Subanesthetic Doses Of Ketamine Research Articles

Evaluating the Influence of IV Ketamine on Postoperative Opioid Use for Surgical Patients at a Tertiary Care Centre.

Subanesthetic doses of ketamine have been shown to improve the efficacy of opioids, increase pain control, and exemplify opioid-sparing effects when used as postoperative analgesia for adults. To determine, for surgical patients, the impact of IV ketamine infusions on opioid use in hospital, overall and within 24 h before discharge, as well as pain scores. A retrospective matched cohort study was conducted, in which surgical patients exposed to ketamine were compared with those not exposed to ketamine, among admissions from January 1, 2018, to February 28, 2020. Patients were matched for age, surgical service, and sex. A total of 104 patients were included in the study. Overall, there was no significant difference in mean total opioid use in hospital for patients exposed and not exposed to ketamine (171.7 mg versus 115.5 mg oral morphine equivalent [OME], p = 0.09), nor was there any difference in opioid use in the 24 h before discharge (28.2 mg versus 18.2 mg OME, p = 0.14). Patient-reported pain scores did not differ between groups. More patients in the ketamine group experienced hallucinations than in the group not exposed to ketamine (5 versus 0, p = 0.024). Overall, subanesthetic doses of IV ketamine used postoperatively in surgical patients did not decrease opioid use or patient-reported pain. More patients who received ketamine had documented hallucinations. These results will help guide postoperative analgesia practice and strategies to reduce opioid use.

A Clinical Study for Removal of Impacted Mandibular Third Molar under Local Anaesthesia, with and without Ketamine - A Split Mouth Comparative Study.

Disimpaction is one of the most common operations done by oral and maxillofacial surgeons around the world. Ketamine is a well-known general anaesthetic and short-acting intraoperative analgesic. The aim of this study was to measure the efficacy of anaesthesia using combined treatment with local anaesthetic plus a subanaesthetic dose of ketamine and local anaesthetic alone in bilaterally impacted mandibular third molar surgery. A total of 24 patients who consented were taken up for a split-mouth study. In the control group, surgical extraction of the impacted lower third molar was done using local anaesthesia (lignocaine 2% with 1:80,000 adrenaline) only, and in the study group, local anaesthesia with ketamine extraction was done using ketamine (0.2 mg/kg) along with local anaesthesia (LA). The time of onset and the duration of anaesthesia intraoperatively were recorded using a digital stopwatch. The depth of anaesthesia was noted on the 10th, 30th and 60th min. After extraction, the post-operative pain on the first, fourth, eighth and 12th hour was evaluated using a Visual Analogue Scale (VAS) score rating of 1-10. The pulse was also noted and compared for any differences in either of the groups. A statistically significant (P < 0.005) difference in result was obtained for the onset, duration, depth and pain score after surgical extraction in both the evaluated groups. The pain index score by the ketamine group was significantly low as compared to the local anaesthesia-only group. Intraoperative onset, duration and depth of anaesthesia obtained had a significant difference. Ketamine can be used as a viable option for surgical third molar extractions with reduced discomfort and post-operative pain.

Ketamine for bipolar depression: an updated systematic review.

The therapeutic potential of subanesthetic doses of ketamine appears promising in unipolar depression; however, its effectiveness in treating bipolar depression (BD) remains uncertain. This systematic review aimed to summarize findings on the use of ketamine for the treatment of BD by assessing its efficacy, safety, and tolerability. Systematic review. We conducted a systematic review of studies that investigated the use of ketamine for adults with BD. We searched PubMed and Embase for relevant randomized-controlled trials, open-label trials, and retrospective chart analyses published from inception to 13 March 2023. Eight studies were identified [pooled n = 235; mean (SD) age: 45.55 (5.54)]. All participants who received intravenous (IV) ketamine were administered a dose of 0.5-0.75 mg/kg as an adjunctive treatment to a mood-stabilizing agent, whereas participants who received esketamine were administered a dosage ranging from 28 to 84 mg. Flexible dosing was used in real-world analyses. A total of 48% of participants receiving ketamine achieved a response (defined as ⩾50% reduction in baseline depression severity), whereas only 5% achieved a response with a placebo. Real-world studies demonstrated lower rates of response (30%) compared to the average across clinical trials (63%). Reductions in suicidal ideation were noted in some studies, although not all findings were statistically significant. Ketamine and esketamine were well tolerated in most participants; however, six participants (2% of the overall sample pool, 5 receiving ketamine) developed hypomanic/manic symptoms after infusions. Significant dissociative symptoms were observed at the 40-min mark in some trials. Preliminary evidence suggests IV ketamine as being safe and effective for the treatment of BD. Future studies should focus on investigating the effects of repeated acute and maintenance infusions using a randomized study design.

Evaluation of Continuous Infusions of Dexmedetomidine versus Propofol as an Adjuvant to Ketamine in Patients Undergoing Elective Upper Limb Surgery under Brachial Plexus Block – A Randomized Control Trial

Abstract Background: The use of anesthetic ketamine at usual doses has been limited by side effects such as sympathetic stimulation, treatment-emergent delirium, and prolonged recovery time. Recently, there has been a growing interest in combining subanesthetic doses of ketamine with subanesthetic doses of drugs such as propofol and dexmedetomidine to mitigate the unwanted effects of ketamine. Hence, we aimed to compare the effectiveness, in terms of postoperative Aldrete scores, intraoperative pain, sedation scores, hemodynamic changes, respiratory effects, surgeon satisfaction, and postoperative delirium, of continuous infusions of ketamine with adjuvant dexmedetomidine versus continuous infusions of ketamine with adjuvant propofol among patients undergoing elective upper limb surgery under brachial plexus block. Methods: We performed a double-blind, randomized, controlled trial among 60 participants randomly allocated into two groups. Group A patients (n = 30) received ketamine 0.5 mg/kg mixed with dexmedetomidine 0.5 μg/kg in 100 mL/h lipid emulsion as an infusion, whereas Group B patients received ketamine 0.5 mg/kg mixed with propofol 1 mg/kg in 100 mL/h normal saline as an infusion. Results: The mean Aldrete score at 0 min, 30 min, and 1 h was significantly higher among Group B patients (P = 0.001, P = 0.001, and P = 0.043, respectively). The mean diastolic blood pressure at 2 h was significantly higher in Group A compared to Group B (87.8 vs. 77.8, P = 0.001). Similarly, the mean arterial pressure at 45 min and 90 min was significantly higher in Group A compared to Group B (97.1 ± 6.7 vs. 92.2 ± 6.0, P = 0.004; 95.5 ± 5.5 vs. 90.8 ± 6.3, P = 0.005, respectively). The mean sedation score was not significantly different between groups. Conclusion: Propofol, when used as an adjuvant to ketamine, provides better hemodynamic stability and better Aldrete score in patients who receive brachial plexus block for elective upper limb surgeries compared to adjuvant dexmedetomidine.

Sedative effects and changes in cardiac rhythm with intravenous premedication of medetomidine, butorphanol and ketamine in dogs

ObjectiveTo determine the sedative effects and characteristics of cardiac rhythm with intravenous (IV) premedication of medetomidine, butorphanol and ketamine in dogs. Study designProspective, blinded, randomized clinical trial. AnimalsA total of 116 client-owned healthy dogs undergoing elective surgery. MethodsDogs were randomly allocated one of four groups: group M, medetomidine 5 μg kg–1; group B, butorphanol 0.2 mg kg–1; group MB, medetomidine 5 μg kg–1 and butorphanol 0.2 mg kg–1; or group MBK, medetomidine 5 μg kg–1, butorphanol 0.2 mg kg–1 and ketamine 1 mg kg–1 IV. Sedation was assessed using a numerical descriptive scale. Heart rate (HR) and rhythm were monitored; propofol dose (mg kg–1 IV) to allow orotracheal intubation was documented. Data were analysed using anova, accounting for multiple testing with the Tukey honest significant difference test. ResultsSedation scores varied significantly between all groups at all time points, except between groups MB and MBK at four time points. HR decreased in all groups: most in groups M and MB, least in group B. HR was initially higher in group MBK than in groups M and MB. Arrhythmias occurred in all groups: group B showed second-degree atrioventricular blocks occasionally, all other groups showed additionally ventricular escape complexes and bundle branch blocks.Dose of propofol required for orotracheal intubation was significantly higher in group B (5.0 ± 2.0 mg kg–1) than in group M (2.6 ± 0.6 mg kg–1). Although no difference could be demonstrated between groups MB (1.4 ± 0.6 mg kg–1) and MBK (0.9 ± 0.8 mg kg–1), both groups required significantly less propofol than group M. Conclusion and clinical relevance:Medetomidine-based premedication protocols led to various bradyarrhythmias. Addition of subanaesthetic doses of ketamine to medetomidine-based protocols resulted in higher HRs, fewer bradyarrhythmias and fewer animals that required propofol for intubation without causing side effects in healthy dogs.

The Effects of Acute and Repeated Administration of Ketamine on Memory, Behavior, and Plasma Corticosterone Levels in Female Mice

Ketamine is an anesthetic drug that has recently been approved for the treatment of treatment-resistant depression. Females are diagnosed with Major Depressive Disorder at higher rates than males, yet most of the pre-clinical research on ketamine has been conducted in male subjects. Additionally, the literature on the acute and long-term behavioral and cognitive effects of ketamine shows conflicting results. It is important to examine the acute and long-term cognitive and behavioral effects of ketamine exposure at lower sub-anesthetic doses, as the recreational use of the drug at higher doses is associated with cognitive and memory impairments. The current study examined the effects of acute and repeated ketamine exposure on anxiety-like behavior, novel object recognition memory, depression-like behavior, and plasma corticosterone levels in 20 adult female C57BL/6J mice. Mice were exposed acutely or repeatedly for 10 consecutive days to saline or 15 mg/kg ketamine and behavior was measured in the open field test, novel object recognition test, and the Porsolt forced swim test. Plasma corticosterone levels were measured following behavioral testing. Acute ketamine exposure decreased locomotor activity and increased anxiety-like behavior in the open field test compared to controls, while repeated ketamine exposure impaired memory in the novel object recognition test. There were no effects of acute or repeated ketamine exposure on depression-like behavior in the Porsolt forced swim test or on plasma corticosterone levels. These findings suggest that a subanesthetic dose of ketamine alters behavior and cognition in female mice and the effects are dependent on the duration of exposure.

C57BL/6N mice show a sub-strain specific resistance to the psychotomimetic effects of ketamine.

Repeated administration of subanesthetic doses of ketamine is a model of psychosis-like state in rodents. In mice, this treatment produces a range of behavioral deficits, including impairment in social interactions and locomotion. To date, these phenotypes were described primarily in the Swiss and C3H/HeHsd mouse strains. A few studies investigated ketamine-induced behaviors in the C57BL/6J strain, but to our knowledge the C57BL/6N strain was not investigated thus far. This is surprising, as both C57BL/6 sub-strains are widely used in behavioral and neuropsychopharmacological research, and are de facto standards for characterization of drug effects. The goal of this study was to determine if C57BL/6N mice are vulnerable to develop social deficits after 5 days withdrawal from sub-chronic ketamine treatment (5 days, 30 mg/kg, i.p.), an experimental schedule shown before to cause deficits in social interactions in C57BL/6J mice. Our results show that sub-chronic administration of ketamine that was reported to cause psychotic-like behavior in C57BL/6J mice does not induce appreciable behavioral alterations in C57BL/6N mice. Thus, we show that the effects of sub-chronic ketamine treatment in mice are sub-strain specific.

Аssessment of the antinociceptive efficacy of varieties of multimodal low-opioid general anesthesia during laparoscopic renal surgery

The main premise for the emergence of the concept of low-opioid general anesthesia was the phenomenon of the formation of drug/opioid dependence in patients undergoing surgery under multicomponent anesthesia with high doses of narcotic analgesics (opioids). Opioids were used as the main analgesics and in the postoperative period. The above factors contributed to the development of opiate addiction in operated patients in the late postoperative period. The mass nature of this phenomenon has become one of the most urgent problems in modern anesthesiology.&#x0D; Our study aimed to evaluate the antinociceptive/antistress efficacy of 3 types of low-opioid multimodal general anesthesia in laparoscopic renal surgery.&#x0D; Methods. Eighty patients who had undergone laparoscopic renal surgery under 3 types of general anesthesia were included in this prospective cohort study. All patients were operated under general anesthesia with tracheal intubation. Induction: intravenous (IV) propofol 2 mg/kg, fentanyl 1.5-2 μg/kg, atracurium 0.6 mg/kg. Maintenance of anesthesia: sevoflurane (MAC - 1.44±0.25% by volume). In group 1 (control group n = 26), analgesia was provided with fentanyl 3,89±2.03 μg/kg/h. In group 2 (n = 25), multimodal low-opioid general anesthesia was performed with fentanyl 1.76±1.2 μg/kg/h and IV lidocaine 1.5 mg/kg/h and subanesthetic doses of ketamine. In group 3 (n = 29), multimodal anesthesia with low opioids was performed with fentanyl 2.38±1.01 μg/kg/h in combination with dexmedetomidine 0.7 μg/kg/h. The efficacy of antinociceptive protection was assessed by the dynamics of changes in stress hormone levels, hemodynamic parameters, and blood glucose concentration.&#x0D; Results. The mean total dose of fentanyl used throughout the anesthetic period was: 369,23±83,75 μg in group 1, 216,0±47,26 μg in group 2, and 272,41±58,14 μg in group 3 (p &lt; 0.001). Mean cortisol levels were significantly different before and after surgery in groups 1 and 2: 371,0±161,61 nmol/l vs 562,72±226,87 nmol/l (p &lt; 0.01) and 531,08±218,02 nmol/l vs 831,33±235,32 nmol/l (p &lt; 0.01), respectively. In group 3, we did not detect any statistical difference: 393,51±134,69 nmol/l and 436,37±188,09 nmol/l, respectively (p &gt; 0.05). The mean level of adrenocorticotropic hormone increased significantly after surgery in all studied groups: 111.86% in group 1 (p &lt; 0.01), 122.02% (p &lt; 0.01) in group 2 and 78.59% (p &lt; 0.01) in group 3. Blood glucose levels in the postoperative (p/o) period did not exceed 6,16±1,67 mmol/l (p &gt; 0.05) in all groups. Hemodynamic parameters and BIS, which were maintained within 44±6.4%, indicated the adequacy of anesthesia and analgesia in the study groups.&#x0D; In group 1, 8 of 26 patients required additional analgesia with opioids during the p/o period (pain intensity on the VAS scale exceeded 4 points). In group 2 and group 3, 4 patients each required opioid analgesia, 16% and 15.38%, respectively. The next day after surgery, all patients were mobilized (sitting in bed, walking). Markers of renal function were also within normal range in all patients.&#x0D; Conclusion. The use of low-opioid multimodal anesthesia with IV lidocaine or dexmedetomidine during laparoscopic renal surgery provides an adequate anesthetic/antinociceptive effect. The use of dexmedetomidine in multimodal general anesthesia provides the greatest antinociceptive protection and reduces the stress response to surgery.

Efficacy of ketamine for comorbid depression and acute or chronic pain: A systematic review.

Pain and depression frequently co-occur. Due to its antidepressant and analgesic properties, ketamine has been used for the management of treatment-resistant depression and pain. This systematic review examined the literature on the efficacy of sub-anesthetic doses of ketamine in individuals experiencing comorbid depression and chronic pain (CDCP), as well as comorbid depression and acute pain (CDAP). A secondary objective was to provide an assessment of dosage, route, and adverse effects of ketamine treatment for CDCP and CDAP. A literature search was conducted on MEDLINE, PsycINFO, and Embase databases, coupled with a manual screening of the bibliography sections of included articles. In addition, registered ongoing and planned trials were searched on Clinicaltrials.gov. The end date of the search was April 9th, 2022. Included studies assessed changes in depression and pain in patients receiving at least one sub-anesthetic dose of ketamine. Assessment of quality was conducted using the GRADE checklist. Of the 7 CDCP clinical trials, 3 reported a reduction in depression and pain, 3 reported a reduction in depression or pain only, and 1 reported no improvement in either comorbidity. Among the 7 CDAP clinical trials, 4 studies found improvements in depression and pain while the remaining 3 reported improvements in only one parameter. Ten of the 12 case studies and 2 of the 3 observational studies assessing CDCP and CDAP found improvements in pain and depression scores post-treatment with effects of variable duration. The planned methodologies of the registered clinical trials are in line with those of the published research. Preliminary evidence supports the efficacy of ketamine in treating CDCP and CDAP. However, the current review identified a small number of heterogeneous studies with mixed results, preventing comprehensive conclusions. More longitudinal placebo-controlled studies are needed to identify the effects of ketamine for patients with CDCP and CDAP.

Pathway-specific GABAergic inhibition contributes to the gain of resilience against anorexia-like behavior of adolescent female mice.

Anorexia nervosa is one of the most debilitating mental illnesses that emerges during adolescence, especially among females. Anorexia nervosa is characterized by severe voluntary food restriction and compulsive exercising, which combine to cause extreme body weight loss. We use activity-based anorexia (ABA), an animal model, to investigate the neurobiological bases of vulnerability to anorexia nervosa. This is a Mini-Review, focused on new ideas that have emerged based on recent findings from the Aoki Lab. Our findings point to the cellular and molecular underpinnings of three ABA phenomena: (1) age-dependence of ABA vulnerability; (2) individual differences in the persistence of ABA vulnerability during adolescence; (3) GABAergic synaptic plasticity in the hippocampus and the prefrontal cortex that contributes to the suppression of the maladaptive anorexia-like behaviors. We also include new data on the contribution to ABA vulnerability by cell type-specific knockdown of a GABA receptor subunit, α4, in dorsal hippocampus. Although the GABA system recurs as a key player in the gain of ABA resilience, the data predict why targeting the GABA system, singularly, may have only limited efficacy in treating anorexia nervosa. This is because boosting the GABAergic system may suppress the maladaptive behavior of over-exercising but could also suppress food consumption. We hypothesize that a sub-anesthetic dose of ketamine may be the magic bullet, since a single injection of this drug to mid-adolescent female mice undergoing ABA induction enhances food consumption and reduces wheel running, thereby reducing body weight loss through plasticity at excitatory synaptic inputs to both excitatory and inhibitory neurons. The same treatment is not as efficacious during late adolescence but multiple dosing of ketamine can suppress ABA vulnerability partially. This caveat underscores the importance of conducting behavioral, synaptic and molecular analyses across multiple time points spanning the developmental stage of adolescence and into adulthood. Since this is a Mini-Review, we recommend additional literature for readers seeking more comprehensive reviews on these subjects.

The effect of ketamine on eye movement characteristics during free-viewing of natural images in common marmosets.

Various eye movement abnormalities and impairments in visual information processing have been reported in patients with schizophrenia. Therefore, dysfunction of saccadic eye movements is a potential biological marker for schizophrenia. In the present study, we used a pharmacological model of schizophrenia symptoms in marmosets and compared the eye movement characteristics of marmosets during free-viewing, using an image set identical to those used for human studies. It contains natural and complex images that were randomly presented for 8 s. As a pharmacological model of schizophrenia symptoms, a subanesthetic dose of ketamine was injected intramuscularly for transient and reversible manipulation. Eye movements were recorded and compared under a ketamine condition and a saline condition as a control. The results showed that ketamine affected eye movement characteristics during free-viewing. Saccades amplitude and scanpath length were significantly reduced in the ketamine condition. In addition, the duration of saccades was longer under the ketamine condition than under the saline condition. A similar tendency was observed for the duration of fixations. The number of saccades and fixations tended to decrease in the ketamine condition. The peak saccades velocity also decreased after ketamine injection whereas there was no difference in the main sequence relationship between saccades amplitude and peak velocity. These results suggest that ketamine affected visual exploration but did not affect the oculomotor aspect of saccades in marmosets, consistent with studies in patients with schizophrenia. Therefore, we conclude that the subanesthetic dose of ketamine is a promising pharmacological model of schizophrenia symptoms in common marmosets and can be used in combination with free-viewing paradigms to establish “translatable markers” for schizophrenia in primates.

Ketamine Pharmacodynamics Entangled: Comment.

We read with interest the study of ketamine psychedelic and analgesic effects by Olofsen et al.1 and the accompanying editorial by Mashour.2 In both articles, the authors refer to the “dissociative” effects of ketamine. Corssen and Domino3 originally used the term “dissociative” in 1966 to describe “patients and subjects who, during recovery from CI-581 [ketamine], felt as though they were in outer space, or had no arms or legs.” This term has been used ever since, although we know considerably more about the subjective effects of ketamine than we did in the 1960s. Olofsen et al. measured the subjective effects of ketamine using a subset of items from a previously validated rating scale (Bowdle Visual Analogue Scale).1 We first used this rating scale in its entirety in 1998,4 along with the Hallucinogen Rating Scale,5 to establish the relationship between plasma concentrations and the subjective effects of ketamine. The Bowdle Visual Analogue Scale and the Hallucinogen Rating Scale are intended to measure the overall psychedelic effects, not specifically dissociative effects. We would suggest that the term “dissociative” may no longer be the best descriptor of the subjective effects of ketamine.Numerous terms have been used to describe the mind-altering effects of ketamine, including “dissociative,” “psychotomimetic,” “hallucinogenic,” “emergence reaction,” and “psychedelic.” Parsing these terms can be difficult because there is no universal agreement about their meaning. Dissociative experiences as described by Corssen and Domino can occur under the influence of a variety of psychedelic drugs and are not specific to ketamine. Psychotomimetic implies a psychotic state, lacking in insight; psychosis is not typical of psychedelic drug experiences because subjects are usually able to reflect on the nature of the experience. Hallucinogenic effects can occur under the influence of psychedelic drugs but are not an essential or universal element of the psychedelic experience. Emergence reaction refers to mind-altering experiences that occur after awakening from anesthesia with ketamine, and so does not apply to subanesthetic doses of ketamine. Psychedelic, meaning “mind manifesting,” was originally proposed by Osmond in 19576 to describe the effects of a variety of mind-altering drugs, including hashish. Subsequently, the term psychedelic has been applied to diverse mind-altering drugs, although some authors have used the term psychedelic more specifically to refer to lysergic acid diethylamide–like serotonergic receptor agonists.7,8Our current understanding of the psychedelic effects of ketamine and other psychedelic drugs comes primarily from narrative descriptions related by subjects who have experienced the effects, or from rating scales constructed to capture the experiences in a standardized fashion. Although scales are useful for measuring drug effects, the results depend on the nature of the items chosen for inclusion in them.Beyond ketamine, a small group of drugs that produce psychedelic experiences, analgesia, and anesthesia has been referred to as “dissociative anesthetics,” implying a similarity to ketamine. This group usually includes phencyclidine, ketamine analogues, dextromethorphan, salvinorin A (produced by the plant, Salvia divinorum),9 and nitrous oxide. The term “dissociative anesthetics” suggests that the mechanisms of action and the subjective experiences of these drugs are similar to ketamine, similar to each other, and different from other psychedelic drugs. In fact, the subjective experiences induced by dissociative anesthetics are not identical to each other and may be similar to nonanesthetic psychedelic drugs. Distortion of body image (a key feature of dissociation) is not confined to the dissociative anesthetics; other psychedelic drugs may induce a similar experience. For example, the subjective experience of ketamine, when assessed using the Hallucinogen Rating Scale, resembles that of the classic psychedelic serotonin receptor agonist dimethyltryptamine.4 The subjective experience of dextromethorphan assessed using a variety of rating scales resembles that of the classic psychedelic psilocybin.10The mechanism of action of these dissociative anesthetics is not identical. Phencyclidine, ketamine, and dextromethorphan (and its metabolite dextrorphan) are antagonists of the N-methyl-d-aspartate (NMDA) receptor. Salvinorin A is a highly selective κ opioid receptor agonist. The mechanism of action of nitrous oxide is uncertain but may involve antagonism of NMDA receptors11; the subjective effects of nitrous oxide have not been as well characterized as the other drugs.12 It is also worth noting that the recently discovered antidepressant effects of ketamine and other psychedelic drugs may or may not be related to the psychedelic effects, although this remains controversial.13We suggest that anesthetic drugs that also have psychedelic effects should no longer be referred to as dissociative anesthetics. Rather, it may be more useful to describe them primarily by their mechanism of action; for example, “the NMDA antagonist ketamine,” “the serotonin agonist psilocybin,” “the κ agonist salvinorin A.”Dr. Sackett declares a financial interest in Resa Health (Paradise Valley, Arizona). The other authors declare no competing interests.

Ketamine induces rapid antidepressant effects via the autophagy-NLRP3 inflammasome pathway.

Sub-anesthetic ketamine has rapid-onset effects for the treatment of major depressive disorder (MDD). However, the mechanism underlying ketamine's antidepressant properties remains unclear. Recent studies have reported an interrelationship between autophagy and the inflammasome, both of which are involved in the pathophysiology of MDD. In this study, we assess whether ketamine exerts its antidepressant effects via an association with the autophagy-NLRP3 inflammasome pathway. We established a depressive-like rat model by treating Wistar Kyoto rats with chronic restraint stress (CRS) for 28days. Microglial cells from newborn Sprague-Dawley rats were used for in vitro experiments. We found sub-anesthetic ketamine treatment reversed depressive-like behavior in CRS rats. Ketamine triggered autophagy in the microglia of prefrontal cortex (PFC) and (hippocampus) HPC, with increased levels of LC3B, decreased levels of p62 protein, and elevated autophagosomes both in vivo and in vitro. Moreover, NLRP3 inflammasome activation was also inhibited by ketamine, with reduced expression of NLRP3-ASC-CASP1 assembly and decreased IL-1β levels in cerebrospinalfluid(CSF) as well as in the serum. Increased BDNF levels and synaptophysin levels were detected in the ketamine-treated group. The rapid anti-depressive effects, elevation of autophagy, reduction in NLRP3, and neuroplasticity-related factors induced by ketamine could be significantly blocked by the autophagy inhibitor Baf A1 (0.1mg/kg). Our findings demonstrate that sub-anesthetic doses of ketamine exert their antidepressant-like effects by inhibiting inflammation and initiating neuroprotection via autophagy activation. These data might help expand future investigations on the antidepressant properties of ketamine.

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;