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The National Institute of Mental Health (NIMH) ‘fast-fail’ approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n  = 45) and placebo ( n  = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F (1,86) = 5.58, P  < 0.01; effect size = 0.58 (95% confidence interval, 0.13–0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the ‘fast-fail’ approach. A phase 2 proof-of-mechanism trial shows that a κ-opioid receptor antagonist improves reward-related functioning in the brain and a clinical measure of anhedonia in patients with mood and anxiety disorders, serving as a model for implementing the ‘fast-fail’ approach to psychiatric treatment development.

The aim of this study was to evaluate the reliability and validity of the Schedule for Affective Disorders and Schizophrenia for School-Age ChildrenPresent and Lifetime Version, DSM-5 November 2016 -Turkish Adaptation (K-SADS-PL-DSM-5-T).  METHOD: A total of 150 children and adolescents between 6 and 17 years of age were assessed with K-SADS-PL-DSM-5-T. The degree of agreement between the DSM-5 criteria diagnoses and the K-SADS-PL-DSM-5-T diagnoses were considered as the measure of consensus validity. In addition, concurrent validity was examined by analyzing the correlation between the diagnoses on K-SADS-PL-DSM-5-T and relevant scales. Interrater reliabilities were assessed on randomly selected 20 participants. Likewise, randomly selected 20 other participants were interviewed with K-SADS-PL-DSM-5-T three weeks after the first interview to evaluate test-retest reliability.  RESULTS: The consistency of diagnoses was almost perfect for eating disorders, selective mutism and autism spectrum disorder (κ=0.92-1.0), substantial for elimination disorders, obsessive-compulsive disorder, oppositional defiant disorder, generalized anxiety disorder, social anxiety disorder, depressive disorders, disruptive mood dysregulation disorder and attention deficit hyperactivity disorder (κ=0.67-0.80). Interrater reliability was perfect for selective mutism (κ=1.0), substantial for oppositional defiant disorder, disruptive mood dysregulation disorder, attention deficit hyperactivity disorder, depressive disorders and social anxiety disorder (κ=0.63-0.73). Test-retest reliability was almost perfect for autism spectrum disorder (κ=0.82), substantial for attention deficit hyperactivity disorder, oppositional defiant disorder, disruptive mood dysregulation disorder, depressive disorders and generalized anxiety disorder (κ=0.62-0.78).  CONCLUSION: The results of this study show that the K-SADS-PL-DSM-5-T is an effective instrument for diagnosing major childhood psychiatric disorders including selective mutism, disruptive mood dysregulation disorder and autism spectrum disorder which have recently been added to the schedule.

Acting on harmful command hallucinations is a major clinical concern. Our COMMAND CBT trial approximately halved the rate of harmful compliance (OR = 0.45, 95% CI 0.23-0.88, p = 0.021). The focus of the therapy was a single mechanism, the power dimension of voice appraisal, was also significantly reduced. We hypothesised that voice power differential (between voice and voice hearer) was the mediator of the treatment effect. The trial sample (n = 197) was used. A logistic regression model predicting 18-month compliance was used to identify predictors, and an exploratory principal component analysis (PCA) of baseline variables used as potential predictors (confounders) in their own right. Stata's paramed command used to obtain estimates of the direct, indirect and total effects of treatment. Voice omnipotence was the best predictor although the PCA identified a highly predictive cognitive-affective dimension comprising: voices' power, childhood trauma, depression and self-harm. In the mediation analysis, the indirect effect of treatment was fully explained by its effect on the hypothesised mediator: voice power differential. Voice power and treatment allocation were the best predictors of harmful compliance up to 18 months; post-treatment, voice power differential measured at nine months was the mediator of the effect of treatment on compliance at 18 months.

IntroductionAnxiety, mood and trauma-related disorders are common, affecting up to 20% of adults. Many of these individuals will experience symptoms of more than one disorder as diagnostically defined. However, most psychological treatments focus on individual disorders and are less effective for those who experience comorbid disorders. The Healthy and Resilient Mind Programme: Building Blocks for Mental Wellbeing (HARMONIC) trial introduces a novel transdiagnostic intervention (Shaping Healthy Minds (SHM)), which synthesises several evidence-based treatment techniques to address the gap in effective interventions for people with complex and comorbid difficulties. This early phase trial aims to estimate the efficacy and feasibility of the transdiagnostic intervention in preparation for a later-phase randomised controlled trial, and to explore mechanisms of change.Methods/analysisWe outline a patient-level two-arm randomised controlled trial (HARMONIC) that compares SHM to treatment-as-usual for individuals aged >18 years (n=50) with comorbid mood, anxiety, obsessive-compulsive or trauma/stressor disorders diagnoses, recruited from outpatient psychological services within the UK National Health Service (NHS). The co-primary outcomes will be 3-month follow-up scores on self-report measures of depressive symptoms, anxiety symptoms, and disability and functional impairment. Secondary outcomes include changes in symptoms linked to individual disorders. We will assess the feasibility and acceptability of SHM, the utility of proposed outcome measures, and refine the treatment manuals in preparation for a later-phase trial.Ethics and disseminationThis trial protocol has been approved by the Health Research Authority of the NHS of the UK (East of England, Reference: 16/EE/0095). We anticipate that trial findings will inform future revisions of clinical guidelines for numerous forms of mood, anxiety and stressor-related disorders. Findings will be disseminated broadly via peer-reviewed empirical journal articles, conference presentations, clinical workshops and a trial website.Trial registration NCT03143634; Pre-results.

Background Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system. MS is significantly associated with a high rate of psychological, behavioral, and emotional consequences. Despite the frequent mental disorders, high rate of psychological comorbidities, and emotional problems in people with MS (PwMS), these conditions are often underdiagnosed and undertreated. This study aimed to examine the efficacy of a group format of the unified protocol for the transdiagnostic treatment of emotional disorders in adult PwMS associated with an emotional disorder. Methods Seventy adult PwMS were randomized using an internet-based computer system to either the unified protocol ( n  = 35) or treatment as usual condition. The assessment protocol included semi-structured clinical interviews and self-reports evaluating diagnostic criteria, depression, anxiety and worry symptoms, emotional dysregulation, and affectivity. Results The parametric test of analysis of covariance, followed the intent to treat analyses, revealed the unified protocol significantly changed depression symptoms (Cohen’s d  = 1.9), anxiety symptoms (Cohen’s d  = 2.16), worry symptoms (Cohen’s d  = 1.27), emotion dysregulation (Cohen’s d  = 0.44), positive affect (Cohen’s d  = 1.51), and negative affect (Cohen’s d  = 1.89) compared with the control group. The unified protocol also significantly improved outcome scores at the end of treatment relative to baseline ( p  < .001). Conclusion The findings support that the unified protocol could be an additional efficient psychological treatment for PwMS. Trial registration IRCT, number: IRCT20190711044173N1. Registered 31october 2019, https://en.irct.ir/user/trial/40779/view .

Background The U.S. Food and Drug Administration can set standards for cigarettes that could include reducing their nicotine content. Such a standard should improve public health without causing unintended serious consequences for sub-populations. This study evaluates the effect of progressive nicotine reduction in cigarettes on smoking behavior, toxicant exposure, and psychiatric symptoms in smokers with comorbid mood and/or anxiety disorders using a two-site, two-arm, double-blind, parallel group, randomized controlled trial (RCT) in four phases over 34 weeks. Methods Adult smokers ( N =  200) of 5 or more cigarettes per day will be randomized across two sites (Penn State and Massachusetts General). Participants must have not had a quit attempt in the prior month, nor be planning to quit in the next 6 months, meet criteria for a current or lifetime unipolar mood and/or anxiety disorder based on the structured Mini-International Neuropsychiatric Interview, and must not have an unstable medical or psychiatric condition. After a week of smoking their own cigarettes, participants receive two weeks of Spectrum research cigarettes with usual nicotine content (11.6 mg). After this baseline period, participants will be randomly assigned to continue smoking Spectrum research cigarettes that contain either (a) Usual Nicotine Content (11.6 mg); or (b) Reduced Nicotine Content: the nicotine content per cigarette is progressively reduced from approximately 11.6 mg to 0.2 mg in five steps over 18 weeks. At the end of the randomization phase, participants will be offered the choice to either (a) quit smoking with assistance, (b) continue smoking free research cigarettes, or (c) return to purchasing their own cigarettes, for the final 12 weeks of the study. The primary outcome measure is blood cotinine; key secondary outcomes are: exhaled carbon monoxide, urinary total NNAL- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and 1-hydroxypyrene, oxidative stress biomarkers including 8-isoprostanes, measures of psychiatric symptoms (e.g., depression, anxiety), smoking behavior and dependence (e.g., cigarette consumption, quit attempts), and health effects (e.g., blood pressure, respiratory symptoms). Discussion Results from this study will inform FDA on the potential effects of regulating the nicotine content of cigarettes and help determine whether smokers with mood and/or anxiety disorders can safely transition to significantly reduced nicotine content cigarettes. Trial registration TRN: NCT01928758 , registered August 21, 2013.

Shelter-recruited adolescents are known to have high rates of substance abuse and co-occurring internalizing and externalizing problem behaviors. Many studies have documented these mental health concerns, but only a small number of studies have tested interventions that may be useful for ameliorating these vulnerabilities. The current study compared three empirically supported psychotherapy interventions, Motivational Interviewing (MI), the Community Reinforcement Approach (CRA), and Ecologically-Based Family Therapy (EBFT) with 179 substance abusing runaway adolescents (47 % female, 74 % minority) and their primary caretaker recruited through a Midwestern runaway crisis shelter. Examining both child and primary caretaker reports, each treatment was associated with significant reductions in internalizing and externalizing behaviors to 24 months post-baseline. However, the trajectory of change differed among the treatments. Adolescents receiving MI showed a quicker reduction in internalizing and externalizing behaviors but also a quicker increase in these behaviors compared to adolescents receiving EBFT, who continued to evidence improvements to 24 months. The findings provide support for continued evaluation of these treatments for use with this vulnerable population of adolescents.

Objectives. To estimate the economic burden of untreated perinatal mood and anxiety disorders (PMADs) among 2017 births in the United States. Methods. We developed a mathematical model based on a cost-of-illness approach to estimate the impacts of exposure to untreated PMADs on mothers and children. Our model estimated the costs incurred by mothers and their babies born in 2017, projected from conception through the first 5 years of the birth cohort’s lives. We determined model inputs from secondary data sources and a literature review. Results. We estimated PMADs to cost$14 billion for the 2017 birth cohort from conception to 5 years postpartum. The average cost per affected mother–child dyad was about $ 31 800. Mothers incurred 65% of the costs; children incurred 35%. The largest costs were attributable to reduced economic productivity among affected mothers, more preterm births, and increases in other maternal health expenditures. Conclusions. The US economic burden of PMADs is high. Efforts to lower the prevalence of untreated PMADs could lead to substantial economic savings for employers, insurers, the government, and society.

Objective:To test the hypothesis that among adolescent smokers hospitalised for psychiatric and substance use disorders, motivational interviewing (MI) would lead to more and longer quit attempts, reduced smoking, and more abstinence from smoking over a 12 month follow up. Design:Randomised control trial of MI versus brief advice (BA) for smoking cessation, with pre- and post-intervention assessment of self efficacy and intentions to change, and smoking outcome variables assessed at one, three, six, nine, and 12 month follow ups. Setting:A private, university affiliated psychiatric hospital in Providence, Rhode Island, USA. Patients or other participants:Consecutive sample (n = 191) of 13–17 year olds, admitted for psychiatric hospitalisation, who smoked at least one cigarette per week for the past four weeks, had access to a telephone, and did not meet DSM-IV criteria for current psychotic disorder. Interventions:MI versus BA. MI consisted of two, 45 minute individual sessions, while BA consisted of 5–10 minutes of advice and information on how to quit smoking. Eligible participants in both conditions were offered an eight week regimen of transdermal nicotine patch upon hospital discharge. Main outcome measures:Point prevalence abstinence, quit attempts, changes in smoking rate and longest quit attempt. Proximal outcomes included intent to change smoking behaviour (upon hospital discharge), and self efficacy for smoking cessation. Results:MI did not lead to better smoking outcomes compared to BA. MI was more effective than BA for increasing self efficacy regarding ability to quit smoking. A significant interaction of treatment with baseline intention to quit smoking was also found. MI was more effective than BA for adolescents with little or no intention to change their smoking, but was actually less effective for adolescents with pre-existing intention to cut down or quit smoking. However, the effects on these variables were relatively modest and only moderately related to outcome. Adolescents with comorbid substance use disorders smoked more during follow up while those with anxiety disorders smoked less and were more likely to be abstinent. Conclusions:The positive effect of MI on self efficacy for quitting and the increase in intention to change in those with initially low levels of intentions suggest the benefits of such an intervention. However, the effects on these variables were relatively modest and only moderately related to outcome. The lack of overall effect of MI on smoking cessation outcomes suggests the need to further enhance and intensify this type of treatment approach for adolescent smokers with psychiatric comorbidity.

Pseudobulbar affect is characterized by uncontrollable, inappropriate laughing and/or crying that is either unrelated or out of proportion to the emotions felt by the patient and occurs in patients with neurological disorders, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis or traumatic brain injury. Dextromethorphan/quinidine is indicated in the US for the treatment of pseudobulbar affect. Dextromethorphan, when its metabolism is inhibited by the coadministration of quinidine, has been shown to have a positive effect on the symptoms of pseudobulbar affect. Dextromethorphan/quinidine 20 mg/10 mg twice daily was associated with a significantly greater decrease in the rate of pseudobulbar affect episodes per day (primary endpoint) than placebo in the 12-week, randomized, double-blind, placebo-controlled, multicentre STAR trial (Safety, Tolerability, And efficacy Results trial of AVP-923 in PBA [pseudobulbar affect]) involving patients with pseudobulbar affect and ALS or multiple sclerosis. Moreover, the mean change from baseline in Center for Neurologic Study-Lability Scale score at 12 weeks was significantly greater among recipients of dextromethorphan/quinidine 20mg/10 mg twice daily than those receiving placebo. Dextromethorphan/quinidine 20mg/10 mg twice daily was generally well tolerated. The drug has been shown to cause dosage-dependent corrected QT interval (QTc) prolongation; however, in the STAR trial, dextromethorphan/quinidine 20mg/10mg twice daily appeared to be well tolerated with regard to QTc prolongation.