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Neurocognitive Outcomes from Memantine: A Pilot, Double-Blind, Placebo-Controlled Trial in Children with Autism Spectrum Disorder.
Soorya, LV, Fogg, L, Ocampo, E, Printen, M, Youngkin, S, Halpern, D, Kolevzon, A, Lee, S, Grodberg, D, Anagnostou, E
Journal of child and adolescent psychopharmacology. 2021;(7):475-484
Abstract
Objective: Studies interrogating therapeutics which alter the excitation-inhibition balance in the treatment of autism spectrum disorder (ASD) have reported mixed results on social and behavioral outcomes. Methods: The aim of this randomized, double-blind placebo-controlled pilot trial was to evaluate neurocognitive effects of memantine over a 24-week trial. Twenty-three children ages 6-12 years old with ASD were randomized to memantine or placebo. Primary outcomes included measures of apraxia and expressive language with evaluations at midpoint (week 12) and endpoint (week 24). Secondary outcomes included memory and adaptive behavior measures. Exploratory outcomes included changes in overall cognitive functioning and behavior (e.g., Aberrant Behavior Checklist). Results: Results suggest that memantine was well-tolerated. Dropout rates were high across groups with only 14 participants completing the 6-month trial. Memantine was not associated with improvements in apraxia and expressive language. Treatment with memantine was associated with improvements in verbal recognition memory as measured by the Narrative Memory-Recognition (NEPSY-II) (F = 5.05, p = .03). In addition, exploratory analyses of changes in Intelligence quotient (IQ) suggest improvements on verbal IQ (d = 1.8). Conclusions: Results suggest future studies of memantine in ASD may benefit from shifting treatment targets from social and behavioral outcomes to exploration of effects of memantine on cognition, potentially as an adjunct to learning and educational interventions. ClinicalTrials.gov: NCT01372449.
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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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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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Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation.
McIntyre, RS, Rosenblat, JD, Nemeroff, CB, Sanacora, G, Murrough, JW, Berk, M, Brietzke, E, Dodd, S, Gorwood, P, Ho, R, et al
The American journal of psychiatry. 2021;(5):383-399
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Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.
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Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants.
Kadriu, B, Greenwald, M, Henter, ID, Gilbert, JR, Kraus, C, Park, LT, Zarate, CA
The international journal of neuropsychopharmacology. 2021;(1):8-21
Abstract
BACKGROUND The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that "classic" serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period. METHODS This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed. RESULTS Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research. CONCLUSIONS Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.
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Using Biomarkers to Predict Memantine Effects in Alzheimer's Disease: A Proposal and Proof-Of-Concept Demonstration.
Swerdlow, NR, Kotz, JE, Joshi, YB, Talledo, J, Sprock, J, Molina, JL, Huisa, B, Huege, SF, Romero, JA, Walsh, MJ, et al
Journal of Alzheimer's disease : JAD. 2021;(4):1431-1438
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Memantine's benefits in Alzheimer's disease (AD) are modest and heterogeneous. We tested the feasibility of using sensitivity to acute memantine challenge to predict an individual's clinical response. Eight participants completed a double-blind challenge study of memantine (placebo versus 20 mg) effects on autonomic, subjective, cognitive, and neurophysiological measures, followed by a 24-week unblinded active-dose therapeutic trial (10 mg bid). Study participation was well tolerated. Subgroups based on memantine sensitivity on specific laboratory measures differed in their clinical response to memantine, some by large effect sizes. It appears feasible to use biomarkers to predict clinical sensitivity to memantine.
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Donepezil plus memantine versus donepezil alone for treatment of concomitant Alzheimer's disease and chronic obstructive pulmonary disease: a retrospective observational study.
Cao, Y, Qian, L, Yu, W, Li, T, Mao, S, Han, G
The Journal of international medical research. 2020;(2):300060520902895
Abstract
OBJECTIVE To assess the clinical outcomes of donepezil plus memantine (DM) and donepezil (DO) alone in Asian patients with a concomitant diagnosis of moderate-to-severe Alzheimer’s disease and mild-to-moderate chronic obstructive pulmonary disease (AD-COPD). METHODS We conducted a retrospective analysis of patients with AD-COPD who received either DM or DO for 6 months, or until the occurrence of unacceptable adverse events or disease progression, between June 2012 and May 2016. The primary endpoint was the score on the Standardized Mini-Mental State Examination (SMMSE). Secondary endpoints were scores on the caregiver-rated Bristol Activities of Daily Living Scale, Neuropsychiatric Inventory, Dementia Quality of Life (DEMQOL)-Proxy, and General Health Questionnaire 12. RESULTS In total, 154 eligible patients received DM, whereas 156 received DO. Compared with patients who received DO, patients who received DM had significantly higher mean scores on the SMMSE by 2.1 points (95% confidence interval, 1.3–2.5). Significant between-group heterogeneity was not detected in outcomes over time. The benefits of treatment with DM were greater than those of treatment with DO, in terms of the primary endpoint. Significant differences were also detected in terms of secondary endpoints. CONCLUSION DM is more effective than DO alone for Asian patients with AD-COPD.
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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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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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Modulation of simultaneously collected hemodynamic and electrophysiological functional connectivity by ketamine and midazolam.
Forsyth, A, McMillan, R, Campbell, D, Malpas, G, Maxwell, E, Sleigh, J, Dukart, J, Hipp, J, Muthukumaraswamy, SD
Human brain mapping. 2020;(6):1472-1494
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The pharmacological modulation of functional connectivity in the brain may underlie therapeutic efficacy for several neurological and psychiatric disorders. Functional magnetic resonance imaging (fMRI) provides a noninvasive method of assessing this modulation, however, the indirect nature of the blood-oxygen level dependent signal restricts the discrimination of neural from physiological contributions. Here we followed two approaches to assess the validity of fMRI functional connectivity in developing drug biomarkers, using simultaneous electroencephalography (EEG)/fMRI in a placebo-controlled, three-way crossover design with ketamine and midazolam. First, we compared seven different preprocessing pipelines to determine their impact on the connectivity of common resting-state networks. Independent components analysis (ICA)-denoising resulted in stronger reductions in connectivity after ketamine, and weaker increases after midazolam, than pipelines employing physiological noise modelling or averaged signals from cerebrospinal fluid or white matter. This suggests that pipeline decisions should reflect a drug's unique noise structure, and if this is unknown then accepting possible signal loss when choosing extensive ICA denoising pipelines could engender more confidence in the remaining results. We then compared the temporal correlation structure of fMRI to that derived from two connectivity metrics of EEG, which provides a direct measure of neural activity. While electrophysiological estimates based on the power envelope were more closely aligned to BOLD signal connectivity than those based on phase consistency, no significant relationship between the change in electrophysiological and hemodynamic correlation structures was found, implying caution should be used when making cross-modal comparisons of pharmacologically-modulated functional connectivity.
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Efficacy of Gabapentin for the Treatment of Alcohol Use Disorder in Patients With Alcohol Withdrawal Symptoms: A Randomized Clinical Trial.
Anton, RF, Latham, P, Voronin, K, Book, S, Hoffman, M, Prisciandaro, J, Bristol, E
JAMA internal medicine. 2020;(5):728-736
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IMPORTANCE Although an estimated 30 million people meet criteria for alcohol use disorder (AUD), few receive appropriate pharmacotherapy. A more personalized, symptom-specific, approach might improve efficacy and acceptance. OBJECTIVE To examine whether gabapentin would be useful in the treatment of AUD, especially in those with the most alcohol withdrawal symptoms. DESIGN, SETTING, AND PARTICIPANTS This double-blind randomized clinical trial conducted between November 2014 and June 2018 evaluated gabapentin vs placebo in community-recruited participants screened and treated in an academic outpatient setting over a 16-week treatment period. A total of 145 treatment-seeking individuals who met Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for AUD and were not receiving other AUD intervention were screened, and 96 who also met recent alcohol withdrawal criteria were randomized to treatment after 3 abstinent days. Daily drinking was recorded, and percentage of disialo carbohydrate-deficient transferrin in the blood, a heavy drinking marker, was collected at baseline and monthly during treatment. INTERVENTIONS Gabapentin up to 1200 mg/d, orally, vs placebo along with 9 medical management visits (20 minutes each). MAIN OUTCOMES AND MEASURES The percentage of individuals with no heavy drinking days and those with total abstinence were compared between treatment groups and further evaluated based on prestudy alcohol withdrawal symptoms. RESULTS Of 96 randomized individuals, 90 were evaluable (44 in the gabapentin arm and 46 in the placebo arm), with a mean (SD) age of 49.6 (10.1) years; 69 were men (77%) and 85 were white (94%). The evaluable participants had 83% baseline heavy drinking days (4 or more drinks/day for women, 5 or more for men) and met 4.5 alcohol withdrawal criteria from the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). More gabapentin-treated individuals had no heavy drinking days (12 of 44 participants [27%]) compared with placebo (4 of 46 participants [9%]), a difference of 18.6% (95% CI, 3.1-34.1; P = .02; number needed to treat [NNT], 5.4), and more total abstinence (8 of 44 [18%]) compared with placebo (2 of 46 [4%]), a difference of 13.8% (95% CI, 1.0-26.7; P = .04; NNT, 6.2). The prestudy high-alcohol withdrawal group had positive gabapentin effects on no heavy drinking days (P < .02; NNT, 3.1) and total abstinence (P = .003; NNT, 2.7) compared with placebo, while within the low-alcohol withdrawal group, there were no significant differences. These findings were similar for other drinking variables, where gabapentin was more efficacious than placebo in the high-alcohol withdrawal group only. Gabapentin caused more dizziness, but this did not affect efficacy. CONCLUSIONS AND RELEVANCE These data, combined with others, suggest gabapentin might be most efficacious in people with AUD and a history of alcohol withdrawal symptoms. Future studies should evaluate sleep changes and mood during early recovery as mediators of gabapentin efficacy. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02349477.
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Gabapentin for Alcohol-Related Disorders: Critical Appraisal of the Symptom-Driven Approach.
Andrade, C
The Journal of clinical psychiatry. 2020;(6)
Abstract
Gabapentin, available as gabapentin and as the prodrug gabapentin enacarbil, is an approved treatment for partial seizures, postherpetic neuralgia, and the restless legs syndrome. Gabapentin has been studied for diverse off-label indications, including alcohol use disorder (AUD). Meta-analyses of randomized controlled trials (RCTs) suggest that gabapentin reduces the severity of alcohol withdrawal symptoms (AWS) as well as the percentage of heavy drinking days in persons with AUD; however, the magnitude of benefit is small, and no benefits are apparent for other drinking outcomes. Furthermore, a recent, large RCT found an extended-release formulation of gabapentin enacarbil ineffective for a wide range of drinking and other outcomes in patients with AUD. Some research suggests that gabapentin may improve drinking outcomes specifically in AUD patients with higher levels of AWS; this may be a result of gabapentin-associated reduction in AWS, precluding AWS-triggered continued drinking. In this context, a recent, large RCT found that gabapentin reduced heavy drinking and increased abstinence, and that these findings were apparent only in patients with higher levels of AWS during the 2 weeks before randomization; disconcertingly, gabapentin appeared to worsen drinking outcomes in the patients with low AWS. Whereas these findings support the conjecture that gabapentin could be considered indicated in AUD patients with high AWS, problems with this RCT and with its findings limit the applicability of the findings to everyday clinical practice. These problems are discussed in detail. It is concluded that, in line with the recommendations of a recent treatment guideline, gabapentin may be considered for patients with AUD only if first line drugs such as naltrexone and acamprosate cannot be used. It may also be worth examining benefits with gabapentin in AUD associated with chronic pain, anxiety, and chronic insomnia because gabapentin is suggested to attenuate these syndromes.