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Influence of combined treatment with naltrexone and memantine on alcohol drinking behaviors: a phase II randomized crossover trial.
Krishnan-Sarin, S, O'Malley, SS, Franco, N, Cavallo, DA, Tetrault, JM, Shi, J, Gueorguieva, R, Pittman, B, Krystal, JH
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2020;(2):319-326
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Abstract
Glutamate and opioid systems play important roles in alcohol drinking behaviors. We examined if combined treatment with the NMDA antagonist memantine and the opioid antagonist naltrexone, when compared with naltrexone alone, would have a greater influence on alcohol drinking behaviors. Fifty-six, non-treatment-seeking heavy drinkers, with alcohol dependence and a positive family history (FHP) of alcoholism, participated in a randomized, double-blind, crossover trial, including two 6-8 days treatment periods, separated by a 6-day washout, and 3 alcohol drinking paradigm (ADP) sessions. After the first baseline (BAS) ADP1 session, participants were randomized to receive either naltrexone (NTX; 50 mg/day) + placebo memantine, or NTX (50 mg/day) + memantine (MEM; 20 mg/day), during the first treatment period, following which they completed ADP2. After a 6-day washout, participants were crossed over to the treatment they did not receive during the first treatment period, following which they completed ADP3. During each ADP, participants received a priming drink of alcohol followed by 3 1-hour, self-administration periods during which they had ad-lib access to 12 drinks. Individually, both NTX and NTX + MEM, when compared to BAS ADP1, significantly reduced the number of drinks consumed (p's < 0.001) and craving (p's < 0.001). When comparing NTX + MEM vs. NTX on number of drinks consumed, there was a significant treatment* sequence interaction (p = 0.004). Specifically, when NTX + MEM followed NTX alone, NTX + MEM resulted in a further reduction in drinking (mean: -1.94; 95% CI: -2.6, -0.8, p = 0.0005). However, when NTX alone followed NTX + MEM, NTX alone did not lead to further reduction in drinking (mean: 0.59; 95% CI: -0.67, 1.43, p = 0.47). Similar patterns were observed for alcohol craving; specifically, a significant reduction in craving was observed when NTX + MEM followed NTX alone (p = 0.009), but craving reduction was maintained when NTX + MEM was followed by NTX alone. Neither treatment condition significantly influenced alcohol-induced stimulation or sedation. Memantine (at a dose of 20 mg/day) enhances the efficacy of naltrexone (50 mg/day) in reducing alcohol drinking and craving among FHP drinkers with beneficial effects that appear to carryover after discontinuation of memantine treatment.
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Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies.
Hardan, AY, Hendren, RL, Aman, MG, Robb, A, Melmed, RD, Andersen, KA, Luchini, R, Rahman, R, Ali, S, Jia, XD, et al
Autism : the international journal of research and practice. 2019;(8):2096-2111
Abstract
Three phase 2 trials were conducted to assess the efficacy and long-term safety of weight-based memantine extended release (ER) treatment in children with autism spectrum disorder. MEM-MD-91, a 50-week open-label trial, identified memantine extended-release treatment responders for enrollment into MEM-MD-68, a 12-week randomized, double-blind, placebo-controlled withdrawal trial. MEM-MD-69 was an open-label extension trial in which participants from MEM-MD-68, MEM-MD-91, and open-label trial MEM-MD-67 were treated ⩽48 weeks with memantine extended release. In MEM-MD-91, 517 (59.6%) participants were confirmed Social Responsiveness Scale responders at week 12; mean Social Responsiveness Scale total raw scores improved two to three times a minimal clinically important difference of 10 points. In MEM-MD-68, there was no difference between memantine and placebo on the primary efficacy parameter, the proportion of patients with a loss of therapeutic response (defined as ⩾10-point increase from baseline in Social Responsiveness Scale total raw score). MEM-MD-69 exploratory analyses revealed mean standard deviation improvement in Social Responsiveness Scale total raw score of 32.4 (26.4) from baseline of the first lead-in study. No new safety concerns were evident. While the a priori-defined efficacy results of the double-blind trial were not achieved, the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.
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Effect of the Glutamate NMDA Receptor Antagonist Memantine as Adjunctive Treatment in Borderline Personality Disorder: An Exploratory, Randomised, Double-Blind, Placebo-Controlled Trial.
Kulkarni, J, Thomas, N, Hudaib, AR, Gavrilidis, E, Grigg, J, Tan, R, Cheng, J, Arnold, A, Gurvich, C
CNS drugs. 2018;(2):179-187
Abstract
BACKGROUND Borderline personality disorder (BPD) is a complex, severe and highly stigmatised psychiatric illness. Several lines of evidence highlight the causal link between chronic stress, glucocorticoid response to stress and glutamatergic overactivity as a key event in the pathophysiology of BPD. Therefore, molecular mechanisms capable of regulating glutamate excitotoxicity represent novel and potentially promising treatment targets. Memantine-HCl is a voltage-dependent N-methyl-D-aspartate (NMDA) receptor 'channel blocker' that selectively blocks pathological glutamate overactivity. OBJECTIVE The aim of the current study was to determine if memantine can improve BPD symptoms. METHOD An 8-week, double-blind, placebo-controlled trial of adjunctive memantine to treatment as usual was conducted. Treatment as usual comprised antidepressants (selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, noradrenergic and specific serotonin antagonists and serotonin noradrenaline reuptake inhibitors), mood stabilisers and antipsychotics, as well as psychotherapy and other psychosocial interventions. Sixteen participants received oral placebo while 17 participants received daily oral memantine 10 mg for 7 days, with subsequent titration to daily oral memantine 20 mg. Eligibility criteria included men and women aged between 16-65 years, with a diagnosis of BPD according to the Diagnostic Interview for Borderline Patients. Primary outcome measures included the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD), assessed fortnightly. Secondary measures included an adverse effect questionnaire administered fortnightly to assess adverse effects known to be related to memantine use. RESULTS According to intention-to-treat, latent growth curve analyses, a significant change in total score of ZAN-BPD symptom severity was observed in the memantine group at 20 mg/daily across time, compared with placebo (p = 0.02). No adverse effects were significantly more frequent among participants receiving active memantine than among those receiving placebo. CONCLUSION Memantine at a 20-mg daily dose is a well tolerated drug that can improve BPD symptomatology and may be a promising novel therapeutic for its treatment. Further studies are needed to explore the efficacy of memantine versus placebo, as well as in comparison with other potential treatments for BPD. ClinicalTrials.gov identifier: NCT02097706.
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A Prospective Open-Label Trial of Memantine Hydrochloride for the Treatment of Social Deficits in Intellectually Capable Adults With Autism Spectrum Disorder.
Joshi, G, Wozniak, J, Faraone, SV, Fried, R, Chan, J, Furtak, S, Grimsley, E, Conroy, K, Kilcullen, JR, Woodworth, KY, et al
Journal of clinical psychopharmacology. 2016;(3):262-71
Abstract
This prospective 12-week open-label trial evaluates the tolerability and efficacy of memantine hydrochloride for the treatment of core social and cognitive deficits in adults with high-functioning autism spectrum disorder (ASD). Measures for assessment of therapeutic response included the Social Responsiveness Scale-Adult Research Version (SRS-A), disorder-specific Clinical Global Impression scales, Behavior Rating Inventory of Executive Functioning-Adult Self-Report, Diagnostic Analysis of Nonverbal Accuracy Scale, and Cambridge Neuropsychological Test Automated Battery. Eighteen adults (mean age, 28 ± 9.5 years) with high-functioning ASD (SRS-A raw score, 99 ± 17) were treated with memantine (mean dose, 19.7 ± 1.2 mg/d; range, 15-20 mg), and 17 (94%) completed the trial. Treatment with memantine was associated with significant reduction on informant-rated (SRS-A, -28 ± 25; P < 0.001) and clinician-rated (Clinical Global Impression-Improvement subscale ≤2, 83%) measures of autism severity. In addition, memantine treatment was associated with significant improvement in ADHD and anxiety symptom severity. Significant improvement was noted in nonverbal communication on the Diagnostic Analysis of Nonverbal Accuracy Scale test and in executive function per self-report (Behavior Rating Inventory of Executive Functioning-Adult Self-Report Global Executive Composite, -6 ± 8.8; P < 0.015) and neuropsychological assessments (Cambridge Neuropsychological Test Automated Battery). Memantine treatment was generally well tolerated and was not associated with any serious adverse events. Treatment with memantine appears to be beneficial for the treatment of ASD and associated psychopathology and cognitive dysfunction in intellectually capable adults. Future placebo-controlled trials are warranted.
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Magnetic resonance imaging and neuropsychological results from a trial of memantine in Alzheimer's disease.
Weiner, MW, Sadowsky, C, Saxton, J, Hofbauer, RK, Graham, SM, Yu, SY, Li, S, Hsu, HA, Suhy, J, Fridman, M, et al
Alzheimer's & dementia : the journal of the Alzheimer's Association. 2011;(4):425-35
Abstract
BACKGROUND This study was designed to assess changes in brain volume and cognitive abilities in memantine-treated patients with Alzheimer's disease (AD) by using an exploratory, single-arm, delayed-start design. METHODS Cholinesterase inhibitor-treated patients with AD (N = 47; Mini-Mental State Examination score range: 15-23) were enrolled in an observational lead-in period (weeks: 1-24), followed by an open-label period of add-on memantine treatment (weeks: 25-48). The patients underwent magnetic resonance imaging at weeks 0 (baseline), 24 (immediately before memantine initiation), and 48 (endpoint), and a battery of neuropsychological tests at weeks 0, 24, 28, 36, and 48. The primary outcome measure was the annualized rate of change (%) in total brain volume (TBV) between the two study periods. Data were analyzed using paired t-tests. RESULTS There were no statistically significant differences in the rates of change in TBV, ventricular volume, or left hippocampal volume between the study periods; however, the memantine treatment period was associated with a significantly slower right hippocampal atrophy (-5.5% ± 12.0% vs -10.8% ± 7.2%; P = .038). Memantine treatment was also associated with superior performances on the Boston Naming Test (P = .034) and the Trail Making Test, Part B (P = .001), but also with a higher number of errors (i.e., repetitions and intrusions) on the California Verbal Learning Test. Memantine was found to be safe and well tolerated. CONCLUSIONS In this study, no difference in the rates of TBV change between the two periods was observed; however, memantine treatment was found to be associated with slowing of right hippocampal atrophy, and with improvement on one test of executive functioning as well as a test of confrontation naming ability. Trials using structural magnetic resonance imaging and a delayed-start design may be a feasible option for the assessment of treatments for AD.
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Sustained effects of once-daily memantine treatment on cognition and functional communication skills in patients with moderate to severe Alzheimer's disease: results of a 16-week open-label trial.
Schulz, JB, Rainer, M, Klünemann, HH, Kurz, A, Wolf, S, Sternberg, K, Tennigkeit, F
Journal of Alzheimer's disease : JAD. 2011;(3):463-75
Abstract
The present study evaluated the effects of once-daily memantine (20 mg) treatment on cognition and communication in patients with moderate to severe Alzheimer's disease (AD). In a multicenter, single-arm open-label study, outpatients diagnosed with AD (MMSE < 20; n = 97) were titrated from 5 mg to 20 mg once-daily memantine over 4 weeks. Once-daily memantine treatment (20 mg) was then continued for 8 weeks, followed by a 4-week wash-out period. The primary efficacy endpoint was the change from baseline in the Consortium to Establish a Registry for Alzheimer's Disease -Neuropsychological Battery (CERAD-NP) total score. Secondary efficacy endpoints included change from baseline in Functional Communication Language Inventory (FLCI) and ADCS-ADL19 total score, and the response from baseline in Clinical Global Impression of Change (CGI-C). The CERAD-NP total score improved significantly after 12 weeks of once-daily memantine treatment compared with baseline (5.9 ± 8.8; p < 0.0001). The FLCI total score improved significantly after 12 weeks compared with baseline (4.4 ± 6.8; p < 0.0001). These significant improvements were already observed after 4 and 8 weeks of once-daily memantine treatment and persisted after a 4-week wash-out period. ADCS-ADL19 total scores showed only slight increases from baseline, and CGI-C indicated that the majority of patients experienced an improvement or stabilization of the disease after 12 weeks. At least one Treatment-Emergent Adverse Event was reported by 38 (39.2%) patients. In patients with moderate to severe AD, once-daily memantine (20 mg) treatment significantly improved cognition and functional communication and was found to have a favorable safety and tolerability profile.
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Crossover trial of gabapentin and memantine as treatment for acquired nystagmus.
Thurtell, MJ, Joshi, AC, Leone, AC, Tomsak, RL, Kosmorsky, GS, Stahl, JS, Leigh, RJ
Annals of neurology. 2010;(5):676-80
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Abstract
We conducted a masked, crossover, therapeutic trial of gabapentin (1,200mg/day) versus memantine (40 mg/day) for acquired nystagmus in 10 patients (aged 28-61 years; 7 female; 3 multiple sclerosis [MS]; 6 post-stroke; 1 post-traumatic). Nystagmus was pendular in 6 patients (4 oculopalatal tremor; 2 MS) and jerk upbeat, hemi-seesaw, torsional, or upbeat-diagonal in each of the others. For the group, both drugs reduced median eye speed (p < 0.001), gabapentin by 32.8% and memantine by 27.8%, and improved visual acuity (p < 0.05). Each patient improved with 1 or both drugs. Side effects included unsteadiness with gabapentin and lethargy with memantine. Both drugs should be considered as treatment for acquired forms of nystagmus.
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The effects of the glutamate antagonist memantine on brain activation to an auditory perception task.
van Wageningen, H, Jørgensen, HA, Specht, K, Eichele, T, Hugdahl, K
Human brain mapping. 2009;(11):3616-24
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Abstract
Glutamate is critically involved in the regulation of cognitive functions in humans. There is, however, sparse evidence regarding how blocking glutamate action at the receptor site during a cognitive task affects brain activation. In the current study, the effects of the glutamate antagonist memantine were examined with functional magnetic resonance imaging (fMRI). Thirty-one healthy adults were scanned twice in a counter-balanced design, either in a no-drug session or after administration of memantine for 21 days. The subjects performed a simple auditory perception task with consonant-vowel stimuli. Group-level spatial independent component analysis (ICA) was used to decompose the data and to extract task-related activations. The focus was on four task-related ICA components with frontotemporal localization. The results showed that glutamate-blockage resulted in a significant enhancement in one component, with no significant effect in the other three components. The enhanced effect of memantine was in the middle temporal gyrus, superior frontal gyrus, and middle frontal gyrus. It is suggested that the results reflect effects of glutamatergic processes primarily through non-N-methyl-D-aspartate (NMDA) receptor pathways. Moreover, the results demonstrate that memantine can be used as a probe which allows for studying the effect of excitatory neurotransmission on neuronal activation.
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Memantine in the preventive treatment of refractory migraine.
Bigal, M, Rapoport, A, Sheftell, F, Tepper, D, Tepper, S
Headache. 2008;(9):1337-42
Abstract
OBJECTIVES To assess the efficacy and tolerability of memantine(MEM)in the preventive treatment of refractory migraine. BACKGROUND Glutamate is of importance in migraine pathophysiology and may be related to progression from episodic to chronic migraine. Furthermore, individuals with chronic pain often report cognitive problems. MEM has the potential to address both issues, justifying this pilot study. METHODS We included subjects with refractory migraine (episodic migraine with 8-14 days of headache per month or transformed migraine, who had previously failed at least 2 trials of adequate preventive therapy). Other preventive drugs were allowed if the patient had been on a stable dose for more than 30 days. MEM dose ranged from 10 mg to 20 mg per day. The treatment phase lasted 3 months. The primary endpoint was number of days with headache at month 3. Cognitive performance was assessed with the trail making tests A and B (TMT-A and B). Statistical analyses were performed on the intent-to-treat (ITT) population, using data subjected to the last observation carried forward algorithm.We also conducted per protocol analyses. RESULTS In the ITT population (n = 28), monthly headache frequency was reduced from 21.8 days at baseline to 16.1 (P < .01) at 3 months. The mean number of days with severe pain was reduced from 7.8 to 3.2 at 3 months (P < .01). The mean disability scores were significantly reduced at 3 months, compared with baseline (36.6 vs 54.9, P < .01). There was a significant reduction in the time to complete TMT-A at termination vs baseline (28.4 vs 23.2,P = .02) and also TMT-B (70.1 vs 50.4,P = .04). Side effects were present in 37.5% of the patients; 5.5% dropped out the study because of poor tolerability. Most adverse events were mild. CONCLUSION This study offers preliminary evidence for the use of MEM in the prevention of refractory migraine.Double-blind studies are now required.
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Effects of NMDA receptor antagonist memantine on mismatch negativity.
Korostenskaja, M, Nikulin, VV, Kicić, D, Nikulina, AV, Kähkönen, S
Brain research bulletin. 2007;(4-6):275-83
Abstract
Mismatch negativity (MMN) and its magnetic counterpart (MMNm) have been shown to be altered in patients with various psychiatric and neurological disorders, e.g. Alzheimer's disease and schizophrenia, indicating deficits in involuntary attention. N-Methyl-D-aspartate (NMDA) receptor-mediated glutamate dysfunction is suggested to underlie these deficits. However, the role of NMDA receptors in involuntary attention is poorly understood. Memantine is an NMDA receptor antagonist that has been demonstrated to be effective in the treatment of patients with Alzheimer's disease. We aimed to investigate whether a single dose of memantine would affect MMN/MMNm in healthy subjects studied with simultaneous electroencephalography (EEG) and magnetoencephalography (MEG). Monaural left-ear auditory stimuli were presented in a passive oddball paradigm with infrequent deviant tones differing in frequency and duration. Neuronal activity was recorded in 13 healthy subjects after oral administration of 30mg of memantine or placebo in a randomized, double-blind, cross-over design. MMNm was analyzed using equivalent current dipoles. MMN was evaluated from frontocentral electrodes. Memantine lowered subjects' arousal level as measured by visual analog scales, and enhanced the amplitude of MMN in EEG. No differences in MMN latency were observed in MEG or EEG. Memantine did not affect the location, strength, amplitude or latency of MMNm, P1m, and N1m components. No changes in amplitude or latency were observed for P1 and N1 peaks. These results indicate that memantine affects involuntary attention without otherwise changing auditory processing of the stimuli. As memantine-induced changes in MMN were detected only in EEG, we suggest that the effect is mostly related to the frontal cortex.