Efficacy Of Ketamine Research Articles

A randomized, placebo-controlled, cross-over trial of ketamine in Rett syndrome

BackgroundPreclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy.DesignThis was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6–12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy.MethodsParticipants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite treatment. Ketamine was dosed twice daily at 0.75 mg/kg/dose (Cohort 1) or 1.5 mg/kg/dose (Cohort 2). An independent safety monitoring committee evaluated safety and approved proceeding to the next dose cohort. Caregivers, participants, outcome assessors, and study staff except pharmacists were blinded to allocation. The primary endpoint was safety and tolerability. Exploratory efficacy endpoints included change in clinician- and caregiver-rated measures of RTT features, brain activity on electroencephalography, and wearable biosensors to measure respiration, heart rate, sleep, and activity.ResultsTwenty-three participants enrolled (11 in Cohort 1, 12 in Cohort 2) from 3/12/2019–11/22/2021. One participant was excluded from analysis due to not meeting inclusion criteria on blinded review prior to analysis. One participant was withdrawn from the study due to an adverse event (vomiting) after the first dose of ketamine. Although planned for four dose cohorts, the trial was stopped after Cohort 2 due to enrollment challenges associated with the COVID-19 pandemic. Ketamine was safe and tolerated in both cohorts, with 1 related treatment emergent adverse event of vomiting. No difference was observed in efficacy between ketamine and placebo. Electroencephalography showed the expected increase in high frequency power with ketamine.ConclusionsShort-term, low-dose oral ketamine was safe and well tolerated in girls with RTT. No clinical efficacy of ketamine in treating symptoms of RTT was observed with 5 days of treatment, despite electroencephalography evidence of ketamine target engagement during the first dose. Further studies are needed to evaluate safety and efficacy of higher dose and longer exposure to ketamine in RTT.Trial registrationRegistered at clinicaltrials.gov NCT03633058.

Associations between hypothalamic-pituitary-adrenal (HPA) axis hormone levels, major depression features and antidepressant effects of ketamine.

Subanesthetic doses of (R,S)-ketamine (ketamine) have demonstrated rapid and robust antidepressant effects in individuals with depression. However, individual variability in response to ketamine exists, and current biomarkers of ketamine treatment response are not entirely understood. Preclinical evidence suggests a link between hypothalamic-pituitary-adrenal (HPA) axis activation, a determinant of the stress response system, and ketamine's efficacy in stressed mice exhibiting enhanced antidepressant responses. Here, we assessed the relationship between HPA axis, major depression features, and antidepressant response to ketamine in humans. We investigated 42 participants following medication washout with treatment-resistant depression who participated in a randomized, placebo-controlled, crossover trial receiving intravenous ketamine. Plasma levels of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline. Ketamine's antidepressant effects were assessed using the Montgomery-Asberg Depression Rating Scale. We found that baseline HPA axis hormone levels did not significantly moderate the antidepressant effects of ketamine. However, a negative association was observed between ACTH and CRF levels and the overall duration of depressive episodes, suggesting potential biomarker implications. Also, a negative correlation between baseline depressive scores and age of onset was observed, suggesting that the severity of depression might be greater if it develops at a younger age, indicating more enduring stress on the brain and body. Although we did not find a moderation effect of the plasma HPA axis hormones on the antidepressant effects of ketamine, moderation effects of the brain HPA axis hormones cannot be precluded and warrants further investigation. Importantly, our results implicate HPA axis components as potential biomarkers for the duration of depressive episodes.

Efficacy of fluoxetine and (R,S)-ketamine in attenuating conditioned fear behaviors in male mice

Post-traumatic stress disorder (PTSD) is caused by exposure to a traumatic or stressful event. Symptoms related to this disorder include persistent re-experiencing of memories and fear of generalization. Current pharmacological treatments for PTSD are insufficient, with fewer than 30% of patients reporting symptom remission. This study aims to determine the efficacy of acute (R,S)-ketamine and chronic fluoxetine (FLX) in reducing fear memory and fear generalization. In rodents, fear conditioning (FC) is commonly used in the literature to induce behaviors related to symptoms of PTSD, and the open field test (OFT) can assess anxiety and fear generalization behaviors during the exploration of a novel environment. In this study, FC consisted of a white noise cue stimulus and 4 inescapable foot shocks. Treatments began 4 hours after FC. Fear and anxiety behaviors were recorded during re-exposure to the FC stimuli at 24 hours and 2 weeks. The OFT was conducted 1 day before the last FC re-exposure. Results support the combined use of acute ketamine and chronic FLX as a treatment for reducing behaviors indicative of fear memory during re-exposure at 2 weeks, but not behaviors indicative of anxiety and fear generalization in the OFT. FLX alone was most effective in reducing behaviors related to fear generalization. This study contributes to the existing literature on pharmacological treatment for fear and anxiety behaviors relating to fear memory and fear generalization. Continued research is necessary to replicate results, optimize treatment protocols, and investigate the molecular adaptations to trauma and treatment. Significance StatementUp to 6% of people in the United States will develop PTSD within their lifetime, and less than half of those individuals will find relief from their symptoms given the current therapeutic options. This study offers preliminary support for the efficacy of ketamine and FLX in reducing PTSD-like behaviors induced by fear-conditioning in mice. Compared with current standard treatments, the results of the current study indicate the potential for a more effective therapeutic option for those with stress-related disorders, such as PTSD.

Ketamine Versus Etomidate for Rapid Sequence Intubation: A Systematic Review and Meta-Analysis of Randomized Trials.

To compare the safety and efficacy of ketamine and etomidate as induction agents to facilitate emergent endotracheal intubation. We searched MEDLINE, Embase, Cochrane Clinical Trials Register, and ClinicalTrials.gov from inception to April 3, 2024. We included randomized controlled trials (RCTs) that compared ketamine to etomidate to facilitate emergent endotracheal intubation in adults. Reviewers screened abstracts, full texts, and extracted data independently and in duplicate. We pooled data using a random-effects model, assessed risk of bias using the modified Cochrane tool and certainty of evidence using the Grading Recommendations Assessment, Development, and Evaluation approach. We pre-registered the protocol on PROSPERO (CRD42023472450). We included seven RCTs (n = 2384 patients). Based on pooled analysis, compared with etomidate, ketamine probably increases hemodynamic instability in the peri-intubation period (relative risk [RR], 1.29; 95% CI, 1.07-1.57; moderate certainty) but probably decreases the need for initiation of continuous infusion vasopressors (RR, 0.75; 95% CI, 0.57-1.00; moderate certainty) and results in less adrenal suppression (RR, 0.54; 95% CI, 0.45-0.66; moderate certainty). Ketamine probably has no effect on successful intubation on the first attempt (RR, 1.01; 95% CI, 0.97-1.05; moderate certainty) or organ dysfunction measured as the maximum Sequential Organ Failure Assessment (SOFA) score during the first 3 days in ICU (mean difference, 0.55 SOFA points lower; 95% CI, 1.12 lower to 0.03 higher; moderate certainty) and may have no effect on mortality (RR, 1.00; 95% CI, 0.83-1.21; low certainty) when compared with etomidate. Compared with etomidate, ketamine probably results in more hemodynamic instability during the peri-intubation period and appears to have no effect on successful intubation on the first attempt or mortality. However, ketamine results in decreased need for the initiation of vasopressor use and decreases adrenal suppression compared with etomidate.

Protocol for Comparing Benzodiazepine-Ketamine and Benzodiazepine-Fentanyl Sedation in Phacoemulsification (BEKEF): A Double-Blind Crossover Non-Inferiority Clinical Trial Study.

Cataract surgery, particularly phacoemulsification, often requires sedation alongside topical anesthesia to manage patient anxiety and discomfort. This protocol proposes a study comparing the efficacy of ketamine and fentanyl, both combined with benzodiazepine, as sedation options for patients undergoing bilateral phacoemulsification. In a randomized, double-blind, crossover clinical trial, at least 48 patients scheduled for bilateral cataract surgery will receive fentanyl with midazolam for one eye and ketamine with midazolam for the other. Sedation levels will be assessed using the Ramsay Sedation Scale, and the SURG-TLX Scale will measure intraoperative difficulties. Secondary outcomes include anesthesia-related complications, pain scores, and patient satisfaction. The primary outcomes, utilizing the Ramsay Sedation Scale, will determine if ketamine combined with a benzodiazepine is non-inferior to fentanyl combined with a benzodiazepine for sedation during phacoemulsification. Secondary outcomes will provide insight into complications, patient and surgeon comfort, and overall satisfaction. This trial will evaluate whether ketamine offers a safe and effective alternative to fentanyl for sedation in cataract surgery, potentially optimizing sedation protocols to enhance patient and surgeon experiences.

An evaluation of the efficacy and side effects of a single dose of ketamine in major depressive disorder.

This study aims to provide a comprehensive overview of the antidepressant and antisuicidal efficacy of ketamine in patients with unipolar depression, with a focus on the clinical evidence and safety profile. In our study, the data of 120 major depressive disorder patients who received single-dose ketamine infusion therapy were evaluated retrospectively, with Montgomery-Asberg Depression Rating Scale (MADRS) applied by the clinician before treatment and at the 4th and 24th hours after treatment and side effects at 4 and 24hours after treatment. There was a statistically significant difference between MADRS and MADRS-Suicide scores of all participants before the ketamine infusion (0th hour) and at the 4th and 24th hours after the ketamine infusion. Also, male and female, RAT(+) and RAT(-), and SA(+) and SA(-) participants have statistically significant differences on all three times for both MADRS and MADRS-S scores. The findings of this study are in line with those from previous research that demonstrated the rapid and robust antidepressant effects of ketamine, even in individuals with severe, treatment-resistant depression. Moreover, the observed reduction in suicidal ideation is particularly noteworthy, given the critical need for interventions that can provide rapid relief in acute suicidal crises. Key message What is already known on this topic - Ketamine is known for its rapid antidepressant and antisuicidal effects in treatment-resistant major depressive disorder, demonstrating significant symptom relief within hours of administration. What this study adds - This study provides additional evidence supporting ketamine's rapid efficacy in reducing depressive symptoms and suicidal ideation, highlighting statistically significant improvements observed at 4 and 24hours post-treatment. How this study might affect research, practice, or policy - The findings may encourage broader clinical adoption of ketamine for acute depressive episodes and suicidality, emphasizing the need for controlled medical settings to manage potential side effects, and could influence future research on optimizing dosing protocols and long-term safety.

Ketamine plus midazolam compared to midazolam infusion for the management of refractory status epilepticus

BackgroundData for the use of ketamine (Ket) in treatment of refractory and super-refractory status epilepticus (RSE, SRSE) is lacking despite its widespread growing use. We examined the efficacy of ketamine plus midazolam (MDZ) infusions for treating RSE versus midazolam alone. We hypothesized that ketamine initiation would result in earlier seizure termination. MethodsData was obtained from electronic health records (EHR) of adult patients who received intravenous anesthetic agents for RSE in our neurointensive care unit. Two cohorts were identified. The MDZ cohort received midazolam as the only intravenous anesthetic agent for RSE. The Ket+MDZ cohort received midazolam infusion followed by ketamine infusion. The primary outcomes were time from midazolam infusion start to SE end in both cohorts, and time from ketamine infusion start (Ket Start) to SE end in the Ket+MDZ cohort versus midazolam infusion start (MDZ start) to SE end in the MDZ cohort. Results73 patients were included (MDZ cohort n=17, Ket + MDZ cohort n=56). Cohorts did not differ significantly in age, sex, race, RSE etiology, or GCS on admission. Mean APACHE II score was higher in the Ket +MDZ cohort (26 ± 7.32 SD) versus the MDZ cohort (22 ± 5.89 SD)(P=.015). In survival analyses, cohorts did not differ significantly in time from midazolam start to SE end (HR=0.965, 95 % CI=0.556–1.673, P=.899; median [IQR]: MDZ: 25 h [4.5–58]; Ket+MDZ: 21.5 h [IQR 13.5–49]). Time from Ket start (Ket+MDZ group) versus time from MDZ start (MDZ group) to SE end was significantly shorter in the Ket+MDZ cohort (HR=1.895, 95 % CI=1.083–3.314, P=.025). The pattern of results was similar when including APACHE II and MDZ maximum dosage as covariates. ConclusionTime to SE end was significantly shorter after addition of ketamine infusion to midazolam infusion, versus after initiation of midazolam infusion monotherapy. Patients with higher disease severity favored Ket+MDZ. Randomized controlled trials are warranted in determining optimal anesthetics in RSE and SRSE.

Efficacy of Ketamine as an Adjuvant to Scalp Block for Hemodynamic Stability in Patients Undergoing Elective Craniotomy for Supratentorial Glioma: A Prospective Randomized Controlled Trial.

Introduction Scalp nerve block (SNB) attenuates the hemodynamic response to pin insertion and delivers excellent postoperative analgesia. This study aimed to evaluate the efficacy of SNB using ketamine as an adjuvant to bupivacaine on perioperative hemodynamic responses and postoperative pain in patients undergoing craniotomy for supratentorial glioma. Materials and Methods Sixty patients were randomized into two groups. They were given scalp nerve block either with bupivacaine and saline (group S) or bupivacaine and ketamine (group K). Primary outcome was to compare the change in mean arterial pressure (MAP) and heart rate (HR) at defined time points from baseline. Secondary outcomes included time to request for first analgesia, total analgesic consumption in intraoperative and postoperative periods till 24 hours, and numeric rating scale pain score at various time points in postoperative period till 24 hours. Results Fifty-seven patients were included in analysis. HR and MAP were comparable intraoperatively till closure. As soon as closure began, a significant increase in HR (group K vs. group S, 69.76 ± 9.03 vs. 93.96 ± 9.98, p -value = < 0.0001) and MAP (group K vs. group S, 79.4 ± 4.12 vs. 87.17 ± 12.67, p -value = 0.002) was noted in group S patients. This increase persisted in the postoperative period as well. The median total opioid consumed during intraoperative period in group K was 200 mcg versus 300 mcg in group S, p -value < 0.0001. Conclusion Adding ketamine as an adjuvant to bupivacaine for SNB not only provides significant hemodynamic stability but also reduces both intra- and postoperative analgesic consumption.

GluN2B on Adult-Born Granule Cells Modulates (R,S)-Ketamine's Rapid-Acting Effects in Mice.

Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the GluN2B subunit of the NMDA receptor on interneurons in the medial prefrontal cortex, no study to our knowledge has investigated the influence of GluN2B-expressing adult-born granule cells. Here, we examined whether (R,S)-ketamine's efficacy depends on adult-born hippocampal neurons using a genetic strategy to selectively ablate the GluN2B subunit of the NMDA receptor from Nestin+ cells in male and female mice, tested across an array of standard behavioral assays. We report that in male mice, GluN2B expression on 6-week-old adult-born neurons is necessary for (R,S)-ketamine's effects on behavioral despair in the forced swim test and on hyponeophagia in the novelty suppressed feeding paradigm, as well on fear behavior following contextual fear conditioning. In female mice, GluN2B expression is necessary for effects on hyponeophagia in novelty suppressed feeding. These effects were not replicated when ablating GluN2B from 2-week-old adult-born neurons. We also find that ablating neurogenesis increases fear expression in contextual fear conditioning, which is buffered by (R,S)-ketamine administration. In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing GluN2B partially modulate (R,S)-ketamine's rapid-acting effects. Future work targeting these 6-week-old adult-born neurons may prove beneficial for increasing the efficacy of (R,S)-ketamine.

Ketamine Therapy in Patients of Alcohol Use Disorder: A Prospective Pilot Study to Evaluate Abstinence Rate with This Add-on Treatment Modality

Background: Alcohol use disorders (AUDs) are emerging as a substance use disorder having various psychological and physical ill effects leading to hampering of individual’s productivity and functioning. Aims: The aim of this study was to evaluate the efficacy of ketamine in enhancing confidence levels to abstain from alcohol. Methods: Eighteen patients were administered ketamine intravenously after detoxification; a total of three doses, with a 3-day gap between each. The Alcohol Abstinence Self-Efficacy Scale was used to measure their confidence in abstaining from alcohol. Results: The study revealed a significant increase in mean confidence scores after three ketamine sessions, with a final assessment showing a 51.98% increase in confidence from baseline. Conclusions: The study found that ketamine therapy significantly increased confidence levels in individuals with AUD to abstain from alcohol, with P = 0.05 threshold. However, the impact may wane over time, suggesting the need for additional support or maintenance treatments.

A Scoping Review: Ketamine for the Prevention of Perioperative Shivering in Patients Undergoing Spinal Anesthesia.

Shivering is a frequently encountered perioperative complication in patients undergoing spinal anesthesia. Numerous different pharmacological agents have been employed to mitigate this issue. This scoping review aims to evaluate the efficacy of ketamine in mitigating the incidence of shivering. This review process utilized PubMed, JAMA, and Cochrane as primary databases. Searches were performed using combinations of key terms: "Ketamine," "Shivering," "Spinal Anesthesia," and "Hypothermia."Reviews of reference lists for additional pertinent data were performed. Whenketamine was compared against a saline control, three out of five studies found ketamine to be more effective (p < 0.05, p < 0.001, p < 0.001) in the prevention of shivering. When compared with tramadol, two studies found ketamine to be more effective (p < 0.001, p < 0.001), one found no difference (p = 0.261), and one found tramadol to be more effective (p < 0.001). Two studies found dexmedetomidine more effective (p < 0.022, p < 0.027) than ketamine and tramadol. When comparing ketamine, ondansetron, and meperidine, all three were effective (p < 0.001) versus saline, with no significant difference between the three. Meperidine demonstrated more efficacy (p < 0.05) in reducing the intensity of shivering than ketamine. Ketamine's effects on hemodynamics were shown to be equivocal or more favorable across several studies.While there is mixed evidence on whether it is better than other treatments, ketamine may have advantages from a hemodynamic standpoint. Dosages of 0.2-0.5 mg/kg with or without a subsequent infusion of 0.1 mg/kg per hour may aid in the prevention of perioperative shivering. Overall, ketamine is a safe and effective drug for the prevention of perioperative shivering. However, other drugs may be equally or more effective; therefore, patient population, hemodynamic status, patient preferences, and provider familiarity with different agents should be considered.

The Efficacy of Ketamine for Acute and Chronic Pain in Patients with Cancer: A Systematic Review of Randomized Controlled Trials.

Managing cancer-related pain poses significant challenges, prompting research into alternative approaches such as ketamine. This systematic review aims to analyze and summarize the impact of ketamine as an adjuvant to opioid therapy for cancer-related pain. We conducted a literature review in MEDLINE, EMBASE, and Scopus from 1 January 1982 to 20 October 2023. Abstracts were screened against inclusion criteria, and eligible studies underwent a full-text review. Data was extracted from the included studies, and a framework analysis approach summarized the evidence regarding ketamine's use in patients with cancer. A total of 21 randomized clinical trials were included, and the quality of all the included studies was good or fair. Significant improvements in pain scores and reduced morphine consumption were consistently observed with intravenous ketamine administration for postoperative pain control, particularly when combined with other analgesics such as morphine. Ketamine was less effective when used as an analgesic for chronic pain management, with several studies on neuropathic pain or chemotherapy-induced neuropathy finding minimal significant effect on reduction of pain scores or morphine requirements. The efficacy of ketamine in pain management appears to depend on factors such as dosage, route of administration, and patient population.

Efficacy of Continuous Infusion Ketamine for Analgosedation in the Medical Intensive Care Unit: A Propensity-Weighted Analysis

Background: Few randomized controlled trials have evaluated the use of ketamine vs opiate-based analgosedation. Methods: A retrospective cohort analysis of 169 mechanically ventilated patients admitted to the medical intensive care unit (MICU) at an academic medical center was conducted to evaluate efficacy of ketamine vs opiate-based analgosedation by comparing the percentage of time within target sedation range. The primary outcome was percentage of time within target sedation range (RASS -1 to +1) within first 72 hours of primary sedation initiation. Secondary outcomes including percentage of time under-sedated, over-sedated, and in coma; use of concomitant analgesic, sedative, and antipsychotic agents; presence of delirium; percentage of CPOT scores at goal; and hemodynamic effects were also evaluated. Results: After weighting, the mean percentage of time at RASS goal for ketamine patients was 43.0% compared to 41.4% for opiate-based sedation patients. Ketamine was not significantly non-inferior to opiate-based sedation for the mean percentage of time at RASS goal (P = .11). The median percentage of CPOT scores at goal was 13.3% higher in the ketamine group (P = .042). Patients in the ketamine group received significantly less additional sedative agents than the patients in the opiate-based sedation group. Conclusion: A similar percent of time at RASS goal was found for the ketamine analgosedation group compared to the opiate-based sedation group, although this did not reach statistical signicance for non-inferiority due to lack of statistical power. This study found a higher percentage of CPOT scores within goal with less additional sedative agents required compared to an opiate-based sedation regimen.

The neurobiological mechanism underlying ketamine’s rapid-acting antidepressant effect

Depression is one of the most common disabling mental disorders. However, first-line treatments for depression are typically slow-acting. Ketamine, a glutamatergic modulator with rapid antidepressant effects, has proven effective in treating both refractory depression and suicidal tendencies. The neurobiological mechanisms underlying the effects of antidepressants have become a research hotspot; yet, the exact processes remain unclear. Brain imaging studies have provided important evidence from macroscopic perspectives, such as brain structure and function, while biochemical studies have made significant discoveries from microscopic perspectives, including proteomics and genomics. Previous reviews have summarized a broad range of biomarkers related to the ketamine response, encompassing studies in imaging, electrophysiology, metabolism, immunology, genetics, and neurotrophy. In this review, we systematically summarize a number of potential biomarkers for predicting and modulating the efficacy of ketamine, from both macroperspectives (such as neuroimaging and neuroelectrophysiological markers) and microperspectives (such as neurobiochemical and genetic markers). Although research in this area is still in its infancy, these biomarkers can help clinicians identify whether ketamine intervention is needed for treatment-resistant depression, thereby reducing the burden on patients and society. However, the majority of biomarkers are still in the preclinical exploratory stage, and existing findings are limited. To realize the clinical application of these biomarkers, future studies should combine biomarkers of different types to investigate the relationships and interactions between them. This approach aims to optimize clinical outcomes by enhancing the involvement of biological targets in new models.

Does Ketamine Reduce Postoperative Pain and Agitation in Septorhinoplasty? A Systematic Review and Meta-analysis

Abstract Background: Agitation and pain following rhino plastic surgery lead to complications that delay recovery and affect patients quality of life. Ketamine is established drug in anaesthesia induction and analgesic agent. It is investigated for the prevention of agitation in children yet it is recently investigated for the prevention of post-operative agitation in adults following rhinoplasty. We conducted this systematic review and meta-analysis of randomised controlled trials to summarise and conclude its role in sub anaesthetic dose for the prevention of agitation and pain relief. Methods: In our research, we explored four digital platforms (Cochrane Central Register of Controlled Trials, PubMed, Scopus and Web of Science) until April 2024, searching for relevant articles that assessed the efficacy of ketamine in managing post-operative pain and agitation. The quality of the trials was evaluated using the risk of bias 2 tool. The data from the selected studies were extracted into a standardised online form and analysed with RevMan 5.4. Results: This study included six studies with a total sample size of 558 patients. We included randomised clinical trials assessing the efficacy of ketamine for pain and agitation management after rhinoplasty, septoplasty, or rhinoseptoplasty. All included studies were of high quality. Results of meta-analysis showed statistically significant reduction in pain score and incidence of agitation post-operative (standardised mean difference = −0.85, 95% confidence interval [CI] [ − 1.26, −0.43], P &lt; 0.0001), (risk ratio = 0.22, 95% CI [0.06, 0.78], P = 0.02), respectively. In addition, meta-analysis showed reduced analgesic requirements after surgery and treatment with ketamine was associated with less risk of nausea and vomiting. Conclusion: This systematic review and meta-analysis highlights ketamine’s potential benefits in post-surgery pain management and agitation reduction but emphasises the need for additional research with diverse and consistent samples to confirm these findings and examine possible side effects such as post-operative nausea and vomiting due to the observed heterogeneity amongst studies.

Ketamine reduces seizure and interictal continuum activity in refractory status epilepticus: a multicenter in-person and teleneurocritical care study.

There is not a preferred medication for treating refractory status epilepticus (RSE) and intravenous ketamine is increasingly used. Ketamine efficacy, safety, dosage, and influence of other variables on seizure cessation while on ketamine infusions are not well studied. We aimed to characterize ketamine effect on RSE, including interictal activity on electroencephalogram (EEG) and when done by Teleneurocritical care (TNCC). We conducted a multicenter, retrospective study from August 2017 to October 2022. Patients 18years or older who had RSE and received ketamine were included. The primary outcome was effect of ketamine on RSE including interictal activity; secondary outcomes were effect of other variables on RSE, care by TNCC, ketamine infusion dynamics, adverse events, and discharge outcomes. Logistic regression was used. Fifty-one patients from five hospitals met inclusion criteria; 30 patients had RSE and interictal activity on EEG. Median age was 56.8years (IQR 18.2) and 26% had previously diagnosed epilepsy. Sixteen (31%) patients were treated virtually by TNCC. In those with RSE on EEG, ketamine was added as the fourth antiseizure medication (mean 4.4, SD 1.6). An initial bolus of ketamine was used in 24% of patients (95mg, IQR 47.5), the median infusion rate was 30.8 mcg/kg/min (IQR 40.4), and median infusion duration was 40h (IQR 37). Ketamine was associated with 50% cessation of RSE and interictal activity at 24h in 84% of patients, and complete seizure cessation in 43% of patients. In linear regression, ASMs prior to ketamine were associated with seizure cessation (OR 2.6, 95% CI 0.9-6.9, p = 0.05), while the inverse was seen with propofol infusions (OR 0.02, 95% CI 0.001-0.43, p = 0.01). RSE management by in-person NCC versus virtual by TNCC did not affect rates of seizure cessation. Ketamine infusions for RSE were associated with reduced seizure burden at 24h, with 84% of patients having 50% seizure reduction. Similar efficacy and safety was observed irrespective of underlying RSE etiology or when done via TNCC vs in-person NCC.

Genetic ablation of the isoform γ of PI3K decreases antidepressant efficacy of ketamine in male mice

About one-third of major depressive disorder (MDD) patients demonstrate unresponsiveness to classic antidepressants, and even the clinical efficacy of fast-acting drugs such as ketamine varies significantly among patients with treatment-resistant depression. Nevertheless, the lack of suitable animal models that mimic a possible ketamine-resistant phenotype challenges the understanding of resistance to drug treatment. In this study, we showed that PI3Kγ knock-out (KO) mice do not respond to classical doses of ketamine and classical antidepressants. PI3Kγ KO mice were unresponsive to both the rapid and sustained antidepressant-like effects of a single dose of ketamine in the forced swimming test. Additionally, they were unresponsive to the antidepressant-like effects induced by the tricyclic antidepressant imipramine and the selective serotonin reuptake inhibitor fluoxetine. However, acute pharmacological inhibition of PI3Kγ did not block the antidepressant-like effect of ketamine, showing that a chronic deficiency of the PI3Kγ-mediated pathway is necessary for the effects of classic doses of ketamine and antidepressants. Therefore, we propose that PI3Kγ participates in the antidepressant activity and is likely implicated in the neurobiology and phenotype observed in patients with MDD who demonstrate treatment resistance.

The N-methyl-d-aspartate receptor hypothesis of ketamine's antidepressant action: evidence and controversies.

Substantial clinical evidence has unravelled the superior antidepressant efficacy of ketamine: in comparison to traditional antidepressants targeting the monoamine systems, ketamine, as an N-methyl-d-aspartate receptor (NMDAR) antagonist, acts much faster and more potently. Surrounding the antidepressant mechanisms of ketamine, there is ample evidence supporting an NMDAR-antagonism-based hypothesis. However, alternative arguments also exist, mostly derived from the controversial clinical results of other NMDAR inhibitors. In this article, we first summarize the historical development of the NMDAR-centred hypothesis of rapid antidepressants. We then classify different NMDAR inhibitors based on their mechanisms of inhibition and evaluate preclinical as well as clinical evidence of their antidepressant effects. Finally, we critically analyse controversies and arguments surrounding ketamine's NMDAR-dependent and NMDAR-independent antidepressant action. A better understanding of ketamine's molecular targets and antidepressant mechanisms should shed light on the future development of better treatment for depression. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Ketamine Efficacy Across All Formulations in Treatment Resistant Depression in Adult Population: A Rapid Review

Ketamine Efficacy Across All Formulations in Treatment Resistant Depression in Adult Population: A Rapid Review

The efficacy of ketamine for pain management in patients with cancer: A systematic review.

e24069 Background: Managing cancer-related pain poses significant challenges, prompting research into alternative approaches such as the study of ketamine. This systematic review aims to analyze and summarize the impact of ketamine as an adjuvant to opioid therapy for cancer-related pain. Methods: We conducted a literature review in MEDLINE, EMBASE, and Scopus, spanning from January 1, 1982, to October 20, 2022. Abstracts were screened against inclusion criteria, and eligible studies underwent a thorough full-text review. Data were extracted from the included studies, and a framework analysis approach was employed to summarize the evidence regarding ketamine's use in patients with cancer. The quality of included studies was assessed using the NIH Quality Assessment Tool for controlled intervention studies. Results: A total of 22 studies conducted between 2001 and 2019 were included, all assessed as having good quality. Three studies focusing on intrathecal administration of ketamine following oncological surgery demonstrated a substantial improvement in pain scores and a reduction in postoperative morphine requirements. Two studies exploring intramuscular use concluded that it led to improved pain scores. In contrast, three studies on subcutaneous administration and two studies on topical ketamine did not exhibit a significant impact on reducing pain scores or alleviating chemotherapy-induced peripheral neuropathy. Findings from two studies on oral administration and eight studies on intravenous administration indicated that intravenous ketamine reduced postoperative morphine requirements, while oral ketamine had no discernible effect on lowering pain scores. Conclusions: The use of intrathecal ketamine demonstrates significant improvement in post-op oncological pain and refractory cancer pain, resulting in lowered pain scores and decreased morphine requirements. Further research is essential to ascertain the extent to which incorporating ketamine with opioids in cancer pain treatment can enhance pain outcomes, especially in morphine-tolerant patients.