Aticaprant: (a κ-opioid receptor antagonist) for major depressive disorder.

INTRODUCTION: Major depression is a common, disabling mental health condition associated with the highest disease burden for any neuropsychiatric disorder worldwide, according to the WHO. Due to the imperfect efficacy and tolerability profiles of existing treatments, investigational compounds in novel treatment classes are needed. Opioid-receptor antagonists are a potential new class of treatments currently under investigation. AREAS COVERED: Major depressive disorder is first overviewed. Existing treatments, both their mechanisms of action and their place within the antidepressant space, are discussed herein. Then, the profile of Aticaprant and the wider context of kappa-opioid antagonism for depression are discussed in focus. EXPERT OPINION: Early evidence indicates that Aticaprant may possess desirable pharmacodynamic and pharmacokinetic properties. A lack of convincing efficacy data at the time of writing precludes any definitive statement on its potential as an antidepressant.

BNC210: an investigational α7-nicotinic acetylcholine receptor modulator for the treatment of anxiety disorders.

INTRODUCTION: Anxiety disorders are common, disabling psychiatric conditions associated with excessive worry, irritability, and physiological symptoms of stress. Following insufficient response to psychological therapies, first-line pharmacological treatments for anxiety disorders suffer from inconsistent efficacy, addiction, and intolerable side-effect profiles (e.g. sedation), especially when used inappropriately or contrary to evidence-based guidelines. Developing anxiolytics acting via cholinergic modulation may provide novel options for the treatment of anxiety disorders, without the drawbacks of existing anxiolytics. AREAS COVERED: We review pharmacological treatment of anxiety disorders and proposed mechanisms of action in relation to the associated neural circuitry. We then consider the mechanism of action, pharmacodynamics, and pharmacokinetics of the negative-allosteric modulator of the alpha7 nicotinic receptor BNC210, an investigational anxiolytic so far employed in studies of those with social anxiety disorder, post-traumatic stress disorder, and agitation in hospitalized elderly. Lastly, we consider the environment of competitor compounds for this indication, and BNC210's place within it, in both the present and near-future. EXPERT OPINION: : There is a relative paucity of data regarding BNC210, albeit the small amount of mostly non-peer reviewed data indicate it is a well-tolerated, effective anxiolytic. Phase III trials are required for proper appraisal of its utility.

Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression.

BACKGROUND: Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions. Adjunctive treatment (augmentation/combination) is recommended for the ~50% of MDD patients who do not adequately respond to first-line treatment. We aimed to evaluate the current evidence for concomitant approaches for people with early-stage treatment-resistant depression (TRD; defined below). METHODS: We systematically searched Medline and Institute for Scientific Information Web of Science to identify randomised controlled trials of adjunctive treatment of ⩾10 adults with MDD who had not responded to ⩾1 adequate antidepressant. The cochrane risk of bias (RoB) tool was used to assess study quality. Pre-post treatment meta-analyses were performed, allowing for comparison across heterogeneous study designs independent of comparator interventions. RESULTS: In total, 115 trials investigating 48 treatments were synthesised. The mean intervention duration was 9 weeks (range 5 days to 18 months) with most studies assessed to have low (n = 57) or moderate (n = 51) RoB. The highest effect sizes (ESs) were from cognitive behavioural therapy (ES = 1.58, 95% confidence interval (CI): 1.09-2.07), (es)ketamine (ES = 1.48, 95% CI: 1.23-1.73) and risperidone (ES = 1.42, 95% CI: 1.29-1.61). Only aripiprazole and lithium were examined in ⩾10 studies. Pill placebo (ES = 0.89, 95% CI: 0.81-0.98) had a not inconsiderable ES, and only six treatments' 95% CIs did not overlap with pill placebo's (aripiprazole, (es)ketamine, mirtazapine, olanzapine, quetiapine and risperidone). We report marked heterogeneity between studies for almost all analyses. CONCLUSIONS: Our findings support cautious optimism for several augmentation strategies; although considering the high prevalence of TRD, evidence remains inadequate for each treatment option.

Protocol for Rhapsody: a longitudinal observational study examining the feasibility of speech phenotyping for remote assessment of neurodegenerative and psychiatric disorders.

INTRODUCTION: Neurodegenerative and psychiatric disorders (NPDs) confer a huge health burden, which is set to increase as populations age. New, remotely delivered diagnostic assessments that can detect early stage NPDs by profiling speech could enable earlier intervention and fewer missed diagnoses. The feasibility of collecting speech data remotely in those with NPDs should be established. METHODS AND ANALYSIS: The present study will assess the feasibility of obtaining speech data, collected remotely using a smartphone app, from individuals across three NPD cohorts: neurodegenerative cognitive diseases (n=50), other neurodegenerative diseases (n=50) and affective disorders (n=50), in addition to matched controls (n=75). Participants will complete audio-recorded speech tasks and both general and cohort-specific symptom scales. The battery of speech tasks will serve several purposes, such as measuring various elements of executive control (eg, attention and short-term memory), as well as measures of voice quality. Participants will then remotely self-administer speech tasks and follow-up symptom scales over a 4-week period. The primary objective is to assess the feasibility of remote collection of continuous narrative speech across a wide range of NPDs using self-administered speech tasks. Additionally, the study evaluates if acoustic and linguistic patterns can predict diagnostic group, as measured by the sensitivity, specificity, Cohen's kappa and area under the receiver operating characteristic curve of the binary classifiers distinguishing each diagnostic group from each other. Acoustic features analysed include mel-frequency cepstrum coefficients, formant frequencies, intensity and loudness, whereas text-based features such as number of words, noun and pronoun rate and idea density will also be used. ETHICS AND DISSEMINATION: The study received ethical approval from the Health Research Authority and Health and Care Research Wales (REC reference: 21/PR/0070). Results will be disseminated through open access publication in academic journals, relevant conferences and other publicly accessible channels. Results will be made available to participants on request. TRIAL REGISTRATION NUMBER: NCT04939818.

The prevalence of anxiety in general hospital inpatients: A systematic review and meta-analysis.

OBJECTIVE: To determine the prevalence of anxiety in general hospital inpatients by conducting a systematic review and meta-analysis of all relevant published studies. METHOD: We searched Ovid Medline, Ovid Embase and Ovid PsycINFO from inception to December 2020. We included studies of the prevalence of anxiety symptoms of clinically significant severity (using cut-off scores on rating scales) and of the prevalence of anxiety disorders (using diagnostic interviews) in general hospital inpatients. Two independent reviewers assessed articles and extracted data. The review is registered with PROSPERO, number CRD42020189722. RESULTS: We included 32 studies. Pooled prevalence estimates in random-effects meta-analyses were: anxiety symptoms 28% (95% CI 19% to 38%, 95% prediction interval 5% to 72%), any anxiety disorder 8% (95% CI 5% to 12%, 95% prediction interval 2% to 33%), panic disorder 3% (95% CI 2% to 4%, 95% prediction interval 1% to 8%), generalized anxiety disorder 5% (95% CI 3% to 8%, 95% prediction interval 1% to 23%). There was high heterogeneity in prevalence, little of which was explained in exploratory analyses of a limited number of potential determinants. CONCLUSION: Anxiety symptoms of clinically significant severity affect more than one in four inpatients and anxiety disorders affect nearly one in ten.

Microsaccade rate as a measure of drug response.

In 22 human subjects we measured microsaccade count across 60 brief fixation trials both pre- and post- administration of 300mg of caffeine. There was a statistically significant reduction in average microsaccade count post-caffeine administration, with a moderate effect size (Cohen's d of 0.42). Microsaccade count was stable within individuals across time points (Pearson's r of 0.89). Sensitivity analysis suggests that the pre/post caffeine effect size is robust to choice of parameters used to identify microsaccades. Bootstrap resampling suggests that both the pre/post-caffeine difference and the across-time stability within individuals could be reliably assessed with far fewer trials. The results support the use of microsaccade count as both a trait measure of individual differences and a state measure of caffeine response. We discuss the results in the context of the theory that the superior colliculus is central to the generation of microsaccades and hence that microsaccade rate may be a useful assay for at least some drug-induced changes at the level of the colliculus: a potentially useful tool in the development of therapies for disorders that may involve collicular dysfunction such as ADHD.