Observational evidence linking psychotropic medicines to the dispensing of opioid agents in later life.

BACKGROUND: The use of opioid medicines is common in developed countries, particularly among older adults and those with mental health disorders. It is unclear if the association between mental disorders and opioid medicines is causal, or is due to reverse causality or confounding. METHODS: We used a 10% random sample of the Australian Pharmaceutical Benefits Scheme (years 2012-2022) to examine the cross-sectional, case-control and longitudinal association between the dispensing of antidepressants, anxiolytics, hypnotics, antipsychotics and lithium, and opioid medicines. We used logistic regression, structural equation models (SEM), and Cox regression to analyze the data. Analyses were adjusted for age (years), sex, and number of non-psychotropic medicines dispensed during the year. RESULTS: The 2022 file contained 804 334 individuals aged 50 years or over (53.1% women), of whom 181 690 (22.6%) received an opioid medicine. The adjusted odds ratio of being dispensed opioid medicines was 1.44 (99% CI = 1.42-1.46) for antidepressants, 1.97 (99% CI = 1.92-2.03) for anxiolytics, 1.55 (99% CI = 1.51-1.60) for hypnotics, 1.32 (99% CI = 1.27-1.38) for antipsychotics, and 0.60 (99% CI = 0.53-0.69) for lithium. Similar associations were noticed when we compared participants who were or not dispensed opioid medicines in 2022 for exposure to psychotropic agents between 2012 and 2021. SEM confirmed that this association was not due to reverse causality. The dispensing of antidepressants was associated with increased adjusted hazard (HR) of subsequent dispensing of opioid medicines (HR = 1.29, 99% CI = 1.27-1.30). Similar associations were observed for anxiolytics, hypnotics and antipsychotics, but not lithium. CONCLUSIONS: The dispensing of opioid medicines is higher among older individuals exposed to antidepressants, anxiolytics, hypnotics and antipsychotics than those who are not. These associations are not due to reverse causality or study design. Preventive strategies seeking to minimise the risk of inappropriate use of opioid medicines in later life should consider targeting this high-risk population.

Easing the Burden of Tinnitus: A Narrative Review for Exploring Effective Pharmacological Strategies.

Many individuals seek medical attention for tinnitus, desiring relief from the distress caused by the condition; however, the treatment process is far from straightforward. The most effective treatments for chronic subjective tinnitus, such as tinnitus retraining therapy (TRT) and cognitive behavioral therapy (CBT), require considerable time and efforts. As a result, many of them express a desire for alleviation through medication. While it is true that medication is not generally recommended in treatment guidelines for chronic subjective tinnitus, in specific situations such as when accompanied by symptoms of depression or anxiety-drugs like antidepressants or anxiolytics may have a meaningful impact on symptom reduction. Additionally, medication can prove effective in certain specialized forms of tinnitus, such as typewriter tinnitus, as opposed to chronic subjective tinnitus. Although intratympanic dexamethasone injections for tinnitus have been reported to lack efficacy compared to a placebo, if patients perceive subjective satisfaction due to a placebo effect, it holds significance. From the perspective of patients suffering from tinnitus, even if the therapeutic mechanism is set aside, experiencing some degree of relief through certain medications can enhance compliance with evidence-based treatments like TRT and CBT.

Orally administered gabapentin and alprazolam induce comparable levels of anxiolysis and sedation in cats.

OBJECTIVE: To assess the level of anxiolysis achieved by alprazolam and gabapentin in hospitalized cats prior to elective ovariohysterectomy and to evaluate the sedative effects of these agents. ANIMALS: 60 client-owned female cats classified as American Society of Anesthesiologists physical status 1, admitted for elective ovariohysterectomy at a veterinary teaching hospital. METHODS: The cats were prospectively and randomly allocated into 3 groups. Ninety minutes before evaluation, group G received gabapentin (100 mg/cat), group A received alprazolam (0.125 mg/cat), and group P received no medication (placebo). Stress, enclosure activity, and sedation scores were blindly evaluated. RESULTS: Stress scores were similar in cats treated with gabapentin and alprazolam and gabapentin-treated cats had significantly lower stress score than those of the placebo group. Enclosure activity levels did not differ among the groups. Additionally, gabapentin and alprazolam resulted in similar sedation levels 90 minutes after treatment, which differed significantly compared to placebo. CLINICAL RELEVANCE: The results of this study suggest that gabapentin provides similar anxiolysis in cats to that of alprazolam when evaluated 90 minutes after administration. Although no difference was noted in sedation levels between gabapentin and alprazolam, both induced deeper sedation than placebo.

Risk of suicide attempts and intentional self-harm on alprazolam.

BACKGROUND: From 2000-2021, U.S. suicide deaths have risen 36 %. Identification of pharmacological agents associated with increased suicide risk and safer alternatives may help reduce this trend. METHODS: An exposure-only within-subject time-to-event pharmacoepidemiologic study of the dynamic association between alprazolam treatment and suicide attempts over 2-years. Parallel analyses were conducted for diazepam, lorazepam and buspirone. Data for 2,495,520 patients were obtained from U.S. private insurance medical claims MarketScan from 2010 to 2019. FINDINGS: Alprazolam was associated with over a doubling of risk of suicide attempts (HR=2.21, 95 % CI=2.06,2.38). A duration-response analysis for the modal dose (0.5 mg) revealed a 5 % increase in suicidal events per additional month of treatment (HR=1.05, 95 % CI=1.04,1.07). Parallel analyses with long-acting (diazepam) and short-acting (lorazepam), found similar associations (diazepam HR=2.87, 95 % CI=2.56,3.21; lorazepam HR=1.83, 95 % CI=1.69,2.00), whereas the non-benzodiazepine anxiolytic, buspirone, showed significantly less risk (HR=1.25, 95 % CI=1.13,1.38), and no increased risk in patients with an attempt history (HR=1.05, 95 % CI=0.70,1.59). INTERPRETATION: This study confirmed an earlier signal linking alprazolam to increased suicide attempt risk. The increased risk extends to benzodiazepines in general, regardless of half-life and risk of withdrawal seizure. Buspirone appears to be a safer treatment than benzodiazepines, particularly in patients at increased risk for suicide.

Comparison of perception of stress and consumption of anxiolytics in hospital and out-hospital conditions: a cross-sectional study.

Background: The workplace is a place where medical workers are exposed to extreme stress, particularly during medical emergencies or events of epidemic or pandemic proportions. Anxiolytic therapy is often used to overcome professional challenges. Deepening knowledge about the prevalence of the use of anxiolytics and the perception of stress among medical workers enables the timely recognition of problems and the preparation of measures to improve the working conditions and quality of life of medical workers. The study's primary objective was to investigate whether there were differences in the usage of anxiolytics among healthcare professionals in and out of the hospital. In addition to the main objective, there are other objectives that have been established: To examine whether there are statistically justified differences in stress perceptions between hospital and outpatient healthcare professionals; 2. To examine the stress factors in the workplace in both hospital and outpatient settings. To compare the frequency of taking anxiolytics with respect to various variables (age, seniority, occupation and level of education); 4. determines the impact of working conditions on stress perception and life satisfaction in healthcare professionals. The design of research: Cross-sectional research. Materials and methods: The research involved 159 healthcare professionals in Slavonski Brod: 96 employees of the General Hospital "Dr. Josip Bencevic" and 63 employees of the Health Center and the Institute for Emergency Medicine of Brodsko-Posavina County. Respondents were able to participate in the study by filling out questionnaires online. The questionnaire was designed to be voluntary and anonymous and contained 53 questions. Results: Statistically significant differences were shown in the perception of stress, which is greater in hospital staff, than in the difference between stressors in the workplace, where hospital staff showed higher values in all categories, but three factors are more significant differences: "Organization of the workplace and financial issues," "Conflicts and communication at work" and "Professional and intellectual requirements." There are significant differences in the frequency of using anxiolytics with the assistance of a psychiatrist. Working conditions have a much greater impact on the perception of stress and life satisfaction in hospital staff, while in hospital staff only a weak link between the perception of stress and life satisfaction is expressed. Anxiolytics are consumed by 27.10% of hospital workers and 23.80% of outside-the-hospital workers. Conclusion: The consumption of anxiolytic drugs by healthcare professionals in hospital and outpatient conditions does not make a significant difference, but they do have statistically significant differences in their perception of stress.

Experimental and pharmacoinformatic approaches unveil the neuropharmacological and analgesic potential of chloroform fraction of Roktoshirinchi (Achyranthes ferruginea Roxb.).

ETHNOPHARMACOLOGICAL RELEVANCE: Achyranthes ferruginea (A. ferruginea) Roxb. is a common plant used in traditional medicine in Asia and Africa. It has a variety of local names, including "Gulmanci" in Nigeria, "Dangar" in Pakistan, "Thola" in Ethiopia, and "Roktoshirinchi" in Bangladesh. It is edible and has several ethnomedical uses for a wide range of illnesses, including hysteria, dropsy, constipation, piles, boils, asthma, and shigellosis. However, the neuropharmacological and analgesic potential of A. ferruginea remains uninvestigated. AIM OF THE STUDY: To assess the neuropharmacological and analgesic potential of A. ferruginea through a multifaceted approach encompassing both experimental and computational models. MATERIALS AND METHODS: Methanol was used to extract the leaves of A. ferruginea. It was then fractionated with low to high polar solvents (n-hexane, chloroform, ethyl acetate, and water) to get different fractions, including chloroform fraction (CLF). The study selected CLF at different doses and conducted advanced chemical element and proximate analyses, as well as phytochemical profiling using GC-MS. Toxicological studies were done at 300 µg per rat per day for 14 days. Cholinesterase inhibitory potential was checked using an in-vitro colorimetric assay. Acetic acid-induced writhing (AAWT) and formalin-induced licking tests (FILT) were used to assess anti-nociceptive effects. The forced swim test (FST), tail suspension test (TST), elevated plus maze (EPM), hole board test (HBT), and light and dark box test (LDB) were among the behavioral tests used to assess depression and anxiolytic activity. Network pharmacology-based analysis was performed on selected compounds using the search tool for interacting chemicals-5 (STITCH 5), Swiss target prediction tool, and search tool for the retrieval of interacting genes and proteins (STRING) database to link their role with genes involved in neurological disorders through gene ontology and reactome analysis. RESULTS: Qualitative chemical element analysis revealed the presence of 15 elements, including Na, K, Ca, Mg, P, and Zn. The moisture content, ash value, and organic matter were found to be 11.12, 11.03, and 88.97%, respectively. GC-MS data revealed that the CLF possesses 25 phytoconstituents. Toxicological studies suggested the CLF has no effects on normal growth, hematological and biochemical parameters, or cellular organs after 14 days at 300 µg per rat. The CLF markedly reduced the activity of both acetylcholinesterase and butyrylcholinesterase (IC50: 56.22 and 13.22 µg/mL, respectively). Promising dose-dependent analgesic activity (p < 0.05) was observed in chemically-induced pain models. The TST and FST showed a dose-dependent substantial reduction in immobility time due to the CLF. Treatment with CLF notably increased the number of open arm entries and time spent in the EPM test at doses of 200 and 400 mg/kg b.w. The CLF showed significant anxiolytic activity at 200 mg/kg b.w. in the HBT test, whereas a similar activity was observed at 400 mg/kg b.w. in the EPM test. A notable increase in the amount of time spent in the light compartment was observed in the LDB test by mice treated with CLF, suggesting an anxiolytic effect. A network pharmacology study demonstrated the relationship between the phytochemicals and a number of targets, such as PPARA, PPARG, CHRM1, and HTR2, which are connected to the shown bioactivities. CONCLUSIONS: This study demonstrated the safety of A. ferruginea and its efficacy in attenuating cholinesterase inhibitory activity, central and peripheral pain, anxiety, and depression, warranting further exploration of its therapeutic potential.

A Comparison of the Anxiolytic Properties of Tofisopam and Diazepam: A Double-Blind, Randomized, Crossover, Placebo-Controlled Pilot Study.

New clinical reports have recently been published on tofisopam-an anxiolytic drug currently registered as a benzodiazepine-after a long break in this research area. Neurobiological studies concerning its properties, which differ from those of benzodiazepines, are underway. The analyses presented in this study aimed to compare the effects of tofisopam, diazepam, and a placebo in the treatment of anxiety symptoms. A total of 66 outpatients (43 women and 23 men) with generalized anxiety disorder aged 19 to 74 years (M = 41.4; SD = 13.2) were randomized in three groups receiving (1) tofisopam (50 mg three times a day), (2) diazepam (5 mg three times a day), or (3) a placebo for 2 weeks. Then, throughout a 2-week washout period, the patients were monitored for withdrawal symptoms. During the last 2 weeks, the effects of tofisopam (50 mg three times a day) and diazepam (5 mg three times a day) were compared (crossover design). The mean improvement on the Hamilton Anxiety Rating Scale was significantly higher in both the tofisopam and diazepam groups compared to the placebo group. There were no significant differences between the effects of diazepam and tofisopam, whereas adverse effects and withdrawal symptoms occurred less frequently in the tofisopam group. Tofisopam did not impair cognitive abilities, and related withdrawal symptoms resembled those of the placebo. If larger future studies corroborate these findings, tofisopam should be classified as a homophtalazine.

Isolation, characterization, and evaluation of anxiolytic bioactive compounds from the seed of Vigna radiata (L.) R. Wilczek in mice.

Recent therapy for managing anxiety disorders is linked with a wide range of adverse effects. The conventional practice of the use of plant extract may indicate an important and new approach to the anxiolytic agent. Seeds of V. radiata belonging to the family Fabaceae is commonly employed to treat several diseases. However, no data is available to screen its viable neuropharmacological effect regardless of its famous use. Hence, the objective of the present study was to isolate the anxiolytic bioactive compound from seeds of V. radiata. Pure bioactive Compounds SU1 and SU2 were obtained from bioactive fraction F9.3 and fraction F9.5 using the bioactivity-guided fractionation method. The current investigation found that 4 mg/kg (o.p.) of kaempferol and γ-aminobutyric acid exhibit significant anxiolytic action in mice that is statistically comparable to diazepam (2 mg/kg.i.p). This study validates the ethnopharmacological use of V. radiata seeds in the management of anxiety disorders.

Anxiety but not menopausal status influences the risk of long-COVID-19 syndrome in women living in Latin America.

OBJECTIVE: To study sociodemographic and clinical factors associated with the long-COVID-19 syndrome among women living in Latin American countries using undirected and directed methods. METHOD: We studied 347 patients with COVID-19 (confirmed by polymerase chain reaction) living in nine Latin American countries between May 2021 and July 2022, including 70 premenopausal, 48 perimenopausal, and 229 postmenopausal women. We compared the sociodemographic and general health information of women with (n = 164) and without (n = 183) the long-COVID-19 syndrome. They also completed the Connor-Davidson Resilience Scale, the Fear of COVID-19 Scale, the Jenkins Sleep Scale, and the Menopause Rating Scale to define the minimum set of variables for adjustment. We designed a directed acyclic graph (DAG) to identify factors related to the long-COVID-19 syndrome. Data were submitted to categorical logistic regression analyses. Results are reported as means and standard deviations or ß-coefficients and 95 % confidence intervals. RESULTS: Women with long-COVID-19 syndrome had a poor lifestyle, severe menopause symptoms, hypertension, insomnia, depression, anxiety, chronic diseases/conditions, risk of hospitalization, sleep disturbance, and low menopause-related quality of life compared to women without the syndrome. The DAG identified the following long-COVID-19 covariates: age, obesity, anxiety, depression, cancer, lifestyle, smoking, and menstrual status. A multivariable logistic model with these covariates indicated that anxiety is the only factor to be significantly associated with long-COVID-19 syndrome, whereas other covariates were confounding factors. There was no significant influence of menopausal status on the long-COVID-19 syndrome. CONCLUSION: Among factors selected by the DAG, only anxiety was significantly associated with the long-COVID-19. There was no significant influence of the menopause status on the long-COVID-19 syndrome in the studied population.

Antidepressant prescribing in transgender and nonbinary individuals diagnosed with gender dysphoria and mood or anxiety disorders.

Introduction: Transgender and nonbinary (TGNB) individuals are highly stigmatized members of society and are significantly at higher risk of having mood or anxiety-related disorders compared to non-TGNB individuals. Methods: In this retrospective cohort study, antidepressant prescribing data were collected from TGNB adults diagnosed with gender dysphoria (GD) and mood or anxiety-related disorder between January 2005 and October 2021. The primary outcome was to compare the number of active outpatient antidepressant prescriptions at the time of GD diagnosis between gender identities. The secondary outcomes were to compare antidepressant class utilization between gender identities as well as the prevalence of concurrent mood or anxiety-related disorder diagnoses between gender identities. Results: Of 131 patients who met inclusion criteria, there was no significant difference in number of active antidepressant prescriptions between gender identities at the time of the GD diagnosis (p = .357). However, transgender females were prescribed bupropion at significantly higher rates than other gender identities (p = .046). Approximately 38% of patients did not have an active antidepressant prescription at the time of GD diagnosis despite concurrent mood or anxiety-related diagnoses. The prevalence of generalized anxiety disorder was significantly greater among transgender males (p = .044). Discussion: Although the number of active antidepressant prescriptions between gender identities were similar in this study, we found 38% of patients were not prescribed any antidepressants at time of GD and mood or anxiety-related disorders. This serendipitous finding elucidates a potential gap in mental health care among transgender adults.

The Role of Medication, Mental Illness, and Social Isolation on the Development of the Fetus in the Context of the COVID-19 Pandemic.

As we enter the COVID-19 post-pandemic period, uncertainty surrounds the impact of the varied effects of medications, mental illness, and social isolation on children born during the pandemic. Medications like selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines during pregnancy, coupled with pandemic-induced social isolation, may contribute to anxiety, depression, and behavioral issues in the offspring. Supporting evidence shows SSRIs' influence on brain development, while third-trimester benzodiazepine use may lead to neonatal withdrawal syndrome. Social isolation during the pandemic has also been linked to increased maternal depression and anxiety. This editorial emphasizes the need for increased surveillance in educational settings and early behavioral assessments by pediatricians. Further research is required to understand the long-term effects of maternal SSRIs. This knowledge can aid in timely interventions to protect the well-being of children born during COVID-19.

Relationship between falls and the use of hypnotics, antidepressants, antipsychotics, and anxiolytics in patients with rheumatoid arthritis: A cross-sectional study.

Objectives This cross-sectional study aimed to determine the relationship between falls and use of psychotropic medications in patients with rheumatoid arthritis. Methods The psychotropic medication group included patients with rheumatoid arthritis prescribed psychotropic medications (hypnotics/sedatives, antidepressants, antipsychotics, and anxiolytic [benzodiazepines] drugs). Poisson regression with robust variance was performed to investigate the relationship between falls and the use of psychotropic medications, with adjustment for age, sex, rheumatoid arthritis disease activity, stroke, dementia, diabetes mellitus, and osteoarthritis. Results Of the 307 patients enrolled, 49 (16.0%) used psychotropic medications, and 70 (22.8%) experienced at least one fall per year. Nineteen of the 49 patients (38.8%) taking psychotropic medications and 51 of 258 (19.8%) not taking psychotropic medications experienced at least one fall per year. Falls were significantly more frequent in the group with psychotropic medications than in the group without psychotropic medications (adjusted incidence rate ratio, 1.63; 95% confidence interval; 1.08-2.48, p = 0.02). No relationship was found between the number of falls and the use of psychotropic medications (adjusted incidence rate ratio, 1.16; 95% confidence interval; 0.39-3.44, p = 0.78). Conclusions There may be a relationship between psychotropic medication use and falls in patients with rheumatoid arthritis.

Trends in the multiple prescriptions of hypnotic drugs in a university outpatient in Japan.

AIMS: In Japan, the daily dosage of hypnotic drugs for insomnia treatment is increasing year by year, and over-dependence on treatment with hypnotic drugs is a major problem. This study aimed to examine the factors related to the elimination of prescriptions of three or more hypnotic drugs within 1 year in our clinic. METHODS: We conducted two surveys. Survey ① assessed the frequency of prescriptions of three or more hypnotic drugs by retrospectively reviewing the medical records of all patients who visited general and psychiatric outpatient clinics from January 2013 to March 2019. Survey ② assessed changes in prescriptions of hypnotic and psychotropic drugs within the subsequent year by retrospectively reviewing the medical records of all patients prescribed three or more hypnotic drugs who visited neuropsychiatric outpatient clinics multiple times between April 2013 and March 2019. RESULTS: The frequency of prescribing three or more hypnotic drugs was six to nine times higher in psychiatry than in other departments. Flunitrazepam and brotizolam were the most common drugs prescribed and had the second lowest discontinuation rate after zolpidem. Conversely, eszopiclone, zopiclone, and suvorexant had the highest discontinuation rates. The success factors for drug reduction were age (odds ratio [OR]: 0.97, p < 0.0037), trazodone addition (OR: 12.86, p < 0.0194) and number of years of psychiatric experience. CONCLUSIONS: The characteristics and success factors in relation to drug reduction in patients with multiple prescriptions of hypnotic drugs identified in this study may contribute to solving the problem of multiple prescriptions of hypnotic drugs.

[Desigualdades de género en el consumo de ansiolíticos e hipnosedantes por parte de adolescentes en España: un estudio transversal.] / Gender inequalities in the consumption of anxiolytics and hypnosedatives by adolescents in Spain: a cross-sectional study.

OBJECTIVE: There is increasing evidence of deterioration in the mental health of the population, especially among women and adolescents. We aimed to analyze gender inequalities in the consumption of anxiolytics and hypnosedatives (AHS) among adolescents in Spain in 2021 and its time trend, from an intersectional approach. METHODS: We conducted a cross-sectional study of time trends based on the ESTUDES national survey (n=22,321), comprising students between the ages of fourteen and eighteen. We calculated prevalences, prevalence ratios (PR) and interaction terms for consumption (both ever and in the last year), based on robust variance Poisson models, by sex, age, place of origin and parents' educational level. We also examine trends in consumption between 2010 and 2021. RESULTS: Female students showed higher consumption in all categories of the studied variables, together with a higher probability of use (PRvital=1.56 [1.47-1.64] and PRannual=1.81 [1.69-1.94]). Likewise, consumption increased with age, more pronounced in the case of male students (18 years old: PRvital=1,93 1,62-2,28]). Place of origin showed no statistically significant differences in AHS consumption. Lower educational level of parents predicts higher consumption among daughters, with mothers´ educational level showing a stronger association. Consumption increased over the 11-year period, and was consistently higher among women. CONCLUSIONS: We observe inequalities by gender and parents' educational level in AHS use among adolescents in Spain. It is critical to apply the model of the social determinants of health, which will lead to effective interventions in public health.

OBJECTIVE: Existen cada vez mayores indicios del deterioro en la salud mental de la población, especialmente en mujeres y adolescentes. El objetivo del estudio fue analizar las desigualdades de género en el consumo de ansiolíticos e hipnosedantes (AHS) por parte de adolescentes en España en 2021, además de su tendencia temporal, aplicando un análisis interseccional. METHODS: Se realizó un estudio transversal de tendencia temporal partiendo de la encuesta de ámbito estatal ESTUDES (n=22.321), con una muestra de estudiantes de catorce a dieciocho años. Se calcularon prevalencias, razones de prevalencia (RP) y términos de interacción del consumo alguna vez en la vida y en el último año, a partir de modelos de Poisson de varianza robusta (según sexo, edad, lugar de origen y nivel educativo de los progenitores). Asimismo, se realizó un análisis temporal del consumo (2010-2021). RESULTS: Las chicas presentaron mayores consumos en todas las categorías de las variables estudiadas, junto con una mayor probabilidad de uso (RPvital=1,56 [1,47-1,64] y RPanual=1,81 [1,69-1,94]). El consumo aumentó con la edad, de manera más pronunciada en los chicos (dieciocho años: RPvital=1,93 [1,62-2,28]). No existieron diferencias estadísticamente significativas según el lugar de origen. El descenso del nivel educativo de los progenitores aumentó significativamente el consumo en las hijas, con mayor impacto de los estudios maternos. La tendencia de consumo fue creciente, siendo superior en chicas durante toda la serie. CONCLUSIONS: El género o el nivel educativo de los progenitores determina de manera desigual el consumo de AHS entre los/las adolescentes en España. Es necesario ahondar en los determinantes sociales de la salud, dando lugar a intervenciones más efectivas en salud pública.

Desigualdades de género en el consumo de ansiolíticos e hipnosedantes por parte de adolescentes en España: un estudio transversal / Gender inequalities in the consumption of anxiolytics and hypnosedatives by adolescents in Spain: a cross-sectional study

Fundamentos: Existen cada vez mayores indicios del deterioro en la salud mental de la población, especialmente en mujeres y adolescentes. El objetivo del estudio fue analizar las desigualdades de género en el consumo de ansiolíticos e hipnosedantes (AHS) por parte de adolescentes en España en 2021, además de su tendencia temporal, aplicando un análisis interseccional. Métodos: Se realizó un estudio transversal de tendencia temporal partiendo de la encuesta de ámbito estatal ESTUDES (n=22.321), con una muestra de estudiantes de catorce a dieciocho años. Se calcularon prevalencias, razones de prevalencia (RP) y términos de interacción del consumo alguna vez en la vida y en el último año, a partir de modelos de Poisson de varianza robusta (según sexo, edad, lugar de origen y nivel educativo de los progenitores). Asimismo, se realizó un análisis temporal del consumo (2010-2021). Resultados: Las chicas presentaron mayores consumos en todas las categorías de las variables estudiadas, junto con una mayor probabilidad de uso (RP vital=1,56 [1,47-1,64] y RP anual=1,81 [1,69-1,94]). El consumo aumentó con la edad, de manera más pronunciada en los chicos (dieciocho años: RP vital=1,93 [1,62-2,28]). No existieron diferencias estadísticamente significativas según el lugar de origen. El descenso del nivel educativo de los progenitores aumentó significativamente el consumo en las hijas, con mayor impacto de los estudios maternos. La tendencia de consumo fue creciente, siendo superior en chicas durante toda la serie. Conclusiones: El género o el nivel educativo de los progenitores determina de manera desigual el consumo de AHS entre los/las adolescentes en España. Es necesario ahondar en los determinantes sociales de la salud, dando lugar a intervenciones más efectivas en salud pública.(AU)

Background: There is increasing evidence of deterioration in the mental health of the population, especially among women and adolescents. We aimed to analyze gender inequalities in the consumption of anxiolytics and hypnosedatives (AHS) among adolescents in Spain in 2021 and its time trend, from an intersectional approach. Methods: We conducted a cross-sectional study of time trends based on the ESTUDES national survey (n=22,321), comprising students between the ages of fourteen and eighteen. We calculated prevalences, prevalence ratios (PR) and interaction terms for consumption (both ever and in the last year), based on robust variance Poisson models, by sex, age, place of origin and parents’ educational level. We also examine trends in consumption between 2010 and 2021. Results: Female students showed higher consumption in all categories of the studied variables, together with a higher probability of use (PRvital=1.56 [1.47-1.64] and PRannual=1.81 [1.69-1.94]). Likewise, consumption increased with age, more pronounced in the case of male students (18 years old: PRvital=1,93 1,62-2,28]). Place of origin showed no statistically significant differences in AHS consumption. Lower educational level of parents predicted higher consumption among daughters, with mothers´ educational level showing a stronger association. Consumption increased over the 11-year period, and was consistently higher among women. Conclusions: We observe inequalities by gender and parents’ educational level in AHS use among adolescents in Spain. It iscritical to apply the model of the social determinants of health, which will lead to effective interventions in public health.(AU)

Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous-Crystalline Composites with a Polymer.

N-butyl-N-methyl-1-phenylpyrrole[1,2-a] pyrazine-3-carboxamide (GML-3) is a potential candidate for combination drug therapy due to its anxiolytic and antidepressant activity. The anxiolytic activity of GML-3 is comparable to diazepam. The antidepressant activity of GML-3 is comparable to amitriptyline. GML-3 is an 18 kDa mitochondrial translocator protein (TSPO) ligand and is devoid of most of the side effects of diazepam, which makes the research on the creation of drugs based on it promising. However, its low water solubility and tendency to agglomerate prevented its release. This research aimed to study the effect of dry grinding, the rapid expansion of a supercritical solution (RESS), and the eutectic mixture (composite) of GML-3 with polyvinylpyrrolidone (PVP) on the particle size, dissolution rate, and lattice retention of GML-3. The use of supercritical CO2 in the RESS method was promising in terms of particle size reduction, resulting in a reduction in the particle size of GML-3 to 20-40 nm with a 430-fold increase in dissolution rate. However, in addition to particle size reduction after RESS, GML-3 began to show signs of a polymorphism phenomenon, which was also studied in this article. It was found that coarse grinding reduced particle size by a factor of 2 but did not significantly affect solubility or crystal structure. Co-milling with the polymer made it possible to level the effect of the appearance of a residual electrostatic charge on the particles, as in the case of grinding, and the increased solubility in the resulting mechanical mixtures of GML-3 with the polymer may also indicate the dissolving properties of polymers (an increase in 400-800 times). The best result in terms of GML-3 solubility was demonstrated by the resulting GML-3:PVP composite at a ratio of 1:4, which made it possible to achieve a solubility of about 80% active pharmaceutical ingredient (API) within an hour with an increase in the dissolution rate by 1600 times. Thus, the creation of composites is the most effective method for improving the solubility of GML-3, superior to micronization.

Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABAA receptors, in a mouse model of Dravet syndrome.

Introduction: Dravet syndrome (DS) is an intractable epilepsy syndrome concomitant with neurodevelopmental disorder that begins in infancy. DS is dominantly caused by mutations in the SCN1A gene, which encodes the α subunit of a voltage-gated Na channel. Pre-synaptic inhibitory dysfunction is regarded as the pathophysiological mechanism, but an effective strategy for ameliorating seizures and behavioral problems is still under development. Here, we evaluated the effects of KRM-II-81, a newly developed positive allosteric modulator for α 2/3 subunit containing GABAA receptors (α2/3-GABAAR) in a mice model of DS both in vivo and at the neuronal level. Methods: We used knock-in mice carrying a heterozygous, clinically relevant SCN1A mutation (background strain: C57BL/6 J) as a model of the DS (Scn1a WT/A1783V mice), knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V). Seizure threshold and locomotor activity was evaluated by using the hyperthermia-induced seizure paradigm and open filed test, respectively. Anxiety-like behavior was assessed by avoidance of the center region in locomotor activity. We estimated a sedative effect by the total distance traveled in locomotor activity and grip strength. Inhibitory post synaptic currents (IPSCs) were recorded from a hippocampal CA1 pyramidal neuron in an acutely prepared brain slice. Results: KRM-II-81 significantly increased the seizure threshold of Scn1a WT/A1783V mice in a dose-dependent manner. A low dose of KRM-II-81 specifically improved anxiety-like behavior of Scn1a WT/A1783V mice. A sedative effect was induced by relatively high dose of KRM-II-81 in Scn1a WT/A1783V mice, the dose of which was not sedative for WT mice. KRM-II-81 potentiated IPSCs by increasing its decay time kinetics. This effect was more prominent in Scn1a WT/A1783V mice. Discussion: Higher activation of α2/3-GABAAR by KRM-II-81 suggests a compensatory modification of post synaptic inhibitory function against presynaptic inhibitory dysfunction in Scn1a WT/A1783V. The increased sensitivity for KRM-II-81 may be relevant to the distinct dose-dependent effect in each paradigm of Scn1a WT/A1783V mice. Conclusion: Selective activation for α2/3-GABAAR by KRM-II-81 could be potential therapeutic strategy for treating seizures and behavioral problems in DS.

A Scoping Review to Assess Risk of Fracture Associated with Anxiolytic Medications.

Introduction: Recent research has focused on evaluating the impact of pharmalogical sources on fracture risk. The purpose of this study was to review the literature on anxiolytic medications that may be associated with an increased risk of fracture. Methods: A search was conducted in MEDLINE and Embase databases to identify primary clinical studies of patients who sustained a fracture while prescribed anxiolytic medications and were published prior to July 2021. Anxiolytics defined by ATC Class N05B, beta blockers, and zolpidem were included. The search terms consisted of variations of the following: ("Psychotropic Drugs" or MeSH terms) AND ("Fracture" or MeSH terms). Results: Of 3,213 studies, 13 (0.4%) met inclusion criteria and were evaluated. Fractures associated with benzodiazepine were reported in 12 of 13 studies; the highest risk occurred in patients aged 60 years and older (RR=2.29, 95% CI (1.48-4.40)). The ATC Class N05B showed an increased fracture risk for those ≤ 55 years of age that differed by sex: for men (RR=5.42, 95% CI(4.86-6.05)) and for women (RR=3.33, 95% CI (3.03-3.66)). Zolpidem also showed an increase fracture risk (RR=2.29, 95% CI(1.48-3.56)), but only during the first four weeks of treatment. A relative risk of 0.77, 95% CI(0.72-0.83) was observed for beta blockers. Conclusions: Fractures are a mainstay of traumatic injuries and are accompanied by economical, physiological, and psychological hardship. With proper assessment and prophylactic measures, fracture risk can be reduced dramatically. Anxiolytic medications have been described widely to increase fracture risk, such as benzodiazepines in 60+ year old patients, and ATC Class N05B anxiolytics increased fracture risk in 55+ year old men and in 55+ year old women. Yet, some studies showed that at low doses, nitrazepam lowered fracture risk. Other anxiolytic medications, such as zolpidem and beta blockers, also showed a decrease in fracture risk. Ultimately, this scoping review helped to illuminate the inconsistency of anxiolytic fracture risk assessment while simultaneously illustrating the necessary steps to guide future research.

How Well Do Dogs Cope with Air Travel? An Owner-Reported Survey Study.

It is estimated that 2 million domestic animals travel on commercial flights every year in the US alone and that dogs make up 58% of pets travelling worldwide. There has been little research on the welfare effects of air travel on dogs. The purpose of this owner-reported study was to understand how well dogs cope with and recover from air travel from a physical, mental, and emotional health perspective. An online survey questionnaire was distributed globally to pet owners whose dogs had travelled by air in the last 12 months, and the results were collected and analysed. Information was received about dog and owner demographics, logistics, and preparation for travel, as well as the dog's experience of air travel. Results showed that most dogs cope with and recover well from air travel but that there is a group of individuals who suffer physical, mental, and emotional ill health consequences during or after air travel, including death. Stress management products such as anxiolytic medication, supplements, and pheromones were underutilised and, in some instances, actively discouraged. More education of all stakeholders of pet air travel is needed to improve the physical, mental, and emotional health and welfare of canine air travellers.

Characteristics of patients with anxiety disorder without selective serotonin reuptake inhibitor prescription over a two-year period of pharmacotherapy.

INTRODUCTION: Pharmacotherapy such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-noradrenaline reuptake inhibitors is recommended for the treatment of anxiety disorders. Although there are patients with persisted symptoms of anxiety disorders who are treated with monotherapy of benzodiazepine anxiolytics without SSRIs, the characteristics of these patients are unclear. In the present study, we investigated the characteristics of patients with persisted symptoms of anxiety disorder without SSRI prescription. METHODS: From a prescription dataset covering 2018 and 2020, the prescriptions of 243 patients with anxiety disorder were analyzed. Patients were classified into two groups: SSRI non-prescription and prescription groups. RESULTS: The SSRI non-prescription group had a higher ratio of females than did the SSRI prescription group (60.1% vs. 44.6%, respectively, p = 3.12 × 10-2 ), but statistically not significant after the Bonferroni correction. No significant differences in age, body mass index, or duration of outpatient visits were found between groups. Among the independent variables, sex (female) was the only variable identified that predicted SSRI non-prescription. CONCLUSION: The present study showed that among patients with anxiety disorders, sex (female) was the only variable that predicted SSRI non-prescription.