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Maladaptive reward memories (MRMs) are involved in the development and maintenance of acquired overconsumption disorders, such as harmful alcohol and drug use. The process of memory reconsolidation - where stored memories become briefly labile upon retrieval - may offer a means to disrupt MRMs and prevent relapse. However, reliable means for pharmacologically weakening MRMs in humans remain elusive. Here we demonstrate that the N-methyl D-aspartate (NMDA) antagonist ketamine is able to disrupt MRMs in hazardous drinkers when administered immediately after their retrieval. MRM retrieval + ketamine (RET + KET) effectively reduced the reinforcing effects of alcohol and long-term drinking levels, compared to ketamine or retrieval alone. Blood concentrations of ketamine and its metabolites during the critical ‘reconsolidation window’ predicted beneficial changes only following MRM reactivation. Pharmacological reconsolidation interference may provide a means to rapidly rewrite maladaptive memory and should be further pursued in alcohol and drug use disorders. Memories linking environmental cues to alcohol reward are involved in the development and maintenance of heavy drinking. Here, the authors show that a single dose of ketamine, given after retrieval of alcohol-reward memories, disrupts the reconsolidation of these memories and reduces drinking in humans.

The antidepressant effects of ketamine are thought to depend on brain-derived neurotrophic factor (BDNF) genotype and dose. The purpose of this study was to characterize the dose-related antidepressant effects of ketamine in patients with treatment-resistant depression drawn from a Chinese population predominately possessing lower activity BDNF genotypes (Val/Met, Met/Met). We conducted a double-blind, randomized, parallel-group, placebo-controlled trial of a single ketamine infusion (saline, 0.2 mg/kg, 0.5 mg/kg). Patients (N=71; BDNF genotype: Val/Val (N=12, 17%), Val/Met (N=40, 56.3%), and Met/Met (N=19, 26.8%)) received mood ratings before infusion, after infusion, and for the subsequent 14 days. Plasma ketamine levels and BDNF genotypes were assessed. This study found a significant dose-related ketamine effect on scores on the Hamilton Depression Rating Scale (HAMD). The responder analysis (>50% reduction from baseline HAMD on at least 2 days between days 2 and 5) also revealed a significant dose-related effect (saline: 12.5%, 0.2 mg/kg: 39.1%; 0.5 mg/kg: 45.8%). This is the first report to our knowledge to demonstrate the dose-related efficacy of R/S-ketamine for treatment-resistant depression and the first to characterize ketamine effects in a genotyped Chinese population in which most (83%) patients possessed at least one copy of the lower functioning Met allele of the BDNF gene.

The N-methyl-D-aspartate antagonist ketamine has rapid antidepressant effects in patients with treatment-resistant major depression (TRD); these effects have been reported to last for 1 week in some patients. However, the extent and duration of this antidepressant effect over longer periods has not been well characterized under controlled conditions. Riluzole, a glutamatergic modulator with antidepressant and synaptic plasticity-enhancing effects, could conceivably be used to promote the antidepressant effects of ketamine. This study sought to determine the extent and time course of antidepressant improvement to a single-ketamine infusion over 4 weeks, comparing the addition of riluzole vs placebo after the infusion. Forty-two subjects (18-65) with TRD and a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥ 22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days (SE=2.2). However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone.

Abstract Objective We sought to explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. Methods Data from a completed trial in suicidal, depressed participants (n = 40) randomly assigned to ketamine was used to examine relationships between ketamine treatment–emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Nonparametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset of participants (n = 28) who provided blood samples immediately post-infusion. Results Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (P  = .064; P =.013 removing 1 outlier). Dehydronorketamine correlated with Clinician-Administered Dissociative States Scale scores at 40 minutes (P = .034), 230 minutes (P = .014), and Day 1 (P = .012). Conclusion We did not find evidence that ketamine’s acute, transient dissociative, or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.

Background The effect of intranasal esketamine on cognitive functioning in healthy participants is assessed in this study. Methods Twenty-four participants (19–49 years) were randomized to one of two treatment sequences in which either esketamine 84 mg or placebo was intranasally administered in a double-blind, two-period crossover design. Primary measures included five tests of Cogstate ® computerized test battery assessed at 1 h predose and 40 min, 2, 4, and 6 h postdose. Secondary measures included the Mental Effort Scale, Karolinska Sleepiness Scale (KSS), and safety. Results Esketamine was associated with significant cognitive performance impairment at 40 min postdose for all five Cogstate® tests (Detection p  = 0.0011, Identification p  = 0.0006, One-Card Learning p  = 0.0040, One Back p  = 0.0017, and Groton Maze Learning Test p  < 0.0001) versus placebo. In contrast, performance on these tests did not differ significantly between esketamine and placebo at 2, 4, or 6 h postdose. Secondary outcomes indicated a significant, transient increase from baseline under esketamine versus placebo at 40 min postdose on the Mental Effort Scale and at 40 min and 2 h postdose on KSS ( p  < 0.0001 for both); however, no significant difference was observed on these outcomes between esketamine and placebo at later timepoints. The most commonly reported adverse events were dizziness (67%), nausea (37.5%), disturbance in attention (29.2%), and fatigue (29.2%); the majority were considered mild in severity. Conclusions Esketamine was associated with cognitive performance decline, and greater effort was required to complete the test battery versus placebo at 40 min postdose, which returned to placebo-comparable levels by 2 h postdose. Trial registration: ClinicalTrials.gov identifier: NCT02094378

Purpose Low-dose ketamine is a lucrative therapeutic approach in cancer pain, perioperative treatment of pain, and management of treatment-resistant depression. The analgesic potency of its main metabolite norketamine is thought to be one third that of ketamine. However, few studies exist on the pharmacokinetics of orally administered S -ketamine. Methods In our study, 11 healthy volunteers received S -ketamine 0.25 mg/kg orally and 0.125 mg/kg intravenously. S -ketamine and norketamine concentrations were measured up to 23.5 h post-dose. A population pharmacokinetic model was built to describe S -ketamine and norketamine pharmacokinetics. Results A three-compartment model for both S -ketamine and norketamine best described the data. To accommodate for the extensive formation of norketamine after oral S -ketamine, a separate presystemic absorption-phase component was included in addition to its systemic formation. The oral bioavailability of S -ketamine was low, 8 % (11 % interindividual variability), and its clearance was high, 95 L/h/70 kg (13 % interindividual variability). Simulations suggested that after oral dosing, norketamine AUC at steady state is 16.5 times higher than that of S -ketamine. Conclusions Given that the analgesic effect of S -ketamine is due to both S -ketamine and norketamine, relatively small oral doses of S -ketamine can be assumed to be a feasible alternative to repeated intravenous dosing, for example in the setting of chronic pain.

Elderly patients with impaired intrinsic capacity are at increased risk for delayed or suboptimal recovery from surgery. S-ketamine has been proven to improve postoperative recovery quality. However, limited trials are studying the postoperative recovery quality in elderly patients with impaired intrinsic capacity. Therefore, the objective of this study was to evaluate the impact of S-ketamine on the quality of recovery in elderly patients with impaired intrinsic capacity following total knee arthroplasty. This is a single-centre, randomised, double-blind, placebo-controlled trial. Participants undergoing total knee arthroplasty will be randomly assigned in a 1:1 ratio to either the S-ketamine group (n=80) or the placebo group (n=80). The S-ketamine group will undergo an intravenous infusion of S-ketamine administered at a dosage rate of 0.2 mg·kg⁻ ·h⁻ for 1 hour. The placebo group will receive an intravenous saline infusion at an identical rate and duration. Postoperatively, the S-ketamine group will continuously infuse S-ketamine for 48 hours using a patient-controlled intravenous device, with a fixed rate of 0.01 mg·kg⁻¹·h⁻¹, a bolus dose of 0.02 mg·kg⁻¹, a lockout period of 10 min and a maximum infusion rate of 0.13 mg·kg⁻¹·h⁻¹. In contrast, the patient-controlled intravenous device for the placebo group will not contain S-ketamine. The primary outcome is the quality of recovery scores at 24 hours following total knee arthroplasty. Secondary outcomes encompass quality of recovery scores at 48 and 72 hours postoperatively, pain scores at rest and during movement, oral morphine equivalents, sleep quality assessments, depression scores, the Barthel Index and the time to meet discharge criteria. Approval for the trial was granted by the Medical Ethics Committee of The Affiliated Hospital of Qingdao University (QYFYEC2024-74). Written informed consent will be obtained from each patient before enrolment. The results of this trial will be presented at scientific conferences and in peer--reviewed scientific journals. ChiCTR2400087028.

Propofol and sufentanil are the most commonly used anesthetics during bronchoscopy. Esketamine is an s-enantiomer of ketamine racemate and has both sedative and analgesic effects, it does not inhibit respiration and maintains hemodynamic stability. We aimed to compare the intraoperative hypoxemia risk of esketamine/propofol with sufentanil/propofol for patients in bronchoscopy. This study was an investigator-initiated, single-center, randomized, double-blind clinical trial. Patients undergoing bronchoscopy were randomly assigned to receive either sufentanil group (n = 33; sufentanil: 0.2 μg/kg) or esketamine group (n = 33; esketamine: 0.2 mg/kg) for sedation and analgesia. Clinical data, anesthetics usage, incidence of intraoperative hypoxemia, total time of hypoxemia, recovery time, and adverse events were recorded. The incidence of intraoperative hypoxemia was significantly lower in the esketamine group than in the sufentanil group (27.2% vs 66.7%, =0.001, OR=5.333, 95% CI=1.859-15.301). Propofol usage was significantly higher in the esketamine group than in the sufentanil group (t=2.952, =0.004). The duration of hypoxia was significantly lower in the esketamine group than in the sufentanil group (Z=-3.445, <0.001), and the minimum oxygen saturation (SpO2) was significantly higher than in the sufentanil group (Z=-2.682, =0.007). Recovery time from anesthesia was significantly lower in the esketamine group than in the sufentanil group (Z=-2.709, =0.007). No difference was found in adverse reactions between the two groups. Esketamine combined with propofol reduced the incidence of intraoperative hypoxemia compared with sufentanil in bronchoscopy. Our results offer the possibility for a novel recommendation for the prevention of intraoperative hypoxemia during bronchoscopy. However, we mentioned the higher propofol use in the esketamine group. Additional clarification is necessary on the indications and the optimal dose of esketamine. Chinese clinical trial registry: ChiCTR2200058990.

Theta cordance is a novel quantitative electroencephalography (QEEG) measure that correlates with cerebral perfusion. A series of clinical studies has demonstrated that the prefrontal theta cordance value decreases after 1 week of treatment in responders to antidepressants and that this effect precedes clinical improvement. Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, has a unique rapid antidepressant effect but its influence on theta cordance is unknown. In a double-blind, cross-over, placebo-controlled experiment we studied the acute effect of ketamine (0.54 mg/kg within 30 min) on theta cordance in a group of 20 healthy volunteers. Ketamine infusion induced a decrease in prefrontal theta cordance and an increase in the central region theta cordance after 10 and 30 min. The change in prefrontal theta cordance correlated with ketamine and norketamine blood levels after 10 min of ketamine infusion. Our data indicate that ketamine infusion immediately induces changes similar to those that monoamineric-based antidepressants induce gradually. The reduction in theta cordance could be a marker and a predictor of the fast-acting antidepressant effect of ketamine, a hypothesis that could be tested in depressive patients treated with ketamine.

Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR ( N -methyl- d -aspartate receptor) antagonist ( R , S )-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of ( R , S )-ketamine to (2 S ,6 S ;2 R ,6 R )-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2 R ,6 R )-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2 R ,6 R )-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of ( R , S )-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants. The metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and the (2R,6R)-HNK enantiomer lacks ketamine-related side effects but exerts rapid and sustained antidepressant actions in mice; these antidepressant effects are independent of NMDAR inhibition but require AMPAR activity. Antidepressant action of a ketamine metabolite The NMDAR antagonist ketamine has rapid and sustained antidepressant effects; this has prompted a search for alternative NMDAR antagonists that have the same antidepressant properties but lack the undesirable side effects of ketamine. Todd Gould and colleagues now show that the metabolism of ( R , S )-ketamine to (2 S ,6 S ;2 R ,6 R )-hydroxynorketamine (HNK) is essential for its antidepressant activity, and that the (2 R ,6 R )-HNK enantiomer exerts rapid and sustained antidepressant actions in mice. These effects are NMDAR-independent but require AMPAR activation. Importantly, (2 R ,6 R )-HNK lacks the side effects associated with ketamine. These findings suggest new options for the development of novel rapid-acting antidepressants.