Introduction

The focus of this review is the pharmacological

treatment of dementia. Pharmacotherapy is often

the central intervention used to improve

symptoms or delay the progression of dementia

syndromes. The available agents vary with respect

to their therapeutic actions, and are supported by

varying levels of evidence for efficacy. This report

is a systematic evaluation of the evidence for

pharmacological interventions for the treatment

of dementia in the domains of cognition, global

function, behavior/mood, quality of life/activities

of daily living (ADL) and caregiver burden.

Many medications have been studied in

dementia patients. These agents can be classified

into three broad categories: 

1. Cholinergic neurotransmitter modifying

agents, such as acetylcholinesterase inhibitors.

2. Non-cholinergic neurotransmitters/

neuropeptide modifying agents.

3. Other pharmacological agents. 

Although only five agents have been approved

by the Food and Drug Administration (FDA) for

the treatment of dementia, many other

pharmacological agents have been evaluated in

trials and may be prescribed in off-label use.

Given the range of pharmacological agents that

have been tested in dementia, a systematic review

of these interventions (using a consistent

methodology) provides a meaningful contribution

in this area. The key questions addressed in this

systematic review are as follows:

1. Does pharmacotherapy for dementia

syndromes improve cognitive symptoms and

outcomes?

2. Does pharmacotherapy delay cognitive

deterioration or delay disease onset of

dementia syndromes?

3. Are certain drugs, including alternative

medicines (non-pharmaceutical), more

effective than others? 

4. Do certain patient populations benefit more

from pharmacotherapy than others?

5. What is the evidence base for the treatment

of ischemic vascular dementia (VaD)? 

This review considers different types of

dementia populations (not just Alzheimer’s

Disease [AD]) in subjects from both community

and institutional settings. The studies eligible in

this systematic review were restricted to parallel

RCTs of high methodological quality.

Methods

A team of content specialists was assembled

from both international and local experts. The

purpose of the expert panel was to assist in the

topic assessment and refinement process; in

addition, complex methodological issues were

evaluated by this expert panel.

Search Strategy

Search strategies were developed and

undertaken in the electronic databases including

Cochrane Central, MEDLINE®,

PreMEDLINE®, EMBASE, AMED,

CINAHL®, AgeLine, and PsycINFO. In addition

to the electronic databases, the bibliographies of

retrieved papers were reviewed. 

Evidence Report/Technology Assessment

Number 97

Pharmacological Treatment of Dementia

Summary

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service

Agency for Healthcare Research and Quality
2

Eligibility Criteria:

Studies were included that met the following criteria:

• Populations included dementia patients who were 18 years

or older in age. 

• Diagnosis of dementia using criteria of International

Classification of Diseases (ICD) 9 or 10, Diagnostic and

Statistical Manual of Mental Disorders (DSM) III, III-R or

IV, National Institute of Neurological and Communication

Disorders and Stroke (NINCDS), Neurological and

Communication Disorders and Stroke-Alzheimer’s Disease

and Related Disorders Association (NINCDS-ADRDA),

or Neurological and Communication Disorders and

Stroke-Association Internationale pour la Recherche et

l’Enseignement en Neurosciences (NINCDS-AIREN).

• Potential populations at high risk of dementia conversion

in order to address the issue of delay in onset. These

populations included: Mild Cognitive Impairment (MCI),

Cognitive Impairment not Dementia (CIND), Cognitive

Loss No Dementia (CLoND).

• Interventions were restricted to pharmacological agents,

including food supplements (as defined by the FDA)

administered for at least 1 day.

• Parallel design randomized control trials (RCT) in the

English language of any sample size.

• Score of 3 or greater on the modified Jadad quality scale.

All types of instruments were considered for this review

within the outcome domains.

Populations of dementias caused by toxic agents (e.g.,

alcohol) and temporary dementia (e.g., side effect of anesthesia)

were excluded.

Data Collection and Reliability of Study

Selection

All studies meeting eligibility criteria were reviewed to assess

quality and data abstracted according to predetermined criteria.

The articles were grouped according to the pharmacological

agent used in the intervention. A team of study assistants were

trained in the criteria for eligibility and quality for the purposes

of this systematic review. Standardized forms and a guide

explaining the criteria were developed from previous templates.

Study outcomes were classified into the following domains: 

1. General cognitive function. 

2. Specific cognitive function. 

3. Global clinical assessment.

4. Behavior/mood. 

5. Quality of life/ADL. 

6. Effects on primary caregiver (also referred to as caregiver

burden). 

7. Safety as measured by the incidence of adverse effects

(particularly serious events). 

8. Acceptability of treatment as measured by withdrawal rate

from trial due to side effects of the medication.

Measurement of Benefits and Harms

Evaluation of efficacy is based upon reported changes for

outcomes in the principal domains of interest. Evaluation of

the potential for harm is considered within three main areas: 1)

the most frequently reported adverse events across studies for a

specific drug, 2) the overall withdrawal rate due to adverse

events for both the control and treatment groups, and 3) the

range of frequencies reported for a subset of specific symptoms

(nausea, diarrhea, dizziness, agitation, eating disorder) selected

a priori and evaluated for all pharmacological interventions. 

Measure of Effect Size and Meta-analysis

Effect sizes (ES) for trials were conducted for those

pharmacological interventions with the same outcomes. In

studies with multiple dosage groups and where sufficient data

were provided, each dose level had an ES estimated separately

relative to placebo. Before calculating a pooled effect size

measure, the reasonableness of pooling was assessed on clinical

and biological grounds, in terms of clinical homogeneity and

therefore statistical meta-analysis was not appropriate for all

outcomes or interventions. 

Results

Question 1: Does pharmacotherapy for

dementia syndromes improve cognitive

symptoms and outcomes? 

Seventy-two studies examined cholinergic neurotransmitter

modifying agents, 61 studies examined non-cholinergic

neurotransmitter/neuropeptide modifying agents and 76 trials

evaluated other agents used to treat dementia. Table 1 lists all

the pharmacological agents and the number of trials (in

brackets) eligible for review in this study. Twenty of these agents

are detailed in this summary. All drug agents are detailed in the

full report.

Summary of Cholinergic Neurotransmitter Modifying

Agents

Carnitine. Six trials1-6 evaluated carnitine in 925 subjects

with mild to moderate severity, recruited predominately from

the community. A dose of 2 to 3 g was compared to placebo

for either 24 or 52 weeks. 

Evidence of benefit is conflicting for the domains of general

or specific cognition. Results were not statistically significant in

any study but the lack of sufficient power may have influenced
these results. Similarly, no statistically significant differences

were found in the domains of global assessment,

behavior/mood, and quality of life/ADL. Statistical power

could not be evaluated for the most of these outcomes.

Four of the six studies scored 3 for quality on reporting

adverse events. Withdrawal rates due to adverse events varied

from 0-3 percent (excluding results from one outlier trial7

), and

gastrointestinal symptoms were the most frequently reported

types of adverse events. 

Donepezil. Ten trials8-17 in 3239 subjects evaluated the

efficacy of donepezil compared to placebo, and one trial18

compared donepezil with vitamin E. Eight of the studies

evaluated AD patients, for which at least half were recruited

from the community (other studies did not specify). The

subjects had predominately mild to moderate disease and doses

of 5 or 10 mg were used with study duration from 12 to 56

weeks. 

There is consistent evidence of benefit in the domains of

general cognitive function and global assessment; the combined

effect sizes for the Alzheimer’s Disease Assessment ScaleCognitive Section (ADAS-cog) and the Clinician’s InterviewBased Impression of Change (CIBIC) were estimated. Based on

the three studies that evaluated two different doses (5 and 10

mg), there was no consistent dose response relationship as the

benefit was of similar magnitude for global assessment

outcomes. Two of the three studies that evaluated

behavior/mood outcomes, using the Neuropsychiatric

Inventory (NPI), showed no statistically significant changes

relative to placebo but these trials lacked sufficient power to

detect a difference. There is evidence of benefit in ADL

outcomes, although this outcome was evaluated by a variety of

instruments. Caregiver burden outcomes were measured in a

single study that did not report the findings for this domain. 

Adverse events quality scores were 3 or greater for the

majority of studies (n=7). Four trials provided evidence of a

dose response for adverse events. One study showed a statistical

difference for balance-related problems and asthenia

(neurological fatigue) between placebo and treatment groups.

Withdrawal due to adverse events ranged from 0–18 percent

for treatment groups and 0–11 percent for placebo. Four out of

6 studies testing for differences between groups were statistically

significant for diarrhea, nausea and vomiting. 

Galantamine. Six trials19-24 in 3530 subjects compared the

efficacy of galantamine with placebo. Doses of 24 and 32 mg

were evaluated in half of these studies. Five studies evaluated

only AD patients and there was limited information regarding

the subjects’ residence (community or institutional settings). All

studies recruited subjects with mild to moderate disease and the

drug was administered from 3 to 6 months duration.

Evidence of benefit is consistent in the domains of general

cognitive function, global assessment and quality of life/ADL.

Two of the three studies that evaluated behavior/ mood found

statistically significant differences in favor of galantamine. A

dose effect was evident in the ADL domain when comparing

the pooled estimates of the Disability Assessment for Dementia

(DAD); no dose effect was observed for outcomes in the global

assessment domain, and this could not be evaluated for the

general cognition domain. Caregiver burden was not evaluated

in any trial.

Five of the six trials scored 3 out of 5 on our quality scale for

rating adverse events. Withdrawal rates due to adverse events

ranged from 4–9 percent for placebo and 8–27 percent for the

treatment group. One study showed a dose response for adverse

events. Although four trials did not report significance testing

for differences between groups, two trials did report a

statistically significant difference in weight loss between the

placebo and treatment group. The most common adverse

events were gastrointestinal symptoms (nausea and vomiting,

diarrhea), eating disorders/weight loss, and dizziness. 

Metrifonate. Nine studies25-33 compared metrifonate to

placebo in 2759 subjects with mild to moderate AD (the

majority of studies did not specify community settings).

Metrifonate doses from 50 to 80 mg were given for 21 days to

26 weeks duration.

All but one study showed metrifonate to have a consistent

positive effect on measures of general cognitive function; none

of the studies evaluated specific cognitive function measures.

Effects on global assessment were less consistent but suggested a

positive effect in four of the eight studies. Evidence for effect in

the domains of behavior/mood and quality of life/ADL were

not statistically significant in the majority of studies that

evaluated these domains; however these were primarily

evaluated as secondary outcomes and likely lacked sufficient

power. 

With the exception of a single study, quality scores for

reporting adverse events were greater than 3. However, only

one trial tested for differences between groups and found

nausea and vomiting, diarrhea, and muscle and joint disorder

to have statistically significantly differences. Withdrawal due to

adverse events varied from 0–9 percent for placebo and 0–12

percent for the treatment group. It was difficult to determine

which types of reported adverse events had the potential to

cause serious harm. This is noteworthy as metrifonate has been

withdrawn from use in North America, and Bayer has

suspended Phase III trials,34 because some patients in clinical

3
4

trials have experienced serious muscle weakness. This decision

was based on the results of an experimental study showing risk

of respiratory paralysis with the use of metrifonate. Other

adverse events of concern included severe leg cramps, dyspepsia,

and bradycardia. None of the studies that we reviewed

indicated that if present, these events differed with statistical

significance between groups. It is not clear if this inconsistency

is a function of the methods used to collect and report adverse

events, or a limitation of RCTs as a source of detecting serious

adverse events when the incidence is low.

Nicergoline. Four trials35-38 in 705 subjects compared

nicergoline to placebo and one trial39 compared it to a second

drug (antagonic-stress) in mixed populations that included AD,

Multi-Infarct Dementia (MID), Progressive Degenerative

Dementia (PDD), Vascular Dementia (VaD), mixed dementia,

and Senile Dementia of the Alzheimer’s Type (SDAT), which

were classified as mild to moderate in severity. 

All placebo-controlled trials found a positive effect for

general cognitive outcomes, but half the results were based on

observed case (OC) analyses. The evidence for benefit was

mixed in the domain of global assessments. No statistically

significant differences were found for behavior/mood, nor

quality of life/ADL outcomes but these were evaluated in few

studies and as secondary outcomes (suggesting that sufficient

power was an issue).

Quality scores for reporting adverse events varied from 2 to 5

for these four trials, and none tested for differences between

groups. Withdrawal due to adverse events varied from 0–8

percent for placebo and 0–9 percent for the treatment group.

With the exception of headache, which was reported in all four

trials, it was difficult to determine which types of adverse events

most characterized exposure to this pharmacological agent. 

Physostigmine. Four studies40-43 in 1198 subjects with mild

to moderate AD evaluated physostigmine administered in

patch and oral form (30 to 60 mg dose) from 6 to 24 weeks

duration. All subjects were recruited from the community. 

There is evidence that physostigmine has a statistically

significant positive effect on general cognitive function, as three

of the four studies showed improvement. Evidence for an effect

on global function was mixed with no consistent effect.

Similarly, for quality of life/ADL outcomes, all three studies

that evaluated this domain showed no statistically significant

difference but these were secondary outcomes and may reflect a

lack of power. Behavior/ mood and caregiver burden outcomes

were not tested.

The quality scores for reporting adverse events were generally

low, scoring 1 or 2 out of 5. Withdrawal rates due to adverse

events varied from 1–5 percent for placebo and 12–55 percent

in the treatment group, with one study not reporting rates. The

high withdrawal rates were in studies with sample sizes that

varied from181 to 475 subjects. A single study tested for

differences between groups, and found that dizziness, tremor,

weight loss, asthenia, confusion, delirium, and respiratory

problems (not detailed) were significantly different statistically.

The cluster of reported types of adverse events suggests that

gastrointestinal problems (abdominal pain, diarrhea, nausea

and vomiting and eating disorder) were most frequently

reported.

Posatirelin. Four trials44-47 evaluated posatirelin in 931

subjects in a variety of mild to moderate dementia populations

(AD, PDD, VaD) using 10 mg per day dose for 3 months

duration. 

Three of the four trials showed statistically significant

improvement in general cognitive function and quality of

life/ADL (as measured by Gottfries-Brane-Steen (GBS)

subscales for these domains). The evidence remains inconsistent

for benefit in global assessment (evaluated in only one trial) and

behavior/mood (mixed results). Caregiver burden and specific

cognitive function were not evaluated.

Quality scores for reporting adverse events varied from 2 to

4. Withdrawal rates due to adverse events ranged from 0–3

percent in placebo and 0–4 percent in the treatment group.

None of the studies tested for statistically significant differences

between groups for adverse events. At least three studies

reported arrhythmia, nausea/vomiting, headache, rash/skin

disorder, and sleep disorder. 

Rivastigmine. Six studies48-53 evaluated 2071 subjects with

three of these studies limited to AD patients. Doses of

rivastigmine varied from 1 to 12 mg, given for 14 to 26 weeks

and only one study specified a community sample. 

Evidence shows that general cognitive function improves

with rivastigmine at dose of 12 mg but there are mixed results

for efficacy at lower doses. Two trials evaluated specific

cognitive function but the results were not consistent within

studies (between general and specific measures); similarly, the

results were not consistent for general and specific cognition

between studies. There is consistent evidence of benefit for

global function but the dosage at which this occurs has

statistically significant variation among studies. In the domains

of behavior/mood, quality of life/ADL, the findings were

neither statistically significant nor consistent; most of these

analyses were not based on intention to treat analysis and lack

of sufficient power cannot be ruled out. Caregiver burden

outcomes were not evaluated.

Quality scores for reporting adverse events varied from 2 to

5. Withdrawal rates due to adverse events ranged from 4–11
percent in the placebo and 11–27 percent in the treatment

group. Two trials demonstrated a dose response; however, one

of these trials showed statistically significant differences for

nausea and vomiting only, and the other trial showed

statistically significant differences for all the adverse events

reported. The majority of studies reported dizziness, nausea and

vomiting, eating disorder/weight loss, and headache. It should

be noted that one study allowed intentional prescribed antiemetic drugs to increase the tolerance of subjects taking

rivastigmine. 

Tacrine. Six studies54-59 evaluated tacrine in 994 subjects

predominately with mild to moderate AD at doses of 80 to 160

mg lasting from either 12/13 or 30/36 weeks in duration. Two

other studies60,61 involving 425 patients were non-placebo

controlled studies. The majority of studies recruited

community-based subjects.

A single trial showed benefit for general cognitive function.

The small effect size was based on a series of related

publications. The five trials showing no benefit for general

cognitive function comprised small sample sizes and much

shorter study duration. Thus, the evidence for benefit in

general cognitive function is limited to a single trial. There is

evidence for benefit in global function in two of the three trials.

Changes in behavior/mood, quality of life/ADL domains,

specific cognitive function, and caregiver burden were all not

statistically significant, but lack of sufficient power cannot be

ruled out.

The quality scores for reporting adverse events varied from 1

to 3. The proportion of subjects withdrawing due to adverse

events ranged from 0–12 percent for placebo and 0– 55

percent in the treatment group. The higher rates of withdrawal

were associated with higher doses. Elevated alanine

transaminase (ALT) or hepatic abnormality (placebo=4–13

percent, all doses tacrine=7–67 percent) was reported in six

studies, raising concerns for the potential for serious liver

damage. None of these trials tested for differences between

treatment and placebo with respect to adverse events. Five

studies reported nausea and vomiting, gastrointestinal

problems, and dizziness. There is evidence for potentially

serious adverse events associated with liver dysfunction in six

trials.

Velnacrine. Three studies62-64 evaluated the effects of

velnacrine in 774 AD patients with a probable severity

classification. Doses between 75 mg twice daily and 225 mg

were given for 15 to 24 weeks duration. Location of

recruitment was not specified. 

Statistically significant positive effects were observed for

general cognitive function, and global assessment in the two

studies with sample sizes over 300 subjects. Behavior/mood and

caregiver burden showed some benefit in one trial62 at the

highest dose only. Quality of life/ADL was tested as a

secondary outcome and showed mixed findings.

Quality scores for reporting adverse events were 3 for all

studies. Withdrawal rates varied from 0–22 percent for the

placebo group and 5–33 percent for the treatment group. None

of the studies reported a dose response. None of the studies

tested for statistical differences between the placebo and

treatment groups. Two studies reported aberrant hematology

and hepatic abnormality62,64; for these two studies the rates of

occurrence were 2–21 percent for placebo, and 32–40 percent

for all doses. The potential for serious effects is not well

specified in these trials. All studies reported diarrhea and nausea

and vomiting. 

Summary of Non-cholinergic

Neurotransmitter/Neuropeptide Modifying Agents

Haloperidol. Five studies65-69 evaluated the effect of

haloperidol relative to placebo in a total of 622 subjects with

mild to moderate disease that included AD patients and mixed

populations (MID/VaD/ PDD). One trial had only 15

patients, and one trial65 lasted only 3 weeks. Two studies

recruited subjects from institutions; one from the community;

and, two did not specify.

Mixed results were observed for improvement in global

assessment. In three of the trials there was benefit in the

domain of behavior/mood which reached statistical

significance. Two trials evaluated caregiver burden and found

no statistically significant differences but lack of sufficient

power cannot be ruled out. Few studies evaluated outcomes in

quality of life/ADL. Haloperidol did not affect general

cognitive function in two trials and was not evaluated in the

other studies. 

The quality scores for reporting adverse events varied from 1

to 5 and only three of five studies reported withdrawal rates;

the proportion of subjects withdrawing due to adverse events

ranged from 5–17 percent for placebo and 17–33 percent in

the treatment group. One trial showed a dose-response effect

but the study lasted only 3 weeks. Three trials tested for

differences between treatment and placebo with respect to

extra-pyramidal symptoms (placebo=17–32 percent, all

doses=34–97 percent), and two found statistically significant

differences.65,66 One study66 found statistically significant

differences between groups for balance-related problems. 

Memantine. Three trials70-72 evaluated memantine in 1066

patients, primarily with VaD, with 10 or 20 mg doses for

durations of 12 or 28 weeks. Disease severity was moderate to

severe in a single study70 and mild to moderate in the remaining

two studies.71,72 One study included patients that were

5
institutionalized; one study included community subjects; and

the other study did not report the source of patients.

Consistent evidence of benefit in general cognitive function

was demonstrated in the two studies that evaluated this

domain. Findings for global assessment are mixed. The only

trial that evaluated mixed dementia populations (including

some VaD) with moderate to severe dementia found statistically

significant improvements in global function, behavior/mood,

and quality of life/ADL outcomes, but did not evaluate general

cognitive function. It should be noted that this trial with mixed

populations used half the dose of memantine for half the study

duration in patients with greater disease severity, and had

approximately half the sample size of the other two trials

evaluated in this systematic review. Despite a lower dose, a

smaller number of more severely affected patients and a shorter

duration, a statistically significant difference was found.

The quality scores for reporting adverse events varied from 3

to 4. Only two of three studies reported withdrawal rates; the

proportion of subjects withdrawing due to adverse events

ranged from 3–7 percent for placebo and 9–12 percent in the

treatment group. A single trial tested for differences between

treatment and placebo, and none of the comparisons were

significantly different statistically. 

Selegiline. Six trials73-78 evaluated selegiline in 733 patients

with AD, PDD, and dementia Alzheimer’s type (DA) with 10

mg per day and study duration of 60 days or 2 years. 

All but one trial that evaluated general cognition showed no

statistically significant changes. A single trial found statistical

improvements in specific cognitive tests (Sternberg Memory

tests); this trial also showed statistically significant

improvements in global assessment and behavior/mood. Only

this trial, which had the highest quality score (7), showed

consistently positive findings across all domains tested. Three of

the five trials that evaluated part or all of these domains had

very small sample sizes and were likely underpowered, possibly

accounting for the inconsistent findings. Based on a single trial

there is evidence that selegiline and selegiline combined with

vitamin E, delays the time to important functional decline

milestones. 

The quality scores for reporting adverse events varied from 0

to 3. The proportion of subjects withdrawing due to adverse

events ranged from 0–4 percent for placebo and 0–9 percent in

the treatment group. Only one trial tested for differences

between the treatment and placebo groups and showed that

balance and falls were statistically significantly different (worse)

between groups (particularly the group with selegiline

combined with vitamin E [22 percent] versus placebo [5

percent]). However, when adjusted for multiple comparisons,

these were no longer statistically significant. 

Summary of Other Pharmacological Agents

Cerebrolysin. Six studies79-84 evaluated the effect of

cerebrolysin in a total of 819 subjects All but one of the trials

included only AD patients with mild to moderate disease. All

of the studies used the same dose of cerebrolysin, 30 ml per day

for 5 days per week for 4 to 24 weeks duration. Location of

recruitment was not specified.

Cerebrolysin showed a statistically significant improvement

in cognition in four of five studies that evaluated this domain.

Although a pooled estimate for the ADAS-cog was calculated,

the model was positive for heterogeneity and the overall

estimate was not statistically significant. The results for specific

cognitive tests for the three trials that evaluated this domain

were inconsistent. Global assessment measures showed a

statistically significant effect in five of the trials. A summary

estimate for the Clinical Global Impression (CGI) was

presented; this model was also positive for heterogeneity but

statistically significant for an overall effect. Two out of three

studies showed an effect for behavior/ mood, but none of the

six studies showed an effect on quality of life/ADL. No study

measured caregiver burden. 

Two of the six trials scored 5 out of 5 on our quality scale for

rating adverse events, but did not report any adverse events.

Two studies scored 4, and the other two trials scored 3 and 2.

All the studies with scores equal to 4 or less tested for statistical

differences in adverse events between placebo and treatment

groups. Withdrawals due to adverse events were not reported in

one study, and were 1 percent in two studies and none

withdrew in three studies. A statistically significant difference

between treatment and control group was reported in one

study for weight change, anxiety, and headache. 

Estrogen. Five studies85-89 evaluated estrogens for dementia in

247 patients with primarily mild to moderate AD from the

community, with the exception of one study that included

moderate to severe dementia patients who were all

institutionalized. One of the studies with AD patients provided

0.10 mg per day by skin patch for 8 weeks and the others used

1.25 mg per day for 12 to 52 weeks duration. The study

including severe subjects used 2.5 mg per day for 4 weeks. 

Three trials evaluated general cognitive function and all

showed statistically non-significant findings; two trials lacked

sufficient power to show changes on the ADAS-cog. Two other

trials evaluated specific cognitive function but results were

mixed. Most of the outcomes evaluated in the domains of

global assessment, behavior/mood, and quality of life/ADL

6
were secondary outcomes and none showed statistically

significant differences (but lack of power could be a factor). 

One of the five trials scored 5 out of 5 on our quality scale

for rating adverse events, but did not report any adverse event.

Withdrawal rates due to adverse events ranged from 0–5

percent for placebo and 0–14 percent for the treatment group.

The most frequently reported adverse event was vaginal

bleeding and a single trial reported a statistically significant

difference between placebo and treatment group for this

symptom. It was not clear from the descriptions provided in

the study if they had ascertained whether vaginal bleeding was

present prior to the trial commencement.

Ginkgo biloba. Three trials90-92 evaluated Ginkgo biloba,

120 to 240 mg per day for 3 to 12 months, in a total of 563

subjects with mixed dementias of mild to moderate severity. All

were recruited from the community. 

The largest trial had the longest treatment duration but the

lowest daily dosage and reported a statistically significant

impact for general cognitive function but had mixed findings

for global assessment. A second large trial found positive

changes for neuropsychological tests, global assessment, and

behavior/mood outcomes with double the dosage of the

previously described trial and half the treatment interval. In this

RCT, clinical efficacy was assessed by using a responder

analysis, with therapy response being defined as response in at

least two of the three variables: CGI—global function,

Syndrome Kurz test (SKT)—special cognitive function, and

Nurnberger-Alters-Beobachtungs-Skala (NAB)—ADL. A single

trial evaluated behavior/mood and the result was not

statistically significant. No trial evaluated caregiver burden or

quality of life/ADL.

All three trials scored 3 or greater on the quality scale for

rating adverse events. Two studies had no withdrawals due to

adverse events, and one trial had a withdrawal rate of 6 percent

for both placebo and treatment groups. Two studies reported

no adverse events. One study reported a statistically significant

difference between the treatment and the placebo group for

skin disorders. The same study reported gastrointestinal and

headache adverse effects, but did not test for statistical

differences between the placebo and the treatment group. 

Idebenone. Four studies93-96 evaluated the drug idebenone in

1153 subjects of mixed dementia populations of mild to

moderate severity; one of these trials evaluated idebenone

relative to tacrine. Doses varied from 30 mg per day to 360 mg

per day, and the treatment interval ranged from 90 days to 60

weeks. 

There was evidence of benefit in general cognitive function

and global assessment. Several studies evaluated behavior/mood

and quality of life/ADL and these outcomes were found to be

statistically different. None of the trials evaluated caregiver

burden. 

Quality scores for reporting adverse events varied from 1 to

5. Rates of withdrawal due to adverse events varied from 0–5

percent for the placebo group and 0–5 percent in the treatment

group; a single trial did not report withdrawal rates. Two trials

tested for statistical differences between groups and found

none. Although no clear pattern emerges, three studies

identified at least one balance-related adverse event. 

Oxiracetam. Five studies97-101 evaluated oxiracetam in 554

subjects with different dementia syndromes of mild to

moderate severity. All studies used 1600 mg daily, with one

exception where the dose ranged between 1600-2400 mg per

day. The treatment interval ranged from 90 days to 26 weeks

duration. 

All outcomes shown to be positive for this drug were based

on Observed Cases (OC) evaluation. The two trials that

evaluated general cognitive function showed benefit. The

findings for specific cognitive function were mixed. A single

trial evaluated global assessment and showed statistically

significant change. Behavior/mood and quality of life/ADL

outcomes showed mixed results. No study evaluated caregiver

burden. 

The quality scores for reporting adverse events varied from 2

to 5. The proportion of withdrawals due to adverse events

varied from 0–9 percent for the placebo group and 0–6 percent

for the treatment group. No clear pattern for adverse events is

evident, but three of the five studies reported gastrointestinal

related problems, primarily abdominal pain. 

Pentoxifylline. Three placebo-controlled studies102-104

evaluated pentoxifylline and one study compared pentoxifylline

to sulodexide, with a total of 482 subjects with predominately

MID. The dose administered in all studies was 1200 mg per

day but varied between once or three times daily. The

treatment intervals ranged from 12 to 36 weeks. 

All three placebo trials showed statistically non-significant

findings for any primary outcome evaluated on all subjects in

the study. Two of these trials had very small sample sizes (n=38,

n=28) and employed Observed Cases (OC) analyses; this

suggests that the trials lacked sufficient power to evaluate

multiple outcomes. The remaining trial had a large sample size

(n=289) and employed an Intention to Treat (ITT) analysis; all

primary outcomes evaluated were not statistically significant. 

The quality scores for reporting adverse events were generally

low, varying from 1 to 3. Withdrawal rates due to adverse

events varied from 0–25 percent in the placebo group and

0–22 percent in the treatment group. The two studies that

7
8

reported adverse events indicated the presence of

gastrointestinal disturbances, including abdominal pain and

nausea and vomiting. 

Propentofylline. Four trials105-108 using propentofylline in

510 patients with AD and VaD were included. A dose of 900

mg per day was consistent across all studies, and the treatment

duration ranged from 3 to 12 months. 

Two studies with small sample sizes (n=30) showed no

statistically significant results for any outcome evaluated but

likely lacked power. There were two trials that found benefit in

general cognitive function based on the Mini-Mental Status

Exam (MMSE). The results for specific cognitive function as

measured by the Digit Symbol Substitution Test (DSST) were

mixed, as were those for global assessment. Behavior/mood

outcomes were evaluated in a single trial and showed no

statistically significant difference; this same trial evaluated

quality of life/ADL and showed no statistically significant

difference. No trial evaluated caregiver burden.

The quality scores for reporting adverse events varied from 1

to 4. The percentage of withdrawals varied from 0–13 percent

for the placebo group and 0–12 percent for the treatment

group. None of the trials tested for differences between groups.

Three of the trials reported gastrointestinal events that included

abdominal pain, constipation, and nausea and vomiting. 

Question 2: Does pharmacotherapy delay

cognitive deterioration or delay disease onset

of dementia syndromes?

Delay of Onset of Dementia

The concept of “delay onset” was operationalized to imply

conversion from a state of cognitive impairment, classified as

MCI, CLoND or CIND, to a true dementia state. No studies

with this population met the final eligibility criteria, although

four trials109-112 advanced to the full text screening stage. The

lack of studies eligible for evaluation in this systematic review

points to a gap in the literature for pharmacological

interventions (attempting to demonstrate a delay in disease

onset) in MCI-type populations. 

Delay of Progression of Dementia

The need for good evaluation of disease progression in trials

was also identified. In general, few studies evaluated subjects in

more severe states of the disease. This suggests that a bias exists

towards evaluating mild to moderate disease in the trials eligible

in this systematic review; this may reflect an underlying

assumption that the less severe groups are most likely to benefit

from drug trials. Since so few studies have evaluated the more

severe groups, this assumption may require some empirical

justification in future research. A consensus is required

regarding the diagnostic criteria to be used to establish levels of

severity. 

Three studies evaluating cerebrolysin, selegiline and vitamin

E, and donepezil have shown statistically significant effects in

delaying disease progress in mild to moderate and moderately

severe disease in patients with AD. This delay in progress was

expressed in terms of delay in days to primary event or

statistical differences between placebo at a specified time

interval. Although these trials coincidentally evaluated dementia

patients over the longest time interval, their protocol did not

withdraw the drug at the end of the study. Theoretically,

conclusive evidence of disease delay would be demonstrated if

the treatment groups did not return to the level of the placebo.

Thus, distinguishing between symptomatic and disease

modifying effects is not possible unless the drug is withdrawn

and the treatment groups are observed for these changes.

When studies attempted to evaluate disease progression,

long-term (1 year or greater) trials continued in an “open-label

fashion,” where blinding was no longer maintained. This limits

the confidence that bias did not affect the subsequent changes

in the outcomes. It was observed that increasing levels of

dropout (for a variety of reasons) also plagued these open-label

phases of evaluation. From a practical perspective, maintaining

adherence in longer-term trials in dementia patients is

challenging, particularly for those in the placebo arm or for

those with interventions that have a high proportion of adverse

events. Although this practical challenge exists, the findings of

this review suggest that there is a gap in the literature showing

delay of the disease process of dementia related disorders.

Question 3: Are certain drugs, including

alternative medicines (non-pharmaceutical)

more effective than others?

Head to head comparisons of drugs in the treatment

of dementia

A total of 26 18,39,47,60,61,65,66,68,69,73,113-128 studies compared efficacy

of the two or more pharmacological agents relative to each

other. In general, few drugs showed statistically significant

differences relative to each other. Those that did include (listed

in declining order of performance):

1. Sulphomucopolysaccharides versus CDP-choline:117

Statistically significant differences were seen in favor of

sulphomucopolysaccharides in measures of behavior and

global assessment in 30 institutionalized patients with mild

to moderate MID. 
2. Donepezil and vitamin E:18 Statistically significant

differences were seen in favor of donepezil in general

cognitive function 54 patients with mild AD.

3. Antagonic stress versus nicergoline:39 Statistically significant

differences were seen in favor of antagonic stress in

cognition as well as a global assessments in 62 subjects with

mild to moderate AD.

4. Antagonic stress versus meclofenate:124 Statistically

significant differences were seen in favor of antagonic stress

in measures of cognition and global assessment in 63

patients with mild to moderate AD.

5. Posatirelin versus citicoline:47 Statistically significant

differences were seen in favor of posatirelin in general

cognitive measure and mood in 222 community living

patients with mild to moderate AD.

6. Pyritinol versus hydergine:125 A significant difference in

favor of pyritinol in a global assessment measure in 102

Hispanic patients with mild to moderate AD.

7. Idebenone61 versus tacrine: Mixed results were observed;

the Efficacy Index Score showing a statistically significant

benefit over tacrine, while the global assessment showed no

difference in 203 individuals with AD, 44 of whom

completed the study.

Current drugs approved in the United States for the

treatment of dementia

What may be most relevant to clinicians are head to head

comparison of the cholinergic modifying neurotransmitter

pharmacological agents, particularly those currently approved

for the treatment of dementia (tacrine, rivastigmine,

galantamine, donepezil) in the United States. The evidence for

each of these drugs has been extensively detailed, and the

relative merits and handicaps of each are outlined in the results

section of the full report (Chapter 3). Relative effectiveness as

demonstrated by effect sizes for the ADAS-cog and the CIBIC

are also compared in Chapter 3. Although, the psychometric

properties of these two outcomes are commonly accepted,

comparison across the populations in these pooled estimates

may not lend themselves to direct comparison across these four

different specific drugs; populations may be different and

reporting of adverse events is not consistent. Thus, inferences

about the relative efficacy of these four medications specific for

the treatment of dementia should be made cautiously as head

to head comparisons were not undertaken.

Question 4: Do certain patient populations

benefit more from pharmacotherapy than

others?

In general, very few trials examined the efficacy of dementia

drugs across different populations or described the population

characteristics in sufficient detail. From the 15 studies 2,3,8,10-

12,23,24,61,84,93,129-132 that reported stratified analyses, eight different

variables were identified, which included age, gender,

Apolipoprotein E gene (APOE) genotype, disease type, disease

severity (as determined by MMSE/ ADAS-cog threshold

levels), treatment center, care dependence, and presence of

depression. Additionally, three trials were identified that

evaluated efficacy in 1) patients with Down’s syndrome and

dementia, 2) different races as a function of treatment center of

a multicenter trial, and 3) depressed patients. Given the

relatively small number of trials evaluating these variables

within different populations and different pharmacological

interventions, the findings of this review are inconclusive with

respect to these variables. A significant gap in the literature has

been identified. 

Question 5: What is the evidence-base for the

treatment of ischemic vascular dementia?

A total of 20 pharmacological interventions in 29 studies

17,36,38,44,46,70-72,81,92,96,98,102-104,106,107,117,126,128,133-141 were applied specifically

to VaD classified dementias. The majority of these

pharmacological interventions (n=14) were represented by

single trials, limiting the ability to judge the evidence; these

interventions included ateroid, buflomedil, cerebrolysin,

sulphomucopolysaccharides (CDP choline), citalopram,

donepezil, Ginkgo biloba, idebenone, minaprine, nimodipine,

oxiracetam, 5-THF (trazodone), vincamine, and

xantinolnicotinate. Six interventions had more than a single

trial, and these included Choto-san (n=2), memantine (n=3),

nicergoline (n=2), pentoxifylline (n=4), posatirelin (n=2), and

propentofylline (n=2). In general, when the drug interventions

were shown to be effective, it was in the domains of cognitive

function (both general and specific) and global assessment.

Other domains were less frequently evaluated. Several trials

attempted to test for differences between VaD groups and other

dementia types.

Discussion

The findings of this report suggest several important areas

for future research using pharmacological treatments for

dementia and these include:

Analytic framework of the intended aim of

the therapy on the disease

• Better conceptualization and research design to capture

“delay in progression.”

• Clearer consensus on defining efficacy (benefits and

clinically important change).

• Longer term studies (> 12 months).

9
Potential for bias

• Clarification of the role of industry sponsorship; one

recommendation should be that all studies are required to

disclose such information in future, including who

analyzed the results.

• More concerted effort to incorporate unpublished studies

and negative trials in future reviews.

Population

• Inclusion of the spectrum of severity in the patient

populations (nothing to suggest that severe patients may

not benefit from pharmacotherapy aimed at cognitive

function improvement).

• The need for validation of trials and testing processes

within cultures other than the traditional white population.

• Examining the efficacy of interventions in different subpopulations (age, disease severity levels, etc.).

• Better measurement and reporting of important patient

characteristics (including baseline cognition scores, comorbid conditions, the use of other medications, etc.).

• Inclusion of MCI type groups of subjects to evaluate “delay

of onset” (studies in progress).

Outcomes

• Expansion of outcomes collected to include more than just

cognitive function, and especially include caregiver burden

and quality of life/ADL.

• Clear operational definitions for determining critical

outcomes (delay to onset, delay to progression, important

effect size, etc.).

• Understanding of how therapies are addressed and what

outcomes are produced in different cultures.

• Production of other testing tools to detect both onset and

responses to therapies across varied cultural groups.

• Improvement in the reporting of adverse events to evaluate

harm and risk vs. benefit.

• Improvement in detailing adverse events associated with

the duration period and those occurring following this

period.

Analysis

• Appropriate analytical strategies that take into account

intention to treat (ITT)/ last observation carried forward

(LOCF) analyses; where possible both observed case and

ITT/LOCF analyses should be presented.

• Sufficient data to estimate effect size, taking into account

variability in both treated and control populations on the

primary measures.

• Reporting the power of the study when findings are

statistically non-significant. 

Intervention

• Undertake more studies with direct comparison of drugs to

determine the relative efficacy of agents.

• Improved description of the titration process.

• Improved collection of adverse events undertaken in a

systematic fashion with standardized instruments.

10
11

Table 1. Pharmacological interventions and the number of trials (#) evaluated in this

systematic review.

Cholinergic neurotransmitter modifying agents

Antagonic Stress (2) Metrifonate (9)

Acetyl-L-Carnitine (6) Nicergoline (5)

Donepezil (11) Physostigmine (4)

Eptastigmine (2) Posatirelin (4)

Galantamine (6) Rivastigmine (6)

Huperzine-A (2) Sabeluzole (1)

Linopirdine (2) Tacrine (8)

Mexofenoxate (1) Velnacrine (3)

Non-cholinergic neurotransmitter/neuropeptide modifying agents

Alaproclate (1) Memantine (3)

Alprazolam (1 Mianserin (1)

Anapsos (1) Minaprine (1)

BMY (Nootropic) (1 Moclobemide (1)

Carbamazepine (2) Naftidrofuryl (1)

Citalopram (2) Olanzapine (2)

Diphenhydramine (1) Oxazepam (1)

Divalproex (2) Paroxetine (1)

Fluoxetine (2) Perphenazine (1)

Fluvoxamine (1) Phosphatidylserine (2)

Haloperidol (8) Risperidone (2)

Imipramine (1) Selegiline (6)

Lisuride (1) Sertraline (2)

Lorazepam (2) Thioridazine (1)

Loxapine (2) Tiapride (2)

Lu25-109 (1) Trazodone (2)

Maprotiline (1) Xanomeline (1)

Melperone (1)

Other agents

5’-MTHF (1) Misoprostol (1)

Aniracetam (1) Monosialotetrahexosylganglioside (GM-1) (1)

Amitriptyline (1) N-Acetylcysteine (1)

Ateroid (1) Nimesulide (1)

Buflomedil (1) Nimodipine (2)

Cerebrolysin (6) Nizatidine (1)

Choro-San (1) Nootropic (1)

Choto-San (1) ORG 2766 (2)

Citicoline (2) Oxiracetam (5)

Cyclandelate (2) Pentoxifylline (4)

Denbufylline (1) Piracetam (1)

Desferrioxamine (1) Prednisone (1)

Diclofenac (1) Propentofylline (4)

Ergokryptine (CMB 36-733) (1) Pyritinol (1)

Ergokryptine (Dek) (1) Silymarin + Tacrine (1)

Estrogens (5) Simvastatin (1)

Ginkgo Biloba (3) Sulphomucopolysaccharides (1)

Glycosaminoglycan Polysulfate (1) Sulodexide (1)

Guanfacine (1) Thiamine (1)

Hydergine (1) Vasopressin (DDAVP) (1)

Hydroxychloroquine (1) Vincamine (1)

Idebenone (5) Vitamin E (2)

Indomethacin (1) Xantinolnicotinate (1)
Availability of the Full Report

The full evidence report from which this summary was taken

was prepared for the Agency for Healthcare Research and

Quality (AHRQ) by McMaster University Evidence-based

Practice Center under Contract No. 290-02-0020. It is

expected to be available in April 2004. At that time, printed

copies may be obtained free of charge from the AHRQ

Publications Clearinghouse by calling 800-358-9295.

Requesters should ask for Evidence Report/Technology

Assessment No. 97, Pharmacological Treatment of Dementia. In

addition, Internet users will be able to access the report and this

summary online through AHRQ’s Web site at www.ahrq.gov.

Suggested Citation

Santaguida PS, Raina P, Booker L, Patterson C, Baldassarre

F, Cowan D, Gauld M, Levine M, Unsal A. Pharmacological

Treatment of Dementia. Summary, Evidence

Report/Technology Assessment No. 97 (Prepared by McMaster

University Evidence-based Practice Center under Contract No.

290-02-0020). AHRQ Publication No. 04-E018-1. Rockville,

MD: Agency for Healthcare Research and Quality. April 2004.

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