Memantine Monotherapy for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

<div><p>Background</p><p>We performed an updated meta-analysis of randomized placebo-controlled trials testing memantine monotherapy for patients with Alzheimer’s disease (AD).</p><p>Methods</p><p>The meta-analysis included randomized controlled trials of memantine monotherapy for AD, omitting those in which patients were also administered a cholinesterase inhibitor. Cognitive function, activities of daily living, behavioral disturbances, global function, stage of dementia, drug discontinuation rate, and individual side effects were compared between memantine monotherapy and placebo groups. The primary outcomes were cognitive function and behavioral disturbances; the others were secondary outcomes.</p><p>Results</p><p>Nine studies including 2433 patients that met the study’s inclusion criteria were identified. Memantine monotherapy significantly improved cognitive function [standardized mean difference (SMD)=−0.27, 95% confidence interval (CI)=−0.39 to −0.14, p=0.0001], behavioral disturbances (SMD=−0.12, 95% CI=−0.22 to −0.01, p=0.03), activities of daily living (SMD=−0.09, 95% CI=−0.19 to −0.00, p=0.05), global function assessment (SMD=−0.18, 95% CI=−0.27 to −0.09, p=0.0001), and stage of dementia (SMD=−0.23, 95% CI=−0.33 to −0.12, p=0.0001) scores. Memantine was superior to placebo in terms of discontinuation because of inefficacy [risk ratio (RR)=0.36, 95% CI=0.17¬ to 0.74, p=0.006, number needed to harm (NNH)=non significant]. Moreover, memantine was associated with less agitation compared with placebo (RR=0.68, 95% CI=0.49 to 0.94, p=0.02, NNH=non significant). There were no significant differences in the rate of discontinuation because of all causes, all adverse events, and individual side effects other than agitation between the memantine monotherapy and placebo groups.</p><p>Conclusions</p><p>Memantine monotherapy improved cognition, behavior, activities of daily living, global function, and stage of dementia and was well-tolerated by AD patients. However, the effect size in terms of efficacy outcomes was small and thus there is limited evidence of clinical benefit.</p></div

Suvorexant for Primary Insomnia: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials

<div><p>Objective</p><p>We performed a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials evaluating suvorexant for primary insomnia.</p><p>Methods</p><p>Relevant studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations through June 27, 2015. We performed a systematic review and meta-analysis of suvorexant trial efficacy and safety outcomes. The primary efficacy outcomes were either subjective total sleep time (sTST) or subjective time-to-sleep onset (sTSO) at 1 month. The secondary outcomes were other efficacy outcomes, discontinuation rate, and individual adverse events. The risk ratio, number-needed-to-treat/harm, and weighted mean difference (WMD) and 95% confidence intervals (CI) based on a random effects model were calculated.</p><p>Results</p><p>The computerized literature database search initially yielded 48 results, from which 37 articles were excluded following a review of titles and abstracts and another eight review articles after full-text review. Thus, we identified 4 trials that included a total of 3,076 patients. Suvorexant was superior to placebo with regard to the two primary efficacy outcomes (sTST: WMD = −20.16, 95% CI = −25.01 to −15.30, 1889 patients, 3 trials, sTSO: WMD = −7.62, 95% CI = −11.03 to −4.21, 1889 patients, 3 trials) and was not different from placebo in trial discontinuations. Suvorexant caused a higher incidence than placebo of at least one side effects, abnormal dreams, somnolence, excessive daytime sleepiness/sedation, fatigue, dry mouth, and rebound insomnia.</p><p>Conclusions</p><p>Our analysis of published trial results suggests that suvorexant is effective in treating primary insomnia and is well-tolerated.</p></div

Efficacy outcome (diary measures) results.

<p>^aP(Z): The significance of the pooled effect size was determined with Z test.</p><p>^bP(Q): Cochrane’s Q statistic test used to assess the heterogeneity.</p><p>Abbreviations: 95% CI, 95% confidence interval; N, number of comparisons; n, number of patients; sFRESH, subjective refreshed feeling on waking (0–4 scale); sNAW, subjective number of awakenings; sQUAL, subjective quality of sleep (1–4 scale); sTSO, subjective time to sleep onset (minutes); sTST, subjective total sleep time (minutes); sWASO, subjective wake after sleep onset (minutes); WMD, weighted mean difference.</p><p>Efficacy outcome (diary measures) results.</p

Risk of bias assessment.

<p>Risk of bias assessment.</p

Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) flow diagram.

<p>Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) flow diagram.</p

Treatment discontinuation and individual adverse events.

<p>^aP(Z): The significance of the pooled effect size was determined using the Z test.</p><p>^bP(Q): Cochrane’s Q statistic test was used to assess data heterogeneity.</p><p>Abbreviations: 95% CI, 95% confidence interval; N, number of comparisons; n, number of patients; NNH, number need to harm; RR, risk ratio; ∞, infinitude.</p><p>Treatment discontinuation and individual adverse events.</p

The results regarding the outcome related to run-out phase.

<p>^aP(Z): The significance of the pooled effect size was determined with Z test.</p><p>^bP(Q): Cochrane’s Q statistic test used to assess the heterogeneity.</p><p>Abbreviations: 95% CI, 95% confidence interval; N, number of comparisons; n, number of patients; NNH, number need to harm; RR, risk ratio; TWSQ, Tyrer Withdrawal Symptom Questionnaire; sTSO, subjective time to sleep onset; sTST, subjective total sleep time.</p><p>The results regarding the outcome related to run-out phase.</p

PRISMA flow diagram.

<p>1-a. Blonanserin. 1-b. Perospirone.</p

Forest plot of behavioral disturbances (9 comparisons, n = 2358).

<p>*Negative SMD values favor memantine; positive SMD values favor placebo.†RR < 1 favors memantine; RR > 1 favors placebo.</p

Analysis of efficacy outcomes from rating scales and polysomnography.

<p>^aP(Z): The significance of the pooled effect size was determined with Z test.</p><p>^bP(Q): Cochrane’s Q statistic test used to assess the heterogeneity.</p><p>*Number need to treat = 8; 95% CI = 6–13; P(Z)<0.00001; I² = 0; P(Q) = 0.73.</p><p>Abbreviations: 95% CI, 95% confidence interval; CGI-I, Clinical Global Impression-Improvement scale (1–7 scale); CGI-S, Clinical Global Impression-Severity scale (1–7 scale); ISI, Insomnia Severity Index (0–28 scale); LPS, latency to onset of persistent sleep (minutes); PGI-I, Patient Global Impression-Improvement scale (1–7 scale); PGI-S, Patient Global Impression-Severity scale (0–5 scale); N, number of comparisons; n, number of patients; RR, risk ratio; WASO, wakefulness after persistent sleep onset (minutes); WMD, weighted mean difference.</p><p>Analysis of efficacy outcomes from rating scales and polysomnography.</p