Accepted Manuscript Memantine for Lewy body disorders: Systematic Review and Meta-analysis Shinji Matsunaga, MD, PhD Taro Kishi, MD, PhD Nakao Iwata, MD, PhD PII:
S1064-7481(13)00420-X
DOI:
10.1016/j.jagp.2013.11.007
Reference:
AMGP 310
To appear in:
The American Journal of Geriatric Psychiatry
Received Date: 25 August 2013 Revised Date:
13 November 2013
Accepted Date: 27 November 2013
Please cite this article as: S. Matsunaga, T. Kishi, N. Iwata, Memantine for Lewy body disorders: Systematic Review and Meta-analysis, The American Journal of Geriatric Psychiatry (2014), doi: 10.1016/j.jagp.2013.11.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
Abstract: 199/250 words Text: 2,446/3,000 words
RI PT
1 Table and 3 Figures
SC
4 Supplementary figures
M AN U
Memantine for Lewy body disorders: Systematic Review and Meta-analysis
Shinji Matsunaga, MD, PhD1,2*; Taro Kishi, MD, PhD1*; Nakao Iwata, MD, PhD1
TE D
* These authors contributed equally to this work
Institutional Affiliations:
Department of Psychiatry, Fujita Health University School of Medicine, Toyoake,
EP
1
2
AC C
Aichi, 470-1192, Japan
Department of Psychiatry, Okehazama Hospital, Toyoake, Aichi, 470-1168, Japan
*Correspondence: Taro Kishi, MD, PhD, Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan. Phone: +81-562-93-9250, fax: +81-562-93-1831, e-mail: [email protected] 1
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
RI PT
No Disclosures to Report No Research Funding
AC C
EP
TE D
M AN U
SC
Keywords: Memantine; Lewy body disorders; Systematic review; Meta-analysis
2
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
Abstract
RI PT
Objectives: To clarify whether memantine is more efficacious in several outcomes and safer than placebo in patients with Lewy body disorders, we performed a meta-analysis of memantine in patients with Lewy body disorders.
SC
Design: The meta-analysis included randomized controlled trials of memantine for
M AN U
Lewy body disorders. Participants: All patients with Lewy body disorders
Measurements: Motor function, activity activities of daily living, Neuropsychiatric Inventory, Mini-Mental State Examination, discontinuation rate and individual side
TE D
effects.
Results: No significant effects of memantine on motor function scores), Mini-Mental
EP
State Examination scores), Neuropsychiatric Inventory scores and activity of daily living scores) were found. However, memantine was superior to placebo in Alzheimer's
AC C
Disease Cooperative Study-Clinical Global Impression of Change scores (standardized mean difference=-0.26, 95% confidence interval=-0.51 to -0.02, Z=2.08, p=0.04; 2 studies, n=258). Dropout due to all causes, inefficacy or adverse events were similar in both groups. Moreover, no significant differences in serious adverse events, somnolence/tiredness, stroke, dizziness/vertigo and confusion were found between the
3
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
groups.
RI PT
Conclusions Our results suggest that memantine did not have a benefit for the treatment of Lewy
body disorders in cognition and motor function. However, memantine may be superior
SC
to placebo for the overall impression of the disorders. Further, memantine is
AC C
Objective
EP
TE D
M AN U
well-tolerated.
Lewy body disorders, such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), are neurodegenerative diseases characterized by accumulation of Lewy bodies in brain cells. Major symptoms of Lewy body disorders are Parkinsonisms. PD is a common neurodegenerative disease in the
4
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
elderly population, with a prevalence estimated at 166.8 per 100,000 (1, 2). PDD and
account for 15–20% of the global incidence of dementia (3).
RI PT
DLB, which are similar diseases, are the second most common causes of dementia, and
SC
The Food and Drug administration (FDA) approved memantine for the treatment of
M AN U
moderate-to-severe Alzheimer's disease in 2003. Memantine is postulated to exert its therapeutic effect through its action as a low-to-moderate affinity noncompetitive (open channel) N-methyl-D-aspartate (NMDA) receptor antagonist, which binds preferentially to the NMDA receptor-operated calcium channels (4, 5). Memantine blocks the effects
TE D
of pathologically elevated sustained levels of glutamate that may lead to neuronal
EP
dysfunction (6).
Recently, memantine has been used for the treatment of Lewy body disorders. Several
AC C
studies have reported that abnormalities in glutaminergic neural transmission were associated with the pathophysiology of Lewy body disorders. First, in a postmortem study, the expression of metabotropic glutamate receptors in patients with DLB was decreased in comparison with age-matched controls (7). Second, an animal model of Parkinsonism showed glutamatergic overactivity in their striatums (8). Third, in rats
5
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
with Parkinsonian syndrome induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,
RI PT
memantine reduced NMDA-dependent glutaminergic hyperactivity and restored akinesia and rigidity (9).
SC
To our knowledge, seven randomized controlled trials (RCTs) of memantine for Lewy
M AN U
body disorders have been performed to date (10-16). Regarding global assessment, the findings of different studies have been controversial. One study (10) reported that memantine was superior to placebo in the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) (17), while another study
TE D
(11) showed that memantine was not superior to placebo in ADCS-CGIC. Finally, another study (12) showed that memantine was not superior to placebo in the clinician’s
EP
interview-based impression of change plus caregiver input (CIBIC-Plus) (18). For cognitive function, two studies (4, 13) reported that memantine was superior to placebo
AC C
in the Mini-Mental State Examination (MMSE) (19), while another study (12) showed that memantine was not superior to placebo in the MMSE. Regarding behavioral disturbance, three studies (10-12) reported that memantine was not superior to placebo using the neuropsychiatric inventory (NPI) (20). With respect to activities of daily living, one study (10) reported that memantine was superior to placebo in disability assessment
6
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
for dementia (DAD) (21), while two studies (11, 15) showed that memantine was not
Alzheimer’s
disease
cooperative
study-activities
of
daily
RI PT
superior to placebo. One study (11) found memantine and placebo were similar in living
23
items
(ADCS-ADL23) (22) while another study (15) showed that memantine was not superior
SC
to placebo in unified Parkinson’s disease rating scale-activities of daily living
M AN U
(UPDRS-ADL). On motor function, two studies (14, 16) reported that memantine was superior to placebo on the unified Parkinson’s disease rating scale-motor (UPDRS-motor). Another study (13) showed that memantine was superior to usual care in UPDRS-motor, while three other studies (11, 12, 15) showed that memantine was not
TE D
superior to placebo on the UPDRS-motor scale. Furthermore, another study (10) showed that memantine was not superior to placebo in the modified UPDRS. These
EP
discrepant results may be due to the small sample sizes of these trials. A meta-analysis produces a weighted summary result (more weight given to larger studies). By
AC C
combining results from more than one study, a meta-analysis has the advantage of increasing statistical power (which is often inadequate in studies with a small sample size) (23). Moreover, we can combine outcomes with different measurements using standardized mean difference (SMD) analyses (24).
7
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
To clarify whether memantine is more efficacious in several outcomes and safer than
RI PT
placebo in patients with Lewy body disorders we performed a meta-analysis of
SC
memantine in patients with Lewy body disorders.
M AN U
Methods
A meta-analysis was conducted according to the guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) group (25).
TE D
Inclusion Criteria, Search Strategy, Data Extraction, and Outcome Measures Included in this study were RCTs of memantine for patients with Lewy body disorders.
EP
We selected only open-label or double-blind randomized placebo-controlled trials using memantine treatment in patients with Lewy body disorders. We allowed inclusion of
AC C
non-double-blinded studies to include more studies in the meta-analysis. To identify relevant studies, we searched PubMed, the Cochrane Library databases, Google Scholar, EMBASE, CINAHL and PsycINFO citations without language restrictions published until November 14, 2013. We used the following key words: “memantine” AND “randomized”, “random”, OR “randomly”, AND “dementia with Lewy bodies,”
8
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
“Parkinson’s disease dementia,” “Parkinson’s disease,” “Lewy body disease,” “Lewy
RI PT
body dementia,” “dementia Lewy body,” “diffuse Lewy body disease” OR “dementia Lewy body.” Additional eligible studies were also sought by a hand search of reference
lists from primary articles and relevant reviews. The first two authors of this review
SC
(S.M. and T.K.) scrutinized the inclusion and exclusion criteria of the studies identified.
M AN U
When the data required for the meta-analysis were missing, the first and/or corresponding authors were contacted for additional information (including endpoint scores). The three authors of this study independently extracted, checked, and entered
TE D
the data into Review Manager.
Data Synthesis and Statistical Analysis
EP
We included the outcome measures of at least two studies for each outcome measure. The primary outcome measure for efficacy was the motor function of Lewy body
AC C
disorders. The motor function measures included the UPDRS-3 (26, 27) from six studies and the modified UPDRS (28) scores from one study. The secondary outcome measures included activities of daily living (UPDRS activity of daily living (27), Disability Assessment for Dementia (21), and Alzheimer's Disease Cooperative Study (ADCS)-Activities of Daily Living 23-item (22)), the NPI (20), the ADCS-CGIC (17),
9
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
the
Mini-Mental
State
Examination
(19),
discontinuation
for
any
cause,
RI PT
discontinuation due to adverse events, and discontinuation due to inefficacy. In addition, we pooled the data for side effects.
SC
We based the analyses on intent-to-treat (ITT) or modified ITT data (i.e., at least one
M AN U
dose or at least one follow-up assessment). However, the data of the completer analysis were not excluded to obtain as much information as possible (Ondo’s study (15): UPDRS activities of daily living scores and UPDRS-3 scores). The meta-analysis was performed using Review Manager Version 5.2 for Windows (Review Manager version
TE D
5.2, Cochrane Collaboration, http://ims.cochrane.org/revman). For continuous data, the SMD was used, combining the effect-size (Hedges’ g) data. For dichotomous data, the
EP
relative risk (RR) was estimated along with its 95% confidence intervals (CIs). We explored study heterogeneity using the I2 statistic; considering values of 50% or higher
AC C
to reflect considerable heterogeneity (29). Overall SMD or RR and their 95% CIs were estimated
with
Mantel-Haenszel
fixed-effects
(30)
or
DerSimonian-Laird
random-effects models (29). The random-effects model is more conservative than the fixed effects model and produces a wider confidence interval. When there is no evidence of heterogeneity, the random-effects model will produce similar results to the
10
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
fixed-effects model. Therefore, when it was confirmed that there was no heterogeneity,
RI PT
we calculated pooled SMD or RR according to the Mantel-Haenszel fixed-effects model. If there was evidence of heterogeneity, we calculated pooled SMD or RR according to
SC
the DerSimonian and Laird random-effects model.
M AN U
In cases of I2 values >50% for the primary outcome measures, we planned to conduct sensitivity analyses to determine the reasons for the heterogeneity. However, as no significant heterogeneity in primary outcomes was found, the analyses were not conducted. Funnel plots were inspected visually to assess the possibility of publication
TE D
bias. We also assessed the methodological qualities of the articles included in the meta-analysis based on the Cochrane Risk of Bias Criteria (Cochrane Collaboration,
AC C
EP
http://www.cochrane.org/).
Results
Study Characteristics The search using the key words given above yielded a total of 63 references (duplication =38 references) (Supplementary Figure 1). Seven RCTs of memantine were included in
11
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
the current meta-analysis; 12 references were excluded based on the title and review of
RI PT
the abstract. Six references were also excluded based on full text, because two were the same as the study included in the current meta-analysis and four were non-RCTs. In total, we identified seven RCTs, including 431 patients with Lewy body disorders, that
SC
met our inclusion criteria (10-16). Within these seven RCTs two DLB and PDD studies,
M AN U
two PDD studies and three PD studies were included (Table 1). While five of seven studies were memantine plus L-dopa studies, the remaining two studies did not distinguish whether or not the patients took L-dopa. The mean study duration was 15.8 weeks, with three trials lasting 24 weeks, one trial lasting 16 weeks, one trial lasting 90
TE D
days, one trial lasting 8 weeks, and one trial lasting 2 weeks. Sample sizes ranged from 12 to 199 patients. The mean age of the study population was 71.2 years. Three of seven
EP
studies were sponsored by the pharmaceutical industry, and one of studies was published in Chinese (13). These seven studies were conducted in one or multiple
AC C
countries. One study was conducted in Norway, Sweden, and the UK; one was conducted in Austria, France, Germany, UK, Greece, Italy, Spain, and Turkey; one was conducted in the UK; one was conducted in the USA; one was conducted in Argentina; one was conducted in China; and one study was conducted in France. The characteristics of the trials included in our study are shown in Table 1. All studies were
12
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
of high methodological quality, based on the Cochrane Risk of Bias Criteria, as six of
RI PT
seven studies were double-blind, placebo-controlled trials and mentioned the required details of the study design (Supplementary Figure 2). The remaining study, published by Li and colleagues (13), was an open-label, randomized, non-placebo-controlled trial. We
SC
did not use the data from the Li study (13) because there was no available data for the
M AN U
meta-analysis. We based the analyses on ITT or modified ITT data. However, the data of the completer analysis were not excluded to obtain as much information as possible (Ondo’s study (15): UPDRS activities of daily living scores and UPDRS-3 scores).
TE D
Meta-analysis Results
Non-significant effects of memantine on motor function scores (Figure 1-a), MMSE
EP
scores (Figure 1-c), NPI scores (Figure 2-a) and activity of daily living scores (Figure 2-b) were found. Also, memantine was superior to placebo in the Alzheimer's Disease
AC C
Cooperative Study-Clinical Global Impression of Change scores (Figure 1-b). The data in each treatment group were simulated with no publication bias (data not shown).
Although we did not find any significant heterogeneity regarding motor function scores and NPI scores, we performed three subgroup analyses as follows: (1) divided by the
13
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
studies which allowed taking L-dopa during the study, (2) divided by the studies which
RI PT
were “DLB and PDD patients” or “PDD and PD patients” and (3) divided by the studies which were “the data of ITT or modified ITT data” or “the data of completer analysis”.
(1) When excluding for cases where L-dopa was allowed or was unknown (12),
SC
memantine also was not superior to placebo in motor function scores (Supplementary
M AN U
Figure 3-a) and NPI scores (Supplementary Figure 3-b). (2) Also, when divided by the “DLB and PDD studies” or “PDD and PD studies”, memantine was not superior to placebo in motor scores of DLB and PDD studies subgroup and PDD and PD studies subgroup (Supplementary Figure 3-c) and in NPI scores of DLB and PDD studies
TE D
subgroup and PDD and PD studies subgroup (Supplementary Figure 3-d). (3) Moreover, when we excluded the data of the completer analysis (15) from the
EP
meta-analysis of motor function scores, there were no significant differences in motor
AC C
function scores between the treatment groups (Supplementary Figure 3-e).
Dropouts due to all causes (Figure 3-a), inefficacy (Figure 3-b) or adverse events (Figure 3-c) were similar in the two groups. No significant differences in serious adverse events, somnolence/tiredness, stroke, dizziness/vertigo (2 studies, n=115) and confusion between the groups were found (Supplementary Figure 4).
14
ACCEPTED MANUSCRIPT
RI PT
Memantine for Lewy body disorders
Discussion
This is the first comprehensive meta-analysis of memantine for the treatment of Lewy
SC
body disorders. The main results indicated that although memantine was superior to
M AN U
placebo in global assessment for efficacy with a small effect size (SMD=-0.26), memantine did not have a benefit for motor function, cognitive function, or activities of daily living in comparison with placebo. We do not know why memantine improved only global outcomes. However, the effect size was small (SMD=-0.26, 95% CI=-0.51
TE D
to -0.02, Z=2.08, p=0.04) and we included only two studies in the meta-analysis for this outcome (n=258), which may account for this finding. Conversely, no significant
EP
differences in discontinuation due to all-causes and side effects between memantine and placebo treatment groups were found. From the above results, memantine does not
AC C
worsen the symptoms of Lewy body disorders and seems to be well-tolerated; thus, memantine may give the impression of reducing the severity of Lewy body disorders.
Emre and colleagues (11) reported that although memantine was not superior to placebo for global assessment and behavioral disturbance in patients with PDD only, memantine
15
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
was more efficacious for these outcomes than placebo in patients with DLB. Therefore,
RI PT
even though both PDD and DLB are classified as Lewy body disorders, the efficacy of memantine differed in the subdiagnoses of Lewy body disorders (31, 32). When we conducted the sensitivity analysis divided by the “DLB and PDD studies” or “PDD
SC
studies and PD studies” motor function scores, memantine was not superior to placebo
M AN U
in “DLB and PDD studies subgroup” or “PDD studies and PD studies subgroup.” The difference in efficacy of NPI scores in each patient group was also not identified.
The main limitation of this study is the small number of studies included. The second
TE D
limitation of this study is that two (14, 15) of the seven studies included in this meta-analysis were of short duration (≤8 weeks). Additional long-term efficacy and
EP
safety data are needed. A third limitation is that although a funnel plot for primary and secondary outcomes did not suggest the presence of publication bias, the number of
AC C
studies included in the meta-analysis was too small to allow any reasonable interpretation of funnel plots. The fourth limitation is that the patients with dementia are known to comply poorly with medication regimens (33), and therefore the effectiveness of pharmacological interventions for patients with dementia may be limited. Finally, because we included several studies that reported mean change and/or endpoint scores
16
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
of the symptoms scales, the results of all outcomes regarding efficacy and safety did not
RI PT
include the data from all of the studies included in this meta-analysis.
SC
Conclusions
M AN U
Our results suggested that memantine did not have a benefit for the treatment of Lewy body disorders in cognition and motor function. However, memantine may be superior to placebo for the overall impression of the disorder. The main limitation of this study is
AC C
EP
TE D
the small number of studies included in the meta-analysis.
17
ACCEPTED MANUSCRIPT
RI PT
Memantine for Lewy body disorders
Acknowledgements
We thank Drs. David Devos and Marcelo Merello for providing information for the
M AN U
SC
study.
Conflicts of Interest and Source of Funding
Dr. Kishi has received speaker’s honoraria from Abbott, Astellas, Daiichi Sankyo, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Yoshitomi, Otsuka, Meiji, Shionogi,
TE D
Janssen, Novartis, Tanabe-Mitsubishi and Pfizer. Dr. Iwata has received speaker’s honoraria from Astellas, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen,
EP
Yoshitomi, Otsuka, Meiji, Shionogi, Novartis and Pfizer. Dr. Matsunaga has received speaker’s honoraria from Eisai, Janssen, Novartis, Daiichi Sankyo, Ono, Takeda and
AC C
Otsuka. Drs. Matsunaga, Kishi and Iwata declare that they have no direct conflict of interest or grant support that is directly related to the content of the study. All authors declare that they have no direct conflict of interest relevant to this study. No grant support or other sources of funding were used to conduct this study or prepare this article.
18
ACCEPTED MANUSCRIPT
Contributors
RI PT
Memantine for Lewy body disorders
Dr. Matsunaga had full access to all of the data in the study and takes responsibility for
SC
the integrity of the data and the accuracy of the data analysis.
M AN U
Study concept and design, analysis and interpretation of data, acquisition of data and statistical analysis were performed by Drs. Matsunaga and Kishi. The manuscript was
AC C
EP
TE D
written by Drs. Matsunaga, Kishi and Iwata. Dr. Iwata supervised the review.
19
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
References 1.
Yamawaki M, Kusumi M, Kowa H, et al: Changes in prevalence and incidence of
RI PT
Parkinson's disease in Japan during a quarter of a century. Neuroepidemiology 2009; 32:263-269 2.
Hoegh M, Ibrahim AK, Chibnall J, et al: Prevalence of Parkinson disease and
Parkinson disease dementia in community nursing homes. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 2013; 21:529-535
Lippa CF, Duda JE, Grossman M, et al: DLB and PDD boundary issues: diagnosis,
SC
3.
treatment, molecular pathology, and biomarkers. Neurology 2007; 68:812-819 4.
Kishi T,Iwata N: NMDA receptor antagonists interventions in schizophrenia:
M AN U
Meta-analysis of randomized, placebo-controlled trials. Journal of psychiatric research 2013; 47:1143-1149 5.
Berman K, Brodaty H, Withall A, et al: Pharmacologic treatment of apathy in
dementia. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 2012; 20:104-122 6.
Danysz W,Parsons CG: The NMDA receptor antagonist memantine as a
symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical
7.
TE D
evidence. International journal of geriatric psychiatry 2003; 18:S23-32 Dalfo E, Albasanz JL, Martin M, et al: Abnormal metabotropic glutamate receptor
expression and signaling in the cerebral cortex in diffuse Lewy body disease is associated with irregular alpha-synuclein/phospholipase C (PLCbeta1) interactions. Brain pathology
EP
2004; 14:388-398 8.
Starr MS: Glutamate/dopamine D1/D2 balance in the basal ganglia and its
relevance to Parkinson's disease. Synapse 1995; 19:264-293 Kucheryanu VG,Kryzhanovskii GN: Effect of glutamate and antagonists of
AC C
9.
N-methyl-D-aspartate receptors on experimental parkinsonian syndrome in rats. Bulletin of experimental biology and medicine 2000; 130:629-632 10.
Aarsland D, Ballard C, Walker Z, et al: Memantine in patients with Parkinson's
disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet neurology 2009; 8:613-618 11.
Emre M, Tsolaki M, Bonuccelli U, et al: Memantine for patients with Parkinson's
disease
dementia
or
dementia
with
Lewy
bodies:
a
randomised,
double-blind,
placebo-controlled trial. Lancet neurology 2010; 9:969-977 12.
Leroi I, Overshott R, Byrne EJ, et al: Randomized controlled trial of memantine in
20
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
dementia associated with Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 2009; 24:1217-1221 13.
Li W, Zhao JH, Sun SG, et al: [Clinical rehabilitative effect of memantine on
RI PT
cognitive and motor disorders in patients with Parkinson's disease]. Zhonghua yi xue za zhi 2011; 91:301-303 14.
Merello M, Nouzeilles MI, Cammarota A, et al: Effect of memantine (NMDA
antagonist) on Parkinson's disease: a double-blind crossover randomized study. Clinical neuropharmacology 1999; 22:273-276 15.
Ondo WG, Shinawi L, Davidson A, et al: Memantine for non-motor features of
SC
Parkinson's disease: a double-blind placebo controlled exploratory pilot trial. Parkinsonism & related disorders 2011; 17:156-159 16.
Moreau C, Delval A, Tiffreau V, et al: Memantine for axial signs in Parkinson's
M AN U
disease: a randomised, double-blind, placebo-controlled pilot study. Journal of neurology, neurosurgery, and psychiatry 2013; 84:552-555 17.
Schneider LS, Olin JT, Doody RS, et al: Validity and reliability of the Alzheimer's
Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer disease and associated disorders 1997; 11 Suppl 2:S22-32 18.
Olin JT, Schneider LS, Doody RS, et al: Clinical evaluation of global change in
Alzheimer's disease: identifying consensus. Journal of geriatric psychiatry and neurology
19.
TE D
1996; 9:176-180
Folstein MF, Folstein SE,McHugh PR: "Mini-mental state". A practical method for
grading the cognitive state of patients for the clinician. Journal of psychiatric research 1975; 12:189-198
Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric Inventory:
EP
20.
comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308-2314 21.
Gelinas I, Gauthier L, McIntyre M, et al: Development of a functional measure for
AC C
persons with Alzheimer's disease: the disability assessment for dementia. The American journal of occupational therapy : official publication of the American Occupational Therapy Association 1999; 53:471-481 22.
Galasko D, Bennett D, Sano M, et al: An inventory to assess activities of daily
living for clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. Alzheimer disease and associated disorders 1997; 11 Suppl 2:S33-39 23.
Cohn LD,Becker BJ: How meta-analysis increases statistical power. Psychological
methods 2003; 8:243-253 24.
DerSimonian R,Laird N: Meta-analysis in clinical trials. Controlled clinical trials
1986; 7:177-188
21
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
25.
Moher D, Liberati A, Tetzlaff J, et al: Preferred reporting items for systematic
reviews and meta-analyses: the PRISMA statement. Bmj 2009; 339:b2535 26.
Ramaker C, Marinus J, Stiggelbout AM, et al: Systematic evaluation of rating
journal of the Movement Disorder Society 2002; 17:867-876 27.
Fahn S,Elton R: UPDRS program members. Unified Parkinson's Disease Rating
Scale. Macmillan Healthcare Information 1987; p153–163, p293–304 28.
RI PT
scales for impairment and disability in Parkinson's disease. Movement disorders : official
Ballard C, McKeith I, Burn D, et al: The UPDRS scale as a means of identifying
extrapyramidal signs in patients suffering from dementia with Lewy bodies. Acta
29.
SC
neurologica Scandinavica 1997; 96:366-371
Higgins JP, Thompson SG, Deeks JJ, et al: Measuring inconsistency in
meta-analyses. BMJ 2003; 327:557-560
Mantel N,Haenszel W: Statistical aspects of the analysis of data from retrospective
M AN U
30.
studies of disease. Journal of the National Cancer Institute 1959; 22:719-748 31.
Weintraub D: Neuropsychiatric symptoms in Parkinson disease and dementia with
lewy bodies: what geriatric psychiatry can learn. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 2013; 21:497-500 32.
Donaghy P, Thomas AJ,O'Brien JT: Amyloid PET Imaging in Lewy Body Disorders.
Geriatric Psychiatry 2013; 33.
TE D
The American journal of geriatric psychiatry : official journal of the American Association for
Boada M,Arranz FJ: Transdermal is better than oral: observational research of the
satisfaction of caregivers of patients with Alzheimer's disease treated with rivastigmine.
AC C
EP
Dementia and geriatric cognitive disorders 2013; 35:23-33
22
ACCEPTED MANUSCRIPT
With L-dopa, Dose Total Study
Age Patients
Diagnosis
Duration
n
(%), (mean or Male, %
Race (%)
Drug
n
Outcomes
(dose
(mean+/-SD)
median dose, mg/day)
DLB and PDD. Outpatients (100%).
PDD: Patients were included
RI PT
+/-SD mg)
MEM
Inclusions: MMSE>12 points or higher.
if they fulfilled UKPDSBB
Exclusions: other brain disease, recent major
for PD and subsequently
changes in health status, MDD, moderate or
developed dementia
severe renal impairment, heart disease,
according to the DSM-IV
pulmonary disease, hepatic impairment,
criteria at 1 year after the
results of laboratory tests deemed to be
onset of motor symptoms.
clinically relevant by the study physician that
DLB: the revised consensus
were higher than the normal values.
operationalize criteria
Aarsland MEM: 76.9±6.1 PLA:
non-industry
DLB and PDD. Outpatients (100%). Inclusions: age 50 years, MMSE=10-24,
Germany,
unstable systemic disease, exposure to toxins
TE D
PDD: Patients were included
(DSM-IV-TR), clinically significant or
DAD, MMSE. MEM=PLA: NPI,
PLA:
PLA
Yes, (67.6),
Modified UPDRS,
AQT
(388, 263-656)
color, AQT form, AQT
40
71.1
M AN U
76.2±5.8
France,
MEM>PLA: ADCS-CGIC,
79.4
(NR),
UK),
Exclusions: any primary psychiatric disorder
(450, 375-675)
Sweden
weeks
Sweden,
(Austria,
MEM:
SC
24
H-Y < 3 on.
[fixed]
(NR),
(Norway,
Emre 2010
Yes, (84.2),
Norway
2009 75
MEM: 20 35
UK (NR) color-form
MEM: 20 MEM
96
Yes, (74), (NR) [fixed]
if they fulfilled UKPDSBB for PD and subsequently developed dementia 199 or severe medical procedures in the past 5
Italy, Spain,
years, patients had taken CHO-I within 6
Turkey),
weeks before screening, or MEM within the
EP
according to the DSM
UK, Greece,
MEM=PLA: ADCS-CGIC,
MEM:
MEM:
24
74.4±5.8
53.1
MEM:
weeks
PLA:
PLA:
white (99)
72.5±7.0
57.6
PLA: white
criteria at 1 year after the
AC C
industry
previous 6 months, or had received treatment
operationalize criteria
with any investigational drug within 30 days of screening.
UPDRS-3, ZBI PLA
onset of motor symptoms.
DLB: the revised consensus
NPI, ADCS-ADL23,
(100)
99
Yes, (71), (NR)
ACCEPTED MANUSCRIPT
With L-dopa, Dose Total Study
Age Patients
Diagnosis
Duration
n
(%), Male, %
Race (%)
Drug
n
(mean or Outcomes
(dose
(mean+/-SD)
median dose, mg/day)
RI PT
+/-SD mg) PDD. Outpatients (NR).
MEM
Inclusions: H-Y =1-5, onset of cognitive symptoms at least 1 year after the onset of
of motor aspects unchanged for 4 weeks prior
16week
UKPDSBB for PD and
procedures (or have a suitable legal substitute
dementia for DSM-IV. All
to give consent). Stable dose of CHO-I > 6
retrospectively met the
months prior to study entry. No recorded
consensus criteria for possible
improvement in cognitive or behavioral
and probable PDD.
Leroi
(From 17
2009 25
weeks to
(UK), industry
Exclusions: sensitivity to NMDAR-ANTs (AMA, RAN and CIM), presence of brain
neurosurgery, or meeting criteria for probable
Inclusions: Specific inclusion criteria were 2011 40
intentionally broad and included both
(USA),
AC C
DLB.
PD. Outpatients (NR).
36.4
Caucasian
PLA:
(100)
PLA: 74.7±7.9
14
MEM
20
NR
Standard criteria
MEM: 20
Yes, (NR), (519,
[fixed]
NR) MEM=PLA: UPDRS ”on”
MEM: MEM:69.2±7.9
60.0,
8 weeks
ADL, UPDRS ”on ”Motor, NR
PLA: 68.9±8.4
PLA: PLA 60.0
Exclusions: MMSE4 weeks prior to randomization.
22weeks:
M AN U
to study entry, stable medical history and general health, and able to consent to study
NR [fixed]
SC
motor symptoms, MMSE=10-27, Treatment
MEM: 20 11
Yes, (NR), (539,
Conner Adult: , HAM-D,
NR)
FSS, ESS, PDQ-39.
20 VAS
ACCEPTED MANUSCRIPT
With L-dopa, Dose Total
Age Patients
Diagnosis
Duration
(%), Male, %
n
Race (%)
n
(mean or
(dose
(mean+/-SD)
Outcomes median dose,
2 weeks
MEM
Merello (crossover
mg/day) +/-SD mg) MEM: 30
MEM>PLA: UPDRS-3 (off
6 [fixed]
and on states), Yes (only day at
Argentina
12
PD: Outpatients (NR).
UKPDSBB
design,
60.6±3
SC
1999
UPDRS-tremor score (off
NR
endpoint), (100),
(100)
(Argentina), washout; 3 days )
M AN U
Non-industry
PDD: Outpatients (NR).
UKPDSBB for PD and
MEM:66.0±5.0
(695,±274)
6
UPDRS-bradykinesia score
MEM: 20 MEM
28
NR [fixed]
UC
27
NR
53.6
Chinese
MEM>PLA: MMSE,
PLA:
(100)
ADAS-cog, UPDRS-3
24weeks Inclusions: MMSE=10-24.
DSM
for dementia
AC C
EP
non-industry
TE D
55
state ), PLA
(off state)
MEM:
Li 2011 (China),
Drug
RI PT
Study
PLA:65.0±7.0
51.9
ACCEPTED MANUSCRIPT
With L-dopa, Dose Total Study
Age Patients
Diagnosis
Duration
n
(%), Male, %
Race (%)
Drug
n
(mean or Outcomes
(dose
(mean+/-SD)
median dose, mg/day)
RI PT
+/-SD mg)
MEM
PD: Outpatients (NR).
UPDRS-3 item 28 2.
related to insufficient doses of L-dopa or Moreau off-periods of motor fluctuation or those 2013
M AN U
Exclusions: The presence of axial disorders
MEM:66.0±NR
25
induced by STN stimulation. The appearance
Yes, (100),
[fixed]
(1000, 700-1400)
SC
Inclusions: UPDRS-3 item 29 2 and
MEM: 20 13
Gibb's criteria
90-day
(France), non-industry of STN stimulation. Inability to walk unaided
DysRS Axial, TH Flexor, France
TH Extensor, TFES Flexor,
(100) PLA
Yes, (100),
TFES Extensor
(1075, 700-1200)
MEM=PLA: Stride length,
12 velocity, Cadence
TE D
while on dopaminergic treatment, dementia
UPDRS-3 Axial, DysRS.
NR
PLA:64.0±NR
of axial signs immediately after the initiation
MEM>PLA: UPDRS-3,
(DSM-IV-TR and Mattis DRS
S1064-7481(13)00420-X
DOI:
10.1016/j.jagp.2013.11.007
Reference:
AMGP 310
To appear in:
The American Journal of Geriatric Psychiatry
Received Date: 25 August 2013 Revised Date:
13 November 2013
Accepted Date: 27 November 2013
Please cite this article as: S. Matsunaga, T. Kishi, N. Iwata, Memantine for Lewy body disorders: Systematic Review and Meta-analysis, The American Journal of Geriatric Psychiatry (2014), doi: 10.1016/j.jagp.2013.11.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
Abstract: 199/250 words Text: 2,446/3,000 words
RI PT
1 Table and 3 Figures
SC
4 Supplementary figures
M AN U
Memantine for Lewy body disorders: Systematic Review and Meta-analysis
Shinji Matsunaga, MD, PhD1,2*; Taro Kishi, MD, PhD1*; Nakao Iwata, MD, PhD1
TE D
* These authors contributed equally to this work
Institutional Affiliations:
Department of Psychiatry, Fujita Health University School of Medicine, Toyoake,
EP
1
2
AC C
Aichi, 470-1192, Japan
Department of Psychiatry, Okehazama Hospital, Toyoake, Aichi, 470-1168, Japan
*Correspondence: Taro Kishi, MD, PhD, Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan. Phone: +81-562-93-9250, fax: +81-562-93-1831, e-mail: [email protected] 1
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
RI PT
No Disclosures to Report No Research Funding
AC C
EP
TE D
M AN U
SC
Keywords: Memantine; Lewy body disorders; Systematic review; Meta-analysis
2
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
Abstract
RI PT
Objectives: To clarify whether memantine is more efficacious in several outcomes and safer than placebo in patients with Lewy body disorders, we performed a meta-analysis of memantine in patients with Lewy body disorders.
SC
Design: The meta-analysis included randomized controlled trials of memantine for
M AN U
Lewy body disorders. Participants: All patients with Lewy body disorders
Measurements: Motor function, activity activities of daily living, Neuropsychiatric Inventory, Mini-Mental State Examination, discontinuation rate and individual side
TE D
effects.
Results: No significant effects of memantine on motor function scores), Mini-Mental
EP
State Examination scores), Neuropsychiatric Inventory scores and activity of daily living scores) were found. However, memantine was superior to placebo in Alzheimer's
AC C
Disease Cooperative Study-Clinical Global Impression of Change scores (standardized mean difference=-0.26, 95% confidence interval=-0.51 to -0.02, Z=2.08, p=0.04; 2 studies, n=258). Dropout due to all causes, inefficacy or adverse events were similar in both groups. Moreover, no significant differences in serious adverse events, somnolence/tiredness, stroke, dizziness/vertigo and confusion were found between the
3
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
groups.
RI PT
Conclusions Our results suggest that memantine did not have a benefit for the treatment of Lewy
body disorders in cognition and motor function. However, memantine may be superior
SC
to placebo for the overall impression of the disorders. Further, memantine is
AC C
Objective
EP
TE D
M AN U
well-tolerated.
Lewy body disorders, such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), are neurodegenerative diseases characterized by accumulation of Lewy bodies in brain cells. Major symptoms of Lewy body disorders are Parkinsonisms. PD is a common neurodegenerative disease in the
4
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
elderly population, with a prevalence estimated at 166.8 per 100,000 (1, 2). PDD and
account for 15–20% of the global incidence of dementia (3).
RI PT
DLB, which are similar diseases, are the second most common causes of dementia, and
SC
The Food and Drug administration (FDA) approved memantine for the treatment of
M AN U
moderate-to-severe Alzheimer's disease in 2003. Memantine is postulated to exert its therapeutic effect through its action as a low-to-moderate affinity noncompetitive (open channel) N-methyl-D-aspartate (NMDA) receptor antagonist, which binds preferentially to the NMDA receptor-operated calcium channels (4, 5). Memantine blocks the effects
TE D
of pathologically elevated sustained levels of glutamate that may lead to neuronal
EP
dysfunction (6).
Recently, memantine has been used for the treatment of Lewy body disorders. Several
AC C
studies have reported that abnormalities in glutaminergic neural transmission were associated with the pathophysiology of Lewy body disorders. First, in a postmortem study, the expression of metabotropic glutamate receptors in patients with DLB was decreased in comparison with age-matched controls (7). Second, an animal model of Parkinsonism showed glutamatergic overactivity in their striatums (8). Third, in rats
5
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
with Parkinsonian syndrome induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,
RI PT
memantine reduced NMDA-dependent glutaminergic hyperactivity and restored akinesia and rigidity (9).
SC
To our knowledge, seven randomized controlled trials (RCTs) of memantine for Lewy
M AN U
body disorders have been performed to date (10-16). Regarding global assessment, the findings of different studies have been controversial. One study (10) reported that memantine was superior to placebo in the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) (17), while another study
TE D
(11) showed that memantine was not superior to placebo in ADCS-CGIC. Finally, another study (12) showed that memantine was not superior to placebo in the clinician’s
EP
interview-based impression of change plus caregiver input (CIBIC-Plus) (18). For cognitive function, two studies (4, 13) reported that memantine was superior to placebo
AC C
in the Mini-Mental State Examination (MMSE) (19), while another study (12) showed that memantine was not superior to placebo in the MMSE. Regarding behavioral disturbance, three studies (10-12) reported that memantine was not superior to placebo using the neuropsychiatric inventory (NPI) (20). With respect to activities of daily living, one study (10) reported that memantine was superior to placebo in disability assessment
6
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
for dementia (DAD) (21), while two studies (11, 15) showed that memantine was not
Alzheimer’s
disease
cooperative
study-activities
of
daily
RI PT
superior to placebo. One study (11) found memantine and placebo were similar in living
23
items
(ADCS-ADL23) (22) while another study (15) showed that memantine was not superior
SC
to placebo in unified Parkinson’s disease rating scale-activities of daily living
M AN U
(UPDRS-ADL). On motor function, two studies (14, 16) reported that memantine was superior to placebo on the unified Parkinson’s disease rating scale-motor (UPDRS-motor). Another study (13) showed that memantine was superior to usual care in UPDRS-motor, while three other studies (11, 12, 15) showed that memantine was not
TE D
superior to placebo on the UPDRS-motor scale. Furthermore, another study (10) showed that memantine was not superior to placebo in the modified UPDRS. These
EP
discrepant results may be due to the small sample sizes of these trials. A meta-analysis produces a weighted summary result (more weight given to larger studies). By
AC C
combining results from more than one study, a meta-analysis has the advantage of increasing statistical power (which is often inadequate in studies with a small sample size) (23). Moreover, we can combine outcomes with different measurements using standardized mean difference (SMD) analyses (24).
7
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
To clarify whether memantine is more efficacious in several outcomes and safer than
RI PT
placebo in patients with Lewy body disorders we performed a meta-analysis of
SC
memantine in patients with Lewy body disorders.
M AN U
Methods
A meta-analysis was conducted according to the guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) group (25).
TE D
Inclusion Criteria, Search Strategy, Data Extraction, and Outcome Measures Included in this study were RCTs of memantine for patients with Lewy body disorders.
EP
We selected only open-label or double-blind randomized placebo-controlled trials using memantine treatment in patients with Lewy body disorders. We allowed inclusion of
AC C
non-double-blinded studies to include more studies in the meta-analysis. To identify relevant studies, we searched PubMed, the Cochrane Library databases, Google Scholar, EMBASE, CINAHL and PsycINFO citations without language restrictions published until November 14, 2013. We used the following key words: “memantine” AND “randomized”, “random”, OR “randomly”, AND “dementia with Lewy bodies,”
8
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
“Parkinson’s disease dementia,” “Parkinson’s disease,” “Lewy body disease,” “Lewy
RI PT
body dementia,” “dementia Lewy body,” “diffuse Lewy body disease” OR “dementia Lewy body.” Additional eligible studies were also sought by a hand search of reference
lists from primary articles and relevant reviews. The first two authors of this review
SC
(S.M. and T.K.) scrutinized the inclusion and exclusion criteria of the studies identified.
M AN U
When the data required for the meta-analysis were missing, the first and/or corresponding authors were contacted for additional information (including endpoint scores). The three authors of this study independently extracted, checked, and entered
TE D
the data into Review Manager.
Data Synthesis and Statistical Analysis
EP
We included the outcome measures of at least two studies for each outcome measure. The primary outcome measure for efficacy was the motor function of Lewy body
AC C
disorders. The motor function measures included the UPDRS-3 (26, 27) from six studies and the modified UPDRS (28) scores from one study. The secondary outcome measures included activities of daily living (UPDRS activity of daily living (27), Disability Assessment for Dementia (21), and Alzheimer's Disease Cooperative Study (ADCS)-Activities of Daily Living 23-item (22)), the NPI (20), the ADCS-CGIC (17),
9
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
the
Mini-Mental
State
Examination
(19),
discontinuation
for
any
cause,
RI PT
discontinuation due to adverse events, and discontinuation due to inefficacy. In addition, we pooled the data for side effects.
SC
We based the analyses on intent-to-treat (ITT) or modified ITT data (i.e., at least one
M AN U
dose or at least one follow-up assessment). However, the data of the completer analysis were not excluded to obtain as much information as possible (Ondo’s study (15): UPDRS activities of daily living scores and UPDRS-3 scores). The meta-analysis was performed using Review Manager Version 5.2 for Windows (Review Manager version
TE D
5.2, Cochrane Collaboration, http://ims.cochrane.org/revman). For continuous data, the SMD was used, combining the effect-size (Hedges’ g) data. For dichotomous data, the
EP
relative risk (RR) was estimated along with its 95% confidence intervals (CIs). We explored study heterogeneity using the I2 statistic; considering values of 50% or higher
AC C
to reflect considerable heterogeneity (29). Overall SMD or RR and their 95% CIs were estimated
with
Mantel-Haenszel
fixed-effects
(30)
or
DerSimonian-Laird
random-effects models (29). The random-effects model is more conservative than the fixed effects model and produces a wider confidence interval. When there is no evidence of heterogeneity, the random-effects model will produce similar results to the
10
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
fixed-effects model. Therefore, when it was confirmed that there was no heterogeneity,
RI PT
we calculated pooled SMD or RR according to the Mantel-Haenszel fixed-effects model. If there was evidence of heterogeneity, we calculated pooled SMD or RR according to
SC
the DerSimonian and Laird random-effects model.
M AN U
In cases of I2 values >50% for the primary outcome measures, we planned to conduct sensitivity analyses to determine the reasons for the heterogeneity. However, as no significant heterogeneity in primary outcomes was found, the analyses were not conducted. Funnel plots were inspected visually to assess the possibility of publication
TE D
bias. We also assessed the methodological qualities of the articles included in the meta-analysis based on the Cochrane Risk of Bias Criteria (Cochrane Collaboration,
AC C
EP
http://www.cochrane.org/).
Results
Study Characteristics The search using the key words given above yielded a total of 63 references (duplication =38 references) (Supplementary Figure 1). Seven RCTs of memantine were included in
11
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
the current meta-analysis; 12 references were excluded based on the title and review of
RI PT
the abstract. Six references were also excluded based on full text, because two were the same as the study included in the current meta-analysis and four were non-RCTs. In total, we identified seven RCTs, including 431 patients with Lewy body disorders, that
SC
met our inclusion criteria (10-16). Within these seven RCTs two DLB and PDD studies,
M AN U
two PDD studies and three PD studies were included (Table 1). While five of seven studies were memantine plus L-dopa studies, the remaining two studies did not distinguish whether or not the patients took L-dopa. The mean study duration was 15.8 weeks, with three trials lasting 24 weeks, one trial lasting 16 weeks, one trial lasting 90
TE D
days, one trial lasting 8 weeks, and one trial lasting 2 weeks. Sample sizes ranged from 12 to 199 patients. The mean age of the study population was 71.2 years. Three of seven
EP
studies were sponsored by the pharmaceutical industry, and one of studies was published in Chinese (13). These seven studies were conducted in one or multiple
AC C
countries. One study was conducted in Norway, Sweden, and the UK; one was conducted in Austria, France, Germany, UK, Greece, Italy, Spain, and Turkey; one was conducted in the UK; one was conducted in the USA; one was conducted in Argentina; one was conducted in China; and one study was conducted in France. The characteristics of the trials included in our study are shown in Table 1. All studies were
12
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
of high methodological quality, based on the Cochrane Risk of Bias Criteria, as six of
RI PT
seven studies were double-blind, placebo-controlled trials and mentioned the required details of the study design (Supplementary Figure 2). The remaining study, published by Li and colleagues (13), was an open-label, randomized, non-placebo-controlled trial. We
SC
did not use the data from the Li study (13) because there was no available data for the
M AN U
meta-analysis. We based the analyses on ITT or modified ITT data. However, the data of the completer analysis were not excluded to obtain as much information as possible (Ondo’s study (15): UPDRS activities of daily living scores and UPDRS-3 scores).
TE D
Meta-analysis Results
Non-significant effects of memantine on motor function scores (Figure 1-a), MMSE
EP
scores (Figure 1-c), NPI scores (Figure 2-a) and activity of daily living scores (Figure 2-b) were found. Also, memantine was superior to placebo in the Alzheimer's Disease
AC C
Cooperative Study-Clinical Global Impression of Change scores (Figure 1-b). The data in each treatment group were simulated with no publication bias (data not shown).
Although we did not find any significant heterogeneity regarding motor function scores and NPI scores, we performed three subgroup analyses as follows: (1) divided by the
13
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
studies which allowed taking L-dopa during the study, (2) divided by the studies which
RI PT
were “DLB and PDD patients” or “PDD and PD patients” and (3) divided by the studies which were “the data of ITT or modified ITT data” or “the data of completer analysis”.
(1) When excluding for cases where L-dopa was allowed or was unknown (12),
SC
memantine also was not superior to placebo in motor function scores (Supplementary
M AN U
Figure 3-a) and NPI scores (Supplementary Figure 3-b). (2) Also, when divided by the “DLB and PDD studies” or “PDD and PD studies”, memantine was not superior to placebo in motor scores of DLB and PDD studies subgroup and PDD and PD studies subgroup (Supplementary Figure 3-c) and in NPI scores of DLB and PDD studies
TE D
subgroup and PDD and PD studies subgroup (Supplementary Figure 3-d). (3) Moreover, when we excluded the data of the completer analysis (15) from the
EP
meta-analysis of motor function scores, there were no significant differences in motor
AC C
function scores between the treatment groups (Supplementary Figure 3-e).
Dropouts due to all causes (Figure 3-a), inefficacy (Figure 3-b) or adverse events (Figure 3-c) were similar in the two groups. No significant differences in serious adverse events, somnolence/tiredness, stroke, dizziness/vertigo (2 studies, n=115) and confusion between the groups were found (Supplementary Figure 4).
14
ACCEPTED MANUSCRIPT
RI PT
Memantine for Lewy body disorders
Discussion
This is the first comprehensive meta-analysis of memantine for the treatment of Lewy
SC
body disorders. The main results indicated that although memantine was superior to
M AN U
placebo in global assessment for efficacy with a small effect size (SMD=-0.26), memantine did not have a benefit for motor function, cognitive function, or activities of daily living in comparison with placebo. We do not know why memantine improved only global outcomes. However, the effect size was small (SMD=-0.26, 95% CI=-0.51
TE D
to -0.02, Z=2.08, p=0.04) and we included only two studies in the meta-analysis for this outcome (n=258), which may account for this finding. Conversely, no significant
EP
differences in discontinuation due to all-causes and side effects between memantine and placebo treatment groups were found. From the above results, memantine does not
AC C
worsen the symptoms of Lewy body disorders and seems to be well-tolerated; thus, memantine may give the impression of reducing the severity of Lewy body disorders.
Emre and colleagues (11) reported that although memantine was not superior to placebo for global assessment and behavioral disturbance in patients with PDD only, memantine
15
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
was more efficacious for these outcomes than placebo in patients with DLB. Therefore,
RI PT
even though both PDD and DLB are classified as Lewy body disorders, the efficacy of memantine differed in the subdiagnoses of Lewy body disorders (31, 32). When we conducted the sensitivity analysis divided by the “DLB and PDD studies” or “PDD
SC
studies and PD studies” motor function scores, memantine was not superior to placebo
M AN U
in “DLB and PDD studies subgroup” or “PDD studies and PD studies subgroup.” The difference in efficacy of NPI scores in each patient group was also not identified.
The main limitation of this study is the small number of studies included. The second
TE D
limitation of this study is that two (14, 15) of the seven studies included in this meta-analysis were of short duration (≤8 weeks). Additional long-term efficacy and
EP
safety data are needed. A third limitation is that although a funnel plot for primary and secondary outcomes did not suggest the presence of publication bias, the number of
AC C
studies included in the meta-analysis was too small to allow any reasonable interpretation of funnel plots. The fourth limitation is that the patients with dementia are known to comply poorly with medication regimens (33), and therefore the effectiveness of pharmacological interventions for patients with dementia may be limited. Finally, because we included several studies that reported mean change and/or endpoint scores
16
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
of the symptoms scales, the results of all outcomes regarding efficacy and safety did not
RI PT
include the data from all of the studies included in this meta-analysis.
SC
Conclusions
M AN U
Our results suggested that memantine did not have a benefit for the treatment of Lewy body disorders in cognition and motor function. However, memantine may be superior to placebo for the overall impression of the disorder. The main limitation of this study is
AC C
EP
TE D
the small number of studies included in the meta-analysis.
17
ACCEPTED MANUSCRIPT
RI PT
Memantine for Lewy body disorders
Acknowledgements
We thank Drs. David Devos and Marcelo Merello for providing information for the
M AN U
SC
study.
Conflicts of Interest and Source of Funding
Dr. Kishi has received speaker’s honoraria from Abbott, Astellas, Daiichi Sankyo, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Yoshitomi, Otsuka, Meiji, Shionogi,
TE D
Janssen, Novartis, Tanabe-Mitsubishi and Pfizer. Dr. Iwata has received speaker’s honoraria from Astellas, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen,
EP
Yoshitomi, Otsuka, Meiji, Shionogi, Novartis and Pfizer. Dr. Matsunaga has received speaker’s honoraria from Eisai, Janssen, Novartis, Daiichi Sankyo, Ono, Takeda and
AC C
Otsuka. Drs. Matsunaga, Kishi and Iwata declare that they have no direct conflict of interest or grant support that is directly related to the content of the study. All authors declare that they have no direct conflict of interest relevant to this study. No grant support or other sources of funding were used to conduct this study or prepare this article.
18
ACCEPTED MANUSCRIPT
Contributors
RI PT
Memantine for Lewy body disorders
Dr. Matsunaga had full access to all of the data in the study and takes responsibility for
SC
the integrity of the data and the accuracy of the data analysis.
M AN U
Study concept and design, analysis and interpretation of data, acquisition of data and statistical analysis were performed by Drs. Matsunaga and Kishi. The manuscript was
AC C
EP
TE D
written by Drs. Matsunaga, Kishi and Iwata. Dr. Iwata supervised the review.
19
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
References 1.
Yamawaki M, Kusumi M, Kowa H, et al: Changes in prevalence and incidence of
RI PT
Parkinson's disease in Japan during a quarter of a century. Neuroepidemiology 2009; 32:263-269 2.
Hoegh M, Ibrahim AK, Chibnall J, et al: Prevalence of Parkinson disease and
Parkinson disease dementia in community nursing homes. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 2013; 21:529-535
Lippa CF, Duda JE, Grossman M, et al: DLB and PDD boundary issues: diagnosis,
SC
3.
treatment, molecular pathology, and biomarkers. Neurology 2007; 68:812-819 4.
Kishi T,Iwata N: NMDA receptor antagonists interventions in schizophrenia:
M AN U
Meta-analysis of randomized, placebo-controlled trials. Journal of psychiatric research 2013; 47:1143-1149 5.
Berman K, Brodaty H, Withall A, et al: Pharmacologic treatment of apathy in
dementia. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 2012; 20:104-122 6.
Danysz W,Parsons CG: The NMDA receptor antagonist memantine as a
symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical
7.
TE D
evidence. International journal of geriatric psychiatry 2003; 18:S23-32 Dalfo E, Albasanz JL, Martin M, et al: Abnormal metabotropic glutamate receptor
expression and signaling in the cerebral cortex in diffuse Lewy body disease is associated with irregular alpha-synuclein/phospholipase C (PLCbeta1) interactions. Brain pathology
EP
2004; 14:388-398 8.
Starr MS: Glutamate/dopamine D1/D2 balance in the basal ganglia and its
relevance to Parkinson's disease. Synapse 1995; 19:264-293 Kucheryanu VG,Kryzhanovskii GN: Effect of glutamate and antagonists of
AC C
9.
N-methyl-D-aspartate receptors on experimental parkinsonian syndrome in rats. Bulletin of experimental biology and medicine 2000; 130:629-632 10.
Aarsland D, Ballard C, Walker Z, et al: Memantine in patients with Parkinson's
disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet neurology 2009; 8:613-618 11.
Emre M, Tsolaki M, Bonuccelli U, et al: Memantine for patients with Parkinson's
disease
dementia
or
dementia
with
Lewy
bodies:
a
randomised,
double-blind,
placebo-controlled trial. Lancet neurology 2010; 9:969-977 12.
Leroi I, Overshott R, Byrne EJ, et al: Randomized controlled trial of memantine in
20
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
dementia associated with Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 2009; 24:1217-1221 13.
Li W, Zhao JH, Sun SG, et al: [Clinical rehabilitative effect of memantine on
RI PT
cognitive and motor disorders in patients with Parkinson's disease]. Zhonghua yi xue za zhi 2011; 91:301-303 14.
Merello M, Nouzeilles MI, Cammarota A, et al: Effect of memantine (NMDA
antagonist) on Parkinson's disease: a double-blind crossover randomized study. Clinical neuropharmacology 1999; 22:273-276 15.
Ondo WG, Shinawi L, Davidson A, et al: Memantine for non-motor features of
SC
Parkinson's disease: a double-blind placebo controlled exploratory pilot trial. Parkinsonism & related disorders 2011; 17:156-159 16.
Moreau C, Delval A, Tiffreau V, et al: Memantine for axial signs in Parkinson's
M AN U
disease: a randomised, double-blind, placebo-controlled pilot study. Journal of neurology, neurosurgery, and psychiatry 2013; 84:552-555 17.
Schneider LS, Olin JT, Doody RS, et al: Validity and reliability of the Alzheimer's
Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer disease and associated disorders 1997; 11 Suppl 2:S22-32 18.
Olin JT, Schneider LS, Doody RS, et al: Clinical evaluation of global change in
Alzheimer's disease: identifying consensus. Journal of geriatric psychiatry and neurology
19.
TE D
1996; 9:176-180
Folstein MF, Folstein SE,McHugh PR: "Mini-mental state". A practical method for
grading the cognitive state of patients for the clinician. Journal of psychiatric research 1975; 12:189-198
Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric Inventory:
EP
20.
comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308-2314 21.
Gelinas I, Gauthier L, McIntyre M, et al: Development of a functional measure for
AC C
persons with Alzheimer's disease: the disability assessment for dementia. The American journal of occupational therapy : official publication of the American Occupational Therapy Association 1999; 53:471-481 22.
Galasko D, Bennett D, Sano M, et al: An inventory to assess activities of daily
living for clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. Alzheimer disease and associated disorders 1997; 11 Suppl 2:S33-39 23.
Cohn LD,Becker BJ: How meta-analysis increases statistical power. Psychological
methods 2003; 8:243-253 24.
DerSimonian R,Laird N: Meta-analysis in clinical trials. Controlled clinical trials
1986; 7:177-188
21
ACCEPTED MANUSCRIPT Memantine for Lewy body disorders
25.
Moher D, Liberati A, Tetzlaff J, et al: Preferred reporting items for systematic
reviews and meta-analyses: the PRISMA statement. Bmj 2009; 339:b2535 26.
Ramaker C, Marinus J, Stiggelbout AM, et al: Systematic evaluation of rating
journal of the Movement Disorder Society 2002; 17:867-876 27.
Fahn S,Elton R: UPDRS program members. Unified Parkinson's Disease Rating
Scale. Macmillan Healthcare Information 1987; p153–163, p293–304 28.
RI PT
scales for impairment and disability in Parkinson's disease. Movement disorders : official
Ballard C, McKeith I, Burn D, et al: The UPDRS scale as a means of identifying
extrapyramidal signs in patients suffering from dementia with Lewy bodies. Acta
29.
SC
neurologica Scandinavica 1997; 96:366-371
Higgins JP, Thompson SG, Deeks JJ, et al: Measuring inconsistency in
meta-analyses. BMJ 2003; 327:557-560
Mantel N,Haenszel W: Statistical aspects of the analysis of data from retrospective
M AN U
30.
studies of disease. Journal of the National Cancer Institute 1959; 22:719-748 31.
Weintraub D: Neuropsychiatric symptoms in Parkinson disease and dementia with
lewy bodies: what geriatric psychiatry can learn. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 2013; 21:497-500 32.
Donaghy P, Thomas AJ,O'Brien JT: Amyloid PET Imaging in Lewy Body Disorders.
Geriatric Psychiatry 2013; 33.
TE D
The American journal of geriatric psychiatry : official journal of the American Association for
Boada M,Arranz FJ: Transdermal is better than oral: observational research of the
satisfaction of caregivers of patients with Alzheimer's disease treated with rivastigmine.
AC C
EP
Dementia and geriatric cognitive disorders 2013; 35:23-33
22
ACCEPTED MANUSCRIPT
With L-dopa, Dose Total Study
Age Patients
Diagnosis
Duration
n
(%), (mean or Male, %
Race (%)
Drug
n
Outcomes
(dose
(mean+/-SD)
median dose, mg/day)
DLB and PDD. Outpatients (100%).
PDD: Patients were included
RI PT
+/-SD mg)
MEM
Inclusions: MMSE>12 points or higher.
if they fulfilled UKPDSBB
Exclusions: other brain disease, recent major
for PD and subsequently
changes in health status, MDD, moderate or
developed dementia
severe renal impairment, heart disease,
according to the DSM-IV
pulmonary disease, hepatic impairment,
criteria at 1 year after the
results of laboratory tests deemed to be
onset of motor symptoms.
clinically relevant by the study physician that
DLB: the revised consensus
were higher than the normal values.
operationalize criteria
Aarsland MEM: 76.9±6.1 PLA:
non-industry
DLB and PDD. Outpatients (100%). Inclusions: age 50 years, MMSE=10-24,
Germany,
unstable systemic disease, exposure to toxins
TE D
PDD: Patients were included
(DSM-IV-TR), clinically significant or
DAD, MMSE. MEM=PLA: NPI,
PLA:
PLA
Yes, (67.6),
Modified UPDRS,
AQT
(388, 263-656)
color, AQT form, AQT
40
71.1
M AN U
76.2±5.8
France,
MEM>PLA: ADCS-CGIC,
79.4
(NR),
UK),
Exclusions: any primary psychiatric disorder
(450, 375-675)
Sweden
weeks
Sweden,
(Austria,
MEM:
SC
24
H-Y < 3 on.
[fixed]
(NR),
(Norway,
Emre 2010
Yes, (84.2),
Norway
2009 75
MEM: 20 35
UK (NR) color-form
MEM: 20 MEM
96
Yes, (74), (NR) [fixed]
if they fulfilled UKPDSBB for PD and subsequently developed dementia 199 or severe medical procedures in the past 5
Italy, Spain,
years, patients had taken CHO-I within 6
Turkey),
weeks before screening, or MEM within the
EP
according to the DSM
UK, Greece,
MEM=PLA: ADCS-CGIC,
MEM:
MEM:
24
74.4±5.8
53.1
MEM:
weeks
PLA:
PLA:
white (99)
72.5±7.0
57.6
PLA: white
criteria at 1 year after the
AC C
industry
previous 6 months, or had received treatment
operationalize criteria
with any investigational drug within 30 days of screening.
UPDRS-3, ZBI PLA
onset of motor symptoms.
DLB: the revised consensus
NPI, ADCS-ADL23,
(100)
99
Yes, (71), (NR)
ACCEPTED MANUSCRIPT
With L-dopa, Dose Total Study
Age Patients
Diagnosis
Duration
n
(%), Male, %
Race (%)
Drug
n
(mean or Outcomes
(dose
(mean+/-SD)
median dose, mg/day)
RI PT
+/-SD mg) PDD. Outpatients (NR).
MEM
Inclusions: H-Y =1-5, onset of cognitive symptoms at least 1 year after the onset of
of motor aspects unchanged for 4 weeks prior
16week
UKPDSBB for PD and
procedures (or have a suitable legal substitute
dementia for DSM-IV. All
to give consent). Stable dose of CHO-I > 6
retrospectively met the
months prior to study entry. No recorded
consensus criteria for possible
improvement in cognitive or behavioral
and probable PDD.
Leroi
(From 17
2009 25
weeks to
(UK), industry
Exclusions: sensitivity to NMDAR-ANTs (AMA, RAN and CIM), presence of brain
neurosurgery, or meeting criteria for probable
Inclusions: Specific inclusion criteria were 2011 40
intentionally broad and included both
(USA),
AC C
DLB.
PD. Outpatients (NR).
36.4
Caucasian
PLA:
(100)
PLA: 74.7±7.9
14
MEM
20
NR
Standard criteria
MEM: 20
Yes, (NR), (519,
[fixed]
NR) MEM=PLA: UPDRS ”on”
MEM: MEM:69.2±7.9
60.0,
8 weeks
ADL, UPDRS ”on ”Motor, NR
PLA: 68.9±8.4
PLA: PLA 60.0
Exclusions: MMSE4 weeks prior to randomization.
22weeks:
M AN U
to study entry, stable medical history and general health, and able to consent to study
NR [fixed]
SC
motor symptoms, MMSE=10-27, Treatment
MEM: 20 11
Yes, (NR), (539,
Conner Adult: , HAM-D,
NR)
FSS, ESS, PDQ-39.
20 VAS
ACCEPTED MANUSCRIPT
With L-dopa, Dose Total
Age Patients
Diagnosis
Duration
(%), Male, %
n
Race (%)
n
(mean or
(dose
(mean+/-SD)
Outcomes median dose,
2 weeks
MEM
Merello (crossover
mg/day) +/-SD mg) MEM: 30
MEM>PLA: UPDRS-3 (off
6 [fixed]
and on states), Yes (only day at
Argentina
12
PD: Outpatients (NR).
UKPDSBB
design,
60.6±3
SC
1999
UPDRS-tremor score (off
NR
endpoint), (100),
(100)
(Argentina), washout; 3 days )
M AN U
Non-industry
PDD: Outpatients (NR).
UKPDSBB for PD and
MEM:66.0±5.0
(695,±274)
6
UPDRS-bradykinesia score
MEM: 20 MEM
28
NR [fixed]
UC
27
NR
53.6
Chinese
MEM>PLA: MMSE,
PLA:
(100)
ADAS-cog, UPDRS-3
24weeks Inclusions: MMSE=10-24.
DSM
for dementia
AC C
EP
non-industry
TE D
55
state ), PLA
(off state)
MEM:
Li 2011 (China),
Drug
RI PT
Study
PLA:65.0±7.0
51.9
ACCEPTED MANUSCRIPT
With L-dopa, Dose Total Study
Age Patients
Diagnosis
Duration
n
(%), Male, %
Race (%)
Drug
n
(mean or Outcomes
(dose
(mean+/-SD)
median dose, mg/day)
RI PT
+/-SD mg)
MEM
PD: Outpatients (NR).
UPDRS-3 item 28 2.
related to insufficient doses of L-dopa or Moreau off-periods of motor fluctuation or those 2013
M AN U
Exclusions: The presence of axial disorders
MEM:66.0±NR
25
induced by STN stimulation. The appearance
Yes, (100),
[fixed]
(1000, 700-1400)
SC
Inclusions: UPDRS-3 item 29 2 and
MEM: 20 13
Gibb's criteria
90-day
(France), non-industry of STN stimulation. Inability to walk unaided
DysRS Axial, TH Flexor, France
TH Extensor, TFES Flexor,
(100) PLA
Yes, (100),
TFES Extensor
(1075, 700-1200)
MEM=PLA: Stride length,
12 velocity, Cadence
TE D
while on dopaminergic treatment, dementia
UPDRS-3 Axial, DysRS.
NR
PLA:64.0±NR
of axial signs immediately after the initiation
MEM>PLA: UPDRS-3,
(DSM-IV-TR and Mattis DRS
