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Background: The new coronavirus disease 2019 (COVID-19), caused by a virus in the coronavirus family called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to lack of effective treatment, the major way to breakdown the disease transmission is by application of preventive measures. For this, a preventive practice questionnaire was used to assess the preventive practice during COVID-19. A definite advantage of this questionnaire is its ability to identify individual level preventive practices. The objective of the study was to validate the Nepali version of Questionnaire to assess preventive practices against the COVID-19 pandemic in the General population. Methods: A web-based descriptive cross-sectional study was conducted from November 2022 to April 2023 using preventive practices against the COVID-19 pandemic questionnaire and was conducted among 351 respondents. The sensitivity and specificity of the questionnaire were calculated for validation. The best cutoff point for the Nepalese version of the questionnaire was identified and the area under the receiver operating characteristic curve (AUC) was calculated. Results: The overall prevalence of good preventive practices was 90.6%. The best cutoff points for the Nepali version of the questionnaire were 93% sensitivity and 67% specificity, respectively at a cutoff level of 47/48. The area under the curve was 0.859. Thus, the Nepalese version of the questionnaire concerning preventive practices during the COVID-19 pandemic in the general population had an accuracy of 85.9% (95% CI 0.757–0.961, p = 0.001). Conclusion: The Nepalese version of the questionnaire on preventive practices during the COVID-19 pandemic in the general population can be successfully used as a survey tool. These findings might help to detect appropriate adherence to preventive practices can be achieved in busy outpatient departments. Detecting adherence to preventive practices may help local health authorities and policymakers in identifying specific populations for future awareness campaigns during infectious disease outbreaks. [ABSTRACT FROM AUTHOR]

Psychedelics have recently (re)emerged as therapeutics of high potential for multiple mental health conditions, including substance use disorders (SUDs). Despite early mid-20th century anecdotal reports and pilot studies demonstrating the possibility of these substances in efficaciously treating conditions such as alcohol and opioid use disorders, legal restrictions and social stigma have historically hindered further research into this area. Nevertheless, concurrent with the rise in SUDs and other mental health conditions, researchers have again turned their attention to these compounds, searching for differing pharmacological targets as well as more holistic treatments that might increase patient adherence and efficacy. The aim of this review is to examine the emerging evidence-based data with regards to the therapeutic treatment of SUDs with the psychedelic compounds psilocybin, ketamine, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), ayahuasca, ibogaine and peyote. [ABSTRACT FROM AUTHOR]

Aims: Diabetes has been indicated to be a risk factor for suicide. We aim to estimate the prevalence of suicide in patients with diabetes. Design: A meta‐analysis using PRISMA methodology was adopted to examine the incidence of suicide in diabetic patients. Data Sources: From inception to October 2022, three online databases (PubMed, China National Knowledge Infrastructure and Web of Science) were used to search studies. Review Methods: We used random‐effects model to analysis. And our primary outcome was the incidence of suicide death per 100 person‐years, and other outcomes were prevalence of suicidal ideation and suicide attempt. To explore the sources of heterogeneity in our study, we performed subgroup and meta‐regression analyses. Results: The suicide death rate in diabetic patients was 0.027 per 100 person‐years, with a higher rate for Type 1 Diabetes Mellitus compared to Type 2 Diabetes Mellitus. The prevalence of suicidal ideation in diabetes patients was 0.175, with a higher prevalence in Type 1 Diabetes Mellitus compared to Type 2 Diabetes Mellitus. The prevalence of suicide attempts in diabetes patients was 0.033, indicating a higher rate for Type 2 Diabetes Mellitus compared to Type 1 Diabetes Mellitus. Conclusions: The results indicate a high rate of suicide among people with diabetes, and this study identifies populations and regions at high risk for suicide. Our review emphasizes interventions in mental health and the improvement of suicide prevention programmes. Impact: The study investigated suicide death, suicidal ideation and suicide attempt in diabetic individuals.Suicide rates are elevated among diabetic patients, and various patient groups face distinct suicide risks.It is important to prioritize the mental well‐being of diabetic individuals and enhance interventions, including personalized approaches, to inform public health efforts aimed at preventing and addressing suicide among diabetic patients. Patient or Public Contribution: No patient or public involvement. [ABSTRACT FROM AUTHOR]

Introduction: Major depressive disorder (MDD), postpartum depression (PPD), and insomnia are neuropsychological conditions in which zuranolone is used to improve symptoms and prognosis of the disorder. This meta-analysis aimed to determine the efficacy of zuranolone in comparison to other drugs used for treating these conditions. Methods: This meta-analysis included patients aged between 18 and 75 years who were diagnosed with major depressive disorder and postpartum depression with or without insomnia and were administered zuranolone for treatment. Only randomized controlled trials (RCTs) were included, and animal studies were excluded. The databases used were PubMed, Scopus, Cochrane, and Clinicaltrials.gov, with MeSH terms and relevant keywords for (Zuranolone) and (Depression). The Cochrane risk of bias tool was used for quality assessment. Results: The meta-analysis included eight RCTs that analyzed data from 2031 patients. The meta-analysis revealed statistically significant changes in the Hamilton Depression Rating Scale (HAM-D), Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), and treatmentemergent adverse effects (TEAE) scores in the PPD subgroup. HAM-D and TEAEs scores were also significant in the MDD subgroup, but the changes in the MADRS, HAM-A, and Bech-6 scores were insignificant. Serious adverse events were insignificant in all subgroups. Conclusion: Meta-analysis found a significant improvement in depressive symptoms with zuranolone treatment, especially on day 15. This suggests that zuranolone is a promising therapeutic option for patients with MDD and PPD with or without insomnia. [ABSTRACT FROM AUTHOR]

ABSTRACT: Background: Depression is a common illness that affects about 3.8% of the population worldwide. Patients with major depression respond to antidepressant treatment, but 10%–20% of them do not improve or show a partial response. It is coupled with functional impairment, poor quality of life, suicide ideation and attempts, self-injurious behavior, and a high relapse rate. Treatment-resistant depression (TRD) is a challenge to clinicians because of its increased loss of functionality and the increased rate of suicide among people diagnosed with the illness. Studies are evolving to combine various treatment options to reduce morbidity and mortality in people suffering from the illness. This study aims at comparing the efficacy of electroconvulsive therapy (ECT) and ketamine transfusion in treating TRD. It hopes to prove that ketamine provides rapid relief for people suffering from TRD. Materials and Methods: A prospective, parallel randomized controlled, open label, noninferiority/superiority trial to compare the efficacy of ECT and ketamine was done. Ninety-six persons suffering from TRD were selected for the study through proportionate stratified random sampling and 46 persons received 6 ECT treatment and 50 persons received six doses of ketamine. Treatment response was measured using Hamilton depression ratings scale (HAM-D) using baseline, mid assessment, and postassessment scores. The scores were used to determine the effectiveness of ECT and ketamine in the treatment of TRD. Results: Ketamine was proven to have the same antidepressant effect in participants as that of ECT. Ketamine was observed to have rapid reduction in depressive symptoms when compared to ECT. Conclusion: This study highlights that ketamine can be considered as an effective alternative to ECT in those with TRD. [ABSTRACT FROM AUTHOR]

Background: Alcohol use disorder (AUD) is a major public health issue, posing harmful consequences for individuals and society. Recent advances in addiction research have highlighted the therapeutic potential of ketamine-assisted therapy for AUD. However, the exact mechanisms underlying its effectiveness remain unknown. Aims: This double-blind, pilot study aimed to investigate esketamine combined with mindfulness-based intervention (MBI) to examine whether esketamine enhances engagement in MBI for individuals with alcohol misuse problems and whether enhanced engagement has any impact on alcohol-related outcomes. Methods: In all, 28 individuals with alcohol problems were randomly assigned to receive sublingual esketamine hydrochloride (AWKN002: 115.1 mg) or vitamin C (placebo) in an oral thin film and took part in 2 weeks of daily MBI. Participants were assessed on various self-report measures, including mindfulness, engagement in MBI (physical and psychological), alcohol cravings and consumption. Results: Esketamine enhanced psychological engagement with a daily MBI, compared to placebo, and led to transient decreases in alcohol cravings. Esketamine also resulted in significantly greater mystical experiences and dissociative states compared to placebo. Conclusions: The findings suggest that esketamine may improve treatment outcomes when combined with mindfulness-based therapies through its ability to increase engagement with meditative practice. [ABSTRACT FROM AUTHOR]

Introduction and aims: Treatment-resistant depression (TRD) occurs when at least two different antidepressants, taken at the right dosage, for adequate period of time and with continuity, fail to give positive clinical effects. Esketamine, the Senantiomer of ketamine, was recently approved for TRD treatment from U.S. Food and Drug Administration and European Medicine Agency. Despite proved clinical efficacy, many misconceptions by clinicians and patients accompany this medication. We aimed to review the most common “false myths” regarding TRD and esketemine, counterarguing with evidence-based facts. Methods: The keywords “esketamine”, “treatment resistance depression”, “depression”, “myth”, “mythology”, “pharmacological treatment”, and “misunderstanding” were entered in the main databases and combined through Boolean operators. Results: Misconceptions regarding the TRD prevalence, clinical features and predictors have been found. With respect of esketamine, criteria to start treatment, dissociative symptoms, potential addiction and aspects of administration and monitoring, were found to be affected by false beliefs by clinicians and patients. Discussion and conclusion: TRD represents a challenging condition, requiring precise diagnosis in order to achieve patient’s full recovery. Esketamine has been proved as an effective medication to treat TRD, although it requires precautions. Evidence can inform clinical practice, in order to offer this innovative treatment to all patients with TRD. [ABSTRACT FROM AUTHOR]

Ketamine displays efficacious rapid-acting antidepressant (RAAD) activity in the rat chronic mild stress (CMS) model. It rapidly reverses anhedonia (CMS-induced sucrose consumption deficit) and attenuates working memory deficit (novel object recognition: NOR) following both systemic (intraperitoneal, i.p.) administration or local administration in the prefrontal cortex (PFC). However, the receptor mechanisms underlying these effects remain to be clarified and may involve activation of serotonin 5-HT1A receptors, as previously found in experiments using the forced swim test. The present study explored the contribution of PFC 5-HT1A receptors in ketamine's RAAD activity in the CMS model. Ketamine (10 mg/kg i.p.) reversed CMS-induced sucrose consumption and working memory (NOR test) deficits. Notably, unilateral PFC microinjections of a 5-HT1A receptor antagonist, WAY-100635 (2 µg), prevented the antidepressant-like and pro-cognitive activity of systemic ketamine on sucrose consumption and working memory deficits. These data indicate that the RAAD activity of ketamine in the rat CMS model requires activation of PFC 5-HT1A receptors. They also reinforce the notion that drugs that directly activate PFC 5-HT1A receptors could constitute an alternative to ketamine as a promising strategy to achieve RAAD effects, with additional benefits against cognitive deficits in depressed patients, but without ketamine's troublesome side-effects and requirements for in-patient supervision., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Though intravenous (IV) ketamine and intranasal (IN) esketamine are noted to be efficacious for treatment-resistant depression (TRD), access to each of these treatments within healthcare systems is limited due to cost, availability, and/or monitoring requirements. IV ketamine has been offered at two public hospital sites in Edmonton, Canada since 2015. Since then, demand for maintenance ketamine treatments has grown. This has required creative solutions for safe, accessible, evidence-based patient care. Objectives: Aims of this paper are twofold. First, we will provide a synthesis of current knowledge with regards to the clinical use of ketamine for TRD. Consideration will be given regarding; off-label racemic ketamine uses versus FDA-approved intranasal esketamine, populations treated, inclusion/exclusion criteria, dosing, assessing clinical response, concomitant medications, and tolerability/safety. Second, this paper will describe our experience as a community case study in applying evidence-based treatment. We will describe application of the literature review to our clinical programming, and in particular focus on cost-effective maintenance treatments, long-term safety concerns, routes of ketamine administration other than via intravenous, and cautious prescribing of ketamine outside of clinically monitored settings. Methodology: We conducted a literature review of the on the use of ketamine for TRD up to June 30, 2023. Key findings are reviewed, and we describe their application to our ketamine program. Conclusion: Evidence for the use of ketamine in resistant depression has grown in recent years, with evolving data to support and direct its clinical use. There is an increasing body of evidence to guide judicious use of ketamine in various clinical circumstances, for a population of patients with a high burden of suffering and morbidity. While large-scale, randomized controlled trials, comparative studies, and longer-term treatment outcomes is lacking, this community case study illustrates that currently available evidence can be applied to real-world clinical settings with complex patients. As cost is often a significant barrier to accessing initial and/or maintenance IV or esketamine treatments, public ketamine programs may incorporate SL or IN ketamine to support a sustainable and accessible treatment model. Three of such models are described. [ABSTRACT FROM AUTHOR]

Aberrant brain‐derived neurotrophic factor (BDNF) signaling has been proposed to contribute to the pathophysiology of depression and other neurological disorders such as Angelman syndrome. We have previously shown that targeting the tropomyosin receptor kinase B/postsynaptic density protein‐95 (PSD‐95) nexus in the BDNF signaling pathway by peptidomimetic inhibitors is a promising approach for therapeutic intervention. Here, we used structure‐based knowledge to develop a new Syn3 peptidomimetic compound series that fuses peptides derived from the PSD‐95‐binding protein SynGAP to our prototype compound CN2097. The new compounds target the PSD‐95 PDZ3 domain and adjoining αC helix to achieve bivalent binding that results in up to 7‐fold stronger affinity compared to CN2097. These compounds were designed to improve CN2097 specificity for the PSD‐95 PDZ3 domain, and structure–activity relationship studies were performed to improve their resistance to proteolysis. [ABSTRACT FROM AUTHOR]

Introduction: The WHO has now declared COVID-19 as endemic and it may be prudent to identify high-risk patients requiring reverse transcriptase-polymerase chain reaction (RT-PCR). During the pandemic, RT-PCR testing and reporting were running around-the-clock. We attempted to validate this scoring system and predict high probable in the obstetric subpopulation based on a modified early warning scoring system (EWSS) score. Materials and Methods: Data were collected from case sheets of pregnant women who were admitted to the obstetrics and gynecology department, according to the EWSS protocol. All the criteria mentioned in the EWSS score were tabulated in an Excel sheet. A modified list of signs, symptoms, and investigations was correlated with RT-PCR. This model obtained was validated with appropriate statistical tests. Patients who had undergone lower-segment cesarean section had hypertension (HTN), and diabetes as comorbidities and were included in the scoring system. Results: The odds ratio of the patient being positive was 3.56 with diabetes mellitus and 0.93 with HTN, most presented with minor symptoms such as expectoration, sore throat, dyspnea, and anosmia and these had odds ratio of 7.03, 12.68, 4.24, and 2.45, respectively, but the confidence interval was very wide. In laboratory investigations, C-reactive protein (CRP) and lactate dehydrogenase (LDH) elevations were found commonly and the odds ratio was 16.09 and 8.78, respectively. Conclusion: We concluded that if a pregnant woman presents with a sore throat, expectoration, dyspnea, or anosmia and presents with raised CRP and LDH with diabetes as a comorbidity there is a very high probability that the patient may have COVID-19 and needs to be tested or isolated. [ABSTRACT FROM AUTHOR]

Objectives: NLX-101 and NLX-204 are highly selective serotonin 5-HT1A 'biased' agonists, displaying potent and efficacious antidepressant-like activity upon acute administration in models such as the forced swim test. Methods: we compared the effects of repeated administration of NLX-101, NLX-204 and ketamine in the chronic mild stress (CMS) model of depression, considered to have high translational potential, on sucrose consumption (anhedonia measure), novel object recognition (NOR; working memory measure) and elevated plus maze (EPM; anxiety measure) in male Wistar and Wistar-Kyoto rats (the latter being resistant to classical antidepressants). Results: in Wistar rats, NLX-204 and NLX-101 (0.08–0.16 mg/kg i.p.), like ketamine (10 mg/kg i.p.) dose-dependently reversed CMS-induced sucrose intake deficit from treatment Day 1, with nearly full reversal observed at the higher dose at Days 8 and 15. These effects persisted for 3 weeks following treatment cessation. In the NOR test, both doses of NLX-101/NLX-204, and ketamine, rescued the deficit in discrimination index caused by CMS on Days 3 and 17; all three compounds increased time spent in open arms (EPM) but only NLX-204 achieved statistical significance on Days 2 and 16. In Wistar-Kyoto rats, all 3 compounds were also active in the sucrose test and, to a lesser extent, in the NOR and EPM. In non-stressed rats (both strains), the three compounds produced no significant effects in all tests. Conclusions: these observations further strengthen the hypothesis that biased agonism at 5-HT1A receptors constitutes a promising strategy to achieve rapid-acting/sustained antidepressant effects combined with activity against TRD, in addition to providing beneficial effects against memory deficit and anxiety in depressed patients. [ABSTRACT FROM AUTHOR]

Rationale: The intravenous anesthetic propofol is known to induce positive mood effects during routine clinical use, suggesting it might be repurposed as an antidepressant, but also raising concerns about abuse potential. How propofol's acute effects vary by dose and with repeated infusions is unknown., Objectives: This exploratory analysis aimed to (1) compare the immediate mood effects of propofol administered at two different doses, (2) describe how those mood effects change with repeated infusions, and (3) evaluate whether acute mood improvement predicts later antidepressant response., Methods: Twenty-four adults with moderate-to-severe treatment-resistant depression were randomized into two dosing groups. Six low- or high-dose propofol infusions were administered under blinded conditions over a two-week period. Self-reported mood states were recorded before and after each infusion using the Positive and Negative Affect Schedule (PANAS-X). Abuse potential was evaluated with the Drug Effects Questionnaire (DEQ-5)., Results: At the first infusion, propofol induced acute improvements in PANAS-X Sadness, Fear, Joviality, and Serenity scales (p < 0.002), independent of dose. Over the series of six infusions, acute changes in Sadness, Fear, and Joviality, but not Serenity, diminished with infusion number (p < 0.002). The DEQ-5 "want more" rating decreased across infusions (p = 0.002). Changes in PANAS-X scales with the first infusion did not predict later improvement in depression severity (p > 0.05)., Conclusion: Cumulative changes in mood states observed with repeated infusions suggest that propofol engages adaptive mechanisms in mood circuitry. Subjective responses with repeated infusions do not indicate increasing potential for abuse in this patient population., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The United States is entering its fourth decade of the opioid epidemic with no clear end in sight. At the center of the epidemic is an increase in opioid use disorder (OUD), a complex condition encompassing physical addiction, psychological comorbidities, and socioeconomic and legal travails associated with the misuse and abuse of opioids. Existing behavioral and medication-assisted therapies show limited efficacy as they are hampered by lack of access, strict regimens, and failure to fully address the non-pharmacological aspects of the disease. A growing body of research has indicated the potential of hallucinogens to efficaciously and expeditiously treat addictions, including OUD, by a novel combination of pharmacology, neuroplasticity, and psychological mechanisms. Nonetheless, research into these compounds has been hindered due to legal, social, and safety concerns. This review will examine the preclinical and clinical evidence that psychoplastogens, such as ibogaine, ketamine, and classic psychedelics, may offer a unique, holistic alternative for the treatment of OUD while acknowledging that further research is needed to establish long-term efficacy along with proper safety and ethical guidelines. [ABSTRACT FROM AUTHOR]

Investigations on the occurrence and biochemical roles of free D‐amino acids and D‐amino acid‐containing peptides and proteins in living systems have increased in frequency and significance. Their occurrence and roles may vary substantially with progression from microbiotic to evermore advanced macrobiotic systems. We now understand many of the biosynthetic and regulatory pathways, which are outlined herein. Important uses for D‐amino acids in plants, invertebrates, and vertebrates are reviewed. Given its importance, a separate section on the occurrence and role of D‐amino acids in human disease is presented. [ABSTRACT FROM AUTHOR]

Background: Ketamine is an emerging treatment for treatment-resistant depression (TRD) associated with rapid and robust improvements in depressive symptoms and suicidality. However, the efficacy and safety of ketamine in transitional age youth (TAY; age 18–25) populations remains understudied. Methods: In this retrospective analysis, TAY patients (n = 52) receiving ketamine for TRD were matched for sex, primary diagnosis, baseline depression severity, and treatment resistance with a general adult (GA) sample (age 30–60). Patients received four ketamine infusions over 2 weeks (0.5–0.75 mg/kg over 40 min). The primary outcome was the change in Quick Inventory of Depressive Symptomatology Self-Report 16-item (QIDS-SR16) over time. Secondary outcomes were changes in QIDS-SR16 suicidal ideation (SI) item, anxiety (Generalized Anxiety Disorder 7-item (GAD-7)), and adverse effects (ClinicalTrials.gov: NCT04209296). Results: A significant main effect of infusions on reduction of total QIDS-SR16 (p < 0.001), QIDS-SR16 SI (p < 0.001), and GAD-7 (p < 0.001) scores was observed in the TAY group with moderate effect sizes, indicative of clinically significant improvements in depression, anxiety, and suicidality. There were no significant differences between TAY and GA groups on these measures over time, suggesting comparable improvements in both groups. Safety and tolerability outcomes were comparable between groups with only mild, transient adverse effects observed. Conclusion: Ketamine was associated with comparable clinical benefits, safety, and tolerability in a TAY sample as compared to a matched GA TRD sample. [ABSTRACT FROM AUTHOR]

Background: Depression is a common mental illness with a complex etiology and is one of the leading causes of disability worldwide, affecting around 10-20% of the general population in their lifetime. Ketamine, a glutamate receptor–blocking drug approved by the U.S. Food and Drug Administration for anesthetic use, has become a target of research for its antidepressant effects, and possible anti-suicidal effects. Aim: To study the effect of subanesthetic dose of ketamine on severity of Depression and Anxiety at 1 hour, 1 week and 1 month post administration. Materials and Methods: A total of 17 patients with severe depression were admitted for the study. Assessments were made at baseline and injection was given at a subanesthetic dose of 0.5 mg/kg intravenous infusion after preparation. Assessments were repeated 1 h after the first dose and patients were followed up and assessments were made at 1 week and 1 month post infusion. Results: There was a significant improvement in the severity of depression, anxiety, after 1 hour post infusion which was maintained till 1 week and 1 month post infusion. Significant reduction in suicidal thoughts was seen at 1 hour post infusion of the first dose and no emergence was seen at 1 week and 1 month follow up. There were transient adverse effects observed in some patients which subsided within 1 hour. Conclusion: Ketamine had a rapid effect on alleviating the symptoms of depression and the effect was maintained till 1 month. [ABSTRACT FROM AUTHOR]

Background: Ketamine is increasingly used for treatment-resistant depression (TRD) while its mechanism of action is still being investigated. In this systematic review, we appraise the current evidence of metabolomic biomarkers for racemic ketamine and esketamine in patients with TRD and healthy controls (HCs)., Methods: A comprehensive search of several databases (Ovid MEDLINE®, Embase, and Epub Ahead of Print) was performed from each database's inception to June 29, 2022, in any language, was conducted. We included studies wherein the metabolomic biomarkers for racemic ketamine or esketamine were investigated in TRD or HCs. Our main outcomes were to examine changes in metabolites among patients treated with ketamine/esketamine and explore the association with response to ketamine/esketamine., Results: A total of 1859 abstracts were screened of which 11 were included for full-text review. Of these, a total of five articles were included (N = 147), including three RCTs (n = 129) and two open-label trials (n = 18). All studies used racemic ketamine; one study additionally used esketamine. The included studies evaluated patients with treatment-resistant bipolar depression (n = 22), unipolar depression (n = 91), and HCs (n = 34). The included studies reported alteration in several metabolites including acylcarnitines, lipids, kynurenine (KYN), and arginine with ketamine in TRD. Studies suggest the involvement of energy metabolism, KYN, and arginine pathways. In HCs, acetylcarnitine decreased post-infusion, whereas inconsistent findings were observed after the ketamine infusion in TRD patients., Conclusions: This systematic review provides preliminary evidence that ketamine may cause changes in several important pathways involved in energy metabolism and inflammation. Larger and more rigorous studies are needed., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Emil Kraepelin believed that dementia praecox, the disorder we now call schizophrenia, was caused by the brain being poisoned with toxins generated in other parts of the body, especially the mouth, intestine or genitals. In this regard, Kraepelin hinted at the microbiome and conceptualized microbial molecules as drivers of severe psychiatric illness. However, it was not until the coronavirus disease (COVID-19) pandemic that Kraepelin's paradigm gained traction, particularly because this virus was associated with both gut barrier disruption and new-onset psychosis. Likewise, despite numerous studies linking severe psychiatric illness to genomic damage and dysfunctional DNA repair, this pathogenetic mechanism was underappreciated before the COVID-19 pandemic. The use of the psychotomimetic anesthetic, ketamine, for treatment-resistant depression has reawakened the interest in endogenous serotonergic hallucinogens, especially tryptamine and N,N-dimethyltryptamine (DMT), which are beneficial for depression but associated with psychosis. In this editorial, we take a closer look at the role of the microbiome in psychopathology, attempting to answer 2 questions: 1. Why may psychosis-predisposing serotonergic hallucinogens alleviate depression? 2. Are microbiota-derived psychedelics part of an inbuilt antidepressant system similar to endogenous opioids? [ABSTRACT FROM AUTHOR]

This study aimed to investigate the influence of genetic variants in neuroplasticity-related genes on antidepressant treatment phenotypes. The BDNF-TrkB signaling pathway, as well as the downstream kinases Akt and ERK and the mTOR pathway, have been implicated in depression and neuroplasticity. However, clinicians still struggle with the unpredictability of antidepressant responses in depressed patients. We genotyped 26 polymorphisms in BDNF, NTRK2, NGFR, CREB1, GSK3B, AKT, MAPK1, MTOR, PTEN, ARC, and SYN1 in 80 patients with major depressive disorder treated according to the Texas Medical Algorithm for 27 months at Hospital Magalhães Lemos, Porto, Portugal. Our results showed that BDNF rs6265, PTEN rs12569998, and SYN1 rs1142636 SNP were associated with treatment-resistant depression (TRD). Additionally, MAPK1 rs6928 and GSK3B rs6438552 gene polymorphisms were associated with relapse. Moreover, we found a link between the rs6928 MAPK1 polymorphism and time to relapse. These findings suggest that the BDNF, PTEN, and SYN1 genes may play a role in the development of TRD, while MAPK1 and GSK3B may be associated with relapse. GO analysis revealed enrichment in synaptic and trans-synaptic transmission pathways and glutamate receptor activity with TRD-associated genes. Genetic variants in these genes could potentially be incorporated into predictive models of antidepressant response. [ABSTRACT FROM AUTHOR]

Purpose: Suicide is a major public health concern with currently no validated and efficacious treatments approved. Preliminary evidence suggests that intravenous ketamine has rapid and sustained antidepressant effects, making it a candidate with therapeutic potential for depressed patients at risk for suicide. We conducted a meta-analysis to evaluate the efficacy of ketamine and esketamine in reducing suicidal ideation (SI), as well as their respective onset and duration of action. Data Sources: We searched PubMed, Embase, Ovid, Cochrane, and Web of Science databases for studies published from inception to September 29, 2022. Study Eligibility Criteria: We conducted a systematic review of all parallel randomized controlled trials (RCTs) examining the effect and duration of ketamine or esketamine on SI. Our primary outcome measure was the Suicide Scale score, which was measured using the Scale for Suicidal Ideation (SSI), Beck Scale for Suicide Ideation (BSS), Beck Depression Inventory (BDI), or Modified Scale for Suicidal Ideation (MSSI). To obtain effect sizes (Cohen's d), we calculated the difference in Suicide Scale scores before and after administration in each group. Results: Our study showed that intravenous sub-anesthetic doses of ketamine and intranasal inhaled esketamine had a significant anti-SI effect. Specifically, ketamine produced a large degree of anti-SI effect within the 4– 6 hours (Cohen's d = 1.16, 95% CI: 0.50, 1.81) and a medium-large degree in the 24 hours (Cohen's d = 0.95, 95% CI: 0.48, 1.41). Esketamine, on the other hand, produced a small-medium degree of anti-SI effect within the 4– 6 hours timeframe (Cohen's d = 0.26, 95% CI: 0.09, 0.44) and the 24 hours (Cohen's d = 0.30, 95% CI: 0.17, 0.47). Conclusion: Intravenous sub-anesthetic doses of ketamine and intranasal inhaled esketamine could reduce SI within 4 hours and last for 24 hours. [ABSTRACT FROM AUTHOR]

Ketamine is known for its antinociceptive effect and is also used for treatment‐resistant depression. However, the efficacy and safety of (2R, 6R)‐hydroxynorketamine (HNK), a ketamine metabolite has been sparingly investigated for acute pain management. The current study aims at investigating the antinociceptive effect of intranasal (2R, 6R)‐HNK using pre‐clinical models of acute pain. Additionally, the behavioural and neurophysiological safety analyses were carried out for the effective time window. Antinociceptive efficacy of (2R, 6R)‐HNK was evaluated using the hot plate test and Hargreaves' plantar test. The formalin test was carried out in both the acute and tonic phases. The neurophysiological and behavioural safety analyses were carried out separately for the haemodynamic function, cortical electroencephalography (EEG), and spontaneous behavioural functions. Analgesic effect of (2R, 6R)‐HNK was evident by a significant increase in paw‐withdrawal latency in both Hargreaves' and hot plate tests. Additionally, the (2R, 6R)‐HNK showed a significant ameliorative effect on pain‐related behaviour in the second phase of the formalin test. (2R, 6R)‐HNK exhibited an anxiolytic effect without causing any significant changes in locomotor activity and haemodynamic parameters. Power spectral density (PSD) analysis of electroencephalogram revealed no significant changes except a comparative increase in the gamma band range. Both the locomotor functions in the open field test and the PSD value of delta wave indicated no sedative effect at the given dose of (2R, 6R)‐HNK. The results demonstrated the pain‐alleviating effect of (2R, 6R)‐HNK without compromising the neurophysiological and behavioural function. Therefore, intranasal (2R, 6R)‐HNK is suggested as a safe candidate for further clinical study in the management of acute pain. [ABSTRACT FROM AUTHOR]

Background: Depression is a common disorder that affects patients' quality of life and incurs health system costs. Due to the resistance to treat depression, better understanding of neurophysiology was considered; one of the implications is the glutamatergic system. This study aims to systematically review clinical trials investigating the antidepressant effects of kainate receptor antagonists. Methods: The study protocol was registered in PROSPERO (CRD42021213912). Scopus, ISI, Embase, PubMed, Cochrane Library, Google Scholar, and two trial registries were searched for randomized controlled trials on the effectiveness of topiramate, phenobarbital, and other ten barbiturates in depression. The difference with control groups in terms of changing depressive symptoms was the primary outcome. Results: Nine trials were identified, in which 784 patients were studied. The efficacy of thiopental was comparable to that of imipramine, with fewer side effects. When administered with electroconvulsive therapy, it had fewer to similar effects and fewer side effects than ketamine. Both monotherapy and adjunctive therapy with topiramate were effective and tolerable in treating depressed patients. Phenobarbital had therapeutic effects compared to imipramine and amitriptyline with fewer side effects. Conclusion: Regarding the glutamatergic hypothesis of depression and obtained promising results, further studies of kainate receptor antagonists in high‐quality trials are recommended. Given the high prevalence of depression in epileptic patients, more problems with its treatment, and the fact that the studied agents were anticonvulsants, it is recommended that future studies prioritize depressed‐epileptic patients. [ABSTRACT FROM AUTHOR]

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

Over 50% of depressed patients show hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis. Conventional therapy takes weeks to months to improve symptoms. Ketamine has rapid onset antidepressant effects. Yet its action on HPA axis activity is poorly understood. Here, we measured the corticosterone (CORT) response to ketamine administered at different times of day in the Wistar–Kyoto (WKY) rat. In male rats, blood was collected every 10 min for 28 h using an automated blood sampling system. Ketamine (5/10/25 mg · kg) was infused through a subcutaneous cannula at two time points–during the active and inactive period. CORT levels in blood were measured in response to ketamine using a radioimmunoassay. WKY rats displayed robust circadian secretion of corticosterone and was not overly different to Sprague Dawley rats. Ketamine (all doses) significantly increased CORT response at both infusion times. However, a dose dependent effect and marked increase over baseline was observed when ketamine was administered during the inactive phase. Ketamine has a robust and rapid effect on HPA axis function. The timing of ketamine injection may prove crucial for glucocorticoid‐mediated action in depression. [ABSTRACT FROM AUTHOR]

Background: Ketamine, a robust antidepressant, has promising potential in the treatment of major depressive disorder (MDD). However, it does not work for all MDD patients, and the mechanism underlying its anti-depressive effects is unclear. Researchers have explored the mechanisms of ketamine action in MDD patients through MRI, a technique that measures brain activity intuitively. Notably, many MRI results were inconsistent because they selected different brain regions as seeds, particularly with respect to functional connectivity (FC) analysis. To eliminate the influence of prior seeds as much as possible, we used the significantly different results in degree centrality (DC) analysis as seeds to explore the FC changes in MDD patients to identify an imaging biomarker of ketamine's effect. Methods: Forty-four MDD patients and 45 healthy controls (HCs) were included in the study. Patients, aged 18-65, received six intravenous ketamine injections over 12 days. Depressive symptoms were estimated and MRI scans were performed at baseline and the day after the sixth infusion. We estimated FC differences between responders, non-responders and HCs using the region that showed significant differences between responders and nonresponders in DC analysis as the seed. The correlation between the MADRS changes and zFC values was performed, and the potential of zFC values to be a neuroimaging biomarker was explored using the receiver operating characteristic curve. Result: Compared with non-responders, responders had significantly decreased DC values in the right middle frontal gyrus (MFG). In the analysis of FC using the region that showed significant differences in DC as a seed, there was a significant difference in the region of the right supplementary motor area (SMA) among responders, non-responders, and HCs. This region also overlapped with the bilateral median cingulate gyrus. In post hoc analysis, responders had higher FC than non-responders and HCs, and nonresponders had lower FC than HCs. Importantly, the FC between the MFG and SMA (overlapping bilateral median cingulate gyrus) was correlated with the improvement of symptoms, which was estimated by the Mongomery-Asberg Depression Scale (MADRS). FC has the potential to be an imaging biomarker that can predict the ketamine effect in MDD patients according to the receiver operating characteristic curve analysis. Conclusion: Our results revealed that FC between the SMG and SMA and mACC was highly correlated with depressive symptoms and has the potential to be a neuroimaging biomarker to predict the effect of ketamine in MDD. [ABSTRACT FROM AUTHOR]

The urgent need for appropriate treatment for suicide, the tenth leading cause of death, has led to numerous studies. This study aims to systematically identify and appraise systematic reviews with or without meta‐analyses investigating ketamine in suicidal ideation and behaviours. Scopus, ISI, Embase, PubMed, CINAHL, PsycINFO, Cochrane Library, Google Scholar and two registries were searched without any restrictions for systematic reviews investigating the efficacy of ketamine on suicidal ideation and behaviours. The primary outcome was the final inference of ketamine effectiveness. A formal narrative synthesis was conducted, and the AMSTAR‐2 tool was used to evaluate the quality of the studies. Of 27 studies that addressed ketamine for suicidal ideation, only four reported mixed or negative results, and out of nine reviews, esketamine was significantly beneficial only in five. A transient rise in pulse rate and blood pressure, dissociation, confusion, blurred vision, nausea and vertigo were the most common adverse effects; however, most were mild. More than two‐thirds of the included studies qualified as of low or critically low quality. Preliminary evidence for the short‐term efficacy of ketamine in suicidality was noted by the majority of reviews; however, long‐term effects remained unknown. Due to the low quality of many studies and the limitations of core studies, further research is required. [ABSTRACT FROM AUTHOR]

Clinical and preclinical studies show evidence that chronic stress or nutritional deficits in dietary zinc (Zn) intake may be risk factors for developing major depressive disorder (MDD). Furthermore, there may be possible links between low serum Zn levels and development of treatment-resistant depression. In the present work, we combined chronic restraint stress (CRS) and a low-zinc diet (ZnD) in mice and carried out a set of behavioral and biochemical studies. The mice were treated with four different antidepressant compounds, namely, ketamine, Ro 25-6981 (Ro), hyperforin and lanicemine (Hyp + Lan), and imipramine (IMI). We show that CRS or ZnD alone or a combination of CRS and ZnD (CRS + ZnD) induces anhedonia observed in the sucrose preference test (SPT). The behavioral effects of CRS were restored by ketamine or IMI. However, only Hyp + Lan restored the deficits in behavioral phenotype in mice subjected to CRS + ZnD. We also showed that the antidepressant-like effects observed in Hyp + Lan-treated CRS + ZnD mice were associated with changes in the morphology of the dendritic spines (restored physiological level) in the hippocampus (Hp). Finally, we studied the metabolism of ketamine and its brain absorption in CRS and CRS + ZnD mice. Our results suggest that CRS + ZnD does not alter the metabolism of ketamine to (2R,6R;2S,6S)-HNK; however, CRS + ZnD can induce altered bioavailability and distribution of ketamine in the Hp and frontal cortex (FC) in CRS + ZnD animals compared to the control and CRS groups. [ABSTRACT FROM AUTHOR]

Anhedonia is a common, persistent, and disabling condition. However, available therapeutics primarily focus on the reduction of depressive and negative symptoms rather than amelioration of deficits in positive affect. As such, extant drug treatments remain largely ineffective in treating symptoms of anhedonia. Ketamine is a rapid-acting and novel therapeutic treatment for treatment-resistant depression, which has also been demonstrated to attenuate symptoms of anhedonia. However, the literature on the anti-anhedonic effects of ketamine is limited—especially within independent dimensions of this symptom domain. Herein, this review examined the impact of ketamine treatment on anhedonia and its dimensions on anticipatory, consummatory, and motivation-related reward deficits. Overall, the findings have shown a trend towards symptom reduction and/or improvements in anhedonia and their respective subdomains, in both human and preclinical studies, as well as its potential to provide additional benefit in reducing suicidality and improving quality-of-life. Although further research is required in understanding the long-term efficacy and mechanism, ketamine may provide an effective and rapid-acting therapeutic in an otherwise unmet domain. [ABSTRACT FROM AUTHOR]

Objective: Available treatments of depression have limited efficacy and unsatisfactory remission rates. This study aims to review randomized controlled trials (RCTs) investigating effects of glutamate receptor modulators in treating patients with resistant depression. Method: The study protocol was registered in PROSPERO (CRD42021225516). Scopus, ISI Web of Science, Embase, Cochrane Library, Google Scholar, and three trial registries were searched up to September 2020 to find RCTs evaluating glutamate receptor modulators for resistant depression. The difference between intervention and control groups in changing depression scores from baseline to endpoint was considered the primary outcome. Version 2 of the Cochrane risk-of-bias tool for randomized trials was used to assess the quality of the RCTs. No funding was received. Results: Thirty-eight RCTs were included. Based on the included studies, compelling evidence was found for ketamine (with or without electroconvulsive therapy, intravenous or other forms), nitrous oxide, amantadine, and rislenemdaz (MK-0657); the results for MK-0657, amantadine, and nitrous oxide were only based on one study for each. Lithium, lanicemine, D-cycloserine, and decoglurant showed mixed results for efficacy, and, riluzole, and 7-chlorokynurenic acid were mostly comparable to placebo. A limited number of studies were available that addressed drugs other than ketamine. Conclusion: The study cannot determine the difference between statistical and clinical significance between the agents and placebo due to high heterogeneity among the RCTs. Nevertheless, ketamine could be used as an efficacious drug in TRD; still, additional studies are needed to delineate the optimum dosage, duration of efficacy, and intervals. Further studies are also recommended on the effectiveness of glutamatergic system modulators other than ketamine on treatment-resistant depression. [ABSTRACT FROM AUTHOR]

Insulin is the most effective glycemic-lowering drug, and for people suffering from type 1 diabetes it is a life-saving drug. Its self-dosing by patients may be associated with a higher risk of overdose, both accidental and deliberate. Insulin-induced hypoglycemia causes up to 100,000 emergency department calls per year. Cases of suicide attempts using insulin have been described in the literature since its introduction into therapy, and one of the important factors in their occurrence is the very fact of chronic disease. Up to 90% of patients who go to toxicology wards overdose insulin consciously. Patients with diabetes are burdened with a 2–3 times higher risk of developing depression compared to the general population. For this reason, it is necessary to develop an effective system for detecting a predisposition to overdose, including the assessment of the first symptoms of depression in patients with diabetes. A key role is played by a risk-conscious therapeutic team, as well as education. Further post-mortem testing is also needed for material collection and storage, as well as standardization of analytical methods and interpretation of results, which would allow for more effective detection and analysis of intentional overdose—both by the patient and for criminal purposes. [ABSTRACT FROM AUTHOR]

Background: Drug repurposing can improve the return of investment as it finds new uses for existing drugs. Literature-based analyses exploit factual knowledge on drugs and diseases, e.g. from databases, and combine it with information from scholarly publications. Here we report the use of the Open Discovery Process on scientific literature to identify non-explicit ties between a disease, namely epilepsy, and known drugs, making full use of available epilepsy-specific ontologies. Results: We identified characteristics of epilepsy-specific ontologies to create subsets of documents from the literature; from these subsets we generated ranked lists of co-occurring neurological drug names with varying specificity. From these ranked lists, we observed a high intersection regarding reference lists of pharmaceutical compounds recommended for the treatment of epilepsy. Furthermore, we performed a drug set enrichment analysis, i.e. a novel scoring function using an adaptive tuning parameter and comparing top-k ranked lists taking into account the varying length and the current position in the list. We also provide an overview of the pharmaceutical space in the context of epilepsy, including a final combined ranked list of more than 70 drug names. Conclusions: Biomedical ontologies are a rich resource that can be combined with text mining for the identification of drug names for drug repurposing in the domain of epilepsy. The ranking of the drug names related to epilepsy provides benefits to patients and to researchers as it enables a quick evaluation of statistical evidence hidden in the scientific literature, useful to validate approaches in the drug discovery process. [ABSTRACT FROM AUTHOR]

Major depressive disorder is one of the most prevalent mental health disorders. Monoamine-based antidepressants were the first drugs developed to treat major depressive disorder. More recently, ketamine and other analogues were introduced as fast-acting antidepressants. Unfortunately, currently available therapeutics are inadequate; lack of efficacy, adverse effects, and risks leave patients with limited treatment options. Efforts are now focused on understanding the etiology of depression and identifying novel targets for pharmacological treatment. In this review, we discuss promising novel pharmacological targets for the treatment of major depressive disorder. Targeting receptors including N-methyl-D-aspartate receptors, peroxisome proliferator-activated receptors, G-protein-coupled receptor 39, metabotropic glutamate receptors, galanin and opioid receptors has potential antidepressant effects. Compounds targeting biological processes: inflammation, the hypothalamic-pituitary-adrenal axis, the cholesterol biosynthesis pathway, and gut microbiota have also shown therapeutic potential. Additionally, natural products including plants, herbs, and fatty acids improved depressive symptoms and behaviors. In this review, a brief history of clinically available antidepressants will be provided, with a primary focus on novel pharmaceutical approaches with promising antidepressant effects in preclinical and clinical studies. [ABSTRACT FROM AUTHOR]