Authors: Matsunaga, Shinji | Fujishiro, Hiroshige | Takechi, Hajime
Article Type: Research Article
Abstract: Background: The efficacy and safety of glycogen synthase kinase 3 (GSK-3) inhibitors in patients with Alzheimer’s disease (AD) is unknown. Objective: A systematic review and meta-analysis of randomized controlled trials (RCTs) to test GSK-3 inhibitors on AD patients. Methods: We included RCTs of GSK-3 inhibitors in AD patients and subjects with mild cognitive impairment (MCI), using cognitive function scores as a primary measure. Results: Five RCTs (three RCTs using lithium and two RCTs using tideglusib) with 568 patients were included. There was no significant difference in cognitive function scores between the GSK-3 inhibitors and placebo groups [standardized mean difference (SMD) = –0.25, …p = 0.11, I 2 = 55% ]. However, significant heterogeneity remained. A sensitivity analysis revealed that the lithium subgroup was more effective on cognitive function scores than placebo for AD and MCI (lithium subgroup: SMD = –0.41, p = 0.04; tideglusib subgroup: SMD = –0.02, p = 0.89). Moreover, a meta-regression analysis showed that the effect size of GSK-3 inhibitors on cognitive function scores was associated with study duration (coefficient, –0.0116). For safety outcomes, tideglusib was associated with a higher incidence of increased aspartate aminotransferase than placebo. There were no significant differences in other secondary outcomes between treatments. Conclusion: Our results suggested that GSK-3 inhibitors were ineffective in treating AD and MCI; however, several studies included in the present meta-analysis were small, and future studies using a larger sample size are needed. Show more
Keywords: Alzheimer’s disease, glycogen synthase kinase 3, lithium, meta-analysis, tideglusib
DOI: 10.3233/JAD-190256
Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1031-1039, 2019
Authors: Kishi, Taro | Matsunaga, Shinji | Iwata, Nakao
Article Type: Research Article
Abstract: We conducted a systematic review and meta-analysis on whether memantine was beneficial for the treatment of depressive symptoms in major depressive disorder (MDD) and bipolar disorder (BD). The analysis included double-blind, randomized, placebo-controlled trials of memantine in MDD and BD. The primary outcome measures for efficacy and safety were response rate and all-cause discontinuation, respectively. Risk ratio (RR) and standardized mean difference with 95% confidence intervals (95% CI) were calculated. We identified six trials including 451 patients: MDD, four trials (n = 189), three of which studied memantine augmentation for antidepressants; BD, two trials (n = 262), both on memantine augmentation for …mood stabilizers. The mean study duration was 8.33 weeks, and the mean age of patients was 39.9 years. Memantine was not superior to placebo with regard to response rate (RR = 0.92, 95% CI = 0.70–1.20, I2 = 72%), remission rate, improvement of depressive symptoms scale score, all-cause discontinuation (RR = 0.84, 95% CI = 0.60–1.18, I2 = 0%), discontinuation due to inefficacy and adverse events, or incidence of individual adverse events including decreased appetite, dizziness, nausea, and sedation. Although we conducted sensitivity analyses of the response rate to determine the reasons for the heterogeneity (diagnosis, age of patients, memantine dose, memantine augmentation, geographical region, and statistical population), we did not seek confounding factors. Memantine did not improve the treatment efficacy for depressive symptoms in MDD and BD patients. Long-term study of memantine for depression is required. Show more
Keywords: Bipolar disorder, major depressive disorder, memantine, meta-analysis, systematic review
DOI: 10.3233/JAD-161251
Citation: Journal of Alzheimer's Disease, vol. 57, no. 1, pp. 113-121, 2017
Authors: Matsunaga, Shinji | Kishi, Taro | Iwata, Nakao
Article Type: Research Article
Abstract: Background: Previous clinical studies found that yokukansan has a therapeutic effect on behavioral and psychological symptoms of dementia (BPSD) in dementia patients. Objective: To perform an updated meta-analysis of randomized controlled trials (RCTs) testing yokukansan for patients with BPSD. Methods: Primary efficacy and safety endpoints were BPSD total scores and all-cause discontinuation, respectively. Secondary outcomes were BPSD subscales, cognitive function scores [Mini-mental state examination (MMSE)], activities of daily living (ADL) scores, discontinuation due to adverse events (AEs), and incidences of AEs. Results: Five RCTs with 381 patients with BPSD were included. Compared with controls [placebo+usual care (UC)], yokukansan significantly decreased …BPSD total scores [standardized mean difference (SMD) = –0.32, 95% confidence interval (CI) = –0.53 to –0.11, p = 0.003, I 2 = 0%, N = 5 studies, n = 361]. Yokukansan was more efficacious in reducing BPSD subscale scores (delusions: SMD = –0.51, 95% CI = –0.98 to –0.04, hallucinations: SMD = –0.54, 95% CI = –0.96 to –0.12, agitation/aggression: SMD = –0.37, 95% CI = –0.60 to –0.15) than placebo+UC. However, yokukansan was not superior to placebo+UC for BPSD total as well as any subscales scores only in Alzheimer’s disease patients. Compared with UC, yokukansan treatment improved ADL scores (SMD = –0.32, 95% CI = –0.62 to –0.01). MMSE scores did not differ between the yokukansan and placebo+UC treatment groups. No significant differences were found in all-cause discontinuation, discontinuation due to AEs, and incidences of AEs between yokukansan and placebo+UC treatments. Conclusions: Our results suggest that yokukansan is beneficial for the treatment of patients with BPSD and is well-tolerated; it was not beneficial for BPSD total and any subscale scores only in Alzheimer’s disease patients. Show more
Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, dementia, meta-analysis, yokukansan
DOI: 10.3233/JAD-160418
Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 635-643, 2016
Combination Therapy with Zonisamide and Antiparkinson Drugs for Parkinson’s Disease: A Meta-Analysis
Authors: Matsunaga, Shinji | Kishi, Taro | Iwata, Nakao
Article Type: Research Article
Abstract: Background: There is uncertainty about the efficacy and tolerability of zonisamide for Parkinson’s disease (PD). Objective: We performed a meta-analysis of zonisamide treatment in PD patients who received antiparkinson drugs such as levodopa. Methods: The primary outcome measures were the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III scores, wearing-off time, and discontinuation rate due to all causes. Secondary outcome measures were UPDRS total and subscale scores; discontinuation rates due to adverse events, inefficacy, and death; and individual adverse events. Results: Four randomized placebo-controlled trials including 1,068 PD patients were analyzed. All studies were conducted in Japan. UPDRS Part III …scores were significantly lower with zonisamide than with placebo (weighted mean difference [WMD], –2.56; 95% confidence interval [CI]; –4.20 to –0.92; p = 0.002). Further, zonisamide significantly decreased the wearing-off time compared with placebo (standardized mean difference, –0.24; 95% CI, –0.39 to –0.09; p = 0.001). Discontinuation rates due to all causes were similar between the zonisamide and placebo groups (risk ratio, 1.29; 95% CI, 0.90 to 1.84; p = 0.16). While zonisamide also decreased both UPDRS Part II (off-time) and UPDRS total scores compared to placebo (UPDRS Part II [off-time] scores: WMD, –0.79; UPDRS total scores: WMD, –2.51), there were no significant differences in other secondary outcomes between the two groups. Conclusions: Our results suggested that zonisamide combination therapy was beneficial in treating motor symptoms in PD patients receiving antiparkinson drugs and was well tolerated in Japanese patients. Future studies in populations other than the Japanese are needed. Show more
Keywords: Meta-analysis, Parkinson’s disease, randomized placebo-controlled trial, systematic review, zonisamide
DOI: 10.3233/JAD-161068
Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1229-1239, 2017
Authors: Matsunaga, Shinji | Fujishiro, Hiroshige | Takechi, Hajime
Article Type: Research Article
Abstract: Background: The clinical benefit of cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) remains inconclusive. Objective: We performed a systematic review and meta-analysis of the efficacy/safety of ChEIs on subjects with MCI. Methods: We included randomized controlled trials (RCTs) of ChEIs in subjects with MCI, using cognitive function scores as a primary outcome measure. Results: Fourteen RCTs (six using donepezil, four using galantamine, and four using rivastigmine) with 5,278 subjects were included. We found no significant difference in cognitive function scores between the ChEIs and placebo groups [standardized mean difference (SMD) = –0.06, p = 0.38, I 2 = 76% ]. However, in the …secondary outcomes, ChEIs were associated with a lower incidence of progression to dementia compared with placebo (risk ratio = 0.76, the number needed to treat = 20). For safety outcomes, ChEIs were associated with a lower prevalence of fall than placebo. On the other hand, compared with placebo, ChEIs were associated with a higher incidence of discontinuation due to all causes, discontinuation due to adverse events, at least one adverse event, abnormal dreams, diarrhea, dizziness, headache, insomnia, loose stools, muscle cramps, nausea, vomiting, and weight loss. Conclusions: Although ChEIs have a slight efficacy in the treatment of MCI, there are many safety issues. Therefore, ChEIs are difficult to recommend for MCI. However, the efficacy and safety of ChEIs on MCI with a biomarker-based diagnosis is unclear. Further RCTs are needed to confirm the efficacy and safety of ChEIs when used for individual neuropathological classifications of MCI. Show more
Keywords: Cholinesterase inhibitors, donepezil, galantamine, meta-analysis, mild cognitive impairment, rivastigmine
DOI: 10.3233/JAD-190546
Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 513-523, 2019
Authors: Okuya, Makoto | Matsunaga, Shinji | Ikuta, Toshikazu | Kishi, Taro | Iwata, Nakao
Article Type: Short Communication
Abstract: A systematic review and meta-analysis of the efficacy/safety of intravenous immunoglobulin (IVIG) administration in mild-to-moderate Alzheimer’s disease (AD) patients was performed. Six randomized double-blind, placebo-controlled trials (n = 801) were included in this study. No significant difference in cognitive function was observed between the groups. Moreover, IVIG was inferior to placebo in behavioral disturbances (mean difference = 2.19). Further, IVIG administration was associated with a higher incidence of rash than placebo. Our results do not support IVIG administration for mild-to-moderate AD, suggesting that IVIG is not effective to treat mild-to-moderate AD and that it deteriorates behavioral and psychological symptoms of dementia in mild-to-moderate …AD. Show more
Keywords: Efficacy, intravenous immunoglobulin, meta-analysis, mild-to-moderate Alzheimer’s disease, safety, systematic review
DOI: 10.3233/JAD-180888
Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1379-1387, 2018
Authors: Kubo, Momoko | Kishi, Taro | Matsunaga, Shinji | Iwata, Nakao
Article Type: Research Article
Abstract: Background: No comprehensive meta-analysis has been performed concerning the efficacy and tolerability of histamine H3 receptor antagonists (H3R-ANTs) in Alzheimer’s disease patients. Objective: We performed a systematic review and meta-analysis of double-blind randomized placebo-controlled trials (RCTs) of H3R-ANTs for Alzheimer’s disease. Methods: Relevant studies were identified through searches of PubMed ® , databases of the Cochrane Library©, and PsycINFO citations up to June 19, 2015. The primary outcome was a change in the Mini-Mental State Examination (MMSE) scores. Secondary outcomes were Neuropsychiatric Inventory (NPI) scores, discontinuation rate, and individual adverse events/side effects. Risk ratios, numbers-needed-to-treat/harm, and standardized mean differences were calculated …based on a random effects model. Results: The computerized search initially yielded 33 studies after excluding duplicates. We excluded 29 of these articles following a review of titles and abstracts and one RCT including healthy subjects after full-text review. We identified three RCTs (two on GSK239512 and one on ABT-288) including 402 patients. Pooled H3R-ANTs were not superior to placebo for improvement in MMSE and NPI scores. Discontinuation rate and individual adverse events/side effects did not differ among the pooled groups. Conclusions: Our results suggest that H3R-ANTs are not effective in treating cognitive dysfunction in Alzheimer’s disease. However, further studies with larger samples are required for definitive conclusions regarding responsive subpopulations. Show more
Keywords: Alzheimer’s disease, histamine H3 receptor antagonist, meta-analysis, systematic review
DOI: 10.3233/JAD-150393
Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 667-671, 2015
Authors: Yasue, Ichiro | Matsunaga, Shinji | Kishi, Taro | Fujita, Kiyoshi | Iwata, Nakao
Article Type: Research Article
Abstract: Background: There is uncertainty about the efficacy and tolerability of serotonin 2A (5-HT2A ) receptor negative modulators for Parkinson’s disease psychosis (PDP). Objective: This is the first meta-analysis of randomized placebo-controlled trials (RCTs) testing negative modulators of the 5-HT2A receptor as a treatment for PDP. Methods: The primary outcome was the Scale for Assessment of Positive Symptoms (SAPS)-hallucinations (H) and -delusions (D) scores (SAPS-H+D). Other outcome measures were SAPS-H, SAPS-D, the Unified Parkinson’s Disease Rating Scale Part II and III (UPDRS-II+III), discontinuation rates, and individual adverse events. Results: Four RCTs were identified that met inclusion criteria, all assessing the 5-HT2A …inverse agonist pimavanserin (including 417 drug-treated and 263 placebo-treated PDP patients). Pimavanserin significantly decreased SAPS-H+D scores compared to placebo [weighted mean differences (WMD) = –2.26, 95% confidence interval (95% CI) = –3.86 to –0.67, p = 0.005, I 2 = 30% , N = 4 studies, n = 502 patients]. Moreover, pimavanserin was superior to placebo for reducing SAPS-H (WMD = –2.15, 95% CI = –3.45 to –0.86, p = 0.001, I 2 = 0% , N = 2, n = 237) and SAPS-D scores (WMD = –1.32, 95% CI = –2.32 to –0.32, p = 0.010, I 2 = 0% , N = 2, n = 237). Pimavanserin was associated with less orthostatic hypotension than placebo (risk ratio = 0.33, 95% CI = 0.15–0.75, p = 0.008, I 2 = 0% , number needed to harm = 17, p = 0.01, N = 3, n = 476). There were no significant differences in rates of all-cause discontinuation, adverse events, and death, UPDRS-II+III scores, and incidences of individual adverse events (other than orthostatic hypotension) between pimavanserin and placebo groups. Conclusions: Pooled RCT results suggest that pimavanserin is beneficial for the treatment of PDP and is well tolerated. We did not identify other negative modulators of the 5-HT2A receptor for the treatment of PDP. Show more
Keywords: 5-HT2A, meta-analysis, Parkinson’s disease, pimavanserin, psychosis
DOI: 10.3233/JAD-150818
Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 733-740, 2016
Authors: Kishi, Taro | Matsunaga, Shinji | Oya, Kazuto | Nomura, Ikuo | Ikuta, Toshikazu | Iwata, Nakao
Article Type: Research Article
Abstract: Background: The clinical benefit of memantine for Alzheimer’s disease (AD) remains inconclusive. Objective: We performed an updated systematic review and meta-analysis of the efficacy/safety of memantine in AD. Methods: We included randomized trials of memantine for AD patients. Cognitive function scores (CF), behavioral disturbances scores (BD), and all-cause discontinuation were used as primary measures. Effect size based on a random-effects model was evaluated in the meta-analyses. Results: Thirty studies (n = 7,567; memantine versus placebo: N = 11, n = 3,298; memantine + cholinesterase inhibitors (M+ChEIs) versus ChEIs: N = 17, n = 4,175) were identified. Memantine showed a significant improvement in CF [standardized mean difference (SMD) = –0.24, …95% confidence intervals (95% CIs) = –0.34, –0.15, p < 0.00001, I2 = 35% ] and BD (SMD = –0.16, 95% CIs = –0.29, –0.04, p = 0.01, I2 = 52%) compared with placebo. In the sensitivity analysis including only patients with moderate–severe AD, memantine was superior to the placebo in reducing BD without considerable heterogeneity (SMD = –0.20, 95% CIs = –0.34, –0.07, p = 0.003, I2 = 36%). Compared with ChEIs, M+ChEIs showed a greater reduction in BD (SMD = –0.20, 95% CIs = –0.36, –0.03, p = 0.02, I2 = 77%) and a trend of CF improvement (SMD = –0.11, 95% CIs = –0.22, 0.01, p = 0.06, I2 = 56%). However, in the sensitivity analysis of double-blind, placebo-controlled studies only, M+ChEIs showed a significant reduction in BD compared with ChEIs without considerable heterogeneity (SMD = –0.11, 95% CIs = –0.21, –0.01, p = 0.04, I2 = 40%). When performing the sensitivity analysis of donepezil studies only, M+ChEIs was superior to ChEIs in improving CF without considerable heterogeneity (SMD = –0.18, 95% CIs = –0.31, –0.05, p = 0.006, I2 = 49%). No differences were detected in all-cause discontinuation between the groups. Conclusions: The meta-analyses suggest the credible efficacy and safety of memantine in treating AD when used alone or in combination with ChEIs. Show more
Keywords: Alzheimer’s disease, behavioral disturbances, cognitive function, memantine, meta-analysis, systematic review
DOI: 10.3233/JAD-170424
Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 401-425, 2017
Authors: Matsunaga, Shinji | Kishi, Taro | Annas, Peter | Basun, Hans | Hampel, Harald | Iwata, Nakao
Article Type: Research Article
Abstract: Background: This is the first meta-analysis of randomized placebo-controlled trials testing lithium as a treatment for patients with Alzheimer’s disease (AD) and individuals with mild cognitive impairment (MCI). Methods: The primary outcome measure was efficacy on cognitive performance as measured through the Alzheimer’s Disease Assessment Scale cognitive subscale or the Mini-Mental State Examination. Other outcome measures were drug discontinuation rate, individual side effects, and biological markers (phosphorylated tau 181, total tau, and amyloid-β42 ) in cerebrospinal fluid (CSF). Results: Three clinical trials including 232 participants that met the study’s inclusion criteria were identified. Lithium significantly decreased cognitive decline as compared …to placebo (standardized mean difference = –0.41, 95% confidence interval = –0.81 to –0.02, p = 0.04, I 2 = 47% , 3 studies, n = 199). There were no significant differences in the rate of attrition, discontinuation due to all causes or adverse events, or CSF biomarkers between treatment groups. Conclusions: The results indicate that lithium treatment may have beneficial effects on cognitive performance in subjects with MCI and AD dementia. Show more
Keywords: Alzheimer’s disease, lithium, meta-analysis, mild cognitive impairment, systematic review
DOI: 10.3233/JAD-150437
Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 403-410, 2015