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

In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0·05) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0·05; somatisation, P < 0·05; depression, P < 0·05; and anger–hostility, P < 0·05), the HADS (HADS global score, P < 0·05; and HADS-anxiety, P < 0·06), and by the CCL (problem solving, P < 0·05) and the UFC level (P < 0·05). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.

This multicenter, randomized, double-blind, placebo-controlled, active-referenced (duloxetine 60 mg), parallel-group study evaluated the short-term efficacy and safety of vortioxetine (10–20 mg) on cognitive function in adults (aged 18–65 years) diagnosed with major depressive disorder (MDD) who self-reported cognitive dysfunction. Efficacy was evaluated using ANCOVA for the change from baseline to week 8 in the digit symbol substitution test (DSST)–number of correct symbols as the prespecified primary end point. The patient-reported perceived deficits questionnaire (PDQ) and physician-assessed clinical global impression (CGI) were analyzed in a prespecified hierarchical testing sequence as key secondary end points. Additional predefined end points included the objective performance-based University of San Diego performance-based skills assessment (UPSA) (ANCOVA) to measure functionality, MADRS (MMRM) to assess efficacy in depression, and a prespecified multiple regression analysis (path analysis) to calculate direct vs indirect effects of vortioxetine on cognitive function. Safety and tolerability were assessed at all visits. Vortioxetine was statistically superior to placebo on the DSST ( P <0.05), PDQ ( P <0.01), CGI-I ( P <0.001), MADRS ( P <0.05), and UPSA ( P <0.001). Path analysis indicated that vortioxetine’s cognitive benefit was primarily a direct treatment effect rather than due to alleviation of depressive symptoms. Duloxetine was not significantly different from placebo on the DSST or UPSA, but was superior to placebo on the PDQ, CGI-I, and MADRS. Common adverse events (incidence ⩾5%) for vortioxetine were nausea, headache, and diarrhea. In this study of MDD adults who self-reported cognitive dysfunction, vortioxetine significantly improved cognitive function, depression, and functionality and was generally well tolerated.

The efficacy of vortioxetine 10 and 20 mg/d vs. placebo on cognitive function and depression in adults with recurrent moderate-to-severe major depressive disorder (MDD) was evaluated. Patients (18–65 yr, N = 602) were randomized (1:1:1) to vortioxetine 10 or 20 mg/d or placebo for 8 wk in a double-blind multi-national study. Cognitive function was assessed with objective neuropsychological tests of executive function, processing speed, attention and learning and memory, and a subjective cognitive measure. The primary outcome measure was change from baseline to week 8 in a composite z-score comprising the Digit Symbol Substitution Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT) scores. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). In the pre-defined primary efficacy analysis, both doses of vortioxetine were significantly better than placebo, with mean treatment differences vs. placebo of 0.36 (vortioxetine 10 mg, p < 0.0001) and 0.33 (vortioxetine 20 mg, p < 0.0001) on the composite cognition score. Significant improvement vs. placebo was observed for vortioxetine on most of the secondary objectives and subjective patient-reported cognitive measures. The differences to placebo in the MADRS total score at week 8 were −4.7 (10 mg: p < 0.0001) and −6.7 (20 mg: p < 0.0001). Path and subgroup analyses indicate that the beneficial effect of vortioxetine on cognition is largely a direct treatment effect. No safety concern emerged with vortioxetine. Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms.

Post-traumatic stress disorder (PTSD) is a disabling psychiatric disorder. As a substantial part of PTSD patients responds poorly to currently available psychotherapies, pharmacological interventions boosting treatment response are needed. Because of its anxiolytic and pro-social properties, the neuropeptide oxytocin (OT) has been proposed as promising strategy for treatment augmentation in PTSD. As a first step to investigate the therapeutic potential of OT in PTSD, we conducted a double-blind, placebo-controlled, cross-over functional MRI study examining OT administration effects (40 IU) on amygdala reactivity toward emotional faces in unmedicated male and female police officers with (n=37, 21 males) and without (n=40, 20 males) PTSD. Trauma-exposed controls were matched to PTSD patients based on age, sex, years of service and educational level. Under placebo, the expected valence-dependent amygdala reactivity (ie, greater activity toward fearful-angry faces compared with happy-neutral faces) was absent in PTSD patients. OT administration dampened amygdala reactivity toward all emotional faces in male and female PTSD patients, but enhanced amygdala reactivity in healthy male and female trauma-exposed controls, independent of sex and stimulus valence. In PTSD patients, greater anxiety prior to scanning and amygdala reactivity during the placebo session were associated with greater reduction of amygdala reactivity after OT administration. Taken together, our results indicate presumably beneficial neurobiological effects of OT administration in male and female PTSD patients. Future studies should investigate OT administration in clinical settings to fully appreciate its therapeutic potential.

Signs of an inflammatory process, in particular increased pro-inflammatory cytokines and increased levels of prostaglandine E 2 (PGE 2 ), have repeatedly been described in major depression (MD). As cyclooxygenase-2 (COX-2) inhibitors inhibit the PGE 2 production and the production of pro-inflammatory cytokines, we performed a therapeutic trial with the COX-2 inhibitor celecoxib. In a prospective, double-blind, add-on study, 40 patients suffering from an acute depressive episode were randomly assigned to either reboxetine and celecoxib or to reboxetine plus placebo. After a wash-out period, 20 patients received 4–10 mg reboxetine plus placebo and 20 received reboxetine plus 400 mg celecoxib for 6 weeks. The treatment effect was calculated by analysis of variance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or reboxetine dose or plasma levels. Over 6 weeks, both groups of patients showed significant improvement in scores of the Hamilton Depression Scale. However, the celecoxib group showed significantly greater improvement compared to the reboxetine-alone group. Additional treatment with celecoxib has significant positive effects on the therapeutic action of reboxetine with regard to depressive symptomatology. Moreover, the fact that treatment with an anti-inflammatory drug showed beneficial effects on MD indicates that inflammation is related to the pathomechanism of the disorder, although the exact mechanisms remain to become elucidated.

Lacerations are the most common traumatic reason for children to visit an emergency department (ED), accounting for almost half of all procedures performed. Children experience considerable distress during laceration repair, despite routine application of local anesthetic. Pharmacologic anxiolysis may mitigate the negative practice of forcefully restraining a child, however, evidence for the most effective agent is lacking. We aim to determine the most effective anxiolytic agent for laceration repair in children. This is a multicentre, phase III, three-arm, adaptive, randomized, open-label, trial. We will include children 2-12 years with a single laceration requiring suture repair in the ED. Participants will be randomized to receive intranasal dexmedetomidine (IND) 3 mcg/kg, intranasal midazolam (INM) 0.4 mg/kg, or inhaled 50% nitrous oxide (N2O). The primary outcome is the weighted mean anxiolysis score using the Observational Scale of Behavioral Distress - Revised (OSBD-R) from initial positioning to tying of the last suture. Secondary outcomes include need for additional anxiolytic, need for physical restraint, adverse events (AEs), and delayed maladaptive behaviors. The primary analysis will be conducted by intention-to-treat. Results will report posterior means, standard deviations (SDs), and 95% high density posterior credible intervals for Total Distress Score on the OSBD-R. We will rank interventions based on the probability that an intervention is superior (Pbest) and the Surface Area Under the Cumulative Ranking Curve (SUCRA) to indicate relative anxiolytic efficacy. The mean difference in Total Distress Score and secondary outcomes will be estimated using Bayesian models. Ethics approval will be obtained from institutional review boards of the participating sites. Informed consent will be obtained from guardians of all participants in addition to assent from all participants. Study data will be submitted for publication. Clinicaltrials.gov NCT05383495.

The evidence is insufficient regarding the association between organizational downsizing and employee mental health. Our aim was to analyze trajectories of prescribed sedatives and anxiolytics with a sufficiently long follow-up time to capture anticipation, implementation and adaption to a downsizing event among stayers, changers and those who become unemployed compared to unexposed employees. Residents in Sweden aged 20-54 years in 2007, with stable employment between 2004 and 2007, were followed between 2005 and 2013 (n = 2,305,795). Employment at a workplace with staff reductions ≥18% between two subsequent years in 2007-2011 (n = 915,461) indicated exposure to, and timing of, downsizing. The unexposed (n = 1,390,334) were randomized into four corresponding sub-cohorts. With generalized estimating equations, we calculated the odds ratios (OR) of purchasing prescribed anxiolytics or sedatives within nine 12-month periods, from four years before to four years after downsizing. In order to investigate whether the groups changed their probability of purchases over time, odds ratios (OR) and their 95% confidence intervals (95% CI) were calculated contrasting the prevalence of purchases during the first and the last 12-month period within four time periods for each exposure group. The odds of purchasing psychotropic drugs increased more for changers (sedatives OR 1.08, 95% CI 1.05-1.11) and unemployed (anxiolytics OR 1.08, 95% CI 1.03-1.14), compared to unexposed before downsizing, while for stayers purchases increased more than for unexposed during and after downsizing. Among those without previous sickness absence, stayers increased their purchases of psychotropic drugs from the year before the event up to four years after the event. This study indicates that being exposed to downsizing is associated with increased use of sedatives and anxiolytics, before the event among those who leave, but especially thereafter for employees who stay in the organization.

Some antidepressant agents generate differential benefit based on gender. Blocking cholinergic muscarinic receptors using scopolamine produces robust and rapid antidepressant effects in males and females combined. This study evaluated if males and females differ in the antidepressant response magnitude following scopolamine administration. A total of 52 male and female outpatients meeting criteria for recurrent major depressive or bipolar disorder participated in a double-blind, randomized, placebo-controlled, crossover clinical trial involving seven i.v. infusions of placebo or scopolamine (4 μg/kg). Following a single-blind placebo lead-in, participants entered either a placebo-block/scopolamine-block or a scopolamine-block/placebo-block sequence. Each block included three sessions. Clinical ratings were acquired before each infusion and included the Montgomery–Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A). A treatment group × block interaction (F=21.0, p <0.001) was observed in MADRS scores across gender, and the reduction was significant by the evaluation following the first scopolamine administration (F=8.4, p =0.006). The treatment group × block interaction was also significant in males (F=3.8, p =0.043) and females (F=35.6, p <0.001) separately. A block × gender interaction (F=7.4, p =0.009) indicated that the response magnitude was larger in women. The treatment × block interaction was significant for the HAM-A across gender (F=12.0, p <0.001), and was significant for females (F=24.9, p <0.001) but not for males (F=1.3, p =0.30). When comparing the baseline block to study end, the block × gender interaction (F=12.6, p =0.001) showed that the antianxiety response was greater in women. Men and women show a rapid antidepressant response following scopolamine, but the magnitude of response is larger in women than in men.

We aimed to evaluate the potential anxiolytic effects of premedication with pregabalin, compared with diazepam and placebo. We conducted this non-inferiority, double-blind, randomized controlled trial in ASA classification I-II patients aged 18–70 years, scheduled for elective surgery under general anesthesia. They were allocated to receive pregabalin (75 mg the night before surgery and 150 mg 2 h before surgery), diazepam (5 and 10 mg in the same manner) or placebo. Preoperative anxiety was evaluated using verbal numerical rating scale (VNRS) and Amsterdam Preoperative Anxiety and Information Scale (APAIS) before and after premedication. Sleep quality, sedation level, and adverse effects were assessed as secondary outcomes. A total of 231 patients were screened and 224 completed the trial. The mean change (95%CI) in anxiety scores from before to after medication in pregabalin, diazepam, and placebo groups for VNRS were − 0.87 (− 1.43, − 0.30), − 1.17 (− 1.74, − 0.60), and − 0.99 (− 1.56, − 0.41), and for APAIS were − 0.38 (− 1.04, 0.28), − 0.83 (− 1.49, − 0.16), and − 0.27 (− 0.95, 0.40). The difference in change for pregabalin versus diazepam was 0.30 (− 0.50, 1.11) for VNRS and 0.45 (− 0.49, 1.38) for APAIS, exceeding the limit of inferiority for APAIS of 1.3. Sleep quality was statistically different between pregabalin and placebo groups ( p  = 0.048). Sedation in pregabalin and diazepam groups were significantly higher than placebo group ( p  = 0.008). No significant differences of other side effects, except dry mouth was higher in placebo group compared with diazepam ( p  = 0.006). The study filed to provide evidence at non-inferiority of pregabalin compared to diazepam. Furthermore, premedication with either pregabalin or diazepam did not significantly reduce the preoperative anxiety in comparison to placebo, despite the fact that both resulted in higher levels of sedation. Clinicians should weigh the benefits and risks of premedication with these 2 drugs. Thai Clinical Trials Registry: TCTR20190424001 (24/04/2019) Registry URL: https://www.thaiclinicaltrials.org/ .