRS hostility factor. Change from baseline at 6 weeks (ITT).
Figures and Tables -
Analysis 1.3

Comparison 1 Divalproex vs placebo, Outcome 3 BPRS hostility factor. Change from baseline at 6 weeks (ITT).

Comparison 1 Divalproex vs placebo, Outcome 4 Overt aggression scale total score. Change from baseline at 6 weeks (ITT).
Figures and Tables -
Analysis 1.4

Comparison 1 Divalproex vs placebo, Outcome 4 Overt aggression scale total score. Change from baseline at 6 weeks (ITT).

Comparison 1 Divalproex vs placebo, Outcome 5 Cohen‐Mansfield Agitation Index. Total Score. Change from baseline at 6 weeks (ITT).
Figures and Tables -
Analysis 1.5

Comparison 1 Divalproex vs placebo, Outcome 5 Cohen‐Mansfield Agitation Index. Total Score. Change from baseline at 6 weeks (ITT).

Comparison 2 Divalproex vs placebo, Outcome 1 Total number of patients who suffered from sedation at 6 weeks.
Figures and Tables -
Analysis 2.1

Comparison 2 Divalproex vs placebo, Outcome 1 Total number of patients who suffered from sedation at 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 2 Total number of patients who suffered from nausea, vomiting, or diarrhea at 6 weeks.
Figures and Tables -
Analysis 2.2

Comparison 2 Divalproex vs placebo, Outcome 2 Total number of patients who suffered from nausea, vomiting, or diarrhea at 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 3 Total number of patients who suffered from an urinary tract infection by 6 weeks.
Figures and Tables -
Analysis 2.3

Comparison 2 Divalproex vs placebo, Outcome 3 Total number of patients who suffered from an urinary tract infection by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 4 Total number of patients who suffered falls without injury by 6 weeks.
Figures and Tables -
Analysis 2.4

Comparison 2 Divalproex vs placebo, Outcome 4 Total number of patients who suffered falls without injury by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 5 Total number of patients who suffered falls with injury by 6 weeks.
Figures and Tables -
Analysis 2.5

Comparison 2 Divalproex vs placebo, Outcome 5 Total number of patients who suffered falls with injury by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 6 Total number of patients who suffered postural instability by 6 weeks.
Figures and Tables -
Analysis 2.6

Comparison 2 Divalproex vs placebo, Outcome 6 Total number of patients who suffered postural instability by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 7 Total number of patients who suffered weakness by 6 weeks.
Figures and Tables -
Analysis 2.7

Comparison 2 Divalproex vs placebo, Outcome 7 Total number of patients who suffered weakness by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 8 Total number of patients who suffered cardiovascular problems by 6 weeks.
Figures and Tables -
Analysis 2.8

Comparison 2 Divalproex vs placebo, Outcome 8 Total number of patients who suffered cardiovascular problems by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 9 Total number of patients who suffered edema by 6 weeks.
Figures and Tables -
Analysis 2.9

Comparison 2 Divalproex vs placebo, Outcome 9 Total number of patients who suffered edema by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 10 Total number of patients who suffered a fever by 6 weeks.
Figures and Tables -
Analysis 2.10

Comparison 2 Divalproex vs placebo, Outcome 10 Total number of patients who suffered a fever by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 11 Total number of patients who suffered a respiratory problem by 6 weeks.
Figures and Tables -
Analysis 2.11

Comparison 2 Divalproex vs placebo, Outcome 11 Total number of patients who suffered a respiratory problem by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 12 Total number of patients who suffered any adverse effect by 6 weeks.
Figures and Tables -
Analysis 2.12

Comparison 2 Divalproex vs placebo, Outcome 12 Total number of patients who suffered any adverse effect by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 13 Total number of patients who suffered from ataxia at 6 weeks.
Figures and Tables -
Analysis 2.13

Comparison 2 Divalproex vs placebo, Outcome 13 Total number of patients who suffered from ataxia at 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 14 Total number of patients who suffered from a skin problem at 6 weeks.
Figures and Tables -
Analysis 2.14

Comparison 2 Divalproex vs placebo, Outcome 14 Total number of patients who suffered from a skin problem at 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 15 Total number of patients who suffered other gastrointestinal problem by 6 weeks.
Figures and Tables -
Analysis 2.15

Comparison 2 Divalproex vs placebo, Outcome 15 Total number of patients who suffered other gastrointestinal problem by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 16 Total number of patients who suffered trauma (other than falls) by 6 weeks.
Figures and Tables -
Analysis 2.16

Comparison 2 Divalproex vs placebo, Outcome 16 Total number of patients who suffered trauma (other than falls) by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 17 Total number of patients who suffered joint problems by 6 weeks.
Figures and Tables -
Analysis 2.17

Comparison 2 Divalproex vs placebo, Outcome 17 Total number of patients who suffered joint problems by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 18 Total number of patients who suffered other infection by 6 weeks.
Figures and Tables -
Analysis 2.18

Comparison 2 Divalproex vs placebo, Outcome 18 Total number of patients who suffered other infection by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 19 Total number of patients who suffered hallucinations by 6 weeks.
Figures and Tables -
Analysis 2.19

Comparison 2 Divalproex vs placebo, Outcome 19 Total number of patients who suffered hallucinations by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 20 Total number of patients who suffered accidental injury by 6 weeks.
Figures and Tables -
Analysis 2.20

Comparison 2 Divalproex vs placebo, Outcome 20 Total number of patients who suffered accidental injury by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 21 Total number of patients who suffered anorexia by 6 weeks.
Figures and Tables -
Analysis 2.21

Comparison 2 Divalproex vs placebo, Outcome 21 Total number of patients who suffered anorexia by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 22 Total number of patients who suffered weight loss by 6 weeks.
Figures and Tables -
Analysis 2.22

Comparison 2 Divalproex vs placebo, Outcome 22 Total number of patients who suffered weight loss by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 23 Total number of patients who suffered dehydration by 6 weeks.
Figures and Tables -
Analysis 2.23

Comparison 2 Divalproex vs placebo, Outcome 23 Total number of patients who suffered dehydration by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 24 Total number of patients who suffered thrombocytopenia by 6 weeks.
Figures and Tables -
Analysis 2.24

Comparison 2 Divalproex vs placebo, Outcome 24 Total number of patients who suffered thrombocytopenia by 6 weeks.

Comparison 2 Divalproex vs placebo, Outcome 25 Total number of patients who suffered serious adverse events by 6 weeks.
Figures and Tables -
Analysis 2.25

Comparison 2 Divalproex vs placebo, Outcome 25 Total number of patients who suffered serious adverse events by 6 weeks.

Table 1. Baseline Characteristics

Name

Country

Population

Mean Age

% Female

Intervention

Diagnoses

Mean MMSE

Porsteinsson 2001

United States

Multicentric, Institutionalised; Alzheimer's dementia, vascular dementia and other dementias

85.0

61.0%

Valproic acid (N=28); placebo (N=28). divalproex sodium titrated to mean dose of 826mg/d; 6 wk course.

Dementia: MMSE; DSM IV; NICDS‐ADRDA. Agitation: CMAI; Aggression: CMAI sub scale. Global: CGI.

6.8

Sival 2002

The Netherlands

Institutionalised, Alzheimer's dementia, vascular dementia, and other dementias.

80.4

59.5%

Valproic acid (N=42); placebo (N=42); Sodium valproate 480mg/d; 3 wk course.

Dementia: MMSE; DSM IV; NINCDS‐ADRDA,Clinical Dementia Rating Scale. Agitation: BPRS subset. Aggression: Patel's method; SDAS‐9 sub scale; CGI; GIP. Global: CGI

Tariot 2001

United States

Multicentric, Institutionalised; Alzheimer's dementia, vascular dementia, and other dementias.

83.3

64.0%

Valproic acid (N=87); placebo (N=85); Divalproex sodium (delayed release); patients titrated to target dose of 20mg/kg/d; median dose 1000mg/d; 6 wk course.

Dementia: MMSE; DSM IV. Agitation: CMAI. Aggression: CMAI sub scale. Global: CGI

7.4

Tariot 2005

United States

Multicentric, Institutionalized, Alzeheimers' Dementia

84.0

68.6%

Divalproex (N=48). placebo (N=78);patients titrated to target dose of 750mg/day; 6 wk course

Alzheimer's Dementia (probable or possible) diagnosed on basis of National Institute of Neurological and Communicative Disorders and Stroke ‐Alzheimr's Disease and Related Disorders Criteria (NINDCDS‐ADRDA). Agitation and hostility, uncooperativeness measured by Brief Psychiatric Rating Scale (BPRS).

10.8

Herrmann 2007

Canada

Multicentric, institutionalized;Alzheimer's Dementia

85.6

42.8%

Valproate (N=14); placebo (N=13); Valproate titrated to dose of 1500mg/day; 6 wk course

Alzheimer's Dementia diagnosed by NINDCDS‐ADRDA criteria;Agitation/aggression diagnosed by Cohen‐Mansfield Agitation Inventory (CMAI).

<15

Figures and Tables -
Table 1. Baseline Characteristics
Table 2. Outcomes, Instruments, and Studies

Outcomes

Instruments

Studies

Agitation

Cohen‐Mansfield Agitation Inventory (CMAI)

Porsteinsson 2001

CMAI

Tariot 2001

CMAI

Tariot 2007

CMAI

Herrmann 2007

Brief Psychiatric Rating Scale Subset (BPRS)

Porsteinsson 2001

Aggression

CMAI

Porsteinsson 2001

CMAI

Tariot 2001

Social Dysfunction and Aggression‐9 Scale (SDAS‐9)14

Sival 2002

Clinical Global Impression Scale (CGI)

Sival 2002

Nurse Observation Scale

Sival 2002

Patel's Method

Sival 2002

Overt Aggression Scale

Porsteinsson 2002

Other Types of Disturbed Behavior

Behavior Scale for Intramural Psychogeriatric Patients (GIP)

Sival 2002

Global Impression

CGI

Porsteinsson 2001

CGI

Sival 2002

CGI

Tariot 2001

CGI

Tariot 2005

Cognitive Function

Mini‐mental State Examination (MMSE)

Porsteinsson 2001

MMSE

Sival 2002

MMSE

Tariot 2001

MMSE

Tariot 2005

MMSE

Herrmann 2007

Side Effects

Number of Adverse Reactions (checklist)

Porsteinsson 2001

Number of Adverse Reactions (checklist)

Sival 2002

Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART 1989)

Tariot 2001

Number of Adverse Reactions (checklist)

Tariot 2005

Number of Adverse Reactions (checklist)

Herrmann 2007

Figures and Tables -
Table 2. Outcomes, Instruments, and Studies
Comparison 1. Divalproex vs placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Brief Psychiatric rating scale Total score. Change from baseline at 6 weeks (ITT) Show forest plot

2

202

Mean Difference (IV, Fixed, 95% CI)

0.23 [‐2.14, 2.60]

2 BPRS agitation factor. Change from baseline at 6 weeks (ITT) Show forest plot

1

55

Mean Difference (IV, Fixed, 95% CI)

‐1.30 [‐2.73, 0.13]

3 BPRS hostility factor. Change from baseline at 6 weeks (ITT) Show forest plot

1

55

Mean Difference (IV, Fixed, 95% CI)

0.10 [‐1.12, 1.32]

4 Overt aggression scale total score. Change from baseline at 6 weeks (ITT) Show forest plot

1

55

Mean Difference (IV, Fixed, 95% CI)

0.10 [‐3.42, 3.62]

5 Cohen‐Mansfield Agitation Index. Total Score. Change from baseline at 6 weeks (ITT) Show forest plot

3

216

Mean Difference (IV, Fixed, 95% CI)

‐2.20 [‐6.38, 1.99]

Figures and Tables -
Comparison 1. Divalproex vs placebo
Comparison 2. Divalproex vs placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total number of patients who suffered from sedation at 6 weeks Show forest plot

3

241

Odds Ratio (M‐H, Fixed, 95% CI)

2.48 [1.37, 4.47]

2 Total number of patients who suffered from nausea, vomiting, or diarrhea at 6 weeks Show forest plot

2

208

Odds Ratio (M‐H, Fixed, 95% CI)

7.09 [1.73, 29.02]

3 Total number of patients who suffered from an urinary tract infection by 6 weeks Show forest plot

2

227

Odds Ratio (M‐H, Fixed, 95% CI)

3.02 [1.04, 8.80]

4 Total number of patients who suffered falls without injury by 6 weeks Show forest plot

3

222

Odds Ratio (M‐H, Fixed, 95% CI)

1.70 [0.84, 3.44]

5 Total number of patients who suffered falls with injury by 6 weeks Show forest plot

2

82

Odds Ratio (M‐H, Fixed, 95% CI)

1.57 [0.38, 6.41]

6 Total number of patients who suffered postural instability by 6 weeks Show forest plot

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

4.33 [0.45, 41.55]

7 Total number of patients who suffered weakness by 6 weeks Show forest plot

1

55

Peto Odds Ratio (Peto, Fixed, 95% CI)

8.00 [1.06, 60.16]

8 Total number of patients who suffered cardiovascular problems by 6 weeks Show forest plot

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

2.0 [0.17, 23.44]

9 Total number of patients who suffered edema by 6 weeks Show forest plot

1

55

Peto Odds Ratio (Peto, Fixed, 95% CI)

7.69 [0.77, 77.21]

10 Total number of patients who suffered a fever by 6 weeks Show forest plot

1

55

Peto Odds Ratio (Peto, Fixed, 95% CI)

7.69 [0.77, 77.21]

11 Total number of patients who suffered a respiratory problem by 6 weeks Show forest plot

1

55

Peto Odds Ratio (Peto, Fixed, 95% CI)

8.34 [1.35, 51.60]

12 Total number of patients who suffered any adverse effect by 6 weeks Show forest plot

4

394

Odds Ratio (M‐H, Fixed, 95% CI)

1.99 [1.29, 3.08]

13 Total number of patients who suffered from ataxia at 6 weeks Show forest plot

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

1.33 [0.27, 6.61]

14 Total number of patients who suffered from a skin problem at 6 weeks Show forest plot

2

227

Odds Ratio (M‐H, Fixed, 95% CI)

1.27 [0.45, 3.58]

15 Total number of patients who suffered other gastrointestinal problem by 6 weeks Show forest plot

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

2.08 [0.35, 12.45]

16 Total number of patients who suffered trauma (other than falls) by 6 weeks Show forest plot

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

0.62 [0.09, 4.01]

17 Total number of patients who suffered joint problems by 6 weeks Show forest plot

1

55

Odds Ratio (M‐H, Fixed, 95% CI)

0.30 [0.03, 3.04]

18 Total number of patients who suffered other infection by 6 weeks Show forest plot

3

380

Odds Ratio (M‐H, Fixed, 95% CI)

1.30 [0.70, 2.45]

19 Total number of patients who suffered hallucinations by 6 weeks Show forest plot

1

55

Peto Odds Ratio (Peto, Fixed, 95% CI)

7.13 [0.14, 359.55]

20 Total number of patients who suffered accidental injury by 6 weeks Show forest plot

1

172

Peto Odds Ratio (Peto, Fixed, 95% CI)

1.52 [0.79, 2.92]

21 Total number of patients who suffered anorexia by 6 weeks Show forest plot

1

172

Peto Odds Ratio (Peto, Fixed, 95% CI)

2.40 [0.95, 6.07]

22 Total number of patients who suffered weight loss by 6 weeks Show forest plot

1

172

Peto Odds Ratio (Peto, Fixed, 95% CI)

2.56 [0.76, 8.66]

23 Total number of patients who suffered dehydration by 6 weeks Show forest plot

1

172

Peto Odds Ratio (Peto, Fixed, 95% CI)

3.13 [0.82, 11.94]

24 Total number of patients who suffered thrombocytopenia by 6 weeks Show forest plot

2

186

Peto Odds Ratio (Peto, Fixed, 95% CI)

7.91 [1.92, 32.57]

25 Total number of patients who suffered serious adverse events by 6 weeks Show forest plot

3

235

Peto Odds Ratio (Peto, Fixed, 95% CI)

1.34 [0.74, 2.45]

Figures and Tables -
Comparison 2. Divalproex vs placebo