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Postpartum Depression (PPD) is one of the most common conditions in the childbearing period, with prominent impairments for the mother and the newborn. Esketamine has shown potent antidepressant effects and appears to be a promising agent in preventing PPD. We aimed to evaluate the potential effect of esketamine in preventing PPD within the first week and within four and six weeks post-delivery as the primary outcome; assess changes in the Edinburgh Postnatal Depression Scale (EPDS) one week and 42 days post-delivery; and evaluate tolerability and changes in inflammatory markers as secondary outcomes. A subanalysis was conducted considering different intervention protocols. A systematic review and meta-analysis (ID: CRD42024513598) were performed considering Randomized Clinical Trials (RCTs) in MEDLINE (PubMed), Embase, and Web of Science from inception until May 5, 2024. The ROB-2 tool assessed the risk of bias. Eleven RCTs were included, totaling 2316 participants. The occurrence of PPD was significantly lower in the intervention group within one week post-delivery (RR 0.44, 95% CI 0.30–0.64, p

Introduction: Esketamine has been approved in Australia and New Zealand as a third-line antidepressant treatment for treatment resistant depression. This study describes changes in quality of life, depressive symptoms and productivity in participants treated with esketamine in real-world settings. Methods: Participants were recruited from an esketamine early access program and had not responded to two or more different antidepressants and not received neurostimulation for their current depressive episode. Participants received esketamine for 16 weeks or longer. Data collected included Assessment of Quality-of-Life scale (AQoL-8D), Hamilton Depression Rating Scale (HAM-D) and Work Productivity Activity Index (WPAI). Results: Participants (n = 105) had a mean age of 38.7 years (standard deviation (SD) = 14.6) and were predominantly female (59.0%). The mean duration of major depressive disorder was 7.2 years (SD = 4.2) and almost half of participants had been treated with 3–5 prior therapies. After 16-weeks on esketamine, participants showed improvement of greater than 10% across all dimensions of AQoL-8D, HAM-D scores decreased 8.0 points, and activity impairment decreased 20.4% as measured by WPAI. Limitations: This was a non-randomized and unblinded study and may have selection and reporting bias. The population was not necessarily representative of the broader Australian and New Zealand population. It is not possible to determine if the results will be sustained or changed if participants received treatment for longer. Conclusions: Esketamine early access program participants, who were a real-world cohort with extensive prior treatment, showed clinically significant improvements in quality of life, depression severity and productivity after 16-weeks on treatment.

Background: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. Objective: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. Methods: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). Results: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. Conclusions: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. Trial registration: ClinicalTrials.gov Identifier NCT03887715.

Treatment-resistant depression, defined as a failure of at least two oral antidepressants of adequate dose and duration in the current episode, is a debilitating condition with low rates of response and remission. Intranasal esketamine is the first medication approved by regulatory authorities for difficult to treat depressive episodes that builds directly on the discovery of the rapid antidepressant effects of intravenously administered racemic ketamine. Approved in the United States in 2019, and subsequently, in many countries worldwide, intranasal esketamine is indicated in conjunction with any new or previously taken oral antidepressant medication of the clinician’s choosing for treatment-resistant depression in adults. It is also indicated for the treatment of major depressive disorder in adults with acute suicidal ideation or behavior who may or may not be treatment-naive or have treatment-resistant depression. This article outlines the case for the efficacy, safety profile, and feasibility of acute, short-term intranasal esketamine followed by the long-term continuation of intranasal esketamine versus long-term off-label intravenous ketamine in treatment-resistant depression. The article further suggests biomarkers to predict response that warrant further study.

Background: Postoperative pain is a prevalent concern following a cesarean section. This study aimed to investigate the effect and mechanism of low-dose (0.1 mg/kg) esketamine on postoperative pain management in pregnant women undergoing cesarean sections, specifically in cases where both patient-controlled intravenous analgesia (PCIA) and patient-controlled epidural analgesia (PCEA) were employed. Methods: Pregnant women intending to undergo elective cesarean section were divided into four subgroups based on the intravenous administration of esketamine and the specific analgesia methods employed: E1 (0.1 mg/kg esketamine + PCEA), E2 (0.1 mg/kg esketamine + PCIA), C1 (saline + PCEA), and C2 (saline + PCIA). The primary outcome was the maximum pain score within 24 h postoperatively. Secondary outcomes included the pressure pain threshold and tolerance at 30 min and 24 h postoperatively, along with the inflammation and adverse event index scores. Results: A total of 118 pregnant women were assigned to the four groups: E1 (n = 29), E2 (n = 29), C1 (n = 30), and C2 (n = 30). Compared with those in the control groups (C1 + C2), the maximum postoperative pain scores within 24 h in the esketamine groups (E1 + E2) were significantly lower (4 [2–5] vs. 4 [4–6], P = 0.002), and the E1 group exhibited superior analgesic effects compared with other groups. No significant differences were observed in postoperative hyperalgesia or inflammation across the four groups. Notably, esketamine combined with PCIA increased the incidence of postoperative nausea and vomiting (7 [25 %] vs. 0 [0 %]; P = 0.005). Conclusion: The administration of low-dose (0.1 mg/kg) esketamine effectively alleviates pain following cesarean section, and the analgesic effect is notably enhanced in combination with PCEA. Importantly, these effects do not appear to be mediated through anti-inflammatory mechanisms or the inhibition of hyperalgesia. Clinical trial registration number: NCT05414006.

Objective: To prospectively determine the median effective dose (ED50) of propofol for inhibiting a response to laryngeal mask airway (LMA) insertion when combined with different doses of esketamine in female patients. Methods: A total of 58 female patients (aged 20–60 years, ASAⅠ–Ⅱ) scheduled for elective hysteroscopy were enrolled and randomly divided into 2 groups, one of which was administered 0.2 mg/kg of esketamine (K1 group, n = 28) and the other 0.3 mg/kg of esketamine (K2 group, n = 30). The 2 groups received the corresponding doses of esketamine intravenously, followed by an intravenous injection of propofol (injection time was 30 s). The initial dose of propofol was 2 mg/kg, and the dose ratio of propofol in the adjacent patients was 0.9. If a positive reaction occurred due to LMA insertion, the dose ratio in the next patient was increased by 1 gradient; if not, the dose ratio was decreased by 1 gradient. The ED50, 95 % effective dose (ED95) and 95 % confidence interval (CI) of propofol for inhibiting a response to LMA insertion in the 2 esketamine groups were calculated using probit analysis. Results: The ED50 of propofol for inhibiting a response to LMA insertion in female patients was 1.95 mg/kg (95 % CI, 1.82–2.08 mg/kg) in the K1 group and 1.60 mg/kg (95 % CI, 1.18–1.83 mg/kg) in the K2 group. The ED95 of propofol for inhibiting a response to LMA insertion in female patients was 2.22 mg/kg (95 % CI, 2.09–2.86 mg/kg) in the K1 group and 2.15 mg/kg (95 % CI, 1.88–3.09 mg/kg) in the K2 group. Conclusion: Propofol combined with 0.3 mg/kg of esketamine has low ED50 and ED95 effective doses for inhibiting an LMA insertion response in female patients undergoing hysteroscopy and surgery. There were no significant adverse effects, but the additional dose of propofol and airway pressure were significantly higher than those in the group administered 0.2 mg/kg of esketamine. Based on the results, we recommend the combination of propofol with 0.2 mg/kg esketamine for optimal conditions during LMA insertion in women undergoing hysteroscopy.

Background: Epidural nonopioid adjuvants also reduce local anesthetic use. We aimed to test the hypothesis that, compared with the present standard fentanyl, the hourly consumption of local anesthetic was at least as good when dexmedetomidine or esketamine was combined with local anesthetic for patient-controlled epidural analgesia (PCEA). Methods: A total of 120 laboring nulliparous subjects requiring labor analgesia were recruited for the final statistical analysis. Subjects were randomized to receive 0.075 % ropivacaine added with one of three equivalent adjuvants: 0.4 μg/mL fentanyl, 0.4 μg/mL dexmedetomidine, or 1.0 mg/mL esketamine. The primary outcome was hourly ropivacaine consumption. Compared with the fentanyl group, a 20 % difference in hourly local anesthetic consumption between the dexmedetomidine and esketamine groups was considered a clinical difference (non-inferiority margin). Results: The hourly ropivacaine consumption of the fentanyl group was 12.4 (95 % confidence interval CI 11.2 to 13.6) ml/h, so the prespecified non-inferiority limit was 2.5 ml/h. The hourly ropivacaine consumption of the fentanyl group was not inferior to that of the dexmedetomidine group (12.4 ml/h vs. 11.9 ml/h, risk difference, 0.5; 95 % confidence interval CI, −1.0 to 2.0, meeting criteria for non-inferiority). However, the hourly ropivacaine consumption of the esketamine group was 14.3 ml/h, and that of the fentanyl group was 12.4 ml/h (risk difference, 1.9, 95 % CI, 0.2 to 3.6), failing to confirm non-inferiority with a non-inferiority margin of 20 %. The incidence of pruritus was highest in the fentanyl group, whereas the occurrence of mild dizziness was highest in the esketamine group. Conclusions: In setting of the conditions of this study, epidural dexmedetomidine was non-inferior compared with epidural fentanyl in combination with ropivacaine for PCEA during labor. Meanwhile, we failed to establish the non-inferiority of epidural esketamine compared with epidural fentanyl in combination with ropivacaine for labor analgesia.

Purpose: Postoperative pain is prevalent and severe complication in elderly surgical patients. Multiple studies propose that a small dose of esketamine administered intraoperatively can alleviate postoperative pain and curtail opioid usage. We aimed to evaluate the impact of esketamine on postoperative acute pain among elderly patients with gastrointestinal tumors. Patients and methods: This is a prospective, parallel-group, randomized controlled trial. Ninety patients aged 60 and above, undergoing resection of gastrointestinal tumors, were randomly assigned to two groups: esketamine group (Group S, a single dose of 0.25 mg/kg and 0.1 mg/kg/h infusion) and control group (Group C, saline). Visual Analogue Scale (VAS) pain scores were the primary outcome. Remifentanil consumption, instances of rescue analgesia, delirium, sleep quality, postoperative recovery quality, serum levels of inflammatory cytokines, and adverse events within 72 h post-surgery were secondary outcomes, respectively. Results: Data of 87 of 99 eligible patients were analyzed. VAS scores at rest in Group S were lower than those in Group C at 6 h [1.2 (0.6, 1.6) vs 1.6 (1.0, 2.0), P = 0.003], 12 h [1.4 (1.0, 2.0) vs 2.0 (1.5, 2.0), P

Background: Pain management after lung resection plays a crucial role in reducing postoperative pulmonary complications (PPCs). This study aimed to examine the effect of postoperative esketamine infusion as an adjunct to opioid analgesia on ventilation and pulmonary complications in patients underwent lung resection. Methods: Patients undergoing video-assisted thoracoscopic lung resection were randomly assigned to either the esketamine group or the control group. The esketamine group received a 24-h infusion of 1.5 mcg/ml sufentanil combined with 0.75 mcg/ml esketamine after surgery, while the control group received 1.5 mcg/ml sufentanil alone. The primary outcome measure was low minute ventilation, and the secondary outcome measures were hypoxemia, PaO2/FiO2 levels, postoperative pulmonary complications, hospital stay duration, ambulation time, Visual Analogue Scale (VAS) score, depression and anxiety levels, sleep quality, and analgesia satisfaction. Results: 80 patients were randomly divided into two groups: the esketamine group (n = 40) and the control group (n = 40). The esketamine group exhibited notably reduced incidence of low minute ventilation (P = 0.014), lower occurrence of postoperative pulmonary complications (PPCs) compared to the control group (P = 0.039), and decreased incidence of hypoxemia (P = 0.003). Furthermore, the esketamine group showed improved outcomes with lower VAS scores on the second postoperative day and enhanced sleep quality (P

Objective: Opioid-sparing anesthesia reduces intraoperative use of opioids and postoperative adverse reactions. The current study investigated the effect of esketamine-based opioid-sparing anesthesia on total laparoscopic hysterectomy patients' recovery. Methods: Ninety patients undergoing total laparoscopic hysterectomy were randomly assigned to esketamine-based group (group K) or opioid-based group (group C). The allocation to groups was unknown to patients, surgeons, and postoperative medical staff. The inability to implement blinding for anesthesiologists was due to the distinct procedures followed by the various groups while administering drugs. The QoR-40 and VAS were used to measure recovery quality. Postoperative adverse events, perioperative opioid consumption, and intraoperative hemodynamics were secondary endpoints. Results: There was an absence of notable discrepancy in the baseline data observed between the two groups. The QoR-40 scores exhibited greater values in group K when compared to group C on the first day following the surgical procedure (160.91 ± 9.11 vs 151.47 ± 8.35, respectively; mean difference 9.44 [95 %CI: 5.78–13.11]; P

Background: Postoperative cognitive decline (POCD) is a common complication after surgery and anesthesia among the elderly. Yet the potential mechanism of POCD remains ambiguous, with limited therapeutic measures currently available. Ketamine has been reported to attenuate POCD after cardiac surgery. Herein, we tried to determine the effect of esketamine (the S-enantiomer of ketamine) on POCD and the possible molecular mechanisms. Methods: We investigated the effects of esketamine (10 mg/kg) on POCD using an exploratory laparotomy model in aged SD rats (24 months). Open field, novel object recognition, and morris water maze tests were performed on day 30 post-surgery. 24 h or 30 d post-surgery, brain tissue from the hippocampus and ventromedial prefrontal cortex (vmPFC) was harvested and subjected to histopathology and molecular biology analysis. During the in vitro experiment, primary astrocytes from the hippocampus and vmPFC were exposed to lipopolysaccharide (LPS) to investigate the pathological changes in astrocytes during the process of POCD. Results: Our results indicated that exploratory laparotomy could induce significant cognitive and memory decline, accompanied by A2-type astrocytes phenotype loss and increased expression of neuron Aβ-42, astrocytes GABA, stimulator of interferon genes (STING) and TANK‐binding kinase 1 (TBK1). In addition, LPS exposure significantly decreased the mitochondrial membrane potential and upregulated the level of pyroptosis-associated proteins, including cleaved caspase-1 and IL-18. Notably, treatment with esketamine reversed these abnormalities in vivo and vitro. However, ADU-S100, a special STING activator, suppressed the protective effects of esketamine to a certain extent. Finally, C-176, an antagonist of STING, further enhanced the protective effects of esketamine against POCD. Conclusions: Findings of our study suggest that esketamine can alleviate surgery-induced POCD in rats via inhibition of the STING/TBK1 signaling pathway.

Introduction: Ketamine and its S-enantiomer esketamine are novel pharmacotherapeutic options for treatment resistant depression (TRD). There is growing evidence on the efficacy for other psychiatric disorders, including posttraumatic stress disorder (PTSD). It is hypothesized that psychotherapy may further potentiate the effects of (es)ketamine in psychiatric disorders. Methods: Repeated oral esketamine was prescribed once or twice weekly in five patients suffering from TRD and comorbid PTSD. We describe the clinical effects of esketamine and report data from psychometric instruments and patients’ perspectives. Results: Esketamine treatment duration ranged from six weeks to a year. In four patients, we observed improvement in depressive symptoms, increased resilience and more receptiveness to psychotherapy. One patient experienced symptom worsening in response to a threatening situation during esketamine treatment, highlighting the need for a safe setting. Discussion: (Es)ketamine treatment within a psychotherapeutic framework appears promising in patients with treatment resistant symptoms of depression and PTSD. Controlled trials are warranted to validate these results and to elucidate the optimal treatment methods.

Background: Ketamine is an anesthetic that appears to be an effective and rapidly acting pharmacological treatment in patients with Treatment-Resistant Depression (TRD). However, the definition of TRD varies greatly between published studies, and studies often did not include patients resistant to electroconvulsive therapy (ECT). Methods: We performed a chart study of 24 ECT-resistant TRD patients who received an open-label course of six esketamine infusions (0.5 mg/kg) over two weeks in the Leiden University Medical Center, Leiden, the Netherlands. Effectiveness was assessed with the Montgomery Åsberg Depression Rating Scale (MADRS) and the Inventory of Depressive Symptomatology (IDS-SR) up to four weeks after the last administration. Results: 23 (95.8%) patients (aged 48.7 ± 14.4 years, 79.2% female), completed the course. During treatment, eight patients (33.3%) achieved response (MADRS decrease ≥50%), five (20.8%) achieved remission (MADRS ≤10), and fourteen (58.3%) achieved a minimal clinically important difference (MADRS decrease >3 points). Relapse before or at follow-up occurred in 12.5%, 20% and 35.7% of these patients, respectively. An average decrease in MADRS scores of 9 points, and IDS-SR scores of 20 points, was observed. Limitations: This retrospective chart review permitted us only to use routinely collected open label and unblinded data. Conclusions: On average, intravenous esketamine demonstrated moderate to clinically meaningful effectiveness in this highly therapy resistant TRD patient population. However, results varied substantially between patients, from clinical deterioration to rapid remission. Despite the relatively lower remission rate compared with published data, a minimal clinically important difference was observed in over half of the patients.

Background: The acute hypoxic ventilatory response is a critical chemoreflex originating at the carotid bodies. This study investigates the impact of low-dose i.v. esketamine on the ventilatory response to 20 min of isocapnic hypoxia to test the hypothesis that esketamine does not affect hypoxic ventilation., Methods: In this open-label study, 18 healthy subjects received a 3-h escalating i.v. infusion of esketamine, totalling 1.0 mg kg -1 . Before the esketamine infusion (control condition) and during the last 30 min of infusion, the ventilatory response to 20 min of isocapnic hypoxia (oxygen saturation ∼80%) was measured. We assessed the increase in ventilation from baseline to its peak during the first 5 min of isocapnic hypoxia (hypoxic ventilatory response) and the increase in ventilation from baseline to 20 min of isocapnic hypoxia (sustained hypoxia). Haemodynamics and acute brain function were also measured., Results: Independent of hypoxia, a small excitatory effect of ketamine on isocapnic ventilation was observed: the mean increase in ventilation (95% confidence interval) was 3.1 (2.4-3.7) L min -1 (P<0.0001). Esketamine had no effect on the isocapnic ventilatory response to acute and sustained hypoxia but increased MAP (+10 mm Hg) and heart rate (+10 beats min -1 ), similarly during normoxia and hypoxia. Esketamine increased anxiety and alertness and affected external perception., Conclusions: I.V. esketamine up to 1 mg kg -1 does not affect the ventilatory response to hypoxia, but affects haemodynamics and acute brain function. Increases in anxiety and alertness could be a cause of the sustained ventilatory response to hypoxia during esketamine infusion., Clinical Trial Registration: The trial was registered at the ISRCTN registry on June 27, 2023 under identifier ISRCTN 42617929 (https://www.isrctn.com/ISRCTN42617929)., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Depression is a significant factor contributing to postoperative occurrences, and patients diagnosed with depression have a higher risk for postoperative complications. Studies on cardiovascular surgery extensively addresses this concern. Several studies report that people who undergo coronary artery bypass graft surgery have a 20% chance of developing postoperative depression. A retrospective analysis of medical records spanning 21 years, involving 817 patients, revealed that approximately 40% of individuals undergoing coronary artery bypass grafting (CABG) were at risk of perioperative depression. Patients endure prolonged suffering from illness because each attempt with standard antidepressants requires several weeks to be effective. In addition, multi-drug combination adjuvants or combination medication therapy may alleviate symptoms for some individuals, but they also increase the risk of side effects. Conventional antidepressants primarily modulate the monoamine system, whereas different therapies target the serotonin, norepinephrine, and dopamine systems. Esketamine is a fast-acting antidepressant with high efficacy. Esketamine is the S-enantiomer of ketamine, a derivative of phencyclidine developed in 1956. Esketamine exerts its effect by targeting the glutaminergic system the glutaminergic system. In this paper, we discuss the current depression treatment strategies with a focus on the pharmacology and mechanism of action of esketamine. In addition, studies reporting use of esketamine to treat perioperative depressive symptoms are reviwed, and the potential future applications of the drug are presented., (Copyright © 2024. Published by Elsevier Inc.)

Ketamine, an N-methyl-D-aspartate receptor antagonist, is a racemic mixture of esketamine and arketamine used to treat unipolar and bipolar depression. Preliminary reports indicate that it may be beneficial for depressed patients reporting symptoms of anhedonia. In this systematic review we aim to assess and analyze the existing body of evidence regarding the therapeutic effects of ketamine on the domain of anhedonia. Electronic databases (PubMed, APA Psycinfo and Web of Science) were searched from inception to November 2023. Protocol was registered in PROSPERO under the identifier CRD42023476603. A total of twenty-two studies, including four randomized-controlled trials and eighteen open-label trials were included. All studies reported alleviation of anhedonia symptoms following ketamine or esketamine administration, regardless of the number of infusions. Several important limitations were included, first and foremost low number of placebo-controlled randomized-controlled trials. This review indicates a potential anti-anhedonic effect of ketamine in patients with depression. Several trials used neuroimaging techniques which confirm ketamine's effect on functional connectivity correlating with the improvement in anhedonia. Despite considerable variations in methodology and the specific brain regions investigated, these studies collectively point towards ketamine's neuroplastic effects in mitigating anhedonia., Competing Interests: Declaration of competing interest Julia Kwaśna has no conflict of interest. Aleksander Kwaśny has received research support from GH Research, MSD, Novartis Alina Wilkowska has received research support from Angelini, Biogen, Eli Lilly and Company, Janssen-Cilag, Lundbeck, Polpharma, Sanofi, and Valeant. Joanna Szarmach has received research support from KCR, Janssen, Otsuka, Apodemus, Novartis, Cortexyme, GH Research and Acadia. Jakub Słupski has received research support from Actavis, Eli Lilly, Minerva, Sunovion, Celon, Janssen, Biogen, Novartis, HMNC Brain Health. Adam Włodarczyk has received research support from KCR, Janssen, Otsuka, Apodemus, Novartis, Cortexyme, GH Research and Acadia. Wiesław Jerzy Cubała has received grants from Acadia, Angelini, Celon, Cortexyme, GH Research, HMNC Brain Health, IntraCellular Therapies, Janssen, MSD, Novartis, Otsuka. He has albo received honoraria from Angelini, Celon, Janssen, Novartis, Sanofi. He is a member of advisory boards in Angelini, Celon (terminated), Douglas Pharmaceuticals, Janssen, MSD, Novartis, Sanofi., (Copyright © 2024 Elsevier B.V. and ECNP. All rights reserved.)

Summary: Background: (S)-ketamine is a glutamatergic drug with potent and rapid acting effects for the treatment of depression. Little is known about the effectiveness of intranasal (S)-ketamine for treating patients with comorbid depression and post-traumatic stress disorder (PTSD). Methods: We performed a retrospective case series analysis of clinical outcomes in 35 Veterans with co-morbid depression and PTSD who were treated with intranasal (S)-ketamine treatments at the VA San Diego Neuromodulation Clinic between Jan 2020 and March 2021. Veterans were not randomized or blinded to treatment. The primary outcome measured was a change in patient health questionnaire-9 (PHQ-9) and PTSD Checklist for DSM-5 (PCL-5) scores across the first 8 treatments (induction period) using a repeated measures analysis of variance (ANOVA). In a smaller sub-group (n = 19) of Veterans who received at least 8 additional treatments, we analyzed whether intranasal (S)-ketamine continued to show treatment effects. Finally, we performed a sub-group and correlation analyses to understand how changes in PHQ-9 and PCL-5 scores were related across treatments. Findings: During the induction phase of treatment there was an absolute reduction of 5.1 (SEM 0.7) on the patient health questionnaire-9 (PHQ-9) rating scale for depression, from 19.8 (SEM 0.7) at treatment 1 to 14.7 (SEM 0.8) at treatment 8 (week 4) (F(7238) = 8.3, p = 1e-6, partial η2 = 0.2). Five Veterans (14%) showed a clinically meaningful response (50% reduction in PHQ-9 score) at treatment 8. There was an absolute reduction of 15.5 +/- 2.4 on the patient checklist 5 (PCL-5) rating scale for PTSD, from 54.8 (SEM 2) at treatment 1 down to 39.3 (SEM 2.5) at treatment 8 (F(7238) = 15.5, p = 2e-7, partial η2 = 0.31). Sixteen Veterans (46%) showed a clinically meaningful response (reduction in PCL-5 of > 30%) in PTSD. Change in PHQ-9 correlated with change in PCL-5 at treatment 8 (r = 0.47, p = 0.005), but a decrease in PTSD symptoms were observable in some individuals with minimal anti-depressant response. Interpretations: While this is an open-label retrospective analysis, our results indicate that both depression and PTSD symptoms in Veterans with dual-diagnoses may improve with repeated intranasal (S)-ketamine treatment. The effects of (S)-ketamine on PTSD symptoms were temporally and individually distinct from those on depression, suggesting potentially different modes of action on the two disorders. This work may warrant formal randomized controlled studies on the effects of intranasal (S)-ketamine for individuals with co-morbid MDD and PTSD. Funding: VA Center of Excellence in Stress and Mental Health, VA ORD (Career Development Award to DSR), Burroughs-Wellcome Fund Award (DSR), NIMH (EL)

Ketamine and esketamine (SPRAVATO) are rapid acting antidepressants that have gained evidence and popularity in recent years in treating depression, and are under investigation for other psychiatric indications. Ketamine is a potential drug of abuse and the addiction potential of these medications has been repeatedly cautioned in the psychiatric literature. However, no studies have included a systematic evaluation of addiction potential in their research so risk of this harm remains theoretically and has not been quantified to place in properly in a risk/benefit perspective. There is currently no easily accessible and ready to use tool for this purpose, which poses a barrier to including measures of addiction potential in ketamine and esketamine research. Based on review of the literature and a recently suggested comprehensive Ketamine Side Effect Tool (KSET), as well as the United States Food and Drug Administration recommendations for evaluation addictive potential of a drug, we created a simple, patient rated visual analog scale specifically for assessing ketamine/esketamine drug likeability, cravings and temptation to misuse. While this scale is not validated, in the absence of other accessible tools, use of this questionnaire would provide researchers and clinicians a simple and easy to use tool to begin monitoring addictive potential in patients taking ketamine or esketamine, and better inform future research, clinical practice and publicy policy regarding these substances.

Study Objective: To investigate whether a single dosage of esketamine injection in the anesthesia period could improve postoperative negative emotions and early cognitive function in patients undergoing non-cardiac thoracic surgery., Design: A prospective single center double blinded randomized placebo-controlled trial., Setting: Perioperative period; operating room, post anesthesia care unit and hospital ward., Patients: 129 adult patients that underwent elective non-cardiac thoracic surgery under general anesthesia., Interventions: During the operation, pharmacologic prevention of postoperative negative emotion and early cognitive disorder with 0.2 mg/kg (Low esketamine group) and 0.5 mg/kg esketamine (High esketamine group) vs. placebo., Measurements: Emotion and early cognitive performance were assessed on the day before surgery (POD-1), postoperative day 1 (POD1) and day 3 (POD3) using HADS-A, HADS-D, Pain Visual Analogue Scale (VAS), Confusion Assessment Method (CAM), Mini-Mental State Examination (MMSE), and serum biomarkers (S100β, BDNF, IL-6, acetylcholine, and norepinephrine)., Main Results: The high esketamine group showed significantly lower HADS-A and HADS-D scores than control group on POD1 and POD3. No significant differences were observed between the low esketamine group and the control group. The esketamine-treated groups showed lower pain VAS scores than the control group at 2 h and on the first day after operation. There were no significant differences among the three groups in CAM and MMSE scores. However, the high esketamine group had lower S100β and IL-6 levels, and higher BDNF levels postoperatively, while serum acetylcholine and norepinephrine were not significantly different., Conclusions: A single intraoperative injection of 0.5 mg/kg esketamine can alleviate postoperative anxiety, depression, and pain to some extent. Although cognitive function behavioral evaluation did not show obvious benefits, it can also reduce the production of pro-inflammatory and brain injury-related factors while promoting the generation of brain-derived neurotrophic factor. Registration Trial registry: http://www.chictr.org.cn/; Identifier: ChiCTR2100047067., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Postpartum depression (PPD) is a psychiatric condition affecting women post-childbirth. Medication combined with psychotherapy, is the current protocol for its treatment. A meta-analysis was conducted using RevMan 5.4 to explore the efficacy and safety of peri-partum administration of esketamine for preventing PPD. After searching several databases to retrieve the relevant RCTs, seven were included in this analysis, with dichotomous data presented as risk ratio and continuous data as mean difference. The study found a lower incidence of PPD in the esketamine group compared to the control group (RR= 0.37), with significant difference in EPDS scores between the two groups (MD= -1.23) in the first week postpartum. The esketamine group reported a lower prevalence of PPD 4-6 weeks postpartum (RR= 0.48), and no significant difference in EPDS scores after 4 weeks postpartum (MD = -0.10). The esketamine group had a significantly higher incidence of hallucination (RR= 13.85). Other adverse effects, such as dizziness (RR= 4.09), nausea (RR= 0.88), vomiting (RR=0.74), headache (RR=1.52), nightmares (RR=1.22), pruritus (RR=0.29), and drowsiness (RR=1.57) did not show significant differences between the two groups. The study found that esketamine, with manageable side effects, reduces the prevalence of post-partum depression (PPD) after one week as well as after four to six weeks. However, the findings are limited by the limited number of available RCTs, and future research should determine the ideal dosage, the most effective method of administration and the long-term safety profile of esketamine so that it may be considered as an adjunct therapy or a potential sole treatment option., Competing Interests: Declaration of Competing Interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Opioid consumption for analgesia in burn patients is enormous. Non-opioid analgesics for burn pain management may result in opioid sparing, reducing opioid-related adverse reactions and drug tolerance or addiction., Methods: A dual-center, randomized controlled trial assessed Esketamine for the perioperative period in patients with severe [20-50 % total body surface area (TBSA)] and extensive (≥ 50 % TBSA) burns, comparing analgesia with standard anesthesia. Sixty patients were randomly allocated (1:1 ratio) to two arms. In the Treatment Arm, patients received intra-operative Esketamine and postoperative intravenous primary intelligent analgesia pump with Esketamine. Patients in the Control Arm received the same intervention as Treatment Arm without Esketamine. The primary endpoint was subjective analgesic efficacy (SAE) evaluated on Day 28 or the day before hospital discharge. Secondary outcomes included the postoperative Numeric Pain Rating (NPR) Scale at rest (NPRr) and during movement (NPRm) and opioid consumption. Gastrointestinal dysfunction Scores (GIDS) and serum markers of intestinal injury [intestinal fatty acid-binding protein 2 (iFabp2) and apolipoproteinA2 (ApoA2)] were measured in the 1st and 4th post-injury weeks. Depression and sleep quality were assessed by relevant questionnaires., Results: Fifty-five patients were included in the analysis. Esketamine-treated Arm recorded a better analgesic efficacy than the Control Arm (proportion of patients with Grade 1 or 2 SAE scores, 67.9 % vs. 40.7 %, p = 0.022). Esketamine-treated patients had lower NPRm values (p = 0.033) and lower daily opioid consumption (p = 0.033) when compared with Controls. Esketamine-treated patients showed comparable gastrointestinal recovery to those in the Control Arm. The overall sleep quality might be improved in the Treatment Arm., Conclusions: Esketamine use is safe for perioperative primary intelligent analgesia of severe burns, resulting in improved resting pain control and lower opioid requirements., Trial Registration: The trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn/) (ChiCTR2000034069)., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This meta-analysis aimed to evaluate the impact of ketamine/esketamine on postoperative subjective quality of recovery (QoR)., Methods: MEDLINE, Embase, Cochrane library, and Google Scholar were searched for randomised controlled trials (RCTs) that examined the impacts of perioperative ketamine/esketamine use and postoperative QoR. The primary outcome was subjective QoR (QoR-9, QoR-15, QoR-40) on postoperative day (POD) 1-3, whereas the secondary outcomes included pain severity, anxiety scores, depression scores, risk of adverse events (i.e. nausea, vomiting, dizziness, drowsiness), and length of stay., Results: The analysis included 18 RCTs (1554 participants; ketamine: seven trials, esketamine: 11 trials), of which 15 were conducted in China. Ketamine/esketamine improved the QoR scores on PODs 1 and 2 compared with the control (standardised mean difference [SMD]: 0.63, P<0.0001 for POD 1; SMD: 0.56, P=0.04 for POD 2), without beneficial effect on POD 3. Subgroup analyses revealed significant differences in QoR scores on POD 1 by regimen (SMD: esketamine 1.14, ketamine 0.01) and country (SMD: China 0.82, other countries -0.21). The emotional domain of QoR was improved from PODs 1 to 3, whereas the other domains were only improved on POD 1. Lower postoperative anxiety (SMD: -0.48, P=0.003) and depression (SMD: -0.72, P=0.001) scores were also observed with ketamine/esketamine use. Furthermore, pain severity was reduced on PODs 1 and 2, with no difference in the risk of adverse events or length of stay., Conclusions: This meta-analysis demonstrated that ketamine/esketamine use in the perioperative period is associated with improved early subjective QoR, pain severity, and psychological symptoms without an increase in the likelihood of adverse events., Systematic Review Protocol: PROSPERO (CRD42023477580)., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Introduction: The antidepressant effect of N-methyl-D-aspartate antagonists is often short lasting, raising the question of the best maintenance strategy, which has remained unanswered. Vagus nerve stimulation (VNS) as a treatment option for refractory and chronic major depression was shown to reduce the need for maintenance treatment sessions in patients receiving electroconvulsive therapy. To our knowledge, there are no published data on the combination of VNS and esketamine in the literature., Materials and Methods: This is a naturalistic prospective and retrospective observational study in patients treated with long-term VNS owing to difficult-to-treat depression. These patients also have received esketamine maintenance sessions in addition to short-term treatment. We have investigated the need for maintenance esketamine sessions per month after VNS implantation (number of sessions/number of months between visits), the change in depression severity (mean Montgomery-Asberg Depression Rating Scale [MADRS] score), and the number of hospitalizations per month (number of hospitalizations/number of postoperative observation months). Follow-up visits have been scheduled every three months after VNS implantation (follow-up period 12-24 months, mean 17)., Results: All patients (n = 8, mean age 53.1 years) had severe difficult-to-treat depression (DTD) (mean MADRS at baseline 30.9). Mean number of hospitalizations per month decreased from 0.17 to 0.11 after VNS implantation (p = 0.041, T = 2.030, df = 7). Mean MADRS at 12 months was 18.3 (40.8% MADRS reduction, p = 0.008, T = 3.146, df = 7). Six of eight patients were offered maintenance esketamine treatment. Mean number of esketamine treatment sessions per month and case decreased from 2.3 at the six-month visit to 0.8 at 12 months (p = 0.076, T = 1,690, df = 5) after VNS implantation. Termination of maintenance esketamine was possible in four cases after a mean of 11.5 months., Conclusions: Combination of esketamine and VNS was effective in patients with DTD to relieve disease severity and reduce hospitalizations. The need for esketamine treatment sessions decreased after 6 months of VNS. No safety concerns arose in this study regarding the combination treatment., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT03320304., Competing Interests: Conflict of Interest Erhan Kavakbasi received speaker and advisor honoraria from LivaNova and Janssen-Cilag. Bernhard T. Baune received speaker/consultation fees from AstraZeneca, Lundbeck, Pfizer, Takeda, Servier, Bristol Myers Squibb, Otsuka, LivaNova, Biogen, Angelini, and Janssen-Cilag. The RESTORE-LIFE study was sponsored by LivaNova, manufacturer of VNS Therapy. The authors' institution received fees for study visits. LivaNova had no influence on the present manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ketamine is an effective antidepressant with a 65–70% response rate and a fast onset of action. Esketamine (S-ketamine) has been found to be twice as potent as R-ketamine, while inducing fewer adverse effects, such as sedation and cognitive impairment, than racemic ketamine. However, little is known about its heterogeneous effects in treating depression. The aim of this study was to evaluate heterogeneity in the trajectory of depression treated with subcutaneous esketamine. Methods: Seventy severely depressed patients were administered repeated subcutaneous esketamine injections, and four assessments on depressive symptoms were performed. A growth mixture model analysis of the sample was utilized to identify potential latent classes. Results: Our model revealed two distinct subgroups: responders (79.1%), those who showed a lower depression score at the first time point and a strong decline in symptoms; and non-responders (20.9%), those who showed a higher initial depression score and a limited decline in symptoms. Limitations: This study has an observational design, with possible confounders. We were unable to analyse class differences in baseline symptoms, probably due to sample size. The group behaviour observed here must be confirmed with different populations. There is currently no clear cutoff to predict group membership. Conclusion: These findings suggest a systematically heterogeneous amelioration of symptoms based on a person-centred analysis. Patients with lower depression scores 24 h after the first injection are more likely to be in the responder subgroup and to present better symptom relief. Further studies should focus on clinical aspects that might predict this heterogeneity.

Background: Depression is a prevalent mood disorder during the perioperative period, with both preoperative concurrent depression and new-onset postoperative depression impacting postoperative recovery. Recent studies have indicated that the dissociative anesthetic esketamine may alleviate perioperative depressive symptoms., Objective: This meta-analysis aimed to assess the efficacy and safety of esketamine in treating perioperative depression., Methods: We selected randomized controlled trials comparing esketamine to placebo in terms of postoperative depressive symptoms. The primary outcome was postoperative depression scores, with secondary outcomes including the prevalence of postoperative depression, pain scores using the Visual Analogue Scale or Numeric Rating Scale, and incidences of adverse reactions such as nausea/vomiting, dizziness, dreams/nightmares, hallucinations., Results: We enrolled a total of 17 studies involving 2462 patients. The esketamine group demonstrated a significant reduction in postoperative depression scores within one week after surgery (SMD -0.47, 95% CI (-0.66, -0.27), P < 0.001) and over the long term (SMD -0.44, 95% CI (-0.79, -0.09), P = 0.01). Furthermore, esketamine significantly decreased the prevalence of postoperative depression both within one week (RR 0.46, 95% CI (0.33, 0.63), P < 0.001) and over the long term (RR 0.50, 95% CI (0.36, 0.70), P < 0.001). Additionally, esketamine effectively relieved pain on the first postoperative day compared to control. However, it also increased the risks of dizziness and hallucinations for a short time., Conclusion: This meta-analysis suggests that the intraoperative or postoperative application of esketamine could be a potentially effective treatment for perioperative depression, although the increased risk of adverse reactions should be considered., Competing Interests: Declaration of Competing Interest Dr. Hashimoto is the inventor of filed patent applications on “The use of R-ketamine in the treatment of psychiatric diseases”, “(S)-norketamine and salt thereof as pharmaceutical”, “R-ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition function disorder”, “Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases”, “R-ketamine and its derivatives as a preventive or therapeutic agent for a neurodevelopmental disorder”, and “TGF-β1 in the treatment of depression” by Chiba University. Dr. K. Hashimoto has also received speakers’ honoraria, consultant fees, or research support from Abbott, Boehringer Ingelheim, Daiichi-Sankyo, Meiji Seika Pharma, Seikagaku Corporation, Sumitomo Pharma, Taisho, Otsuka, Murakami Farm and Perception Neuroscience. The other authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Suicide is a major cause of death in adolescents with limited treatment options. Ketamine and its enantiomers have shown rapid anti-suicidal effects in adults with major depressive disorder (MDD), but their efficacy in adolescents is unknown. We conducted an active, placebo-controlled trial to determine the safety and efficacy of intravenous esketamine in this population., Method: A total of 54 adolescents (aged 13-18 years) with MDD and suicidal ideation were included from an inpatient setting and randomly assigned (1:1) to receive 3 infusions of esketamine (0.25 mg/kg) or midazolam (0.02mg/kg) over 5 days, with routine inpatient care and treatment. Changes from baseline to 24 hours after the final infusion (day 6) in the scores of the Columbia Suicide Severity Rating Scale (C-SSRS) Ideation and Intensity (primary outcome) and the Montgomery-Åsberg Depression Rating Scale (MADRS, key secondary outcome) were analyzed using linear mixed models. In addition, the 4-week clinical treatment response was a key secondary outcome., Results: The mean changes in C-SSRS Ideation and Intensity scores from baseline to day 6 were significantly greater in the esketamine group than in the midazolam group (Ideation, -2.6 [SD = 2.0] vs -1.7 [SD = 2.2], p = .007; Intensity, -10.6 [SD = 8.4] vs -5.0 [SD = 7.4], p = .002), and the changes in MADRS scores from baseline to day 6 were significantly greater in the esketamine group than in the midazolam group (-15.3 [SD = 11.2] vs -8.8 [SD = 9.4], p = .004). The rates of antisuicidal and antidepressant responses at 4 weeks posttreatment were 69.2% and 61.5% after esketamine, and were 52.5% and 52.5% after midazolam, respectively. The most common adverse events in the esketamine group were nausea, dissociation, dry mouth, sedation, headache, and dizziness., Conclusion: These preliminary findings indicate that 3-dose intravenous esketamine, added to routine inpatient care and treatment, was an effective and well-tolerated therapy for treating adolescents with MDD and suicidal ideation., Clinical Trial Registration Information: A study to evaluate the efficacy and safety of Esketamine combined with oral antidepressants in the treatment of major depressive disorder with suicidal ideation; http://www.chictr.org.cn; ChiCTR2000041232., Diversity & Inclusion Statement: We worked to ensure that the study questionnaires were prepared in an inclusive way. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. We actively worked to promote sex and gender balance in our author group., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to investigate the effect of Esketamine (ESK) on the Hypoxia/Reoxygenation (H/R) injury of cardiomyocytes by regulating TRPV1 and inhibiting the concentration of intracellular Ca 2+ ., Methods: The H/R injury model of H9c2 cardiomyocytes was established after 4h hypoxia and 6h reoxygenation. H9c2 cells were treated with different concentrations of ESK or TRPV1 agonist capsaicin (10 μM) or TRPV1 inhibitor capsazepine (1 μM). Cell viability was detected by CCK-8 method, and apoptosis by flow cytometry. Intracellular Ca 2+ concentration was evaluated by Fluo-4 AM. LDH, MDA, SOD, and GSH-Px were detected with corresponding commercial kits. TRPV1 and p-TRPV1 proteins were detected by Western blot., Results: After H/R, H9c2 cell viability decreased, apoptosis increased, intracellular Ca 2+ concentration increased, LDH and MDA levels increased, SOD and GSH-Px levels decreased, and p-TRPV1 expression increased. ESK treatment rescued these changes induced by H/R. After up-regulating TRPV1, the protective effect of ESK on H/R injury of H9c2 cells was weakened, while down-regulating TRPV1 could further protect against H/R injury., Conclusion: ESK alleviates H/R injury of cardiomyocytes by regulating TRPV1 expression and inhibiting intracellular Ca 2+ concentration., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Background: LHPP was recently shown to be a risk gene for major depressive disorder. LHPP has been proven to dephosphorylate the residues of histidine, serine, threonine, and tyrosine. However, much remains unknown about how LHPP contributes to depression., Methods: In the current study, we addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing, and electrophysiology., Results: We found that levels of LHPP were upregulated in glutamatergic neurons of the ventral hippocampus in mice that displayed stress-induced depression-like behaviors. Knockout of LHPP in glutamatergic neurons of the brain improved the spontaneous activity of LHPP flox/flox ·CaMKIIαCre+ (conditional knockout) mice. Adeno-associated virus-mediated LHPP knockdown in the ventral hippocampus enhanced resistance against chronic social defeat stress in mice. Manipulations of LHPP levels impacted the density of dendritic spines and excitability of CA1 pyramidal neurons by mediating the expressions of BDNF (brain-derived neurotrophic factor) and PSD95 via the modulation of the dephosphorylation of CaMKIIα and ERK. Notably, compared with wild-type LHPP, human mutant LHPP (E56K, S57L) significantly increased the activity of the CaMKIIα/ERK-BDNF/PSD95 signaling pathway. Finally, esketamine, not fluoxetine, markedly alleviated the LHPP upregulation-induced depression-like behaviors., Conclusions: These findings provide evidence that LHPP contributes to the pathogenesis of depression via threonine and serine hydrolases, thereby identifying LHPP as a potential therapeutic target in treating patients with major depressive disorder., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention., Objective: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine., Methods: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE)., Results: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials., Conclusions: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT., Trial Registration: ClinicalTrials.gov Identifier NCT03887715., Competing Interests: Declaration of competing interest MAB, BJM, and CLK have no conflicts of interest to declare. CRC has received research support from the American Foundation for Suicide Prevention, Assurex Health, August Busch IV Foundation, Barnes-Jewish Hospital Foundation, LivaNova, National Institute of Mental Health, and the Taylor Family Institute for Innovative Psychiatric Research; consulted for LivaNova and Sage Therapeutics; and was a part-time employee at the John Cochran VA Medical Center in St. Louis. STA is a consultant to Genomind, LivaNova, Janssen, Neuronetics, and Sage Therapeutics; and has received research support from Compass Pathways and Neuronetics. HAS serves as a scientific adviser and receives consulting fees from Cerebral Therapeutics, Holmusk Technologies, LivaNova, MECTA Corporation, Neurolief, Neuronetics, Parow Entheobiosciences, and SigmaStim; receives honoraria and royalties from Elsevier and Oxford University Press; is the inventor of non-remunerative US patents for Focal Electrically Administered Seizure Therapy (FEAST), titration in the current domain in ECT, and the adjustment of current in ECT devices, each held by the SigmaStim Corporation; and is also the originator of Magnetic Seizure Therapy (MST). WD has consulted for Corium and Abbott; and has been on the LivaNova Advisory Board. MS is a Principal Investigator for Cassava Sciences, Eisai, Lilly, and LivaNova. JQ received clinical research support from LivaNova; has speaker bureau membership with Myriad Neuroscience and AbbVie; consultant for Eurofarma; stockholder at Instituto de Neurociencias; and receives copyrights from Artmed Editora, Artmed Panamericana, and Elsevier/Academic Press. RMA is one of the owners of a multi-site interventional psychiatry and clinical trials company, Seattle Neuropsychiatric Treatment Center; receives research funding from LivaNova and Compass Pathways; and previously received research funding from Alto Neuroscience. PR-P is a consultant for LivaNova, Janssen Pharmaceuticals, MotifNeuro, and Abbott Neuromodulation. GA receives Research Support from AbbVie, Accera, Axsome, Axovant, Biogen, Eisai, Eli-Lily, Neurotrope, Genentech, Intra Cellular, Janssen, Lundbeck, Neurim, Novartis, Otsuka, Roche, Sage, Suven, and Trans Tech; and is on the Speakers Bureau and Consultant for AbbVie, Acadia, Alkermes, Axsome, Biogen, Janssen, Idorsia, Lundbeck, Myriad, Neurocrine, Nestle, Otsuka, Sage, Sunovion, Teva and Takeda. MAM has received research support and/or speaker honoraria from Axsome, AbbVie, Alkermes, Intracellular, Janssen, Neurocrine, Otsuka, and Teva. DLD receives payment for clinical services for a former research patient from LivaNova; speaker for Janssen (esketamine nasal spray); and conducts forensic consultations, independent medical evaluations, and legal testimony for various firms. IC is co-owner of Mindful Behavioral Health, PLLC and receives speaker fees from Johnson and Johnson (Janssen). HL has received consulting and/or speaking fees from Alkermes, Axsome, Intracellular, Janssen, Karuna, Sage, and Teva; and conducts forensic consultations, independent medical evaluations, and legal testimony for various firms and co-owns Florida Center for TMS. JZ receives research support from Boehringer-Ingelheim, Compass Pathways, Hoffman-LaRoche, Johnson and Johnson (Janssen), LivaNova, Otsuka, Neurocrine Bioscience, and Sage Therapeutics; and received consulting fees from Alphasigma USA and Johnson and Johnson (Janssen). ZN is a consultant to LivaNova, Magnus Medical, and Motif; and has also received research support from LivaNova. ASK has received research support from Alto Neuroscience, Axial Therapeutics, BEAM Diagnostics, Curemark, Gilead Sciences, Liva Nova, and the National Institutes of Health. MTB is a former employee and a current consultant of LivaNova. Y-CL and OS are employees of LivaNova. SM, BO, and QT are employees of LivaNova and hold stock options. AJR has received consulting fees from Compass, Curbstone Consultant, Emmes, Evecxia Therapeutics, Holmusk Technologies, ICON, Johnson and Johnson (Janssen), LivaNova, MindStreet, Neurocrine Biosciences, Otsuka-US; speaking fees from LivaNova, Johnson and Johnson (Janssen), and Wolters Kluwer Health; royalties from Guilford Press and UT Southwestern Medical Center (for the Inventory of Depressive Symptoms and its derivatives); named co-inventor on US Patent 7,795,033 (Methods to Predict the Outcome of Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S, Wilson AS) and US Patent 7,906,283 (Methods to Identify Patients at Risk of Developing Adverse Events During Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Delayed emergence from general anaesthesia poses a significant perioperative safety hazard. Subanaesthetic doses of ketamine not only deepen anaesthesia but also accelerate recovery from isoflurane anaesthesia; however, the mechanisms underlying this phenomenon remain elusive. Esketamine exhibits a more potent receptor affinity and fewer adverse effects than ketamine and exhibits shorter recovery times after brief periods of anaesthesia. As the paraventricular thalamus (PVT) plays a pivotal role in regulating wakefulness, we studied its role in the emergence process during combined esketamine and isoflurane anaesthesia., Methods: The righting reflex and cortical electroencephalography were used as measures of consciousness in mice during isoflurane anaesthesia with coadministration of esketamine. The expression of c-Fos was used to determine neuronal activity changes in PVT neurones after esketamine administration. The effect of esketamine combined with isoflurane anaesthesia on PVT glutamatergic (PVT Glu ) neuronal activity was monitored by fibre photometry, and chemogenetic technology was used to manipulate PVT Glu neuronal activity., Results: A low dose of esketamine (5 mg kg -1 ) accelerated emergence from isoflurane general anaesthesia (474 [30] s vs 544 [39] s, P=0.001). Esketamine (5 mg kg -1 ) increased PVT c-Fos expression (508 [198] vs 258 [87], P=0.009) and enhanced the population activity of PVT Glu neurones (0.03 [1.7]% vs 6.9 [3.4]%, P=0.002) during isoflurane anaesthesia (1.9 [5.7]% vs -5.1 [5.3]%, P=0.016) and emergence (6.1 [6.2]% vs -1.1 [5.0]%, P=0.022). Chemogenetic suppression of PVT Glu neurones abolished the arousal-promoting effects of esketamine (459 [33] s vs 596 [33] s, P<0.001)., Conclusions: Our results suggest that esketamine promotes recovery from isoflurane anaesthesia by activating PVT Glu neurones. This mechanism could explain the rapid arousability exhibited upon treatment with a low dose of esketamine., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Intraoperative opioid use has a positive relationship with postoperative nausea and vomiting (PONV), and opioid-free anaesthesia (OFA) might reduce PONV. We investigated whether OFA compared with opioid-based anaesthesia would reduce PONV during the first 2 postoperative days among patients undergoing thoracoscopic lung resection., Methods: In this randomised controlled trial, 120 adult patients were randomly assigned (1:1, stratified by sex) to receive either OFA with esketamine, dexmedetomidine, and sevoflurane, or opioid-based anaesthesia with sufentanil and sevoflurane. A surgical pleth index (SPI) of 20-50 was applied for intraoperative analgesia provision. All subjects received PONV prophylaxis (dexamethasone and ondansetron) and multimodal analgesia (flurbiprofen axetil, ropivacaine wound infiltration, and patient-controlled sufentanil). The primary outcome was the occurrence of PONV during the first 48 h after surgery., Results: The median age was 53 yr and 66.7% were female. Compared with opioid-based anaesthesia, OFA significantly reduced the incidence of PONV (15% vs 31.7%; odds ratio [OR]=0.38, 95% confidence interval [CI], 0.16-0.91; number needed to treat, 6; P=0.031). Secondary and safety outcomes were comparable between groups, except that OFA led to a lower rate of vomiting (OR=0.23, 95% CI, 0.08-0.77) and a longer length of PACU stay (median difference=15.5 min, 95% CI, 10-20 min). The effects of OFA on PONV did not differ in the prespecified subgroups of sex, smoking status, and PONV risk scores., Conclusions: In the context of PONV prophylaxis and multimodal analgesia, SPI-guided opioid-free anaesthesia halved the incidence of PONV after thoracoscopic lung resection, although it was associated with a longer stay in the PACU., Clinical Trial Registration: Chinese Clinical Trial Registry (ChiCTR2200059710)., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Introduction: Treatment-resistant depression (TRD) is a serious and debilitating psychiatric disorder that frequently affects older patients. Esketamine nasal spray (ESK-NS) has recently been approved as a treatment for TRD, with multiple studies establishing its efficacy and tolerability. However, the real-world effectiveness, tolerability, and safety of this treatment in older adults is still unclear., Objectives: To evaluate the efficacy and tolerability of ESK-NS in older subjects with TRD., Methods: This is a post-hoc analysis of the REAL-ESK study, a multicenter, retrospective, observational study. Participants here selected were 65 years or older at baseline. The Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A) were used to assess depressive and anxiety symptoms, respectively. Data were collected at three-time points: baseline, 1 month after the start of treatment (T1), and 3 months after treatment (T2)., Results: The sample included older adults with TRD (n = 30). MADRS and HAM-A values decreased significantly at T1 (T0 versus T1: p holm <0.001, Cohen's d = 0.840) and T2 follow-ups (T0 versus T2: p holm <0.001, Cohen's d = 1.419). At T2, 53.3% of subjects were responders (MADRS score reduced ≥50%), while 33.33% were in remission (MADRS<10). ESK-NS-related adverse effects were in order of frequency dizziness (50%), followed by dissociation (33.3%), sedation (30%), and hypertension (13.33%). Six out of 30 participants (20%) discontinued treatment., Conclusions: Our findings provide preliminary evidence of ESK-NS effectiveness in older adults with TRD, a highly debilitating depressive presentation. Furthermore, we observe high levels of treatment-emergent adverse events, which, in the majority of instances, did not require treatment suspension., Competing Interests: DISCLOSURES Giovanni Martinotti has been a consultant and/or a speaker and/or has received research grants from Angelini, Doc Generici, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, Neuraxpharm, Rovi, and Recordati. Giorgio Di Lorenzo has been a speaker and / or a consultant for Angelini, Janssen-Cilag, Livanova, Lundbeck, Neuraxpharm, Otsuka, and Recordati. Dr. Roger McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is the CEO of Braxia Scientific Corp. The remaining authors declare that the research was conducted without any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Esketamine, the S-enantiomer of ketamine, has recently emerged as a therapy for treatment-resistant depression (TRD), showing both rapid antidepressant action and good efficacy and high safety. It is also indicated for the acute short-term treatment of psychiatric emergency due to major depressive disorder (MDD) and for depressive symptoms in adults with MDD with acute suicidal thoughts/behavior. We here provide preliminary insights on esketamine nasal spray (ESK-NS) effectiveness and safety among patients with a substance use disorder (SUD) within the sample of patients with TRD collected for the observational, retrospective, multicentre REAL-ESK study. Twenty-six subjects were retrospectively selected according to the presence of a SUD in comorbidity. Subjects enrolled completed the three different follow-up phases (T0/baseline, T1/after one month, and T2/after three months) and there were no dropouts. A decrease in Montgomery-Asberg depression rating scale (MADRS) scores was recorded, thus highlighting the antidepressant efficacy of ESK-NS (MADRS decreased from T0 to T1, t = 6.533, df=23, p<0.001, and from T1 to T2, t = 2.029, df=20, p = 0.056). Considering tolerability and safety issues, one or more side effects were reported by 19/26 subjects (73%) after treatment administration. All reported side effects were time-dependent and did not cause significant sequelae; among them, dissociative symptoms (38%) and sedation (26%) were the most frequently reported. Finally, no cases of abuse or misuse of ESK-NS were reported. Despite study limitations related to the inherent nature of the study, a limited number of patients, and a short follow-up period, ESK-NS showed to be effective and safe in patients diagnosed with TRD comorbid with a SUD., Competing Interests: Declaration of Competing Interest Giovanni Martinotti has been a consultant and/or a speaker and/or has received research grants from Angelini, Doc Generici, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Recordati. Ileana Andriola was speaker at Janssen-sponsored conferences. Bernardo Dell'Osso has received lecture honoraria from Angelini, Lundbeck, Janssen, Pfizer, Neuraxpharm, Arcapharma, and Livanova. Antonio Vita received grant/research support and speaker/consultant fees from Angelini, Boheringer Ingelheim, Innovapharma, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Recordati, Roche, Rovi Pharma, and Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Patients often experience severe pain after scoliosis correction surgery. Esketamine and dexmedetomidine each improves analgesia but can produce side-effects. We therefore tested the hypothesis that a mini-dose esketamine-dexmedetomidine combination safely improves analgesia., Methods: Two hundred male and female adults having scoliosis correction surgery were randomised to patient-controlled sufentanil analgesia (4 μg kg -1 in normal saline) with either a combined supplement (esketamine 0.25 mg ml -1 and dexmedetomidine 1 μg ml -1 ) or placebo. The primary outcome was the incidence of moderate-to-severe pain within 72 h, defined as a numeric rating scale (NRS: 0=no pain and 10=worst pain) score ≥4 at any of seven time points. Amongst secondary outcomes, subjective sleep quality was assessed with an NRS score (0=best sleep and 10=worst sleep) for the first five postoperative nights., Results: There were 199 subjects included in the intention-to-treat analysis. Mean infusion rates were 5.5 μg kg -1 h -1 for esketamine and 0.02 μg kg -1 h -1 for dexmedetomidine. The primary outcome incidence was lower with the combined supplement (65.7% [65/99]) than with placebo (86.0% [86/100]; relative risk 0.76; 95% confidence interval: 0.65-0.90; P=0.001). Subjects given the combined supplement had lower pain intensity at rest at five time points (median difference -1 point; P≤0.005), lower pain intensity with movement at six time points (median difference -1 point; P≤0.001), and better subjective sleep quality for the first 5 postoperative nights (median difference -2 to -1 points; P<0.001). Adverse events did not differ between groups., Conclusions: The mini-dose esketamine-dexmedetomidine combination safely improved analgesia and subjective sleep quality after scoliosis correction surgery., Clinical Trial Registration: NCT04791059., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: N-methyl-d-aspartate receptor (NMDAR) antagonist antidepressants have known potential for abuse liability. The aim of this study was to evaluate the abuse liability of D-cycloserine (DCS), using a self-administration paradigm in which DCS was tested for its efficacy in substituting for ketamine in ketamine-dependent rats., Methods: A standard intravenous self-administration study was conducted in male adult Sprague-Dawley rats to study abuse liability. Potential for self-administration was assessed in ketamine-habituated subjects. Subjects were trained to press a lever to obtain food, prior to connection of the lever to the intravenous drug administration apparatus. DCS was provided for self-infusion by test subjects at doses of 1.5, 5.0, and 15 mg/kg per lever press., Results: S-ketamine was seen to substitute for ketamine and to result in self-administration at the same frequency. DCS was not seen to result in self-administration at any of the test doses. The self-infusion behavior of DCS was similar to control (saline)., Conclusion: D-cycloserine, a partial agonist of the NMDAR glycine site, which has been shown to have antidepressant and anti-suicidal properties in clinical studies, has no apparent potential for abuse liability in a standard rodent self-administration model., Competing Interests: Declaration of competing interest JCJ owns equity in NRx Pharmaceuticals and derives compensation from NRx pharmaceuticals., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Ketamine and esketamine, the S-enantiomer of the racemic mixture, have recently generated considerable interest as potential therapeutic agents for Treatment-Resistant Depression (TRD), a complex disorder that includes various psychopathological dimensions and distinct clinical profiles (e.g., comorbid personality disorder, bipolar spectrum, dysthymic disorder). This perspective article provides a comprehensive overview of the action of ketamine/esketamine from a dimensional point of view, taking into account the high prevalence of bipolarity in TRD and the evidence of the efficacy of these substances on mixed features, anxiety, dysphoric mood, and, generally, bipolar traits. Additionally, the article underscores the complexity of the pharmacodynamic mechanisms of action of ketamine/esketamine, which goes beyond the non-competitive antagonism of NMDA-R. The need for further research and evidence is highlighted, mainly to evaluate the efficacy of esketamine nasal spray in bipolar depression, the presence of bipolar elements as a predictor of response, and the potential role of these substances as mood stabilizers. The article implies that, in the future, ketamine/esketamine could be used with fewer limitations, not only as antidepressants for the most severe form of depression but also as valuable tools to stabilize subjects with mixed symptoms or bipolar spectrum., Competing Interests: Conflict of interest Giorgio Di Lorenzo has been a speaker and / or a consultant for Angelini, Livanova, Lundbeck, Neuraxpharm, Otsuka, and Recordati. Dr. Roger McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is the CEO of Braxia Scientific Corp. Giovanni Martinotti has been a consultant and/or a speaker and/or has received research grants from Angelini, Doc Generici, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Recordati. The remaining authors declare that the research was conducted without any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)