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Psychopharmacology

https://doi.org/10.1007/s00213-018-4867-y

ORIGINAL INVESTIGATION

The treatment of cognitive dysfunction in dementia: a multiple


treatments meta-analysis
Cheng-Hwang Perng 1 & Yue-Cune Chang 2 & Ruu-Fen Tzang 3,4,5

Received: 21 September 2017 / Accepted: 20 February 2018


# Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Objective No cure is currently available for dementia; however, various treatments and interventions have been reported to be
effective. The factors influencing the efficacy of dementia treatment have not been comprehensively evaluated. This study
evaluated the factors influencing treatment effects on cognitive dysfunction in dementia by comparing the results obtained from
a meta-analysis based on meta-regression.
Methods We searched for articles, clinical trials, and meta-analyses on the efficacy of pharmacotherapy or psychosocial treat-
ment for dementia published between 2000 and 2016 in the MEDLINE/PubMed, Cochrane Library, SCOPUS, and Airiti Library
databases.
Results The 235 selected studies involved 44,854 patients with dementia (mainly vascular dementia, Alzheimer disease, and mild
cognitive impairment). A preliminary random effects meta-analysis yielded a positive overall effect. The pooled standardized
mean difference of the treatment effects on cognitive dysfunction was 0.439 (95% confidence interval 0.374, 0.504). The results
of meta-regression showed that in young patients (β = − 0.036, p value < 0.001) with vascular dementia (β = 0.603, p value <
0.001), the efficacies of treatment 2 (symptomatic treatment for vascular dementia with piracetam, nimodipine, aniracetam,
flunarizine, vinpocetine, hyperbaric oxygen, oxiracetam, or EGB761) and treatment 5 (treatment with other alternative therapies
including acupuncture, premarin, statin, butylphthalide soft capsules, donepezil, huperzine A, and lithium treatment) were higher
than those of other existing treatments for cognitive dysfunction (β = 0.308 and 0.321, p values = 0.010 and < 0.001,
respectively).
Conclusion The most effective intervention for dementia available is symptomatic treatment for vascular dementia.
Antipsychotic treatment for dementia alleviates cognitive dysfunction less effectively than does symptomatic treatment.
Alternative therapies are also effective at present. Further research on causes and very early diagnosis of Alzheimer disease is
warranted.

Keywords Dementia . Alzheimer disease . Vascular dementia . Cognitive impairment . Cognitive function . Meta-regression

Electronic supplementary material The online version of this article


(https://doi.org/10.1007/s00213-018-4867-y) contains supplementary
material, which is available to authorized users.

* Ruu-Fen Tzang 2
Department of Mathematics, Tamkang University, New Taipei
rf.tzang@msa.hinet.net City, Taiwan
3
Cheng-Hwang Perng Department of Psychiatry, Mackay Memorial Hospital, Number 92,
chperng@gmail.com Sec. 2, Zhong Shan N Road, Taipei 104, Taiwan
4
Yue-Cune Chang Mackay Junior College of Medicine, Nursing, and Management,
ycchang414@gmail.com Taipei, Taiwan
5
Mackay Medical College, New Taipei City, Taiwan
1
Department of Statistics and Actuarial Science, Aletheia University,
New Taipei City, Taiwan, Republic of China
Psychopharmacology

Introduction ginkgo biloba folium extract (EGB761) (Jiang et al. 2013;


Tan et al. 2015b), and yinxingdamo (Wang 2013), has been
Dementia is a major cause of becoming dependent on their reported to be effective in increasing cognitive function by
family members for an aged individual (Singleton et al. 2017). reducing the risk of VaD. Third, the behavior therapies, includ-
Such dependence includes adverse physical, psychological, ing exercise therapy (Strohle et al. 2015), music therapy (Chang
social, and economic effects on the aged individuals them- et al. 2015), reminiscence therapy (Huang et al. 2015), rehabil-
selves and their entire families (Aigbogun et al. 2017). The itation, cognitive intervention (Huntley et al. 2015), physical
prevalence rate of dementia was approximately 5% among activity (aerobic, nonaerobic, or both) (Groot et al. 2016), and
individuals older than 65 years but it increased to 20–40% tai chi (Wayne et al. 2014), have been reported to be effective
among individuals older than 85 years. Significantly in recent for treating dementia. Fourth, complementary and alternative
years, the number of patients with dementia appears to in- medicine has also been reported to be effective in treating VaD,
crease with the mean overall prevalence of dementia reaching including Chinese herbal medicine adjunctive therapy
9.33 ± 8.21% (Cova et al. 2017). (CHMAT), Chinese medicine (CM) (Qin et al. 2013; Zeng
The symptoms of dementia include gradual memory loss et al. 2015) and rehabilitation, CM and acupuncture (Chen
and decline in thinking skills as well as problems concerning et al. 2011b); Danhong (He et al. 2012), Honghua, and Xixin
language, emotions, understanding, judgment, orientation, decoctions, and Danshen, Bushen, and Huoxie decoctions
and walking (Gehrman et al. 2017). Although Alzheimer dis- (Tang et al. 2005). Fifth, other alternative treatments, including
ease (AD) is the most common type of dementia (accounting scalp acupuncture (Zhang et al. 2015), premarin (Wang and Liu
for approximately 60 to 70% of dementia cases), the underly- 2000), statin (Li and Xu 2013), butylphthalide soft capsules
ing causes of AD remain unclear. The secondary type of de- (Wu 2013), donepezil (Liao and Pan 2014; Pan et al. 2006;
mentia, vascular dementia (VaD), is mainly caused by stroke Rockwood et al. 2013; Zhong et al. 2006), huperzine A (Xing
and accounts for approximately 25% of dementia cases. et al. 2014; Zheng et al. 2006), and lithium treatment
Theoretically, the treatment of dementia was determined by (Matsunaga et al. 2015), have all been reported to be effective
its cause. According to the etiology of dementia, there are for improving cognitive function in patients with dementia.
unknown etiology typed including minimal cognitive impair- During our literature review, we found at least 288 articles
ment (MCI) and Alzheimer dementia (AD) and known etiol- from the MEDLINE/PubMed database indexed as meta-
ogy typed including vascular dementia (VaD) and mixture of analyses of the efficacy of treatments for dementia. Among
MCI, AD, and VaD. The high efficacy of treatment of demen- them, only 19 articles were studies from China. Many articles
tia depends on how early the treatment of individuals with that were written in Chinese in other electronic databases were
dementia started (Tsoi et al. 2016). Especially, reducing the not included in previous research. This exclusion might have
risk of vascular dementia was reported to be a highly effective hindered the depth of the meta-analyses. Network meta-
intervention (Chen et al. 2011a). analyses and umbrella reviews involve combining data from
According to literature review, the following types of treat- multiple meta-analyses to explore the current ranking of the
ment were reported effective: (1) antipsychotic drugs and cog- treatment effects of different interventions. Such meta-
nitive enhancers, (2) symptomatic treatment drugs for VaD, (3) analyses based on meta-regression may improve the reliability
behavior therapy, (4) adjunctive therapy, and (5) other treat- of results by reducing the heterogeneity or number of confound-
ments. First, for a patient with Alzheimer disease (AD) without ing factors as well as by offering additional interesting possibil-
visible known etiology characterized by delusion, auditory hal- ities for a broader view of the evidence (Shenkin et al. 2017).
lucination, or confabulation, typical antipsychotic drugs, such Hence, in this study, we performed a meta-analysis based
as haloperidol and perphenazine, and atypical antipsychotic on meta-regression to clarify the potential prognostic factors
drugs (Tan et al. 2015a), such as olanzapine (Cao and Zhong affecting the efficacy of treatment with currently used drugs
2015), risperidone (Sheng et al. 2004), aripiprazole, and and non-drug treatments for the cognitive dysfunction ob-
quetiapine, have been reported to be effective (Tricco et al. served in dementia. This study might further increase the
2013). In addition, cognitive enhancers, such as memantine awareness of dementia-related experts regarding the current
(He et al. 2015; Rive et al. 2013), rivastigmine, and galanta- trends of the efficacies of treatments for dementia.
mine, have been reported to be effective in controlling the
symptoms of dementia. Second, in patients with dementia
caused by stroke, symptomatic treatment for VaD with blood Methods
system medication, brain-metabolism-improving agents, car-
diovascular system medication, and peripheral vasodilator cy- Study selection
clic enhancers, such as piracetam, nimodipine, aniracetam,
flunarizine (Huang and Chen 2014), vinpocetine, hyperbaric We searched four databases (PubMed, Cochrane Library,
oxygen (Wang et al. 2009), oxiracetam (Cheng et al. 2014), SCOPUS, and Airiti Library) for articles published between
Psychopharmacology

2000 and 2016. We identified articles on meta-analysis of the treatment 5, others, including acupuncture, premarin, stat-
efficacies of treatments for dementia. The keyword strategies in, butylphthalide soft capsules, donepezil, huperzine A,
used to search for such articles were presented in the supple- and lithium treatment. The standardized mean difference
mentary 1. To avoid overlooking any crucial studies, we also (SMD) is the most commonly used measure of effect size
searched the reference lists of the retrieved articles to identify in meta-analyses for evaluating treatment effects in ran-
additional eligible studies. We also searched for papers on domized control trials. However, the value of the SMD is
treatment efficacy of dementia-related meta-analyses as well affected significantly by the choice of the control group,
as systematic review papers. Among all the published meta- which depends mainly on whether the study is an active
analysis papers comparing the efficacies of pharmacotherapy control (e.g., risperidone vs. haloperidol) or a placebo
and non-pharmacotherapies as treatments for dementia, we control study. For ensuring comparability, in this study,
selected only the papers that met our inclusion criteria. we classified the types of study design data for calculating
the SMD as follows: (1) type 1: pretest data were not
Inclusion criteria available in both groups. The SMD of Hedges’ g was
calculated using the post-test means and standard devia-
Papers were included in the meta-analysis if they met the tions from both treatment and control groups. (2) Type 2:
following criteria: (1) studies were published between 2000 pretest and posttest data (or the differences between pre-
and 2016, (2) participants were older adults formally diag- test and post-test data) in both treatment and control
nosed with any type of dementia included in the Diagnostic groups were available. The SMD of Hedges’ g was cal-
and Statistical Manual of Mental Disorders IV, and (3) the culated using the differences between pretest and posttest
published quantitative data were sufficient for computing an data in both treatment and control groups. (3) Type 3: data
effect size. from active control trial. For comparability, we calculated
two SMDs of Hedges’ g for the treatment and active con-
Data extraction trol groups, using the differences between pretest and
posttest data in each group. For convenience, we used
The following characteristics, if possible, were extracted from 0.7 as the correlation coefficient between the pretest and
each study: (1) the last name of the first author, (2) publication posttest data to estimate the standard errors of the differ-
year, (3) method of treatment, (4) treatment duration (in ences between the two groups.
weeks), (5) number of patients in the analysis, (6) mean age We recoded the measurement tools for cognitive function by
of the patients included in the study, (7) type of dementia, and using the following four scales: (1) scale 1: Mini-Mental State
(8) type of cognition measurement tool. Examination (MMSE), (2) scale 2: Alzheimer Disease
For exploring the factors potentially affecting treatment Assessment Scale-Cognitive Subscale (ADAS-Cog), (3) scale
efficacy and reducing heterogeneity, we recoded the treat- 3: mixture of scale 1, scale 2, and others (e.g., mental subscale
ment type, cognitive function measurement scales, and the of the functional assessment of communication skills, total cog-
types of disease. To be consistent (with the previous sec- nition domain, rapid evaluation of cognitive function, Hopkins
tion), treatment interventions were classified as follows: Verbal Learning Test, Cambridge Neuropsychological Test
(1) treatment 1, antipsychotic drugs and cognitive en- Automated Battery: matching to sample delayed recall sub-
hancers, which are also collectively called central nervous scale), and (4) scale 4: Severe Impairment Battery.
system medication, including memantine, rivastigmine, The types of dementia were classified as follows: (1) dis-
galantamine, risperidone, haloperidol, olanzapine, perphe- ease 1: mild cognitive impairment (MCI); (2) disease 2: AD;
nazine, aripiprazole, and quetiapine; (2) treatment 2, (3) disease 3: VaD; (4) disease 4: mixture of the aforemen-
symptomatic treatment drugs for VaD, such as blood sys- tioned three types.
tem medications; brain-metabolism-improving agents;
cardiovascular system medication; and peripheral vasodi- Statistical analysis
lator cyclic enhancers, including piracetam, nimodipine,
aniracetam, flunarizine, vinpocetine, hyperbaric oxygen, We used STATA/SE version V13.0 for Windows (Stata
oxiracetam, and EGB761; (3) treatment 3, behavior ther- Corporation, College Station, TX) for all statistical analyses.
apy, namely exercise therapy, music therapy, reminiscence We first used the fixed effects meta-analysis to evaluate the
therapy, rehabilitation, cognitive intervention, physical ac- pooled effects size. The random effects meta-analysis will be
tivity (aerobic, nonaerobic, or both), and Tai Chi; (4) followed if the testing results of between studies’ heterogene-
treatment 4, adjunctive therapy, namely CHMAT; CM ity is highly significant.
and rehabilitation; CM and acupuncture; CM, recovery, The effect sizes (in terms of the SMD of Hedges’ g) were
and acupuncture; Danhong, Honghua, and Xixin decoc- expected to be comparable but not identical across studies
tions; and Danshen, Bushen, and Huoxie decoctions; (5) because of highly significant heterogeneity among them
Psychopharmacology

(e.g., differences in intervention types and cognitive improve- Results


ment outcome measures). To explore the potential factors that
contribute to the between studies’ heterogeneity, the meta- In total, 235 studies, including 44,854 patients with dementia
regression analysis was used. The dependent variable was (mainly MCI, VaD, AD, and a mixture of MCI, VaD, and
the SMD of Hedges’ g and assessed according to the afore- AD), were extracted from 33 published papers for this meta-
mentioned three types of study data. The independent vari- analysis (Table 1). Of the included studies, three were con-
ables were publication year, treatment duration, mean age, ducted in Taiwan, and six were from Canada, the USA, the
and aforementioned recoded treatment type, cognitive func- Netherlands, Japan, Canada, and Germany. The remainders
tion measurement scales, the types of disease, and types of were published in China. Table 1 presents a summary of the
SMD. The level of significance was set at p < 0.05. characteristics of all the included clinical trials. With the

Table 1 Summary of study characteristics of all included clinical trials

Paper Year Country No. of Measurements No. of Duration Type of disease Treatment
studies patients

Tricco AC et al. 2013 Canada 6 MMSE, 3483 24~158 weeks MCI Galantamine, donepezil
ADAS-Cog
Xing S-H et al. 2014 China 8 MMSE 733 8~24 weeks AD Huperzine
Matsunaga S et al. 2015 Japan 3 MMSE, 199 10~65 weeks MCI, AD Lithium
ADAS-Cog
Tan M-S et al. 2015 China 6 ADAS-Cog 1030 22~26 weeks AD EGb761
He RL et al. 2015 China 8 MMSE, 2405 24~30 weeks AD Memantine
ADAS-Cog
Zhong H et al. 2006 China 1 MMSE 52 12 weeks AD Donepezil, risperidone
Tan L et al. 2015 China 13 MMSE 1940 6~36 weeks AD, VaD, Psychosis Aripiprazole, olanzapine,
risperidone, quetiapine
Wang P-N et al. 2000 Taiwan 1 MMSE 50 6 and 12 weeks AD Premarim
Jiang LJ et al. 2013 China 8 MMSE, 1917 24~52 weeks AD, VaD EGb761
ADAS-Cog
Chen L-P et al. 2011 China 1 MMSE 134 12 weeks VaD CHMAT, piracetam
Tsoi KKF et al. 2016 Hong Kong 8 MMSE, 1415 34~80 weeks AD Rivastigmine, galantamine,
ADAS-Cog, SIB memantine, donepezil
Zhang JF et al. 2015 China 1 MMSE 60 8 weeks MCI Acupuncture, nimodipine
Wu C-H 2013 China 1 MMSE 95 13 weeks VaD Butylphthalide, nimodipine
He S-J et al. 2012 China 1 MMSE 72 4 weeks VaD Danhong
Zheng GL et al. 2006 China 1 MMSE 80 24 weeks VaD Huperzine A, piracetam
Pan DJ et al. 2006 China 1 MMSE 69 8 weeks VaD Donepezil
Liao K-C et al. 2014 China 1 MMSE 100 52 weeks AD Donepezil, danshen
Sheng JH et al. 2004 China 1 MMSE 53 8 weeks AD, VaD Risperidone, haloperidol
Tang XJ et al. 2005 China 1 MMSE 80 12 weeks VaD Bushen Huoxie decoction,
nimodipine
Huang XY et al. 2014 China 1 MMSE 64 2 weeks VaD Vinpocetine w/o flunarizine
Wang S-P et al. 2009 China 1 MMSE 64 12 weeks VaD Donepezil w/o hyperbaric
oxygen (HBO)
Wang R-D 2013 China 1 MMSE 90 8 weeks VaD EGB761 w/o piracetam
Cheng Q-S 2014 China 1 MMSE 75 3 weeks VaD Piracetam, oxiracetam
Cao LQ 2015 China 1 MMSE 60 8 weeks AD Olanzapine, perphenazine
Zeng LF et al. 2015 China 20 MMSE 1282 4~24 weeks VaD CHMAT vs. RP
Li S et al. 2013 China 13 MMSE 1024 12~24 weeks VaD Statin
Chang Y-S et al. 2015 Taiwan 5 MMSE 195 8~16 weeks AD, VaD Music therapy
Huang H-C 2015 Taiwan 11 MMSE 966 4~18 weeks AD, VaD Reminiscence therapy
Huntley JD et al. 2016 UK 17 MMSE, 1106 4~104 weeks AD, VaD Cognitive intervention
ADAS-Cog
Groot et al. 2016 Netherlands 19 MMSE, 838 6~52 weeks AD, VaD Physical activity
ADAS-Cog
Qin XD et al. 2013 China 26 MMSE 2439 2~24 weeks VaD Chinese herbal medicine
Ströhle A et al. 2015 Germany 69 MMSE, 21,785 6~208 weeks MCI, AD Drug or exercise
ADAS-Cog, SIB
Wayne PM et al. 2014 USA 8 MMSE 899 12~52 weeks MCI, VaD Tai Chi

RP routine pharmacotherapy, MCI mild cognition impairment, AD Alzheimer’s disease, VaD vascular dementia, MMSE Mini-Mental State Examination,
ADAS-Cog Alzheimer’s Disease Assessment Scale-Cognitive Subscale, SIB Severe Impairment Battery
Psychopharmacology

prespecified SMD as the effect size, the preliminary results of the other factors were ignored, using the type 2 SMD was
the random effects meta-analysis yielded a positive overall significantly less effective than using type 1 (p < 0.001).
effect (pooled effect size (ES) = 0.439 with 95% confidence We further used the multiple meta-regression models to
interval of 0.374, 0.504). The variation in ES attributable to explore the effects of influential factors after adjustment for
heterogeneity, I2, was 91.9%. The estimate of between-study the effects of other factors in the model. The results of multiple
variance, τ2, was 0.2609. In addition, the result of testing meta-regression are shown in Table 3. The treatment effects
heterogeneity was highly significant (χ2 = 3527.85 [d.f. = on cognitive dysfunction increased with the publication year,
285], p < 0.001). To explore the factors potentially affecting although not significantly (p = 0.164), after adjustment for the
treatment effects on cognitive function in dementia, we used effects of other factors in the model. Upon an increase in the
meta-regression for further analysis. mean age of patients with dementia by 1 year, the treatment
The results of univariate meta-regression are shown in effect on cognitive dysfunction significantly decreased by
Table 2. The treatment efficacy of dementia significantly be- 3.6% (p < 0.001). Treatment 1 remained the least efficacious
came increased with publication year (indicating newer stud- in treating cognitive dysfunction. Treatment 2, treatment 3,
ies) (p < 0.001). By contrast, the treatment efficacy became and treatment 5 exhibited significantly higher efficacies in
decreased with treatment duration (in weeks) and mean age treating cognitive dysfunction than that of treatment 1 (p =
(p = 0.007 and p < 0.001, respectively). 0.054 (borderline), 0.002, and 0.003, respectively). The two
A comparison of the efficacies of the five treatments most common and effective measurement scales for cognitive
showed the following: treatment 1 exhibited the lowest function were the MMSE and ADAS-Cog, although the p-
efficacy for treating cognitive dysfunction. Treatment 2 values for both scales were higher than 0.05. The treatment
exhibited the highest efficacy for treating cognitive dys- effect evaluated using the within-group differences (between
function in dementia. Treatment 4 exhibited a similar ef- pretest and posttest scores) was significantly higher than that
ficacy to that of treatment 2 (both p < 0.001). Among the obtained by directly comparing the posttest measurements of
four types of dementia, patients with VaD exhibited the treatment and placebo groups (type 1, p = 0.003) after adjust-
highest cognitive function improvement (p < 0.001). The ment for the effects of other factors (Table 3). The correspond-
MMSE was the most commonly used and effective mea- ing residual variation due to the heterogeneity for this meta-
surement scale for cognitive function assessment among regression, the I2 residual, was 86.97%. The proportion of
the four selected scales (all p < 0.01). When the effects of between-study variance explained by the meta-regression

Table 2 Results of univariate meta-regression analysis

SMD Coefficients SE t p τ2 I2_residual (%) Adjusted_R2 (%) No.

Year 0.034 0.007 5.00 < 0.001 0.2475 91.14 9.89 285
Duration (weeks) − 0.003 0.001 − 2.70 0.007 0.2668 91.42 2.87 285
Mean age − 0.038 0.006 − 6.34 < 0.001 0.2828 90.93 21.91 176
Treatment 0.2293 90.52 16.18 286
Treat_2 vs. treat_1 0.551 0.116 4.73 < 0.001
Treat_3 vs. treat_1 0.213 0.088 2.42 0.016
Treat_4 vs. treat_1 0.557 0.095 5.89 < 0.001
Treat_5 vs. treat_1 0.428 0.089 4.78 < 0.001
Disease 0.2195 89.06 19.77 286
AD vs. MCI 0.060 0.108 0.56 0.577
VaD vs. MCI 0.564 0.113 4.98 < 0.001
Mixed_D vs. MCI 0.039 0.118 0.33 0.740
Evaluation scale 0.2436 90.54 10.95 286
ADAS_Cog vs. MMSE − 0.399 0.083 − 4.78 < 0.001
Mixed_s vs. MMSE − 0.301 0.114 − 2.64 0.009
SIB vs. MMSE − 0.462 0.168 − 2.75 0.006
Type of SMD 0.2294 88.64 16.34 286
Type_2 vs. type_1 − 0.365 0.078 − 4.69 < 0.001
Type_3 vs. type_1 0.102 0.100 1.02 0.306
Psychopharmacology

Table 3 Results of multiple meta-regression analysis

SMD Coefficients SE t p τ2 I2_residual (%) Adjusted_R2 (%) No.

0.221 86.97 39.18 174


Year 0.015 0.011 1.40 0.164
Duration (weeks) − 0.001 0.002 − 0.35 0.729
Mean age − 0.036 0.010 − 3.70 < 0.001
Treat_2 vs. treat_1 0.383 0.197 1.94 0.054
Treat_3 vs. treat_1 0.441 0.138 3.20 0.002
Treat_4 vs. treat_1 0.079 0.216 0.36 0.716
Treat_5 vs. treat_1 0.562 0.186 3.02 0.003
AD vs. MCI − 0.084 0.214 − 0.39 0.694
VaD vs. MCI 0.209 0.215 0.97 0.334
Mixed_D vs. MCI 0.095 0.239 0.40 0.690
ADAS_Cog vs. MMSE − 0.043 0.152 − 0.28 0.778
Mixed_s vs. MMSE − 0.308 0.161 − 1.91 0.059
SIB vs. MMSE − 0.073 0.386 − 0.19 0.850
Type_2 vs. type_1 0.208 0.183 1.41 0.257
Type_3 vs. type_1 0.417 0.137 3.05 0.003

τ2 , the estimate of between-study variance; I2 _residual, residual variation due to heterogeneity in percentage; adjusted_R2 , proportion of between-study
variance explained; MCI, mild cognition impairment; AD, Alzheimer’s disease; VaD, vascular dementia; MMSE, Mini-Mental State Examination;
ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; Mixed_s, mixture of MMSE, ADAS-Cog, and others; SIB, Severe
Impairment Battery

model, adjusted R2, was 39.18%. The corresponding meta- of dementia, patients with vascular dementia exhibited the
regression plot is shown in Fig. 1. greatest improvement in cognitive function (p < 0.001) after
Notably, comparing the results in Tables 2 and 3 reveals adjustment for the effects of other factors. The corresponding
that 176 of 286 evaluable data set (61.54%) contained infor- meta-regression plot is shown in Fig. 2.
mation on the mean age. Thus, 110 data (38.46%) were ex- In summary, treatment 2 and treatment 5 exhibited signif-
cluded from the meta-regression analysis in Table 3 because icantly higher efficacies than did treatment 1 in treating cog-
of the unavailability of information on the mean age. The nitive dysfunction in young patients with VaD, and the MMSE
results of excluding the mean age from a previous meta- is the primary scale used.
regression model are shown in Table 4. Most of the results The risk of bias was evaluated by funnel plots and Egger’s
in Tables 3 and 4 are similar. However, among the four types regression intercept tests for bias. As shown in Fig. 3a, b,
using all selected papers (without using mean age informa-
tion), the publication bias was significant (p value < 0.001).
3

On the other hand, the publication bias was not significant (p


value = 0.229) after excluding those papers with missing
mean age information.
2
SMD
1

Discussion
0

The present study analyzed the efficacy of treatment in 44,854


patients with dementia (mainly MCI, VaD, AD, and a mixture
of MCI, VaD, and AD) from 235 studies to determine the most
-1

effective intervention for aged patients with dementia by using


0 .5 1 1.5 2 meta-regression analysis. The SMD was used to synchronize
Linear prediction
the treatment efficacy by exploring the differences in cogni-
Fig. 1 The meta-regression plot of SMD as a function of the linear
predicted values (τ2 = 0.221, I2_residual = 86.97%, adjusted_R2 =
tive function scores from studies conducted in different coun-
39.18%, n = 174); the circles are in proportion to the study weights in tries. We found that the factors affecting the efficacy of treat-
the meta-regression (with mean age) ments for dementia are the publication year (higher values for
Psychopharmacology

Table 4 Results of multiple meta-regression analysis (without mean age)

SMD Coefficients SE t p τ2 I2_residual (%) Adjusted_R2 (%) No.

0.1809 85.98 34.27 283


Year 0.023 0.008 3.08 0.002
Duration (weeks) 0.0004 0.001 − 0.31 0.755
Treat_2 vs. treat_1 0.308 0.118 2.6 0.010
Treat_3 vs. treat_1 0.145 0.099 1.47 0.143
Treat_4 vs. treat_1 0.116 0.141 0.82 0.412
Treat_5 vs. treat_1 0.321 0.090 3.58 < 0.001
AD vs. MCI 0.186 0.123 1.51 0.133
VaD vs. MCI 0.603 0.162 3.72 < 0.001
Mixed_D vs. MCI 0.090 0.136 0.67 0.505
ADAS_Cog vs. MMSE − 0.084 0.091 − 0.92 0.358
Mixed_s vs. MMSE − 0.161 0.107 − 1.5 0.134
SIB vs. MMSE − 0.258 0.147 − 1.76 0.080
Type_2 vs. type_1 0.218 0.138 1.58 0.116
Type_3 vs. type_1 0.344 0.115 2.98 0.003

τ2 , REML estimate of between-study variance; I2 _residual, % residual variation due to heterogeneity; adjusted_R2 , proportion of between-study
variance explained; MCI, mild cognition impairment; AD, Alzheimer’s disease; VaD vascular dementia; MMSE, Mini-Mental State Examination;
ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; Mixed_s, mixture of MMSE, ADAS-Cog, and others; SIB, Severe
Impairment Battery

more recent studies) and the age of the patients with dementia. within-group differences was higher than that evaluated using
The treatment efficacy significantly increased with publica- between-group differences.
tion year (p < 0.001). By contrast, the treatment efficacy de- We explain our study findings as follows. As we reviewed
creased with treatment duration (in weeks) and mean age (p = the literature on dementia, we found that currently, a relatively
0.007 and p < 0.001, respectively). The treatment efficacy in high number of studies on the efficacy of dementia treatment
older patients with AD was lower than that in younger patients have focused on VaD. Possibly, because the causes of AD
with VaD. The results of the treatment efficacy comparison in remain unknown, a high number of published studies focus
44,854 patients with dementia revealed that treatment 2 and on the treatment efficacy of VaD. To manage this heterogene-
treatment 5 exhibited the highest efficacy in relatively young ity, we conducted a meta-regression involving dementia stud-
patients with vascular dementia, the MMSE is the primary ies from different countries to understand the efficacy of de-
scale used, and the treatment efficacy evaluated using mentia treatment. The objective of this study was to identify
which treatment is effective when the etiology of AD is un-
3

known. We found that controlling the underlying pathology of


VaD improved cognitive dysfunction more effectively than
did antipsychotics and cognitive enhancers. Here, we suggest
2

that clinicians recognize younger patients with VaD and treat


them earlier by using anti-stroke medication. In addition, we
identified other alternative medications including donepezil,
SMD
1

cholinesterase inhibitors, and huperzine as new promising


drugs for effective treatment for dementia.
Several patients and their families doubt the efficacy of
0

alternative treatments, particularly Chinese herbal medicine.


The strength of this study is that alternative therapy is a suit-
-1

able and efficacious choice for patients with dementia. For


0 .5 1 1.5 improved outcomes in patients with dementia, we suggest
Linear prediction
providing a personalized treatment such as pharmacotherapy
Fig. 2 The meta-regression plot of SMD as a function of the linear
predicted values (τ2 = 0.1809, I2_residual = 85.98%, adjusted_R2 =
in combination with behavior therapy, alternative therapy, or
34.27%, n = 283); the circles are in proportion to the study weights in other therapy. Although further studies to determine the etiol-
the meta-regression (without mean age) ogy of dementia are currently required, the clinician can be
Psychopharmacology

(a) (b)
Funnel plot with pseudo 95% confidence limits (Without Mean Age) Funnel plot with pseudo 95% confidence limits (With Mean Age)

0
0

.2
.2

se(SMD)
se(SMD)

.4
.4

.6
.6

-1 0 1 2 3 -1 0 1 2 3
SMD SMD

Fig. 3 Funnel plots for treatment effects of cognitive dysfunction in p value < 0.001. b With mean age in the meta-regression (174 studies),
dementia patients. a Without mean age in the meta-regression (283 the Egger’s regression intercept testing for bias was non-significant, p
studies), the Egger’s regression intercept testing for bias was significant, value = 0.229

optimistic about using combination therapy to improve the meta-regression are that it included articles written in English
current quality of treatment. and Chinese. We used multiple meta-regression statistical
In this study, we mainly focused on exploring the factors methods with the SMD as the response variable to explore
influencing treatment efficacy (by pharmacotherapy or non- the factors potentially affecting the heterogeneity noticed
pharmacotherapy) on cognitive dysfunction in dementia. First among various meta-analyses based on the inclusion and ex-
of all, a study of pharmacotherapy included in this study clusion criteria, the use of pharmacotherapy or other therapies,
should be confirmed as effective first. Some recent monoclonal and the use of various rating scales. Such a meta-regression
antibodies, such as Bapineuzumab or Solanezumab, these drug can provide a comprehensive overview of all existing thera-
originally attracted extensive media coverage proclaiming they pies for dementia. In view of this, some others local languages
were kind of breakthrough. But we did not include them in our database, such as Korea, Japan, and Indian, were recommend-
study. Because, on August 6, 2012, Pfizer Inc. and Johnson & ed to be worked on a similar meta-analysis as we did in the
Johnson said they are ending development of an intravenous near future since dementia mainly affects older people
formulation of Bapineuzumab. This drug did not work better worldwide.
than placebo in two late-stage trials in mild to moderate AD In summary, this meta-regression is the first attempt to
patients. The results were further confirmed by a recent meta- collate all the published meta-analyses and randomized
analysis that the Bapineuzumab group was not superior to the control trials on dementia conducted in Western and
placebo group in ADAS-Cog11 and MMSE (Abushouk et al. Eastern countries. Various dementia treatment modalities
2017). On the other hand, Also Solanezumab is a monoclonal such as antipsychotics, symptomatic drug treatment for
antibody being investigated by Eli Lilly as a neuroprotector for cerebrovascular accident, and other alternative treatments
AD patients. The drug also failed to show promising result in were included in this study. Among the treatment modal-
Phase III trials (Doody et al. 2014). ities, we found that the most effective dementia interven-
Our present study has some limitations. We planned to tion on the market was symptomatic treatment for VaD.
identify all the studies from Western and Eastern countries; Antipsychotic treatment for dementia is the least effica-
however, we could not include unpublished or published arti- cious method for improving cognitive function. Other al-
cles in local languages. In this study, most of the included ternative therapies are effective at present. Additional
published papers were conducted in China, particularly those studies on the causes and very early diagnosis of AD
on alternative therapy (for example, acupuncture, premarin, are warranted.
statin, butylphthalide soft capsules, donepezil, and huperzine
A); this might hinder generalized conclusion based on the Acknowledgments The authors thank the Ministry of Science and
Technology of Taiwan, ROC, for grant support (MOST 105-2118-M-
findings of this study. At least some of the traditional
032-003). This manuscript was edited by Wallace Academic Editing.
Chinese medicine or new alternative treatments are effective.
The weakness of previous meta-analyses is the use of elec-
Compliance with ethical standards
tronic databases containing only English articles or those with
an official English language translation. The strengths of this Conflict of interest The authors declare they have no conflict of interest.
Psychopharmacology

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