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Neuronal glutamatergic changes and peripheral markers of cytoskeleton dynamics change synchronically 24 h after sub-anaesthetic dose of ketamine in healthy subjects.
Colic, L, McDonnell, C, Li, M, Woelfer, M, Liebe, T, Kretzschmar, M, Speck, O, Schott, BH, Bianchi, M, Walter, M
Behavioural brain research. 2019;:312-319
Abstract
Ketamine acts as a rapid-acting antidepressant by restoring glutamatergic deficits and activating synaptic plasticity processes, with peak activity 24 h after infusion. Microtubule dynamics are known to play a key role in modulation of cytoskeleton and synaptic plasticity, as well as in signalling events in peripheral blood cells. Here, we correlated ketamine-induced change in glutamate/creatinine (Glu/Cr) levels in the pregenual anterior cingulate cortex (pgACC) with peripheral markers of microtubule dynamics, namely acetylated α-tubulin (Acet-Tub), with particular attention to gender specificity. Eighty healthy controls (age = 25.89 ± 5.29, 33 women) were administered intravenous infusion of either ketamine (0.5 mg/kg) or placebo (saline). Blood samples were obtained at baseline and 24 h after infusion and plasma levels of Acet-Tub and transferrin (TRF; loading control) were measured via infrared western blotting. Glu/Cr levels were measured via high-field (7 T) proton magnetic resonance spectroscopy [1H-MRS] in the pgACC at the same time points. Gender differences were observed in baseline Acet-Tub/TRF levels (p < 0.001), and an interaction of time by treatment by gender (F = 5.13, p = 0.027) was found, with a significant increase in Acet-Tub/TRF for ketamine group in females only (p = 0.038). Ketamine-induced gender-independent Glu/Cr changes at 24 h (F(1, 69) = 4.08, p = 0.047), and changes in the pgACC were negatively correlated with the Acet-Tub/TRF expression (r= -0.464, p = 0.010) in the ketamine group, in which, separated by sex, only women showed significant correlation. Our findings indicate a temporal association between changes in central ketamine-induced glutamatergic effects and peripheral markers of cytoskeleton reorganization, particularly in females.
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Current and Future Treatments in Alzheimer's Disease.
Atri, A
Seminars in neurology. 2019;(2):227-240
Abstract
The foundation of current Alzheimer's disease (AD) treatment involves pharmacological and nonpharmacological management and care planning predicated on patient-centered psychoeducation, shared goal-setting, and decision-making forged by a strong triadic relationship between clinician and the patient-caregiver dyad. Food and Drug Administration (FDA) approved AD medications, cholinesterase-inhibitors (ChEIs), and the N-methyl-d-aspartate (NMDA) antagonist memantine, when utilized as part of a comprehensive care plan, while generally considered symptomatic medications, can provide modest "disease course-modifying" effects by enhancing cognition, and reducing loss of independence. When combined, pharmacologic and nonpharmacologic treatments can meaningfully mitigate symptoms and reduce clinical progression and care burden. AD pharmacotherapy first involves identification and elimination of potentially harmful medications and supplements. First line treatment for neuropsychiatric symptoms and problem behaviors is nonpharmacological and involves psychoeducation, trigger identification, and implementation, iterative evaluation, and adjustment of behavioral and environmental interventions. Intensive research efforts are underway to develop more accurate and practical AD diagnostic biomarkers and clinical tools and better therapeutics. Ongoing research studies for primary and secondary prevention of AD and clinical trials evaluating symptomatic and disease-modifying treatments in symptomatic AD are directed at diverse therapeutic targets including neurochemicals, amyloid and tau pathological processes, mitochondria, inflammatory pathways, neuroglia, and multimodal lifestyle interventions.
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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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The Therapeutic Impact of New Migraine Discoveries.
Vécsei, L, Lukács, M, Tajti, J, Fülöp, F, Toldi, J, Edvinsson, L
Current medicinal chemistry. 2019;(34):6261-6281
Abstract
BACKGROUND Migraine is one of the most disabling neurological conditions and associated with high socio-economic costs. Though certain aspects of the pathomechanism of migraine are still incompletely understood, the leading hypothesis implicates the role of the activation of the trigeminovascular system. Triptans are considered to be the current gold standard therapy for migraine attacks; however, their use in clinical practice is limited. Prophylactic treatment includes non-specific approaches for migraine prevention. All these support the need for future studies in order to develop innovative anti-migraine drugs. OBJECTIVE The present study is a review of the current literature regarding new therapeutic lines in migraine research. METHODS A systematic literature search in the database of PUBMED was conducted concerning therapeutic strategies in a migraine published until July 2017. RESULTS Ongoing clinical trials with 5-HT1F receptor agonists and glutamate receptor antagonists offer promising new aspects for acute migraine treatment. Monoclonal antibodies against CGRP and the CGRP receptor are revolutionary in preventive treatment; however, further long-term studies are needed to test their tolerability. Preclinical studies show positive results with PACAP- and kynurenic acid-related treatments. Other promising therapeutic strategies (such as those targeting TRPV1, substance P, NOS, or orexin) have failed to show efficacy in clinical trials. CONCLUSION Due to their side-effects, current therapeutic approaches are not suitable for all migraine patients. Especially frequent episodic and chronic migraine represents a therapeutic challenge for researchers. Clinical and preclinical studies are needed to untangle the pathophysiology of migraine in order to develop new and migraine-specific therapies.
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Effectiveness of Gabapentin in Reducing Cravings and Withdrawal in Alcohol Use Disorder: A Meta-Analytic Review.
Ahmed, S, Stanciu, CN, Kotapati, PV, Ahmed, R, Bhivandkar, S, Khan, AM, Afridi, A, Qureshi, M, Esang, M
The primary care companion for CNS disorders. 2019;(4)
Abstract
OBJECTIVE The current meta-analysis synthesizes previous findings on the effect of gabapentin on alcohol withdrawal and craving. DATA SOURCES Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, a search for relevant English-language literature published between January 1999 and February 2019 was conducted using PubMed and Google Scholar with the keywords alcohol use disorder, alcohol dependence, alcohol withdrawals, alcohol craving, "gabapentin in alcohol use, consumption," and "gabapentin in alcohol withdrawals." STUDY SELECTION AND DATA EXTRACTION Studies were included wherein gabapentin was used as an adjunctive or primary treatment of alcohol dependence/withdrawal. Studies included participants diagnosed with alcohol use disorder using DSM-IV, DSM-IV-TR, DSM-5, or the International Classification of Diseases, Tenth Revision (ICD-10). The search, as well as data extraction, was carried out by 3 blinded authors to preserve precision, using a template in Microsoft Excel to extract the needed data. Following the review of the initial 65 returns, 2 authors independently judged each trial by applying the inclusionary and exclusionary criteria, and any remaining disagreements were resolved by involving a third independent author. A total of 10 studies met the inclusion criteria and were selected for analysis. Subjects in these 10 studies were pooled using standard techniques of meta-analysis. DATA SYNTHESIS Three sets of meta-analyses examined outcomes from (1) single-group pretest-posttest changes, (2) posttest differences between independent groups, and (3) differences in pretest-posttest change scores between independent groups. Statistically significant effect sizes were found for craving (P < .01) and withdrawal (P < .01, P < .001) in the meta-analysis of single-group pretest-posttest outcome changes and were associated with a high level of heterogeneity. In contrast, the meta-analyses of posttest differences between independent groups-that of differences in pretest-posttest change scores between independent groups-did not yield significant effect sizes. CONCLUSIONS Our analysis of pooled data provides evidence that the use of gabapentin to manage alcohol withdrawal symptomatology and related cravings is at least moderately effective. However, given the limited number of available well-designed studies, these findings require further support through more rigorously designed studies.
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NMDA receptor antagonists and pain relief: A meta-analysis of experimental trials.
Thompson, T, Whiter, F, Gallop, K, Veronese, N, Solmi, M, Newton, P, Stubbs, B
Neurology. 2019;(14):e1652-e1662
Abstract
OBJECTIVE We conducted a meta-analysis of controlled trials that used experimental models of acute pain and hyperalgesia to examine the analgesic effects of NMDA receptor (NMDAR) antagonists. METHODS Six major databases were systematically searched (to March 2018) for studies using human evoked pain models to compare NMDAR antagonists with no-intervention controls. Pain outcome data were analyzed with random-effects meta-analysis. RESULTS Searches identified 70 eligible trials (n = 1,069). Meta-analysis found that low-dose ketamine (<1 mg/kg) produced a decrease in hyperalgesic area (standardized mean difference 0.54, 95% confidence interval [CI] 0.34, 0.74, p < 0.001) and a 1.2-point decrease (95% CI 0.88, 1.44, p < 0.001) in pain ratings from 4.6 to 3.4 on a 0-10 scale (a 26% reduction). Similar analgesia was observed for acute and hyperalgesic models and was constant across the dosing range (0.03-1.00 mg/kg). Moderate to high variability in effect size was observed and mild side effects (e.g., sedation, sensory disturbance) were common. No effects of dextromethorphan were found. CONCLUSIONS Findings provide robust evidence for analgesic and antihyperalgesic effects of ketamine, supporting its utility for acute and chronic pain management. However, pain relief was modest, suggesting ketamine may potentially be most useful when opioids are contraindicated, rapid analgesia is required, or for pain resistant to conventional medication.
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7.
Dextromethorphan Analgesia in a Human Experimental Model of Hyperalgesia.
Martin, E, Narjoz, C, Decleves, X, Labat, L, Lambert, C, Loriot, MA, Ducheix, G, Dualé, C, Pereira, B, Pickering, G
Anesthesiology. 2019;(2):356-368
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Abstract
BACKGROUND Central pain sensitization is often refractory to drug treatment. Dextromethorphan, an N-methyl-D-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models. The hypothesis is that dextromethorphan is also antihyperalgesic in humans. METHODS This randomized, double-blind, placebo-controlled, crossover study explores the antihyperalgesic effect of single and repeated 30-mg dose of oral dextromethorphan in 20 volunteers, using the freeze-injury pain model. This model leads to development of primary and secondary hyperalgesia, which develops away from the site of injury and is associated with central sensitization and activation of N-methyl-D-aspartate receptor in the spinal cord. The primary outcome was antihyperalgesia calculated with the area under the curve of the percentage change in mechanical pain threshold (electronic von Frey) on the area of secondary hyperalgesia. The secondary outcomes were mechanical pain threshold on the area of primary hyperalgesia and cognitive (reaction time) effect. RESULTS Single 30-mg results are reported. Antihyperalgesia (% · min) is significantly higher on the area of secondary hyperalgesia with dextromethorphan than placebo (median [interquartile range]: 3,029 [746; 6,195] vs. 710 [-3,248; 4,439], P = 0.009, Hedge's g = 0.8, 95% CI [0.1; 1.4]). On primary hyperalgesia area, mechanical pain threshold 2 h after drug intake is significantly higher with dextromethorphan (P = 0.011, Hedge's g = 0.63, 95% CI [0.01; 1.25]). No difference in antinociception is observed after thermal painful stimuli on healthy skin between groups. Reaction time (ms) is shorter with placebo than with dextromethorphan (median [interquartile range]: 21.6 [-37.4; 0.1] vs. -1.2 [-24.3; 15.4], P = 0.015, Hedge's g = 0.75, 95% CI [0.12; 1.39]). Nonserious adverse events occurrence (15%, 3 of 20 volunteers) was similar in both groups. CONCLUSIONS This study shows that low-dose (30-mg) dextromethorphan is antihyperalgesic in humans on the areas of primary and secondary hyperalgesia and reverses peripheral and central neuronal sensitization. Because dextromethorphan had no intrinsic antinociceptive effect in acute pain on healthy skin, N-methyl-D-aspartate receptor may need to be sensitized by pain for dextromethorphan to be effective.
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Prophylactic use of ketamine reduces postpartum depression in Chinese women undergoing cesarean section✰.
Ma, JH, Wang, SY, Yu, HY, Li, DY, Luo, SC, Zheng, SS, Wan, LF, Duan, KM
Psychiatry research. 2019;:252-258
Abstract
This study aimed to explore the effect of prophylactic ketamine administration on postpartum depression in Chinese woman undergoing cesarean section. This randomized controlled study included 654 Chinese women undergoing cesarean section. At 10 min after child birth, patients in the ketamine group were given 0.5 mg/kg ketamine, whereas patients in the control group received standard postpartum care. At the end of operation, all patients were armed with a patient-controlled intravenous analgesia device. The primary outcome was the prevalence of postpartum depression (PPD), as assessed by the Edinburgh Postnatal Depression Scale (EPDS), and the secondary outcomes included the safety assessment and the Numerical Rating Scale (NRS) of postoperative pain. The prevalence of postpartum blues and postpartum depression were significantly lower in the ketamine group than in the control group. Logistic analysis showed that ketamine administration protected against postpartum depression, and PPD-associated risk factors included stress during pregnancy, antenatal depressive symptom and antenatal suicidal ideation. In addition, the antidepressive effect of prophylactic ketamine was stronger in mothers with a history of moderate stress during pregnancy, antenatal depressive symptom and antenatal suicidal ideation. Our findings suggest that ketamine functions as a prophylactic agent against PPD.
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Adjunctive memantine for major mental disorders: A systematic review and meta-analysis of randomized double-blind controlled trials.
Zheng, W, Zhu, XM, Zhang, QE, Cai, DB, Yang, XH, Zhou, YL, Ungvari, GS, Ng, CH, He, SH, Peng, XJ, et al
Schizophrenia research. 2019;:12-21
Abstract
OBJECTIVE As a non-competitive N-methyl-d-aspartate receptor antagonist, memantine has been used to treat major mental disorders including schizophrenia, bipolar disorder, and major depressive disorder (MDD). This meta-analysis systematically investigated the effectiveness and tolerability of adjunctive memantine for patients with schizophrenia, bipolar disorder, and MDD. METHODS Only randomized controlled trials (RCTs) were identified and included in the study. Data of the three disorders were separately synthesized using the RevMan 5.3 software. RESULTS Fifteen RCTs (n = 988) examining memantine (5-20 mg/day) as an adjunct treatment for schizophrenia (9 trials with 512 patients), bipolar disorder (3 trials with 319 patients), and MDD (3 trials with 157 patients) were analyzed. Memantine outperformed the comparator regarding total psychopathology with a standardized mean difference (SMD) of -0.56 [95% confidence interval (CI): -1.01, -0.11; I2 = 76%, P = 0.01] and negative symptoms with an SMD of -0.71 (95% CI: -1.09, -0.33; I2 = 74%, P = 0.0003) in schizophrenia, but no significant effects were found with regard to positive symptoms and general psychopathology in schizophrenia, or depressive and manic symptoms in bipolar disorder or depressive symptoms in MDD. Memantine outperformed the comparator in improving cognitive performance in schizophrenia with an SMD of 1.07 (95% CI: 0.53, 1.61; P < 0.0001, I2 = 29%). No group differences were found in the rates of adverse drug reactions and discontinuation due to any reason in the three major mental disorders. CONCLUSIONS Memantine as an adjunct treatment appears to have significant efficacy in improving negative symptoms in schizophrenia. The efficacy and safety of adjunctive memantine for bipolar disorder or MDD needs to be further examined. REVIEW REGISTRATION PROSPERO 42018099045.
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Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports.
Martial, C, Cassol, H, Charland-Verville, V, Pallavicini, C, Sanz, C, Zamberlan, F, Vivot, RM, Erowid, F, Erowid, E, Laureys, S, et al
Consciousness and cognition. 2019;:52-69
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Abstract
The real or perceived proximity to death often results in a non-ordinary state of consciousness characterized by phenomenological features such as the perception of leaving the body boundaries, feelings of peace, bliss and timelessness, life review, the sensation of traveling through a tunnel and an irreversible threshold. Near-death experiences (NDEs) are comparable among individuals of different cultures, suggesting an underlying neurobiological mechanism. Anecdotal accounts of the similarity between NDEs and certain drug-induced altered states of consciousness prompted us to perform a large-scale comparative analysis of these experiences. After assessing the semantic similarity between ≈15,000 reports linked to the use of 165 psychoactive substances and 625 NDE narratives, we determined that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine consistently resulted in reports most similar to those associated with NDEs. Ketamine was followed by Salvia divinorum (a plant containing a potent and selective κ receptor agonist) and a series of serotonergic psychedelics, including the endogenous serotonin 2A receptor agonist N,N-Dimethyltryptamine (DMT). This similarity was driven by semantic concepts related to consciousness of the self and the environment, but also by those associated with the therapeutic, ceremonial and religious aspects of drug use. Our analysis sheds light on the long-standing link between certain drugs and the experience of "dying", suggests that ketamine could be used as a safe and reversible experimental model for NDE phenomenology, and supports the speculation that endogenous NMDA antagonists with neuroprotective properties may be released in the proximity of death.