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Introduction: Opioid use disorder (OUD) is a major public health crisis worldwide. Patients with OUD inevitably experience withdrawal symptoms when they attempt to taper down on their current opioid use, abstain completely from opioids, or attempt to transition to certain medications for opioid use disorder. Acute opioid withdrawal can be debilitating and include a range of symptoms such as anxiety, pain, insomnia, and gastrointestinal symptoms. Whereas acute opioid withdrawal only lasts for 1-2 weeks, protracted withdrawal symptoms can persist for months after the cessation of opioids. Insufficient management of opioid withdrawal often leads to devastating results including treatment failure, relapse, and overdose. Thus, there is a critical need for cost-effective, nonopioid medications, with minimal side effects to help in the medical management of opioid withdrawal syndrome. We discuss the potential consideration of cannabidiol (CBD), a nonintoxicating component of the cannabis plant, as an adjunctive treatment in managing the opioid withdrawal syndrome. Materials and Methods: A review of the literature was performed using keywords related to CBD and opioid withdrawal syndrome in PubMed and Google Scholar. A total of 144 abstracts were identified, and 41 articles were selected where CBD had been evaluated in clinical studies relevant to opioid withdrawal. Results: CBD has been reported to have several therapeutic properties including anxiolytic, antidepressant, anti-inflammatory, anti-emetic, analgesic, as well as reduction of cue-induced craving for opioids, all of which are highly relevant to opioid withdrawal syndrome. In addition, CBD has been shown in several clinical trials to be a well-tolerated with no significant adverse effects, even when co-administered with a potent opioid agonist. Conclusions: Growing evidence suggests that CBD could potentially be added to the standard opioid detoxification regimen to mitigate acute or protracted opioid withdrawal-related symptoms. However, most existing findings are either based on preclinical studies and/or small clinical trials. Well-designed, prospective, randomized-controlled studies evaluating the effect of CBD on managing opioid withdrawal symptoms are warranted.

N‐methyl‐D‐aspartate ionotropic glutamatergic receptor (NMDAR) modulators, including rapastinel and ketamine, elicit rapid and sustained antidepressant responses in patients with treatment‐resistant major depressive disorder. This phase I, randomized, multicenter, placebo‐controlled, five‐period, crossover, single‐dose study evaluated simulated driving performance of healthy participants (N = 107) after single doses of rapastinel slow intravenous (i.v.) bolus 900 and 1800 mg, alprazolam oral 0.75 mg (positive control), ketamine i.v. infusion 0.5 mg/kg (clinical comparator), and placebo ~ 45 min before driving. The primary end point was SD of lateral position (SDLP) during the 60‐min 100‐km simulated driving scenario. Additional measures of driving performance, sleepiness, and cognition were also evaluated. To assess effects over time, mean SDLP was calculated for each 10‐min interval of driving. Sensitivity of the assays was confirmed with alprazolam (all placebo comparisons p 0.5). Both rapastinel doses resulted in significantly less impaired driving compared to alprazolam or ketamine (all p

Rationale Triangulation of approaches (i.e., using several tests of the same construct) can be extremely useful for increasing the robustness of the findings being widely used when working with behavioral testing, especially when using rodents as a translational model. Although zebrafish are widely used in neuropharmacology research due to their high-throughput screening potential for new therapeutic drugs, behavioral test battery effects following pharmacological manipulations are still unknown. Methods Here, we tested the effects of an anxiety test battery and test time following pharmacological manipulations in zebrafish by using two behavioral tasks: the novel tank diving task (NTT) and the light–dark test (LDT). Fluoxetine and conspecific alarm substance (CAS) were chosen to induce anxiolytic and anxiogenic-like behavior, respectively. Results For non-drug-treated animals, no differences were observed for testing order (NTT → LDT or LDT → NTT) and there was a strong correlation between performances on the two behavioral tasks. However, we found that during drug treatment, NTT/LDT responses are affected by the tested order depending on the test time being fluoxetine effects higher at the second behavioral task (6 min later) and CAS effects lower across time. Conclusions Overall, our data supports the use of baseline behavior assessment using this anxiety test battery. However, when working with drug exposure, data analysis must carefully consider time-drug-response and data variability across behavioral tasks.

Cholinergic crisis and oxidative stress in the hippocampus of the brain have been known to induce anxiety disorders upon ageing. BOTOX® is a widely used therapeutic form of botulinum neurotoxin that acts by inhibiting the release of acetylcholine (ACh) from the nerve terminals at the neuromuscular junction. BOTOX® can migrate from the muscle to the brain through retrograde axonal transport and modulate neuroplasticity. While a mild dose of BOTOX® has been used to manage various neurological deficits and psychiatric complications including depression, the efficacy and experimental evidence for its anxiolytic effects and antioxidant properties remain limited. In this study, we have investigated the effect of BOTOX® on the innate anxiety-like behaviours in ageing mice upon exposure to different behavioural paradigms like open field test, elevated plus maze and light-dark box test, and estimated the enzymatic activities of key antioxidants in the hippocampus. Results revealed that animals injected with a mild intramuscular dosage of BOTOX® showed reduced level of innate anxiety-related symptoms and increased activities of hippocampal antioxidant enzymes compared to the control group. This study strongly supports that BOTOX® could be implemented to prevent or treat anxiety and hippocampal oxidative stress resulting from ageing, emotional and mood disorders.

Abutilon indicum Linn (A. indicum) is native to tropical and subtropical zones and traditionally used in ulcer, diabetes, piles, jaundice, gonorrhoea and leprosy. Erstwhile phytochemical analysis showed the presence of flavonoids, sesquiterpenes, gallic acid, β-sitosterols, geraniol, and caryophyllene. The study identifies the antidepressant potential of the crude methanolic extract of A. indicum (Ai.Cr). Crude methanolic extract of leaves and bark was prepared using maceration and freeze-drying. Forty Swiss-albino mice were divided into five groups containing eight mice each. Designated groups were administered with normal saline, Ai.Cr (30, 50, and 100 mg/kg) and diazepam (1 mg/kg) or fluoxetine (10 mg/kg) intra-peritoneally. Light and Dark Exploration (LDE), Elevated Plus Maze (EPM) and Hole Board (HB) test were used for anxiolytic activity testing, while forced swim and tail suspension model were used for the evaluation of antidepressant potential of Ai.Cr. Results showed that mice spent more time in light; passed more duration in open arms and raised number of head poking in respective anxiolytic LDE, EPM, and HB tests. Similarly, mobility time was raised in forced swim and tail suspension antidepressant testing. Ai.Cr has significant dose dependent antidepressant and anxiolytic potential, which peaks at highest dose (100 mg/kg) used in this study. A. indicum has significant pharmacological potential against anxiety and depression.

Purpose/background Bipolar disorder and major depressive disorder are heterogeneous conditions characterized by marked variations in mood. High levels of anxiety are often present in these conditions and are associated with increased suicidal risk, increased disease duration, and treatment resistance. Mood stabilizers or antipsychotics are recommended for the treatment of bipolar disorder in comorbidity with anxiety disorders. This study examines current knowledge to evaluate the efficacy of quetiapine in the treatment of anxiety in mood disorders. Methods/procedures A systematic review was conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) and Cochrane guidelines, selecting randomized control trials that evaluated the efficacy of quetiapine on anxiety symptoms in patients diagnosed with bipolar disorder or major depressive disorder and included anxiety evaluation scales. Findings/results We collected 27 studies (19 with primary data analysis, 8 with secondary data analysis) regarding the use of quetiapine in mood disorders. Quetiapine was more effective than placebo and active comparators in reducing anxiety in unipolar and bipolar patients in 20 of these studies. In 7 studies, quetiapine was not superior to psychoactive comparators or placebo on the anxiety dimension. Implications/conclusions Statistical power might be limited by small sample size in 5 of the studies included in our review. Moreover, data on anxiety were a secondary outcome in most studies. Nevertheless, the reported studies show with good levels of concordance that quetiapine is effective in controlling anxiety symptoms in patients with mood disorders. This evidence supports current guidelines and recommendations concerning the use of quetiapine in clinical practice.

Solithromycin is a novel fluoroketolide antibiotic that is both a substrate and time-dependent inhibitor of CYP3A. Solithromycin has demonstrated efficacy in adults with community-acquired bacterial pneumonia and has also been investigated in pediatric patients. The objective of this study was to develop a framework for leveraging physiologically based pharmacokinetic (PBPK) modeling to predict CYP3A-mediated drug-drug interaction (DDI) potential in the pediatric population using solithromycin as a case study. To account for age, we performed in vitro metabolism and time-dependent inhibition studies for solithromycin for CYP3A4, CYP3A5, and CYP3A7. The PBPK model included CYP3A4 and CYP3A5 metabolism and time-dependent inhibition, glomerular filtration, P-glycoprotein transport, and enterohepatic recirculation. The average fold error of simulated and observed plasma concentrations of solithromycin in both adults (1966 plasma samples) and pediatric patients from 4 days to 17.9 years (684 plasma samples) were within 0.5- to 2.0-fold. The geometric mean ratios for the simulated area under the concentration versus time curve (AUC) extrapolated to infinity were within 0.75- to 1.25-fold of observed values in healthy adults receiving solithromycin with midazolam or ketoconazole. DDI potential was simulated in pediatric patients (1 month to 17 years of age) and adults. Solithromycin increased the simulated midazolam AUC 4- to 6-fold, and ketoconazole increased the simulated solithromycin AUC 1- to 2-fold in virtual subjects ranging from 1 month to 65 years of age. This study presents a systematic approach for incorporating CYP3A in vitro data into adult and pediatric PBPK models to predict pediatric CYP3A-mediated DDI potential. SIGNIFICANCE STATEMENT: Using solithromycin, this study presents a framework for investigating and incorporating CYP3A4, CYP3A5, and CYP3A7 in vitro data into adult and pediatric physiologically based pharmacokinetic models to predict CYP3A-mediated DDI potential in adult and pediatric subjects during drug development. In this study, minor age-related differences in inhibitor concentration resulted in differences in the magnitude of the DDI. Therefore, age-related differences in DDI potential for substrates metabolized primarily by CYP3A4 can be minimized by closely matching adult and pediatric inhibitor concentrations.

Clinicians often encounter agitated patients, and current treatment options include benzodiazepines and antipsychotics. Ketamine rapidly induces dissociation, maintains cardiovascular stability, spontaneous respirations, and airway reflexes. There are no prospective, randomized studies comparing ketamine to other agents in the initial management of acute agitation in the Emergency Department (ED).Determine the efficacy and safety of ketamine compared to parenteral haloperidol plus lorazepam for initial control of acute agitation.This study was a prospective, single-institution, randomized, open-label, real world, standard of care pilot study. Adult patients with combative agitation were randomized to ketamine (4 mg/kg IM or 1 mg/kg IV) or haloperidol/lorazepam (haloperidol 5-10 mg IM or IV + lorazepam 1-2 mg IM or IV). The primary outcome was sedation within 5 min, and secondary outcomes included sedation within 15 min, time to sedation, and safety.Ninety three patients were enrolled from January 15, 2018 to October 10, 2018. Significantly more patients who received ketamine compared to haloperidol/lorazepam were sedated within 5 min (22% vs 0%, p = 0.001) and 15 min (66% vs 7%, p 0.001). The median time to sedation in patients who received ketamine compared to haloperidol/lorazepam was 15 vs 36 min respectively (p 0.001). Patients who received ketamine experienced a significant, but transient tachycardia (p = 0.01) and hypertension (p = 0.01).In patients with combative agitation, ketamine was significantly more effective than haloperidol/lorazepam for initial control of acute agitation, and was not associated with any significant adverse effects.

There has been an increase in cases of drug addiction and prescription drug abuse worldwide. Recently, pregabalin abuse has been a focus for many healthcare agencies, as highlighted by epidemiological studies. We previously evaluated the possibility of pregabalin abuse using the conditioned place preference (CPP) paradigm. We observed that a 60 mg/kg dose could induce CPP in mice and that pregabalin-rewarding properties were mediated through glutamate neurotransmission. Notably, the dopaminergic reward circuitry is also known to play a crucial role in medication-seeking behavior. Therefore, this study aimed to explore the possible involvement of dopaminergic receptor-1 in pregabalin-induced CPP. Mice were randomly allocated to receive saline or the dopamine-1 receptor antagonist SKF-83566 (0.03 mg/kg, intraperitoneal). After 30 min, the mice received either saline or pregabalin (60 mg/kg) during the conditioning phase. Among the control groups that received saline or SKF-83566, the time spent in the two conditioning chambers was not significantly altered. However, among the pregabalin-treated group, there was a marked increase in the time spent in the drug-paired chamber compared to the time spent in the vehicle-paired chamber. Notably, blocking dopamine-1 receptors with SKF-83566 completely prevented pregabalin-induced place preference, thus demonstrating the engagement of the dopaminergic system in pregabalin-induced reward-related behavior.

Objective: The aim of this study was to test the hypothesis that synthesis of nitric oxide (NO) and activation of CB1 receptors have opposite effects in a behavioural animal model of panic and anxiety. Methods: To test the hypothesis, male Wistar rats were exposed to the elevated T-maze (ETM) model under the following treatments: L-Arginine (L-Arg) was administered before treatment with WIN55,212-2, a CB1 receptor agonist; AM251, a CB1 antagonist, was administered before treatment with L-Arg. All treatments were by intraperitoneal route. Results: The CB1 receptor agonist, WIN55,212-2 (1 mg/kg), induced an anxiolytic-like effect, which was prevented by pretreatment with an ineffective dose of L-Arg (1 mg/kg). Administration of AM251 (1 mg/kg), a CB1 antagonist before treatment with L-Arg (1 mg/kg) did not produce anxiogenic-like responses. Conclusion: Altogether, this study suggests that the anxiolytic-like effect of cannabinoids may occur through modulation of NO signalling.

Background/aim The aim of this study is to evaluate the effects of preemptive oral pregabalin on hemodynamic response, anxiety, sedation, and recovery in patients who underwent endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) under sedation with intravenous ketamine-propofol combination. Materials and methods Sixty patients were included in this study, and patients were randomly divided into two equal groups to receive the placebo (Group 1) versus pregabalin 150 mg (Group 2) one hour prior to EBUS- TBNA procedure. Patients received 0.25 mg kg-1 ketamine and 0.25 mg kg-1 propofol mixture (ketofol) for sedation. Timing of the parameters was defined as follows; T0: in hospital ward before pregabalin or placebo administration, T1: premedication, T2: in operating room, T3: before the procedure, T4: initiation, T5: 3 min after induction, T6: 6 min after induction, T7: 9 min after induction, and T8: 12 min after induction. Hemodynamic parameters, severity of coughing, sedation and anxiety scores, and complications were recorded. The level of satisfaction of the bronchoscopist and the patients were evaluated at the end of the procedure. Results The heart rate and mean arterial pressure were significantly higher in Group 1 (P = 0.008, P = 0.04). Total doses of anesthetics, recovery time, and desaturation rate were significantly higher in Group 1 (P = 0.014, P = 0.001, P = 0.045). In Group 2, SpO2 level was significantly higher at various time periods (T1; P = 0.025, T4; P =0.043, T6; P = 0.001, T7; P = 0.003, T8; P < 0.001). The severity of coughing was found significantly lower in Group 2 (T4; P = 0.011, T5; P = 0.01, T6; P = 0.02, T7; P = 0.03, T8; P < 0.01). Anxiety scores were significantly lower in Group 2 (P < 0.001). Conclusion Preemptive oral pregabalin, in addition to sedation with ketamine-propofol combination, was effective in providing limited hemodynamic response, restricted coughing reflex, and lower anxiety during EBUS-TBNA. Besides, with pregabalin usage, decreased anesthetics consumption, lower complication rate, and shorter recovery time might have contributed to safety of the procedure and comfort of the bronchoscopist.

Introduction: Benzodiazepines (BZD) are efficient drugs used to reduce anxiety, treat insomnia, or used as myorelaxants. BZDs are generally recommended for short-term use due to numerous side-effects and addiction. Objective: To investigate the prescribing pattern in family medicine outpatient clinics, in patients without the diagnosis of a mental disorder, and the influence of sociodemographic characteristics on BZD use. Method: A retrospective study of BZDs use, in a tenyear period (2009-2019), was conducted in patients treated in five family medicine teams of three primary health care centers in the Republic of Srpska. The study was carried out by reviewing electronic health records (EHRs) of patients above 18 years of age. The patients with the diagnosis of mental disorders were not recruited in the study. The study included 8560 EHRs, and 259 patients with the diagnosis of the mental disorders were excluded from the study. Results: Out of a total of 8301 analyzed EHRs, in 1044 (12.58%) patients at least one prescription for BZDs was found in a ten-year period. Females used BZDs in a greater percentage (71.07%), persons older than 65 years (44.54%), patients with secondary school education (60.44%), patients with chronic diseases (88.60%), patients living in an urban environment (75.96%). The most prescribed BZD was bromazepam (80.17%). Conclusion: The use of BZDs in our patients is quite considerable when compared to recommendations. The strategies to reduce BZD prescribing are necessary to reduce the chronic use of these drugs.

Sleep is essential to and an integral part of life and when lacking or disrupted, a multitude of mental and physical pathologies ensue, including cardiovascular (CV) disease, which increases health care costs. Several prospective studies and meta-analyses show that insomnia, short (9h) sleep and other sleep disorders are associated with an increased risk of hypertension, metabolic syndrome, myocardial infarction, heart failure, arrhythmias, CV disease risk and/or mortality. The mechanisms by which insomnia and other sleep disorders lead to increased CV risk may encompass inflammatory, immunological, neuro-autonomic, endocrinological, genetic and microbiome perturbations. Guidelines are emerging that recommend a target of >7 h of sleep for all adults >18 years for optimal CV health. Treatment of sleep disorders includes cognitive-behavioral therapy considered the mainstay of non-pharmacologic management of chronic insomnia, and drug treatment with benzodiazepine receptor agonists binding to gamma aminobutyric acid type A (benzodiazepine and non-benzodiazepine agents) and some antidepressants. However, observational studies and meta-analyses indicate an increased mortality risk of anxiolytics and hypnotics, although bias may be involved due to confounding and high heterogeneity in these studies. Nevertheless, it seems that the risk incurred by the non-benzodiazepine hypnotic agents (Z drugs) may be relatively less than the risk of anxiolytics, with evidence indicating that at least one of these agents, zolpidem, may even confer a lower risk of mortality in adjusted models. All these issues are herein reviewed.

Toxicity from antimuscarinic agents precipitates a constellation of signs and symptoms; two of the most significant are agitation and delirium. Benzodiazepines are commonly used for treatment; physostigmine is also effective but is underutilized due to concerns for safety and short duration of action. The objective of this study was to compare lorazepam to physostigmine for the treatment of antimuscarinic delirium and agitation.This was a blinded, randomized clinical trial in patients presenting for antimuscarinic toxidrome. Inclusion criteria were: ≥10-18 years old, at least one central and two peripheral antimuscarinic symptoms, delirium and moderate agitation. Subjects were randomized to either (1) lorazepam bolus (0.05 mg/kg) followed by a 4-h normal saline infusion, or (2) physostigmine 0.02 mg/kg bolus followed by a 4-h physostigmine infusion (0.02 mg/kg/h). Primary outcomes were the control of delirium and agitation after bolus and during the infusion.Ten (53%) subjects were enrolled in the lorazepam arm, 9 (47%) in the physostigmine arm. Diphenhydramine was the most common agent ingested (16, 84%). Fewer patients receiving physostigmine had delirium after the initial bolus (44% vs 100%,Physostigmine was superior to lorazepam in controlling antimuscarinic delirium and agitation after bolus dosing, and control of delirium after a 4-h infusion. There were no serious adverse events in either treatment arm. Physostigmine bolus and infusion should be considered in adolescent patients with significant delirium and agitation from antimuscarinic agents.

Aim There are potential clinical, ethical and legal concerns with overdosing benzodiazepines (or barbiturates) for the treatment of moderate to severe alcohol withdrawal symptoms (AWS) through telemedicine or ambulatory outpatients. A rapid systematic review to (a) qualitatively summarize the non-benzodiazepine treatment alternatives, (b) evaluate the quality of evidence for the same to effectively manage moderate to severe AWS. Methods We conducted searches on PubMed (January 1990 to 31 March 2020), Cochrane Central Register of Controlled Trials, and Google Scholar. We selected the English language randomized controlled trials (RCTs) assessing the efficacy and adverse effects of non-benzodiazepine and non-barbiturate medications among adults with a diagnosis of AWS. Data extraction was done in a predefined format. Risk of bias (RoB) assessment and qualitative synthesis of evidence was done with the RoB2 tool and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) proGDT. Results Thirty-four RCTs were included. Gabapentin (n = 6), carbamazepine (n = 5), baclofen (n = 5), valproate (n = 3), clonidine/lofexidine (n = 3) and acamprosate (n = 2) had more than one trial with a particular comparison group. Four studies were found to have a low ROB. The GRADE evidence summary showed gabapentin had a ‘moderate’ level of evidence against standard benzodiazepine treatments for reducing the severity of AWS. The level of certainty was ‘low’ for carbamazepine, baclofen and valproate and ‘very low’ for acamprosate and clonidine/lofexidine. Reported adverse events between these alternative medications and benzodiazepines or placebo were generally unremarkable. Conclusions Although benzodiazepines remain the treatment of choice for AWS, during particular circumstances, gabapentin could be an alternative although like benzodiazepines is not without risk when used in the community. Future RCTs must aim to improve upon the quality of evidence.

Introduction In Parkinson's disease (PD), anxiety is common, associated with lower health-related quality of life, and undertreated. The primary objective of this study was to determine the tolerability of buspirone for the treatment of anxiety in PD. Methods Individuals with PD and clinically significant anxiety were randomized 4:1 to flexible dosage buspirone or placebo for 12 weeks. Treatment was initiated at 7.5 mg twice daily and titrated based on response and tolerability to an optimal dosage (maximum 30 mg twice daily). The primary outcome was the proportion of participants who failed to complete the study on study drug. Secondary outcomes included adverse events, dosage reductions, motor function, dyskinesias, and anxiety. Results A total of 21 participants enrolled, 4 were randomized to placebo and 17 to buspirone (mean (SD) age 65.5 (9.8), 76.5% male, 88% on concomitant antidepressant or anxiolytic). In the buspirone group, 7 (41%) failed to complete the study on drug, 5 due to intolerability. The median buspirone dosage was 7.5 mg twice daily. No serious adverse events occurred. A total of 9 (53%) buspirone participants experienced adverse events consistent with worsened motor function. In the buspirone group, mean (SD) improvement from baseline to week 12 in Hamilton Anxiety Rating Scale was −3.9 (3.8) and Parkinson Anxiety Scale −7.1 (6.4). Conclusion Tolerability concerns do not support moving immediately forward with a large-scale efficacy trial. However, concomitant anxiolytics may have affected tolerability and a signal of efficacy was seen suggesting that future studies of buspirone monotherapy be considered.

Background Silexan is a lavender essential oil with established anxiolytic and calming efficacy. Here we asked whether there is a potential for abuse in human patients. Methods We carried out a phase I abuse liability single-center, double-blind, 5-way crossover study in healthy users of recreational central nervous system depressants. They received single oral doses of 80 mg (therapeutic dose) and 640 mg Silexan, 2 mg and 4 mg lorazepam (active control) and placebo in randomized order, with 4- to 14-day washout periods between treatments. Pharmacodynamic measures included validated visual analogue scales assessing positive, negative, and sedative drug effects and balance of effects; a short form of the Addiction Research Center Inventory; and a drug similarity assessment. The primary outcome measure was the individual maximum value on the drug liking visual analogue scale during 24 hours post-dose. Results Forty participants were randomized and 34 were evaluable for pharmacodynamic outcomes. In intraindividual head-to-head comparisons of the drug liking visual analogue scale maximum value, both doses of Silexan were rated similar to placebo whereas differences were observed between Silexan and lorazepam and between placebo and lorazepam (P Conclusions Silexan did not exhibit any abuse potential in a standard abuse potential detection screen study and is unlikely to be recreationally abused.

Anxiety disorders have high prevalence and generate major disability. But they have poor treatment targeting because psychiatry lacks diagnostic biomarkers. Right frontal goal-conflict-specific-rhythmicity (GCSR) in the simple stop signal task appears homologous to hippocampal "theta" as an anxiety-process biomarker but is weak and transient. An anticipatory response inhibition task (ARIT) elicits strong subjective conflict and so might generate stronger GCSR. Healthy participants provided EEG during an ARIT, which allowed direct comparison of selective (left, SG; right, GS), and nonselective (both, SS) handed stopping. We assessed GCSR as intermediate versus the average of short and long delay stop-specific power. SG produced right frontal 5-12 Hz GCSR that, as in the SST: significantly correlated with trait anxiety and neuroticism; and was sensitive to pregabalin (75 mg), buspirone (10 mg), and perhaps triazolam (0.25 mg). GS and SS produced faster stopping and only 9-10Hz GCSR, which did not correlate significantly with trait anxiety or neuroticism and was sensitive to pregabalin and buspirone but not triazolam. Source localization suggested that GCSR, like stopping, involves multiple right frontal circuits that depend on response speed. Anxiolytic-sensitive GCSR generalizes from the speeded stop signal task to fixed-time anticipatory response inhibition tasks. GCSR, and the circuits engaged, vary with stop signal RTs conditions. Tasks with longer stop times may be optimal to generate GCSR homologous with rodent hippocampal theta as (a) the first direct anchor of a specific neural form of trait anxiety; (b) a single-dose screen in normal humans for novel anxiolytics; and (c) a potential clinical anxiety biomarker. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: There is a lack of evidence to guide treatment of comorbid depression and anxiety. Preliminary evidence suggests mirtazapine may be effective in treating patients with both depression and anxiety symptoms. Methods: We undertook a secondary analysis of mirtazapine (MIR): a placebo-controlled trial of the addition of mirtazapine to a selective serotonin reuptake inhibitor or serotonin–norepinephrine reuptake inhibitor in treatment-resistant depression (TRD) in primary care. We subdivided participants into three groups by baseline generalized anxiety disorder score (GAD-7): severe (GAD-7 ⩾ 16), moderate (GAD-7 = 11–15), no/mild (GAD-7 ⩽ 10). We used linear regression including likelihood-ratio testing of interaction terms to assess how baseline anxiety altered the response of participants to mirtazapine as measured by 12-week GAD-7 and Beck Depression Inventory II (BDI-II) scores. Results: Baseline generalized anxiety moderated mirtazapine’s effect as measured by GAD-7 ( p = 0.041) and BDI-II ( p = 0.088) at 12 weeks. Participants with severe generalized anxiety receiving mirtazapine had lower 12-week GAD-7 score (adjusted difference between means (ADM) −2.82, 95% confidence interval (CI) −0.69 to −4.95) and larger decreases in BDI-II score (ADM −6.36, 95% CI −1.60 to −10.84) than placebo. Conversely, there was no anxiolytic benefit (ADM 0.28, 95% CI −1.05 to 1.60) or antidepressant benefit (ADM −0.17, 95% CI −3.02 to 2.68) compared with placebo in those with no/mild generalized anxiety. Conclusions: These findings extend the evidence for the effectiveness of mirtazapine to reduce generalized anxiety in TRD in primary care. These results may inform targeted prescribing in depression based on concurrent anxiety symptoms, although these conclusions are constrained by the post-hoc nature of this analysis.

Background: Preliminary evidence is promising regarding the anxiolytic effects of statins in animal models of anxiety. Hence, this study aimed to evaluate the efficacy of simvastatin augmentation versus placebo in the treatment of patients with generalized anxiety disorder (GAD) with residual symptoms despite treatment with selective serotonin reuptake inhibitors (SSRIs). Methods: A double-blind, 8-week controlled trial was conducted from August 2018 to December 2019 in an outpatient psychiatry clinic in Hamadan, Iran. A total of 138 patients with a diagnosis of GAD were assessed for eligibility. Of them, 84 patients who met the study criteria were randomly assigned either to the adjuvant simvastatin (20 mg/day) or to the placebo group. Standard medication consisting of SSRIs was consistent 2 months prior to and during the study. The severity of anxiety symptoms for each patient was assessed based on the Hamilton Anxiety Rating Scale (HAM-A) score at baseline, week 4, and week 8 after treatment. Additionally, blood lipid values were assessed at baseline and on completion of the study. Results: Thirty-three out of 42 patients in the intervention group and 35 out of 42 patients in the control group completed the 8 weeks of the study period. Compared to the placebo group, in the simvastatin group cholesterol, triglycerides, and low-density lipoprotein significantly decreased, and high-density lipoprotein significantly increased over time. General linear model analysis demonstrated that although over time a higher decrease in mean HAM-A scores was observed in the intervention group compared to the control group, this difference was not statistically significant (p = 0.11). In addition, at the end of the study, the number of responders and remitters was comparable in the two groups. Conclusions: The results from this clinical study did not support the potential efficacy of adjunctive simvastatin in the treatment of patients with GAD. Thus, large-scale and long-term clinical trials are required to more accurately assess the potential efficacy of statins in the treatment of patients with anxiety disorders.

BackgroundCannabis has been documented for use in alleviating anxiety. However, certain research has also shown that it can produce feelings of anxiety, panic, paranoia and psychosis. In humans, Δ9-tetrahydrocannabinol (THC) has been associated with an anxiogenic response, while anxiolytic activity has been attributed mainly to cannabidiol (CBD). In animal studies, the effects of THC are highly dose-dependent, and biphasic effects of cannabinoids on anxiety-related responses have been extensively documented. A more precise assessment is required of both the anxiolytic and anxiogenic potentials of phytocannabinoids, with an aim towards the development of the ‘holy grail’ in cannabis research, a medicinally-active formulation which may assist in the treatment of anxiety or mood disorders without eliciting any anxiogenic effects.ObjectivesTo systematically review studies assessing cannabinoid interventions (e.g. THC or CBD or whole cannabis interventions) both in animals and humans, as well as recent epidemiological studies reporting on anxiolytic or anxiogenic effects from cannabis consumption.MethodThe articles selected for this review were identified up to January 2020 through searches in the electronic databases OVID MEDLINE, Cochrane Central Register of Controlled Trials, PubMed, and PsycINFO.ResultsAcute doses of CBD were found to reduce anxiety both in animals and humans, without having an anxiogenic effect at higher doses. Epidemiological studies tend to support an anxiolytic effect from the consumption of either CBD or THC, as well as whole plant cannabis. Conversely, the available human clinical studies demonstrate a common anxiogenic response to THC (especially at higher doses).ConclusionBased on current data, cannabinoid therapies (containing primarily CBD) may provide a more suitable treatment for people with pre-existing anxiety or as a potential adjunctive role in managing anxiety or stress-related disorders. However, further research is needed to explore other cannabinoids and phytochemical constituents present in cannabis (e.g. terpenes) as anxiolytic interventions. Future clinical trials involving patients with anxiety disorders are warranted due to the small number of available human studies.

Flupirtine is a non-opioid centrally acting analgesic that has been in clinical use, and is reported to act on neuronal ion channels and neurotransmitter receptors. However, its action on emotional aspects of pain is still unknown. In this study, we examined whether flupirtine has anxiolytic action and assayed its direct actions on the anterior cingulate cortex (ACC) at the single neuronal and synaptic levels. Anti-nociceptive and anxiolytic effects of flupirtine were evaluated by von Frey test and elevated plus-maze (EPM) in adult rats. The effects of flupirtine on firings and synaptic currents in the rat ACC were examined using in vivo extracellular and brain slice patch-clamp recording techniques, respectively. Systemic administration of flupirtine increased paw withdrawal threshold, and reduced anxiety-like behavior in the EPM. ACC neurons fired spontaneously. Mechanical stimulation of the contralateral hind paw with the von Frey filaments increased firing from the basal spontaneous activity. Intravenous administration of flupirtine reduced both spontaneous and stimulus-evoked firing frequency in the ACC. Flupirtine microinjected into the ACC also inhibited the spontaneous and evoked-responses. In brain slices, flupirtine did not induce any detectable outward currents, but it prolonged the decay time of GABAergic inhibitory synaptic responses. These results suggest that flupirtine directly augments GABAergic synaptic currents and suppresses evoked mechanical nociceptive responses in the ACC. This direct action in the ACC may reduce emotional aspect of pain and induce anxiolytic action.

Background: Plant lectins have shown promising biological activities in the central nervous system (CNS). Objective: This study evaluated the effect of DAL, a lectin isolated from the seeds of the Dioclea altissima species, having binding affinity to D-glucose or D-mannose residues, on mice behavior. Methods: Mice (n=6/group) were treated (i.p.) with DAL (0.25, 0.5 or 1 mg/kg) or vehicle and subjected to several tests (open field/OFT, marble-burying/MBT, hole-board/HBT, elevated plus maze/PMT, tail suspension/ TST, forced swimming/FST or rotarod/RRT). Pizotifen, cyproheptadine, flumazenil, L-NAME, 7-NI, Larginine or yohimbine were administered 15 min before DAL (0.5 mg/kg) and the animals were evaluated on PMT. It was also verified whether the DAL effect depended on its structural integrity and ability to interact with carbohydrates. Results: The results showed there were no neurobehavioral changes in the mice at the RRT, FST and locomotion in the OFT. DAL (0.25, 0.5 or 1 mg/kg) increased the behavior of grooming and rearing in the OFT, head dips in the HBT, pedalling in the TST and decreased the number of marbles hidden in the MBT. In the PMT, DAL (0.25, 0.5 and 1 mg/kg) and Diazepam increased the frequency of entries in the open arms and the time of permanence in the open arms without affecting the locomotor activity. The effect of DAL was dependent on carbohydrate interaction and protein structure integrity and it prevented by pizotifen, cyproheptadine, flumazenil, L-NAME and 7-NI, but not by L-arginine or yohimbine. Conclusion: DAL was found to have an anxiolytic-like effect mediated by the 5-HT and GABAergic receptors and NO pathway.

Highlights • COVID-19 patients with psychiatric disorders should be managed on a personalized basis. • Risks of pharmacological interaction are not absolute and should be contextualized. • Essential psychopharmacological ongoing treatments should be maintained. • Most psychotropic drugs should be reduced 25–50% if given with lopinavir/ritonavir. • Dose titration should be progressive and with ECG monitoring if cardiotoxic risk., Background : The management of coronavirus disease 2019 (COVID-19) in patients with comorbid psychiatric disorders poses several challenges, especially regarding drug interactions. Methods : We report three representative case-scenarios on patients with psychiatric disorders and COVID-19 to provide a practical approach based on the existing literature and the clinical experience of an expert team in consultation-liaison psychiatry. Case-centered recommendations : Psychopharmacological ongoing treatments should be prioritized and most doses should be reduced 25–50% of original dose if the patient receives lopinavir/ritonavir, with some exceptions including quetiapine, asenapine, olanzapine, sertraline, lamotrigine, bupropion, and methadone. If the psychopharmacological usual doses are in the low-to-median range levels, a dose change during COVID-19 drugs co-administration is not recommended, but only ECG and clinical monitoring of adverse effects and drug levels if required. Furthermore, when introducing a psychopharmacological drug, dose titration should be progressive, with ECG monitoring if cardiotoxic interactions are present. (A) In agitated delirium, olanzapine is recommended as first-line antipsychotic and quetiapine should be avoided. (B) In severe mental illness (SMI), essential treatments should be maintained. (C) In non-SMI with depressive/anxiety symptoms, psychological support should be provided and symptoms identified and treated. Limitations : Most recommendations on pharmacological interactions provide only a limited qualitative approach and quantitative recommendations are lacking. Conclusions : Patients with psychiatric disorders and COVID-19 should be managed on a personalized basis considering several clinical criteria and, should not be excluded from receiving COVID-19 treatments. Risks of pharmacological interaction are not absolute and should be contextualized, and most psychopharmacological treatments should include an ECG with special attention to QTc interval.

Aim: The aim of this study is to examine the effect of etifoxine on β-amyloid-induced toxicity models. Background: Etifoxine is an anxiolytic compound with a dual mechanism of action; it is a positive allosteric modulator of GABAergic receptors as well as a ligand for the 18 kDa mitochondrial Translocator Protein (TSPO). TSPO has recently raised interest in Alzheimer’s Disease (AD), and experimental studies have shown that some TSPO ligands could induce neuroprotective effects in animal models. Objective: In this study, we examined the potential protective effect of etifoxine in an in vitro and an in vivo model of amyloid beta (Aβ)-induced toxicity in its oligomeric form, which is a crucial factor in AD pathologic mechanisms. Method: Neuronal cultures were intoxicated with Aβ1-42, and the effects of etifoxine on oxidative stress, Tau-hyperphosphorylation and synaptic loss were quantified. In a mice model, behavioral deficits induced by intracerebroventricular administration of Aβ25-35 were measured in a spatial memory test, the spontaneous alternation and in a contextual memory test, the passive avoidance test. Results: In neuronal cultures intoxicated with Aβ1-42, etifoxine dose-dependently decreased oxidative stress (methionine sulfoxide positive neurons), tau-hyperphosphorylation and synaptic loss (ratio PSD95/synaptophysin). In a mice model, memory impairments were fully alleviated by etifoxine administered at anxiolytic doses (12.5-50mg/kg). In addition, markers of oxidative stress and apoptosis were decreased in the hippocampus of these animals. Conclusion: Our results have shown that in these two models, etifoxine could fully prevent neurotoxicity and pathological changes induced by Aβ. These results confirm that TSPO ligands could offer an interesting therapeutic approach to Alzheimer’s disease.

Pregabalin is a gamma-aminobutyric acid analog that binds to the α2-δ subunits of the pre-synaptic voltage-dependent calcium channels of nerves with a high affinity and selectivity. In this study, the retinal teratogenic potential of pregabalin was investigated in a chick embryo model.Fertilised chicken eggs were divided into groups for administration with different doses of pregabalin. All eggs were opened on the 10th day of incubation. The embryos were dissected and the effects of pregabalin on the retina were investigated histopathologically, morphometrically, and immunohistochemically (Caspase-3).There was no statistically significant difference between the low dose pregabalin, control, or vehicle control groups in terms of the number of retina layers and retinal thickness. Medium and high dose pregabalin caused a statistically significant decrease in the number of retina layers, as well as sensory retinal and pigment epithelium layer thicknesses. The outer nuclear and outer plexiform layer did not form in the group administered a medium dose. Similarly, the outer nuclear, outer plexiform, inner nuclear, and inner plexiform layer did not form in the high-dose group. No statistically significant difference was observed between the groups in terms of cellular damage and Caspase-3 expression.The use of pregabalin during pregnancy compromises retinal development in a dose-dependent manner. The use of pregabalin in pregnancy causes the aforementioned defects in this system and it may have developmental effects that needs to be further evaluated.

BACKGROUND Pruritus is one of the most common problems in patients with chronic renal failure. Of all patients with end-stage renal disease (ESRD), 60-80% report pruritus during their life. AIM To compare the effect of gabapentin (GBP) and hydroxyzine (HYDZ) in treating pruritus in patients on dialysis. METHODS In a double-blind, randomized, crossover clinical trial, 32 patients on dialysis who reported pruritus were assigned randomly to receive either GBP or HYDZ for 6 weeks; the first group received GBP 100 mg/day orally and the second group received HYDZ 25 mg/day orally for 6 weeks. After this 6-week period (Period 1) there was a washout period of 2 weeks then patients were crossed over to the other drug (the first group receiving HYDZ and second group receiving GBP) and followed up for a further 6 weeks (Period 2). A visual analogue scale was used to measure pruritus intensity in the groups before and after the first and second period. RESULTS In Period 1, pruritus severity decreased from 7.1 ± 1.46 at baseline to 2.17 ± 1.82 at 6 weeks in the GBP group (P = 0.001) and from 6.83 ± 2.11 to 2.86 ± 1.67 in the HYDZ group (P = 0.001). In Period 2, pruritus severity decreased from 5.1 ± 1.61 at baseline to 1.56 ± 0.82 at 6 weeks in the GBP group (P

High trait anxiety is a substantial risk factor for developing anxiety disorders and depression. While neuroinflammation has been identified to contribute to stress-induced anxiety, little is known about potential dysregulation in the neuroinflammatory system of genetically determined pathological anxiety or high trait anxiety individuals. We report microglial alterations in various brain regions in a mouse model of high trait anxiety (HAB). In particular, the dentate gyrus (DG) of the hippocampus of HABs exhibited enhanced density and average cell area of Iba1+, and density of phagocytic (CD68+/Iba1+) microglia compared to normal anxiety (NAB) controls. Minocycline was used to assess the capacity of a putative microglia ‘inhibitor’ in modulating hyperanxiety behavior of HABs. Chronic oral minocycline indeed reduced HAB hyperanxiety, which was associated with significant decreases in Iba1+ and CD68+Iba1+ cell densities in the DG. Addressing causality, it was demonstrated that longer (10 days), but not shorter (5 days), periods of minocycline microinfusions locally into the DG of HAB reduced Iba-1+ cell density and attenuated hyperanxiety-related behavior, indicating that neuroinflammation in the DG is at least partially involved in the maintenance of pathological anxiety. The present data reveal evidence of disturbances in the microglial system of individuals with high trait anxiety. Minocycline attenuated HAB hyperanxiety, likely by modulation of microglial activity within the DG. Thus, the present data suggest that drugs with microglia-targeted anti-inflammatory properties could be promising as novel alternative or complimentary anxiolytic therapeutic approaches in specific subgroups of individuals genetically predisposed to hyperanxiety.

Anxiety disorders are common worldwide and novel compounds are investigated for anxiolytic effect. A few studies have demonstrated the anxiolytic-like activity of natural and synthetic flavonoids. 5-methoxyflavone, a synthetic flavone derivative, has been reported to exhibit central nervous system depressant (sedative-hypnotic) effect in an earlier study. The present study was designed to investigate whether 5-methoxyflavone possesses anxiolytic-like activity in mice by employing two unconditioned models of anxiety such as elevated plus maze and light-dark box test. The possible role played by GABAergic (GABAA) and serotonergic (5HT1A) systems in the anxiolytic-like effect of 5-methoxyflavone was also investigated in the elevated plus maze test. Molecular docking studies were performed to ascertain the interaction of 5-methoxyflavone with GABAA (α2 subunit-containing) and 5HT1A receptors. 5-methoxyflavone treatment in mice (10, 20 or 40 mg/kg, i.p) increased the number of entries and time spent in the open arms in an elevated plus maze (p < 0.001). In the light-dark box test a significant increase in the time spent in light compartment (p < 0.001) and prolonged latency to enter the dark compartment (p < 0.01) were also observed. Pretreatment of mice with 5HT1A antagonist pindolol (10 mg/kg, i.p) or GABAA antagonist bicuculline (2 mg/kg, i.p) significantly attenuated the effect of 5-methoxyflavone in the elevated plus maze test. In silico studies provided evidences for good binding affinity of 5-methoxyflavone towards GABAA (α2 subunit-containing) and serotonergic (5HT1A) receptors by H-bond interactions. In conclusion, the present study identified a novel anxiolytic-like effect of 5-methoxyflavone involving GABAergic and serotonergic mechanisms.

Anxiety is one of the most comorbid conditions with major depressive disorder (MDD). Depression-associated anxiety often stems from the dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and its altered regulation by the amygdala. Furthermore, MDD is associated with altered glutamatergic processing leading to anxiety and impaired regulation of the HPA axis. Recent studies have demonstrated that N-acetyl cysteine (NAC), a pleiotropic drug, exerts antidepressant-like effect by modulation of hippocampal functions, periterminal release of glutamate, and/or redox systems. However, the effects of NAC on depression-associated anxiety, HPA axis hyperactivity, and amygdalar dysfunctions are relatively unknown. Accordingly, we evaluated the effect of NAC on neonatal clomipramine (CLI)-induced adulthood anxiety and accompanying changes in plasma corticosterone levels, amygdalar volumes, neuronal/glial densities, levels of monoamines, and their metabolites in the amygdalar complex. We found that chronic treatment with NAC reverses CLI-induced anhedonia and enhanced anxiety. Interestingly, attenuation of CLI-associated anxiety in NAC-treated rats were accompanied by a reversal of adrenal and spleen hypertrophy, and normalization of enhanced plasma corticosterone levels, indicating improved HPA axis functioning. Furthermore, NAC treatment was sufficient to reverse volumetric hypertrophy of basolateral amygdala (BLA), and altered noradrenaline (NA) metabolism in the amygdalar complex. The effects of NAC in the reversal of CLI-induced impairments were similar to that of fluoxetine (FLX). We suggest that beneficial effects of NAC on antidepressive- and antianxiety-like behaviors are at least in part mediated via restoration of amygdalar and HPA axis functioning. Our results support the hypothesis that NAC might be evolved as a therapeutic strategy for reversal of amygdalar dysfunction in depression.

Sodium nitroprusside (SNP) is a nitric oxide (NO) donor which actually is under assessment as a potential candidate for the treatment of schizophrenia. It is well documented that anxiety symptoms are a prominent future in various psychiatric diseases comprising schizophrenia. Prior research has shown that acute challenge with SNP (1–3 mg/kg) induced anti-anxiety effects in rats but these effects at high doses were confounded by sedation and were disappeared after repeated application of it. It is still unknown if administration of a lower SNP dose range, either acutely or sub-chronically, could induce anxiolytic-like behaviour. The present study was designed to investigate this issue in rats. For this aim, the light/dark and the open field tests were used. Acute challenge with SNP (0.1 and 0.3 mg/kg, 30 min before testing) did not affect rodents' performance in the above mentioned behavioural paradigms. Conversely, rats treated sub-chronically with SNP (0.1 and 0.3 mg/kg, once per day, for 5 consecutive days), displayed longer time spent in the light chamber of the light/dark box and in the central area of the open field with respect to their vehicle-treated counterparts. Interestingly, SNP did not influence the first latency to enter the dark chamber and the number of transitions between the light and dark compartments of the apparatus in the light/dark test and did not modify the number of squares crossed, grooming episodes and rearings in the open field test. Finally, acute administration of SNP (0.1, 0.3 and 1 mg/kg, 10 min before testing) also did not influence rats’ performance in the light/dark test. The present results indicate that short-term repeated but not acute application of a range of low doses of the NO donor SNP in a dose-independent manner induced an anti-anxiety behaviour in the rat which was not accompanied by undesired effects.

Translocator protein 18 kDa (TSPO) is mainly distributed in the outer mitochondrial membrane of steroid-synthesizing cells in the central and peripheral nervous systems. It mediates cholesterol transportation across the phospholipid membrane, which is a prerequisite for neurosteroid synthesis. Though the ligand of TSPO has clinical value in the diagnosis and treatment of neuropsychiatric disorders, the pharmacological study of TSPO for anti-postpartum depression has not been reported. In this study, the classical method of reproductive hormone withdrawal was used to construct a rat model of postpartum depression (PPD). The effect of YL-IPA08, a new ligand compound of TSPO, on PPD was evaluated using multiple behavioral tests at progressive time points. Additionally, real-time quantitative PCR, Western-blotting and an enzyme linked immunosorbent assay were conducted to elucidate the potential molecular mechanism of such effect. We report that the levels of TSPO and neurosteroids in the hippocampus and prefrontal cortex were significantly decreased in PPD rats compared to healthy controls. After 3 weeks of drug treatment, the levels of TSPO and neurosteroids in the hippocampus of PPD rats were increased, and anxiety and depressive like behaviors were alleviated. Meanwhile, compared with sertraline treatment, a positive control in this study, YL-IPA08 treatment had a shorter onset time. Our results suggest that the anxiolytic and anti-depressive activity of YL-IPA08 has significant value in the treatment of PPD and that TSPO may be a potential new target for the treatment of PPD.

Background/Aims The treatment of refractory functional dyspepsia (FD) is a challenge. Clidinium/chlordiazepoxide is a combination of antispasmodic and anxiolytic drugs that has been used as an adjunct treatment for FD in clinical practice with limited supporting evidence of efficacy. The aim of the study is to assess the efficacy and safety of clidinium/chlordiazepoxide as an adjunct treatment to a proton pump inhibitor (PPI) in refractory dyspepsia. Methods We performed a study of patients who met the Rome IV criteria for FD who failed to respond to PPIs. Patients were randomly assigned to groups that received clidinium/chlordiazepoxide or placebo as an add-on treatment to PPI for 4 weeks. The primary outcome was the rate of responders, which was defined as a > 50% reduction in dyspepsia symptom score after 4 weeks of treatment. The secondary outcomes were an improvement in the quality of life and the safety profile. Results Between March 2017 and February 2018, 78 patients were enrolled. The rates of responders in the clidinium/chlordiazepoxide group and placebo groups were 41.03 % and 5.13% at week 4 (P < 0.001). The clidinium/chlordiazepoxide group also showed significant improvement in overall quality of life over placebo. However, the clidinium/chlordiazepoxide group had more frequent drowsiness than the placebo group (30.27% vs 6.52%, P = 0.034). There were no major adverse events in either group. Conclusions Clidinium/chlordiazepoxide significantly improved dyspeptic symptoms and quality of life. This combination may be used as an add-on therapy in FD patients without major adverse events.

Phenibut is a nootropic drug that exerts anxiolytic and antinociceptive effects by acting on the GABAB receptor and the α2-δ subunit of voltage-dependent calcium channels. An increased number of reports of dependence to and intoxication by phenibut purchased online on the one hand and the wide prescription of phenibut in Eastern Europe for more than half a century on the other hand have resulted in a number of controversies regarding its use. In this review, we have summarized currently available information from case reports of phenibut dependence and intoxication and safety data from clinical trials. We included 14 dependence and intoxication case reports (16 patients) and reviewed 11 phenibut clinical trials (583 patients). The clinical symptoms in the case reports included cardiovascular effects, insomnia, anxiety and agitation, hallucinations, and depressed level of consciousness. In addition, the doses used (0.5–100 g/day) were much higher than the recommended daily dose (0.25–2 g/day). An analysis of phenibut side effects described in the clinical trials showed adverse events in only 5.66% of patients, and the most reported side effect was somnolence (1.89%). There are discrepancies in the reported side effects of phenibut in clinical trials compared to those reported in cases of online-purchased phenibut dependence and intoxication. The current systematic review provides evidence that, at therapeutic doses, phenibut is safe and well tolerated with minor adverse effects, but questions regarding the quality of phenibut obtained online and the contribution of alcohol and other drug abuse to phenibut dependence and intoxication remain open.

This work describes the neuropharmacological (sedative, anxiolytic, antidepressant, and anticonvulsant) actions of Gardenin A (GA) (0.1-25 mg/kg p.o.), a flavonoid found in medicinal plants. The sedative effects of GA were assessed with the pentobarbital-induced sleep test. The anxiolytic actions of GA were evaluated with the elevated plus-maze, the light-dark box test, the exploratory cylinder assay, and the open field test. Motor coordination was evaluated with the rotarod test and the open field test. The antidepressant-like actions of GA were evaluated with the tail suspension test and forced swimming test. The mechanisms of the anxiolytic-like and antidepressant-like effects of GA were assessed using inhibitors of neurotransmission pathways. The anticonvulsant activity of GA was evaluated with the strychnine-induced seizure test. The sedative effects of GA were evident only at a dose of 25 mg/kg, which increased the duration of sleep but did not alter sleep onset. GA showed anxiolytic-like actions with activity comparable to that of clonazepam in all experimental tests. The GABAA receptor antagonist bicuculline reversed the anxiolytic-like effects of GA. Furthermore, GA showed significant antidepressant-like actions in both models with activity comparable to that of fluoxetine. Yohimbine, an α2-adrenoceptor blocker, inhibited the antidepressant-like actions of GA. In addition, GA (1-10 mg/kg) did not affect locomotor coordination in mice and delayed the onset of convulsions. These findings suggest that GA induces anxiolytic-like effects and has anticonvulsant actions by the possible involvement of the GABAergic system. The antidepressant-like actions of GA may be mediated by noradrenergic neurotransmission.

The endocannabinoid system (ECS) has received extensive attention for its neuroprotective effect on the brain. This system comprises endocannabinoids, endocannabinoid receptors, and the corresponding ligands and proteins. The molecular players involved in their regulation and metabolism are potential therapeutic targets for neuropsychiatric diseases including anxiety, depression and neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The inhibitors of two endocannabinoid hydrolases, i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), have the capacity to increase the level of endocannabinoids indirectly, causing fewer side effects than those associated with direct supplementation of cannabinoids. Their antidepressant and anxiolytic mechanisms are considered to modulate the hypothalamic-pituitary-adrenal axis and regulate synaptic and neural plasticity. In terms of AD/PD, treatment with FAAH/MAGL inhibitors leads to reduction in amyloid β-protein deposition and inhibition of the death of dopamine neurons, which are commonly accepted to underlie the pathogenesis of AD and PD, respectively. Inflammation as the cause of depression/anxiety and PD/AD is also the target of FAAH/MAGL inhibitors. In this review, we summarize the application and involvement of FAAH/MAGL inhibitors in related neurological diseases. Focus on the latest research progress using FAAH/MAGL inhibitors is expected to facilitate the development of novel approaches with therapeutic potential.

Parenteral ketamine has fast-onset antidepressant and antianxiety effects; however, it causes dissociation, hypertension, and tachycardia shortly after dosing. Ketamine's antidepressant effects may be due to active metabolites rather than to ketamine itself. We hypothesized that oral controlled-release ketamine tablets would improve safety and tolerability compared with injected ketamine by reducing peak ketamine exposures compared with dosing by injection. In this randomized, placebo-controlled ascending-dose study, ketamine doses of 60, 120, or 240 mg or matching placebo (single dose followed by every-12-hours dosing for 5 doses) were given to 24 healthy volunteers. Pharmacokinetics, pharmacodynamics (brain-derived neurotropic factor), adverse events, and vital signs were assessed up to 72 hours. Drug release occurred over ∼10 hours, with most drug substance present as norketamine (∼90%). Area under the concentration-time curve and peak concentration were dose proportional. Elimination half-life was prolonged (7-9 hours) compared with published data from immediate-release oral formulations. There were no changes in blood pressure or heart rate after any dose. Mild dissociation was reported after 240 mg but not lower doses; mean dissociation ratings in this group were minimal (1-2/76). There were no clinically significant changes in ECGs or safety laboratory tests at any time. Compared with injected ketamine, oral controlled-release ketamine tablets did not increase blood pressure or heart rate, and only at doses of 240 mg was dissociation of mild intensity reported. Reducing and delaying ketamine peak concentration by oral dosing with controlled-release ketamine tablets improve this drug's tolerability for patients with depression/anxiety.

Objective:The aim of this paper was to provide a systematic review and update on the pharmacotherapy of social anxiety disorder (SAD), including the efficacy and tolerability of these agents, the ranking of interventions, and the grading of results by quality of evidence.Methods:The Common Mental Disorder Controlled Trial Register and two trial registries were searched for randomised controlled trials (RCTs) comparing any pharmacological intervention or placebo in the treatment of SAD. We performed a standard pairwise meta-analysis using a random effects model and carried out a network meta-analysis (NMA) using the statistical package, R. Quality of evidence was also assessed.Results:We included 67 RCTs in the review and 21 to 45 interventions in the NMA. Paroxetine was most effective in the reduction of symptom severity as compared to placebo. Superior response to treatment was also observed for paroxetine, brofaromine, bromazepam, clonazepam, escitalopram, fluvoxamine, phenelzine, and sertraline. Higher dropout rates were found for fluvoxamine. Brofaromine, escitalopram, fluvoxamine, paroxetine, pregabalin, sertraline, and venlafaxine performed worse in comparison to placebo for the outcome of dropouts due to adverse events. Olanzapine yielded a relatively high rank for treatment efficacy and buspirone the worse rank for dropouts due to any cause.Conclusion:The differences between drugs and placebo were small, apart from a significant reduction in symptom severity and response for paroxetine. We suggest paroxetine as a first-line treatment of SAD, with the consideration of future research on the drug olanzapine as well as brofaromine, bromazepam, clonazepam, escitalopram, fluvoxamine, phenelzine, and sertraline because we observed a response to treatment.

Reinwardtia indica belongs to Linaceae family and used as a folk medicine in Asian countries. Traditionally, it has been used in the treatment of paralysis and anti-microbial in wound healing, etc. The current study was undertaken in order to investigate the antioxidant and memory protective effect of the alcoholic (99.90%) (AERI) and hydro-alcoholic (70:30) leaves extract (HAERI) of Reinwardtia indica, against scopolamine-induced memory impairment in animals and also tried to determine the possible mechanism of action. In addition, phytochemical profiling of alcoholic leaves extract was also conducted through gas chromatography-mass spectrometry (GC-MS/MS). Rats were pretreated with AERI, HAERI (dose 250 and 500 mg/kg) and Donepezil (standard drug) along with scopolamine (1 mg/kg) for a period of 14 days followed by different test like elevated plus maze, passive avoidance, and Morris water maze to assess learning and memory ability. Acetylcholine levels, acetylcholinesterase (AChE), antioxidant enzymes (SOD, CAT & GSH), histopathology of the brain and biochemical test were also performed at the end of the treatment period. The scopolamine treatment resulted in learning and memory deficits which were partially and significantly ameliorated by the AERI at higher dose among other doses of extracts. The AERI at higher dose also counteracted the scopolamine-induced decrease in acetylcholine levels, increase in AChE activity, and decrease in antioxidant enzymes activities. No significant changes observed in the biochemical estimation of all dose of extracts. Histology of brain tissue showed the marked cellular changes in only scopolamine treated group while the standard, AERI and HAERI treated group were showing less damage at hippocampus region of the brain. The phytochemicals found after chemical profiling through GC-MS also supported the activity because of the presence of chemicals already reported for the neuroprotective, memory-enhancing and antioxidant activity, etc. The results demonstrated that the ability of the AERI at higher dose among all doses of extracts has more potential to revert the scopolamine-induced learning and memory deficits in rats by attenuating the decreased level of acetylcholine and antioxidant enzymes.

We studied the influence of intraperitoneal injection of ATP-sensitive potassium channels inhibitor glibenclamide in doses of 0.01, 0.1, 1, and 10 mg/kg on the effects of a new pyrazolo[C]pyridine derivative GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1Hpyrazolo[ 4,3-C]pyridine-3-on, chloral hydrate; 20 mg/kg, intraperitoneally) in the marble burying and open-field tests in mice. It was found that glibenclamide produced an anxiolytic effect in the open-field test (in a dose of 0.01 mg/kg) and anticompulsive effect in the marble burying test (in doses of 1 and 10 mg/kg). The observed behavioral effects of glibenclamide did not depend on blood glucose level. At the same time, glibenclamide in subeffective (0.01 and 0.1 mg/kg) and effective (1 and 10 mg/kg) doses potentiated the psychotropic effects of GIZh-72 in these tests. It can be assumed that the psychotropic effects of GIZh-72 depend on functional activity of ATP-sensitive potassium channels.

Linalool is an enanitomer monoterpene compound identified as the pharmacologically active constituent in a number of essential oils and has been reported to display anxiolytic properties in humans and in animal models and to exert both GABAergic and glutamatergic effects. In Experiment 1 linalool (100, 200, and 300, i.p.) had no significant effects compared with saline in an activity tracker with C57BL/6j mice. Experiment 2 assessed the effects on operant extinction with mice of chlordiazepoxide at a dose (15 mg/kg, i.p.) previously shown to facilitate extinction, and the same doses of linalool, compared with saline. Linalool had a dose-related facilitatory effect on extinction. While the effects of the highest dose of linalool most closely resembled the effects of chlordiazepoxide, the pattern of results suggested that linalool may affect both the acquisition of extinction learning, which is influenced by glutamatergic processes, and the expression of extinction, known to be affected by GABAergic agents such as chlordiazepoxide.

Introduction: Considering the multiplicity of adenotonsillectomy in children 2–10-year old at the paediatric surgery centres, patient anxiety leads to an increase in surgical and anaesthetic complications. Patients' unfamiliarity with surgical and anaesthetic interventions may increase their stress. Midazolam premedication reduces patient anxiety. In previous studies, psychological preparation before surgery using understandable terms to children, has reduced their anxiety. The aim of this study was to compare and study behavioural reflections among the children in two groups: the first group was prescribed oral midazolam, and the second group received psychological preparation with the booklet about anaesthesia and anaesthesia-resident explanation. Materials and Methods: This study is a clinical trial conducted on 48 children undergoing adenotonsillectomy. Children in the first group (midazolam group) received oral midazolam 0.5 mg/kg, 20 min before surgery. A booklet containing pictures and information about anaesthesia and the operating room was given to the second group (psychological preparation group) the night before surgery and anaesthesia resident explained the booklet to the children. The anxiety level was measured in both groups using the State-Trait Anxiety Inventory for Children questionnaire the night before surgery and on the morning of surgery (after giving midazolam to Group II). The results were analysed using SPSS. Results: In this study, 58.3% of the first group and 45.8% of the second group were male. The mean age of the first and second groups was 8.45 ± 1.86 and 9.12 ± 1.72 years, respectively. The anxiety in the first group significantly decreased in the morning before surgery compared to the night before operation (P < 0.001). The anxiety in the second group significantly decreased in the morning before surgery compared to the night before as well (P < 0.001). Conclusion: The results showed that midazolam and psychological preparation prior to surgery can reduce the anxiety of children before adenotonsillectomy.

Made available in DSpace on 2022-04-28T19:47:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-02-10 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The antidepressant effect of ketamine has been widely acknowledged and the use of one of its enantiomers, S-ketamine (esketamine), has recently been approved for the clinical management of treatment-resistant depression. As with ketamine, the non-selective opioid receptor-interacting drug buprenorphine is reported to have antidepressant and anxiolytic properties in humans and rodents. Given the fact that antidepressant drugs are also first line treatment for panic disorder, it is surprising that the potential panicolytic effect of these compounds has been scarcely (ketamine), or not yet (buprenorphine) investigated. We here evaluated the effects of ketamine (the racemic mixture), esketamine, and buprenorphine in male Wistar rats submitted to a panicogenic challenge: acute exposure to hypoxia (7% O2). We observed that esketamine (20 mg/kg), but not ketamine, decreased the number of escape attempts made during hypoxia, and this effect could be observed even 7 days after the drug administration. A panicolytic-like effect was also observed with MK801, which like esketamine, antagonizes NMDA glutamate receptors. Buprenorphine (0.3 mg/kg) also impaired hypoxia-induced escape, an effect blocked by the non-selective opioid receptor antagonist naloxone, indicating an interaction with classical ligand sites, such as µ and kappa receptors, but not with nociception/orphanin FQ receptors. Altogether, the results suggest that esketamine and buprenorphine cause rapid-onset panicolytic-like effects, and may be alternatives for treating panic disorder, particularly in patients who are refractory to standard pharmacological treatment. Department of Pharmacology School of Medicine of Ribeirão Preto University of São Paulo Department of Biomolecular Sciences School of Pharmaceutical Sciences University of São Paulo Aarhus Institute of Advanced Studies (AIAS) Aarhus University Behavioural Neurosciences Institute (INeC) Department of Pharmacology and Therapeutics State University of Maringá (UEM) Department of Biological Sciences School of Sciences São Paulo State University (UNESP) Department of Biological Sciences School of Sciences São Paulo State University (UNESP) CNPq: 142509/2018-3 FAPESP: 2018/00153-5

Patient: Female, 55-year-old Final Diagnosis: Trazodone overdose Symptoms: Altered mental status • seizure • shock • arrhythmia Medication: — Clinical Procedure: — Specialty: Toxicology Objective: Rare disease Background: Trazodone is widely used in the treatment of depression, anxiety, and insomnia. It is thought to have a safe cardiac profile due to the relative lack of anticholinergic effects. Publications about cardiac toxicities of trazodone are scant. Case Report: A 55-year-old woman presented with acute disorder of consciousness secondary to an intentional trazodone overdose. She was found to have seizure activity without cerebral edema. The initial electrocardiogram was unremarkable, with a normal QTc interval. She eventually developed QTc prolongation that evolved into ventricular tachycardia, and then into a transient right bundle-branch block, left anterior fascicular block, and variable degrees of atrioventricular nodal blocks at 12–24 h after ingestion. She then developed generalized tonic-clonic seizures, cardiogenic shock, and respiratory arrest. She was intubated and treated with antiepileptics, norepinephrine, and dopamine infusion. QTc interval prolongation gradually resolved and the various forms of heart block did not recur after at 24–36 h. She did not require transcutaneous pacing, and was successfully extubated with intact neurological function. Conclusions: Fatal arrhythmias can occur in trazodone overdose. Close monitoring and supportive care are crucial for patient survival.

Background\ud Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia.\ud \ud Methods\ud This parallel-group, double-blind, placebo-controlled trial—the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)—was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897.\ud \ud Findings\ud Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference –1·74, 95% CI –7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065).\ud \ud Interpretation\ud This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia.\ud \ud Funding\ud UK National Institute for Health Research Health Technology Assessment Programme.

The essential oil from C. aurantium has been widely studied due to its potential anxiolytic action on several receptors in the Central Nervous System (CNS). Although it presents variations in its phytochemical composition depending on its origin, we can highlight that many compounds remain present, such as linalool that demonstrated antagonistic activity on glutamatergic receptors, possible inhibitory action of noradrenaline and serotonin receptors, besides the ability to activate GABA receptors in association with some flavonoids present in the oil. It is globally known that the underlying pathology called anxiety influences worldwide as an antecedent of conflicting psychological and physical disorders, which are associated with various neuronal disorders. In this regard, the oil extracted from C. aurantium flowers shows a potential therapeutic application for the treatment of anxiety disorders. However, more studies are needed to elucidate its complete role on the CNS and to verify and prove its safety and efficacy profile. El acero esencial de C. aurantium ha sido ampliamente estudiado por su potencial acción ansiolítica neroli sobre varios receptores del Sistema Nervioso Central (SNC). Aunque presenta variaciones en su composición fitoquímica dependiendo de su origen, podemos destacar que muchos compuestos siguen presentes, como el linalol que demostró actividad antagonista sobre los receptores glutamatérgicos, posible acción inhibidora de los receptores de noradrenalina neroli serotonina, además de la capacidad de activar los receptores GABA en asociación con algunos flavonoides presentes en el aceite. Es mundialmente conocido que la patología subyacente llamada ansiedad influye en todo el mundo como antecedente de trastornos psicológicos neroli físicos conflictivos, que se asocian a diversas alteraciones neuronales. Por todo ello, el aceite extraído de las flores de C. aurantium muestra una potencial aplicación terapéutica para el tratamiento de los trastornos de ansiedad. Sin embargo, se necesitan más estudios para dilucidar todo su papel en el SNC para verificar i probar su perfil de seguridade i eficacia. O óleo essencial da C. aurantium tem sido amplamente estudado devido a seu potencial ação ansiolítico e sobre diversos receptores do Sistema Nervoso Central (SNC). Apesar de apresentar variações em sua composição fitoquímica a depender da sua origem, podemos destacar que muitos compostos se mantêm presentes, como o linalol que demostrou atividade antagônica sobre receptores glutamatérgicos, possível ação inibitória da receptação de noradrenalina e serotonina, além disso, capacidade ativar receptores GABA em associação com alguns flavonoides presente no óleo. É de conhecimento global que a patologia subjacente denominada como ansiedade, influi mundialmente como antecedente de conflitantes transtornos psicológicos e físicos, os quais estão associados a diversos distúrbios neuronais. Diante do exposto o óleo extraído das flores de C. aurantium demonstra um potencial aplicação terapêutica para o tratamento de transtornos de ansiedade. Entretanto, faz-se necessário mais estudos para a elucidação do seu papel completo sobre o SNC e para que seu perfil de segurança e eficácia, possam ser verificados e comprovados.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social behaviors and communication. In rodents and humans, prenatal exposure to antiepileptic valproic acid is associated with an increased risk for autistic-like characteristics. One potential treatment is oxytocin, a prosocial neuropeptide that can be delivered intranasally. However, the sex-specific effects of valproic acid exposure and intranasal oxytocin treatment on behavior have not been fully explored. Pregnant Long Evans rats were administered valproic acid (500 mg/kg) or saline midday on gestational day 12, and after weaning, male and female pups were assigned to control (saline-saline), valproic acid-saline, or valproic acid-oxytocin groups. Oxytocin (0.8 IU/kg) or saline was delivered intranasally 30-60 min before tests for anxiety-like behaviors (elevated plus maze), social interactions (sociability) and sociosexual behaviors (partner preference, 50 kHz vocalizations and scent marking). Prenatal exposure to valproic acid resulted in sex-specific differences in behavior. When compared to controls, valproic acid males showed enhanced anxiety-like behaviors in adolescence and fewer scent marks in adulthood, while valproic acid females showed reduced sexual (partner) preference as adults. Intranasal oxytocin was anxiolytic for valproic acid males, but moderately anxiogenic for valproic acid females, and in both sexes it surprisingly impaired social interactions in the sociability test. Furthermore, intranasal oxytocin failed to improve sociosexual deficits in valproic acid rats. These findings highlight the importance of conducting preclinical studies in both sexes, and suggest that oxytocin may be an effective treatment in animal models with heightened anxiety-like behaviors.

Objectives Medicine reviews are an opportunity to identify and address inappropriate prescribing. The aim of this study was to explore changes in benzodiazepine use among older Australians following a medicine review. Study type Retrospective observational cohort study using linked administrative data. Methods We used Medicare Benefits Schedule and Pharmaceutical Benefits Scheme claims from a random 10% sample of Medicare beneficiaries. We identified people aged 65 years or older who received a medicine review in 2013-14 and were using benzodiazepines at the time of review. We identified a propensity score matched comparison cohort of those using benzodiazepines who did not receive a review. Two outcome measures were used: any benzodiazepine use and changes to the quantity of benzodiazepines dispensed (diazepam equivalents) from baseline to 90 and 180 days following a medicine review. Results We identified 4002 people using benzodiazepines on the day of their medicine review, of whom approximately one-third discontinued benzodiazepines within 90 days (29.7%) and 180 days (36.4%;) after the review. We observed a similar discontinuation rate in the comparison group (32.6%, p = 0.006; and 38.0%, p = 0.12, respectively). In people who were dispensed lower quantities of benzodiazepines (less than 250 mg of diazepam equivalents in the 90 days before the medicine review), we found that 50.3% ceased using benzodiazepines or used lower quantities (measured as diazepam equivalents) following the medicine review (28.7% and 19.7% respectively). We also observed a reduction in the quantities used in people where initial exposure was high (3.4% ceased; 59.4% decreased). We observed a similar change in volume within the matched comparison group. Conclusions Medicine reviews are not associated with any additional reduction in benzodiazepine use among older adults, up to 180 days after review, beyond what was observed in the general population.

Background Oxytocin (OXT), a neuropeptide involved in mammal reproductive and prosocial behaviors, has been reported to interact with various stressor-provoked neurobiological changes, including neuroendocrine, neurotransmitter, and inflammatory processes. In view of disturbances in psychosocial relationships due to social isolation and physical distancing measures amid the COVID-19 pandemic, being one of the triggering factors for the recent rise in depression and anxiety, OXT is a potential candidate for a new antidepressant. Methods In this present study, we have aimed to investigate the effects of oral administration of Rosmarinus officinalis extract (RE), extracted from distillation residue of rosemary essential oil, on central OXT level in the context of other stress biomarkers and neurotransmitter levels in mice models. Tail suspension test (TST) and elevated plus maze test (EPMT) following LPS injection were employed to assess depressive- and anxiety-like behavior in mice, respectively. Findings Pretreatment with RE for seven days significantly improved behavior in TST and EPMT. Whole-genome microarray analysis reveals that RE significantly reversed TST stress-induced alterations in gene expressions related to oxytocinergic and neurotransmitter pathways and inflammatory processes. In both models, RE significantly increased central Oxt and Oxtr expressions, as well as OXT protein levels. RE also significantly attenuated stress-induced changes in serum corticosterone, brain and serum BDNF levels, and brain neurotransmitters levels in both models. Interpretation Altogether, our study is the first to report antidepressant- and anxiolytic-like activities of RE through modulating oxytocinergic system in mice brain and thus highlights the prospects of RE in the treatment of depressive disorders of psychosocial nature.

Objective To perform a systematic review of the diagnosis and treatment of patients with pulsatile tinnitus secondary to middle ear myoclonus. Databases reviewed PubMed, EMBASE, and Scopus. Methods A systematic review was performed using standardized methodology. Computerized and manual searches were performed to identify studies of all ages (patients) who had middle ear myoclonus (intervention). All study designs were assessed. Extracted data included demographics, clinical features, duration of followup as well as the diagnosis and reversibility of symptoms with medical or surgical intervention. Studies were included if they included subjects with middle ear myoclonus. Exclusion criteria included letters/commentaries and reviews. Results Twenty articles representing 115 subjects with middle ear myoclonus were included. The mean age was 29.7 (range 6–67). The follow-up period ranged from 5 weeks to 36 months. Primary treatment consists of medical therapy utilising anxiolytics, antiepileptics, botulinum toxin and surgical treatment involving division of middle ear muscular tendon(s). In total, 60 patients underwent middle ear muscular tenotomies, with division of both stapedius and tensor tympani tendons being the most prevalent (88%). Limitations in the data arose from study design, related comorbidities such as palatal myoclonus, and concomitant drug administration. No study provided any objective criteria to diagnose this condition or evaluate post-treatment outcome. Conclusion Middle ear myoclonus is an entity that is poorly assessed in the literature. There is a lack of consensus regarding the criteria and strategies for both diagnosing and treating this condition. Although level of evidence of current studies remains modest, it is felt that a stepwise approach is deemed best, with therapeutic decisions being made on an individual basis, evaluating each patient's specific circumstances and priorities.