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Application of Real-World Data and the REWARD Framework to Detect Unknown Benefits of Memantine and Identify Potential Disease Targets for New NMDA Receptor Antagonists.
Kern, DM, Cepeda, MS, Flores, CM, Wittenberg, GM
CNS drugs. 2021;(2):243-251
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Abstract
BACKGROUND Observational data may inform novel drug development programs by identifying previously unappreciated, clinical benefits of existing drugs. Several preclinical and clinical studies have suggested emergent therapeutic utility of drugs acting on the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, including the antidementia drug memantine. METHODS Using a self-controlled cohort study design, the association of exposure to the NMDA receptor antagonist memantine with the incidence of all observed disease outcomes in four US administrative claims databases, spanning from January 2000 through January 2019, was assessed. The databases used in this study were the IBM MarketScan® Commercial Database (CCAE), the IBM MarketScan® Multi-State Medicaid Database (MDCD), the IBM MarketScan® Medicare Supplemental Database (MDCR), and the Optum© De-Identified Clinformatics® Data Mart Database. Outcomes were defined according to the unique Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) classification system codes and required a diagnosis on two or more distinct dates. Of 20,953 outcomes assessed, only those for which memantine was associated with a ≥ 50% reduction in risk in two or more databases were included. A meta-analysis with random effects was used to pool data across the databases. RESULTS Overall, 312,336 patients were exposed to memantine during the study. After removing conditions related to dementia and memory loss, 60 outcomes met the threshold criteria. Results fell into five disease categories: mental disorders, substance use disorders, pain, gastrointestinal and colon disorders, and demyelinating disease. The bulk of findings fell into the first two groups, with 28 outcomes related to mental disorders and 24 related to substance use disorders. CONCLUSION The present results confirm that NMDA receptor antagonism may have broader therapeutic utility than previously recognized. Further observational and clinical research may be warranted to explore the therapeutic benefit of NMDA antagonists for the outcomes found in this study.
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Efficacy and safety of gabapentin and pregabalin in patients with vasomotor symptoms: a systematic review and meta-analysis.
Shan, D, Zou, L, Liu, X, Shen, Y, Cai, Y, Zhang, J
American journal of obstetrics and gynecology. 2020;(6):564-579.e12
Abstract
OBJECTIVE Vasomotor symptoms are common among postmenopausal women and patients receiving hormone deprivation therapies, and emerging studies are exploring gabapentin's and pregabalin's effects as nonhormonal treatment options. We aimed to assess the efficacy and safety of these 2 drugs. DATA SOURCES Based on a preregistered protocol (Prospective Register of Systematic Reviews -CRD42019133650), we searched 10 databases (PubMed, Embase, Web of Science, PsycINFO, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Chinese Biological Medical Literature, Chinese National Knowledge Infrastructure, Chinese Journals Full-text Database [VIP], and Wanfang) as well as the World Health Organization international clinical trials registry platform and reference lists of related literatures. STUDY ELIGIBILITY CRITERIA Randomized controlled trials and randomized crossover studies exploring gabapentin and pregabalin among women patients with vasomotor symptoms were included. STUDY APPRAISAL AND SYNTHESIS METHODS The Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement was followed. Two reviewers independently selected studies, assessed bias, and extracted data. Mean difference and standardized mean difference with 95% confidence intervals were assessed by random-effects models. Heterogeneities were assessed by I2 statistics, and the quality of evidence was evaluated by the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS Nineteen randomized controlled trials and 2 randomized crossover trials reporting results from 3519 participants were included. Gabapentin could reduce hot flash frequency (mean difference, -1.62, 95% confidence interval, -1.98 to -1.26 after 4 weeks; mean difference, -2.77, 95% confidence interval, -4.29 to -1.24 after 12 weeks) and composite score (standardized mean difference, -0.47, 95% confidence interval, -0.71 to -0.23 after 4 weeks; standardized mean difference, -0.77, 95% confidence interval, -1.15 to -0.40 after 12 weeks) compared with placebo. Both menopausal participants and patients with breast cancer benefited from treatment. Higher risks of dizziness and somnolence were found in the gabapentin group than in the control group (risk ratio, 4.45, 95% confidence interval, 2.50-7.94; risk ratio, 3.29, 95% confidence interval, 1.97-5.48, respectively). Estrogen was more effective in reducing hot flash frequency than gabapentin. No statistically significant difference in reduction of hot flash severity score was found between gabapentin and antidepressants. The trials comparing gabapentin or pregabalin with the other interventions were too limited to make a conclusion. CONCLUSION Favorable effects of gabapentin in relieving vasomotor symptoms were observed, compared with controls, but were less effective than those of estrogen. Evidence supporting the therapeutic effect of pregabalin is still lacking.
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Adjunctive memantine for major mental disorders: A systematic review and meta-analysis of randomized double-blind controlled trials.
Zheng, W, Zhu, XM, Zhang, QE, Cai, DB, Yang, XH, Zhou, YL, Ungvari, GS, Ng, CH, He, SH, Peng, XJ, et al
Schizophrenia research. 2019;:12-21
Abstract
OBJECTIVE As a non-competitive N-methyl-d-aspartate receptor antagonist, memantine has been used to treat major mental disorders including schizophrenia, bipolar disorder, and major depressive disorder (MDD). This meta-analysis systematically investigated the effectiveness and tolerability of adjunctive memantine for patients with schizophrenia, bipolar disorder, and MDD. METHODS Only randomized controlled trials (RCTs) were identified and included in the study. Data of the three disorders were separately synthesized using the RevMan 5.3 software. RESULTS Fifteen RCTs (n = 988) examining memantine (5-20 mg/day) as an adjunct treatment for schizophrenia (9 trials with 512 patients), bipolar disorder (3 trials with 319 patients), and MDD (3 trials with 157 patients) were analyzed. Memantine outperformed the comparator regarding total psychopathology with a standardized mean difference (SMD) of -0.56 [95% confidence interval (CI): -1.01, -0.11; I2 = 76%, P = 0.01] and negative symptoms with an SMD of -0.71 (95% CI: -1.09, -0.33; I2 = 74%, P = 0.0003) in schizophrenia, but no significant effects were found with regard to positive symptoms and general psychopathology in schizophrenia, or depressive and manic symptoms in bipolar disorder or depressive symptoms in MDD. Memantine outperformed the comparator in improving cognitive performance in schizophrenia with an SMD of 1.07 (95% CI: 0.53, 1.61; P < 0.0001, I2 = 29%). No group differences were found in the rates of adverse drug reactions and discontinuation due to any reason in the three major mental disorders. CONCLUSIONS Memantine as an adjunct treatment appears to have significant efficacy in improving negative symptoms in schizophrenia. The efficacy and safety of adjunctive memantine for bipolar disorder or MDD needs to be further examined. REVIEW REGISTRATION PROSPERO 42018099045.
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NMDA receptor antagonists and pain relief: A meta-analysis of experimental trials.
Thompson, T, Whiter, F, Gallop, K, Veronese, N, Solmi, M, Newton, P, Stubbs, B
Neurology. 2019;(14):e1652-e1662
Abstract
OBJECTIVE We conducted a meta-analysis of controlled trials that used experimental models of acute pain and hyperalgesia to examine the analgesic effects of NMDA receptor (NMDAR) antagonists. METHODS Six major databases were systematically searched (to March 2018) for studies using human evoked pain models to compare NMDAR antagonists with no-intervention controls. Pain outcome data were analyzed with random-effects meta-analysis. RESULTS Searches identified 70 eligible trials (n = 1,069). Meta-analysis found that low-dose ketamine (<1 mg/kg) produced a decrease in hyperalgesic area (standardized mean difference 0.54, 95% confidence interval [CI] 0.34, 0.74, p < 0.001) and a 1.2-point decrease (95% CI 0.88, 1.44, p < 0.001) in pain ratings from 4.6 to 3.4 on a 0-10 scale (a 26% reduction). Similar analgesia was observed for acute and hyperalgesic models and was constant across the dosing range (0.03-1.00 mg/kg). Moderate to high variability in effect size was observed and mild side effects (e.g., sedation, sensory disturbance) were common. No effects of dextromethorphan were found. CONCLUSIONS Findings provide robust evidence for analgesic and antihyperalgesic effects of ketamine, supporting its utility for acute and chronic pain management. However, pain relief was modest, suggesting ketamine may potentially be most useful when opioids are contraindicated, rapid analgesia is required, or for pain resistant to conventional medication.
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Effectiveness of Gabapentin in Reducing Cravings and Withdrawal in Alcohol Use Disorder: A Meta-Analytic Review.
Ahmed, S, Stanciu, CN, Kotapati, PV, Ahmed, R, Bhivandkar, S, Khan, AM, Afridi, A, Qureshi, M, Esang, M
The primary care companion for CNS disorders. 2019;(4)
Abstract
OBJECTIVE The current meta-analysis synthesizes previous findings on the effect of gabapentin on alcohol withdrawal and craving. DATA SOURCES Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, a search for relevant English-language literature published between January 1999 and February 2019 was conducted using PubMed and Google Scholar with the keywords alcohol use disorder, alcohol dependence, alcohol withdrawals, alcohol craving, "gabapentin in alcohol use, consumption," and "gabapentin in alcohol withdrawals." STUDY SELECTION AND DATA EXTRACTION Studies were included wherein gabapentin was used as an adjunctive or primary treatment of alcohol dependence/withdrawal. Studies included participants diagnosed with alcohol use disorder using DSM-IV, DSM-IV-TR, DSM-5, or the International Classification of Diseases, Tenth Revision (ICD-10). The search, as well as data extraction, was carried out by 3 blinded authors to preserve precision, using a template in Microsoft Excel to extract the needed data. Following the review of the initial 65 returns, 2 authors independently judged each trial by applying the inclusionary and exclusionary criteria, and any remaining disagreements were resolved by involving a third independent author. A total of 10 studies met the inclusion criteria and were selected for analysis. Subjects in these 10 studies were pooled using standard techniques of meta-analysis. DATA SYNTHESIS Three sets of meta-analyses examined outcomes from (1) single-group pretest-posttest changes, (2) posttest differences between independent groups, and (3) differences in pretest-posttest change scores between independent groups. Statistically significant effect sizes were found for craving (P < .01) and withdrawal (P < .01, P < .001) in the meta-analysis of single-group pretest-posttest outcome changes and were associated with a high level of heterogeneity. In contrast, the meta-analyses of posttest differences between independent groups-that of differences in pretest-posttest change scores between independent groups-did not yield significant effect sizes. CONCLUSIONS Our analysis of pooled data provides evidence that the use of gabapentin to manage alcohol withdrawal symptomatology and related cravings is at least moderately effective. However, given the limited number of available well-designed studies, these findings require further support through more rigorously designed studies.
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Memantine in Japanese patients with moderate to severe Alzheimer's disease: meta-analysis of multiple-index responder analyses.
Okuizumi, K, Kamata, T, Matsui, D, Saito, K, Matsumoto, T, Fukuchi, Y
Expert opinion on pharmacotherapy. 2018;(5):425-430
Abstract
BACKGROUND Responder analyses assessing clinical worsening have attempted to clarify clinically meaningful drug efficacy enhancements in patients with Alzheimer's disease (AD). RESEARCH DESIGN AND METHODS This was a meta-analysis of two multicenter, randomized, double-blind, parallel-group, 24-week studies of 633 Japanese patients with moderate to severe AD receiving memantine 20 mg/day (n = 318) or placebo (n = 315). The clinical trial registration number is UMIN000026013. RESULTS Overall odds ratios (OR) for a reduced likelihood of clinical worsening (memantine versus placebo) were statistically significant on the following individual and combined rating scales: Severe Impairment Battery-Japanese version (SIB-J, OR 0.52; 95% CI: 0.37, 0.73; p = 0.0001); Behavioral Pathology in AD Rating Scale (BEHAVE-AD, OR 0.53; 95% CI: 0.37, 0.75; p = 0.0003); and SIB-J + Clinician's Interview-Based Impression of Change-plus-Japanese version (SIB-J + CIBIC-plus-J; OR 0.53; 95% CI: 0.37, 0.77; p = 0.0009). A significantly reduced risk of triple worsening was evident in the memantine versus placebo group on the combined SIB-J + CIBIC-plus-J + BEHAVE-AD rating scales (OR 0.38; 95% CI: 0.22, 0.65; p = 0.0003). CONCLUSIONS Memantine is a viable treatment option for patients with AD presenting not only with cognitive impairment, but also with a broader range of symptoms, including the behavioral and psychological symptoms of dementia.
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Significant treatment effect of add-on ketamine anesthesia in electroconvulsive therapy in depressive patients: A meta-analysis.
Li, DJ, Wang, FC, Chu, CS, Chen, TY, Tang, CH, Yang, WC, Chow, PC, Wu, CK, Tseng, PT, Lin, PY
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2017;(1):29-41
Abstract
Add-on ketamine anesthesia in electroconvulsive therapy (ECT) has been studied in depressive patients in several clinical trials with inconclusive findings. Two most recent meta-analyses reported insignificant findings with regards to the treatment effect of add-on ketamine anesthesia in ECT in depressive patients. The aim of this study is to update the current evidence and investigate the role of add-on ketamine anesthesia in ECT in depressive patients via a systematic review and meta-analysis. We performed a thorough literature search of the PubMed and ScienceDirect databases, and extracted all relevant clinical variables to compare the antidepressive outcomes between add-on ketamine anesthesia and other anesthetics in ECT. Total 16 articles with 346 patients receiving add-on ketamine anesthesia in ECT and 329 controls were recruited. We found that the antidepressive treatment effect of add-on ketamine anesthesia in ECT in depressive patients was significantly higher than that of other anesthetics (p<0.001). This significance persisted in both short-term (1-2 weeks) and moderate-term (3-4 weeks) treatment courses (all p<0.05). However, the side effect profiles and recovery time profiles were significantly worse in add-on ketamine anesthesia group than in control group. Our meta-analysis highlights the significantly higher antidepressive treatment effect of add-on ketamine in depressive patients receiving ECT compared to other anesthetics. However, clinicians need to take undesirable side effects into consideration when using add-on ketamine anesthesia in ECT in depressive patients.
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Memantine for Alzheimer's Disease: An Updated Systematic Review and Meta-analysis.
Kishi, T, Matsunaga, S, Oya, K, Nomura, I, Ikuta, T, Iwata, N
Journal of Alzheimer's disease : JAD. 2017;(2):401-425
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.
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Pharmacological Management of Lewy Body Dementia: A Systematic Review and Meta-Analysis.
Stinton, C, McKeith, I, Taylor, JP, Lafortune, L, Mioshi, E, Mak, E, Cambridge, V, Mason, J, Thomas, A, O'Brien, JT
The American journal of psychiatry. 2015;(8):731-42
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Abstract
OBJECTIVE The authors examined research on effects, costs, and patient and caregiver views of pharmacological management strategies for Lewy body dementia. METHOD Studies were identified through bibliographic databases, trials registers, gray literature, reference lists, and experts. The authors used the search terms "Lewy or parkinson" and "dementia" through March 2015 and used the following inclusion criteria: participants with diagnoses of Lewy body dementia, dementia with Lewy bodies, or Parkinson's disease dementia (or participants' caregivers); investigation of pharmacological management strategies; outcome measures and test scores reported. Data extraction and quality assessment were conducted by at least two authors. Meta-analyses were conducted, and when studies could not be combined, summaries were provided. RESULTS Forty-four studies examining 22 strategies were included in the review. Meta-analysis indicated beneficial effects of donepezil and rivastigmine for cognitive and psychiatric symptoms. Rivastigmine, but not donepezil, was associated with greater risk of adverse events. Meta-analysis of memantine suggested that it is well tolerated but with few benefits. Descriptive summaries provide some evidence of benefits for galantamine, modafinil, levodopa, rotigotine, clozapine, duloxetine, clonazepam, ramelteon, gabapentin, zonisamide, and yokukansan. Piracetam, amantadine, selegiline, olanzapine, quetiapine, risperidone, and citalopram do not appear to be effective. CONCLUSIONS High-level evidence related to pharmacological strategies for managing Lewy body dementia is rare. Strategies for important areas of need in Lewy body dementia, such as autonomic symptoms and caregiver burden, have not been investigated, nor have the views of patients and caregivers about pharmacological strategies.
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EFNS-ENS/EAN Guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer's disease.
Schmidt, R, Hofer, E, Bouwman, FH, Buerger, K, Cordonnier, C, Fladby, T, Galimberti, D, Georges, J, Heneka, MT, Hort, J, et al
European journal of neurology. 2015;(6):889-98
Abstract
BACKGROUND AND PURPOSE Previous studies have indicated clinical benefits of a combination of cholinesterase inhibitors (ChEI) and memantine over ChEI monotherapy in Alzheimer's disease (AD). Our objective was the development of guidelines on the question of whether combined ChEI/memantine treatment rather than ChEI alone should be used in patients with moderate to severe AD to improve global clinical impression (GCI), cognition, behaviour and activities of daily living (ADL). METHODS A systematic review and meta-analysis of randomized controlled trials based on a literature search in ALOIS, the register of the Cochrane Dementia and Cognitive Improvement Group, was carried out with subsequent guideline development according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS Pooled data from four trials including 1549 AD patients in the moderate to severe disease stage demonstrated significant beneficial effects of combination therapy compared to ChEI monotherapy for GCI [standardized mean difference (SMD) -0.20; 95% confidence interval (CI) -0.31; -0.09], cognitive functioning (SMD -0.27, 95% CI -0.37; -0.17) and behaviour (SMD -0.19; 95% CI -0.31; -0.07). The quality of evidence was high for behaviour, moderate for cognitive function and GCI and low for ADL. Agreement of panellists was reached after the second round of the consensus finding procedure. The desirable effects of combined ChEI and memantine treatment were considered to outweigh undesirable effects. The evidence was weak for cognition, GCI and ADL so that the general recommendation for using combination therapy was weak. CONCLUSIONS We suggest the use of a combination of ChEI plus memantine rather than ChEI alone in patients with moderate to severe AD. The strength of this recommendation is weak.