Subanesthetic Doses Of Ketamine Research Articles

The NMDA receptor antagonist ketamine impairs and delays context-dependent decision making in the parietal cortex

Flexible decision making is an indispensable ability for humans. A subanesthetic dose of ketamine, an N-methyl-D-aspartate receptor antagonist, impairs this flexibility in a manner that is similar to patients with schizophrenia; however how it affects neural processes related to decision making remains unclear. Here, we report that ketamine administration impairs neural processing related to context-dependent decision making, and delays the onset of decision making. We recorded single unit activity in the lateral intraparietal area (LIP) while monkeys switched between a direction-discrimination task and a depth-discrimination task. Ketamine impaired choice accuracy for incongruent stimuli that required different decisions depending on the task, for the direction-discrimination task. Neural sensitivity to irrelevant depth information increased with ketamine during direction discrimination in LIP, indicating impaired processing of irrelevant information. Furthermore, the onset of decision-related neural activity was delayed in conjunction with an increased reaction time irrespective of task and stimulus congruency. Neural sensitivity and response onset of the middle temporal area (MT) were not modulated by ketamine, indicating that ketamine worked on neural decision processes downstream of MT. These results suggest that ketamine administration may impair what information to process and when to process it for the purpose of achieving flexible decision making.

Effect of Subanaesthetic Dose of Ketamine on Pneumoperitoneal Response and Clinical Recovery in Patients Undergoing Laparoscopy.

Objective:Although suppression of intraperitoneal gas insufflation response is possible with a higher dose of opioids, sedatives, and inhalational agents, delayed emergence and poor clinical recovery are still a matter of concern. Here our primary aim was to assess the quality of recovery and the secondary aim includes postinsufflation response, postoperative pain intensity, total opioid requirement, and looking for adverse effects, if any.Methods:This prospective randomized double-blinded controlled study was conducted among 75 American Society of Anesthesiologist physical status I and II patients scheduled for laparoscopic surgeries under general anaesthesia. Group 1 received injection tramadol 1 mg kg−1 iv−1 5 minutes after intubation. Similarly, groups 2 and 3 received 0.25 mg kg−1 and 0.5 mg kg−1 injection of ketamine iv, respectively. Intraperitoneal insufflation response was observed from the beginning of insufflation till 15 minutes. Clinical recovery was measured in terms of vigilance, cognition, orientation, and comfort. Postoperative pain intensity was assessed at varying movement activities using numerical rating scale pain score and with the total opioid requirement. The collected data were analyzed using three-way ANOVA.Results:Groups 1 and 2 had a fair clinical recovery. Postoperative pain intensity was least in group 2, and the postinsufflation mean arterial pressure was higher in groups 1 and 3. A total of 32% of participants had delirium in group 3.Conclusions:Clinical recovery and perioperative analgesia were better in ketamine group (0.25 mg kg−1) without any perturbations in intra-operative pneumoperitoneal response. Hence it can be considered an optimal adjuvant in laparoscopic surgeries.

Effect of a single sub-dose of ketamine on postoperative fatigue syndrome in colorectal cancer patients undergoing radical laparoscopic surgery: A double-blind, pilot study

BackgroundThis study aimed at examining the effect of a single sub-anesthetic dose of ketamine on postoperative fatigue syndrome (POFS) in patients undergoing radical laparoscopic surgery for colorectal cancer (CRC). MethodsThis prospective, double-blind, pilot study enrolled patients scheduled for radical laparoscopic surgery for CRC under general anesthesia. Eligible patients were randomized into the placebo and ketamine groups. The primary outcome was christensen score change at day 3. The secondary outcomes were the difference of Identity Consequence Fatigue Scale (ICFS) score between the placebo group and ketamine group at day 3 and level of serum tumor necrosis factor (TNF)-α, interleukin (IL)-6, S100β protein, and neuron-specific enolase (NSE). Results32 participants were assigned to the ketamine group and 31 to the placebo group. Compared with placebo group, the Christensen score was lower in ketamine group at day 3 (absolute difference, −1.13; 95 % confidence interval [CI], −2.02 to −0.24; P = 0.012). Ketamine group was superior to the placebo group with regard to the ICFS scores at day 3 (absolute difference, −6.4; 95 % CI, −11.4 to −1.4; P = 0.013). The plasma TNF-α, IL-6, S100β, and NSE levels were increased after operation compared with baseline in both groups and were significantly higher in placebo group than in ketamine group within 24 h after surgery (all P < 0.05). There was no significant difference of each safety evaluation indicator between the two groups (all P > 0.05). ConclusionA single sub-anesthetic dose of ketamine may improve POFS in patients undergoing radical laparoscopic surgery for CRC, without postoperative adverse reactions.

Magnetoencephalography biomarkers of suicide attempt history and antidepressant response to ketamine in treatment-resistant major depression

BackgroundThis study examined magnetoencephalographic (MEG) correlates of suicidal ideation (SI) and suicide attempt history in patients with treatment-resistant major depression (TRD) at baseline and following subanesthetic-dose ketamine infusion. MethodsTwenty-nine drug-free TRD patients (12 suicide attempters/17 non-attempters) participated in a crossover randomized trial of ketamine. MEG data were collected during an attentional dot probe task with emotional face stimuli at baseline and several hours post-ketamine infusion. Synthetic aperture magnetometry was used to project source power in the theta, alpha, beta, and gamma frequencies for angry-neutral, happy-neutral, and neutral-neutral face pairings during a one-second peristimulus period. Mixed models were used to test for clinical, behavioral, and electrophysiological effects of group, emotion, session, and SI score. ResultsKetamine significantly reduced SI and depression across the sample. Post-ketamine, attempters had improved accuracy and non-attempters had reduced accuracy on the task. SI was positively associated with gamma power in regions of the frontal and parietal cortices across groups. In an extended amygdala-hippocampal region, attempters differed significantly in their emotional reactivity to angry versus happy faces as indexed by theta power differences, irrespective of drug. Ketamine significantly reduced the association between alpha power and SI for angry compared with happy faces in a fronto-insular/anterior cingulate region important for regulating sensory attentiveness. LimitationsLimitations include a small sample size of attempters. ConclusionsThe findings highlight key differences in band-limited power between attempters and non-attempters and reinforce previous findings that ketamine has distinct response properties in patients with a suicide history.

Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2

A single sub-anesthetic dose of ketamine produces a rapid and sustained antidepressant response, yet the molecular mechanisms responsible for this remain unclear. Here, we identified cell-type-specific transcriptional signatures associated with a sustained ketamine response in mice. Most interestingly, we identified the Kcnq2 gene as an important downstream regulator of ketamine action in glutamatergic neurons of the ventral hippocampus. We validated these findings through a series of complementary molecular, electrophysiological, cellular, pharmacological, behavioral, and functional experiments. We demonstrated that adjunctive treatment with retigabine, a KCNQ activator, augments ketamine's antidepressant-like effects in mice. Intriguingly, these effects are ketamine specific, as they do not modulate a response to classical antidepressants, such as escitalopram. These findings significantly advance our understanding of the mechanisms underlying the sustained antidepressant effects of ketamine, with important clinical implications.

Rewarding and Antidepressant Properties of Ketamine and Ethanol: Effects on the Brain-Derived Neurotrophic Factor and TrkB and p75NTR Receptors

There is a high level of comorbidity between depression and alcohol use disorder. Subanesthetic doses of ketamine induce short-acting and enduring antidepressant effects after a single or a few administrations. Considering such comorbidity, we assessed, in Swiss male mice, if ketamine-induced antidepressant-like effects would alter ethanol’s rewarding effects; and, if ethanol pretreatment would alter the rewarding and antidepressant effects of ketamine. The role of the brain-derived neurotrophic factor (BDNF) and its high and low affinity receptors TrkB and p75NTR, respectively, in both reward and depression-related behaviors is well established. The present study assessed, in outbred Swiss male mice, the expression of these proteins in the prefrontal cortex and hippocampus. Ketamine did not alter the development of ethanol-induced conditioned place preference (CPP), yet ethanol inhibited the expression of CPP induced by 50 mg/kg ketamine. The antidepressant action of 50 mg/kg ketamine was attenuated after repeated treatment (i.e., developed tolerance), an effect blocked by ethanol preexposure; ethanol also inhibited the antidepressant effect of 30 mg/kg ketamine. Ketamine (50 mg/kg) and Ethanol–Ketamine (50 mg/kg) groups showed lower levels of 145 kDa TrkB in the hippocampus than Saline-treated group. Ethanol–Ketamine (50 mg/kg) decreased the hippocampal expression of p75NTR compared to Saline–Saline and Saline–Ethanol groups. Ketamine (50 mg/kg) induced hippocampal downregulation of 145 kDa TrkB may contribute to ketamine-induced antidepressant tolerance. Likewise, a relationship between low hippocampal levels of p75NTR in the Ethanol–Ketamine (50 mg/kg) and ketamine-induced CPP blockade may be considered. The findings underscore potential ethanol–ketamine interactions likely to undermine ketamine putative antidepressant effects.

Ketamine for Adults With Treatment-Resistant Depression or Post-Traumatic Stress Disorder

&#x0D; Two randomized controlled trials reported mixed evidence on the efficacy of repeated IV ketamine infusions for improving post-traumatic stress disorder. One randomized controlled trial with small sample size found that repeated IV ketamine infusions significantly improved post-traumatic stress disorder symptoms compared with midazolam in civilian population, while the other randomized controlled trial with larger sample size could not demonstrate a significant efficacy on post-traumatic stress disorder symptoms compared with placebo in military population. The antidepressant effects of ketamine were rapid, but the effects were not sustained after few weeks of post-treatment follow-up.&#x0D; One randomized controlled trial comparing IV ketamine with IV esketamine found both treatments had comparable acute antidepressant effects for treatment-resistant depression 24 hours following infusion.&#x0D; Two randomized controlled trials provided mixed evidence on the efficacy of single infusion of IV ketamine that was used as anesthetic agent for electroconvulsive therapy for treatment-resistant depression. One randomized controlled trial involving military population showed that patients undergoing electroconvulsive therapy for treatment-resistant depression with ketamine anesthesia had similar improvement of depression when compared with patients undergoing electroconvulsive therapy with methohexital anesthesia. However, in other randomized controlled trial comparing with propofol-based anesthesia in a civilian population, ketamine-based anesthesia provided faster improvement in depressive symptoms and fewer electroconvulsive therapy treatments to achieve disease remission.&#x0D; In a small randomized controlled trial, alternate infusions of subanesthetic dose of ketamine or midazolam with alternate electroconvulsive therapy showed no significant difference in antidepressant effects between groups.&#x0D; The efficacy of oral ketamine was demonstrated in 1 randomized controlled trial that repeated administration of oral ketamine significantly reduced depressive symptoms compared with placebo.&#x0D; A small retrospective chart review study showed that repeated administration of intramuscular ketamine had no significant differences in the improvement of depressive and anxiety symptoms compared with repeated transcranial magnetic stimulation.&#x0D; Findings suggest overall safety and tolerability of ketamine for treatment of post-traumatic stress disorder or treatment-resistant depression. Most frequent side effects associated with ketamine were dissociative symptoms and cardiovascular changes such as increased blood pressure and heart rate, but these effects were transient.&#x0D; The Danish guideline recommend against the use of IV ketamine in patients with treatment-resistant depression, due to low quality and insufficient evidence regarding the lack of long-term efficacy and the risk of abuse of ketamine. Likewise, the Canadian guideline recommends IV ketamine be considered as third-line treatment for adults with TRD, because of the short-lived efficacy of ketamine, its side effects, and the lack of strategies for relapse prevention after ketamine infusions.&#x0D;

Effects of a Single Sub-Anesthetic Dose of Ketamine on Postoperative Emotional Responses and Inflammatory Factors in Colorectal Cancer Patients.

Objective: To investigate the effect of a single sub-anesthetic dose of ketamine on postoperative anxiety, depression, and inflammatory factors in patients with colorectal cancer. Methods: A total of 104 patients undergoing selective colorectal surgery in our hospital from Jan 2015 to Oct 2017 were included and randomly assigned (1:1:1:1) into a 0.1 mg kg−1 ketamine group (K1 group), 0.2 mg kg−1 ketamine group (K2 group), 0.3 mg kg−1 ketamine group (K3 group), or control group (C group). Corresponding doses of ketamine were given intravenously in the K groups (K1, K2, and K3 groups) 5 min before operation, and the same amount of normal saline was given in the C group. The intravenous analgesia program was identical in the four groups. The patients’ emotional reactions (anxiety and depression) were assessed by the Hospital Anxiety and Depression Scale (HAD), the quality of postoperative recovery was evaluated by the Quality of Recovery-40 (QoR-40) questionnaire, and the levels of IL-6, IL-8, and TNF-α in peripheral blood were detected by enzyme-linked immunosorbent assay (ELISA) on the day before operation and within 24, 48, and 72 h post-operation respectively. Pain was estimated by the visual analog scale (VAS), and sedation was assessed with Ramsay score 30 min after extubation. The time points of anesthetic end and extubation were recorded. The complications during anesthesia and recovery such as cough and agitation 30 min after extubation were recorded. Results: The anxiety score (HAD-A) and depression score (HAD-D) of the K3 group were significantly lower than those of the C group post-operation (p < 0.05). The QoR-40 score of the K3 group was significantly higher than that of the C group (p < 0.05). The serum levels of IL-6, IL-8, and TNF-α in the K3 group were significantly lower than those in the C group (p < 0.05 and p < 0.01). There were no significant differences in HAD-A, HAD-D, and QoR-40 scores or serum levels of IL-6, IL-8, and TNF-α between the K1 and K2 groups and the C group. There were no significant differences in VAS pain score or Ramsay sedation score among the four groups 30 min after extubation. There were no significant differences in extubation time, postoperative cough, emergence agitation, or delirium among the four groups. Dizziness, nausea, vomiting, diplopia, or other adverse reactions were not found 30 min after extubation. Conclusion: A single sub-anesthetic dose (0.3 mg kg−1) of ketamine can significantly improve the postoperative anxiety and depression of colorectal cancer patients and reduce the levels of IL-6, IL-8, and TNF-α.

Ketamine and sleep modulate neural complexity dynamics in cats.

There is increasing evidence that the level of consciousness can be captured by neural informational complexity: for instance, complexity, as measured by the Lempel Ziv (LZ) compression algorithm, decreases during anaesthesia and non‐rapid eye movement (NREM) sleep in humans and rats, when compared with LZ in awake and REM sleep. In contrast, LZ is higher in humans under the effect of psychedelics, including subanaesthetic doses of ketamine. However, it is both unclear how this result would be modulated by varying ketamine doses, and whether it would extend to other species. Here, we studied LZ with and without auditory stimulation during wakefulness and different sleep stages in five cats implanted with intracranial electrodes, as well as under subanaesthetic doses of ketamine (5, 10, and 15 mg/kg i.m.). In line with previous results, LZ was lowest in NREM sleep, but similar in REM and wakefulness. Furthermore, we found an inverted U‐shaped curve following different levels of ketamine doses in a subset of electrodes, primarily in prefrontal cortex. However, it is worth noting that the variability in the ketamine dose–response curve across cats and cortices was larger than that in the sleep‐stage data, highlighting the differential local dynamics created by two different ways of modulating conscious state. These results replicate previous findings, both in humans and other species, demonstrating that neural complexity is highly sensitive to capture state changes between wake and sleep stages while adding a local cortical description. Finally, this study describes the differential effects of ketamine doses, replicating a rise in complexity for low doses, and further fall as doses approach anaesthetic levels in a differential manner depending on the cortex.

Observation and Analysis of the Postoperative Analgesic Effect of Subanaesthetic Dose of Ketamine in Kashin-Beck Disease Patients after Total Knee Arthroplasty.

With the transformation of modern medical models, the medical needs of patients have changed from treatment to safe, comfortable, and painless treatment. Therefore, it is clinically important to find an ideal analgesia model to reduce the pain after total knee arthroplasty and minimize the impact of surgical trauma on the body pressure. This article aims to study the effects of lower limb nerve block combined with local infiltration analgesia of the joint cavity on the hemodynamics and postoperative analgesia effects of knee joint replacement in elderly patients by comparing the effects of the subanaesthetic dose of ketamine on the hemodynamics and postoperative analgesia effect of knee joint replacement in elderly patients' intraoperative analgesia program. This article proposes that 90 patients requiring unilateral total knee replacement were randomly divided into 3 groups, with 30 patients in each group, age 65–85 years, average age 75 years, ASA I ∼ II grade, and body mass index 13.89 ∼ 37.26. Use a multifunctional monitor to monitor the patient's continuous blood pressure (SBP/DBP) and mean arterial pressure (MAP), heart rate (HR), electrocardiogram (ECG), intraoperative pulse oxygen saturation (SpO2), and end-tidal carbon dioxide (PETCO2). The following are monitored: record the heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure before induction of anesthesia (T0), before the upper tourniquet (T1), and after the upper tourniquet (T2), before tourniquet withdrawal (T3), and after tourniquet withdrawal (T4), mean arterial pressure (MAP). The three groups of patients had different degrees of itching, vomiting, nausea, and other adverse reactions. The experimental results in this article show that, in elderly patients with epidural anesthesia, the use of propofol and dexmedetomidine to maintain the patient's BIS value between 60 and 70 can meet the depth of sedation required for surgery without important surgical operation knowledge.

Clinical predictors of depressive symptom remission and response after racemic ketamine and esketamine infusion in treatment-resistant depression.

Major depressive disorder (MDD) is a leading cause of disability worldwide and most people do not achieve symptom remission. Treatment-resistant depression (TRD) is characterized by the failure of at least one adequate trial of a major class of antidepressant, with adequate time and dosage. We aimed to identify clinical predictors of depressive symptom remission and response 24h and 7days after racemic ketamine and esketamine infusions. A randomized, double-blind, active-controlled, non-inferiority trial using ketamine and esketamine in TRD. Individuals diagnosed with MDD according to Diagnostic and Statistical Manual of Mental Disorders version IV and fulfilling TRD criteria were recruited from March 2017 to June 2018. Participants received a single subanesthetic dose of ketamine (0.5mg/kg) or esketamine (0.25mg/kg) for 40min. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) and symptom remission was defined as a MADRS score ≤7 and response defined as ≥50% reduction in depressive symptom severity, 24h and 7days after the infusion. Clinical variables were selected based on previous clinical trials. Stepwise backward logistic regression was used, considering a confidence level of 95%. 61 subjects were included: 39 (63.9%) were females with a mean age of 47.2±14.9. Higher number of therapeutic failures (Odds Ratio (OR)=0.677; 95% confidence interval (CI): 0.47-0.97) and higher severity of illness (OR=0.912; 95% CI: 0.83-0.99) were associated with fewer remissions of depressive symptoms 7days after intervention, and with fewer response in 24h (OR=0.583; 95% CI: 0,40; 0,84 and OR=0.909; 95% CI: 0,83; 0,99, respectively). Number of treatment failures and severity of illness were predictors of fewer remissions and responses of depressive symptoms in this TRD population. Study of predictors of remission may contribute to better selection patients that may benefit from receiving ketamine.

Glycine attenuates impairments of stimulus-evoked gamma oscillations in the ketamine model of schizophrenia

Although a substantial number of studies suggests some clinical benefit concerning negative symptoms in schizophrenia through the modulation of NMDA-receptor function, none of these approaches achieved clinical approval. Given the large body of evidence concerning glutamatergic dysfunction in a subgroup of patients, biomarkers to identify those with a relevant clinical benefit through glutamatergic modulation are urgently needed. A similar reduction of the early auditory evoked gamma-band response (aeGBR) as found in schizophrenia patients can be observed in healthy subjects following the application of an NMDA-receptor antagonist in the ketamine-model, which addresses the excitation / inhibition (E/I) imbalance of the disease. Moreover, this oscillatory change can be related to the emergence of negative symptoms. Accordingly, this study investigated whether glycine-related increases of the aeGBR, through NMDA-receptor co-agonism, accompany an improvement concerning negative symptoms in the ketamine-model. The impact of subanesthetic ketamine doses and the pretreatment with glycine was examined in twenty-four healthy male participants while performing a cognitively demanding aeGBR paradigm with 64-channel electroencephalography. Negative Symptoms were assessed through the PANSS. S-Ketamine alone caused a reduction of the aeGBR amplitude associated with more pronounced negative symptoms compared to placebo. Pretreatment with glycine attenuated both, the ketamine-induced alterations of the aeGBR amplitude and the increased PANSS negative scores in glycine-responders, classified based on relative aeGBR increase. Thus, we propose that the aeGBR represents a possible biomarker for negative symptoms in schizophrenia related to insufficient glutamatergic neurotransmission. This would allow to identify patients with negative symptoms, who might benefit from glutamatergic treatment.

A hippocampus dependent neural circuit loop underlying the generation of auditory mismatch negativity

Extracting relevant information and transforming it into appropriate behavior, is a fundamental brain function, and requires the coordination between the sensory and cognitive systems, however, the underlying mechanisms of interplay between sensory and cognition systems remain largely unknown. Here, we developed a mouse model for mimicking human auditory mismatch negativity (MMN), a well-characterized translational biomarker for schizophrenia, and an index of early auditory information processing. We found that a subanesthetic dose of ketamine decreased the amplitude of MMN in adult mice. Using pharmacological and chemogenetic approaches, we identified an auditory cortex–entorhinal cortex–hippocampus neural circuit loop that is required for the generation of MMN. In addition, we found that inhibition of dCA1→MEC circuit impaired the auditory related fear discrimination. Moreover, we found that ketamine induced MMN deficiency by inhibition of long-range GABAergic projection from the CA1 region of the dorsal hippocampus to the medial entorhinal cortex. These results provided circuit insights for ketamine effects and early auditory information processing. As the entorhinal cortex is the interface between the neocortex and hippocampus, and the hippocampus is critical for the formation, consolidation, and retrieval of episodic memories and other cognition, our results provide a neural mechanism for the interplay between the sensory and cognition systems.

Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review.

In the past two decades, subanaesthetic doses of ketamine have been demonstrated to have rapid and sustained antidepressant effects, and accumulating research has demonstrated ketamine's therapeutic effects for a range of psychiatric conditions. In light of these findings surrounding ketamine's psychotherapeutic potential, we systematically review the extant evidence on ketamine's effects in treating mental health disorders. The systematic review protocol was registered in PROSPERO (identifier CRD42019130636). Human studies investigating the therapeutic effects of ketamine in the treatment of mental health disorders were included. Because of the extensive research in depression, bipolar disorder and suicidal ideation, only systematic reviews and meta-analyses were included. We searched Medline and PsycINFO on 21 October 2020. Risk-of-bias analysis was assessed with the Cochrane Risk of Bias tools and A Measurement Tool to Assess Systematic Reviews (AMSTAR) Checklist. We included 83 published reports in the final review: 33 systematic reviews, 29 randomised controlled trials, two randomised trials without placebo, three non-randomised trials with controls, six open-label trials and ten retrospective reviews. The results were presented via narrative synthesis. Systematic reviews and meta-analyses provide support for robust, rapid and transient antidepressant and anti-suicidal effects of ketamine. Evidence for other indications is less robust, but suggests similarly positive and short-lived effects. The conclusions should be interpreted with caution because of the high risk of bias of included studies. Optimal dosing, modes of administration and the most effective forms of adjunctive psychotherapeutic support should be examined further.

Role of Different Doses of Ketamine in Postoperative Neurocognitive Function in Aged Mice Undergoing Partial Hepatectomy by Regulating the Bmal1/NMDA/NF-Κb Axis

Background: The current study set out to probe the function of different doses of ketamine in postoperative neurocognitive disorder (PND) in aged mice undergoing partial hepatectomy (PH) with the involvement of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1)/n-methyl-D-aspartate (NMDA)/nuclear factor-kappa B (NF-κB) axis. Methods: First, aged mice were intraperitoneally injected with different doses of ketamine prior to surgery, followed by hepatic lobectomy. Afterward, mice cognitive function was assessed. In addition, Bmal1 mRNA expression patterns were quantified, while NMDA 2B receptor, NF-κB p65, synapsin 1, and postsynaptic density 95 (PSD95) levels were determined; the release of inflammatory factors was detected, and ionized calcium-binding adapter molecule-1 expression was measured to quantify microglia activation. In addition, Bmal1-knockout (Bmal1-KO) mice were intraperitoneally injected with a subanesthetic dose of ketamine to verify the mechanism of Bmal1 in regulating the NMDA 2B subunit (NR2B)/NF-κB axis to affect PH in aged patients. Results: After PH, hippocampal-dependent memory was impaired, and synapsin 1 and PSD95 levels were downregulated. On the other hand, PH diminished Bmal1 expression but elevated NR2B and NF-κB p65 levels and anesthetic doses of ketamine further regulated the Bmal1/NMDA/NF-κB axis. In Bmal1-KO mice, the NMDA/NF-κB axis was activated, the release of inflammatory cytokines was promoted, and hippocampus-dependent memory was impaired, which were reversed by a subanesthetic dose of ketamine. Conclusion: Altogether, findings obtained in our study indicated that a subanesthetic dose of ketamine activated Bmal1, downregulated the NMDA/NF-κB axis, and reduced inflammation and microglia activation to alleviate PND in aged mice undergoing PH.

Effect of ketamine on binge drinking patterns in crossed high alcohol-preferring (cHAP) mice.

Previous research has demonstrated the utility of subanesthetic doses of ketamine in decreasing binge (Drinking-in-the-Dark, or DID) 20% alcohol intake in female inbred (C57BL/6J) mice when administered 12 hours prior to alcohol access (Crowley etal., 2019). In the current study, we assess the efficacy of a similar ketamine pretreatment using male and female selectively bred, crossed High Alcohol Preferring (cHAP) mice, which also drink to intoxication, but are not inbred. We hypothesized that ketamine would decrease binge alcohol intake without impacting locomotor activity. Subjects were 28 adult cHAP mice. Mice first received a 2-week DID drinking history using 2-h/day alcohol access. On day 12, prior to ketamine treatment, the average blood ethanol concentration (BEC) was 130mg/dL, confirming that mice reliably reached intoxicating BECs. On day 15, mice were given 0, 3, or 10mg/kg of ketamine 12 hours prior to the DID session. Ketamine did not decrease total (2-h) alcohol consumption or locomotion. Interestingly, the 10mg/kg dose of ketamine did alter the drinking pattern in male mice, decreasing front-loading for a single day. We opted to then increase the doses to 32 or 100mg/kg (i.e., an anesthetic dose) two days after the initial treatment, keeping the saline control. Mice of both sexes decreased total binge alcohol intake at the 100mg/kg dose only, but again, the effect only lasted one day. The current study found that cHAP mice reached more than double the BECs observed in C57BL/6J mice during DID, but did not respond to subanesthetic ketamine. Modest efficacy was found for ketamine pretreatment at anesthetic doses. Differences in findings may be due to differential intake during DID, or genetic differences between C57Bl/6J mice and cHAP mice. Drug efficacy in multiple models is important for discovering reliable pharmacotherapies for alcoholism.

Ketamine: Neuroprotective or Neurotoxic?

Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has been employed clinically as an intravenous anesthetic since the 1970s. More recently, ketamine has received attention for its rapid antidepressant effects and is actively being explored as a treatment for a wide range of neuropsychiatric syndromes. In model systems, ketamine appears to display a combination of neurotoxic and neuroprotective properties that are context dependent. At anesthetic doses applied during neurodevelopmental windows, ketamine contributes to inflammation, autophagy, apoptosis, and enhances levels of reactive oxygen species. At the same time, subanesthetic dose ketamine is a powerful activator of multiple parallel neurotrophic signaling cascades with neuroprotective actions that are not always NMDAR-dependent. Here, we summarize results from an array of preclinical studies that highlight a complex landscape of intracellular signaling pathways modulated by ketamine and juxtapose the somewhat contrasting neuroprotective and neurotoxic features of this drug.

Evaluation of the Effect of Continuous Infusion of Dexmedetomidine or a Subanesthetic Dose Ketamine on Transcranial Electrical Motor Evoked Potentials in Adult Patients Undergoing Elective Spine Surgery under Total Intravenous Anesthesia: A Randomized Controlled Exploratory Study.

Study DesignProspective, randomized, placebo-controlled, double-blind exploratory study.PurposeTo compare effects of dexmedetomidine or a subanesthetic dose of ketamine on the amplitude and latency of transcranial electrically generated motor evoked potentials.Overview of LiteratureTotal intravenous anesthesia (TIVA) is a standard anesthesia technique for transcranial electrical motor evoked potential monitoring in spine surgery. We aimed to determine whether the use of dexmedetomidine and ketamine as a component of TIVA exerted any beneficial effect on the quality of monitoring.MethodsA total of 90 American Society of Anesthesiologist grade I–III patients, aged 18–65 years, with a motor power of ≥4/5 grade as per the Medical Research Council Scale in all four limbs who were scheduled for elective spine surgery under transcranial electrical motor evoked potential monitoring were enrolled. The subjects were randomly allocated into the following three groups: group PD who received 0.5 μg/kg/hr dexmedetomidine infusion, group PK who received 0.5 mg/kg/hr ketamine infusion, and group PS who received normal saline infusion, along with standard propofol–fentanyl based TIVA regime. Amplitude and latency of bilateral motor evoked potentials of the tibialis anterior and abductor halluces muscle were recorded at Ti (at train-of-four ratio >90%), T30 (30 minutes post-Ti), T60 (60 minutes post-Ti), and Tf (at the end of spine manipulation).ResultsBaseline median amplitudes were comparable among the study groups. In group PK, we noted a gradually enhanced response by 24%–100% from the baseline amplitude. The median amplitudes of all the muscles were higher in group PK than those in groups PS and PD at time points T60 and Tf (p<0.05).ConclusionsThe present study demonstrated that compared with dexmedetomidine and control treatment, a subanesthetic dose of ketamine caused gradual improvement in amplitudes without affecting the latency.

Ketamine Infusion in an Outpatient Surgical Facility

<h3>Background Information</h3> Cancer and the treatment plans associated with its management has the potential to impact a patient physically and physiologically. With the common complication being chronic pain, management can be challenging and at times suboptimal. Ketamine in subanesthetic dose is a widely used phencyclidine derivative for the management of chronic pain when inadequate response to multimodal treatments such as opioid therapy occurs. The Josie Robertson Surgery Center (JRSC) has established a ketamine infusion program to manage chronic pain in our cancer population. <h3>Objectives of Project</h3> To provide ketamine intravenous infusions for the management of chronic cancer pain in conjunction with opioid and/or non-steroidal anti-inflammatory drugs in a controlled setting of a perianesthesia unit; to acquire an extended period of pain relief. <h3>Process of Implementation</h3> A core group of eight nurses were educated in implementing the program within a limited time frame, in partnership with an interdisciplinary team including the office practice pain service. Education included hands-on training of multiple equipment, electronic documentation in a training environment, review of the potential side effects to anticipate and how to navigate effectively the various healthcare technological systems available for monitoring patients during their individualized outpatient visit. Nurses use their perianesthesia clinical judgment in following the titration order of four-hour ketamine infusion in accordance with potential side effects that patients might exhibit. Nursing competency for this program is accomplished by maintaining BLS and ACLS certifications, evaluation of knowledge of moderate sedation through a yearly examination and frequent re-evaluation of workflow created to provide an efficient service. <h3>Statement of Successful Practice</h3> Centered on patient's self-reporting of pain relief as evident by vocalizing improvement in their quality of life through reduction of pain intensity, increase in their ability to perform ADLs and repeat infusions based on long-lasting effect. <h3>Implications for Advancing the Practice of Perianesthesia Nursing</h3> Provides perianesthesia nurses with an autonomous role to translate their perianesthesia skills for an outpatient pain service.

Structural basis of ketamine action on human NMDA receptors.

Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors1. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants2,3. Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant4. Here we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids-leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1-were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants.