Endocannabinoid Hydrolase Inhibitors: Potential Novel Anxiolytic Drugs.

Over the past decade, the idea of targeting the endocannabinoid system to treat anxiety disorders has received increasing attention. Previous studies focused more on developing cannabinoid receptor agonists or supplementing exogenous cannabinoids, which are prone to various adverse effects due to their strong pharmacological activity and poor receptor selectivity, limiting their application in clinical research. Endocannabinoid hydrolase inhibitors are considered to be the most promising development strategies for the treatment of anxiety disorders. More recent efforts have emphasized that inhibition of two major endogenous cannabinoid hydrolases, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), indirectly activates cannabinoid receptors by increasing endogenous cannabinoid levels in the synaptic gap, circumventing receptor desensitization resulting from direct enhancement of endogenous cannabinoid signaling. In this review, we comprehensively summarize the anxiolytic effects of MAGL and FAAH inhibitors and their potential pharmacological mechanisms, highlight reported novel inhibitors or natural products, and provide an outlook on future directions in this field.

Microbiome Metabolomic Analysis of the Anxiolytic Effect of Baihe Dihuang Decoction in a Rat Model of Chronic Restraint Stress.

Purpose: The Baihe Dihuang decoction (BDD) is a representative traditional Chinese medicinal formula that has been used to treat anxiety disorders for thousands of years. This study aimed to reveal mechanisms of anxiolytic effects of BDD with multidimensional omics. Methods: First, 28-day chronic restraint stress (CRS) was used to create a rat model of anxiety, and the open field test and elevated plus maze were used to assess anxiety-like behavior. Enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin staining, and immunofluorescence staining were used to evaluate inflammatory response. Besides, 16S rRNA gene sequencing assessed fecal microbiota composition and differential microbiota. Non-targeted metabolomics analysis of feces was performed to determine fecal biomarkers, and targeted metabolomics was used to observe the levels of hippocampus neurotransmitters. Finally, Pearson correlation analysis was used to examine relationships among gut microbiota, fecal metabolites, and neurotransmitters. Results: BDD significantly improved anxiety-like behaviors in CRS-induced rats and effectively ameliorated hippocampal neuronal damage and abnormal activation of hippocampal microglia. It also had a profound effect on the diversity of microbiota, as evidenced by significant changes in the abundance of 10 potential microbial biomarkers at the genus level. Additionally, BDD led to significant alterations in 18 fecal metabolites and 12 hippocampal neurotransmitters, with the majority of the metabolites implicated in amino acid metabolism pathways such as D-glutamine and D-glutamate, alanine, arginine and proline, and tryptophan metabolism. Furthermore, Pearson analysis showed a strong link among gut microbiota, metabolites, and neurotransmitters during anxiety and BDD treatment. Conclusion: BDD can effectively improve anxiety-like behaviors by regulating the gut-brain axis, including gut microbiota and metabolite modification, suppression of hippocampal neuronal inflammation, and regulation of neurotransmitters.

An ultra-short-acting benzodiazepine in thalamic nucleus reuniens undermines fear extinction via intermediation of hippocamposeptal circuits.

Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, here we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

Unraveling the multi-faceted role of Rosmarinus officinalis L. (rosemary) and diosmetin in managing gut motility.

ETHNOPHARMACOLOGICAL RELEVANCE: Rosmarinus officinalis L. (Rosemary) is a popular herb with reported effectiveness against diarrhea, anxiety and constipation, albeit with limited pharmacological evidence. AIM OF THE STUDY: The current study was aimed at evaluating the therapeutic potential, possible pharmacological mechanisms of action and active constituents of hydro-ethanolic extract of rosemary (Rs.Cr), as potential anti-diarrheal, laxative and anxiolytic agent. METHOD: Rs.Cr was analyzed through reverse-phase high pressure liquid chromatography (RP-HPLC). Laxative, antidiarrheal, and anxiolytic activities were assessed using in vivo models. Spasmogenic and spasmolytic mechanisms were studied on isolated guinea pig ileum and rabbit jejunum tissues, respectively. Possible role of diosmetin, one of the active constituents of Rs.Cr was also evaluated. RESULTS: RP-HPLC analysis revealed presence of diosmetin, rutin and apigenin in Rs.Cr. Laxative effect was seen at low doses, which was partially reversed in atropinized mice. The spasmogenic mechanism was mediated by cholinergic and histaminergic receptors stimulation. At higher doses, antidiarrheal activity was evident, with reduction in gastrointestinal motility and secretions using charcoal meal and enteropooling assays, respectively. Rs.Cr also showed dose-dependent anxiolytic effect. The antispasmodic mechanisms were mediated by anti-muscarinic and K+ channel opening-like effect (predominant KATP-dependent). Diosmetin exhibited antidiarrheal and antispasmodic activities, but spasmogenic effect was not seen. CONCLUSION: Rosemary leaves have dual antidiarrheal and laxative effects, and as well as anxiolytic activity. In addition, the possible modulation of muscarinic and histaminergic receptors, and KATP channels show it as potential herb to be explored for irritable bowel syndrome. Diosmetin is possibly one of its constituents that contributes to its antidiarrheal activity.

Evaluation of the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol oral solution (150 mg/mL) versus placebo in mild to moderate anxiety subjects: A double blind multicenter randomized clinical trial.

BACKGROUND: Anxiety disorders, an increasingly prevalent global mental health illness, affected approximately 301 million individuals worldwide in 2019. There is an unmet need for the treatment of anxiety disorders, as current therapies are associated with limited response rates, residual symptoms, and adverse effects. OBJECTIVES: To evaluate the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol (CBD) oral solution versus placebo for the treatment of mild to moderate anxiety disorders. METHODS: This phase 3 prospective, randomized, double blind, parallel group, placebo-controlled, 15-week cohort study took place at multiple sites across India. Eligible participants were randomly assigned to one of the two treatment arms (CBD or placebo) in a 1:1 ratio. RESULTS: 178 participants were randomized to receive CBD (n=89) or placebo (n=89). The study met both primary (GAD-7 and HAM-A scores) and secondary outcomes (CGI-I, CGI-S, PHQ-9 and PSQI scores). The GAD-7 score difference between the end of treatment and baseline for the CBD versus the placebo was -7.02 (S.E: 0.25, 95% CI -7.52; -6.52), p<0.0001. Similarly, the HAM-A score difference at the end of treatment compared to baseline for the CBD versus the placebo was -11.9 (S.E: 0.33, 95% CI -12.6; -11.3), p<0.0001. CONCLUSIONS: Nanodispersible CBD was therapeutically safe with no serious adverse events, well tolerated, and effective for the treatment of mild to moderate anxiety disorders, as well as associated depression and sleep quality disturbances. These results pave way for probable prospective use of nanodispersible CBD formulation for various psychiatry disorders alone or in conjunction with other drugs.

Synthesis, evaluation of biological activity and SAR of new thioalkyl derivatives of pyridine.

BACKGROUND: Pyridine and its derivatives play a vital role in medicinal chemistry, serving as key scaffolds for drugs. The ability to bind to biological targets makes pyridine compounds significant, sparking interest in creating new pyridine-based drugs. Thus, the purpose of the research is to synthesize new thioalkyl derivatives of pyridine, predict their biological spectrum, study their psychotropic properties, and based on these findings, perform structure-activity relationships to assess pharmacophore functional groups. METHODS: Classical organic methods were employed for synthesizing new thioalkyl derivatives of pyridine, with a multifaceted pharmacological profiles. Various software packages and methods were employed to evaluate the biological spectrum of the newly synthesized compounds. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. RESULTS: Effective synthetic methods for 6-amino-4-phenyl-2-thio-2H-thiopyran-5-carboxylic acid ethyl ester, 2-amino substituted thiopyridine derivatives and 6-cycloamino-2-thioalkyl-4-phenylnicotinate derivatives were obtained in high yield. Predicted biological spectra and pharmacokinetic data indicated high gastrointestinal absorption and low blood-brain barrier passage for most compounds and demonstrated potential various biological effects, particularly psychotropic properties. Studied compounds demonstrated high anticonvulsant activity through antagonism with pentylenetetrazole. They exhibited low toxicity without inducing muscle relaxation in the studied doses. In psychotropic studies, the compounds displayed activating, sedative, and anxiolytic effects. Notably, the 6-amino-2-thioalkyl-4-phenylnicotinate derivatives demonstrated significant anxiolytic activity (about four times more compared to diazepam). They also exhibited pronounced sedative effects. Ethyl 2-({2-[(diphenylmethyl)amino]-2-oxoethyl}thio)-4-phenyl-6-pyrrolidin-1-ylnicotinate exhibited anxiolytic activity even two times greater than diazepam. Moreover, all studied compounds showed statistically significant antidepressant effects. Noteworthy ethyl 2-({2-oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}thio)-4-phenyl-6-pyrrolidin-1-ylnicotinate showcasing its unique psychotropic effect. CONCLUSIONS: The selected compounds demonstrate anticonvulsant properties, activating behavior, and anxiolytic effects, while simultaneously exhibiting antidepressant effects and these compounds as promising candidates for further exploration in the development of therapeutics with a broad spectrum of neuropsychiatric applications.

Anxiolytic-like effects of milk proteins.

Milk varieties and specific proteins exhibit anxiolytic-like actions in mice and rats exposed to several tests, the most prominent being the elevated plus-maze. Administrations of αs1-casein, its 91-100 (α-casozepine), 91-97, 91-93, and 91-92 fragments, the 60-69 fragment of ß-casein, lactoferrin, ß-lactotensin, wheylin-1, wheylin-2, and α-lactalbumin have been reported to increase open arm exploration relative to enclosed arm exploration. Anxiolytic-like actions have also been described for 91-93 and 91-92 fragments of αs1-casein, wheylin-1, α-lactalbumin, and lactoferrin in the open-field. Some effects appear to be mediated by the GABAA receptor complex, since antagonists mitigated the anxiolytic-like actions of αs1-casein, the 91-92 fragment of αs1-casein, and wheylin-1. Other neurotransmitters purported to affect such behaviors include 5HT, dopamine, and neurotensin. Further research is needed to identify their neuropharmacological actions.

Preoperative Anxiolytic and Sedative Effects of Intranasal Remimazolam and Dexmedetomidine: A Randomized Controlled Clinical Study in Children Undergoing General Surgeries.

Purpose: Remimazolam, an ultra-short-acting and fast-metabolized sedative, has only been sporadically investigated in children. This study was performed to determine the beneficial effects of intranasal remimazolam or dexmedetomidine on preoperative anxiety in children undergoing general surgeries. Patients and Methods: Ninety children were randomly and equally assigned to Group R (intranasal remimazolam 1.5mg kg-1), Group D (intranasal dexmedetomidine 2 mcg kg-1), and Group C (intranasal distilled water). The primary outcomes were the preoperative anxiety scores using the modified Yale preoperative anxiety scale (m-Ypas). The secondary outcomes included the cooperation behaviour of intranasal drug application, preoperative sedation levels, parental separation anxiety scores (PSAS), and mask acceptance scores (MAS). Results: Group R showed a significant low anxiety at 10 min after intranasal premedication (vs group C, P=0.010; vs group D, P = 0.002) and at anaesthesia induction (vs group C, P = 0.004). Group D showed a significantly low anxiety score only prior to anaesthesia induction (vs group C, P = 0.005). Most children in group R achieved mild sedation at 10 min (vs group C, P < 0.001; vs group D, P < 0.001), with a few progressing to deep sedation afterwards, while group D tended toward deep sedation. Compared to Group C, patients in Group R performed significantly better on the MAS (P = 0.014) and PSAS (P = 0.008). However, remimazolam did cause poor cooperation behavior to the intranasal application due to its mucosal irritation (vs group C, P = 0.001; vs group D, P = 0.010). Conclusion: Both intranasal remimazolam and dexmedetomidine can effectively alleviate preoperative anxiety in children. While intranasal remimazolam has a rapid onset, it produces only mild sedation and causes substantial nasal irritation. Trial Registration: NCT04720963, January 22, 2021, ClinicalTrials.Gov.

Geraniol mitigates anxiety-like behaviors in rats by reducing oxidative stress, repairing impaired hippocampal neurotransmission, and normalizing brain cortical-EEG wave patterns after a single electric foot-shock exposure.

Anxiety-like conditions can interfere with daily activities as the adaptive mechanism fails to cope with stress. These conditions are often linked with increased oxidative stress, and abrupt neurotransmission and electroencephalography (EEG) wave pattern. Geraniol, a monoterpenoid, has antioxidant and anti-inflammatory activities, as well as brain-calming effects. Therefore, in this study, geraniol was tested for the potential anxiolytic effects in a rat model of anxiety. The rats were exposed to an electric foot shock (1 mA for 1 s) to develop anxiety-like symptoms. Treatment was carried out using geraniol (10 and 30 mg/kg) and the standard diazepam drug. The behavior of the rats was analyzed using the open field test, light-dark test, and social interaction test. Afterward, the rats were decapitated to collect samples for neurochemical and biochemical analyses. The cortical-EEG wave pattern was also obtained. The study revealed that the electric foot shock induced anxiety-like symptoms, increased oxidative stress, and altered hippocampal neurotransmitter levels. The power of low-beta and high-beta was amplified with the increased coupling of delta-beta waves in anxiety group. However, the treatment with geraniol and diazepam normalized cortical-EEG wave pattern and hippocampal serotonin and catecholamines profile which was also reflected by reduced anxious behavior and normalized antioxidant levels. The study reports an anxiolytic potential of geraniol, which can be further explored in future.

Analgesic and Psychotropic Effects of a New Bradykinin Antagonist.

A bradykinin B1 receptors antagonist PAV-0056, an 1,4-benzodiazepin-2-one derivative, intragastrically administrated to mice at doses of 0.1 and 1 mg/kg causes analgesia in the "formalin test" not inferior to that of diclofenac sodium (10 mg/kg) and tramadol (20 mg/kg). PAV-0056 at doses of 0.1 and 10 mg/kg has no anxiolytic and central muscle relaxant effects in mice and does not damage the gastric mucosa in rats. Based on the results of the conditioned place preference test, PAV-0056 also does not induce addiction in mice.

Synergistic anxiolytic efficacy exploring the combined effects of diazepam and zinc chloride in wistar albino rats.

Combinations of medications are frequently employed when their effects are similar. Beyond aiding in the reduction of medication dosages, this approach may yield additional positive outcomes. Studies have shown that zinc can mitigate anxiety-related behavior in laboratory animals. This study aimed to investigate the potential stabilizing effects of zinc chloride and diazepam in Wistar albino rats.Five groups, each comprising six animals. Test groups included two combinations of zinc chloride and diazepam, each with two different doses of diazepam (1 and 2 mg/kg) and 10 mg/kg of zinc chloride. Four established anxiety models-the Elevated Plus Maze (EPM), the hole board, the light and dark box, and the mirror chamber-were employed to assess the anxiolytic effects. The combination of zinc chloride and diazepam proved to be more effective than the individual doses of zinc chloride and diazepam, indicating enhanced anxiolytic effects.

Indulging Curiosity: Preliminary Evidence of an Anxiolytic-like Effect of Castor Oil and Ricinoleic Acid.

In the process of validating the elevated zero maze, a common test of anxiety-like behavior, in our laboratory, we demonstrated an anxiolytic-like effect of castor oil and its primary component, ricinoleic acid. We tested the effects of vehicle and chlordiazepoxide in male mice in the elevated zero maze following a 30-min pretreatment time. Chlordiazepoxide is a United States Food and Drug Administration-approved drug that was previously shown to exert anxiolytic-like effects in both the elevated zero maze and elevated plus maze. Chlordiazepoxide was administered at doses of 5 or 10 mg/kg. We used 5% polyoxyl 35 castor oil (Kolliphor® EL) and saline as treatment vehicles and found that the effect of chlordiazepoxide on open zone occupancy and open zone entries was blunted when 5% Kolliphor was used as the vehicle. These tests demonstrated that chlordiazepoxide increased open zone occupancy and entries in the elevated zero maze more effectively when saline was used as the treatment vehicle and that Kolliphor dampened the anxiolytic-like effect of chlordiazepoxide when it was used as the treatment vehicle. Notably, 5% Kolliphor alone slightly increased baseline open zone occupancy and entries. Given that Kolliphor is a derivative of castor oil, we next tested the effect of 5% castor oil and 5% ricinoleic acid, which is a major component of castor oil. We found that both castor oil and ricinoleic acid increased open zone occupancy but not entries compared with saline. Altogether, our findings demonstrate that Kolliphor, castor oil, and ricinoleic acid may exert anxiolytic-like effects in male mice in the elevated zero maze. This potential anxiolytic-like effect of castor oil is consistent with its well-established beneficial effects, including anti-inflammatory, antioxidant, antifungal, and pain-relieving properties.

Dexmedetomidine alleviates acute postoperative anxiety in rats by suppressing the NF-ĸB pathway.

Evidence suggests that surgical procedures can effect the central nervous system and lead to changes in mood and behavior, rarely understood about the role of acute inflammation in promoting acute anxiety postoperatively. This study was designed to explore the possible mechanism of dexmedetomidine (DEX, a2-adrenergic receptor agonist) for reducing acute postoperative anxiety, which may be related to the activation of nuclear factor kappa B (NF-κB) and downstream signal pathway in the hippocampus. Experiments were conducted with rat, the elevated plus-maze and open field test were performed to evaluate anxiety-like behavior. Inhibit DEX with Atipamezole (AT, α2-adrenergic receptor antagonist) and inhibit NF-κB with Pyrrolidinedithiocarbamate (PDTC, inhibit phosphorylation of IκB, prevent the activation of NF-κB), the level of interleukin-6 (IL-6), IL-1ß, IL-10 and Tumor necrosis factor-α (TNF-α); the nuclear translocation of NF-κB in the hippocampus and anxiety-like behavior were measured. Rats exhibited anxiety-like behavior at 6h and 12h after surgery. Preoperative administration of DEX significantly alleviated postoperative anxiety-like behavior. DEX premedication inhibited the nuclear translocation of NF-κB alleviate acute postoperative anxiety. These findings are the first to show that acute postoperative anxiety may be related to NF-κB nuclear translocation in the hippocampus in rats, which can be alleviated by DEX premedication.

Consensus Panel Recommendations for the Pharmacological Management of Breastfeeding Women with Postpartum Depression.

INTRODUCTION: Our consensus statement aims to clarify the use of antidepressants and anxiolytics during breastfeeding amidst clinical uncertainty. Despite recent studies, potential harm to breastfed newborns from these medications remains a concern, leading to abrupt discontinuation of necessary treatments or exclusive formula feeding, depriving newborns of benefits from mother's milk. METHODS: A panel of 16 experts, representing eight scientific societies with a keen interest in postpartum depression, was convened. Utilizing the Nominal Group Technique and following a comprehensive literature review, a consensus statement on the pharmacological treatment of breastfeeding women with depressive disorders was achieved. RESULTS: Four key research areas were delineated: (1) The imperative to address depressive and anxiety disorders during lactation, pinpointing the risks linked to untreated maternal depression during this period. (2) The evaluation of the cumulative risk of unfavorable infant outcomes associated with exposure to antidepressants or anxiolytics. (3) The long-term impact on infants' cognitive development or behavior due to exposure to these medications during breastfeeding. (4) The assessment of pharmacological interventions for opioid abuse in lactating women diagnosed with depressive disorders. CONCLUSIONS: The ensuing recommendations were as follows: Recommendation 1: Depressive and anxiety disorders, as well as their pharmacological treatment, are not contraindications for breastfeeding. Recommendation 2: The Panel advocates for the continuation of medication that has demonstrated efficacy during pregnancy. If initiating an antidepressant during breastfeeding is necessary, drugs with a superior safety profile and substantial epidemiological data, such as SSRIs, should be favored and prescribed at the lowest effective dose. Recommendation 3: For the short-term alleviation of anxiety symptoms and sleep disturbances, the Panel determined that benzodiazepines can be administered during breastfeeding. Recommendation 4: The Panel advises against discontinuing opioid abuse treatment during breastfeeding. Recommendation 5: The Panel endorses collaboration among specialists (e.g., psychiatrists, pediatricians, toxicologists), promoting multidisciplinary care whenever feasible. Coordination with the general practitioner is also recommended.

Neuro-protective effect of pre-treatment with Sorghum bicolor and vitamin C on tramadol induced brain oxidative stress and anxiety-like behaviour in male albino rats.

The study focused on the neuroprotective role of Sorghum bicolor and vitamin C in the amelioration of oxidative stress and anxiety-like behavoiur induced by tramadol in male albino rats. The study design involved 7 groups and a control group with 5 male albino rats in each group. Tramadol (40 mg/kg) treatment was administered for 21 days. Tramadol 40mg/kg was administered in all groups. Pretreatment with varying doses of Sorghum bicolor and Vitamin C was done in three of the groups. Behavioral assessment of anxiety and locomotors actions of the groups were compared using Elevated Plus Maze (EPM) and Open Field Test (OFT). In conclusion, Sorghum bicolor and Vitamin C tramadol ameliorated oxidative stress and anxiety-like behaviour induced by tramadol. Pretreatment with Sorghum bicolor or vitamin C (100mg) can also reduced anxiogenic responses in male albino rats that are induced by chronic tramadol use.

Behavioural impacts of following administration of Ficus carica leaves extract in animal model of acute and chronic unpredictable mild stressed exposed rats.

Stress is described as a noxious stimulus that affects the health of an individual and alters body homeostasis resulting in changes the individual behavioural and metabolic condition. Synthesis of drug from plants has main interest due the significant medicinal values. The recent investigation was designed to examine the pharmacological impacts of Ficus carica leaves extract on stress. In this experiment, the rodents were randomly distributed as (n=6) control rats were kept at standard condition, second group of rats were exposed with different stressors and Third group of rodents was exposed to stress and treated with extract of ficus carica leaves at the dose of 100 mg/kg. Acute behavioural alteration was observed after 7 days and prolonged impact was monitored after the 28 days. The current finding showed that administration of Ficus carica leaves extract produced anxiolytic behaviours and decreased depression like symptoms in CUMS treated rats. It also increased stimulatory, ambulatory, locomotor activity and enhanced spatial working memory and recognition memory in CUMS exposed rats. So, it can be concluded from recent study that leaves of Ficus carica can be utilized as secure drug for curing physiological stress with less side effect profile.

Jnk1 and downstream signalling hubs regulate anxiety-like behaviours in a zebrafish larvae phenotypic screen.

Current treatments for anxiety and depression show limited efficacy in many patients, indicating the need for further research into the underlying mechanisms. JNK1 has been shown to regulate anxiety- and depressive-like behaviours in mice, however the effectors downstream of JNK1 are not known. Here we compare the phosphoproteomes from wild-type and Jnk1-/- mouse brains and identify JNK1-regulated signalling hubs. We next employ a zebrafish (Danio rerio) larvae behavioural assay to identify an antidepressant- and anxiolytic-like (AA) phenotype based on 2759 measured stereotypic responses to clinically proven antidepressant and anxiolytic (AA) drugs. Employing machine learning, we classify an AA phenotype from extracted features measured during and after a startle battery in fish exposed to AA drugs. Using this classifier, we demonstrate that structurally independent JNK inhibitors replicate the AA phenotype with high accuracy, consistent with findings in mice. Furthermore, pharmacological targeting of JNK1-regulated signalling hubs identifies AKT, GSK-3, 14-3-3 ζ/ε and PKCε as downstream hubs that phenocopy clinically proven AA drugs. This study identifies AKT and related signalling molecules as mediators of JNK1-regulated antidepressant- and anxiolytic-like behaviours. Moreover, the assay shows promise for early phase screening of compounds with anti-stress-axis properties and for mode of action analysis.

Management of physical and psychological trauma resulting from motor vehicle crashes in Australian general practice: a mixed-methods approach.

BACKGROUND: In Australia, motor vehicle crashes (MVC)-related health data are available from insurance claims and hospitals but not from primary care settings. This study aimed to identify the frequency of MVC-related consultations in Australian general practices, explore the pharmacological management of health conditions related to those crashes, and investigate general practitioners' (GPs) perceived barriers and enablers in managing these patients. METHODS: Mixed-methods study. The quantitative component explored annual MVC-related consultation rates over seven years, the frequency of chronic pain, depression, anxiety or sleep issues after MVC, and management with opioids, antidepressants, anxiolytics or sedatives in a sample of 1,438,864 patients aged 16 + years attending 402 Australian general practices (MedicineInsight). Subsequently, we used content analysis of 81 GPs' qualitative responses to an online survey that included some of our quantitative findings to explore their experiences and attitudes to managing patients after MVC. RESULTS: MVC-related consultation rates remained stable between 2012 and 2018 at around 9.0 per 10,000 consultations. In 2017/2018 compared to their peers, those experiencing a MVC had a higher frequency of chronic pain (48% vs. 26%), depression/anxiety (20% vs. 13%) and sleep issues (7% vs. 4%). In general, medications were prescribed more after MVC. Opioid prescribing was much higher among patients after MVC than their peers, whether they consulted for chronic pain (23.8% 95%CI 21.6;26.0 vs. 15.2%, 95%CI 14.5;15.8 in 2017/2018, respectively) or not (15.8%, 95%CI 13.9;17.6 vs. 6.7%, 95% CI 6.4;7.0 in 2017/2018). Qualitative analyses identified a lack of guidelines, local referral pathways and decision frameworks as critical barriers for GPs to manage patients after MVC. GPs also expressed interest in having better access to management tools for specific MVC-related consequences (e.g., whiplash/seatbelt injuries, acute/chronic pain management, mental health issues). CONCLUSION: Chronic pain, mental health issues and the prescription of opioids were more frequent among patients experiencing MVC. This reinforces the relevance of appropriate management to limit the physical and psychological impact of MVC. GPs identified a lack of available resources (e.g. education, checklists and management support tools) for managing MVC-related consequences, and the need for local referral pathways and specific guidelines to escalate treatments.

Toxicity of benzodiazepines in the treatment of insomnia disorders in older adults: a systematic literature review.

AIM: To review the literature data on the prevalence of benzodiazepines abuse and poisoning in older adults; the prevalence of polypharmacy with benzodiazepines in this demographic; and determine whether benzodiazepine anxiolytics or hypnotics were more frequently implicated in the cases of abuse and poisoning. METHODS: We searched PubMed and Scopus for relevant studies published from January 1, 2013, to May 1, 2023. Twelve studies were included in the final selection. RESULTS: The review highlights the diverse prevalence rates of benzodiazepine abuse and poisoning in the older adult population. Benzodiazepine anxiolytics were more frequently associated with negative outcomes than benzodiazepine hypnotics. Concurrent use of benzodiazepines, benzodiazepine-related medications, and opioids was reported, although these medications were not the only ones commonly used by the elderly. CONCLUSION: It is essential to increase awareness about adhering to prescribed pharmacological therapies to mitigate issues related to drug abuse and poisoning among older adults.

Treatment of Anxiety Disorders in Primary Care: What Nurse Practitioners Need to Know.

Anxiety disorders are the most common mental illnesses and frequently co-occur with other mental and somatic symptoms or disorders. Primary care nurse practitioners (NPs) are key in reducing the treatment gap through early identification, treatment, and/or referral to behavioral health providers. Confronting primary care NPs are problems with time constraints, multiple comorbidities, and limited mental health training, particularly in relation to the differences in pharmacokinetic and pharmacodynamic actions of first-line anxiety disorder medications across age groups. The current article provides a brief summary of evidence-based treatment focusing on pharmacotherapy for anxiety disorders in the primary care setting. [Journal of Psychosocial Nursing and Mental Health Services, 62(5), 7-10.].