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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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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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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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Abstract
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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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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Abstract
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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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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Efficacy and safety of gabapentin and pregabalin in patients with vasomotor symptoms: a systematic review and meta-analysis.
Shan, D, Zou, L, Liu, X, Shen, Y, Cai, Y, Zhang, J
American journal of obstetrics and gynecology. 2020;(6):564-579.e12
Abstract
OBJECTIVE Vasomotor symptoms are common among postmenopausal women and patients receiving hormone deprivation therapies, and emerging studies are exploring gabapentin's and pregabalin's effects as nonhormonal treatment options. We aimed to assess the efficacy and safety of these 2 drugs. DATA SOURCES Based on a preregistered protocol (Prospective Register of Systematic Reviews -CRD42019133650), we searched 10 databases (PubMed, Embase, Web of Science, PsycINFO, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Chinese Biological Medical Literature, Chinese National Knowledge Infrastructure, Chinese Journals Full-text Database [VIP], and Wanfang) as well as the World Health Organization international clinical trials registry platform and reference lists of related literatures. STUDY ELIGIBILITY CRITERIA Randomized controlled trials and randomized crossover studies exploring gabapentin and pregabalin among women patients with vasomotor symptoms were included. STUDY APPRAISAL AND SYNTHESIS METHODS The Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement was followed. Two reviewers independently selected studies, assessed bias, and extracted data. Mean difference and standardized mean difference with 95% confidence intervals were assessed by random-effects models. Heterogeneities were assessed by I2 statistics, and the quality of evidence was evaluated by the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS Nineteen randomized controlled trials and 2 randomized crossover trials reporting results from 3519 participants were included. Gabapentin could reduce hot flash frequency (mean difference, -1.62, 95% confidence interval, -1.98 to -1.26 after 4 weeks; mean difference, -2.77, 95% confidence interval, -4.29 to -1.24 after 12 weeks) and composite score (standardized mean difference, -0.47, 95% confidence interval, -0.71 to -0.23 after 4 weeks; standardized mean difference, -0.77, 95% confidence interval, -1.15 to -0.40 after 12 weeks) compared with placebo. Both menopausal participants and patients with breast cancer benefited from treatment. Higher risks of dizziness and somnolence were found in the gabapentin group than in the control group (risk ratio, 4.45, 95% confidence interval, 2.50-7.94; risk ratio, 3.29, 95% confidence interval, 1.97-5.48, respectively). Estrogen was more effective in reducing hot flash frequency than gabapentin. No statistically significant difference in reduction of hot flash severity score was found between gabapentin and antidepressants. The trials comparing gabapentin or pregabalin with the other interventions were too limited to make a conclusion. CONCLUSION Favorable effects of gabapentin in relieving vasomotor symptoms were observed, compared with controls, but were less effective than those of estrogen. Evidence supporting the therapeutic effect of pregabalin is still lacking.
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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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Ketamine in seizure management and future pharmacogenomic considerations.
Borsato, GS, Siegel, JL, Rose, MQ, Ojard, M, Feyissa, AM, Quinones-Hinojosa, A, Jackson, DA, Rogers, ER, Freeman, WD
The pharmacogenomics journal. 2020;(3):351-354
Abstract
Ketamine is a noncompetitive N-methyl-D-aspartate antagonist with emerging evidence for use in medically refractory epilepsy. We describe the novel use of low-dose intravenous (IV) ketamine transitioning to enteral formulation in a patient with drug-resistant localization-related refractory epilepsy. We performed a National Library of Medicine (NLM) literature review using search terms "ketamine", "low dose", and "seizure" for similar cases, followed by an illustrative clinical case. Our NLM search engine methodology yielded 24 hits, none of which described use of low-dose ketamine for seizures. Anesthetic doses are used for status epilepticus, but we show that in a patient with postoperative worsening of his chronic seizure burden, low-dose IV ketamine can be used to avoid oversedation and intubation. We demonstrate that IV ketamine can be transitioned to oral regimen to shorten length of stay in the intensive care unit and hospital and has future CYP2B6 pharmacogenomic considerations for further dose individualization.
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Riluzole for the treatment of amyotrophic lateral sclerosis.
Saitoh, Y, Takahashi, Y
Neurodegenerative disease management. 2020;(6):343-355
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the death of motor neurons. Riluzole is a benzothiazole derivative that blocks glutamatergic neurotransmission in the CNS, which is thought to exert neuroprotective effects. Riluzole was approved by the US FDA in 1995 as the first drug to treat ALS. Although riluzole is generally safe and well tolerated in clinical practice, its efficacy in ALS is modest, prolonging tracheostomy-free survival by only 2-3 months. In this article, we will first provide an overview of the ALS field, followed by a discussion of riluzole regarding its physical properties; pharmacology; clinical efficacy in ALS; safety and tolerability; and recommended administration.
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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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Abstract
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.