Subanesthetic Doses Of Ketamine Research Articles

Resting-State Electroencephalogram Complexity Is Associated With Oral Ketamine Treatment Response: A Bayesian Analysis of Lempel-Ziv Complexity and Multiscale Entropy.

Subanesthetic doses of ketamine are a promising novel treatment for suicidality; however, the evidence for predictive biomarkers is sparse. Recently, measures of complexity, including Lempel-Ziv complexity (LZC) and multiscale entropy (MSE), have been implicated in ketamine's therapeutic action. We evaluated electroencephalogram (EEG)-derived LZC and MSE differences between responders and nonresponders to oral ketamine treatment. A total of 31 participants received six single, weekly (titrated) doses of oral racemic ketamine (0.5-3mg/kg) and underwent EEG scans at baseline (Week 0), post-treatment (Week 6), and follow-up (Week 10). Resting-state (eyes closed and open) recordings were processed in EEGLAB, and complexity metrics were extracted using the Neurokit2 package. Participants were designated responders or nonresponders by clinical response (Beck Suicide Scale [BSS] score reduction of ≥50% from baseline to the respective timepoint or score ≤6) and then compared in terms of complexity across resting-state conditions and time. Employing a Bayesian mixed effects model, we found strong evidence that LZC was higher in the eyes-open compared to eyes-closed condition, as were MSE scales 1-3. At a global level, responders displayed elevated eyes-open baseline complexity compared to nonresponders, with these values decreasing from baseline to post-treatment (Week 6) in responders only. Exploratory analyses revealed that the elevated baseline eyes-open LZC in responders was spatially localized to the left frontal lobe (F1, AF3, FC1, and F3). EEG-complexity metrics may be sensitive biomarkers for evaluating and predicting oral ketamine treatment response, with the left prefrontal cortex bein a possible treatment response region.

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.

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.

Effect of Dexamethasone versus Low Dose Ketamine on Post Spinal Hypotension in Caesarian Section

Abstract Background Spinal anesthesia is the preferred method for elective cesarean sections due to considerable risks regarding airway management associated with physiological changes of pregnancy. Cesarean sections normally require an anesthetic block at T4 level, so hypotension is reported in up to 80% of spinal anesthesia cases. Aim of the Work To assess the effect of prophylactic sub-anesthetic dose of ketamine versus the effect of Dexamesathone to prevent maternal hypotension after spinal anaesthesia in cesarean section. Patients and Methods This study is a randomized controlled study this study done in obstetrics and Gynecology Department, Ain Shams hospitals at 3 months and the females undergoing caesarian section under spinal anesthesia. Results The study revealed that ketamine group showed significant lower incidence of postspinal hypotension compared to the control group 5, 10, 15, 20 minutes. Whereas the dexamethasone group showed significant reduction in incidence of postspinal hypotension when compared to the control group only at the first 5 minutes, while comparing both ketamine and dexamethasone groups the incidence of hypotension was not significant. 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 the randomized controlled study conducted in the Obstetrics and Gynecology Department at Ain Shams hospitals investigated the effects of dexamethasone and low-dose ketamine on post-spinal hypotension in caesarean deliveries. The study compared three groups: a ketamine group, a dexamethasone group, and a control group.

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.

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 ameliorates post-traumatic social avoidance by erasing the traumatic memory encoded in VTA-innervated BLA engram cells

Erasing traumatic memory during memory reconsolidation is a promising retrieval-extinction strategy for post-traumatic stress disorder (PTSD). Here, we developed an acute social defeat stress (SDS) mouse model with short-term and re-exposure-evoked long-term social avoidance. SDS-associated traumatic memories were identified to be stored in basolateral amygdala (BLA) engram cells. A single intraperitoneal administration of subanesthetic-dose ketamine within, but not beyond, the re-exposure time window significantly alleviates SDS-induced social avoidance, which reduces the activity and quantity of reactivated BLA engram cells. Furthermore, activation or inhibition of dopaminergic projections from the ventral tegmental area to the BLA effectively mimics or blocks the therapeutic effect of re-exposure with ketamine and is dopamine D2 receptor dependent. Single-cell RNA sequencing reveals that re-exposure with ketamine triggered significant changes in memory-related pathways in the BLA. Together, our research advances the understanding of how ketamine mitigates PTSD symptoms and offers promising avenues for developing more effective treatments for trauma-related disorders.

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.

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.

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.

Design, Synthesis and Biological Evaluation of Novel Ketamine Derivatives as NMDAR Antagonists.

Depression is a chronic, severe, and often life-threatening neurological disorder. It not only causes depression in patients and affects daily life but, in severe cases, may lead to suicidal behavior and have adverse effects on families and society. In recent years, it has been found that sub-anesthetic doses of ketamine have a rapid antidepressant effect on patients with treatment-resistant depression and can significantly reduce the suicidal tendencies of patients with major depressive disorder. Current studies suggest that ketamine may exert antidepressant effects by blocking NMDAR ion channels, but its anesthetic and psychotomimetic side effects limit its application. Here, we report efforts to design and synthesize a novel series of ketamine derivatives of NMDAR antagonists, among which compounds 23 and 24 have improved activity compared with ketamine, introducing a new direction for the development of rapid-acting antidepressant drugs.

Ketamine enhanced ECT in refractory recurrent depression.

IntroductionRecurrent Depressive Disorder is a chronic condition that significantly impacts the quality of life. Despite various treatment options, some patients face severe and treatment-resistant relapses. This case is related to research on ketamine in Electroconvulsive Therapy (ECT) for RDD. One study highlighted the efficacy and safety of ketamine compared to other anaesthetic agents in ECT for major depression. Additionally, another study explored subanesthetic doses of ketamine before each ECT session to improve therapeutic outcomes and sleep quality in patients with major depressive disorder.ObjectivesTo present a clinical case of a patient with Recurrent Depressive Disorder (RDD) who improved following a change in the Electroconvulsive Therapy (ECT) protocol using ketamine as an anaesthetic inducer.Methods We examined the patient’s medical records, including her medical history, previous treatments, and therapeutic responses.ResultsA 65-year-old childless woman with a history of stroke, bilateral carotid atheromatosis, and hypothyroidism suffered from RDD. Despite multiple prior treatments and ECT, she experienced a severe depressive relapse. Eight intensive ECT sessions were administered, with observed memory lapses. Due to the lack of response, the anaesthetic inducer etomidate was replaced with ketamine, resulting in a positive response. The patient continued pharmacological treatment with improved mood, but recent and evident memory alterations persisted, possibly related to anterograde amnesia.Conclusions This case highlights the complexity of RDD in patients with comorbidities and treatment-resistant relapses. The change in the ECT protocol using ketamine was effective, emphasizing the importance of alternative therapeutic approaches in refractory cases. The successful treatment of RDD in this patient using ketamine in ECT underscores the need for personalized therapeutic options in treatment-resistant patients. These scientific resources reinforce the relevance of exploring therapeutic alternatives in contemporary clinical practice. We need more research to understand the underlying mechanisms and how this approach could be enhanced in similar cases.Disclosure of InterestNone Declared

Ketamine for Adults With Substance Use Disorders

What Is the Issue
 
 Accumulating research has demonstrated that subanesthetic doses of ketamine have rapid and sustained antidepressant effects. In 2019, the US FDA approved the S-enantiomer of ketamine (esketamine) for the treatment of patients with treatment-resistant depression.
 Since then, there has been interest in the development of ketamine for the treatment of a broad range of mental health conditions beyond depression, including substance use disorders (SUDs).
 Decision-makers want to know if there is any evidence to support the use of ketamine for treating SUDs in adults.
 
 What Did We Do?
 
 To inform decisions about using ketamine for treating SUDs, we sought to identify and summarize the literature comparing the clinical and cost-effectiveness of ketamine with placebo or no treatment, with alternative interventions, or among ketamine administered via different routes for SUDs. We also searched for evidence-based recommendations for the use of ketamine for SUDs.
 A research information specialist conducted a literature search of peer-reviewed and grey literature sources published between January 1, 2018, and November 28, 2023. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings.
 
 What Did We Find?
 
 We found 2 systematic reviews (SRs) and 1 randomized controlled trial (RCT) on the use of ketamine for the treatment of patients with alcohol use disorder (AUD), cocaine use disorder (CUD), and opioid use disorder (OUD).
 Evidence from 2 SR suggests that a combination of ketamine infusion and psychotherapy treatment may be effective in promoting abstinence and reduced consumption of alcohol and cocaine use. There were mixed results regarding the effect of ketamine on withdrawal and craving.
 The effects of ketamine on OUD were inconclusive as the results were derived from a single study with a small sample size. Similarly, the effects of ketamine on health care utilization (e.g., hospital readmission, emergency department visit) in patients with severe AUD reported in a RCT were also inconclusive due to the small sample size.
 Adverse events associated with ketamine treatment included the dissociative and psychotomimetic effects and nondissociative effects. The authors of the included SR reported that these events were mild and transient.
 We did not find any studies on the cost-effectiveness or evidence-based guidelines of ketamine for treating SUDs that met our criteria for this review.
 
 What Does It Mean?
 
 The conclusions on the positive effects of ketamine for AUD and CUD should be interpreted with caution due to the high risk of bias of the studies included in the SRs.
 There is a need for more robust clinical trials with larger sample sizes, blinding, and low risk of bias to provide more accurate findings on clinical efficacy, dosing strategies, and safety profile of ketamine for the treatment of AUD, CUD, and OUD.
 Additional studies on other substances of abuse (e.g., nicotine, amphetamines, and cannabis) may provide important insights into the overall efficacy of ketamine in the treatment of SUDs.

Ketamine’s rapid and sustained antidepressant effects are driven by distinct mechanisms

Administration of multiple subanesthetic doses of ketamine increases the duration of antidepressant effects relative to a single ketamine dose, but the mechanisms mediating this sustained effect are unclear. Here, we demonstrate that ketamine’s rapid and sustained effects on affective behavior are mediated by separate and temporally distinct mechanisms. The rapid effects of a single dose of ketamine result from increased activity of immature neurons in the hippocampal dentate gyrus without an increase in neurogenesis. Treatment with six doses of ketamine over two weeks doubled the duration of behavioral effects after the final ketamine injection. However, unlike ketamine’s rapid effects, this more sustained behavioral effect did not correlate with increased immature neuron activity but instead correlated with increased numbers of calretinin-positive and doublecortin-positive immature neurons. This increase in neurogenesis was associated with a decrease in bone morphogenetic protein (BMP) signaling, a known inhibitor of neurogenesis. Injection of a BMP4-expressing lentivirus into the dentate gyrus maintained BMP signaling in the niche and blocked the sustained – but not the rapid – behavioral effects of ketamine, indicating that decreased BMP signaling is necessary for ketamine’s sustained effects. Thus, although the rapid effects of ketamine result from increased activity of immature neurons in the dentate gyrus without requiring an increase in neurogenesis, ketamine’s sustained effects require a decrease in BMP signaling and increased neurogenesis along with increased neuron activity. Understanding ketamine’s dual mechanisms of action should help with the development of new rapid-acting therapies that also have safe, reliable, and sustained effects.

Effects of nitrous oxide and ketamine on electrophysiological and molecular responses in the prefrontal cortex of mice: A comparative study

Nitrous oxide (N2O; laughing gas) has recently reported to produce rapid antidepressant effects, but little is known about the underlying mechanisms. We performed transcriptomics, in situ hybridization, and electrophysiological studies to examine the potential shared signatures induced by 1 h inhalation of 50% N2O and a single subanesthetic dose of ketamine (10 mg/kg, i.p.) in the medial prefrontal cortex (mPFC) in adult mice. Both treatments similarly affected the transcription of several negative regulators of mitogen-activated protein kinases (MAPKs), namely, dual specificity phosphatases (DUSPs). The effects were primarily located in the pyramidal cells. Notably, the overall effects of N2O on mRNA expression were much more prominent and widespread compared to ketamine. Ketamine caused an elevation of the spiking frequency of putative pyramidal neurons and increased gamma activity (30–100 Hz) of cortical local field potentials. However, N2O produced no such effects. Spiking amplitudes and spike-to-local field potential phase locking of putative pyramidal neurons and interneurons in this brain area showed no uniform changes across treatments. Our findings suggest that N2O and subanesthetic-dose ketamine target MAPK pathway in the mPFC but produce varying acute electrophysiological responses.

Ketamine for depressive symptoms: A retrospective chart review of a private ketamine clinic.

There is currently no published evidence demonstrating the effectiveness and safety of subanaesthetic doses of ketamine, when administered intravenously as an adjunct treatment for depressive symptoms, in a real world setting in South Africa. This retrospective chart review reports the clinical response (change in Patient Health Questionnaire - 7 score) to an initial infusion series of ketamine added to usual treatment, and the pattern of its subsequent maintenance use, for depressive symptoms. A private ketamine clinic in Hilton, KwaZulu-Natal. The medical records of all patients who attended a private ketamine clinic between August 2019 and 31 May 2021 were retrospectively analysed. Depression symptoms were evaluated using the Patient Health Questionaire-9 (PHQ-9) administered immediately before and 24 h after each treatment. Response was defined as a score decrease of more than 50%. Among the 154 patients who received ketamine infusions for depression, 67 completed a six infusion initial series, with a response rate of 60.6% and remission rate of 32.4%. Of the 154, 50% no longer experienced any suicidal ideation after treatment and adverse events were uncommon, with 6.2% of infusions requiring intervention for adverse events, mostly nausea. In addition, 48.5% of those who completed the initial series continued to receive maintenance infusions, with no evidence of escalating use or abuse. Incorporating intravenous ketamine into the existing treatment regimens at a private clinic was associated with reduced acuteness of depression severity and suicidal ideation. This approach appeared safe and tolerable, showing no signs of abuse or dependence. This is the first known naturalistic study reporting on ketamine use for depressive symptoms in South Africa.

Efficacy and Safety of Ketamine Compared with Placebo and Other Medications for Preventing Propofol Injection Pain in Adults: A Systematic Review and Meta-Analysis.

To systematically evaluate the effectiveness and safety of ketamine in preventing propofol injection pain (PIP). The electronic databases including PubMed, Embase, Web of Science, and Cochrane Library were searched from their inception until 2 August 2023. Randomized controlled trials (RCT) comparing ketamine with placebo or other interventions to alleviate PIP in adults were included. Fixed-effects or random-effects models were used to calculate pooled risk ratios (RR) and corresponding 95% confidence intervals (CI) based on the heterogeneity of the studies included. Thirteen RCTs involving 2105 patients were included. In terms of reducing the incidence of PIP, ketamine is more effective than placebo (RR = 0.43, 95% CI = [0.34, 0.55], P < 0.00001), lidocaine (RR = 0.70, 95% CI = [0.55, 0.90], P = 0.005), dexmedetomidine (RR = 0.52, 95% CI = [0.40, 0.66], P < 0.00001), and thiopental (RR = 0.25, 95% CI = [0.08, 0.83], P = 0.02). In reducing the incidence of severe PIP, ketamine is superior to placebo (RR = 0.12, 95% CI = [0.08, 0.19], P < 0.00001), and lidocaine (RR = 0.34, 95% CI = [0.21, 0.56], P < 0.0001), except dexmedetomidine (RR = 0.20, 95% CI = [0.04, 1.13], P = 0.07), and thiopental (RR = 0.33, 95% CI = [0.04, 3.10], P = 0.33). Compared with mixed injection, separate injection of ketamine and propofol showed no significant difference in the incidence of PIP (RR = 0.96, 95% CI = [0.31, 3.00], P = 0.95) and severe PIP (RR = 1.19, 95% CI = [0.07, 21.29], P = 0.90). Based solely on the reports from the studies included, subanesthetic doses of ketamine are generally safe in preventing PIP. A subanesthetic dose of ketamine can effectively and safely reduce the incidence of PIP and severe PIP in adults, and is more effective than lidocaine, dexmedetomidine, and thiopental. PROSPERO CRD42023455093.

Ketamine in Chronic Pain: A Review.

Ketamine has been used in the treatment of several pain syndromes, particularly those with a relevant neuropathic component. Sub-anesthetic doses of ketamine produce a potent analgesic effect, due to its inhibition of N-methyl-D-aspartate receptors and enhancement of descending inhibitory pathways. Its short-term analgesic effect is well-documented perioperatively, with an associated reduction in postoperative chronic pain and opioid consumption. Despite some evidence regarding its long-term benefits, the number of clinical studies is still limited. In addition to its analgesic effects, ketamine also possesses an anti-depressive action, which might be useful in the treatment of chronic pain patients. Several side effects have been described, the psychomimetic ones being the most relevant due to their impact on treatment adhesion. At present, co-administration of ketamine and benzodiazepines or α2-agonists facilitates its clinical application. Despite current evidence and increasing use, further investigation is still needed regarding its long-term safety profile and clearer risk-benefit analysis.

Pre-adolescence repeat exposure to sub-anesthetic doses of ketamine induces long-lasting behaviors and cognition impairment in male and female rat adults

In pre-adolescence, repeated anesthesia may be required for therapeutic interventions. Adult cognitive and neurobehavioral problems may result from preadolescent exposure to anesthetics. This study examined the long-term morphological and functional effects of repeated sub-anesthetic doses of ketamine exposure on male and female rat adults during pre-adolescence. Weaned 48 pre-adolescent rats from eight mothers and were randomly divided into four equal groups: control group and the ketamine group of males and females (20 mg/kg daily for 14 days); then animals received care for 20–30 days. Repeated exposure to sub-anesthetic doses of ketamine on cognitive functions was assayed using Social discrimination and novel object tests. Besides, an elevated plus maze and fear conditioning apparatus were utilized to determine exploratory and anxiety-like behavior in adults. Toluidine blue stain was used to evaluate the number of dead neurons in the hippocampus, and the effects of ketamine on synaptic plasticity were compared in the perforant pathway of the CA1 of the hippocampus. Our study indicates that repeated exposure to sub-anesthetic doses of ketamine during pre-adolescence can result in neurobehavioral impairment in male and female rat adulthood but does not affect anxiety-like behavior. We found a significant quantifiable increase in dark neurons. Recorded electrophysiologically, repeat sub-anesthetic doses of ketamine resulted in hampering long-term potentiation and pair pulse in male adult animals. Our results showed that repeated exposure to sub-anesthetic doses of ketamine during pre-adolescence can induce hippocampus and neuroplasticity changes later in adulthood. This study opens up a new line of inquiry into potential adverse outcomes of repeated anesthesia exposure in pre-adolescent rats.