Case report: a unique presentation of memantine overdose causing echolalia and hypertension.

BACKGROUND: Since 2003 when memantine was first approved for use in the management of moderate-severe Alzheimer's dementia, its use has become more widespread and is being explored in other diseases like neuropathic pain, epilepsy, and mood disorders. Our case uniquely highlights two important adverse effects in a patient who overdosed on memantine. One is hypertension, which is easy to overlook as a medication side effect. The other is echolalia which is the repetition of words and phrases spoken by another person. It is commonly seen in children with autism spectrum disorder and has been reported in older adults with head injuries, delirium, and neurocognitive disorders. The aim of this patient story is to highlight the importance of medication reconciliation with caregivers and knowledge of adverse drug reactions in patient management. This case report has been presented previously in the form of an abstract at the American Geriatrics Society Presidential poster session in May 2023. CASE PRESENTATION: Our patient is an 86-year-old man with mild dementia and hypertension, who was brought to the emergency department (ED) due to abrupt onset of altered mental status and auditory hallucinations. Investigations including blood work, CT head and an electroencephalogram (EEG) did not reveal an etiology for this change in his condition. Due to elevated blood pressure on presentation, a nicardipine drip was started, and he was given IV midazolam to assist with obtaining imaging. While reviewing medications with his daughter, it was noted that sixty memantine pills were missing from the bottle. Poison control was contacted and they confirmed association of these features with memantine. With supportive care, his symptoms resolved in less than 100 h, consistent with the half-life of memantine. Notably, our patient was started on Memantine one month prior to this presentation. CONCLUSIONS: Hypertensive urgency and echolalia were the most striking symptoms of our patient's presentation. Though hypertension is a known sign of memantine overdose, it can easily be contributed to medication non-compliance in patients with dementia, being treated for hypertension. According to our literature review, this the first case of memantine overdose presenting with echolalia, a sign that is not commonly associated with adverse reactions to medications. This highlights the importance of an early medication review, especially with caregivers of people with dementia.

Adverse Drug Event Profile Associated with Anti-dementia Drugs: Analysis of a Spontaneous Reporting Database.

Adverse drug events (ADEs) rates associated with anti-dementia acetylcholinesterase inhibitors are estimated to be 5%-20% and show a wide range of symptoms. No report has examined whether there is a difference in the anti-dementia drugs' ADEs profile. This study aimed to establish whether anti-dementia drugs' ADEs profile differed. Data was based on the Japanese Adverse Drug Event Report (JADER) database. The reporting odds ratios (RORs) was used to analyze data for ADEs from April 2004-October 2021. The target drugs were donepezil, rivastigmine, galantamine, and memantine. The top ten most frequently occurring adverse events were selected. The association between the RORs and antidementia drug ADEs was evaluated, and compared the distribution rate of expression age related to ADEs and each ADEs' timing of onset due to anti-dementia drugs. The primary outcome was RORs. Secondary outcome were expression age and time-to-onset of ADE associated with anti-dementia drugs. A total of 705,294 reports were analyzed. The adverse events incidence differed. Bradycardia, loss of consciousness, falls, and syncope incidence were significantly diverse. The Kaplan-Meier curve results for the cumulative ADEs incidence showed that donepezil had the slowest onset, while galantamine, rivastigmine, and memantine had approximately the same timing of onset.

Effects of thymoquinone and memantine alone and in combination on memory and hippocampal morphology in rats with streptozotocin-induced Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease. Thymoquinone (TQ) has broad biological functions, including antiinflammatory, antioxidant, neuroprotective properties. Memantine (MEM) is indicated for the symptomatic treatment of moderate to severe AD. We aimed to evaluate the effect of TQ alone or in combination with MEM on memory and hippocampal morphology in an STZ-induced rat AD model. METHODS: Thirty male rats were included in this study. The AD model was created by giving ICV STZ. The rats were divided into 5 groups (n = 6 each). Group 1 (control group): The rats received only ICV-STZ 3 mg/kg for 2 weeks. Group 2 (sham group): In addition to ICV STZ, 9% NaCl, 1 mL/day i.p. for 2 weeks of injection, was applied. Group 3 (TQ group): In addition to ICV STZ, rats received TQ 10 mg/kg i.p. for 2 weeks. Group 4 (MEM group): In addition to ICV STZ, rats were given MEM at a dose of 5 mg/kg for two weeks. Group 5 (TQ+MEM group): In addition to ICV STZ, this group was given TQ (10 mg/kg/day, i.p.) and MEM (5 mg/kg/day, i.p.) for 2 weeks. On the 15th day, passive avoidance learning (PAL) was applied to all groups. Then, rats were sacrificed, neurons in the hippocampal CA1, CA2, CA3 regions were evaluated. RESULTS: Groups 3, 4, 5 had longer latency periods than groups 1 and 2. The neuron density in the CA1, CA2, CA3 regions had decreased in groups 1 and 2 compared to groups 3, 4, 5. There were significantly more neurons in groups 3, 4, 5 than in groups 1 and 2. DISCUSSION: We found that TQ alone and in combination with MEM showed ameliorative effects on memory and hippocampal morphology. TQ may offer a promising treatment strategy for AD.

Association between NMDAR antagonists, drug abuse and dependence: A disproportionality analysis from the WHO pharmacovigilance database.

Ketamine and dextromethorphan are widely abused psychoactive substances. Inhibition of N-methyl-d-aspartate receptors (NMDARs) results in neurobehavioural effects including hallucinations, "out of body" sensations and dissociative effects. However, little is known about a possible extended addictive class effect linked to pharmacologically-related amino-adamantane derivatives (e.g., amantadine and memantine). Using a quasi-Bayesian analytic method, we investigated the potential association between the use of approved NMDAR antagonists (i.e., dextromethorphan, ketamine, amantadine and memantine) and the reporting of drug abuse and dependence in the WHO pharmacovigilance database (VigiBase®), which includes >21 million individual case safety reports collected from >130 countries. This disproportionality analysis identified a significant association for all investigated drugs: dextromethorphan (IC = 3.03 [2.97-3.09]), ketamine (IC = 1.70 [1.57-1.83]), amantadine (IC = 0.21 [0.06-0.35]) and memantine (IC = 0.27 [0.13-0.40]), suggesting a class effect for drug abuse and dependence. This first signal requires further investigations, but health professionals need to be alert to the potential of abuse of NMDAR antagonists, especially in the current "opioid epidemic" context, due to their growing interest as non-opioid antinociceptive drugs.

Alzheimer's Disease: Efficacy of Mono- and Combination Therapy. A Systematic Review.

IMPORTANCE: Alzheimer's disease (AD) is a complex neurodegenerative disorder and the most prevalent cause of dementia. In spite of the urgent need for more effective AD drug therapy strategies, evidence of the efficacy of combination therapy with existing drugs remains unclear. OBJECTIVE: To assess the efficacy of combined drug therapy on cognition and progress in patients with AD in comparison to single agent drug therapy. METHODS: The electronic databases MEDLINE and EMBASE were systematically searched to identify relevant publications. Only randomized controlled clinical trials were included, but no limits were applied to language or time published. Data were extracted from May 27th until December 29th, 2020. RESULTS: Three trials found that a combination of ChEI with additional memantine provides a slight benefit for patients with moderate to severe AD over ChEI monotherapy and placebo. However, a further 4 trials could not replicate this effect. One trial reported benefits of add-on Gingko biloba in donepezil-treated patients with moderate AD (using a formula containing Gingko and other antioxidants) compared to donepezil with placebo. A further trial found no significant effect of combining EGb 761® and donepezil in patients with probable AD over donepezil with placebo. Approaches with idalopirdine, atorvastatin or vitamin supplementation in combination with ChEI have not proven effective and have not been retried since. Fluoxetine and ST101 have shown partial benefits in combination with ChEI over ChEI monotherapy and placebo. However, these effects must be replicated by further research. CONCLUSION: Additional memantine in combination with ChEI might be of slight benefit in patients with moderate to severe AD, but evidence is ambiguous. Longer trials are needed. No major cognitive benefit is missed, if solely appropriate ChEI monotherapy is initiated.

Analysis of clinically-reported, memantine-induced cardiovascular adverse responses using the halothane-anesthetized dogs: Reverse translational study.

Although NMDA receptor antagonist memantine is considered to be better tolerated than cholinesterase inhibitors on treating Alzheimer's disease, several types of cardiovascular adverse events have been associated with memantine treatment, including hypertension, myocardial infarction, severe bradycardia and QT-interval prolongation. In order to clarify how memantine induces these cardiovascular adverse events, we assessed its electropharmacological effects using the halothane-anesthetized dogs (n = 4). Memantine hydrochloride was intravenously administered in doses of 0.01, 0.1 and 1 mg/kg over 10 min, providing subtherapeutic, clinically-relevant and supratherapeutic concentrations, respectively. The low to high doses increased the mean blood pressure and left ventricular contraction and enhanced the atrioventricular nodal conduction, suggesting an increase of sympathicotonic output from the central nervous system similarly to donepezil, which might induce myocardial ischemia in patients with coronary artery disease. Meanwhile, the high dose suppressed the intra-atrial conduction and the low to high doses inhibited the intra-ventricular conduction, indicating potential to induce severe bradycardic adverse event by advanced cardiac conduction block in susceptible patients. Memantine alone did not induce repolarization delay, indicating lack of risk for inducing torsade de pointes. Thus, these in vivo experimental findings may provide basic information to better understand the clinically observed adverse events of memantine.

Evaluation of memantine's efficacy and safety in the treatment of children with autism spectrum disorder: A systematic review and meta-analysis.

BACKGROUND: The United States Food and Drug Administration has approved drugs that address only autism-related symptoms rather than the underlying impairments. N-Methyl-D-Aspartate  receptor antagonists have recently emerged as a promising treatment option for a variety of neurologic and developmental problems, including autism. AIMS: To review (systematically), for the first time, the medical literature that explores the safety in and efficacy of memantine in autism. METHODS AND PROCEDURES: A comprehensive electronic search for relevant randomized controlled trials was conducted in four databases. Using RevMan software, we extracted and pooled data as a risk ratio (RR) or normalized mean differences in an inverse variance strategy. RESULTS: This systematic review and meta-analysis includes five trials. There was no difference in enhancing social responsiveness when compared to placebo, though memantine lowered the likelihood of anxiety (RR = 0.25; 95% Confidence interval: [0.07; 0.87], p = 0.03). However, memantine aggravated impulsive behaviors. Additionally, in another trial that compared memantine added to risperidone versus risperidone added to placebo, memantine was found to be effective and safe. CONCLUSION: Memantine showed safety in reducing acute symptoms of anxiety and other symptoms encountered in pediatric patients with autism spectrum disorders. However, memantine does not improve the core symptoms of autism. Nevertheless, further long-term trials are needed to explore its potential efficacy.

Role of memantine in the prophylactic treatment of episodic migraine: A systematic review.

OBJECTIVE: The purpose of this systematic review is to assess the efficacy and safety of memantine for the prophylactic treatment of episodic migraine. BACKGROUND: Migraine is a prevalent chronic disease with significant costs to the health care system. Although various prophylactic treatment options are available, these medications have limitations based on efficacy, potential side effects, and patient preference. Memantine is an N-methyl-d-aspartate receptor antagonist used in dementia treatment that may have potential benefit for migraine prophylaxis. METHODS: A systematic search of PubMed, Embase, and CENTRAL databases was conducted to identify relevant published studies through December 2020 using the search terms: migraine disorders, migraine, headache disorders, or headache and memantine. Studies selected for the systematic review included prospective, interventional designs and evaluated memantine for prophylaxis of migraine. Animal studies, case reports, abstracts, review articles, protocols without results, and studies not written in English were excluded. Data were extracted using a standardized systematic process and included author, publication date, study design, sample size, patient characteristics, treatment regimen, clinical efficacy outcomes, and adverse drug effects. RESULTS: Four articles were identified for inclusion representing two prospective open-label studies and two randomized, double-blind trials, evaluating 183 patients on memantine overall. A reduction in number of migraine days and headache severity were shown in all four studies in the participants treated with memantine. The most common adverse effects included somnolence, sedation, and nausea, none of which were severe. CONCLUSION: The studies in this review establish that memantine has the potential for use as a treatment option for episodic migraine. Additional long-term studies using an active comparator would be useful to further elucidate its role.

Withdrawal or continuation of cholinesterase inhibitors or memantine or both, in people with dementia.

BACKGROUND: Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment. OBJECTIVES: To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. SELECTION CRITERIA: We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to 2 months after randomisation), medium term (3-11 months) and long term (12 months or more). We assessed the overall certainty of the evidence for each outcome using GRADE methods. MAIN RESULTS: We included six trials investigating cholinesterase inhibitor withdrawal, and one trial investigating withdrawal of either donepezil or memantine. No trials assessed withdrawal of memantine only. Drugs were withdrawn abruptly in five trials and stepwise in two trials. All participants had dementia due to Alzheimer's disease, with severities ranging from mild to very severe, and were taking cholinesterase inhibitors without known adverse effects at baseline. The included trials randomised 759 participants to treatment groups relevant to this review. Study duration ranged from 6 weeks to 12 months. There were too few included studies to allow planned subgroup analyses. We considered some studies to be at unclear or high risk of selection, performance, detection, attrition or reporting bias. Compared to continuing cholinesterase inhibitors, discontinuing treatment may be associated with worse cognitive function in the short term (standardised mean difference (SMD) -0.42, 95% confidence interval (CI) -0.64 to -0.21; 4 studies; low certainty), but the effect in the medium term is very uncertain (SMD -0.40, 95% CI -0.87 to 0.07; 3 studies; very low certainty). In a sensitivity analysis omitting data from a study which only included participants who had shown a relatively poor prior response to donepezil, inconsistency was reduced and we found that cognitive function may be worse in the discontinuation group in the medium term (SMD -0.62; 95% CI -0.94 to -0.31). Data from one longer-term study suggest that discontinuing a cholinesterase inhibitor is probably associated with worse cognitive function at 12 months (mean difference (MD) -2.09 Standardised Mini-Mental State Examination (SMMSE) points, 95% CI -3.43 to -0.75; moderate certainty). Discontinuation may make little or no difference to functional status in the short term (SMD -0.25, 95% CI -0.54 to 0.04; 2 studies; low certainty), and its effect in the medium term is uncertain (SMD -0.38, 95% CI -0.74 to -0.01; 2 studies; very low certainty). After 12 months, discontinuing a cholinesterase inhibitor probably results in greater functional impairment than continuing treatment (MD -3.38 Bristol Activities of Daily Living Scale (BADLS) points, 95% CI -6.67 to -0.10; one study; moderate certainty). Discontinuation may be associated with a worsening of neuropsychiatric symptoms over the short term and medium term, although we cannot exclude a minimal effect (SMD - 0.48, 95% CI -0.82 to -0.13; 2 studies; low certainty; and SMD -0.27, 95% CI -0.47 to -0.08; 3 studies; low certainty, respectively). Data from one study suggest that discontinuing a cholinesterase inhibitor may result in little to no change in neuropsychiatric status at 12 months (MD -0.87 Neuropsychiatric Inventory (NPI) points; 95% CI -8.42 to 6.68; moderate certainty). We found no clear evidence of an effect of discontinuation on dropout due to lack of medication efficacy or deterioration in overall medical condition (odds ratio (OR) 1.53, 95% CI 0.84 to 2.76; 4 studies; low certainty), on number of adverse events (OR 0.85, 95% CI 0.57 to 1.27; 4 studies; low certainty) or serious adverse events (OR 0.80, 95% CI 0.46 to 1.39; 4 studies; low certainty), and on mortality (OR 0.75, 95% CI 0.36 to 1.55; 5 studies; low certainty). Institutionalisation was reported in one trial, but it was not possible to extract data for the groups relevant to this review. AUTHORS' CONCLUSIONS: This review suggests that discontinuing cholinesterase inhibitors may result in worse cognitive, neuropsychiatric and functional status than continuing treatment, although this is supported by limited evidence, almost all of low or very low certainty. As all participants had dementia due to Alzheimer's disease, our findings are not transferable to other dementia types. We were unable to determine whether the effects of discontinuing cholinesterase inhibitors differed with baseline dementia severity. There is currently no evidence to guide decisions about discontinuing memantine. There is a need for further well-designed RCTs, across a range of dementia severities and settings. We are aware of two ongoing registered trials. In making decisions about discontinuing these drugs, clinicians should exercise caution, considering the evidence from existing trials along with other factors important to patients and their carers.

A Randomized Double-Blind Placebo-Controlled Trial of Combined Escitalopram and Memantine for Older Adults With Major Depression and Subjective Memory Complaints.

OBJECTIVE: Geriatric depression is difficult to treat and frequently accompanied by cognitive complaints that increase risk for dementia. New treatment strategies targeting both depression and cognition are urgently needed. METHODS: We conducted a 6-month double-blind placebo-controlled trial to assess the efficacy and tolerability of escitalopram + memantine (ESC/MEM) compared to escitalopram + placebo (ESC/PBO) for improving mood and cognitive functioning in depressed older adults with subjective memory complaints (NCT01902004). Primary outcome was change in depression as assessed by the HAM-D post-treatment (at 6 months). Remission was defined as HAM-D ≤6; naturalistic follow-up continued until 12 months. RESULTS: Of the 95 randomized participants, 62 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Mean daily escitalopram dose was 11.1 mg (SD = 3.7; range: 5-20 mg). Mean daily memantine dose was 19.3 mg (SD = 2.6; range 10-20 mg). Remission rate within ESC/MEM was 45.8% and 47.9%, compared to 38.3% and 31.9% in ESC/PBO, at 3 and 6 months, respectively (χ2(1) = 2.0, p = 0.15). Both groups improved significantly on the HAM-D at 3, 6, and 12 months, with no observed between-group differences. ESC/MEM demonstrated greater improvement in delayed recall (F(2,82) = 4.3, p = 0.02) and executive functioning (F(2,82) = 5.1, p = 0.01) at 12 months compared to ESC/PBO. CONCLUSIONS: The combination of memantine with escitalopram was well tolerated and as effective as escitalopram and placebo in improving depression using HAM-D. Combination memantine and escitalopram was significantly more effective than escitalopram and placebo in improving cognitive outcomes at 12 months. Future reports will address the role of biomarkers of aging in treatment response.

Determinants of antidementia drug prescription in patients older than 65: A latent class analysis.

BACKGROUND: Antidementia drugs (cholinesterase inhibitors and memantine) are still widely prescribed despite their controversial effects and 2011 guidelines that no longer encourage their prescription. The objective was to assess which factors remained determinants of antidementia drug prescriptions. METHODS: A cross-sectional study was performed in 2013. Patients suffering from dementia, aged 65 and over, identified in the French national health insurance database were included. Because we anticipated a high correlation between age, comorbidities, and health care use, we first identified the patients' health status by a latent class analysis. Second, we performed adjusted logistic regression models. The explanatory variables were patients' health status, gender, prescription of nonpharmacological treatments (physical and speech therapies), prescription of psychotropic drugs, and access to health care. RESULTS: Among the 3873 patients included, 38% received antidementia drugs. Three latent classes of patients with different health status were identified. Patients with poor health status received significantly fewer antidementia drugs (P < .001). Patients with speech therapy or antidepressant drugs received significantly more antidementia drugs (P < .001), whereas patients with physical therapy received significantly fewer antidementia drugs (P = .006). CONCLUSION: Antidementia drugs were less likely to be prescribed for patients with poor health status. This result is encouraging for these frail patients who are more vulnerable to the adverse effects of treatments. At the same time, this result encourage targeting specifically patients in good health status for the use of a decision aid, in an attempt to limit prescriptions by involving patients and families.

Memantine misuse and social networks: A content analysis of Internet self-reports.

PURPOSE: Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist currently used for moderate-to-severe Alzheimer's disease. Although the risk of memantine abuse is very low, other NMDA receptor antagonists, such as phencyclidine and ketamine, are well known to drug users. The purpose of this study was to collect data on social networks in order to identify unexpected forms of memantine abuse. METHOD: A Google Trends search was used to highlight reddit.com as a major source of social discussions about memantine. Self-reported users experiences posted on reddit.com were recorded and sorted using representative keywords. RESULTS: From 2010 to November 2019, 307 topics citing memantine were identified on reddit.com and 136 users experiences extracted from the topics were recorded. The main use identified was "self-medication" based on off-label uses of memantine such as anxiety, depression, attention-deficit hyperactivity disorder, or obsessive-compulsive disorder (n = 87 reports), followed by nootropic (42) and recreational (39) uses. The average reported doses for acute and chronic uses were 156 ± 110 mg and 23 ± 24 mg respectively. For chronic use, the average duration was 15 ± 29 weeks. Most chronic users (77 out of 100) reported at least one side effect. CONCLUSION: Memantine misuse seems to be a growing phenomenon. Beyond expected use for recreational purpose; the main uses identified on reddit.com were not reported in the medical literature. Off-label uses and nootropic purposes seemed to be key features of memantine misuse.

Acute and Long-term Memantine Add-on Treatment to Risperidone Improves Cognitive Dysfunction in Patients with Acute and Chronic Schizophrenia.

INTRODUCTION: Patients with schizophrenia are mainly characterized by negative symptoms and cognitive dysfunction. In this proof-of-concept study we tested effects on cognition and negative symptoms of a 6- or 24-week memantine add-on treatment to risperidone in patients with acute or chronic schizophrenia. MATERIALS AND METHODS: Patients with an acute episode of schizophrenia (n=11) and predominating positive symptoms were randomized to a 6-week add-on treatment with memantine (10 mg twice a day) versus placebo and patients with chronic schizophrenia (n=13) and negative symptoms were randomized to a 24-week add-on treatment with memantine (10 mg twice a day) versus placebo. All patients received antipsychotic medication with risperidone (2-8 mg/day). Psychopathological changes were assessed with the Positive and Negative Syndrome Scale (PANSS) at baseline and after 2, 4, 6, 12, and 24 weeks. Cognitive function was measured at baseline, after 6 weeks, and 24 weeks. RESULTS: Patients with acute schizophrenia who received add-on treatment with memantine showed a significantly higher performance in attention intensity (p=0.043), problem-solving (p=0.043), verbal learning (p=0.050), and flexibility (p=0.049). Patients with chronic schizophrenia showed a significantly higher immediate memory in the memantine group compared to the placebo group (p=0.033) and a significantly greater reduction of the PANSS sum score if compared to the placebo group. DISCUSSIONS: Our study gives further evidence that memantine add-on treatment to risperidone may have neuroprotective effects and improve cognitive function in patients with schizophrenia. ClinicalTrials.gov Number: NCT00148590 and NCT00148616.

Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma.

BACKGROUND: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ). METHODS: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design. RESULTS: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%. CONCLUSIONS: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.

The effect of memantine in adult patients with attention deficit hyperactivity disorder.

BACKGROUND: Hyperactivity disorder and attention deficit are common neurological disorders in children and adolescents. The symptoms of hyperactivity are decreased in adults, and attention deficit is more noticeable. This study was carried out to evaluate the effect of memantine on adult patients with attention deficit hyperactivity disorder (ADHD). MATERIALS AND METHODS: In a double-blind clinical trial study, 40 patients aged 18 to 45 years with ADHD were selected on the basis on the Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria, and randomly assigned memantine or placebo. Before starting the treatment, Conners' screening questionnaire was completed for each patient, and the subjects were entered the study after acquiring minimum acceptable score in the questionnaire. RESULTS: The mean age of patients who were receiving memantine and placebo was about 34.7 ± 4.48 and 31.5 ± 7.4 years, respectively. The results have shown a significant difference in the behavior and attention deficit between the two groups treated with memantine and placebo during 6 weeks (p < 0.001). Also, there was a significant difference in the third and sixth weeks between treatment groups in hyperactivity and attention deficit index (p = 0.001). CONCLUSION: The results of this study indicated that memantine was effective in reducing symptoms of Inattention/Memory Problems, Hyperactivity/Restlessness, Impulsivity/Emotional Lability.

Memantine for dementia.

BACKGROUND: Memantine is a moderate affinity uncompetitive antagonist of glutamate NMDA receptors. It is licensed for use in moderate and severe Alzheimer's disease (AD); in the USA, it is also widely used off-label for mild AD. OBJECTIVES: To determine efficacy and safety of memantine for people with dementia. To assess whether memantine adds benefit for people already taking cholinesterase inhibitors (ChEIs). SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register of trials (http://www.medicine.ox.ac.uk/alois/) up to 25 March 2018. We examined clinical trials registries, press releases and posters of memantine manufacturers; and the web sites of the FDA, EMEA and NICE. We contacted authors and companies for missing information. SELECTION CRITERIA: Double-blind, parallel group, placebo-controlled, randomised trials of memantine in people with dementia. DATA COLLECTION AND ANALYSIS: We pooled and analysed data from four clinical domains across different aetiologies and severities of dementia and for AD with agitation. We assessed the impact of study duration, severity and concomitant use of ChEIs. Consequently, we restricted analyses to the licensed dose (20 mg/day or 28 mg extended release) and data at six to seven months duration of follow-up, and analysed separately results for mild and moderate-to-severe AD.We transformed results for efficacy outcomes into the difference in points on particular outcome scales. MAIN RESULTS: Across all types of dementia, data were available from almost 10,000 participants in 44 included trials, most of which were at low or unclear risk of bias. For nearly half the studies, relevant data were obtained from unpublished sources. The majority of trials (29 in 7885 participants) were conducted in people with AD.1. Moderate-to-severe AD (with or without concomitant ChEIs). High-certainty evidence from up to 14 studies in around 3700 participants consistently shows a small clinical benefit for memantine versus placebo: clinical global rating (CGR): 0.21 CIBIC+ points (95% confidence interval (CI) 0.14 to 0.30); cognitive function (CF): 3.11 Severe Impairment Battery (SIB) points (95% CI 2.42 to 3.92); performance on activities of daily living (ADL): 1.09 ADL19 points (95% CI 0.62 to 1.64); and behaviour and mood (BM): 1.84 Neuropsychiatric Inventory (NPI) points (95% CI 1.05 to 2.76). There may be no difference in the number of people discontinuing memantine compared to placebo: risk ratio (RR) 0.93 (95% CI 0.83 to 1.04) corresponding to 13 fewer people per 1000 (95% CI 31 fewer to 7 more). Although there is moderate-certainty evidence that fewer people taking memantine experience agitation as an adverse event: RR 0.81 (95% CI 0.66 to 0.99) (25 fewer people per 1000, 95% CI 1 to 44 fewer), there is also moderate-certainty evidence, from three additional studies, suggesting that memantine is not beneficial as a treatment for agitation (e.g. Cohen Mansfield Agitation Inventory: clinical benefit of 0.50 CMAI points, 95% CI -3.71 to 4.71) .The presence of concomitant ChEI does not impact on the difference between memantine and placebo, with the possible exceptions of the BM outcome (larger effect in people taking ChEIs) and the CF outcome (smaller effect).2. Mild AD (Mini Mental State Examination (MMSE) 20 to 23): mainly moderate-certainty evidence based on post-hoc subgroups from up to four studies in around 600 participants suggests there is probably no difference between memantine and placebo for CF: 0.21 ADAS-Cog points (95% CI -0.95 to 1.38); performance on ADL: -0.07 ADL 23 points (95% CI -1.80 to 1.66); and BM: -0.29 NPI points (95% CI -2.16 to 1.58). There is less certainty in the CGR evidence, which also suggests there may be no difference: 0.09 CIBIC+ points (95% CI -0.12 to 0.30). Memantine (compared with placebo) may increase the numbers of people discontinuing treatment because of adverse events (RR 2.12, 95% CI 1.03 to 4.39).3. Mild-to-moderate vascular dementia. Moderate- and low-certainty evidence from two studies in around 750 participants indicates there is probably a small clinical benefit for CF: 2.15 ADAS-Cog points (95% CI 1.05 to 3.25); there may be a small clinical benefit for BM: 0.47 NOSGER disturbing behaviour points (95% CI 0.07 to 0.87); there is probably no difference in CGR: 0.03 CIBIC+ points (95% CI -0.28 to 0.34); and there may be no difference in ADL: 0.11 NOSGER II self-care subscale points (95% CI -0.35 to 0.54) or in the numbers of people discontinuing treatment: RR 1.05 (95% CI 0.83 to 1.34).There is limited, mainly low- or very low-certainty efficacy evidence for other types of dementia (Parkinson's disease and dementia Lewy bodies (for which CGR may show a small clinical benefit; four studies in 319 people); frontotemporal dementia (two studies in 133 people); and AIDS-related Dementia Complex (one study in 140 people)).There is high-certainty evidence showing no difference between memantine and placebo in the proportion experiencing at least one adverse event: RR 1.03 (95% CI 1.00 to 1.06); the RR does not differ between aetiologies or severities of dementia. Combining available data from all trials, there is moderate-certainty evidence that memantine is 1.6 times more likely than placebo to result in dizziness (6.1% versus 3.9%), low-certainty evidence of a 1.3-fold increased risk of headache (5.5% versus 4.3%), but high-certainty evidence of no difference in falls. AUTHORS' CONCLUSIONS: We found important differences in the efficacy of memantine in mild AD compared to that in moderate-to-severe AD. There is a small clinical benefit of memantine in people with moderate-to-severe AD, which occurs irrespective of whether they are also taking a ChEI, but no benefit in people with mild AD.Clinical heterogeneity in AD makes it unlikely that any single drug will have a large effect size, and means that the optimal drug treatment may involve multiple drugs, each having an effect size that may be less than the minimum clinically important difference.A definitive long-duration trial in mild AD is needed to establish whether starting memantine earlier would be beneficial over the long term and safe: at present the evidence is against this, despite it being common practice. A long-duration trial in moderate-to-severe AD is needed to establish whether the benefit persists beyond six months.

Caregivers' perspectives and experiences of withdrawing acetylcholinesterase inhibitors and memantine in advanced dementia: a qualitative analysis of an online discussion forum.

BACKGROUND: There is considerable uncertainty surrounding the medications used to delay the progression of dementia, especially their long-term efficacy and when to withdraw treatment with these agents. Current research regarding the optimal use of antidementia medication is limited, contributing to variability in practice guidelines and in clinicians' prescribing practices. Little is currently known about the experiences encountered by caregivers of people with dementia after antidementia medication is withdrawn. AIM: To investigate the experiences and perspectives of carers and family members when antidementia medications (cholinesterase inhibitors and/or memantine) are stopped, by analysing archived threads and posts of an online discussion forum for people affected by dementia. METHODS: Archived discussions from Talking Point, an online discussion forum hosted by the Alzheimer's Society UK, were searched for threads discussing antidementia medication withdrawal and relevant threads were analysed thematically using the Framework method. Participant demographics were not established due to usernames which ensured anonymity. RESULTS: Four key themes emerged: (1) expectations about withdrawal, (2) method of withdrawal, (3) clinical condition on withdrawal, and (4) the effect of withdrawal on caregivers. CONCLUSIONS: Online discussion forums such as Talking Point provide dementia carers with an outlet to seek help, offer advice and share experiences with other members. The study findings highlight the complexity surrounding optimising dementia pharmacotherapy and antidementia medication withdrawal, highlighting the need for treatment to be person-centred and highly individualised.

Diagnosis and Management of Dementia: Review.

Importance: Worldwide, 47 million people live with dementia and, by 2050, the number is expected to increase to 131 million. Observations: Dementia is an acquired loss of cognition in multiple cognitive domains sufficiently severe to affect social or occupational function. In the United States, Alzheimer disease, one cause of dementia, affects 5.8 million people. Dementia is commonly associated with more than 1 neuropathology, usually Alzheimer disease with cerebrovascular pathology. Diagnosing dementia requires a history evaluating for cognitive decline and impairment in daily activities, with corroboration from a close friend or family member, in addition to a thorough mental status examination by a clinician to delineate impairments in memory, language, attention, visuospatial cognition such as spatial orientation, executive function, and mood. Brief cognitive impairment screening questionnaires can assist in initiating and organizing the cognitive assessment. However, if the assessment is inconclusive (eg, symptoms present, but normal examination findings), neuropsychological testing can help determine whether dementia is present. Physical examination may help identify the etiology of dementia. For example, focal neurologic abnormalities suggest stroke. Brain neuroimaging may demonstrate structural changes including, but not limited to, focal atrophy, infarcts, and tumor, that may not be identified on physical examination. Additional evaluation with cerebrospinal fluid assays or genetic testing may be considered in atypical dementia cases, such as age of onset younger than 65 years, rapid symptom onset, and/or impairment in multiple cognitive domains but not episodic memory. For treatment, patients may benefit from nonpharmacologic approaches, including cognitively engaging activities such as reading, physical exercise such as walking, and socialization such as family gatherings. Pharmacologic approaches can provide modest symptomatic relief. For Alzheimer disease, this includes an acetylcholinesterase inhibitor such as donepezil for mild to severe dementia, and memantine (used alone or as an add-on therapy) for moderate to severe dementia. Rivastigmine can be used to treat symptomatic Parkinson disease dementia. Conclusions and Relevance: Alzheimer disease currently affects 5.8 million persons in the United States and is a common cause of dementia, which is usually accompanied by other neuropathology, often cerebrovascular disease such as brain infarcts. Causes of dementia can be diagnosed by medical history, cognitive and physical examination, laboratory testing, and brain imaging. Management should include both nonpharmacologic and pharmacologic approaches, although efficacy of available treatments remains limited.

Predictors of discontinuation, efficacy, and safety of memantine treatment for Alzheimer's disease: meta-analysis and meta-regression of 18 randomized clinical trials involving 5004 patients.

BACKGROUND: The risk-benefit relationship of memantine treatment for Alzheimer's disease (AD) remains unclear. In addition, variability between the results of clinical trials has been observed. The aim of this study was to investigate the risk-benefit relationship of memantine treatment in patients with AD and to determine the predictor effect of patient, intervention, and study design related covariates. METHODS: A systematic review and meta-analysis of double-blind, placebo controlled clinical trials was performed. Primary outcomes were all-cause discontinuation, discontinuation due to adverse events (AE) and efficacy on cognitive function. Odds ratio (OR) and standard mean difference (SMD) with 95% confidence intervals were calculated. Meta-regression was conducted to identify related covariates. Cochrane Collaboration tool was used to evaluate the risk of bias of included trials. RESULTS: Eighteen studies involving 5004 patients were included. No differences between memantine and placebo were found for all-cause treatment discontinuation (OR=0.97 [0.82, 1.14]) and discontinuation due to AE (OR=1.18 [0.91, 1.53]). Memantine showed small improvement on cognitive function (SMD=0.15 [0.08, 0.22]). Baseline functional ability was positively associated with all-cause treatment discontinuation and discontinuation due to AE. CONCLUSIONS: Our study suggests that memantine has a very small efficacy on AD symptomatology and its safety profile is similar to that of placebo. No evidence of treatment discontinuation improvement with memantine is found, indicating a dubious risk-benefit relationship. No intervention characteristic or subgroup of patients clearly shows a significantly better risk-benefit relationship. PROSPERO REGISTRATION: CRD42014015696 .