[Ketamin: a harmful recreational drug]. / Kétamine : une substance récréative qui fait mal.

Adolescence is a developmental phase that exposes young people to exploratory behaviors, including substance abuse. In Switzerland, recreational ketamine use among young people is on the rise and is likely to lead to irreversible somatic complications. Primary care physicians play an essential role in identifying ketamine users, and should offer brief interventions, risk-reduction advice and a psychosocial assessment of the situation, involving close relatives. In the event of secondary damage, particularly urological damage, coordinated management by specialists is essential to achieve symptom regression. Primary and secondary prevention measures are also essential in the fight against addiction among young people.

L'adolescence est une phase développementale exposant les jeunes à des comportements exploratoires, dont la prise de substances. En Suisse, la consommation récréative de kétamine chez les jeunes est en augmentation et est susceptible d'entraîner des complications somatiques irréversibles. Le médecin de premier recours joue un rôle essentiel dans l'identification des usager-e-s de kétamine et doit proposer des interventions brèves, des conseils de réduction des risques et une évaluation globale de la situation (anamnèse psychosociale), en impliquant les proches. En cas d'atteinte secondaire, en particulier urologique, une prise en charge coordonnée entre spécialistes est primordiale pour viser une régression des symptômes. Des mesures de prévention primaires et secondaires sont également essentielles dans la lutte contre les addictions chez les jeunes.

Low-dose ketamine safely reduces acute pain in the ED with a more rapid and shorter effect than morphine.

SOURCE CITATION: Guo J, Zhao F, Bian J, et al. Low-dose ketamine versus morphine in the treatment of acute pain in the emergency department: a meta-analysis of 15 randomized controlled trials. Am J Emerg Med. 2024;76:140-149. 38071883.

Challenges of acute pain management in older patients.

Adequate management of acute pain in the older population is crucial. However, it is inherently complex because of multiple physiological changes that significantly impact both the pharmacokinetics and pharmacodynamics of medications. Current guidelines promote paracetamol as the first-line analgesic for acute pain in older adults, whereas opioids are advised cautiously for moderate to severe acute pain. However, opioids come with a significant array of side effects, which can be more pronounced in older individuals. Ketamine administered via intranasal (IN) and nebulised inhalation in the emergency department for managing acute pain in older patients shows promising potential for improving pain management and reducing opioid reliance Kampan, Thong-on, Sri-on (2024, Age Ageing, 53, afad255). Nebulised ketamine appears superior in terms of adverse event incidence. However, the adoption of IN or nebulised ketamine in older adult acute pain management remains unclear because of the lack of definitive conclusions and clear guidelines. Nevertheless, these modalities can be valuable options for patients where opioid analgesics are contraindicated or when intravenous morphine titration is impractical or contraindicated. Here, we review these concepts, the latest evidence and propose avenues for research.

[Lung-protective effect of esketamine combined with distal limb ischemic preconditioning in elderly patients undergoing thoracoscopic radical surgery for lung cancer: a randomized controlled trial in 160 cases].

OBJECTIVE: To evaluate the effect of esketamine combined with distal limb ischemic preconditioning (LIP) for lung protection in elderly patients undergoing thoracoscopic radical surgery for lung cancer. METHODS: This randomized trial was conducted in 160 patients undergoing elective thoracoscopic surgery for lung cancer, who were randomized into control group (with saline injection and sham LIP), esketamine group, LIP group, and esketamine + LIP group (n=40). Before anesthesia induction, according to the grouping, the patients received an intravenous injection with 0.5 mg/kg esketamine or 10 ml saline (in control group). LIP was induced by applying a tourniquet 1-2 cm above the popliteal fossa in the left lower limb to block the blood flow for 5 min for 3 times at the interval of 5 min, and sham LIP was performed by applying the tourniquet without pressurization for 30 min. Oxygenation index (OI) and alveolar-arterial PO2 difference (A-aDO2) were calculated before induction (T0), at 30 min (T0.5) and 1 h (T1) of one-lung ventilation (OLV), and at 1 h after two-lung ventilation (T3). Serum levels of SP-D, CC-16 and TNF-α were measured by ELISA at T0, T1, T2 (2 h of OLV), T3, and 24 h after the operation (T4). The length of hospital stay and postoperative pulmonary complications of the patients were recorded. RESULTS: Compared with those in the control group, the patients in the other 3 groups had significantly lower CC-16, SP-D and TNF-α levels, shorter hospital stay, and lower incidences of lung infection and lung atelectasis (all P < 0.05). Serum CC-16, SP-D and TNF-α levels, hospital stay, incidences of complications were significantly lower or shorter in the combined treatment group than in esketamine group and LIP group (all P < 0.05). CONCLUSION: In elderly patients undergoing thoracoscopic radical surgery for lung cancer, treatment with esketamine combined with LIP can alleviate acute lung injury by enhancing anti-inflammatory response to shorten postoperative hospital stay, reduce lung complications and promote the patients' recovery.

Effect of intraoperative and/or postoperative esketamine administration on preventing postpartum depression: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to evaluate the impact of intraoperative and/or postoperative esketamine application on the prevention of postpartum depression (PPD). PubMed, Embase, and Web of Science were thoroughly searched for eligible randomized controlled trials (RCTs) regarding the application of esketamine for postnatal depression prevention. Nine RCTs including 1277 participants were involved in the final analysis. It was found that intraoperative and/or postoperative administration of esketamine significantly reduced the PPD incidence and the Edinburgh Postnatal Depression Scores in the early postoperative period. Meanwhile, esketamine lowered the occurrence of postoperative nausea and vomiting with no influence on other psychiatric symptoms.

Spectral signatures of psilocybin, lysergic acid diethylamide (LSD) and ketamine in healthy volunteers and persons with major depressive disorder and treatment-resistant depression: A systematic review.

BACKGROUND: Electrophysiologic measures provide an opportunity to inform mechanistic models and possibly biomarker prediction of response. Serotonergic psychedelics (SPs) (i.e., psilocybin, lysergic acid diethylamide (LSD)) and ketamine represent new investigational and established treatments in mood disorders respectively. There is a need to better characterize the mechanism of action of these agents. METHODS: We conducted a systematic review investigating the spectral signatures of psilocybin, LSD, and ketamine in persons with major depressive disorder (MDD), treatment-resistant depression (TRD), and healthy controls. RESULTS: Ketamine and SPs are associated with increased theta power in persons with depression. Ketamine and SPs are also associated with decreased spectral power in the alpha, beta and delta bands in healthy controls and persons with depression. When administered with SPs, theta power was increased in persons with MDD when administered with SPs. Ketamine is associated with increased gamma band power in both healthy controls and persons with MDD. LIMITATIONS: The studies included in our review were heterogeneous in their patient population, exposure, dosing of treatment and devices used to evaluate EEG and MEG signatures. Our results were extracted entirely from persons who were either healthy volunteers or persons with MDD or TRD. CONCLUSIONS: Extant literature evaluating EEG and MEG spectral signatures indicate that ketamine and SPs have reproducible effects in keeping with disease models of network connectivity. Future research vistas should evaluate whether observed spectral signatures can guide further discovery of therapeutics within the psychedelic and dissociative classes of agents, and its prediction capability in persons treated for depression.

Current concepts in ketamine therapy in the emergency department.

Ketamine has been in use since its development as a dissociative anesthetic in the 1960s, but it was largely confined to the operating theater or austere environments until used by emergency physicians to facilitate painful procedures in children. As the unique effects of ketamine across its dose-response curve were understood, new applications emerged. In low doses, ketamine has found an important role alongside or instead of opioids in the management of severe pain, and methods to slow its absorption allow higher, more effective doses while attenuating psychoperceptual effects. Ketamine's unique anesthetic properties have inspired its use as an induction agent for intubation without a paralytic and for the rapid, safe control of dangerously agitated patients. Emerging uses for ketamine in acute care include treatment for status epilepticus and alcohol withdrawal syndrome; however, its most important rising indication may be as an emergency treatment of depression and suicidality.

Effects of (2R,6R)-hydroxynorketamine in assays of acute pain-stimulated and pain-depressed behaviors in mice.

Ketamine has been shown to produce analgesia in various acute and chronic pain states; however, abuse liability concerns have limited its utility. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to produce antidepressant-like effects similar to ketamine without abuse liability concerns. (2R,6R)-HNK produces sustained analgesia in models of chronic pain, but has yet to be evaluated in models of acute pain. The present study evaluated the efficacy of acute (2R,6R)-HNK administration (one injection) in assays of pain-stimulated (52- and 56-degree hot plate test and acetic acid writhing) and pain-depressed behavior (locomotor activity and rearing) in male and female C57BL/6 mice. In assays of pain-stimulated behaviors, (2R,6R)-HNK (1-32 mg/kg) failed to produce antinociception in the 52- and 56-degree hot plate and acetic acid writhing assays. In assays of pain-depressed behaviors, 0.56% acetic acid produced a robust depression of locomotor activity and rearing that was not blocked by pretreatment of (2R,6R)-HNK (3.2-32 mg/kg). The positive controls morphine (hot plate test) and ketoprofen (acetic acid writhing, locomotor activity, and rearing) blocked pain-stimulated and pain-depressed behaviors. Finally, the effects of intermittent (2R,6R)-HNK administration were evaluated in 52-degree hot plate and pain-depressed locomotor activity and rearing. Intermittent administration of (2R,6R)-HNK also did not produce antinociceptive effects in the hot plate or pain-depressed locomotor activity assays. These results suggest that (2R,6R)-HNK is unlikely to have efficacy in treating acute pain; however, the efficacy of (2R,6R)-HNK in chronic pain states should continue to be evaluated.

Ketamine induces multiple individually distinct whole-brain functional connectivity signatures.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV). Clinical trial number: NCT03842800.

Ketamine is a widely used anesthetic as well as a popular illegal recreational drug. Recently, it has also gained attention as a potential treatment for depression, particularly in cases that don't respond to conventional therapies. However, individuals can vary in their response to ketamine. For example, the drug can alter some people's perception, such as seeing objects as larger or small than they are, while other individuals are unaffected. Although a single dose of ketamine was shown to improve depression symptoms in approximately 65% of patients, the treatment does not work for a significant portion of patients. Understanding why ketamine does not work for everyone could help to identify which patients would benefit most from the treatment. Previous studies investigating ketamine as a treatment for depression have typically included a group of individuals given ketamine and a group given a placebo drug. Assuming people respond similarly to ketamine, the responses in each group were averaged and compared to one another. However, this averaging of results may have masked any individual differences in response to ketamine. As a result, Moujaes et al. set out to investigate whether individuals show differences in brain activity and behavior in response to ketamine. Moujaes et al. monitored the brain activity and behavior of 40 healthy individuals that were first given a placebo drug and then ketamine. The results showed that brain activity and behavior varied significantly between individuals after ketamine administration. Genetic analysis revealed that different gene expression patterns paired with differences in ketamine response in individuals ­ an effect that was hidden when the results were averaged. Ketamine also caused greater differences in brain activity and behavior between individuals than other drugs, such as psychedelics, suggesting ketamine generates a particularly complex response in people. In the future, extending these findings in healthy individuals to those with depression will be crucial for determining whether differences in response to ketamine align with how effective ketamine treatment is for an individual.

Recreational ketamine use can lead to irreversible bladder damage.

An increasing number of young patients with severe bladder overactivity syndrome potentially caused by recreational ketamine use has been treated in our department. Ketamine has become a popular and increasingly used recreational drug in New Zealand. Ketamine bladder syndrome has been reported internationally; however, local New Zealand data do not exist. It can lead to irreversible damage to the bladder, and internationally, surgical procedures like cystectomy and urinary diversion or augmentation cystoplasty have been reported as necessary treatments.

Efficacy and Clinical Value of Commonly Used Ingredients in Pain Management Compounds: A Literature Review.

The need for continued improvement in pain management is growing. This review is aimed towards identifying the literature regarding clinical and therapeutic value of the commonly used ingredients in pain management compounds: lidocaine, tetracaine, ketoprofen, ketamine, and gabapentin. Prospectively, future studies should be conducted to identify the exact benefits and side effects of compounded pain management therapies, such that these compounds can be effectively utilized when deemed appropriate.

Brain-derived neurotrophic factor Val66Met and CYP2B6 polymorphisms as predictors for ketamine effectiveness in patients with treatment-resistant depression.

BACKGROUND: Converging lines of evidence indicate that ketamine is a rapid antidepressant for individuals with treatment-resistant depression. Hitherto, no reliable a priori predictors of ketamine response have been reported. Pharmacogenetic biomarkers have yielded mixed results regarding potential candidate genes associated with ketamine's biochemistry as reliable predictors of response. AIMS: No studies have examined the effects of Val66Met and CYP2B6 genotypes on patients receiving repeated infusions of intravenous ketamine. METHODS: In all, 85 participants with major depressive disorder who had previously received four infusions of intravenous ketamine were recruited to the foregoing study. Buccal swabs were collected and genotype variants across the Val66Met and CYP2B6 genes were analyzed. A repeated measures mixed linear model was used to assess change in depressive symptoms, suicidality, and anxiety, correcting for sex and age. Multiple regression was run to determine whether these genetic markers were associated with treatment efficacy for depressive severity, suicidal ideation, anxiolytic response, and degree of dissociation to intravenous ketamine. RESULTS: Participants experienced significant overall reductions in depression, suicide, and anxiety. Overall, 25% met the response criteria and 15% met the remission criteria. However, Val66Met and CYP2B6 did not significantly predict changes in symptoms of depression, suicide, anxiety, or average dissociation. CONCLUSIONS: This study contributes to the growing literature that ketamine efficacy is unlikely to be predicted by single genes, and a pleiotropic approach may likely be necessary for developing reliable predictors of clinical benefits.

Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation - Clinical and safety results.

INTRODUCTION: We investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy. MATERIAL AND METHODS: Patients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis. RESULTS: Twenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (-5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01). Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment. DISCUSSION: Our results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.

Time-dependent antidepressant-like effects of reelin and ketamine in the repeated-corticosterone model of chronic stress.

There is an urgent need for novel antidepressants, given that approximately 30% of those diagnosed with depression do not respond adequately to first-line treatment. Additionally, monoaminergic-based antidepressants have a substantial therapeutic time-lag, often taking months to reach full therapeutic effect. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist is the only current effective rapid-acting antidepressant, demonstrating efficacy within hours and lasting up to two weeks with an acute dose. Reelin, an extracellular matrix glycoprotein, has demonstrated rapid-acting antidepressant-like effects at 24 h, however the exact timescale of these effects has not been investigated. To determine the short and long-term effects of reelin, female Long Evans rats (n = 120) underwent a chronic corticosterone (CORT; or vehicle) paradigm (40 mg/kg, 21 days). On day 21, rats were treated with reelin (3µg; i.v.), ketamine (10 mg/kg; i.p.), both reelin and ketamine (same doses), or vehicle (saline). Behavioural and biological effects were then evaluated at 1 h, 6 h, 12 h, and 1 week after treatment. The 1-week cohort continued CORT injections to ensure the effect of chronic stress was not lost. Individually, both reelin and ketamine significantly rescued CORT-induced behaviour and hippocampal reelin expression at all timepoints. Ketamine rescued a decrease in dendritic maturity as induced by CORT. Synergistic effects of reelin and ketamine appeared at 1-week, suggesting a potential additive effect of the antidepressant-like actions. Taken together, this study provides further support for reelin-based therapeutics to develop rapid-acting antidepressant.

Antidepressant effects of esketamine via the BDNF/AKT/mTOR pathway in mice with postpartum depression and their offspring.

Postpartum depression (PPD) is a serious mental health problem that can negatively affect future generations. BDNF/AKT/mTOR signaling in the frontal lobe and hippocampus in mice is associated with depression, but its role in mice with PPD and their offspring is unknown. This study was aimed at investigating the effects of esketamine (ESK), a drug approved for treatment of refractory depression, on the BDNF/AKT/mTOR pathway in mice with PPD and their offspring. A model of chronic unpredictable mild stress with pregnancy was used. ESK was injected into postpartum mice, and behavioral tests were conducted to predict the severity of symptoms at the end of lactation and in the offspring after adulthood. Both mice with PPD and their offspring showed significant anxiety- and depression-like behaviors that were ameliorated with the ESK intervention. ESK enhanced exploratory behavior in unfamiliar environments, increased the preference for sucrose, and ameliorated the impaired BDNF/AKT/mTOR signaling in the frontal and hippocampal regions in mice. Thus, ESK may have great potential in treating PPD and decreasing the incidence of depression in offspring.

Efficacy and safety of ketamine for pediatric and adolescent super-refractory status epilepticus and the effect of cerebral inflammatory conditions.

OBJECTIVE: To investigate the short-term benefits and adverse effects of ketamine in the treatment of pediatric and adolescent super-refractory status epilepticus (SRSE), with a focus on the inflammatory etiology. METHODS: This retrospective observational cohort study included a consecutive series of 18 pediatric to adolescent patients with SRSE admitted between 2008 and 2023 and treated with ketamine. Seizure frequency per hour before and after ketamine administration and response rate were calculated. Neurological decline, catecholamine administration, and adverse effects were also assessed. The patients were divided into inflammatory and non-inflammatory etiology groups. RESULTS: The median age at SRSE onset was 1 year 5 months (range: 11 days-24 years), and 78% of the patients were male individuals. The median duration of treatment was 7.5 days (interquartile range: 2.8-15.5 days). Fifteen (83%) patients achieved >50% seizure reduction. The median seizure frequency before and after ketamine treatment was 5.9 and 0.9, respectively, showing a significant reduction in seizure frequency (p < 0.0001). Ten patients had inflammatory etiologies including bacterial meningitis (n = 2), viral encephalitis (n = 3), and febrile infection related epilepsy syndrome (n = 5). The inflammatory etiology group required a longer treatment duration (p = 0.0453) and showed lower seizure reduction (p = 0.0264), lower response rate (p = 0.0044), and higher neurological decline (p = 0.0003) than the non-inflammatory etiology group. Three (17%) patients experienced transient adverse events requiring intervention within 24 h of initiating ketamine administration. CONCLUSIONS: Ketamine administration was associated with fewer serious adverse events and a reduced seizure frequency. Additionally, inflammatory conditions may weaken the efficacy of ketamine in patients with SRSE.