Ketamine in the treatment of refractory and super-refractory status epilepticus: Experience from two centres.

PURPOSE: There is insufficient evidence on the management of refractory status epilepticus (RSE) and super-RSE (SRSE). Ketamine is a N-methyl-d-aspartate receptor antagonist in the treatment of these entities. Our objectives were to study the effectiveness and safety of ketamine in the treatment of adult patients with RSE and SRSE, to determine the factors that can influence the response to ketamine, and to explore its use in patients without mechanical ventilation. METHODS: Adult patients who had received intravenous ketamine for the treatment of RSE or SRSE at Hospital Universitario Clínico San Carlos (Madrid, Spain) or Hospital Universitari Vall d'Hebron (Barcelona, Spain) from 2017 to 2023 were retrospectively analysed. RESULTS: This study included 58 adult patients, mean (standard deviation) age 60.2 (15.7) years, of whom 41 (70.7 %) were male; 33 (56.9 %) patients responded to ketamine without recurrence, with a low rate of adverse effects (8.6 %). The presence of SRSE at the time of ketamine initiation (OR 0.287, p = 0.028) and the time elapsed between status epilepticus onset and ketamine administration (OR 0.991, p = 0.034) were associated with worse response to ketamine. Patients treated without mechanical ventilation had similar rates of response without recurrence (62.5% vs 56.9 %) and lower mortality (37.5% vs 53.5 %) compared to the overall group. CONCLUSION: Ketamine is an effective drug with few adverse effects. Prompt administration should be considered in patients with RSE requiring anaesthesia, in patients with SRSE, and in patients with RSE who do not respond to standard antiseizure drugs and in whom mechanical ventilation is not advised.

Neuroprotective effects of riluzole in Alzheimer's disease: A comprehensive review.

BACKGROUND: Despite several hundred clinical trials of drugs that initially showed promise, there has been limited clinical improvement in Alzheimer's disease (AD). This may be attributed to the existence of at least 25 abnormal cellular pathways that underlie the disease. It is improbable for a single drug to address all or most of these pathways, thus even drugs that show promise when administered alone are unlikely to produce significant results. According to previous studies, eight drugs, namely, dantrolene, erythropoietin, lithium, memantine, minocycline, piracetam, riluzole, and silymarin, have been found to target multiple pathways that are involved in the development of AD. Among these drugs, riluzole is currently indicated for the treatment of medical conditions in both adult patients and children and has gained increased attention from scientists due to its potential in the excitotoxic hypothesis of neurodegenerative diseases. OBJECTIVE: The aim of this study was to investigate the effects of drugs on AD based on cellular and molecular mechanisms. METHODS: The literature search for this study utilized the Scopus, ScienceDirect, PubMed, and Google Scholar databases to identify relevant articles. RESULTS: Riluzole exerts its effects in AD through diverse pathways including the inhibition of voltage-dependent sodium and calcium channels, blocking AMPA and NMDA receptors and inhibiting the release of glutamic acid release and stimulation of EAAT1-EAAT2. CONCLUSION: In this review article, we aimed to review the neuroprotective properties of riluzole, a glutamate modulator, in AD, which could benefit patients with the disease.

One-Year Outcomes Following Intravenous Ketamine Plus Digital Training Among Patients with Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial.

This secondary analysis of a randomized clinical trial examines whether automated self-association training can prolong the antidepressant effect of a single infusion of ketamine beyond 1 month in patients with treatment-resistant depression.

The NMDA receptor antagonists memantine and ketamine as anti-migraine agents.

Migraine is a debilitating disorder affecting females more frequently than males. There is some evidence that drugs targeting glutamate receptors: memantine and ketamine might be beneficial in the therapy of this entity. Therefore, the purpose of this work is to present NMDA receptor antagonists, memantine and ketamine, as potential anti-migraine agents. We searched PubMed/MEDLINE, Embase, and clinical trials submitted to ClinicalTrials.gov to find publications describing eligible trials published between database inception and December 31, 2021. This comprehensive literature review summarizes data on the use of the NMDA receptor antagonists memantine and ketamine in the pharmacotherapy of migraine. Results from 20 previous and recent preclinical experiments are discussed and correlated with 19 clinical trials (including case series, open-label, and randomized placebo-controlled trials). For the purposes of this review, the authors hypothesized that the propagation of SD is a major mechanism in the pathophysiology of migraine. In several animal studies and in vitro studies, memantine and ketamine inhibited or reduced propagation of the SD. In addition, the results of clinical trials suggest that memantine or ketamine may be an effective treatment option for migraine. However, most studies on these agents lack control group. Although further clinical trials are needed, the results suggest that ketamine or memantine may be promising molecules for the treatment of severe migraine. Particular attention should be paid to people who have a treatment-resistant form of migraine with aura or have exhausted existing treatment options. For them, the drugs under discussion could represent an interesting alternative in the future.

Randomized placebo-controlled crossover trial of memantine in children with epileptic encephalopathy.

Memantine is an N-methyl-D-aspartate receptor antagonist, approved for dementia treatment. There is limited evidence of memantine showing benefit for paediatric neurodevelopmental phenotypes, but no randomized placebo-controlled trials in children with developmental and epileptic encephalopathy. In this randomized double-blind placebo-controlled crossover trial (Trial registration: https://clinicaltrials.gov/ct2/show/NCT03779672), patients with developmental and epileptic encephalopathy received memantine and placebo, each for a 6-week period separated by a 2-week washout phase. Electroencephalography, seizure diary, patient caregivers' global impression, serum inflammatory markers and neuropsychological evaluation were performed at baseline and after each treatment phase. The primary outcome measure was classification as a 'responder', defined as ≥2 of: >50% seizure frequency reduction, electroencephalography improvement, caregiver clinical impression improvement or clear neuropsychological testing improvement. Thirty-one patients (13 females) enrolled. Two patients withdrew prior to initiating medication and two (twins) had to be removed from analysis. Of the remaining 27 patients, nine (33%) were classified as responders to memantine versus two (7%) in the placebo group (P < 0.02). Electroencephalography improvement was seen in eight patients on memantine compared to two on placebo (P < 0.04). Seizure improvement was observed in eight patients on memantine and two on placebo (P < 0.04). Caregivers reported overall clinical improvement in 10 patients on memantine compared to seven on placebo (not significant). Statistical analysis of neuropsychological evaluation suggested improvements in symptoms of attention-deficit hyperactivity disorder and autism. Memantine is a safe and effective treatment for children with developmental and epileptic encephalopathy, having the potential to improve both seizure control and cognitive function.

A Novel, Brief, Fully Automated Intervention to Extend the Antidepressant Effect of a Single Ketamine Infusion: A Randomized Clinical Trial.

OBJECTIVE: Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing neuroplasticity. The authors tested whether an automated, computer-based approach could efficiently leverage enhanced neuroplasticity to extend the durability of rapid clinical response. METHODS: A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression were randomized in a double-blind, parallel-arm design to receive an active/active treatment combination (ketamine plus active "automated self-association training" [ASAT]; N=53) or one of two control arms that lacked either the active drug component (saline plus active ASAT; N=51) or the active behavioral component (ketamine plus sham ASAT; N=50). One day after a single infusion of intravenous ketamine (0.5 mg/kg over 40 minutes) or inert placebo (saline), active ASAT-targeting self-worth through automated "evaluative conditioning" training delivered by computer-or sham ASAT (consisting of identical computer tasks that included no positive or self-referential stimuli) was given, delivered twice daily over 4 consecutive days (eight sessions, ≤20 minutes per session). The prespecified primary outcome measure throughout the main (30-day) study period was score on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Ketamine rapidly and significantly reduced depression scores at 24 hours postinfusion (group-by-time interaction: standardized beta [ß]=-1.30, 95% CI=-1.89, -0.70; t=-4.29, df=150). In intent-to-treat linear mixed models, depression scores in the ketamine+ASAT group remained significantly and stably low over the 30-day study period relative to those of the saline+ASAT group (ß=-0.61, 95% CI=-0.95, -0.28; t=-3.62, df=148). By contrast, depression scores following ketamine+sham treatment followed a significant, increasing linear trajectory from 24 hours to 30 days, approaching the levels observed in the saline+ASAT group (group-by-time interaction relative to the saline+ASAT group: ß=0.015, 95% CI=0.003, 0.03; t=2.35, df=568). CONCLUSIONS: After priming the brain with ketamine, training positive self-associations could provide an efficient, low-cost, portable, noninvasive, and highly dissemination-ready strategy for leveraging and extending ketamine's rapid antidepressant effects.

The multimodal serotonin compound Vilazodone alone, but not combined with the glutamate antagonist Amantadine, reduces l-DOPA-induced dyskinesia in hemiparkinsonian rats.

Parkinson's disease (PD) is a progressive, neurodegenerative movement disorder caused by loss of nigrostriatal dopamine (DA) neurons. DA replacement therapy using L-3,4-dihydroxyphenylalanine (l-DOPA) improves motor function but often results in l-DOPA-induced dyskinesia (LID) typified by abnormal involuntary movements (AIMs). In states of DA depletion, striatal serotonin (5-HT) hyperinnervation and glutamate overactivity are implicated in LID. To target these co-mechanisms, this study investigated the potential anti-dyskinetic effects of FDA-approved Vilazodone (VZD), a 5-HT transport blocker and partial 5-HT1A agonist, and Amantadine (AMAT), a purported NMDA glutamate antagonist, in 6-hydroxydopamine-lesioned hemiparkinsonian Sprague-Dawley rats. Dose-response curves for each drug against l-DOPA-induced AIMs were determined to identify effective threshold doses. A second cohort of rats was tested using the threshold doses of VZD (1, 2.5 mg/kg, s.c.) and/or AMAT (40 mg/kg, s.c.) to examine their combined, acute effects on LID. In a third cohort, VZD and/or AMAT were administered daily with l-DOPA for 14 days to determine prophylactic effects on LID development. In a final cohort, rats with established LID received VZD and/or AMAT injections for 2 weeks to examine their interventional properties. Throughout experiments, AIMs were rated for dyskinesia severity and forepaw adjusting steps (FAS) were monitored l-DOPA motor efficacy. Results revealed that acute and chronic VZD + l-DOPA treatment significantly decreased AIMs and maintained FAS compared to l-DOPA alone. AMAT + l-DOPA co-administration did not exert any significant effects on AIMs or FAS, while the co-administration of VZD and AMAT with l-DOPA demonstrated intermediate effects. These results suggest that co-administration of low-dose VZD and AMAT with l-DOPA does not synergistically reduce LID in hemiparkinsonian rats. Importantly, low doses of VZD (2.5, 5 mg/kg) did reduce the development and expression of LID while maintaining l-DOPA efficacy, supporting its potential therapeutic utility for PD patients.

Neurocognitive effects of repeated ketamine infusions in comorbid posttraumatic stress disorder and major depressive disorder.

BACKGROUND: The glutamate N-methyl-d-aspartate (NMDA) receptor antagonist ketamine rapidly ameliorates posttraumatic stress disorder (PTSD) and depression symptoms in individuals with comorbid PTSD and major depressive disorder (MDD). However, concerns over ketamine's potential neurocognitive side effects have yet to be assessed in this population. The current study investigated 1) changes in neurocognitive performance after a repeated ketamine dosing regimen and 2) baseline neurocognitive performance as a predictor of ketamine treatment effect. METHOD: Veterans with comorbid PTSD and MDD (N = 15) received six infusions of 0.5 mg/kg ketamine over a 12-day period. Neurocognitive and clinical outcomes assessments occurred at baseline and within 7 days of infusion-series completion using the CogState battery. RESULTS: Repeated ketamine infusions did not significantly worsen any measures of cognition. Rather, significant improvement was observed in working memory following completion of the infusion series. In addition, greater improvements in PTSD and MDD symptoms were associated with lower working memory, slower processing speed and faster set shifting at baseline. Lower verbal learning was also predictive of improvement in depression. LIMITATIONS: This study applied an open-label design without a placebo control. As such, it is not known to what extent the correlations or improvement in neurocognitive performance may have occurred under placebo conditions. CONCLUSION: This is the first study to examine the neurocognitive effects of repeated ketamine in participants with comorbid PTSD and MDD. Our findings suggest potential baseline neurocognitive predictors of ketamine response for comorbid PTSD and MDD symptoms.

Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant.

GRIA3 at Xq25 encodes glutamate ionotropic receptor AMPA type 3 (GluA3), a subunit of postsynaptic glutamate-gated ion channels mediating neurotransmission. Hemizygous loss-of-function (LOF) variants in GRIA3 cause a neurodevelopmental disorder (NDD) in male individuals. Here, we report a gain-of-function (GOF) variant at GRIA3 in a male patient. We identified a hemizygous de novo missense variant in GRIA3 in a boy with an NDD: c.1844C > T (p.Ala615Val) using whole-exome sequencing. His neurological signs, such as hypertonia and hyperreflexia, were opposite to those in previous cases having LOF GRIA3 variants. His seizures and hypertonia were ameliorated by carbamazepine, inhibiting glutamate release from presynapses. Patch-clamp recordings showed that the human GluA3 mutant (p.Ala615Val) had slower desensitization and deactivation kinetics. A fly line expressing a human GluA3 mutant possessing our variant and the Lurcher variant, which makes ion channels leaky, showed developmental defects, while one expressing a mutant possessing either of them did not. Collectively, these results suggest that p.Ala615Val has GOF effects. GRIA3 GOF variants may cause an NDD phenotype distinctive from that of LOF variants, and drugs suppressing glutamatergic neurotransmission may ameliorate this phenotype. This study should help in refining the clinical management of GRIA3-related NDDs.

The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia.

Focal cortical dysplasia (FCD) is one of the most common malformations causing refractory epilepsy. Dysregulation of glutamatergic systems plays a critical role in the hyperexcitability of dysplastic neurons in FCD lesions. The pharmacoresistant nature of epilepsy associated with FCD may be due to a lack of well-tolerated and precise antiepileptic drugs that can target glutamate receptors. Here, for the first time in human FCD brain slices, we show that the established, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, perampanel has potent antiepileptic action. Moreover, we demonstrate that this effect is due to a reduction in burst firing behavior in human FCD microcircuits. These data support a potential role for the treatment of refractory epilepsy associated with FCD in human patients.

New onset tinnitus in the absence of hearing changes following COVID-19 infection.

BACKGROUND: A variety of neurosensory symptoms including tinnitus have been associated with COVID-19 infection. While most cases of tinnitus are associated with hearing loss, here we report a case of severe tinnitus following COVID-19 infection with normal thresholds through 8000 Hz. CASE REPORT: A 49-year-old male presented with new onset severe tinnitus following COVID-19 infection. Tinnitus was bilateral, constant and nonpulsatile. Audiometric evaluation revealed normal threshold through 8000 Hz, with mild hearing loss at 16,000 Hz. Conservative measures including masking strategies failed to mitigate symptoms. A trial of gabapentin 300 mg twice per day improved tinnitus with no notable side effects. CONCLUSION: This patient may represent a subpopulation of patients who suffer from severe tinnitus following COVID-19 infection in the setting of largely normal hearing. The pathophysiology may be distinct from the more common hearing loss associated tinnitus and perhaps neuromodulators may play a larger role in mitigating tinnitus in this patient subset.

Analysis of Gabapentin's Efficacy in Tinnitus Treatment: A Systematic Review.

OBJECTIVES: Tinnitus can be a chronic symptom that brings disability and distress. Some studies suggested that gabapentin might be effective on tinnitus relief. The objective of the study is to perform a systematic review in order to evaluate the efficacy of oral gabapentin in patients with tinnitus. METHODS: A literature search was conducted in English and following the recommendations from PRISMA. The terms used were: ("tinnitus" OR "subjective tinnitus") AND ("gabapentin"). The study selection was performed following the eligibility criteria in accordance to the PICOS (population, intervention, comparison, outcome, study design) strategy-patients with tinnitus; oral gabapentin; placebo; reduction of tinnitus severity questionnaires scores; prospective, double-blind, randomized controlled trial, respectively. The selected studies were included in qualitative synthesis. The studies were analyzed according to Joanna Briggs Institute's critical appraisal checklist for randomized controlled trials. RESULTS: One hundred twenty-one studies were found in 9 databases and 8 studies were found in gray literature. After study selection, 6 articles were read in full. Then, 2 studies were excluded and 4 were included in qualitative synthesis. All 4 articles were analyzed according to critical evaluation checklist. CONCLUSIONS: There is insufficient evidence to recommend the use of gabapentin for patients with tinnitus.

Spinal neurochemical mechanisms of acute stress-induced visceral hypersensitivity in healthy rats.

Psychological stress has been demonstrated to increase reports of pain in humans with pelvic pain of urologic origin. In rodent models, conditioning with acute footshock (AFS) has been demonstrated to increase measures of stress/anxiety as well as bladder hypersensitivity. The spinal neurochemical mechanisms of this pro-nociceptive process are unknown and so the present study administered antagonists for multiple receptors that have been associated with facilitatory mechanisms into the spinal intrathecal space. Bladder hypersensitivity was induced through use of an AFS paradigm in which female Sprague-Dawley rats received a 15-min intermittent shock treatment. Visceromotor responses (VMRs; abdominal muscle contractions) to air pressure-controlled urinary bladder distension (UBD) were used as nociceptive endpoints. Immediately following AFS treatments, rats were anesthetized (inhaled isoflurane, IP urethane) and surgically prepared. Pharmacological antagonists were administered via an intrathecal (IT) catheter onto the lumbosacral spinal cord and VMRs to graded UBD determined 15 min later. Administration of IT naloxone hydrochloride (10 µg) and IT phentolamine hydrochloride (10 µg) resulted in VMRs that were more robust than VMRs in rats that received AFS and IT normal saline whereas there was no significant effect of these drugs on VMRs in rats which underwent non-footshock procedures. In contrast, a low dose of the NMDA-receptor antagonist, MK-801 (30 µg), significantly reduced VMRs in rats made hypersensitive to UBD by AFS, but had no significant effect on rats that underwent non-footshock procedures. This study suggests that pro-nociceptive effects of AFS in otherwise healthy rats involve a spinal NMDA-linked mechanism. The effects of IT naloxone and IT phentolamine suggest the presence of inhibitory influences that are opioidergic and/or alpha-adrenergic and that are masked by the pro-nociceptive mechanisms. Other agents with no statistically significant effect on VMRs include methysergide (30 µg), ondansetron (10 µg), mecamylamine (50 µg), antalarmin (24 µg), aSVG30 (12 µg), and SSR149415 (50 µg).

Mechanisms of ketamine and its metabolites as antidepressants.

Treating major depression is a medical need that remains unmet by monoaminergic therapeutic strategies that commonly fail to achieve symptom remission. A breakthrough in the treatment of depression was the discovery that the anesthetic (R,S)-ketamine (ketamine), when administered at sub-anesthetic doses, elicits rapid (sometimes within hours) antidepressant effects in humans that are otherwise resistant to monoaminergic-acting therapies. While this finding was revolutionary and led to the FDA approval of (S)-ketamine (esketamine) for use in adults with treatment-resistant depression and suicidal ideation, the mechanisms underlying how ketamine or esketamine elicit their effects are still under active investigation. An emerging view is that metabolism of ketamine may be a crucial step in its mechanism of action, as several metabolites of ketamine have neuroactive effects of their own and may be leveraged as therapeutics. For example, (2R,6R)-hydroxynorketamine (HNK), is readily observed in humans following ketamine treatment and has shown therapeutic potential in preclinical tests of antidepressant efficacy and synaptic potentiation while being devoid of the negative adverse effects of ketamine, including its dissociative properties and abuse potential. We discuss preclinical and clinical studies pertaining to how ketamine and its metabolites produce antidepressant effects. Specifically, we explore effects on glutamate neurotransmission through N-methyl D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), synaptic structural changes via brain derived neurotrophic factor (BDNF) signaling, interactions with opioid receptors, and the enhancement of serotonin, norepinephrine, and dopamine signaling. Strategic targeting of these mechanisms may result in novel rapid-acting antidepressants with fewer undesirable side effects compared to ketamine.

Kynurenic acid in neurodegenerative disorders-unique neuroprotection or double-edged sword?

AIMS: The family of kynurenine pathway (KP) metabolites includes compounds produced along two arms of the path and acting in clearly opposite ways. The equilibrium between neurotoxic kynurenines, such as 3-hydroxykynurenine (3-HK) or quinolinic acid (QUIN), and neuroprotective kynurenic acid (KYNA) profoundly impacts the function and survival of neurons. This comprehensive review summarizes accumulated evidence on the role of KYNA in Alzheimer's, Parkinson's and Huntington's diseases, and discusses future directions of potential pharmacological manipulations aimed to modulate brain KYNA. DISCUSSION: The synthesis of specific KP metabolites is tightly regulated and may considerably vary under physiological and pathological conditions. Experimental data consistently imply that shift of the KP to neurotoxic branch producing 3-HK and QUIN formation, with a relative or absolute deficiency of KYNA, is an important factor contributing to neurodegeneration. Targeting specific brain regions to maintain adequate KYNA levels seems vital; however, it requires the development of precise pharmacological tools, allowing to avoid the potential cognitive adverse effects. CONCLUSIONS: Boosting KYNA levels, through interference with the KP enzymes or through application of prodrugs/analogs with high bioavailability and potency, is a promising clinical approach. The use of KYNA, alone or in combination with other compounds precisely influencing specific populations of neurons, is awaiting to become a significant therapy for neurodegenerative disorders.

Memantine Modulates Oxidative Stress in the Rat Brain following Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an animal model most commonly used in research on the pathomechanisms of multiple sclerosis (MS). The inflammatory processes, glutamate excitotoxicity, and oxidative stress have been proposed as determinants accompanying demyelination and neuronal degeneration during the course of MS/EAE. The aim of the current study was to characterize the role of NMDA receptors in the induction of oxidative stress during the course of EAE. The effect of memantine, the uncompetitive NMDA receptor antagonist, on modulation of neurological deficits and oxidative stress in EAE rats was analyzed using several experimental approaches. We demonstrated that the expression of antioxidative enzymes (superoxide dismutases SOD1 and SOD2) were elevated in EAE rat brains. Under the same experimental conditions, we observed alterations in oxidative stress markers such as increased levels of malondialdehyde (MDA) and decreased levels of sulfhydryl (-SH) groups, both protein and non-protein (indicating protein damage), and a decline in reduced glutathione. Importantly, pharmacological inhibition of ionotropic NMDA glutamate receptors by their antagonist memantine improved the physical activity of EAE rats, alleviated neurological deficits such as paralysis of tail and hind limbs, and modulated oxidative stress parameters (MDA, -SH groups, SOD's). Furthermore, the current therapy aiming to suppress NMDAR-induced oxidative stress was partially effective when NMDAR's antagonist was administered at an early (asymptomatic) stage of EAE.