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.

Elevated circulating adiponectin levels do not prevent anxiety-like behavior in a PCOS-like mouse model.

Polycystic ovary syndrome (PCOS) is associated with symptoms of moderate to severe anxiety and depression. Hyperandrogenism is a key feature together with lower levels of the adipocyte hormone adiponectin. Androgen exposure leads to anxiety-like behavior in female offspring while adiponectin is reported to be anxiolytic. Here we test the hypothesis that elevated adiponectin levels protect against the development of androgen-induced anxiety-like behavior. Pregnant mice overexpressing adiponectin (APNtg) and wildtypes were injected with vehicle or dihydrotestosterone to induce prenatal androgenization (PNA) in the offspring. Metabolic profiling and behavioral tests were performed in 4-month-old female offspring. PNA offspring spent more time in the closed arms of the elevated plus maze, indicating anxiety-like behavior. Intriguingly, neither maternal nor offspring adiponectin overexpression prevented an anxiety-like behavior in PNA-exposed offspring. However, adiponectin overexpression in dams had metabolic imprinting effects, shown as lower fat mass and glucose levels in their offspring. While serum adiponectin levels were elevated in APNtg mice, cerebrospinal fluid levels were similar between genotypes. Adiponectin overexpression improved metabolic functions but did not elicit anxiolytic effects in PNA-exposed offspring. These observations might be attributed to increased circulating but unchanged cerebrospinal fluid adiponectin levels in APNtg mice. Thus, increased adiponectin levels in the brain are likely needed to stimulate anxiolytic effects.

Comparison of S-ketamine and midazolam for intravenous preoperative sedative and anxiolytic effects in preschool children: study protocol for a randomized controlled clinical trial.

BACKGROUND: Preoperative anxiety management is gaining particular attention in paediatric anaesthesia. Pharmacological and non-pharmacological resorts can be implemented to address this special issue. Despite the various approaches currently used for preoperative sedation in children, the different sedative and anti-anxiety effects between the newly marketed anaesthetic, S-ketamine, and the traditional sedative, midazolam, are still unclear. METHODS: This is a patient- and assessor-blinded randomized controlled clinical trial. Participants (n = 110) will receive S-ketamine (0.5 mg/kg) or midazolam (0.08 mg/kg) intravenously administrated at a ratio of 1:1 in the anaesthesia holding area. The primary outcome of this study is the sedative effect evaluated via the change in the modified Yale preoperative anxiety scale. It will be performed at two timepoints: in the pre-anaesthetic holding area before premedication (baseline, marked as T0) and about 5 min after premedication in the operating room without the existence of their guardians (marked as T1). Our secondary objectives include the parent separation anxiety score, postoperative agitation, caregivers' and anaesthesia care providers' satisfaction, and mask compliance. DISCUSSION: This randomized controlled trial is the first study to compare the anti-anxiety effect of intravenous S-ketamine and midazolam. We will provide a new approach for the clinical management of preoperative anxiety in preschool children posted for elective surgery. TRIAL REGISTRATION: ChiCTR2300069998. Registered on 30 March 2023.

Anxiolytics cause anxiety in pancreatic cancer.

Benzodiazepines (BZDs) are commonly prescribed for pancreatic cancer patients. To investigate the correlation between BZDs and survival outcomes a recent study by Cornwell et al. found that lorazepam (LOR) correlates with poor survival. The mechanistic study shows that LOR increases interleukin 6 (IL6) expression in cancer-associated fibroblasts via GPR68.

Efficacy and Safety of Anxiolytics in Mohs Micrographic Surgery: A Randomized, Double-Blinded, Placebo-Controlled Trial.

BACKGROUND: Patient anxiety can complicate surgical outcomes by elevating blood pressure, increasing the need for postoperative pain management, and reducing overall patient satisfaction. Despite the use of anxiolytic medications in outpatient procedures, there is limited comparative evidence on the efficacy and safety of these agents in Mohs micrographic surgery. OBJECTIVE: To compare the effectiveness and safety of different preprocedural anxiolytic agents in Mohs surgery on perioperative patient anxiety and patient satisfaction. MATERIALS AND METHODS: A double-blinded, randomized, placebo-controlled trial was conducted of 6 different preprocedural anxiolytic agents (lorazepam, diazepam, alprazolam, gabapentin, pregabalin, and melatonin) in 350 patients undergoing Mohs surgery. Anxiety and vital signs were recorded. RESULTS: Diazepam demonstrated a statistically significant, sustained reduction in anxiety levels compared with placebo ( p = .03). Gabapentin significantly reduced early anxiety ( p = .02). Alprazolam showed a trend to early anxiety reduction ( p = .08). Lorazepam ( p = .73), pregabalin ( p = .53), and melatonin ( p = .24) failed to reduce patient anxiety compared with placebo at any time point. No anxiolytic significantly impacted any patient vital sign or cognition. CONCLUSION: Although short-acting benzodiazepines and gamma-aminobutyric acid medications may have transient anxiolytic effects, a single oral dose of 5 mg of diazepam can provide a sustained anxiolytic effect in Mohs surgery, with excellent patient safety.

Losing a child to adolescent cancer: A register-based cohort study of psychotropic medication use in bereaved parents.

PURPOSE: To investigate the short- and long-term risk of psychotropic medication use in parents who lose a child to cancer diagnosed in adolescence. METHODS: This is a Swedish nationwide register-based study including 184 bereaved mothers and 184 bereaved fathers of 184 children diagnosed with cancer in adolescence. Logistic regression analyses, adjusted for sociodemographic characteristics and history of mental health problems, were performed to estimate risk of a prescription of psychotropic medication (anxiolytics, hypnotics/sedatives, antidepressants) in cancer-bereaved parents from 1 year before to 5 years after the child's death, with a general population sample of non-bereaved parents (n = 3291) as referents. RESULTS: At the year of the child's death, 28%-36% of mothers and 11%-20% of fathers had a prescription of anxiolytics, hypnotics/sedatives or antidepressants. The corresponding percentages for non-bereaved mothers and fathers were 7%-12% and 4%-7%, respectively. Compared to non-bereaved mothers, bereaved mothers showed higher odds of prescriptions from 1 year before up to four (anxiolytics) and 5 years (hypnotics/sedatives and antidepressants) after the child's death. Bereaved fathers showed higher odds than non-bereaved fathers of prescriptions from 1 year before up to the year of (anxiolytics and hypnotics/sedatives) and 1 year after (antidepressants) the child's death. No differences in odds between bereaved and non-bereaved fathers were found at 2 years after the child's death. Being unmarried, born outside Sweden, and having a history of mental health problems were associated with higher odds of prescribed medications. CONCLUSIONS: Indicative of mental health problems of clinical importance, cancer-bereaved parents had a higher prevalence of use of psychotropic medication. A decrease in medication use was evident with time, but still at 5 years after the child's death mothers displayed a higher use while fathers showed no difference to non-bereaved fathers after 2 years.

The role of prenatal exposure to antidepressants, anxiolytic, and hypnotics and its underlying illness on the risk of miscarriage using BIFAP database.

PURPOSE: Despite the notable increase on the prescription of antidepressants and anxiolytics during pregnancy, recommendation on maintaining the treatment during prenatal period is still controversial. We aimed to separately assess the role of effects of the antidepressants and anxiolytic and the underlying illness, controlled by potential confounding associated with miscarriage onset. METHODS: We used data from a validated pregnant cohort aged 15-49 years from 2002 to 2016 using BIFAP database. All confirmed miscarriages were used to perform a nested control analysis using conditional logistic regression. Women were classified according to use of each drug of interest into four mutually exclusive groups: nonusers, users only during prepregnancy, continuers, and initiators during first trimester. Adjusted odds ratios (aORs) for major confounders during pregnancy such as number of visits to primary care practitioners visits, obesity, smoking, HTA, diabetes with 95% confidence intervals were calculated. RESULTS: Compared with nonusers, antidepressants continuers had the highest increased risk of miscarriage aOR (95%) of 1.29 (1.13-1.46), being continuers of paroxetine and fluoxetine the antidepressants with the strongest association. Likewise, continuers of anxiolytics and initiators showed an increased risk of 1.19 (1.04-1.37) and 1.30 (1.13-1.50). When separating the effect between the condition itself or the treatment, women exposed during first trimester, regardless treatment duration and/or the underlying illness, had the highest risk 1.27 (1.08-1.51) for antidepressants and 1.25 (1.13-1.39) for anxiolytics. CONCLUSIONS: Our analysis showed an association between prenatal exposure to antidepressants and anxiolytics and miscarriage onset after controlling by potential confounding adjusting for confounders and the underlying illness. This association was not supported for hypnotic medications. Further studies are warranted to evaluate the risk of miscarriage among subpopulation of pregnant women requiring these medications.

Insights into patient characteristics and documentation of the use of sedative-hypnotic/anxiolytics in primary care: a retrospective chart review study.

BACKGROUND: Despite the known safety risks of long-term use of sedative-hypnotic/anxiolytic medications, there has been limited guidance for the safe and effective use of their chronic use in a primary care clinic setting. Understanding the characteristics of patients who receive sedative-hypnotic/anxiolytic medication and the clinical documentation process in primary care is the first step towards understanding the nature of the problem and will help inform future strategies for clinical research and practice. OBJECTIVES: Characterize patients who received a sedative-hypnotic/anxiolytic prescription in primary care, and (2) gain an understanding of the clinical documentation of sedative-hypnotic/anxiolytic indication and monitoring in electronic medical records (EMR). METHODS: A random selection of patients who received a prescription for a benzodiazepine or Z-drug hypnotic between January 2014 and August 2016 from four primary care clinics in Winnipeg were included. Data was collected retrospectively using the EMR (Accuro®). Patient variables recorded included sex, age, comorbidities, medications, smoking status, and alcohol status. Treatment variables included drug type, indication, pattern of use, dose, adverse events, psychosocial intervention, tapering attempts, social support, life stressor, and monitoring parameters for sedative-hypnotic use. Demographic and clinical characteristics were described using descriptive statistics. RESULTS: Records from a sample of 200 primary care patients prescribed sedative-hypnotic/anxiolytics were analyzed (mean age 55.8 years old, 61.5% ≥ 65 years old, 61.0% female). Long-term chronic use (≥ 1 year) of a sedative-hypnotic/anxiolytic agent was observed in 29.5% of the sample. Zopiclone (30.7%) and lorazepam (28.7%) were the most common agents prescribed. Only 9.5% of patients had documentation of a past tapering attempt of their sedative-hypnotic/anxiolytic. The most common indications for sedative-hypnotic/anxiolytic use recorded were anxiety (33.0%) and sleep (18.0%), but indication was undetermined for 57.0% of patients. Depression (33.5%) and falls (18.5%) were reported by patients after the initiation of these agents. CONCLUSIONS: A higher proportion of females and users 65 years and older received a prescription for a sedative-hypnotic/anxiolytic, consistent with previous studies on sedative-hypnotic use. We found inconsistencies in the documentation surrounding sedative-hypnotic/anxiolytic use. The indication for their use was unclear in a large number of patients. These findings will help us understand the state of the problem in primary care and inform future strategies for clinical research.

Prevalence of Gabapentinoids and Central Nervous System Depressant Drugs, and Their Association with Risk Factors for Respiratory Depression in Primary Care Patients.

BACKGROUND AND OBJECTIVES: Warnings have been published regarding an increased risk of severe respiratory depression in patients receiving gabapentinoids either alone or in combination with opioids and/or anxiolytics/hypnotics, especially in individuals with a respiratory risk factor. The aim is to report the prevalence of the use of gabapentinoids alone and associated with central nervous system depressant drugs, and possible associated risk factors for respiratory depression, in order to identify the most fragile population and establish intervention strategies. METHODS: We performed a cross-sectional study using computerized prescription records from the northern area of Barcelona at Catalan Institute of Health for 363,007 inhabitants registered during 2021. Patients aged ≥ 18 years with one or more gabapentinoid prescription were included. Age, gender, polypharmacy, adjusted morbidity groups, quantity of chronic diseases, and the number of consultations per year were independent variables. Four age categories were defined (18-64 years, then 64-74, 75-84, and those aged 85 years or older). Descriptive and inferential statistics were employed. Level of statistical significance was 5% (p ≤ 0.05). For the analysis, the SPSS program (version 22) was employed. RESULTS: Of the study sample, 9218 were prescribed gabapentidoids. Overall prevalence of use was 3.0% (women 3.6%, men 2.4%). On the whole, women used more drugs than men. In contrast to their younger counterparts, consumption increased 2.6 times, 3.8 times, and 4.0 times in the 65-74 age group, 75-84 age group, and those aged ≥ 85 years, respectively. Mean age was 65.59 (±15.80) years. Polypharmacy (5-9 drugs) was present in 41.7% of the patients and extreme polypharmacy (≥ 10 drugs) was present in 39.3% of the patients. Regarding renal function, 2396 patients (25.9%) had glomerular filtration that required dose adjustment (76.1% with gabapentin and 23.8% with pregabalin). In 141 patients (5.9%), a total daily dose higher than that authorized (109 with gabapentin, 29 with pregabalin) had been prescribed. The prescription of gabapentinoids combined with opioids and/or anxiolytics/hypnotics was significantly associated with (i) polypharmacy (5-9 drugs, OR: 3.42 [95% CI 3.00-3.88]; ≥ 10 drugs, OR 8.72 [95% CI 7.42-10.25]); (ii) quantity of chronic diseases, OR: 1.14 (95% CI 1.11-1.17); (iii) augmented number of consultations/year, OR: 1.01 (95% CI 1.00-1.01); (iv) female gender, OR: <  1 for men, OR: 0.66 (95% CI 0.60-0.73); (v) being elderly: 65-74 years, OR: 0.71 (95% CI 0.62-0.81); 75-84 years, OR: 0.62 (95% CI 0.54-0.71); ≥85 years, OR: 0.68 (95% CI 0.58-0.81); and (vi) adjusted morbidity groups, OR: 0.90 (95% CI 0.88-0.92), (p <  0.0001). CONCLUSION: Exposure to gabapentinoids occurs in a non-negligible percentage of the population. Greater numbers of combinations of gabapentinoids and opioids and/or anxiolytics/hypnotics were associated with polypharmacy, quantity of chronic diseases, and augmented number of consultations, but not with male gender, older age, and adjusted morbidity groups.

Safety and Efficacy of Oral Benzodiazepines for Periprocedural Anxiolysis: A Systematic Review.

BACKGROUND: Oral benzodiazepines (BZDs) are useful tools for periprocedural anxiolysis. The United States Food and Drug Administration (FDA) recently issued a black-box warning of their risks of abuse and dependence. We performed a systematic review evaluating the safety and efficacy of oral BZDs for periprocedural anxiolysis in outpatient dermatologic, plastic surgery, dental, and ophthalmologic procedures performed under local anesthesia. METHODS: A systematic review of 5 databases was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Oral benzodiazepine safety and efficacy data were extracted from eligible articles. RESULTS: A total of 43 articles and 4,060 subjects were included. Oral BZDs consistently imparted a positive anxiolytic effect and demonstrated superior or equivalent scores in patient satisfaction, surgeon satisfaction, pain, and anxiety to comparator groups in most studies. Thirty-five subjects experienced transient hypoxia, and 2 experienced transient hypertension. A total of 195 mild, self-limited adverse effects were reported. None of the studies addressed the risks of abuse and dependence in this clinical setting. CONCLUSION: Short-term use of oral BZDs for periprocedural anxiolysis seems to be safe and effective. The 2020 FDA black-box warning should not deter their appropriate use in dermatologic surgery and other low-risk outpatient procedures.

Mental Health in New Mothers: A Randomised Controlled Study into the Effects of Dietary Flavonoids on Mood and Perceived Quality of Life.

The postnatal period is a significant period of physical, physiological and psychological change for mothers, rendering them particularly vulnerable to changes in mood or disorders such as postnatal depression (PND). Previous interventions with foods high in flavonoids have demonstrated beneficial acute and chronic mood effects in healthy child, adolescent and adult populations. It is unclear whether mood effects persist in populations who are potentially at-risk of developing mood disorders, such as postnatal mothers. This exploratory study investigated the effects of a 2-week daily dietary flavonoid intervention on mood (PANAS-NOW), anxiety (STAI), depressive symptoms (PHQ-8) and perceived quality of life (WHOQOL-BREF) in forty-one new mothers in the 0-12-month postnatal period, before and after flavonoid intervention. Mothers either added high flavonoid foods to their daily diet, or did not include additions following a randomised, between-groups, controlled design. Significant effects were observed in the flavonoid group with mothers reporting lower state anxiety and higher perceived quality of physical health at the 2-week timepoint. These findings suggest that regular dietary consumption of flavonoids may benefit mothers' anxiety and perceived quality of life in the postnatal period. Replication of these results may indicate the potential for dietary flavonoids to promote healthy mood regulation in mothers or prevent the onset or severity of symptoms in postnatal psychological disorders, both of which would be beneficial for women's health services and public mental health.

Global survey of medicinal plants during lactation and postpartum recovery: Evolutionary perspectives and contemporary health implications.

ETHNOPHARMACOLOGICAL RELEVANCE: Cross-cultural comparison of plants used during lactation and the postpartum period offers insight into a largely overlooked area of ethnopharmacological research. Potential roles of phytochemicals in emerging models of interaction among immunity, inflammation, microbiome and nervous system effects on perinatal development have relevance for the life-long health of individuals and of populations in both traditional and contemporary contexts. AIM OF THE STUDY: Delineate and interpret patterns of traditional and contemporary global use of medicinal plants ingested by mothers during the postpartum period relative to phytochemical activity on immune development and gastrointestinal microbiome of breastfed infants, and on maternal health. MATERIALS AND METHODS: Published reviews and surveys on galactagogues and postpartum recovery practices plus ethnobotanical studies from around the world were used to identify and rank plants, and ascertain regional use patterns. Scientific literature for 20 most-cited plants based on frequency of publication was assessed for antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, antidepressant, analgesic, galactagogic and safety properties. RESULTS: From compilation of 4418 use reports related to 1948 species, 105 plant taxa were recorded ≥7 times, with the most frequently cited species, Foeniculum vulgare, Trigonella foenum-graecum, Pimpinella anisum, Euphorbia hirta and Asparagus racemosus, 81, 64, 42, 40 and 38 times, respectively. Species and use vary globally, illustrated by the pattern of aromatic plants of culinary importance versus latex-producing plants utilized in North Africa/Middle East and Sub-Saharan Africa with opposing predominance. For 18/20 of the plants a risk/benefit perspective supports assessment that positive immunomodulation and related potential exceed any safety concerns. Published evidence does not support a lactation-enhancing effect for nearly all the most-cited plants while antidepressant data for the majority of plants are predominately limited to animal studies. CONCLUSIONS: Within a biocultural context traditional postpartum plant use serves adaptive functions for the mother-infant dyad and contributes phytochemicals absent in most contemporary diets and patterns of ingestion, with potential impacts on allergic, inflammatory and other conditions. Polyphenolics and other phytochemicals are widely immunologically active, present in breast milk and predominately non-toxic. Systematic analysis of phytochemicals in human milk, infant lumen and plasma, and immunomodulatory studies that differentiate maternal ingestion during lactation from pregnancy, are needed. Potential herb-drug interaction and other adverse effects should remain central to obstetric advising, but unless a plant is specifically shown as harmful, considering potential contributions to health of individuals and populations, blanket advisories against postpartum herbal use during lactation appear empirically unwarranted.

Is there any difference between oral preemptive pregabalin vs. placebo administration on response to EBUS-TBNA under sedation?

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.

Melatonin for preoperative and postoperative anxiety in adults.

BACKGROUND: Anxiety in relation to surgery is a well-known problem. Melatonin offers an alternative treatment to benzodiazepines for ameliorating this condition in the preoperative and postoperative periods. OBJECTIVES: To assess the effects of melatonin on preoperative and postoperative anxiety compared to placebo or benzodiazepines. SEARCH METHODS: We searched the following databases on 10 July 2020: CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science. For ongoing trials and protocols, we searched clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform. SELECTION CRITERIA: We included randomized, placebo-controlled or standard treatment-controlled (or both) studies that evaluated the effects of preoperatively administered melatonin on preoperative or postoperative anxiety. We included adult patients of both sexes (15 to 90 years of age) undergoing any kind of surgical procedure for which it was necessary to use general, regional, or topical anaesthesia. DATA COLLECTION AND ANALYSIS: One review author conducted data extraction in duplicate. Data extracted included information about study design, country of origin, number of participants and demographic details, type of surgery, type of anaesthesia, intervention and dosing regimens, preoperative anxiety outcome measures, and postoperative anxiety outcome measures. MAIN RESULTS: We included 27 randomized controlled trials (RCTs), involving 2319 participants, that assessed melatonin for treating preoperative anxiety, postoperative anxiety, or both. Twenty-four studies compared melatonin with placebo. Eleven studies compared melatonin to a benzodiazepine (seven studies with midazolam, three studies with alprazolam, and one study with oxazepam). Other comparators in a small number of studies were gabapentin, clonidine, and pregabalin. No studies were judged to be at low risk of bias for all domains. Most studies were judged to be at unclear risk of bias overall. Eight studies were judged to be at high risk of bias in one or more domain, and thus, to be at high risk of bias overall. Melatonin versus placebo Melatonin probably results in a reduction in preoperative anxiety measured by a visual analogue scale (VAS, 0 to 100 mm) compared to placebo (mean difference (MD) -11.69, 95% confidence interval (CI) -13.80 to -9.59; 18 studies, 1264 participants; moderate-certainty evidence), based on a meta-analysis of 18 studies. Melatonin may reduce immediate postoperative anxiety measured on a 0 to 100 mm VAS compared to placebo (MD -5.04, 95% CI -9.52 to -0.55; 7 studies, 524 participants; low-certainty evidence), and may reduce delayed postoperative anxiety measured six hours after surgery using the State-Trait Anxiety Inventory (STAI) (MD -5.31, 95% CI -8.78 to -1.84; 2 studies; 73 participants; low-certainty evidence). Melatonin versus benzodiazepines (midazolam and alprazolam) Melatonin probably results in little or no difference in preoperative anxiety measured on a 0 to 100 mm VAS (MD 0.78, 95% CI -2.02 to 3.58; 7 studies, 409 participants; moderate-certainty evidence) and there may be little or no difference in immediate postoperative anxiety (MD -2.12, 95% CI -4.61 to 0.36; 3 studies, 176 participants; low-certainty evidence). Adverse events Fourteen studies did not report on adverse events. Six studies specifically reported that no side effects were observed, and the remaining seven studies reported cases of nausea, sleepiness, dizziness, and headache; however, no serious adverse events were reported. Eleven studies measured psychomotor and cognitive function, or both, and in general, these studies found that benzodiazepines impaired psychomotor and cognitive function more than placebo and melatonin. Fourteen studies evaluated sedation and generally found that benzodiazepine caused the highest degree of sedation, but melatonin also showed sedative properties compared to placebo. Several studies did not report on adverse events; therefore, it is not possible to conclude with certainty, from the data on adverse effects collected in this review, that melatonin is better tolerated than benzodiazepines. AUTHORS' CONCLUSIONS: When compared with placebo, melatonin given as premedication (as tablets or sublingually) probably reduces preoperative anxiety in adults (measured 50 to 120 minutes after administration), which is potentially clinically relevant. The effect of melatonin on postoperative anxiety compared to placebo (measured in the recovery room and six hours after surgery) was also evident but was much smaller, and the clinical relevance of this finding is uncertain. There was little or no difference in anxiety when melatonin was compared with benzodiazepines. Thus, melatonin may have a similar effect to benzodiazepines in reducing preoperative and postoperative anxiety in adults.

ANTECEDENTES: La ansiedad relacionada con la cirugía es un problema conocido. La melatonina ofrece un tratamiento alternativo a las benzodiazepinas para mejorar esta afección en los períodos pre y posoperatorio. OBJETIVOS: Evaluar los efectos de la melatonina en la ansiedad pre y posoperatoria en comparación con el placebo o las benzodiazepinas. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en las siguientes bases de datos el 10 de julio de 2020: CENTRAL, MEDLINE, Embase, CINAHL y Web of Science. Para los ensayos y protocolos en curso, se buscó en clinicaltrials.gov y en la Plataforma de registros internacionales de ensayos clínicos de la Organización Mundial de la Salud (OMS). CRITERIOS DE SELECCIÓN: Estudios aleatorizados controlados con placebo o controlados con tratamiento estándar, o ambos, que evaluaron los efectos de la melatonina administrada de forma preoperatoria para la ansiedad preoperatoria o posoperatoria. Se incluyeron pacientes adultos de ambos sexos (15 a 90 años de edad) a los que se les realizó cualquier clase de procedimiento quirúrgico donde fue necesario utilizar anestesia general, regional o tópica. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Un autor de la revisión realizó la extracción de los datos por duplicado. Los datos que se extrajeron incluyeron información acerca del diseño del estudio, el país de origen, el número de participantes y los detalles demográficos, el tipo de cirugía, el tipo de anestesia, la intervención y el régimen de dosis, medidas de desenlace de ansiedad preoperatoria y medidas de desenlace de ansiedad posoperatoria. RESULTADOS PRINCIPALES: Se incluyeron 27 ensayos controlados aleatorizados (ECA), con 2319 participantes, que evaluaron la melatonina para el tratamiento de la ansiedad preoperatoria, la ansiedad posoperatoria o ambas. Veinticuatro estudios compararon la melatonina con el placebo. Once estudios compararon la melatonina con una benzodiazepina (siete estudios con midazolam, tres estudios con alprazolam y un estudio con oxazepam). Otros comparadores en un escaso número de estudios fueron la gabapentina, la clonidina y la pregabalina. No se consideró que ningún estudio tuviera un riesgo bajo de sesgo en todos los dominios. La mayoría de los estudios se consideraron con riesgo incierto de sesgo en general. Se consideró que ocho estudios tenían un alto riesgo de sesgo en uno o más dominios y, por lo tanto, un alto riesgo de sesgo en general. Melatonina versus placebo La melatonina probablemente da lugar a una reducción de la ansiedad preoperatoria medida por una escala visual analógica (EVA, 0 a 100 mm) en comparación con el placebo (diferencia de medias [DM] ­11,69; intervalo de confianza [IC] del 95%: ­13,80 a ­9,59; 18 estudios, 1264 participantes; evidencia de certeza moderada), sobre la base de un metanálisis de 18 estudios. La melatonina podría reducir la ansiedad posoperatoria inmediata medida en una EVA de 0 a 100 mm en comparación con el placebo (DM ­5,04; IC del 95%: ­9,52 a ­0,55; siete estudios, 524 participantes; evidencia de certeza baja), y podría reducir la ansiedad posoperatoria tardía medida seis horas después de la cirugía mediante el State­Trait Anxiety Inventory (STAI) (DM ­5,31; IC del 95%: ­8,78 a ­1,84; dos estudios; 73 participantes; evidencia de certeza baja). Melatonina versus benzodiazepinas (midazolam y alprazolam) La melatonina probablemente da lugar a poca o ninguna diferencia en la ansiedad preoperatoria medida en una EVA de 0 a 100 mm (DM 0,78; IC del 95%: ­2,02 a 3,58; siete estudios, 409 participantes; evidencia de certeza moderada) y podría haber poca o ninguna diferencia en la ansiedad posoperatoria inmediata (DM ­2,12; IC del 95%: ­4,61 a 0,36; tres estudios, 176 participantes; evidencia de certeza baja). Eventos adversos Catorce estudios no informaron sobre los eventos adversos. Seis estudios informaron específicamente que no se observaron efectos secundarios y los siete estudios restantes informaron casos de náuseas, somnolencia, mareos y cefalea; sin embargo, no se informaron eventos adversos graves. Once estudios midieron la función psicomotora y cognitiva, o ambas, y en general, estos estudios encontraron que las benzodiazepinas deterioraron la función psicomotora y cognitiva más que el placebo y la melatonina. Catorce estudios evaluaron la sedación y en general encontraron que la benzodiazepina causaba el mayor grado de sedación, pero la melatonina también mostró propiedades sedantes en comparación con el placebo. Varios estudios no informaron sobre los efectos adversos; por lo tanto, no es posible concluir con certeza, a partir de los datos sobre los efectos adversos obtenidos en esta revisión, que la melatonina se tolera mejor que las benzodiazepinas. CONCLUSIONES DE LOS AUTORES: Cuando se compara con el placebo, la melatonina administrada como premedicación (en forma de comprimidos o sublingual) probablemente reduce la ansiedad preoperatoria en los adultos (medida entre 50 y 120 minutos después de la administración), lo que es potencialmente relevante desde el punto de vista clínico. El efecto de la melatonina sobre la ansiedad posoperatoria en comparación con el placebo (medido en la sala de recuperación y seis horas después de la cirugía) también fue evidente, pero fue mucho menor, y la relevancia clínica de este hallazgo no está clara. Hubo poca o ninguna diferencia en la ansiedad cuando la melatonina se comparó con las benzodiazepinas. Por lo tanto, la melatonina puede tener un efecto similar al de las benzodiazepinas en la reducción de la ansiedad pre y posoperatoria en los adultos.

Flavonoids as therapeutic candidates for emotional disorders such as anxiety and depression.

Emotional disorders such as anxiety and depression are widespread psychological diseases that affect up to 20% of the world's population. There are many approaches to the discovery of novel agents for the treatment of depressive- and anxiety-like symptoms. However, the efficacy of existing drugs for emotional disorders is only exerted after a few weeks of treatment and have serious side effects. Due to this, new strategies to find suitable and safe options are being sought by many researchers. Among them, a lot of interest has been attracted by plant-derived natural compounds due to their wide range of beneficial effects for new agent development. Flavonoids are natural polyphenol-like compounds found commonly in plants, fruits, vegetables, and medicinal herbs. A diverse range of flavonoids have been studied to investigate their potential therapeutic activities for the treatment of brain-associated disorders, including anxiety and depression. The main aim of this review is to understand the associations between the various flavonoids and the emotional disorders and discuss the therapeutic effects of these natural compounds that were demonstrated during the conduction of recent studies. The current work shows advances in the latest research of some flavonoids as a potential candidate for the treatment of emotional disorders. We summarize their behavioral, molecular, physiological, and neurochemical effects in various in vitro and in vivo models. Therefore, in the present work, the latest studies were collected on the most important flavonoid compounds and their underlying mechanisms of action in emotion-related disorders were discussed.

Safety of Oral Midazolam as a Perioperative Anxiolytic for Outpatient Dermatologic Procedures.

BACKGROUND: Perioperative anxiety can negatively impact patient satisfaction and can complicate outpatient dermatologic procedures. OBJECTIVE: Evaluate adverse events associated with oral midazolam as a perioperative anxiolytic during dermatologic surgery and assess whether an enhanced monitoring approach is associated with an increased detection rate. MATERIALS AND METHODS: Five hundred cases (250 before and after change in monitoring) where patients were administered oral midazolam between July 2015 and May 2017 were retrospectively reviewed. The number of procedures, type of procedures, dose in milligrams, number of doses, major and minor adverse events, and vital signs were recorded. RESULTS: The difference in number of treatment sites, types of procedures, and total dose administered was not significant. There were minor but significant differences in the mean change in blood pressure, heart rate, respiratory rate, and Richmond Agitation and Sedation Scale score before and after the procedure but not oxygen saturation. These vital sign changes were not clinically significant. There were zero major adverse events in both groups. There were 2 patients who became transiently hypoxic. CONCLUSION: Oral midazolam administration was not associated with major adverse events including in the more intensively monitored group. This supports its use as an anxiolytic for outpatient dermatologic procedures.

Antidepressants for smoking cessation.

BACKGROUND: Whilst the pharmacological profiles and mechanisms of antidepressants are varied, there are common reasons why they might help people to stop smoking tobacco. Firstly, nicotine withdrawal may produce depressive symptoms and antidepressants may relieve these. Additionally, some antidepressants may have a specific effect on neural pathways or receptors that underlie nicotine addiction. OBJECTIVES: To assess the evidence for the efficacy, safety and tolerability of medications with antidepressant properties in assisting long-term tobacco smoking cessation in people who smoke cigarettes. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Specialized Register, which includes reports of trials indexed in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO, clinicaltrials.gov, the ICTRP, and other reviews and meeting abstracts, in May 2019. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that recruited smokers, and compared antidepressant medications with placebo or no treatment, an alternative pharmacotherapy, or the same medication used in a different way. We excluded trials with less than six months follow-up from efficacy analyses. We included trials with any follow-up length in safety analyses. DATA COLLECTION AND ANALYSIS: We extracted data and assessed risk of bias using standard Cochrane methods. We also used GRADE to assess the certainty of the evidence. The primary outcome measure was smoking cessation after at least six months follow-up, expressed as a risk ratio (RR) and 95% confidence intervals (CIs). We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed-effect model. Similarly, we presented incidence of safety and tolerance outcomes, including adverse events (AEs), serious adverse events (SAEs), psychiatric AEs, seizures, overdoses, suicide attempts, death by suicide, all-cause mortality, and trial dropout due to drug, as RRs (95% CIs). MAIN RESULTS: We included 115 studies (33 new to this update) in this review; most recruited adult participants from the community or from smoking cessation clinics. We judged 28 of the studies to be at high risk of bias; however, restricting analyses only to studies at low or unclear risk did not change clinical interpretation of the results. There was high-certainty evidence that bupropion increased long-term smoking cessation rates (RR 1.64, 95% CI 1.52 to 1.77; I2 = 15%; 45 studies, 17,866 participants). There was insufficient evidence to establish whether participants taking bupropion were more likely to report SAEs compared to those taking placebo. Results were imprecise and CIs encompassed no difference (RR 1.16, 95% CI 0.90 to 1.48; I2 = 0%; 21 studies, 10,625 participants; moderate-certainty evidence, downgraded one level due to imprecision). We found high-certainty evidence that use of bupropion resulted in more trial dropouts due to adverse events of the drug than placebo (RR 1.37, 95% CI 1.21 to 1.56; I2 = 19%; 25 studies, 12,340 participants). Participants randomized to bupropion were also more likely to report psychiatric AEs compared with those randomized to placebo (RR 1.25, 95% CI 1.15 to 1.37; I2 = 15%; 6 studies, 4439 participants). We also looked at the safety and efficacy of bupropion when combined with other non-antidepressant smoking cessation therapies. There was insufficient evidence to establish whether combination bupropion and nicotine replacement therapy (NRT) resulted in superior quit rates to NRT alone (RR 1.19, 95% CI 0.94 to 1.51; I2 = 52%; 12 studies, 3487 participants), or whether combination bupropion and varenicline resulted in superior quit rates to varenicline alone (RR 1.21, 95% CI 0.95 to 1.55; I2 = 15%; 3 studies, 1057 participants). We judged the certainty of evidence to be low and moderate, respectively; in both cases due to imprecision, and also due to inconsistency in the former. Safety data were sparse for these comparisons, making it difficult to draw clear conclusions. A meta-analysis of six studies provided evidence that bupropion resulted in inferior smoking cessation rates to varenicline (RR 0.71, 95% CI 0.64 to 0.79; I2 = 0%; 6 studies, 6286 participants), whilst there was no evidence of a difference in efficacy between bupropion and NRT (RR 0.99, 95% CI 0.91 to 1.09; I2 = 18%; 10 studies, 8230 participants). We also found some evidence that nortriptyline aided smoking cessation when compared with placebo (RR 2.03, 95% CI 1.48 to 2.78; I2 = 16%; 6 studies, 975 participants), whilst there was insufficient evidence to determine whether bupropion or nortriptyline were more effective when compared with one another (RR 1.30 (favouring bupropion), 95% CI 0.93 to 1.82; I2 = 0%; 3 studies, 417 participants). There was no evidence that any of the other antidepressants tested (including St John's Wort, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs)) had a beneficial effect on smoking cessation. Findings were sparse and inconsistent as to whether antidepressants, primarily bupropion and nortriptyline, had a particular benefit for people with current or previous depression. AUTHORS' CONCLUSIONS: There is high-certainty evidence that bupropion can aid long-term smoking cessation. However, bupropion also increases the number of adverse events, including psychiatric AEs, and there is high-certainty evidence that people taking bupropion are more likely to discontinue treatment compared with placebo. However, there is no clear evidence to suggest whether people taking bupropion experience more or fewer SAEs than those taking placebo (moderate certainty). Nortriptyline also appears to have a beneficial effect on smoking quit rates relative to placebo. Evidence suggests that bupropion may be as successful as NRT and nortriptyline in helping people to quit smoking, but that it is less effective than varenicline. There is insufficient evidence to determine whether the other antidepressants tested, such as SSRIs, aid smoking cessation, and when looking at safety and tolerance outcomes, in most cases, paucity of data made it difficult to draw conclusions. Due to the high-certainty evidence, further studies investigating the efficacy of bupropion versus placebo are unlikely to change our interpretation of the effect, providing no clear justification for pursuing bupropion for smoking cessation over front-line smoking cessation aids already available. However, it is important that where studies of antidepressants for smoking cessation are carried out they measure and report safety and tolerability clearly.

Efficacy and safety of Shu-gan-qing-re formula for generalized anxiety disorder: study protocol for a multi-center, prospective, double-blind, double-dummy, randomized controlled trial.

BACKGROUND: Generalized anxiety disorder (GAD) is a persistent and common mental disorder that entails significant impairments in role functioning and quality of life. Currently available effective interventions include psychological therapies, self-help approaches, and pharmacological treatments, which do not quite meet clinical needs, and the ideal anxiolytic is still being sought. Shu-gan-qing-re (SGQR) formula, a Chinese patent medicine, has been well received by patients with GAD in Chinese clinical practice for years. The present prospective, double-blind, double-dummy, randomized controlled trial is designed to investigate the efficacy and safety of SGQR formula for GAD. METHODS/DESIGN: A total of 200 eligible participants will be recruited from four hospitals in different parts of China. They will be randomly assigned to either the study group or the control group in a ratio of 1:1. Participants allocated to the study group will receive SGQR formula and buspirone placebo, while buspirone and SGQR placebo will be applied in the control group. Six scheduled visits will be conducted over the course of 8 weeks. Outcome measurements include Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale-17 (HAMD-17), Clinical Global Impression-Improvement Scale (CGI-I), Traditional Chinese Medicine Syndrome Scale for GAD, and pro-inflammatory cytokine tests: interleukin-1 beta (IL-1ß), IL-6, and tumor necrosis factor-alpha. Adverse reactions will be evaluated by using the Treatment Emergent Symptom Scale (TESS). Safety outcomes and adverse events will also be recorded. DISCUSSION: The study will provide scientific and objective assessments for the efficacy and safety of SGQR formula for patients with GAD, hopefully offering clinicians an alternative approach to GAD. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR-IPR-17013058. Registered on October 20, 2017.