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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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Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study.
Fang, T, Al Khleifat, A, Meurgey, JH, Jones, A, Leigh, PN, Bensimon, G, Al-Chalabi, A
The Lancet. Neurology. 2018;(5):416-422
Abstract
BACKGROUND Riluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a dose of 100 mg, was associated with a 35% reduction in mortality in a clinical trial. A key question is whether the survival benefit occurs at an early stage of disease, late stage, or is spread throughout the course of the disease. To address this question, we used the King's clinical staging system to do a retrospective analysis of data from the original dose-ranging clinical trial of riluzole. METHODS In the original dose-ranging trial, patients were enrolled between December, 1992, and November, 1993, in Belgium, France, Germany, Spain, Canada, the USA, and the UK if they had probable or definite ALS as defined by the El Escorial criteria. The censor date for the riluzole survival data was set as the original study end date of Dec 31, 1994. For this analysis, King's clinical ALS stage was estimated from the electronic case record data of the modified Norris scale, UK Medical Research Council score for muscle strength, El Escorial category, vital capacity, and gastrostomy insertion data. The lowest allocated stage was 2 because the original trial only included patients with probable or definite ALS. We used a χ2 test to assess the independence of stage at trial enrolment and treatment group, Kaplan-Meier product limit distribution to test the transition from each stage to subsequent stages, and Cox regression to confirm an effect of treatment group on time in stage, controlling for covariates. We did sensitivity analyses by combining treatment groups, using alternative strategies to stage, stratifying by stage at trial enrolment, and using multistate outcome analysis of treatments (MOAT). FINDINGS We analysed the case records of all 959 participants from the original dose-ranging trial, 237 assigned to 50 mg/day riluzole, 236 to 100 mg/day, 244 to 200 mg/day, and 242 to daily placebo. Clinical stage at enrolment did not significantly differ between treatment groups (p=0·22). Time in stage 4 was longer for patients receiving 100 mg/day riluzole than for those receiving placebo (hazard ratio [HR] 0·55, 95% CI 0·36-0·83; log-rank p=0·037). Combining treatment groups and stratifying by stage at enrolment showed a similar result (HR 0·638, 95% CI 0·464-0·878; p=0·006), as did analysis with MOAT where the mean number of days spent in stage 4 was numerically higher for patients given riluzole at higher doses compared with patients receiving placebo. Time from stages 2 or 3 to subsequent stages or death did not differ between riluzole treatment groups and placebo (p=0·83 for stage 2 and 0·88 for stage 3). INTERPRETATION We showed that riluzole prolongs survival in the last clinical stage of ALS; this finding needs to be confirmed in a prospective study, and treatment effects at stage 1 still need to be analysed. The ALS stage at which benefit occurs is important for counselling of patients before starting treatment. Staging should be used in future ALS clinical trials to assess the stage at which survival benefit occurs, and a similar approach could be used for other neurodegenerative diseases. FUNDING NIHR Maudsley Biomedical Research Centre, The European Union Joint Programme on Neurodegeneration, and the King's Summer Undergraduate Studentship.
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Chemotherapy-induced nausea and vomiting: incidence and characteristics of persistent symptoms and future directions NCCTG N08C3 (Alliance).
Kottschade, L, Novotny, P, Lyss, A, Mazurczak, M, Loprinzi, C, Barton, D
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2016;(6):2661-7
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Abstract
BACKGROUND Despite newer agents, chemotherapy-induced nausea and vomiting (CINV) continues to remain a distressing side effect to a proportion of patients undergoing systemic anti-cancer therapy. METHODS We recently performed an unplanned secondary analysis on a previously reported negative phase III trial (N08C3) looking at the efficacy of gabapentin/placebo in combination with dexamethasone and a 5HT3 receptor antagonist in the prevention of CINV for 413 patients undergoing regimens with highly emetogenic chemotherapy (HEC). In the current study, we attempted to better understand the higher than expected rate of overall patient satisfaction, despite a low complete response rate in both arms. Additionally, we looked at patient variables and their relationship to rates of CINV. RESULTS Approximately one third of patients experienced more than mild nausea and reported scores on the Functional Living Index-Emesis that indicated interference with activities. Thirty-five percent reported nausea greater than 2.5 on a scale of 0 to 10 (0 being none), 19 % reported at least one emetic episode, and 49 % reported taking rescue medication. Nausea and vomiting on day 1, cisplatin therapy, and history of motion sickness significantly predicted delayed CINV. Age, combination chemotherapy (HEC with moderately emetogenic), and getting treatment for breast cancer predicted CINV on day 1. DISCUSSION These data confirm previous reports that subgroups of patients may be more prone to acute and delayed CINV. Future CINV study design may benefit from a more individualized approach to CINV management, targeting those patients who are truly at risk for CINV despite continued drug development efforts.
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Rating depression over brief time intervals with the Hamilton Depression Rating Scale: standard vs. abbreviated scales.
Luckenbaugh, DA, Ameli, R, Brutsche, NE, Zarate, CA
Journal of psychiatric research. 2015;:40-5
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Abstract
Although antidepressant trials typically use weekly ratings to examine changes in symptoms over six to 12 weeks, antidepressant treatments may improve symptoms more quickly. Thus, rating scales must be adapted to capture changes over shorter intervals. We examined the use of the 17-item Hamilton Depression Rating Scale (HDRS) to evaluate more rapid changes. Data were examined from 58 patients with major depressive disorder or bipolar disorder enrolled in double-blind, placebo-controlled, crossover studies who received a single infusion of ketamine (0.5 mg/kg) or placebo over 40 min then crossed over to the other condition. HDRS subscales, a single HDRS Depressed mood item, and a visual analogue scale were used at baseline, after a brief interval (230 min), and one week post-infusion. Effect sizes for the ketamine-placebo difference were moderate (d > 0.50), but one and two-item HDRS subscales had the smallest effects. Response rates on active drug were lowest for the complete HDRS (43%); the remaining scales had higher response rates to active drug, but the shortest subscales had higher response rates to placebo. Correlations between the changes from baseline to 230 min post-ketamine across scores were similar for most subscales (r = 0.82-0.97), but correlations using the single items were lower (r < 0.74). Overall, effect sizes for drug-placebo differences and correlations between changes were lower for one- and two-item measures. Response rates were lower with the full HDRS scale. The data suggest that, to best identify rapid antidepressant effects, a scale should have more than two items, but fewer items than a full scale.
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An open-label multicenter study to assess the safety of dextromethorphan/quinidine in patients with pseudobulbar affect associated with a range of underlying neurological conditions.
Pattee, GL, Wymer, JP, Lomen-Hoerth, C, Appel, SH, Formella, AE, Pope, LE
Current medical research and opinion. 2014;(11):2255-65
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Abstract
BACKGROUND Pseudobulbar affect (PBA) is associated with neurological disorders or injury affecting the brain, and characterized by frequent, uncontrollable episodes of crying and/or laughing that are exaggerated or unrelated to the patient's emotional state. Clinical trials establishing dextromethorphan and quinidine (DM/Q) as PBA treatment were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This trial evaluated DM/Q safety in patients with PBA secondary to any neurological condition affecting the brain. OBJECTIVE To evaluate the safety and tolerability of DM/Q during long-term administration to patients with PBA associated with multiple neurological conditions. METHODS Fifty-two-week open-label study of DM/Q 30/30 mg twice daily. Safety measures included adverse events (AEs), laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations. CLINICAL TRIAL REGISTRATION #NCT00056524. RESULTS A total of 553 PBA patients with >30 different neurological conditions enrolled; 296 (53.5%) completed. The most frequently reported treatment-related AEs (TRAEs) were nausea (11.8%), dizziness (10.5%), headache (9.9%), somnolence (7.2%), fatigue (7.1%), diarrhea (6.5%), and dry mouth (5.1%). TRAEs were mostly mild/moderate, generally transient, and consistent with previous controlled trials. Serious AEs (SAEs) were reported in 126 patients (22.8%), including 47 deaths, mostly due to ALS progression and respiratory failure. No SAEs were deemed related to DM/Q treatment by investigators. ECG results suggested no clinically meaningful effect of DM/Q on myocardial repolarization. Differences in AEs across neurological disease groups appeared consistent with the known morbidity of the primary neurological conditions. Study interpretation is limited by the small size of some disease groups, the lack of a specific efficacy measure and the use of a DM/Q dose higher than the eventually approved dose. CONCLUSIONS DM/Q was generally well tolerated over this 52 week trial in patients with PBA associated with a wide range of neurological conditions.
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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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Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder.
DiazGranados, N, Ibrahim, LA, Brutsche, NE, Ameli, R, Henter, ID, Luckenbaugh, DA, Machado-Vieira, R, Zarate, CA
The Journal of clinical psychiatry. 2010;(12):1605-11
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OBJECTIVE Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacologic interventions that could address this problem. Ketamine, an N-methyl-D-asparate antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment-resistant major depressive disorder (MDD). METHOD Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg) and were rated at baseline and at 40, 80, 120, and 230 minutes postinfusion with the Scale for Suicide Ideation (SSI), the Montgomery-Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. The study was conducted between October 2006 and January 2009. RESULTS Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes; these decreases remained significant through the first 4 hours postinfusion (P < .001). Ten subjects (30%) had an SSI score ≥ 4 at baseline; all these scores dropped below 4 (9 dropped by 40 minutes and 1 by 80 minutes). For those patients with a starting score below 4 on the SSI, only 1 reached a score of 4. Depression, anxiety, and hopelessness were significantly improved at all time points (P < .001). CONCLUSIONS Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to 4 hours postinfusion. Future studies with ketamine in suicidal ideation are warranted due to the potential impact on public health. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00088699.
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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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Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms.
Sanacora, G, Kendell, SF, Levin, Y, Simen, AA, Fenton, LR, Coric, V, Krystal, JH
Biological psychiatry. 2007;(6):822-5
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BACKGROUND Excessive glutamatergic neurotransmission may contribute to the pathophysiology of major depressive disorder (MDD). Recent evidence suggests that riluzole and other agents that target glutamate neurotransmission may show antidepressant activity. METHODS Ten patients with treatment-resistant depression had riluzole added to their ongoing medication regimen for 6 weeks, followed by an optional 6-week continuation phase. Depression and anxiety severity were assessed using the Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS). Linear mixed models were used to test for a linear trend in HDRS and HARS scores across time with treatment. RESULTS Subjects' HDRS and HARS scores declined significantly following the initiation of riluzole augmentation therapy. The effect of riluzole was significant at the end of the first week of treatment and persisted for the 12-week duration of the study. CONCLUSIONS These data suggest that riluzole augmentation produces antidepressant and anxiolytic effects in patients with treatment-resistant depression.