Non-competitive NMDA antagonist MK-801 prevents memory reconsolidation impairment caused by protein synthesis inhibitors in young chicks.

Introduction: Reactivation of already consolidated memory can initiate its destabilization, making the memory trace labile. Normally, this destabilization is followed by reconsolidation of the memory trace, enriched by newly acquired experience. Disrupting the reconsolidation process, for example, by inhibiting protein synthesis, impairs subsequent memory retrieval, leading to reminder-related amnesia. Previous studies in various species have shown that this impairment can be prevented by using NMDA receptor antagonists, which interfere with memory destabilization. Methods: In the present study we examined this phenomenon using a one-trial passive avoidance learning model in newborn chicks, the hypothesis being that inactivation of the NMDA-mediated transmission during memory reactivation would inhibit the memory trace labilization and thus prevent the reminder-related amnesia. Results: We found that reminder-associated administration of the NMDA receptor antagonist MK-801 or one of the protein synthesis inhibitors (anisomycin, cycloheximide, 2-deoxygalactose) each alone produced amnesia. However, when combined, injection of MK-801 before the reminder prevented amnesia induced by protein synthesis inhibitors. Discussion: We suggest that the observed paradoxical effect implicates the involvement of NMDA receptors in both protein synthesis-independent engram destabilization upon its retrieval and protein synthesismediated engram stabilization after its updating. This puzzling dual role of NMDA receptors in memory destabilization/restabilization requires further investigation.

The Clinical Course of a Severe Case of Malignant Catatonia.

Catatonia is a psychomotor syndrome predominantly associated with mental illness disorders, most commonly bipolar disorder and schizophrenia. Catatonia is classified as malignant when, in addition to catatonic symptoms, dysautonomia is present. Autonomic abnormalities can include changes in temperature, labile blood pressure, and changes in heart and respiratory rates. Because malignant catatonia is life-threatening, prompt recognition and management are essential to prevent mortality. We present a severe case of catatonia with malignant features that highlight the importance of early diagnosis and treatment.

Perspectives on the pharmacological management of complex regional pain syndrome.

INTRODUCTION: Complex regional pain syndrome (CRPS) is a chronic pain condition that is notoriously difficult to treat. Therapies for CRPS include cognitive behavioral, physical, and occupational therapy, single or multidrug pharmacotherapy, and a variety of interventional techniques. Unfortunately, randomized clinical trials of these therapies are limited. The large number of potential pharmacologic options can be overwhelming for providers in their attempts to develop a treatment plan. AREAS COVERED: This article will review the literature on the pharmacologic management of CRPS. It is based on a systematic search of PubMed using keywords, followed by evaluation of the bibliographies for relevant articles. EXPERT OPINION: No single drug has amassed enough evidence to suggest clear efficacy, but a handful of agents with at least modest evidence are commonly used, including gabapentinoids, bisphosphonates, ketamine, and pulsed dose steroids. Meanwhile, other agents that lack significant evidence specifically in CRPS but have evidence in other neuropathic conditions are commonly prescribed, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SNRIs). In our opinion, careful selection and prompt initiation of appropriate pharmacotherapy may optimize pain relief and improve functionality in patients burdened with this debilitating condition.

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial.

OBJECTIVES: Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD). METHODS: Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards. RESULTS: There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms. CONCLUSION: There was no significant treatment impact on BDNF serum levels - neither with ketamine nor esketamine - despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion.

Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial

Abstract Objectives Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD). Methods Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards. Results There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms. Conclusion There was no significant treatment impact on BDNF serum levels - neither with ketamine nor esketamine - despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion. This clinical trial is registered on the Japan Primary Registries Network: UMIN000032355.

Nonketotic Hyperglycinemia: Insight into Current Therapies.

Nonketotic hyperglycinemia (NKH) is a rare inborn error of glycine metabolism that is characterized by the accumulation of glycine in all tissues, especially in the central nervous system (CNS). Based on clinical outcomes, NKH can be divided into two forms, i.e., severe and attenuated NKH. A poor prognosis, including no developmental progress and intractable epilepsy, is typical of severe NKH, whereas patients with the attenuated form present with varied symptoms and neurodevelopmental outcomes. So far, no causal treatment of NKH is known. Currently, the therapy is based on sodium benzoate and NMDA (The N-methyl-D-aspartate receptor) receptor site antagonists (dextromethorphan, ketamine). Different clinical outcomes of the therapy raise doubts about the effectiveness of the treatment. The purpose of this review is to summarize the therapeutic potential, challenges and effectiveness of different NKH therapies.

Virtual Therapy with the NMDA Antagonist Memantine in Hippocampal Models of Moderate to Severe Alzheimer's Disease, in Silico Trials.

The variability in clinical trial results on memantine treatment of Alzheimer's disease remains incompletely explained. The aim of this in silico study is a virtual memantine therapy for Alzheimer's disease that provides a different perspective on clinical trials; An in silico randomised trial using virtual hippocampi to treat moderate to severe Alzheimer's disease with doses of memantine 3-30 µM compared to placebo. The primary endpoint was the number of impulses (spikes). Secondary endpoints included interspike interval and frequency; The number of virtual moderate-AD hippocampal spikes was significantly lower, at 1648.7 (95% CI, 1344.5-1952.9), versus those treated with the 3 µM dose, 2324.7 (95% CI, 2045.9-2603.5), and the 10 µM dose, 3607.0 (95% CI, 3137.6-4076.4). In contrast, the number of virtual spikes (spikes) of severe AD of the hippocampus was significantly lower, at 1461.8 (95% CI, 1196.2-1727.4), versus those treated with the 10 µM dose, at 2734.5 (95% CI, 2369.8-3099.2), and the 30 µM dose, at 3748.9 (95% CI, 3219.8-4278.0). The results of the analysis of secondary endpoints, interspike intervals and frequencies changed statistically significantly relative to the placebo; The results of the in silico study confirm that memantine monotherapy is effective in the treatment of moderate to severe Alzheimer's disease, as assessed by various neuronal parameters.

Computational Modeling of Therapy with the NMDA Antagonist in Neurodegenerative Disease: Information Theory in the Mechanism of Action of Memantine.

(1) Background: in patients with neurodegenerative diseases, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists provide neuroprotective advantages. We performed memantine therapy and proved mathematical and computer modeling of neurodegenerative disease in this study. (2) Methods: a computer simulation environment of the N-methyl-D-aspartate receptor incorporating biological mechanisms of channel activation by high extracellular glutamic acid concentration. In comparison to controls, pathological models were essentially treated with doses of memantine 3−30 µM. (3) Results: the mean values and 95% CI for Shannon entropy in Alzheimer's disease (AD) and memantine treatment models were 1.760 (95% CI, 1.704−1.818) vs. 2.385 (95% CI, 2.280−2.490). The Shannon entropy was significantly higher in the memantine treatment model relative to AD model (p = 0.0162). The mean values and 95% CI for the positive Lyapunov exponent in AD and memantine treatment models were 0.125 (95% CI, NE−NE) vs. 0.058 (95% CI, 0.044−0.073). The positive Lyapunov exponent was significantly higher in the AD model relative to the memantine treatment model (p = 0.0091). The mean values and 95% CI for transfer entropy in AD and memantine treatment models were 0.081 (95% CI, 0.048−0.114) vs. 0.040 (95% CI, 0.019−0.062). The transfer entropy was significantly higher in the AD model relative to the memantine treatment model (p = 0.0146). A correlation analysis showed positive and statistically significant correlations of the memantine concentrations and the positive Lyapunov exponent (correlation coefficient R = 0.87, p = 0.0023) and transfer entropy (TE) (correlation coefficient R = 0.99, p < 0.000001). (4) Conclusions: information theory results of simulation studies show that the NMDA antagonist, memantine, causes neuroprotective benefits in patients with AD. Our simulation study opens up remarkable new scenarios in which a medical product, drug, or device, can be developed and tested for efficacy based on parameters of information theory.

The Computer Simulation of Therapy with the NMDA Antagonist in Excitotoxic Neurodegeneration in an Alzheimer's Disease-like Pathology.

(1) Background: The use of uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists results in neuroprotective benefits in patients with moderate to severe Alzheimer's disease. In this study, we demonstrated mathematical and computer modelling of the excitotoxicity phenomenon and performed virtual memantine therapy. (2) Methods: A computer simulation environment of the N-methyl-D-aspartate receptor combining biological mechanisms of channel activation by means of excessive extracellular glutamic acid concentration in three models of excitotoxicity severity. The simulation model is based on sliding register tables, where each table is associated with corresponding synaptic inputs. Modelling of the increase in extracellular glutamate concentration, through over-stimulation of NMDA receptors and exacerbation of excitotoxicity, is performed by gradually increasing the parameters of phenomenological events by the power function. Pathological models were virtually treated with 3−30 µM doses of memantine compared to controls. (3) Results: The virtual therapy results of memantine at doses of 3−30 µM in the pathological models of excitotoxicity severity show statistically significant neuroprotective benefits in AD patients with moderate severity, 1.25 (95% CI, 1.18−1.32) vs. 1.76 (95% CI, 1.71−1.80) vs. 1.53 (95% CI, 1.48−1.59), (p < 0.001), to severe, 1.32 (95% CI, 1.12−1.53) vs. 1.77 (95% CI, 1.72−1.82) vs. 1.73 (95% CI, 1.68−1.79), (p < 0.001), in the area of effects on memory. A statistically significant benefit of memantine was demonstrated for all neuronal parameters in pathological models. In the mild severity model, a statistically significant increase in frequency was obtained relative to virtual memantine treatment with a dose of 3 µM, which was 23.5 Hz (95% CI, 15.5−28.4) vs. 38.8 Hz (95% CI, 34.0−43.6), (p < 0.0001). In the intermediate excitotoxicity severity model, a statistically significant increase in frequency was obtained relative to virtual memantine therapy with a 3 µM dose of 26.0 Hz (95% CI, 15.7−36.2) vs. 39.0 Hz (95% CI, 34.2−43.8) and a 10 µM dose of 26.0 Hz (95% CI, 15.7−36.2) vs. 30.9 Hz (95% CI, 26.4−35.4), (p < 0.0001). A statistically significant increase in frequency was obtained in the advanced excitotoxicity severity model as in the medium. (4) Conclusions: The NMDA antagonist memantine causes neuroprotective benefits in patients with moderate to severe AD. One of the most important benefits of memantine is the improvement of cognitive function and beneficial effects on memory. On the other hand, memantine provides only symptomatic and temporary support for AD patients. Memantine is prescribed in the US and Europe if a patient has moderate to severe AD. Memantine has also been approved for mild to moderate AD patients. However, its very modest effect provides motivation for further research into new drugs in AD. We are the first to present a mathematical model of the NMDA receptor that allows the simulation of excitotoxicity and virtual memantine therapy.

Adjuvant Drugs for Peripheral Nerve Blocks: The Role of NMDA Antagonists, Neostigmine, Epinephrine, and Sodium Bicarbonate.

The potential for misuse, overdose, and chronic use has led researchers to look for other methods to decrease opioid consumption in patients with acute and chronic pain states. The use of peripheral nerve blocks for surgery has gained increasing popularity as it minimizes peripheral pain signals from the nociceptors of local tissue sustaining trauma and inflammation from surgery. The individualization of peripheral nerve blocks using adjuvant drugs has the potential to improve patient outcomes and reduce chronic pain. The major limitations of peripheral nerve blocks are their limited duration of action and dose-dependent adverse effects. Adjuvant drugs for peripheral nerve blocks show increasing potential as a solution for postoperative and chronic pain with their synergistic effects to increase the duration of action and decrease the required dosage of local anesthetic. N-methyl-d-aspartate (NMDA) receptor antagonists are a viable option for patients with opioid resistance and neuropathic pain due to their affinity to the neurotransmitter glutamate, which is released when patients experience a noxious stimulus. Neostigmine is a cholinesterase inhibitor that exerts its effect by competitively binding at the active site of acetylcholinesterase, which prevents the hydrolysis of acetylcholine and subsequently retaining acetylcholine at the nerve terminal. Epinephrine, also known as adrenaline, can potentially be used as an adjuvant to accelerate and prolong analgesic effects in digital nerve blocks. The theorized role of sodium bicarbonate in local anesthetic preparations is to increase the pH of the anesthetic. The resulting alkaline solution enables the anesthetic to more readily exist in its un-ionized form, which more efficiently crosses lipid membranes of peripheral nerves. However, more research is needed to show the efficacy of these adjuvants for nerve block prolongation as studies have been either mixed or have small sample sizes.

Low dose intraoperative ketamine infusion with multilevel paravertebral block for pain after video-assisted thoracic surgery: a randomized-controlled study.

BACKGROUND: Intraoperative low-dose ketamine infusion has been reported to be an effective adjuvant to opioids for postoperative pain control without major side effects, but it has not been tested in video-assisted thoracic surgery (VATS). The aim of this study was to examine the effect of low-dose intraoperative intravenous ketamine infusion on 24-hour morphine requirement and acute postoperative pain following VATS for lung resection. METHODS: This study was a single center, randomized, double-blind, placebo-controlled study. Thirty-two patients undergoing elective VATS for lung resection in a university hospital were included. Patients were randomly allocated (1:1 ratio) to receive either intraoperative low-dose ketamine (0.2 mg/kg/h) or normal saline infusion starting from intubation to the beginning of chest closure. All patients received multilevel thoracic paravertebral block (TPVB) and morphine was administered postoperatively via the patient-controlled analgesia pump using the same protocol. Time to first analgesia, postoperative cumulative morphine doses at 10, 30 minutes, and the consecutive 1, 2, 6, 12, 18, and 24 hours were recorded. Pain intensity during rest and deep breathing were also assessed by numeric rating scale (NRS) score at 1- and 24-hour postoperatively. RESULTS: There was no significant difference in median (P25, P75) cumulative 24-hour morphine requirement between the ketamine and the control groups [15 (5.5, 29.5) vs. 22.5 (15.3, 40.8) mg, P=0.090]. Patients in ketamine group had significantly longer median pain free time than the control group (27 vs. 2 minutes, P=0.006). No difference in overall NRS score at rest or during deep breathing at 1- and 24-hour postoperatively was demonstrated (P=0.861). CONCLUSIONS: Intraoperative low dose ketamine infusion in addition to TPVB does not reduce postoperative morphine consumption or pain intensity but may prolong pain free time in patients undergoing VATS for lung resection.

Comparative effectiveness of esketamine in the treatment of anhedonia in bipolar and unipolar depression.

BACKGROUND: Anhedonia is a symptom associated with poorer outcomes in depression treatment, including resistance to treatment, higher functional impact and suicidality. Few drugs are known to adequately treat anhedonia in both unipolar and bipolar depression. The NMDA antagonist ketamine has been demonstrated to be effective in rapidly ameliorating anhedonia in depressive episodes. The main aim of present study is to evaluate the anti-anhedonic effect of esketamine, the S-enantiomer of ketamine recently approved for treatment-resistant depression, in unipolar and bipolar depression. METHODS: 70 patients with unipolar or bipolar depression were treated with 6 weekly subcutaneous esketamine infusions (0.5-1mg/kg). Anhedonia was measured through MADRS item 8 before and 24h after each infusion. RESULTS: A significant reduction in anhedonia severity was observed (p<0.0001) after 6 infusions. The effect was statistically significant 24h after the first infusion (p<0.001) in both unipolar and bipolar groups and increased with repeated infusions. Anti-anhedonic effect of esketamine did not differ between groups. LIMITATIONS: This is an open-label, real-world study. Lack of blinding and of a placebo arm may limit the interpretation of findings. CONCLUSION: Although preliminary, present findings suggest that repeated subcutaneous esketamine infusions are effective for the treatment of anhedonia in both unipolar and bipolar depressed patients. These results need to be confirmed through replication in larger double-blinded controlled trials.

The recognition and management of protracted alcohol withdrawal may improve and modulate the pharmacological treatment of alcohol use disorder.

About 50% of persons with an alcohol use disorder may have symptoms of alcohol withdrawal syndrome (AWS) when they reduce or discontinue their alcohol consumption. Protracted alcohol withdrawal (PAW), an underestimated and not yet clearly defined clinical condition that follows the acute stage of AWS, is characterized by the presence of substance-specific signs and symptoms (i.e. anxiety, irritability, mood instability, insomnia, craving) common to acute AWS, but persisting beyond the generally expected acute AWS time frames. Considering that PAW symptoms are mainly related to the neuro-adaptive changes of gamma-aminobutyric acid (GABA) and N-methyl-d-aspartate (NMDA) systems, naltrexone, nalmefene, and disulfiram may not be able to suppress the symptoms of PAW. After treatment of the acute phase of AWS, a more specifically pharmacological therapy able to suppress PAW symptoms could perhaps be used earlier and may be more helpful in preventing the risk of alcohol relapse, which remains higher during the first months of treatment. In light of this, medications acting on GABA and NMDA neurotransmitter systems to counterbalance the up-regulation of NMDA and the down-regulation of GABA could be employed in combination and started as soon as possible.

Relative effectiveness of augmentation treatments for treatment-resistant depression: a systematic review and network meta-analysis.

Most interventions for treatment-resistant depression (TRD) are added as augmenters. We aimed to determine the relative effectiveness of augmentation treatments for TRD. This systematic review and network meta-analysis (NMA) sought all randomized trials of pharmacological and psychological augmentation interventions for adults meeting the most common clinical criteria for TRD. The NMA compared the intervention effectiveness of depressive symptoms for TRD augmentation. Of 36 included trials, 27 were suitable for inclusion in NMA, and no psychological trials could be included in the absence of a common comparator. Antipsychotics (13 trials), mood stabilizers (three trials), NMDA-targeting medications (five trials), and other mechanisms (3 trials) were compared against placebo. NMDA treatments were markedly superior to placebo (ES = 0.91, 95% CI 0.67 to 1.16) and head-to-head NMA suggested that NMDA therapies had the highest chance of being an effective treatment option compared to other pharmacological classes. This study provides the most comprehensive evidence of augmenters' effectiveness for TRD, and our GRADE recommendations can be used to guide guidelines to optimize treatment choices. Although conclusions are limited by paucity of, and heterogeneity between, trials as well as inconsistent reports of treatment safety. This work supports the use of NMDA-targeting medications such as ketamine.

N-Methyl-D-Aspartate Antagonists and Steroids for the Prevention of Persisting Post-Surgical Pain After Thoracoscopic Surgeries: A Randomized Controlled, Factorial Design, International, Multicenter Pilot Trial.

PURPOSE: We conducted a feasibility 2×2 factorial trial comparing N-methyl-D-aspartate (NMDA) antagonists (intravenous ketamine and oral memantine) versus placebo and intravenous steroids versus placebo, in patients having elective video-assisted thoracic surgery lobectomies, at St. Joseph's Hamilton, Canada, and Cleveland Clinic, Cleveland, USA. Our feasibility objectives were: 1) recruitment rate/week; 2) recruitment of ≥90% of eligible patients; and 3) >90% follow-up. Secondary objectives were incidence and intensity of persistent post-surgical pain (PPSP) and other clinical and safety outcomes. METHODS: Using computerized randomization, patients were allocated to one of four groups: NMDA active with steroid placebo; NMDA placebo with steroid active; both NMDA and steroid active; both NMDA and steroid placebo. Patients, health providers, and data analysts were blinded to allocation. Patients were followed for 3 months after randomization. RESULTS: The trial was initiated in May 2017 at Hamilton and, after subsequent regulatory and ethics approval, in April 2018 at Cleveland. The trial had to be stopped after only 1 month of recruitment in Cleveland because the packaged study medications (memantine) expired and we were unable to procure the dosage required. Among 41 eligible patients, 27 (66%) were randomized. The recruitment rate/week was 0.63, 95% confidence interval (CI): 0.47-0.79 in Hamilton; and 1, 95% CI: 0.83-1.17 in Cleveland. Follow-up was complete for all 24 patients (100%) in Hamilton, and 3 of 4 patients in Cleveland. In total, only 4 patients (15%), and 2 patients (7%) had persistent pain at rest and with movement, respectively. There were no significant differences between groups for other outcomes. CONCLUSION: The trial had to be stopped prematurely due to non-availability of study medications. Trial feasibility objectives of recruiting 90% of eligible patients and recruiting at least one patient/week per site were not met. Consideration for protocol changes will be necessary for the full trial. TRIAL REGISTRATION: NCT02950233.

NMDA Receptor Antagonists: Repositioning of Memantine as a Multitargeting Agent for Alzheimer's Therapy.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes problems with memory, thinking, and behavior. Currently, there is no drug that can reduce the pathological events of this degenerative disease but symptomatic relief is possible that can abate the disease condition. N-methyl-D-aspartate (NMDA) receptors exert a critical role for synaptic plasticity as well as transmission. Overstimulation of glutamate receptors, predominantly NMDA type, may cause excitotoxic effects on neurons and is recommended as a mechanism for neurodegeneration. Atypical activation of the NMDA receptor has been suggested for AD by synaptic dysfunction. NMDA receptor antagonists especially memantine block the NMDA receptor and can reduce the influx of calcium (Ca2+) ions into neuron, thus, toxic intracellular events are not activated. This review represents the role of NMDA receptors antagonists as potential therapeutic agents to reduce AD. Moreover, this review highlights the repositioning of memantine as a potential novel therapeutic multitargeting agent for AD.

A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors.

The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 µM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.

NMDA receptor antagonists traxoprodil and lanicemine improve hippocampal-prefrontal coupling and reward-related networks in rats.

RATIONALE: The N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is known to have not only a rapid antidepressant effect but also dissociative side effects. Traxoprodil and lanicemine, also NMDA antagonists, are candidate antidepressant drugs with fewer side effects. OBJECTIVES: In order to understand their mechanism of action, we investigated the acute effects of traxoprodil and lanicemine on brain connectivity using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Functional connectivity (FC) alterations were examined using interregional correlation networks. Graph theoretical methods were used for whole brain network analysis. As interest in NMDAR antagonists as potential antidepressants was triggered by the antidepressant effect of ketamine, results were compared to previous findings from our ketamine studies. RESULTS: Similar to ketamine but to a smaller extent, traxoprodil increased hippocampal-prefrontal (Hc-PFC) coupling. Unlike ketamine, traxoprodil decreased connectivity within the PFC. Lanicemine had no effect on these properties. The improvement of Hc-PFC coupling corresponds well to clinical result, showing ketamine to have a greater antidepressant effect than traxoprodil, while lanicemine has a weak and transient effect. Connectivity changes overlapping between the drugs as well as alterations of local network properties occurred mostly in reward-related regions. CONCLUSION: The antidepressant effect of NMDA antagonists appears to be associated with enhanced Hc-PFC coupling. The effects on local network properties and regional connectivity suggest that improvement of reward processing might also be important for understanding the mechanisms underlying the antidepressant effects of these drugs.

Pharmacokinetic properties of enantiomerically pure GluN2B selective NMDA receptor antagonists with 3-benzazepine scaffold.

Recently, the eutomers of highly potent GluN2B selective NMDA receptor antagonists with 3-benzazepine scaffold were identified. Herein, pharmacokinetic properties regarding lipophilicity, plasma protein binding (PPB) and metabolism are analyzed. The logD7.4 values of 1.68 for phenol 1 and 2.46 for methyl ether 2 are in a very good range for CNS agents. A very similar logD7.4 value was recorded for the prototypical GluN2B antagonist ifenprodil (logD7.4 = 1.49). The herein developed high performance affinity chromatography (HPAC) method using human serum albumin as stationary phase led to PPB of 3-benzazepines (R)-1-3 and (S)-1-3 of 76-98%. Upon incubation with mouse liver microsomes, (R)-1-3 and (S)-1-3 showed moderate to high metabolic stability. The (R)-configured eutomers turned out to be metabolically more stable than their (S)-configured distomers. During phase I metabolism of 3-benzazepines 1-3 hydroxylations at both aromatic rings, the aliphatic side chain and the seven-membered ring were observed. O-demethylation of methyl ether (S)-2 was faster than O-demethylation of its enantiomer (R)-2. In phase I biotransformation the phenol eutomer (R)-1 showed comparable stability as ifenprodil. In phase II biotransformation, glucuronidation of the phenolic (only 1) and benzylic hydroxy groups was observed. Both enantiomers formed the same type of metabolites, respectively, but in different amounts. Whereas, the benzylic hydroxy group of (R)-2 was glucuronidated preferably, predominant benzylic glucuronidation of (S)-3 was detected. Mouse liver microsomes produced the glucuronide of phenol 1 (main metabolite) in larger amounts than rat liver microsomes.

NMDA Antagonists for Treatment-Resistant Depression.

Fifteen to thirty percent of patients with major depressive disorder do not respond to antidepressants that target the monoaminergic systems. NMDA antagonists are currently being actively investigated as a treatment for these patients. Ketamine is the most widely studied of the compounds. A brief infusion of a low dose of this agent produces rapid improvement in depressive symptoms that lasts for several days. The improvement occurs after the agent has produced its well characterized psychotomimetic and cognitive side effects. Multiple infusions of the agent (e.g., 2-3× per week for several weeks) provide relief from depressive symptoms, but the symptoms reoccur once the treatment has been stopped. A 96-h infusion of a higher dose using add-on clonidine to mitigate the psychotomimetic effects appears to also provide relief and resulted in about 40% of the subjects still having a good response 8 weeks after the infusion. As this was a pilot study, additional work is needed to confirm and extend this finding. Nitrous oxide also has had positive results. Of the other investigational agents, CERC-301 and rapastinel remain in clinical development. When careful monitoring of neuropsychiatric symptoms has been conducted, these agents all produce similar side effects in the same dose range, indicating that NMDA receptor blockade produces both the wanted and unwanted effects. Research is still needed to determine the appropriate dose, schedule, and ways to mitigate against unwanted side effects of NMDA receptor blockade. These hurdles need to be overcome before ketamine and similar agents can be prescribed routinely to patients.