Effects Of Ketamine Research Articles

Effects of (S)-ketamine on depression-like behaviors in a chronic variable stress model: a role of brain lipidome.

Introduction: Compelling evidence indicates that a single sub-anesthetic dose of (S)-ketamine elicits rapid and robust antidepressant effects. However, the underlying mechanisms behind the antidepressant effects of (S)-ketamine remain unclear. Methods: Here, using a chronic variable stress (CVS) model in mice, we analyzed changes inthe lipid compositions of the hippocampus and prefrontal cortex (PFC) with a mass spectrometry-based lipidomic approach. Results: Similar to previous research outcomes, the current study also showed that (S)-ketamine reversed depressive-like behaviors in mice produced by CVS procedures. Moreover, CVS induced changes inthe lipid compositions of the hippocampus and PFC, notably in the contents of sphingolipids, glycerolipids, and fatty acyls. With the administration of (S)-ketamine, CVS-induced lipid disturbances were partially normalized, particularly in the hippocampus. Conclusion: Altogether, our results indicated that (S)-ketamine could rescue CVS-induced depressive-like behaviors in mice through region-specific modulation of the brain lipidome, contributing to the understanding of (S)-ketamine's antidepressant effects.

A comparison of the behavioral effects of ketamine and propofol sedation in the pediatric endoscopy unit

Introduction: Hospitalization and anesthesia can have a harmful psychological impact on children, leading to behavioral abnormalities. Using the Post Hospitalization Behavior Questionnaire for Ambulatory Surgery (PHBQ-AS) version of the Post Hospitalization Behavior Questionnaire for daycase patients, the objective of this study is to assess the differences between ketamine and propofol and propofol alone use following anesthesia. Materials and methods: After receiving approval from the ethics committee, 84 children ages 2 to 18 who would undergo sedation surgery at the pediatric endoscopy-colonoscopy unit at Ankara City Hospital were enrolled in the study. Group K consisted of 27 patients sedated with ketamine and propofol, while group P consisted of 57 children sedated with propofol. To detect postoperative behavioral alterations in these youngsters, a questionnaire (POBQ-AS) was administered soon prior to the procedure and on the third day following it. Results: Pre-procedural Behavior Assessment Questionnaire Total scores were comparable for both groups. The measures on the third day following the surgery were also comparable. The Post-procedure Behavior Evaluation Questionnaire Total Score increased significantly (p 0.05) in both groups compared to the pre-procedure score. In Group K, the answers to the questions "Is he disconnected to his environment?" and "Does he become depressed when left alone?" increased significantly more than in the other group (p 0.05). Conclusion: Pediatric perioperative behavioral problem may be common. On the third postoperative day, sedative applications involving ketamine and propofol induce detrimental behavioral alterations, according to this study. In our patient group selected from the endoscopy unit to exclude factors such as mask induction, muscle relaxants, inhalation anesthetics, and surgical incision pain, we believe that only the negative behavioral changes of the intravenous anesthetics ketamine and propofol, as well as factors such as inflammation, surgical stress, and neurotoxicity, should be the focus of future research.

Effects of Intraoperative Low Dose Ketamine on Hemodynamic Changes and Postoperative Opioid Consumption in Patients Undergoing Laparoscopic Cholecystectomy

Background: Laparoscopic Cholecystectomy (LC) as a minimally invasive surgery has become extremely common in recent decades. Despite being less invasive, these surgeries require postoperative analgesia. In this regard Ketamine, can reduce postoperative pain and opioid consumption.
 Owing to the wide heterogeneity of studies on efficacy of ketamine in pain management in different operations, anesthetics methods, and the way and dose of consumption, the present study sought to evaluate the effects of intraoperative low-dose ketamine on postoperative pain, opioid consumption, and hemodynamic changes of patients undergoing LC in the 5th Azar hospital of Gorgan in 2019.
 Methods: 66 patients with the need for LC were randomly selected. After induction of anesthesia and intubation, and before surgical incision, 0.5 mg/kg of Ketamine was injected as a bolus for target group (n=33), and the equivalent volume of normal saline for control group (n=33). Systolic, diastolic and mean arterial pressure were recorded before, during, after anesthesia and during surgery at 5-minute intervals. Postoperative pain was evaluated through Visual Analog Scale(VAS). We recorded the time of the first dose of opioid, total amounts of opioid consumption during the first 24 hours after surgery and doses of antihypertensive drug.
 Results: VAS score (opioid requirement) were lower in the intervention group only in the recovery period (p=0.049). There was no difference between two groups in total amounts of opioid consumption during 24 hours even in cases with increase of the length of surgery (p= 0.742). Blood pressure trend increased from the beginning of induction to the end of anesthesia (p-value<0.001); however, there was no statistically significant difference between two groups (p=0.786). The need for labetalol was higher in control group (p<0.0001).
 Conclusion: Although 0.5 mg/kg ketamine could not reduce overall opioid consumption within 24 hours after surgery, it had significant pain relief during awakening and recovery. Additionally, it reduced the need for further interventions, such as labetalol and other drugs and therefore was associated with lower costs.

Cytokine- and Vascular Endothelial Growth Factor-Related Gene-Based Genome-Wide Association Study of Low-Dose Ketamine Infusion in Patients with Treatment-Resistant Depression.

Ketamine may work as an anti-inflammatory agent, and it increases the levels of vascular endothelial growth factor (VEGF) in patients with treatment-resistant depression. However, whether genes related to pro-inflammatory and anti-inflammatory cytokines and VEGF may predict the treatment response to ketamine remains unknown.Therefore the aim of this study was to analyze whether specific genes related to inflammatory processes and VEGF were associated with treatment response to low-dose ketamine in patients with treatment-resistant depression. Based on the genome data from our clinical trial, this study was a secondary analysis of candidate genes correlated with different timepoints of depressive symptoms. In total, 65 patients with treatment-resistant depression (n = 21 for ketamine 0.5 mg/kg, 20 for ketamine 0.2 mg/kg, and 24 for normal saline) were genotyped for 684,616 single nucleotide polymorphisms. Genes associated with 80 cytokines (i.e., interleukin [IL]-1, IL-6, tumor necrosis factor-α, and adiponectin) and VEGF (i.e., VEGF and VEGF receptors) were selected for the gene-based genome-wide association study on the antidepressant effect of a ketamine infusion. Specific single nucleotide polymorphisms, including rs2540315 and rs75746675 in IL1R1 and rs79568085 in VEGFC, were related to the rapid (within 240 min) antidepressant effect of a ketamine infusion; specific single nucleotide polymorphisms, such as Affx-20131665 in PIGF and rs8179353, rs8179353, and rs8179353 in TNFRSF8, were associated with the sustained (up to 2 weeks) antidepressant effect of low-dose (combined 0.5mg/kg and 0.2mg/kg) ketamine. Our findings further revealed that genes related to both anti-inflammatory and pro-inflammatory cytokines (i.e., IL-1, IL-2, IL-6, tumor necrosis factor-α, C-reactive protein, and adiponectin) and VEGF-FLK signaling predicted the treatment response to a ketamine infusion in patients with treatment-resistant depression. The synergic modulation of inflammatory and VEGF systems may contribute to the antidepressant effect of ketamine. University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number: UMIN000016985.

“Anti-cancer” effect of ketamine in comparison with MK801 on neuroglioma and lung cancer cells

Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, is commonly used to induce anaesthesia during cancer surgery and relieve neuropathic and cancer pain. This study was conducted to assess whether ketamine has any inhibiting effects on neuroglioma (H4) and lung cancer cells (A549) in vitro.The cultured H4 and A549 cells were treated with ketamine and MK801 (0.1, 1, 10, 100, or 1000 μM) for 24 h. The expressions of glutamate receptors on both types of cancer cells were assessed with qRT-PCR. In addition, cell proliferation and migration were assessed with cell counting Kit-8 and wound healing assays. Cyclin D1, matrix metalloproteinase 9 (MMP9), phosphorylation of extracellular signal-regulated kinase (pERK), and cleaved-caspase-3 expression together with reactive oxygen species (ROS) were also assessed with Western blot, immunostaining, and/or flowcytometry.NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors were expressed on both H4 and A549 cells. Ketamine inhibited cancer cell proliferation and migration in a dose-dependent manner by suppressing the cell cycle and inducing apoptosis. Ketamine decreased cyclin D1, pERK, and MMP9 expression. In addition, ketamine increased ROS and cleaved caspase-3 expression and induced apoptosis. The anti-cancer effect of ketamine was more pronounced in A549 cells when compared with H4 cells. MK801 showed similar effects to those of ketamine.Ketamine suppressed cell proliferation and migration in both neuroglioma and lung cancer cells, likely through the antagonization of NMDA receptors.

Evaluation of paradoxical effect of small dose ketamine as adjuvant in deep sedation for endoscopy patients

ABSTRACT Background This study tested the hypothesis that use of ketamine as an ‎adjuvant to propofol in the induction of deep sedation for ‎endoscopy patients could lead, paradoxically, to faster ‎emergence.‎ Methods We conducted a single-center, prospective randomized ‎controlled study on 154 adult ASA I or II patients‎, admitted for ‎gastrointestinal endoscopies‎. Patients were sedated with 25 µg ‎fentanyl and 1 mg/kg propofol bolus over 30 s. Patients ‎were divided into two groups: Group P (n = 77), sedated with ‎propofol only, and Group PK (n = 77), who received additionally a ‎single dose of ketamine (0.1 mg/kg) at induction. If the patient ‎moved or Ramsay Sedation Score (RSS) regressed to <4, ‎increments of 0.25 mg/kg of propofol were given. After the end ‎of the procedure, emergence from sedation was assessed with ‎modified Aldrete score, 5 and 10 m after admission to the ‎recovery room.‎ Results Adding a small dose of ketamine did not significantly achieve ‎deep sedation (RSS ≥4) more quickly or result in lesser ‎propofol increments. Patients who received ketamine showed a ‎statistically significant improvement in the Modified Aldrete ‎score when recorded 5 min after admission to the recovery ‎room (Group P 8.73 ± 1.02, Group PK 9.1 ± 0.96, P value = ‎‎0.02), but not after 10 min (Group P 9.03 ± 0.74, Group PK ‎‎9.21 ± 0.8, P value = 0.146).‎ Conclusion Inclusion of a small single dose of ketamine in the induction of sedation for gastrointestinal endoscopy significantly improves emergence from sedation.

Prenatal ketamine exposure impairs prepulse inhibition via arginine vasopressin receptor 1A-mediated GABAergic neuronal dysfunction in the striatum

Ketamine is a widely used anesthetic with N-methyl-D-aspartate (NMDA) receptor antagonism. Exposure to ketamine and NMDA receptor antagonists may induce psychosis. However, the mechanism underlying the effects of ketamine on the immature brain remains unclear. In this study, NMDA receptor antagonists, ketamine and methoxetamine, were administered to pregnant F344 rats (E17). These regimens induce psychosis-like behaviors in the offspring, such as hyperlocomotion induced by MK-801, a non-competitive NMDA receptor antagonist. We also observed that prepulse inhibition (PPI) was significantly reduced. Interestingly, ketamine administration increased the arginine vasopressin receptor 1A (Avpr1a) expression levels in the striatum of offspring with abnormal behaviors. Methoxetamine, another NMDA receptor antagonist, also showed similar results. In addition, we demonstrated a viral vector-induced Avpr1a overexpression in the striatum-inhibited PPI. In the striatum of offspring, ketamine or methoxetamine treatment increased glutamate decarboxylase 67 (GAD67) and δ-aminobutyric acid (GABA) levels. These results show that prenatal NMDA receptor antagonist treatment induces GABAergic neuronal dysfunction and abnormalities in sensorimotor gating via regulating Avpr1a expression in the striatum.

Modulatory Effects of Ketamine and Lamotrigine on Cognition: Emotion Interaction in the Brain

Introduction: Cognition and emotion are fundamentally integrated in the brain and mutually contribute to behavior. The relation between working memory (WM) and emotion is particularly suited to investigate cognition-emotion interaction since WM is an essential component of many higher cognitive functions. Ketamine affects not only WM but also has a profound impact on emotional processing. Effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Accordingly, a combination of these approaches should be particularly suited to investigate cognition-emotion interaction. Methods: Seventy five healthy subjects were investigated in a double-blind, placebo-controlled, randomized, single-dose, parallel-group study with three treatment conditions. All subjects underwent two scanning sessions (acute/post 24 h). Results: Compared to placebo, acute ketamine administration induced significant dissociative, psychotomimetic, and cognitive effects, as well as an increase in neural activity during WM for positive stimuli. Inhibition of glutamate release by pretreatment with lamotrigine did not influence ketamine’s subjective effects, but significantly attenuated its impact on emotional WM and associated neural activity. There was no effect on these measures 24 h after ketamine administration. Conclusion: Our results demonstrate differential acute effects of modulated glutamate release and a swift restoration of disturbed neurobehavioral homeostasis in healthy subjects.

Functional connectivity of the amygdala and the antidepressant and antisuicidal effects of repeated ketamine infusions in major depressive disorder.

Dysfunction of the amygdala is the core pathogenesis of major depressive disorder (MDD). However, it remains unclear whether ketamine treatment could modulate characteristics of amygdala-related networks. We aimed to explore the relationship between changes in the resting-state functional connectivity (RSFC) of the amygdala and the treatment of ketamine in MDD patients and to identify important neuroimaging predictors of treatment outcome. Thirty-nine MDD patients received six subanesthetic dose infusions of ketamine. Depressive and suicidal symptoms were assessed and magnetic resonance imaging (MRI) scans were performed before and after six ketamine infusions. Forty-five healthy controls also underwent once MRI scans. Seed-based RSFC analyses were performed, focusing on the bilateral amygdala. After ketamine treatment, the RSFC between the left amygdala (LA) and the left medial superior frontal gyrus (mSFG) of MDD patients enhanced significantly, and this change was positively correlated with the reduction in depressive symptoms (r = 0.40, p = 0.012). The combination baseline RSFC of LA - right putamen and right amygdala (RA) - right putamen was related to the antidepressant and antisuicidal effects of ketamine. The combination baseline RSFC of LA - right putamen and RA - right putamen could predict the ineffective antidepressant (AUC = 0.739, p = 0.011) and antisuicidal effects of ketamine (AUC = 0.827, p = 0.001). Ketamine can regulate the relevant circuits of amygdala and mSFG, and the baseline RSFC between bilateral amygdala and right putamen may be a predictor of the response of ketamine's antidepressant and antisuicidal treatment. https://www.chictr.org.cn/showproj.aspx?proj=20875, identifier ChiCTR-OOC-17012239.

Effects of ketamine or dexmedetomidine on postoperative cognitive dysfunction after cataract surgery: A randomized controlled trial.

Ketamine and dexmedet omidine have neuroprotective effects that may reduce the occurrence of postoperative cognitive dysfunction (POCD) when they are used by intravenous infusion in geriatric patients scheduled for cataract extraction. Ninety patients aged 65-85 years old, ASA physical status II and III, and scheduled for cataract extraction under peribulbar block were randomly distributed equally among three groups: control group, in which patients received normal saline; ketamine group, in which patients received 0.3 mg/kg/h of ketamine; and dexmedetomidine group, in which patients received 0.5 µg/kg/h of dexmedetomidine. Medications were administrated by intravenous infusion and started 10 min before the surgery and continued throughout the duration of surgery. The analysed parameters included the incidence of POCD (primary outcome) through composite score of neuropsychological testing at one week and 3 months after surgery, postoperative pain score, postoperative sedation score, changes in haemodynamic parameters, changes in intraocular pressure, and incidence of complications. In comparison with control group, ketamine and dexmedetomidine groups exhibited a significant decline in number of patients who developed POCD (P < 0.0001), a decrease in the postoperative pain score 4 h after surgery (P = 0.038), and an increase in the postoperative Ramsay sedation Score (P = 0.0002, 0.0003, and 0.011), without significant changes in the vital parameters, intraocular tension, or incidence of complications. Ketamine and dexmedetomidine groups were comparable. Intravenous administration of ketamine or dexmedetomidine in elderly patients undergoing cataract surgery under peribulbar anesthesia significantly decreases the incidence of POCD.

Comparison of the effects of intravenous lignocaine and ketamine on postoperative pain after lower abdominal surgeries under general anaesthesia.

As a component of multimodal analgesia, the administration of systemic lignocaine and ketamine is a well-known technique. This study was designed to compare the effect of intravenous lignocaine and ketamine on postoperative pain in the patients undergoing lower abdominal surgeries under general anaesthesia. Total 126 patients, aged between18 to 60 years, American Society of Anesthesiologists (ASA) physical status I and II, were randomly allocated into lignocaine (Group L), ketamine (Group K), or control (Group C). We assessed the mean fentanyl consumption 24 hours postoperatively, visual analogue score (VAS), time to first rescue analgesia, haemodynamic parameters, postoperative complications patient satisfaction score, and duration of hospital stay among three groups. The mean fentanyl consumption in first 24 hours postoperatively was higher in group C (194.65 ± 48.48 μg) compared to group L (139.69 ± 46.96 μg) and group K (161.37 ± 46.31 μg) (P < 0.05). The VAS pain scores were lower in group L and group K compared to group C (P < 0.05). The time to first rescue analgesia was prolonged in group L and group K as compared to group C (P < 0.05). The patients were more satisfied in group L and group K as compared to group C (P < 0.05). The mean fentanyl consumption in 24 hours postoperatively and pain intensity were less with intraoperative lignocaine and ketamine infusion with improved patient satisfaction in patients undergoing lower abdominal surgery under general anaesthesia.

Oscillatory effects of ketamine using focused ultrasound sensitive liposomes

The blood brain barrier (BBB) poses a significant challenge in the treatment of neurological disorders by preventing the diffusion of medications into the brain. Focused ultrasound (FUS) enables noninvasive modulation of the central nervous system by targeting millimeter-sized regions of the cortical and sub-cortical brain. We have synthesized ultrasound-sensitive nanoparticles (NPs) to encapsulate small, hydrophobic neuromodulators. Recent data has shown that our NPs deliver pharmacological drugs across the BBB when paired with FUS to the desired region of the brain with targeted accuracy. This method enables us to study the impact of small hydrophobic anesthetics across different regions of the brain. The aim of the study is to determine the electrophysiological effects of FUS neuromodulation in an awake small animal model. Specifically, we aim to understand the oscillatory effects of localized ketamine activity on the thalamocortical system. We hypothesized that localized delivery of ketamine in the central thalamus (CL) will induce slow-delta and gamma oscillations comparable to the recorded frequencies obtained from systemic delivery of ketamine. Using in-house electrocorticogram (ECoG) hardware, we recorded signals from the prefrontal cortex, CL, and visual cortex in awake-restraint rats. Preliminary results suggest that FUS-only neuromodulation of the brain induced undetectable oscillatory differences from baseline signals. We then investigated the electrophysiologic signatures of localized ketamine activity. Ketamine-loaded NPs were administered intravenously to rats via bolus injection and FUS was applied to the desired brain region for site-specific drug uncaging. Initial evidence indicated localized delivery of ketamine induced similar slow-delta and gamma oscillations in a smaller timeframe than those recorded after systemic ketamine administration. These results provide insight into the impacts of pharmacological modulation in relation to brain activity. Future directions include analyzing the thalamocortical system as a potential binding site for ketamine to induce anesthetic-specific oscillations.

Changes in white matter microstructure following serial ketamine infusions in treatment resistant depression.

Ketamine produces fast-acting antidepressant effects in treatment resistant depression (TRD). Though prior studies report ketamine-related changes in brain activity in TRD, understanding of ketamine's effect on white matter (WM) microstructure remains limited. We thus sought to examine WM neuroplasticity and associated clinical improvements following serial ketamine infusion (SKI) in TRD. TRD patients (N= 57, 49.12% female, mean age: 39.9) received four intravenous ketamine infusions (0.5mg/kg) 2-3 days apart. Diffusion-weighted scans and clinical assessments (Hamilton Depression Rating Scale [HDRS-17]; Snaith Hamilton Pleasure Scale [SHAPS]) were collected at baseline and 24-h after SKI. WM measures including the neurite density index (NDI) and orientation dispersion index (ODI) from the neurite orientation dispersion and density imaging (NODDI) model, and fractional anisotropy (FA) from the diffusion tensor model were compared voxelwise pre- to post-SKI after using Tract-Based Spatial Statistics workflows to align WM tracts across subjects/time. Correlations between change in WM metrics and clinical measures were subsequently assessed. Following SKI, patients showed significant improvements in HDRS-17 (p-value=1.8 E-17) and SHAPS (p-value=1.97 E-10). NDI significantly decreased in occipitotemporal WM pathways (p< .05, FWER/TFCE corrected). ΔSHAPS significantly correlated with ΔNDI in the left internal capsule and left superior longitudinal fasciculus (r= -0.614, p-value=6.24E-09). No significant changes in ODI or FA were observed. SKI leads to significant changes in the microstructural features of neurites within occipitotemporal tracts, and changes in neurite density within tracts connecting the basal ganglia, thalamus, and cortex relate to improvements in anhedonia. NODDI may be more sensitive for detecting ketamine-induced WM changes than DTI.

Evaluation of Candidates for Systemic Analgesia and General Anesthesia in the Emerging Model Cephalopod, Euprymna berryi.

Cephalopods' remarkable behavior and complex neurobiology make them valuable comparative model organisms, but studies aimed at enhancing welfare of captive cephalopods remain uncommon. Increasing regulation of cephalopods in research laboratories has resulted in growing interest in welfare-oriented refinements, including analgesia and anesthesia. Although general and local anesthesia in cephalopods have received limited prior study, there have been no studies of systemic analgesics in cephalopods to date. Here we show that analgesics from several different drug classes may be effective in E. berryi. Buprenorphine, ketorolac and dexmedetomidine, at doses similar to those used in fish, showed promising effects on baseline nociceptive thresholds, excitability of peripheral sensory nerves, and on behavioral responses to transient noxious stimulation. We found no evidence of positive effects of acetaminophen or ketamine administered at doses that are effective in vertebrates. Bioinformatic analyses suggested conserved candidate receptors for dexmedetomidine and ketorolac, but not buprenorphine. We also show that rapid general immersion anesthesia using a mix of MgCl2 and ethanol was successful in E. berryi at multiple age classes, similar to findings in other cephalopods. These data indicate that systemic analgesia and general anesthesia in Euprymna berryi are achievable welfare enhancing interventions, but further study and refinement is warranted.

Neural Correlates of the DEEPP (Anti-suicidal Response to Ketamine in Treatment-Resistant Bipolar Depression) Study: Protocol for a Pilot, Open-Label Clinical Trial.

Suicide is among the top 10 leading causes of death worldwide. Of people who died by suicide, the majority are diagnosed with depression. It is estimated that 25%-60% of people with bipolar depression (BD) will attempt suicide at least once, and 10%-15% will die by suicide. Several treatments, such as lithium, clozapine, electroconvulsive therapy, and cognitive behavioral therapy, have been shown to be effective in treating suicidality. However, these treatments can be difficult to tolerate or may take months to take effect. Ketamine, a glutamate N-methyl-D-aspartate antagonist, has been shown to have rapid antisuicidal effect and antidepressant qualities, and is thus a promising intervention to target acute suicidality in patients with BD. However, the biological mechanism underlying its therapeutic action remains poorly understood. Enhancing our understanding of underlying mechanisms of action for ketamine's effectiveness in reducing suicidality is critical to establishing biological markers of treatment response and developing tailored, personalized interventions for patients with BD. This is an open-label clinical trial to test the safety and feasibility of repeated ketamine infusions to treat acute suicidality. The primary objective is to test the safety and feasibility of ketamine intervention. The secondary objective is to examine ketamine's potential neurophysiological mechanisms of action by assessing cortical excitation and inhibition to determine potential biomarkers of clinical response. Other objectives are to evaluate the effect of ketamine on acute suicidality and other clinical outcomes, such as depressive symptoms and quality of life, to inform a future larger trial. This open-label clinical trial aims to test the safety and feasibility of repeated ketamine infusions in patients with BD for suicidality and to assess ketamine's neurophysiological effects. A sterile form of racemic ketamine hydrochloride will be administered over a 40-minute intravenous infusion 2 times per week on nonconsecutive days for 4 weeks (8 sessions). We will recruit 30 adults (24-65 year olds) over 2 years from an academic psychiatric hospital in Toronto, Canada. This study is currently ongoing and actively recruiting participants. So far, 5 participants have completed the trial, 1 is currently in active treatment, and 8 participants are on the waitlist to be screened. We anticipate initial results being available in the fall of 2023. This proposal was presented as a poster presentation at the Research to Reality Global Summit on Psychedelic-Assisted Therapies and Medicine, held in May 2022 in Toronto, Canada. Developing effective interventions for acute suicidality in high-risk populations such as those with BD remains a major therapeutic challenge. Ketamine is a promising treatment due to its rapid antidepressant and antisuicidal effects, but its underlying neurophysiological mechanisms of action remain unknown. ClinicalTrials.gov NCT05177146; https://clinicaltrials.gov/ct2/show/NCT05177146. DERR1-10.2196/41013.

Comparing the Effects of Low-Dose Ketamine, Fentanyl, and Morphine on Hemorrhagic Tolerance and Analgesia in Humans

Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Ketamine, fentanyl, and morphine are recommended analgesics for use in the prehospital (i.e., field) setting to reduce pain. However, it is unknown whether any of these analgesics reduce hemorrhagic tolerance in humans. We tested the hypothesis that fentanyl (75 µg) and morphine (5 mg), but not ketamine (20 mg), would reduce tolerance to simulated hemorrhage in conscious humans. Each of the three analgesics was evaluated independently among different cohorts of healthy adults in a randomized, crossover (within drug/placebo comparison), placebo-controlled fashion using doses derived from the Tactical Combat Casualty Care Guidelines for Medical Personnel. One minute after an intravenous infusion of the analgesic or placebo (saline), we employed a pre-syncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (CSI), which is the sum of products of the LBNP and the duration (e.g., [40 mmHg x 3 min] + [50 mmHg x 3 min] …). Compared with ketamine (p = 0.002 post hoc result) and fentanyl (p = 0.02 post hoc result), morphine reduced the CSI (ketamine (n = 30): 99 [73–139], fentanyl (n = 28): 95 [68–130], morphine (n = 30): 62 [35–85]; values expressed as a % of the respective placebo trial’s CSI; median [IQR]; Kruskal-Wallis test p = 0.002). Morphine-induced reductions in tolerance to central hypovolemia were not well explained by a prediction model including biological sex, body mass, and age (R2=0.05, p = 0.74). These experimental data demonstrate that morphine reduces tolerance to simulated hemorrhage while fentanyl and ketamine do not affect tolerance. Thus, these laboratory-based data, captured via simulated hemorrhage, suggest that morphine should not be used for a hemorrhaging individual in the prehospital setting.

Several reasons why ketamine as a neuroplastic agent may have failed to prevent postoperative delirium: Implications for future protocols

Ketamine exerts anti-inflammatory, neuroprotective and neuroplastic activity, therefore it may counteract the neurotoxic processes underlying postoperative delirium. However, the majority of studies in this field failed. We identified several pharmacological reasons why these studies may have failed, together with suggestions of how to remediate them.Among them, the interaction with intravenous general anesthetics exerting the opposite effect on GABA interneurons than ketamine may be of principal importance. We suggest biomarkers which may elucidate the influence of this interaction on the different steps of neuroplastic pathways. We hypothesize that administering ketamine before or after general anesthesia could both prevent the interactions and strengthen the effect of ketamine by timing surgery within the climax of ketamine-induced neuroplastic changes or by stabilizing AMPA receptors. It is vital to deal with these questions because the protocols of ongoing studies are based again on the administration of ketamine during general anesthesia (the major identified pitfall).

Treating Prehospital Pain in Children: A Retrospective Chart Review Comparing the Safety and Efficacy of Prehospital Pediatric Ketamine and Opioid Analgesia

Prior to 2020, pain management in the Washtenaw/Livingston County Medical Control Authority (W/L MCA) Emergency Medical Service (EMS) system in Southeast Michigan was limited to morphine, fentanyl, ketorolac, and acetaminophen. Based on the increasing evidence describing its safety and efficacy, ketamine was added to local protocols for pain management. This study aimed to evaluate differences in pain management and adverse effects of ketamine and opioid administration. Data from pediatric patients who received ketamine or an opioid in the W/L MCA EMS system from October 2019 to March 2021 were analyzed. The primary outcome was the difference in pain score, and the secondary outcome was adverse effects observed after analgesic administration. The decrease in pain scores was greater among ketamine patients (mean: 5.2) compared to opioid patients (mean: 2.9), p < 0.001. The prevalence of adverse effects was higher among patients in the ketamine group (28.6%) compared to patients in the opioid group (2.4%, p < 0.001). Of 14 patients who received ketamine, one 17-year-old male experienced mild anxiety (7.1%), two teenage females experienced mild dissociation (14.3%), and one 20-year-old female experienced mild nausea (7.1%). Overall, ketamine is a safe and effective option compared to opioids for pediatric patients experiencing moderate to severe prehospital pain.

Ketamine-induced hippocampal functional connectivity alterations associated with clinical remission in major depression

ObjectiveHippocampal functional connectivity (FC) alterations, which may happen following ketamine treatment, play a key role in major depression remission. This study aims to investigate the resting-state FC changes of the hippocampus associated with clinical remission after repeated ketamine infusions. MethodsForty-four major depressive patients received six intravenous ketamine (0.5 mg/kg) infusions in 12 days. The FC change of the hippocampus subregions following ketamine treatment was compared between remitters (MADRS score ≤ 10 post-treatment) and nonremitters. We also investigated whether baseline hippocampus FC predicted the antidepressant efficiency of ketamine using Receiver Operating Characteristic Curve analyses. ResultsThirty-nine patients were included in the analysis. There were significant differences in change of left rostral hippocampus FC with the right angular gyrus (the key node of the default mode network, DMN), left inferior parietal cortex and the right superior parietal cortex (parts of the dorsal attention network, dAN) between remitters and nonremitters following ketamine treatment. Specifically, while the remitters showed significantly less negative hippocampus FC than the nonremitters at baseline, the FC significantly decreased in remitters but increased in nonremitters after ketamine injections. Moreover, baseline hippocampus FC with the above three regions predicted the antidepressant effect of ketamine, with the highest predictive strength identified in the hippocampus-right angular gyrus FC (Area-Under-Curve = 0.8179, p < 0.05). ConclusionKetamine treat depression by modulating the left rostral hippocampus resting-state FC with the DMN and dAN. The FC between the hippocampus and parts of the DMN and dAN may show promising potential in predicting remission after ketamine treatment in MDD.

Prehospital Use of Ketamine versus Benzodiazepines for Sedation among Pediatric Patients with Behavioral Emergencies

Introduction Ketamine is an emerging alternative sedation agent for prehospital management of agitation, yet research is limited regarding its use for children. Our objective was to compare the effectiveness and safety of ketamine and benzodiazepines when used for emergent prehospital sedation of pediatric patients with behavioral emergencies. Methods We performed a retrospective review of 9-1-1 EMS records from the 2019-2020 ESO Data Collaborative research datasets. We included patients ≤18 years of age who received ketamine or benzodiazepines for EMS primary and secondary impressions indicating behavioral conditions. We excluded patients with first Glasgow Coma Scale (GCS) scores ≤8, those receiving ketamine or benzodiazepines prior to EMS arrival, those receiving both ketamine and benzodiazepines, and interfacility transfers. Effectiveness outcomes included general clinician assessment of improvement, decrease in GCS, and administration of a subsequent sedative. Safety outcomes included mortality; advanced airway placement; ventilatory assistance without advanced airway placement; or marked sedation (GCS ≤8). Chi-square and t-tests were used to compare the ketamine and benzodiazepines groups. Results Of 57,970 pediatric patients with behavioral complaints and GCS scores >8, 1,539 received ketamine (13.3%, n = 205) or a benzodiazepine (86.7%, n = 1,334). Most patients were ≥12 years old (89.2%, n = 1,372), predominantly Caucasian (48.3%, n = 744), and were equally distributed by sex (49.7% male, n = 765). First treatment with ketamine was associated with a greater likelihood of improvement (88.8% vs 70.5%, p < 0.001) and a greater average GCS reduction compared to treatment with benzodiazepines (-2.5 [SD:4.0] vs −0.3 [SD:1.7], p < 0.001). Fewer patients who received ketamine received subsequent medication compared to those who received benzodiazepines (12.2% vs 27.0%, p < 0.001). Marked sedation was more frequent with ketamine than benzodiazepines (28.8% vs 2.9%, p < 0.001). Provision of ventilatory support (1.5% vs 0.5%, p = 0.14) and advanced airway placement (1.0% vs 0.2%, p = 0.09) were similar between ketamine and benzodiazepine groups. No prehospital deaths were reported. Conclusion In this pediatric cohort, prehospital sedation with ketamine was associated with greater patient improvement, less subsequent sedative administration, and greater sedation compared to benzodiazepines. Though we identified low rates of adverse events in both groups, ketamine was associated with more instances of marked sedation, which bears further study.