Trauma-Related Dissociation and the Dissociative Disorders:: Neglected Symptoms with Severe Public Health Consequences.

Trauma-related dissociation is a major public health risk warranting the attention of the healthcare professions. Severe dissociative pathology or dissociative disorders (DDs) are more prevalent than some commonly assessed psychiatric disorders (e.g., Bipolar Disorder, Obsessive Compulsive Disorder, Schizophrenia), yet are often under-recognized and undertreated, despite being associated with significant disability and chronic medical issues, among many other severe and costly public health consequences. In fact, people living with DDs spend an average of 5 to 12.4 years actively engaged in treatment before receiving an accurate diagnosis. Detection and treatment of trauma-related dissociation and DDs leads to a myriad of positive outcomes including improved quality of life, treatment outcomes, reduction in health and social risks, decreased healthcare utilization and costs (25-64% reduction), and significant economic advantages for society. It is imperative that healthcare professionals are trained in recognizing, assessing, and treating dissociation in service of preventing the discussed public health consequences. This article provides a comprehensive review of the important public health implications resulting from often neglected or untreated trauma-related dissociation and DDs while offering a summary of assessment methods, treatments, and resources to empower individuals and healthcare professionals to effect change.

Phosphodiesterase 10A Inhibitor Monotherapy Is Not an Effective Treatment of Acute Schizophrenia.

BACKGROUND: Current treatments for psychotic symptoms associated with schizophrenia often provide inadequate efficacy with unacceptable adverse effects. Improved therapeutics have long been a goal of research. Preclinical testing suggests that phosphodiesterase 10A (PDE10A) inhibitors may provide a novel approach to treating psychosis associated with schizophrenia. METHODS: The efficacy and safety of a highly selective PDE10A inhibitor, PF-02545920, was evaluated in a phase 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Eligible patients (18-65 years) with an acute exacerbation of schizophrenia were randomized 2:2:1:2 to PF-02545920 (5 or 15 mg every 12 hours [Q12H] titrated), risperidone (3 mg Q12H), or placebo for 28 days (n = 74:74:37:74). The primary objectives were to evaluate the efficacy of PF-02545920 using the Positive and Negative Syndrome Scale (PANNS) and safety/tolerability. RESULTS: At day 28, PF-02545920 (either dose) was not significantly different from placebo for mean change from baseline in the PANNS total score (primary end point) or most other end points. Pharmacokinetics exposures seemed adequate for binding/inhibiting PDE10A enzyme. Risperidone was statistically different from placebo for the PANNS total score, demonstrating study sensitivity. Incidence rates for adverse events were similar among the groups. Both doses of PF-02545920 were generally well tolerated. Dystonia occurred in 1, 6, 0, and 3 patients in the PF-02545920 5 mg Q12H, PF-02545920 15 mg Q12H, risperidone, and placebo groups, respectively. CONCLUSIONS: Neither dose of PF-02545920 was superior to placebo for the primary and most secondary end points. This indicates that PDE10A inhibition does not produce an antipsychotic effect in patients with acute exacerbation of schizophrenia.

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial of CX-8998, a Selective Modulator of the T-Type Calcium Channel in Inadequately Treated Moderate to Severe Essential Tremor: T-CALM Study Design and Methodology for Efficacy Endpoint and Digital Biomarker Selection.

Background: Essential tremor (ET) is a common, progressive neurological syndrome with bilateral upper-limb dysfunction of at least 3-year duration, with or without tremor in other body locations. This disorder has a negative impact on daily function and quality of life. A single oral therapy has been approved by FDA for ET. Off-label pharmacotherapies have inadequate efficacy and poor tolerability with high rates of patient dissatisfaction and discontinuation. Safe and efficacious pharmacotherapies are urgently needed to decrease tremor and improve daily living. T-CALM (Tremor-CAv3 modulation) protocol is designed to assess safety and efficacy of CX-8998, a selective modulator of the T-type calcium channel, for ET therapy. Methods/Design: T-CALM is a phase 2, proof of concept, randomized, double-blind, placebo-controlled trial. Titrated doses of CX-8998 to 10 mg BID or placebo will be administered for 28 days to moderate to severe ET patients who are inadequately treated with existing therapies. The primary endpoint will be change from baseline to day 28 of The Essential Tremor Rating Assessment Performance Subscale (TETRAS-PS). Secondary efficacy endpoints for clinician and patient perception of daily function will include TETRAS Activity of Daily Living (ADL), Quality of Life in Essential Tremor Questionnaire (QUEST), Clinical Global Impression-Improvement (CGI-I), Patient Global Impression of Change (PGIC), and Goal Attainment Scale (GAS). Kinesia One, Kinesia 360, and iMotor will biometrically evaluate motor function and tremor amplitude. Safety will be assessed by adverse events, physical and neurological exams and laboratory tests. Sample size of 43 patients per group is estimated to have 90% power to detect a 5.5-point difference between CX-8998 and placebo for TETRAS-PS. Efficacy analyses will be performed with covariance (ANCOVA) and 2-sided test at 0.05 significance level. Discussion: T-CALM has a unique design with physician rating scales, patient-focused questionnaires and scales and objective motor measurements to assess clinically meaningful and congruent efficacy. Patient perception of ET debilitation and therapy with CX-8998 will be key findings. Overall goal of T-CALM is generation of safety and efficacy data to support a go, no-go decision to further develop CX-8998 for ET. Design of T-CALM may guide future clinical studies of ET pharmacotherapies. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03101241.

Item response theory analysis of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised in the Pooled Resource Open-Access ALS Clinical Trials Database.

Our objective was to examine dimensionality and item-level performance of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) across time using classical and modern test theory approaches. Confirmatory factor analysis (CFA) and Item Response Theory (IRT) analyses were conducted using data from patients with amyotrophic lateral sclerosis (ALS) Pooled Resources Open-Access ALS Clinical Trials (PRO-ACT) database with complete ALSFRS-R data (n = 888) at three time-points (Time 0, Time 1 (6-months), Time 2 (1-year)). Results demonstrated that in this population of 888 patients, mean age was 54.6 years, 64.4% were male, and 93.7% were Caucasian. The CFA supported a 4* individual-domain structure (bulbar, gross motor, fine motor, and respiratory domains). IRT analysis within each domain revealed misfitting items and overlapping item response category thresholds at all time-points, particularly in the gross motor and respiratory domain items. Results indicate that many of the items of the ALSFRS-R may sub-optimally distinguish among varying levels of disability assessed by each domain, particularly in patients with less severe disability. Measure performance improved across time as patient disability severity increased. In conclusion, modifications to select ALSFRS-R items may improve the instrument's specificity to disability level and sensitivity to treatment effects.

A randomized, double-blind, placebo-controlled phase 2 study of the augmentation of a nicotinic acetylcholine receptor partial agonist in depression: is there a relationship to leptin levels?

This randomized, double-blind, placebo-controlled trial evaluated the efficacy of CP-601,927, an α4ß2 nicotinic acetylcholine receptor partial agonist and an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to selective serotonin reuptake inhibitors (SSRIs). After open-label treatment with an SSRI for 8 weeks, subjects with a Hamilton Depression Scale 17 score greater than or equal to 16 were entered into a double-blind phase and randomized to CP-601,927 2 mg twice daily or placebo for 6 weeks. The primary end point was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from double-blind baseline to week 14. There was no significant difference in change from baseline to week 14 in the MADRS score for CP-610,927 versus placebo (least square mean difference [80% confidence interval], -1.30 [-3.32-0.71]). Post hoc analyses revealed that the drug-placebo difference in change from baseline (SE) to week 14 in MADRS score was greater in subjects with body mass index (BMI) less than or equal to 35 kg/m (-3.43 [1.87], P = 0.069) than those with BMI greater than 35 kg/m (3.37 [2.8], P = 0.230). Analysis of biomarkers associated with increased BMI suggests that baseline leptin had a significant effect on treatment outcome. P values for the effect of treatment on mean change in MADRS score for subjects with baseline leptin levels below and above the median were 0.055 and 0.0055, respectively. CP-601,927 was equivalent to placebo as an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to SSRIs. However, post hoc analyses suggest that BMI, particularly elevated leptin levels, may have affected the response to CP-601,927; however, further study may be needed to confirm these results.

Current practices in the monitoring of cardiac rhythm devices in pediatrics and congenital heart disease.

Although guidelines for routine follow-up of pacemakers and implantable cardioverter defibrillators (ICDs) are available for adults, minimal data supports their appropriateness in pediatrics and congenital heart disease. This study aimed to define current practices of cardiac rhythm device (CRD) follow-up among pediatric electrophysiologists. Pediatric and Congenital EP Society (PACES) members were surveyed regarding frequency of CRD in-person follow-up as well as transtelephonic monitoring (TTM) and remote monitoring (RM) practices. If home monitoring was used, the effect on in-person follow-up was also evaluated. A total of 106 PACES members responded to the survey. Uncomplicated pacemaker and ICD patients were both followed in-person at a median interval of 6 months (range 1-12 months). TTM was utilized by 67 % of responders (median interval 3 months; range 1-6 months), while RM was used by 87 % for pacemakers (median interval 3 months; range 1-6 months) and 92 % for ICDs (median interval 3 months; range 2 weeks-6 months). When TTM was used, 21 % of responders reduced their frequency of pacemaker clinic visits. In comparison, RM reduced the frequency of clinic visits for pacemakers and ICDs in 32 and 31 % of responders, respectively. Patient age was an independent factor in determining CRD follow-up for 49 % of responders. While CRD follow-up by pediatric electrophysiologists in general follows adult guidelines, individual practices widely vary. In contrast to published recommendations in adults, TTM and RM utilization does not reduce the frequency of in-person visits for the majority of pediatric electrophysiologists.