The Quick Inventory of Depressive Symptomatology, Adolescent Version (QIDS-A17): A Psychometric Evaluation.

Objective: The current study aimed to evaluate the psychometric features of the Quick Inventory of Depressive Symptomatology, Adolescent version (QIDS-A17) and the clinician-rated Children's Depression Rating Scale-Revised (CDRS-R). Methods: Altogether, 103 outpatients (8 to 17 years) completed the self-report QIDS-A17-SR. Clinician interviews of adolescents (QIDS-A17-C (Adolescent)) and of parents (QIDS-A17-C (Parent)) were combined to create the QIDS-A17-C(Composite) and the CDRS-R. Results: All QIDS-A17 measures and the CDRS-R evidenced high total score correlations and internal consistency. Factor analysis found all four measures to be unidimensional. Item Response Theory (IRT) analysis found results that complemented the reliability results found in CTT. All four also demonstrated discriminant diagnostic validity based on logistic regression and ANOVA analyses. Conclusion: The psychometric properties of the self-report and composite versions of the QIDS-A17 suggest acceptability as a measure of depression in adolescents either as a measure of depressive symptoms or severity of illness in adolescents. The self-report version may be a helpful tool in busy clinical practices.

Improving the management of acutely agitated patients in the emergency department through implementation of Project BETA (Best Practices in the Evaluation and Treatment of Agitation).

Agitated patients presenting to the emergency department (ED) can escalate to aggressive and violent behaviors with the potential for injury to themselves, ED staff, and others. Agitation is a nonspecific symptom that may be caused by or result in a life-threatening condition. Project BETA (Best Practices in the Evaluation and Treatment of Agitation) is a compilation of the best evidence and consensus recommendations developed by emergency medicine and psychiatry experts in behavioral emergencies to improve our approach to the acutely agitated patient. These recommendations focus on verbal de-escalation as a first-line treatment for agitation; pharmacotherapy that treats the most likely etiology of the agitation; appropriate psychiatric evaluation and treatment of associated medical conditions; and minimization of physical restraint/seclusion. Implementation of Project BETA in the ED can improve our ability to manage a patient's agitation and reduce the number of physical assaults on ED staff. This article summarizes the BETA guidelines and recent supporting literature for managing the acutely agitated patient in the ED followed by a discussion of how a large county hospital integrated these recommendations into daily practice.

Adaptive Affect: The Nature of Anxiety and Depression.

An approach viewing anxiety and depression as extensions of normal adaptive biologic drives is discussed. Anxiety is viewed as the result of an underlying biological drive to preserve and maintain our wellbeing. At the extremes, if unresolved, this drive can be maladaptive, particularly if activated over prolonged periods of time. This paper proposes that depression is the result of a biological drive that mediates the effects of maladaptive levels of anxiety. These two processes are thought to be acting simultaneously. When operating in the normal range, these drives are helpful; in the extremes, they are associated with impairment. Over time, if unresolved, symptoms of anxiety will begin to become associated with increasing levels of depression.

Evaluating psychiatric readmissions in the emergency department of a large public hospital.

INTRODUCTION: Hospital emergency departments (EDs) around the country are being challenged by an ever-increasing volume of patients seeking psychiatric services. This manuscript describes a study performed to identify internal and external factors contributing to repeated psychiatric patient admissions to the hospital main ED. METHODS: Data from ED visits of patients who were admitted to the Parkland Memorial Hospital ED (the community hospital for Dallas County, TX, USA) with a psychiatric complaint more than once within a 30-day period were evaluated (n=202). A 50-item readmission survey was used to collect information on demographic and clinical factors associated with 30-day readmission, as well as to identify quality improvement opportunities by assessing related moderating factors. An analysis of acute readmission visits (occurring within 3 days of previous discharge) was also performed. RESULTS: Patients readmitted to the ED commonly present with a combination of acute psychiatric symptoms, substance use (especially in the case of acute readmission), and violent or suicidal behavior. The vast majority of cases reviewed found that readmitted patients had difficulties coordinating care outside the ED. A number of moderating factors were identified and targeted for quality improvement including additional support for filling prescriptions, transportation, communication with family and outside providers, drug and alcohol treatment, intensive case management, and housing. CONCLUSION: Many of the resources necessary to reduce psychiatric patient visits to hospital EDs are available within the community. There is no formal method of integrating and insuring the continuity of community services that may reduce the demand for psychiatric and related services in the ED. While agreements between community service providers may be challenging and require considerable vigilance to maintain equitable agreements between parties, this route of improving efficiency may be the only available method, given the current and projected patient care needs.

Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC): Rationale and design.

UNLABELLED: Remission rates for Major Depressive Disorder (MDD) are low and unpredictable for any given antidepressant. No biological or clinical marker has demonstrated sufficient ability to match individuals to efficacious treatment. Biosignatures developed from the systematic exploration of multiple biological markers, which optimize treatment selection for individuals (moderators) and provide early indication of ultimate treatment response (mediators) are needed. The rationale and design of a multi-site, placebo-controlled randomized clinical trial of sertraline examining moderators and mediators of treatment response is described. The target sample is 300 participants with early onset (≤30 years) recurrent MDD. Non-responders to an 8-week trial are switched double blind to either bupropion (for sertraline non-responders) or sertraline (for placebo non-responders) for an additional 8 weeks. Clinical moderators include anxious depression, early trauma, gender, melancholic and atypical depression, anger attacks, Axis II disorder, hypersomnia/fatigue, and chronicity of depression. Biological moderator and mediators include cerebral cortical thickness, task-based fMRI (reward and emotion conflict), resting connectivity, diffusion tensor imaging (DTI), arterial spin labeling (ASL), electroencephalograpy (EEG), cortical evoked potentials, and behavioral/cognitive tasks evaluated at baseline and week 1, except DTI, assessed only at baseline. The study is designed to standardize assessment of biomarkers across multiple sites as well as institute replicable quality control methods, and to use advanced data analytic methods to integrate these markers. A Differential Depression Treatment Response Index (DTRI) will be developed. The data, including biological samples (DNA, RNA, and plasma collected before and during treatment), will become available in a public scientific repository. CLINICAL TRIAL REGISTRATION: Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC). Identifier: NCT01407094. URL: http://clinicaltrials.gov/show/NCT01407094.

Using Multiple Antibiotic Resistance Profiles of Coliforms as a Tool to Investigate Combined Sewer Overflow Contamination.

Studies have shown that fecal contamination can be determined by conducting multiple antibiotic resistance (MAR) analyses. The hypothesis is if bacteria exhibit resistance, they are likely to be derived from organisms exposed to antimicrobial agents. Therefore, this project seeks to apply MAR analysis to nonpoint source (NPS) and combined sewer overflow (CSO) areas along the Anacostia River in Washington, DC. Presumptive E. coli was isolated from NPS and CSO samples and tested with eight different antimicrobial agents to assess MAR indices. Isolates from CSO sources showed significantly greater resistance (p < .05) and higher MAR indices, with an average MAR index of 0.36 for CSO samples and 0.07 for NPS samples. It was also revealed that 96.9% of CSO isolates exhibited resistance, versus only 43.8% of NPS isolates. Our study on the Anacostia River using this approach clearly shows fecal coliforms are associated with CSO overflows, indicating that pollution-derived coliform levels are strongly linked to antimicrobial resistance. The implementation of this method as an index for water quality in the remediation of the Anacostia River has the ability to serve as a model and monitoring tool for the rehabilitation of urban watersheds.

Evaluation of anhedonia with the Snaith-Hamilton Pleasure Scale (SHAPS) in adult outpatients with major depressive disorder.

Anhedonia or inability to experience pleasure not only is a core symptom of major depressive disorder (MDD), but also is identified as an important component of the positive valence system in the NIMH Research Domain Criteria. The Snaith-Hamilton Pleasure Scale (SHAPS) has been developed for the assessment of hedonic experience or positive valence, but has not been well-studied in depressed outpatient populations. The current study examined the reliability and validity of the SHAPS using a sample of adult outpatients with treatment resistant MDD. Data for the current study were obtained from 122 adult outpatients with a diagnosis of MDD and non-response to adequate treatment with an SSRI and who participated in Project TReatment with Exercise Augmentation for Depression (TREAD). A Principal Components Analysis was used to define the dimensionality of the SHAPS. Convergent and discriminant validity were evaluated via correlations of the SHAPS total score with "gold standard" measures of depression severity and quality of life. The SHAPS was found to have high internal consistency (Cronbach's coefficient α = .82). A Principal Components Analysis suggests that the SHAPS is mainly "unidimensional" and limited to hedonic experience among adult outpatients with MDD. Convergent and discriminant validity were assessed by examining the Spearman rank-order correlation coefficient between the SHAPS total score and the HRSD17 (rs = 0.22, p < .03), IDS-C30 (rs = 0.26, p < .01), IDS-SR30 (rs = 0.23, p < .02), QIDS-C16 (rs = 0.22, p < .03), QIDS-SR16 (rs = 0.17, p < .10), QLES-Q (rs = -0.32, p < .002), and the pleasure/enjoyment item (sub-item 21) of the IDS-C (rs = 0.44, p < .0001) and IDS-SR (rs = 0.38, p < .0002). The self-administered SHAPS showed modest sensitivity (76%) and specificity (54%) with the self-administered pleasure/enjoyment single item (sub-item 21) of IDS-SR30. The current study shows that the SHAPS is a reliable and valid instrument to assess hedonic experience or positive valence in adult outpatients with MDD and provides a broader assessment of this important domain.

Research staff training in a multisite randomized clinical trial: Methods and recommendations from the Stimulant Reduction Intervention using Dosed Exercise (STRIDE) trial.

BACKGROUND: Descriptions of and recommendations for meeting the challenges of training research staff for multisite studies are limited despite the recognized importance of training on trial outcomes. The STRIDE (STimulant Reduction Intervention using Dosed Exercise) study is a multisite randomized clinical trial that was conducted at nine addiction treatment programs across the United States within the National Drug Abuse Treatment Clinical Trials Network (CTN) and evaluated the addition of exercise to addiction treatment as usual (TAU), compared to health education added to TAU, for individuals with stimulant abuse or dependence. Research staff administered a variety of measures that required a range of interviewing, technical, and clinical skills. PURPOSE: In order to address the absence of information on how research staff are trained for multisite clinical studies, the current manuscript describes the conceptual process of training and certifying research assistants for STRIDE. METHODS: Training was conducted using a three-stage process to allow staff sufficient time for distributive learning, practice, and calibration leading up to implementation of this complex study. RESULTS: Training was successfully implemented with staff across nine sites. Staff demonstrated evidence of study and procedural knowledge via quizzes and skill demonstration on six measures requiring certification. Overall, while the majority of staff had little to no experience in the six measures, all research assistants demonstrated ability to correctly and reliably administer the measures throughout the study. CONCLUSIONS: Practical recommendations are provided for training research staff and are particularly applicable to the challenges encountered with large, multisite trials.

Guidance on the conversion of the Chinese versions of the Quick Inventory of Depressive Symptomatology-Self-Report (C-QIDS-SR) and the Montgomery-Asberg Scale (C-MADRS) in Chinese patients with major depression.

BACKGROUND: The 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) is a newly introduced screening tool, while the Montgomery-Asberg Scale (MADRS) is commonly used in research and clinical practice in China. Converting the total scores between the two instruments could facilitate the comparison of different studies. METHODS: This study included 1164 patients with major depressive disorder (MDD). The diagnosis was established using the Mini International Neuropsychiatric Interview (MINI). The severity of depressive symptoms was assessed with the Chinese versions of MADRS (C-MADRS) and QIDS-SR (C-QIDS-SR) at baseline and 6 weeks later (exit point). Total scores of both scales were converted using Item Response Theory (IRT) analysis. RESULTS: At baseline, the C-MADRS and C-QIDS-SR were not unifactorial, therefore the conversion between them could not be performed. At exit, the C-MADRS and C-QIDS-SR were unifactorial, meeting the unidimensionality assumption of the IRT approach. Depression severity thresholds for the QIDS-SR are suggested as 6-10 for mild, 11-15 for moderate, 16-20 for severe, 21+ for very severe depression and ≤ 5 for remission (www.ids-qids.org). Based on the results of this study, the corresponding C-MADRS thresholds are 9-17 for mild, 18-24 for moderate, 25-33 for severe, 34+ for very severe depression and ≤ 7 or 8 (7.5) for remission. CONCLUSIONS: The conversion of C-QIDS-SR and C-MADRS total scores would help researchers understand findings across different studies using these scales.

Relationship between obesity and depression: characteristics and treatment outcomes with antidepressant medication.

OBJECTIVE: Obesity and major depressive disorder often co-occur. However, differences between obese and normal-weight depressed patients and the moderating effect of obesity on antidepressant treatment outcome are not well studied. METHODS: Adults (n = 662) with major depressive disorder in the Combining Medications to Enhance Depression Outcomes study were randomized to treatment with escitalopram plus placebo, bupropion plus escitalopram, or venlafaxine plus mirtazapine for a 12-week primary treatment phase and 16-week follow-up. Body mass index (BMI) was calculated at baseline and categorized according to World Health Organization criteria: normal or low weight (NW), overweight, Obese I and Obese II+. A repeated-effects model, unadjusted and adjusted for baseline variables, assessed outcomes. RESULTS: Obesity was common (46.2%), only 25.5% were NW. Higher BMI was associated with greater medical illness (p < .001), social phobia (p = .003), and bulimia (p = .026). Lower BMI was associated with more frequent post-traumatic stress disorder (p = .002) and drug abuse (p < .001). Treatment outcomes did not differ including Week 12 remission rates (NW 36%, overweight 40%, Obese I 43%, Obese II+ 37%; p = .69). Lower BMI was associated with more frequent (p = .024 [unadjusted] and .053 [adjusted]) and more severe (p = .008 [unadjusted] and .053 [adjusted]) adverse effects. CONCLUSIONS: BMI was related to clinical presentation and prevalence of comorbidities, but not antidepressant outcomes. Lower BMI classes had more psychiatric comorbidities, potentially obscuring the relationship between BMI and antidepressant effects. Trial Registration ClinicalTrials.gov identifier: NCT00590863.

Clinical phenotypes of psychosis in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP).

OBJECTIVE: Developing categorical diagnoses that have biological meaning within the clinical phenotype of psychosis (schizophrenia, schizoaffective disorder, and bipolar I disorder with psychosis) is as important for developing targeted treatments as for nosological goals. The Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) was formed to examine a broad array of intermediate phenotypes across psychotic disorders and to test the hypothesis that intermediate phenotype characteristics are homogeneous within phenomenologically derived DSM-IV diagnoses. METHOD: The consortium recruited 933 stable probands with schizophrenia, schizoaffective disorder, or psychotic bipolar I disorder, 1,055 of their first-degree relatives, and 459 healthy comparison subjects for clinical characterization and dense phenotyping. Clinical, psychosocial, and family characteristics were contrasted. RESULTS: All proband groups showed lower psychosocial functioning than the relatives or comparison group. On average, schizophrenia probands showed more symptoms and lower psychosocial functioning than probands with psychotic bipolar disorder, but there was considerable overlap in clinical manifestations. The characteristics of schizoaffective disorder were more often similar to schizophrenia than to psychotic bipolar disorder. The rates of lifetime suicide attempts were high across all proband groups, with the highest reported frequencies in the schizoaffective and bipolar groups. Proband family lineages included both families with "pure" psychosis diagnoses and families with mixed schizophrenia-bipolar diagnoses. CONCLUSIONS: Symptoms, psychosocial functioning, and familial lineage overlap across the three DSM-IV psychosis diagnoses used in B-SNIP. The comingling of psychosis diagnoses within families suggests overlapping genetic determinants across psychoses. These data provide scant evidence for distinct phenotypic clustering around traditional phenomenological diagnoses.

Randomized study of asunaprevir plus pegylated interferon-α and ribavirin for previously untreated genotype 1 chronic hepatitis C.

BACKGROUND: Asunaprevir is a selective NS3 protease inhibitor with in vitro activity against HCV genotypes 1 and 4. METHODS: In this Phase IIa double-blind study, treatment-naive HCV genotype-1-infected patients in the United States and France were randomly assigned 1:1:1:1 to placebo or asunaprevir 200 mg twice daily, 600 mg twice daily or 600 mg once daily in combination with pegylated interferon (PEG-IFN)-α2a and ribavirin for 48 weeks. The primary efficacy end point was undetectable HCV RNA at weeks 4 and 12 (extended rapid virological response [eRVR]). Other end points included safety and undetectable HCV RNA at 24 weeks post-treatment (24-week sustained virological response [SVR24]). RESULTS: A total of 47 patients were randomized and treated. eRVR was achieved by 75% (9/12), 75% (9/12) and 92% (11/12) of patients in the asunaprevir 200 mg twice-daily, 600 mg twice-daily and 600 mg once-daily groups, respectively, versus 0% (0/11) in the placebo group. Corresponding SVR24 rates were 83% (10/12), 83% (10/12) and 92% (11/12) in the asunaprevir groups and 46% (5/11) in the placebo group. There was no virological breakthrough in any asunaprevir group. Following the 12-week analysis, the 600 mg doses were reduced to 200 mg twice daily because of a greater frequency of transaminase elevations at the 600 mg dose. The most common grade 3-4 laboratory abnormalities were consistent with those reported for PEG-IFN and ribavirin. CONCLUSIONS: Asunaprevir plus PEG-IFN and ribavirin achieved higher response rates than placebo plus PEG-IFN and ribavirin, with a tolerable adverse event profile at the 200 mg twice-daily dose. This dose is being evaluated in the Phase IIb and Phase III studies.

Increase in work productivity of depressed individuals with improvement in depressive symptom severity.

OBJECTIVE: The authors sought to identify baseline clinical and sociodemographic characteristics associated with work productivity in depressed outpatients and to assess the effect of treatment on work productivity. METHOD: Employed depressed outpatients 18-75 years old who completed the Work Productivity and Activity Impairment scale (N=1,928) were treated with citalopram (20-40 mg/day) in the Sequenced Treatment Alternatives to Relieve Depression study. For patients who did not remit after an initial adequate antidepressant trial (level 1), either a switch to sertraline, sustained-release bupropion, or extended-release venlafaxine or an augmentation with sustained-release bupropion or buspirone was provided (level 2). Participants' clinical and demographic characteristics and treatment outcomes were analyzed for associations with baseline work productivity and change in productivity over time. RESULTS: Education, baseline depression severity, and melancholic, atypical, and recurrent depression subtypes were all independently associated with lower benefit to work productivity domains. During level 1 treatment, work productivity in several domains improved with reductions in depressive symptom severity. However, these findings did not hold true for level 2 outcomes; there was no significant association between treatment response and reduction in work impairment. Results were largely confirmed when multiple imputations were employed to address missing data. During this additional analysis, an association was also observed between greater impairment in work productivity and higher levels of anxious depression. CONCLUSIONS: Patients with clinically significant reductions in symptom severity during initial treatment were more likely than nonresponders to experience significant improvements in work productivity. In contrast, patients who achieved symptom remission in second-step treatment continued to have impairment at work. Patients who have demonstrated some degree of treatment resistance are more prone to persistent impairment in occupational productivity, implying a need for additional, possibly novel, treatments.

Clinical and sociodemographic characteristics associated with suicidal ideation in depressed outpatients.

OBJECTIVE: To identify clinical and sociodemographic characteristics associated with suicidal ideation (SI) among patients seeking care for depression in routine primary and psychiatric care settings. METHODS: We examined data from 4041 treatment-seeking outpatients with major depressive disorder (MDD) to compare baseline sociodemographic and clinical characteristics of those with and without SI, and the presence or absence of baseline depressive symptoms and psychiatric comorbidities in those with SI. RESULTS: SI was significantly (P < 0.01) associated with numerous sociodemographic characteristics (that is, lower level of education, Caucasian or African American, male, unemployed, and treated in psychiatric care) and clinical features (that is, previous suicide attempt, younger age of MDD onset, greater baseline depressive symptom severity, greater number of depressive symptoms, and presence of agoraphobia and [or] generalized anxiety disorder). Elevated levels of SI at baseline were associated with decreased remission rates. CONCLUSIONS: Consistent with past findings, increased rates of SI were associated with greater depressive symptom severity as well as other features suggestive of severity of illness. Our results confirm previous findings of associations between SI and panic and (or) phobic symptoms and anxiety, but did not confirm previous findings of an association between SI and alcohol or drug use and (or) dependence. While selective serotonin reuptake inhibitor monotherapy appeared significantly helpful in reducing SI during the course of treatment, the presence of SI at baseline was found to be a associated with decreased treatment response, with patients reporting SI at the start of treatment being less likely to achieve remission. CLINICAL TRIAL REGISTRATION NUMBER: Sequenced Treatment Alternatives to Relieve Depression, NCT00021528.

The impact of chronic depression on acute and long-term outcomes in a randomized trial comparing selective serotonin reuptake inhibitor monotherapy versus each of 2 different antidepressant medication combinations.

OBJECTIVE: To compare sociodemographic and clinical features, acute and continuation treatment outcomes, and adverse events/side effect burden between outpatients with chronic (current episode > 2 years) versus nonchronic major depressive disorder (MDD) who were treated with combination antidepressant therapy or selective serotonin reuptake inhibitor (SSRI) monotherapy. METHOD: 663 outpatients with chronic (n = 368) or nonchronic (n = 295) moderate to severe DSM-IV-TR MDD (17-item Hamilton Depression Rating Scale score ≥ 16) were enrolled from March 2008 through September 2009 in a single-blind 7-month prospective randomized trial conducted at 6 primary and 9 psychiatric care sites across the United States. Participants were treated with escitalopram monotherapy plus placebo or 1 of 2 combination treatments (bupropion sustained-release [SR] + escitalopram or venlafaxine extended-release [XR] + mirtazapine). Analyses compared baseline sociodemographic and clinical characteristics, rates of remission (at least 1 of the last 2 consecutive scores on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report [QIDS-SR16] < 6, with the other < 8), and adverse events/side effect burden (Frequency, Intensity, and Burden of Side Effects Ratings) obtained at 12 and 28 weeks. RESULTS: Participants with chronic MDD were at greater socioeconomic disadvantage and had greater medical and psychiatric disease burden. The chronic and nonchronic groups did not differ in rates of remission at 12 weeks (35.9% vs 42.0%, respectively; odds ratio [OR] = 0.778, P = .1500; adjusted OR [AOR] = 0.956, P = .8130) or at 28 weeks (41.0% vs 49.8%, respectively; OR = 0.706, P = .0416; AOR = 0.837, P = .3448). Participants with chronic MDD had higher final QIDS-SR(16) scores and smaller overall percent changes in QIDS-SR(16) from baseline to exit, but these differences did not remain after adjusting for covariates. There were no significant differences in adverse events or side effect burden. No significant interactions were found between chronicity and type of treatment at 12 or 28 weeks. CONCLUSION: Chronicity of illness does not appear to differentially impact acute or longer-term outcomes with SSRI monotherapy or combination antidepressant medication treatment in patients with moderate to severe nonpsychotic MDD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00590863.

Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial.

BACKGROUND: Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. METHODS: In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 µg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770. FINDINGS: 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. INTERPRETATION: Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. FUNDING: Bristol-Myers Squibb.

Memory generalization is selectively altered in the psychosis dimension.

Global deficits in declarative memory are commonly reported in individuals with schizophrenia and psychotic bipolar disorder, and in their biological relatives. However, it remains unclear whether there are specific components within the global declarative memory dysfunction that are unique to schizophrenia and bipolar disorder, or whether these impairments overlap the two psychoses. This study sought to characterize differential components of learning and memory in individuals within the psychosis dimension: probands with schizophrenia (SZP, n=33), probands with psychotic bipolar I disorder (BDP, n=20), and biological relatives of SZP (SZR, n=21), contrasted with healthy controls (HC, n=26). A computerized cognitive paradigm, the Acquired Equivalence test, with probes for associative learning, memory for learned associations, and memory generalization was administered, along with standardized neuropsychological measures of declarative memory. All study groups were able to learn and remember the associations, although SZP were slower than HC in the initial learning stages. Both SZP (significantly) and BDP (at a trend level) showed altered memory generalization compared to HC (SZP vs. HC, p=.038, d=.8; BDP vs. HC, p=.069, d=.95). SZR showed memory generalization intermediate between SZP and HC, although their performance did not differ significantly from either group. These findings indicate that probands with schizophrenia and bipolar psychoses have similar alteration in the ability to flexibly generalize learned knowledge when probed with novel stimuli, despite overall sufficient associative learning and memory for what they learned. These results suggest that the two disorders present a clinical continuum with overlapping hippocampus-mediated memory generalization dysfunction underlying the psychosis phenotype.

Cognitive endophenotypes of psychosis within dimension and diagnosis.

This study sought to characterize the psychosis phenotype, contrasting cognitive features within traditional diagnosis and psychosis dimension in a family sample containing both schizophrenia and psychotic bipolar I disorder. Seventy-six probands with psychosis [44 probands with schizophrenia, 32 probands with psychotic bipolar I disorder] and 55 first-degree relatives [30 relatives of schizophrenia probands, 25 relatives of bipolar probands] were recruited. Standardized clinical and neuropsychological measures were administered. No differences in cognitive performance emerged between probands with schizophrenia and probands with psychotic bipolar disorder, or between relatives of probands with schizophrenia and relatives of probands with bipolar disorder in the domains of working and declarative memory, executive function and attention. Relatives overall showed higher cognitive performance compared to probands, as expected. However, when we segmented the probands and relatives along a psychosis dimension, independent of diagnostic groups, results revealed lower cognitive performance in probands compared to relatives without psychosis spectrum disorders, whereas relatives with psychosis spectrum disorders showed an intermediate level of performance across all cognitive domains. In this study, cognitive performance did not distinguish either probands or their first-degree relatives within traditional diagnostic groups (schizophrenia and psychotic bipolar disorder), but distinguished probands and relatives with and without lifetime psychosis manifestations independent of diagnostic categories. These data support the notion that schizophrenia and psychotic bipolar disorder present a clinical continuum with overlapping cognitive features defining the psychosis phenotype.