Subanesthetic Doses Research Articles

Ketamine and Esketamine in Clinical Trials: FDA-Approved and Emerging Indications, Trial Trends With Putative Mechanistic Explanations.

Ketamine has a long and very eventful pharmacological history. Its enantiomer, esketamine ((S)-ketamine), was approved by the US Food and Drug Administration (FDA) and EMA for patients with treatment-resistant depression (TRD) in 2019. The number of approved indications for ketamine and esketamine continues to increase, as well as the number of clinical trials. This analysis provides a quantitative overview of the use of ketamine and its enantiomers in clinical trials during 2014-2024. A total of 363 trials were manually assessed from clinicaltrial.gov with the search term "Ketamine." The highest number of trials were found for the FDA-approved indications: anesthesia (~22%) and pain management (~28%) for ketamine and TRD for esketamine (~29%). Clinical trials on TRD for both ketamine and esketamine also comprised a large proportion of these trials, and interestingly, have reached phase III and phase IV status. Combinatorial treatment of psychiatric disorders and non-psychiatric conditions with pharmacological and non-pharmacological combinations (electroconvulsive therapy, psychotherapeutic techniques, virtual reality, and transcranial magnetic stimulation) is prevalent. Sub-anesthetic doses of ketamine may represent novel therapeutic avenues in neuropsychiatric conditions, that is, major depression, schizophrenia, and bipolar disorder, where glutamate excitotoxicity and oxidative stress are likely to be involved. The study suggests that the number of ketamine studies will continue to grow and possible ketamine variants can be approved for treatment of additional indications.

Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors.

Ketamine is a glutamate receptor antagonist that was developed over 50 years ago as an anesthetic agent. At subanesthetic doses, ketamine and some metabolites are analgesics and fast-acting antidepressants, presumably through targets other than glutamate receptors. We tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors expressed as recombinant receptors in heterologous systems and with native receptors in rodent brain; signaling was examined by measuring GTP binding, β-arrestin recruitment, MAPK activation, and neurotransmitter release. Although micromolar concentrations of ketamine alone had weak agonist activity at μ opioid receptors, the combination of submicromolar concentrations of ketamine with endogenous opioid peptides produced robust synergistic responses with statistically significant increases in efficacies. All three opioid receptors (μ, δ, and κ) showed synergism with submicromolar concentrations of ketamine and either methionine-enkephalin (Met-enk), leucine-enkephalin (Leu-enk), and/or dynorphin A17 (Dyn A17), albeit the extent of synergy was variable between receptors and peptides. S-ketamine exhibited higher modulatory effects compared with R-ketamine or racemic ketamine, with ∼100% increase in efficacy. Importantly, the ketamine metabolite 6-hydroxynorketamine showed robust allosteric modulatory activity at μ opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors. Ketamine enhanced potency and efficacy of Met-enkephalin signaling both in mouse midbrain membranes and in rat ventral tegmental area neurons as determined by electrophysiology recordings in brain slices. Taken together, these findings support the hypothesis that some of the therapeutic effects of ketamine and its metabolites are mediated by directly engaging the endogenous opioid system. SIGNIFICANCE STATEMENT: This study found that ketamine and its major biologically active metabolites function as potent allosteric modulators of μ, δ, and κ opioid receptors, with submicromolar concentrations of these compounds synergizing with endogenous opioid peptides, such as enkephalin and dynorphin. This allosteric activity may contribute to ketamine's therapeutic effectiveness for treating acute and chronic pain and as a fast-acting antidepressant drug.

Experience of using multimodal opioid-saving anesthesia in children: single-center prospective randomized study

BACKGROUND: In the protocols of rapid recovery after surgery, it is recommended to avoid long-term administration and/ or high doses of opioids in order to reduce the severity of their adverse reactions in the postoperative period. In this regard, opioid-sparing anesthesia (OSA) may become a promising approach to the treatment of cancer patients. AIM. To evaluate the effectiveness of multimodal OSA in the scheme "dexmedetomidine+ketamine (in subanesthetic doses)+lidocaine (intravenous infusion)" in pediatric oncosurgery. MATERIALS AND METHODS: A single-center prospective randomized study involved 40 children aged 12 to 18 years. Patients were divided into 2 groups depending on the method of anesthesia: in group I (n=20), combined endotracheal anesthesia with opioids was performed, in group II (n=20) — multimodal OCA based on intravenous infusion of lidocaine, dexmedetomidine and subanesthetic doses of ketamine. The patients underwent extended operations in the head and neck area in the volume of thyroidectomy with fascial-sheath lymph dissection and excision of the central tissue of the neck from 2 sides. RESULTS: With stable intraoperative hemodynamic parameters, the median total intraoperative need for analgesics in group II was: for lidocaine— 351 (289.6; 418.5) mg (which is 1.75mg/kg per hour), for dexmedetomidine— 88.2 (38.5; 119.7) µg, for ketamine — 21.6 (17.4; 27.3mg. In group I, the median total intraoperative need for fentanyl was 273.7 (406; 240.9)µg. In addition, in group I, the median amount required for postoperative analgesia of the synthetic opioid analgesic tramadol was 419 (365.6; 479)mg (which is 7.8mg/kg; p=0.01). In group II, the median amount of lidocaine required for postoperative analgesia (1 mg/kg per hour) turned out to be 1377.3 (735.7; 1894)mg, while additional tramadol administration at a dose of 57.3 (28.5; 107.7)mg was required in only 7(35%) patients. CONCLUSION: Multimodal OSA based on dexmedetomidine, lidocaine, ketamine and sevoflurane is an effective and safe method of anesthesia in children from 12 to 18 years old, which is not inferior to opioid analgesics in the treatment of perioperative pain during surgical interventions on the thyroid and parathyroid glands in cancer patients, and also reduces the number of adverse reactions characteristic of opioids.

Ketamine modulates the exploratory dynamics and homebase-related behaviors of adult zebrafish

Anxiety is a protective behavior when animals face aversive conditions, but commonly associated with various neuropsychiatric disorders when exacerbated. Drug repurposing has emerged as a valuable strategy to use existing pharmaceuticals for new therapeutic purposes. Ketamine, traditionally used as an anesthetic, acts as a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, and evidence has shown potential anxiolytic and antidepressant effects at subanesthetic doses. However, the influence of ketamine on multiple behavioral domains in vertebrates is not completely understood. Here, we evaluated the potential modulatory effect of ketamine on the spatio-temporal exploratory dynamics and homebase-related behaviors in adult zebrafish using the open field test (OFT). Animals were exposed to subanesthetic concentrations of ketamine (0, 2, 20, and 40 mg/L) for 20 min and locomotion- exploration- and homebase-related behaviors were assessed in a single 30-min trial. Our data revealed that ketamine (20 and 40 mg/L) induced hyperlocomotion, as verified by the increased total distance traveled. All concentrations tested elicited circling behavior, a stereotyped-like response which gradually reduced across the periods of test. We also observed modulatory effects of ketamine on the spatio-temporal exploratory pattern, in which the reduced thigmotaxis and homebase activity, associated with the increased average length of trips were suggestive of anxiolytic-like effects. Collectively, our novel findings support the modulatory effects of ketamine on the spatio-temporal exploratory activity, as well as the utility of homebase-related measurements to evaluate the behavioral dynamics of zebrafish.

Characterization of Oral Ketamine Use: A Retrospective Review

Ketamine is an N-methyl D-aspartate (NMDA) receptor antagonist used to treat pain at subanesthetic doses. Ketamine is beneficial for pain control in patients who have a high tolerance to opioids and are experiencing opioid-induced hyperalgesia. This study characterizes oral ketamine use for analgesia at a large academic hospital and reports safety outcomes for hospitalized patients. This study was a retrospective electronic health record (EHR) review of patients ≥ 18 years or older receiving oral ketamine. The primary endpoint was median ketamine starting dose and maximum dose (mg/kg/day) during treatment duration. Secondary outcomes included oral Morphine Milligram Equivalents (MMEs), buprenorphine dose, minimum and maximum pain scores on the first and last day of therapy. Safety endpoints were reported. The median starting dose was 1 mg/kg/day, and the median maximum dose was 1.6 mg/kg/day. Median MMEs decreased from the first day to the last day of oral ketamine therapy. The study population experienced a low incidence of safety events overall. Oral ketamine was administered safely for analgesia, with patients receiving ketamine doses that were on the lower end of the established therapeutic range. Evaluation of the efficacy and safety of oral ketamine use for analgesia should be further studied.

ОЦЕНКА ЭФФЕКТИВНОСТИ СУБАНЕСТЕТИЧЕСКИХ ДОЗ КЕТАМИНА ПРИ КАРДИОХИРУРГИЧЕСКИХ ОПЕРАТИВНЫХ ВМЕШАТЕЛЬСТВАХ

Background: to evaluate the effectiveness of general anesthesia (GA) in combination with a subanesthetic dose of ketamine during cardiac surgery under cardiopulmonary bypass (CPB). Material and methods. Cardiac surgery patients were divided into two groups: group 1 (n=21) – GMEA based on sevoflurane (before and after CPB), propofol (during CPB), fentanyl and pipecuronium; Group 2 (n=18) – GA in combination with ketamine administration (bolus – 25 mg, then titrated – 25 mg/h). The comparison of the parameters of anesthesia, endocrine-metabolic monitoring, perioperative hemodynamic parameters, and pain level was made. Results. In the patient groups at the study stages no statistically significant differences in the values of cortisol, prolactin, glucose and blood lactate were found. The duration of mechanical ventilation, pain, doses of morphine and paracetamol did not differ in the postoperative period. Conclusions. The studied methods of anesthesia during cardiac surgery with CPB did not have differences in the parameters of endocrine-metabolic monitoring. The use of GA in combination with ketamine is characterized by less fluctuation in blood pressure during the study phases: 5 minutes after sternotomy, 15 minutes before the start of CPB and the patient's admission to the intensive care unit.

Effect of a subanesthetic dose of esketamine combined with propofol on postoperative fatigue syndrome in patients undergoing gastroenterological endoscopy under anaesthesia: A retrospective study.

To assess the effect of subanesthetic dose of esketamine in combination with propofol on the incidence of postoperative fatigue syndrome (POFS) in patients who underwent gastroenterological endoscopy under anaesthesia. Clinical data of 160 patients who underwent gastroenterological endoscopy under anaesthesia in Huzhou Maternity & Child Health Care Hospital from January to December 2022, ASA Grade- I and II, were retrospectively selected. According to the records, patients were grouped based on the administered anesthetic. Patients who received 0.2 mg/kg of esketamine and 2~2.5mg/kg of propofol comprised Group-E, and patients who were administered one μg/kg of fentanyl and 2 - 2.5mg/kg of propofol comprised Group-F. Mean arterial pressure (MAP), oxygen saturation (SpO2) and heart rate (HR) were recorded before the operation (T0), after anesthesia (T1), three minutes after the gastroscope was inserted (T2), five minutes after the colonoscope was inserted (T3) and at the end of the operation (T4). Operating time, recovery time, propofol dosage and incidence of adverse reactions in the two groups were recorded. The Christensen scores and the incidence of POFS of all patients on Day-I before operation and 1st, 3rd, and 5th days after the operation were recorded. Compared with T0, MAP, SpO2 and HR in both groups of patients decreased at T1, T2, T3 and T4 (P<0.05). MAP, SpO2 and HR of patients in Group-E were significantly higher compared to Group-F at T1, T2, T3 and T4 (P<0.05). Compared with Group-F, the recovery time, intraoperative bradycardia and respiratory depression in Group-E were significantly lower (P<0.05), and Christensen scores and the incidence of POFS decreased significantly on the 1st, 3rd, and 5th day after the operation (P<0.05). Subanesthetic dose of esketamine combined with propofol can reduce POFS and postoperative adverse reactions in patients undergoing gastroenterological endoscopy.

Ketamine-assisted buprenorphine initiation: a pilot case series

BackgroundMany people with opioid use disorder who stand to benefit from buprenorphine treatment are unwilling to initiate it due to experience with or fear of both spontaneous and buprenorphine-precipitated opioid withdrawal (BPOW). An effective means of minimizing withdrawal symptoms would reduce patient apprehensiveness, lowering the barrier to buprenorphine initiation. Ketamine, approved by the FDA as a dissociative anesthetic, completely resolved BPOW in case reports when infused at a sub-anesthetic dose range in which dissociative symptoms are common. However, most patients attempt buprenorphine initiation in the outpatient setting where altered mental status is undesirable. We explored the potential of short-term use of ketamine, self-administered sublingually at a lower, sub-dissociative dose to assist ambulatory patients undergoing transition to buprenorphine from fentanyl and methadone.MethodsPatients prescribed ketamine were either (1) seeking transition to buprenorphine from illicit fentanyl and highly apprehensive of BPOW or (2) undergoing transition to buprenorphine from illicit fentanyl or methadone and experiencing BPOW. We prescribed 4–8 doses of sublingual ketamine 16 mg (each dose bioequivalent to 3–6% of an anesthetic dose), monitored patients daily or near-daily, and adjusted buprenorphine and ketamine dosing based on patient response and prescriber experience.ResultsOver a period of 14 months, 37 patients were prescribed ketamine. Buprenorphine initiation was completed by 16 patients, representing 43% of the 37 patients prescribed ketamine, and 67% of the 24 who reported trying it. Of the last 12 patients who completed buprenorphine initiation, 11 (92%) achieved 30-day retention in treatment. Most of the patients who tried ketamine reported reduction or elimination of spontaneous opioid withdrawal symptoms. Some patients reported avoidance of severe BPOW when used prophylactically or as treatment of established BPOW. We developed a ketamine protocol that allowed four of the last patients to complete buprenorphine initiation over four days reporting only mild withdrawal symptoms. Two patients described cognitive changes from ketamine at a dose that exceeded the effective dose range for the other patients.ConclusionsKetamine at a sub-dissociative dose allowed completion of buprenorphine initiation in the outpatient setting in the majority of patients who reported trying it. Further research is warranted to confirm these results and develop reliable protocols for a range of treatment settings.

Optimizing esketamine administration for postoperative depression: a comprehensive study on laparoscopic bariatric surgery patients.

Previous studies have reported conflicting findings regarding the efficacy of esketamine in managing postoperative depression. While the positive effects of subanesthetic doses esketamine have been observed in treatment-resistant depression, the response to this medication in patients experiencing depression following surgery has not been consistent. Building upon the known impact of anesthesia on brain function, we have formulated a hypothesis suggesting that the timing of esketamine administration in relation to anesthesia may significantly affect its efficacy in managing postoperative depression. The aim of this study was to investigate the effect of esketamine administered at different time points before and after anesthesia. Our randomized, double-blind, controlled study involved 120 patients undergoing laparoscopic bariatric surgery, randomly divided into three groups. Group Post- ESK received an intravenous injection of esketamine at a dose of 0.2mg/kg after anesthesia induction. Group Pre- ESK received the same esketamine dosage 2h prior to anesthesia induction. Group Placebo served as the control group and received a 0.9% saline solution after induction. The primary outcome measures of the study were depression scores as measured by Patient Health Questionnaire-9 (PHQ-9) and plasma brain-derived neurotrophic factor (BDNF) levels. On the first postoperative day, the PHQ-9 scores, incidence and severity of postoperative depression in the Pre-ESK group were significantly lower than those in the Post-ESK and placebo groups (P < 0.05). Additionally, plasma BDNF levels in the Pre-ESK group were significantly higher than those in the Post-ESK and placebo groups (P < 0.05). Notably, there was a negative correlation between PHQ-9 scores and plasma BDNF levels. Our study supports the potential for subanesthetic dose esketamine to alleviate postoperative depression symptoms following laparoscopic bariatric surgery, and anesthetic drugs have a significant effect on its efficacy. The use of subanesthetic dose esketamine after anesthesia does not improve postoperative depression symptoms in patients undergoing laparoscopic bariatric surgery, while the use of sub-anesthetic dose esketamine before anesthesia can improve postoperative depression symptoms.

Sex-specific effects of subchronic NMDA receptor antagonist MK-801 treatment on hippocampal gamma oscillations.

N-methyl-D-aspartate (NMDA) receptor antagonists are widely used to pharmacologically model schizophrenia and have been recently established in the treatment of treatment-resistant major depression demonstrating that the pharmacology of this substance class is complex. Cortical gamma oscillations, a rhythmic neuronal activity associated with cognitive processes, are increased in schizophrenia and deteriorated in depressive disorders and are increasingly used as biomarker in these neuropsychiatric diseases. The opposite use of NMDA receptor antagonists in schizophrenia and depression raises the question how their effects are in accordance with the observed disease pathophysiology and if these effects show a consequent sex-specificity. In this study in rats, we investigated the effects of subchronic (14 days) intraperitoneal injections of the NMDA receptor antagonist MK-801 at a subanesthetic daily dose of 0.2 mg/kg on the behavioral phenotype of adult female and male rats and on pharmacologically induced gamma oscillations measured ex vivo from the hippocampus. We found that MK-801 treatment leads to impaired recognition memory in the novel object recognition test, increased stereotypic behavior and reduced grooming, predominantly in female rats. MK-801 also increased the peak power of hippocampal gamma oscillations induced by kainate or acetylcholine only in female rats, without affecting the peak frequency of the oscillations. The findings indicate that blockade of NMDA receptors enhances gamma oscillations predominantly in female rats and this effect is associated with behavioral changes in females. The results are in accordance with clinical electrophysiological findings and highlight the importance of hippocampal gamma oscillations as a biomarker in schizophrenia and depression.

Subanesthetic Dose of Esketamine Improves the Sedative and Analgesic Effects of Dexmedetomidine and Remifentanil in Liposuction Anesthesia: A Prospective, Double-Blinded, Randomized Controlled Trial.

Esketamine have anesthetic and analgesic properties. This study aimed to observe the enhancing effect of subanesthetic doses of esketamine (0.15-0.3 mg/kg/h) with dexmedetomidine and remifentanil during anesthesia for liposuction surgery. A total of 155 subjects were randomized with a 1:1 ratio to Group E (esketamine-dexmedetomidine/remifentanil, n=78) or Group C (saline-dexmedetomidine/remifentanil group, n=77). The primary outcome was satisfaction of patient and surgical team with the procedure. The secondary outcomes were the postoperative Athens Insomnia Scale (AIS) and Hospital Anxiety and Depression Scale (HADS) scores, hemodynamic and respiratory changes, drug consumption, adverse event rates, and predictors associated with patient satisfaction. Patient and surgical team satisfaction with the procedure was significantly higher in Group E than in Group C (4.7 ± 0.6 vs 4.2 ± 0.7, P < 0.001; 4.7 ± 0.5 vs 4.4 ± 0.7, P = 0.005). The postoperative AIS (4 [1, 6] vs 5 [2, 9], P = 0.012) and HADS-A (1 [0, 3] vs 2 [0, 6], P = 0.012) scores were significantly lower in Group E than in Group C. Hemodynamic and respiratory parameters were more stable in Group E than in Group C, with the lower opioids consumption of sufentanil (0 [0, 4] vs 5 [2.5, 7.7], P < 0.001) and remifentanil (700 [480, 900] vs 800 [500, 1200], P = 0.023) in Group E compared to Group C. On ordinal logistics regression, postoperative sleep quality (OR, 0.70; 95% CI, 0.62-0.79), anxiety level (OR, 0.77; 95% CI, 0.62-0.95) and recovery time in post-anesthesia care unit (PACU) (OR, 0.69; 95% CI, 0.56-0.98) were identified as significant predictors associated with patient satisfaction. A subanesthetic dose of esketamine (0.15-0.3 mg/kg/h) as an adjuvant can improves the sedative and analgesic effects of dexmedetomidine and remifentanil during anesthesia for liposuction surgery. ChiCTR2400080363.

Ketamine Infusion for Reducing Post-Operative Pain and Opioid Use in Gynecological Surgery

This analysis aimed to evaluate the efficacy of ketamine infusion for reducing post-operative pain and opioid use in gynecological surgeries. A comprehensive review of recent studies revealed that ketamine consistently demonstrates significant pain-reducing and opioid-sparing effects across various surgical contexts, including gynecological procedures. Sub-anesthetic doses of ketamine were found to be effective and well-tolerated. However, optimal dosing regimens and timing of administration specific to gynecological surgeries require further investigation. The analysis recommends conducting large-scale, procedure-specific trials to establish tailored protocols for different gynecological surgeries. Additionally, long-term follow-up studies are needed to assess the impact on chronic pain development and persistent opioid use. This analysis is significant for refining pain management strategies in gynecological surgeries, potentially improving patient outcomes and addressing opioid-related concerns. It underscores the need for more flexible regulations to facilitate ketamine's clinical use in this context.

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i. p.) 1 h prior to ketamine or HNKs (10 mg/kg, i. p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 h post-injection (t24 h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.

Thalamocortical functional connectivity and rapid antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression.

Previous studies have shown an association between the thalamocortical dysconnectivity and treatment-resistant depression (TRD). Whether a single subanesthetic dose of ketamine may change thalamocortical connectivity among patients with TRD is unclear. Whether these changes in thalamocortical connectivity is associated with the antidepressant and antisuicidal effects of ketamine treatment is also unclear. Two resting-state functional MRIs were collected in two clinical trials of 48 patients with TRD (clinical trial 1; 32 receiving ketamine, 16 receiving a normal saline placebo) and 48 patients with TRD and strong suicidal ideation (clinical trial 2; 24 receiving ketamine, 24 receiving midazolam), respectively. All participants underwent rs-fMRI before and 3 days after infusion. Seed-based functional connectivity (FC) was analyzed in the left/right thalamus. FCs between the bilateral thalamus and right middle frontal cortex (BA46) and between the left thalamus and left anterior paracingulate gyrus (BA8) increased among patients in the ketamine group in clinical trials 1 and 2, respectively. FCs between the right thalamus and bilateral frontal pole (BA9) and between the right thalamus and left rostral paracingulate gyrus (BA10) decreased among patients in the ketamine group in clinical trials 1 and 2, respectively. However, the associations between those FC changes and clinical symptom changes did not survive statistical significance after multiple comparison corrections. Whether ketamine-related changes in thalamocortical connectivity may be associated with ketamine's antidepressant and antisuicidal effects would need further investigation. Clinical trials registration: UMIN Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000016985 and UMIN000033916.

Impact of Sub-Anesthetic Dose of Ketamine on Post Spinal Hypotension in Cesarean Delivery

Abstract Background Spinal anesthesia is the commonest technique used in Cesarean Section (CS) and most frequently associated with maternal hypotension, for whicha lot of techniques have been described to prevent but an effective method is yet to be found. Objectives The aim was to study the effect of using a sub-anesthetic dose of ketamine to prevent post-spinal hypotension in CS delivery. Methods This double-blinded randomized controlled study was conducted on 60 participating parturients who were ASA І, П term pregnant. All the parturients received spinal anesthesia. The parturients were then randomly divided into two equal groups (n = 30 in each); ketamine group received a sub- anesthetic dose of ketamine of 0.5 mg/kg IV bolus in 3 ml saline and control group received the same volume of normal saline IV bolus. Heart Rate (HR) and Mean Arterial blood Pressure (MAP) were recorded at baseline (5 minutes prior to the intrathecal injection), at 5, 10, 15 and 20 minutes after the injection and then every 15 minutes till the end of the operation. Incidences of hypotension and severe hypotension were recorded. The total dose of ephedrine was recorded. Modified Ramsay sedation score was recorded at baseline then 5, 10, 15, 30, 45 minutes after injection and then at the end of the operation. Results The study revealed that ketamine didn’t prevent hypotension, it only delayed it for 10 min compared to control group 5 min. Also, observed that total ephidren dose significantly decreased in ketamine group compared to control group. And sedation scores in the first 30 min were higher in ketamine group. HR wasn’t affected. No changes in APGAR score were noticed between the two groups. No side effects from ketamine except for nystagmus. Conclusion This study concluded that the use of intravenous ketamine in low dose (0.5mg/kg) doesn’t prevent postspinal hypotension but it only decreases ephidren requirements.

A single subanaesthetic dose of the rapid-acting antidepressant S-ketamine raises presynaptic SV2A density in limbic regions of the Wistar Kyoto rat model of depression

The N-methyl-D-aspartate receptor (NMDA-R) antagonist S-ketamine has been approved as a rapid-acting antidepressant for treatment-resistant depression (TRD). The antidepressant mechanisms have not fully been elucidated; however, alterations of synaptic proteins and mechanisms may play a vital role. Here, we study the effect of a single subanaesthetic dose of 15 mg/kg S-ketamine vs saline 1 h after administration in the Wistar Kyoto rat model of depression on the density of synaptic vesicle glycoprotein 2A (SV2A) and the metabotropic glutamate receptor 5 (mGluR5) using [3H]UCB-J and [3H]MPEPγ autoradiography, respectively, compared with control Wistar Hannover rats. In a separate cohort of Wistar Kyoto rats, we investigate the transcriptional regulation of presynaptic markers Sv2a, Syn 1–3, Syt 1–3, Synaptophysin, Vamp1, 2, 5, and 7, postsynaptic markers Homer1-3, Nrg 1, Nlgn 2, Nlgn 3, Psd95, NMDA receptor subunits Nr2a, Nr2b, AMPA receptor subunits Gria1-3, GABA type A receptor-associated protein (Gabarap), glutamate metabotropic receptor subtype 5 (Grm5), and brain-derived neurotrophic factor (Bdnf) using real-time quantitative polymerase chain reaction (qPCR) in hippocampus in response to S-ketamine vs saline injection. In Wistar Kyoto rats, S-ketamine increases [3H]UCB-J binding to SV2A compared to saline-injected controls in the nucleus accumbens and dorsal and ventral hippocampus, an effect absent in the Wistar Hannover strain. No changes were observed in [3H]MPEPγ binding to mGluR5, nor in gene regulation. S-ketamine can regulate presynaptic SV2A density in brain areas relevant to depression in the Wistar Kyoto model, but not in controls, suggesting a role for SV2A in the antidepressant effects of S-ketamine.

Neural Mechanisms of Visual Search and Working Memory

Visual search is a useful experimental paradigm investigating various aspects of attention. For efficient search, participants must avoid revisiting previously viewed objects. Inhibitory tagging and inhibition of return are phenomena related to this process, but their neural mechanisms are yet to be elucidated. Recent studies have shown that the rate of revisit behavior during visual search correlates with working memory capacity. This suggests that top-down signals from the frontal executive system alter the priority map that guides attention and eye movements. With this in mind, we have developed a novel visual search paradigm with many identical distractors and an evaluation model that assesses multiple parameters of working memory. The model incorporated memory capacity, memory decay, and utility rate, and when applied to data obtained from experimental animals, these parameters could be reliably evaluated. Furthermore, using the behavioral paradigm and model, we found that systemic administration of subanesthetic dose of ketamine decreased utility rate and memory capacity, while nicotine administration increased utility rate. Since our behavioral paradigm does not require complex instruction, it can be applied to a variety of patients in future clinical studies.

Subanesthetic S-ketamine does not acutely alter striatal dopamine transporter binding in healthy Sprague Dawley female rats.

Major depressive disorder is one of the most prevalent mental health disorders, posing a global socioeconomic burden. Conventional antidepressant treatments have a slow onset of action, and 30% of patients show no clinically significant treatment response. The recently approved fast-acting antidepressant S-ketamine, an N-methyl-D-aspartate receptor antagonist, provides a new approach for treatment-resistant patients. However, knowledge of S-ketamine's mechanism of action is still being established. Depressed human subjects have lower striatal dopamine transporter (DAT) availability compared to healthy controls. Rodent studies report increased striatal dopamine concentration in response to acute ketamine administration. In vivo [18F]FE-PE2I ([18F]-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl-phenyl) nortropane) positron emission tomography (PET) imaging of the DAT has not previously been applied to assess the effect of acute subanesthetic S-ketamine administration on DAT availability. We applied translational in vivo [18F]FE-PE2I PET imaging of the DAT in healthy female rats to evaluate whether an acute subanesthetic intraperitoneal dose of 15mg/kg S-ketamine alters DAT availability. We also performed [3H]GBR-12935 autoradiography on postmortem brain sections. We found no effect of acute S-ketamine administration on striatal DAT binding using [18F]FE-PE2I PET or [3H]GBR-12935 autoradiography. This negative result does not support the hypothesis that DAT changes are associated with S-ketamine's rapid antidepressant effects, but additional studies are warranted.

Molecular signatures of astrocytes and microglia maladaptive responses to acute stress are rescued by a single administration of ketamine in a rodent model of PTSD

Stress affects the brain and alters its neuroarchitecture and function; these changes can be severe and lead to psychiatric disorders. Recent evidence suggests that astrocytes and microglia play an essential role in the stress response by contributing to the maintenance of cerebral homeostasis. These cells respond rapidly to all stimuli that reach the brain, including stressors. Here, we used a recently validated rodent model of post-traumatic stress disorder in which rats can be categorized as resilient or vulnerable after acute inescapable footshock stress. We then investigated the functional, molecular, and morphological determinants of stress resilience and vulnerability in the prefrontal cortex, focusing on glial and neuronal cells. In addition, we examined the effects of a single subanesthetic dose of ketamine, a fast-acting antidepressant recently approved for the treatment of resistant depression and proposed for other stress-related psychiatric disorders. The present results suggest a prompt glial cell response and activation of the NF-κB pathway after acute stress, leading to an increase in specific cytokines such as IL-18 and TNF-α. This response persists in vulnerable individuals and is accompanied by a significant change in the levels of critical glial proteins such as S100B, CD11b, and CX43, brain trophic factors such as BDNF and FGF2, and proteins related to dendritic arborization and synaptic architecture such as MAP2 and PSD95. Administration of ketamine 24 h after the acute stress event rescued many of the changes observed in vulnerable rats, possibly contributing to support brain homeostasis. Overall, our results suggest that pivotal events, including reactive astrogliosis, changes in brain trophic factors, and neuronal damage are critical determinants of vulnerability to acute traumatic stress and confirm the therapeutic effect of acute ketamine against the development of stress-related psychiatric disorders.

Sevoflurane acts as an antidepressant by suppression of GluN2D-containing NMDA receptors on interneurons.

Sevoflurane, a commonly used inhaled anaesthetic known for its favourable safety profile and rapid onset and offset, has not been thoroughly investigated as a potential treatment for depression. In this study, we reveal the mechanism through which sevoflurane delivers enduring antidepressant effects. To assess the antidepressant effects of sevoflurane, behavioural tests were conducted, along with in vitro and ex vivo whole-cell patch-clamp recordings, to examine the effects on GluN1-GluN2 incorporated N-methyl-d-aspartate (NMDA) receptors (NMDARs) and neuronal circuitry in the medial prefrontal cortex (mPFC). Multiple-channel electrophysiology in freely moving mice was performed to evaluate sevoflurane's effects on neuronal activity, and GluN2D knockout (grin2d-/-) mice were used to confirm the requirement of GluN2D for the antidepressant effects. Repeated exposure to subanaesthetic doses of sevoflurane produced sustained antidepressant effects lasting up to 2 weeks. Sevoflurane preferentially inhibited GluN2C- and GluN2D-containing NMDARs, causing a reduction in interneuron activity. In contrast, sevoflurane increased action potentials (AP) firing and decreased spontaneous inhibitory postsynaptic current (sIPSC) in mPFC pyramidal neurons, demonstrating a disinhibitory effect. These effects were absent in grin2d-/- mice, and both pharmacological blockade and genetic knockout of GluN2D abolished sevoflurane's antidepressant actions, suggesting that GluN2D is essential for its antidepressant effect. Sevoflurane directly targets GluN2D, leading to a specific decrease in interneuron activity and subsequent disinhibition of pyramidal neurons, which may underpin its antidepressant effects. Targeting the GluN2D subunit could hold promise as a potential therapeutic strategy for treating depression.