Audio-digital recordings to assess ratings reliability in clinical trials of schizophrenia.

We examined ratings reliability in 5 clinical trials of subjects with schizophrenia experiencing an acute exacerbation of psychosis. Audio-digital recordings of site-based interviews of the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) were used to obtain blinded, site-independent scores to evaluate paired scoring concordance. High intraclass correlations were noted between 1810 paired site-based and site-independent PANSS scores (r = 0.801) and 1837 paired BPRS scores (r = 0.897) with high limits of agreement such that 93.9% of paired scores were within the calculated 95% confidence intervals. In 2 studies where sufficient PANSS data was available at baseline and endpoint, blinded site-independent ratings yielded a predictive value of 84.2% for replicating site-based response/nonresponse treatment outcomes. There was a significant positive correlation between site-based scores and paired scoring deviations (PANSS: r = 0.246; p < 0.0001; BPRS: r = 0.176; p < 0.0001). The magnitude (symptom severity) of PANSS or BPRS scores affected the directionality of paired scoring deviations in each study. Site-based raters scored the most symptomatic subjects higher and less symptomatic subjects lower than the paired site-independent raters on either instrument. This analysis affirms the utility of paired audio-digital scoring of site-based interviews as a surveillance strategy for schizophrenia studies. We noted a high predictive value of blinded site-independent raters to replicate site-based treatment outcomes. The bi-directionality of paired scoring deviations observed for both the PANSS and BPRS is consistent with findings found for depression rating instruments.

Ratings surveillance and reliability in a study of major depressive disorder with subthreshold hypomania (mixed features).

OBJECTIVES: Site-independent ratings surveillance assessed ratings reliability in a clinical trial. METHODS: Inter-rater reliability was assessed at the screen visit in a 6-week, double-blind, placebo-controlled study of lurasidone for the treatment of major depressive disorder (MDD) with subthreshold hypomanic ("mixed") symptoms (clinicaltrials.gov NCT01421134). Site-based Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) interviews were paired with 184 site-independent ratings derived from audio-digital recordings. RESULTS: The paired MADRS and YMRS scores were highly correlated (r = 0.708 and 0.885, respectively) and generated minimal scoring discordance. The surveillance program identified 14 MADRS scores (7.6% of this sample) that were below the study entry criterion (MADRS ≥26) and resulted in screen failure. When present, paired scoring discordance was associated with symptom severity, interview length, interview quality, and the level of patient cooperation. Higher severity scores (MADRS ≥40 and YMRS ≥15) were associated with greater paired scoring discordance. Further, MADRS scores <30 and short MADRS interviews conducted in ≤12 min revealed significantly more pairs of discordant outliers (p = 0.04 and 0.009, respectively). CONCLUSIONS: The findings suggest that MDD patients with mixed features can be reliably assessed, that paired site-based and site-independent assessments were generally concordant, and that ratings surveillance may reinforce ratings precision.

Cognitive Impairment Associated with Cancer: A Brief Review.

This brief review explores the areas of cognitive impairment that have been observed in cancer patients and survivors, the cognitive assessment tools used, and the management of the observed cognitive changes. Cognitive changes and impairment observed in patients with cancer and those in remission can be related to the direct effects of cancer itself, nonspecific factors or comorbid conditions that are independent of the actual disease, and/or the treatments or combination of treatments administered. Attention, memory, and executive functioning are the most frequently identified cognitive domains impacted by cancer. However, the prevalence and extent of impairment remains largely unknown due to marked differences in methodology, definitions of cognitive impairment, and the assessment measures used. Assessment of cognitive functioning is an important and necessary part of a comprehensive oncological care plan. Research is needed to establish a better understanding of cognitive changes and impairments associated with cancer so that optimal patient outcomes can be achieved.

Effect of patient age on treatment response in a study of the acute exacerbation of psychosis in schizophrenia.

Younger patients with schizophrenia have most likely experienced fewer adverse consequences of the illness than older patients who may have experienced a lifetime of treatment as well as socio-economic problems as a consequence of the illness. There is limited information regarding differential efficacy of long-acting injectable (LAI) antipsychotic medications across the age span in patients with schizophrenia. We conducted a post hoc age and gender analysis of treatment response to aripiprazole lauroxil (AL; ARISTADA®; Alkermes, Inc.), in a 12-week, double-blind, placebo-controlled, multinational, Phase 3 study evaluating two doses of AL (441mg and 882mg) versus placebo in adult patients experiencing an acute exacerbation of schizophrenia within the previous 2months. We examined change in the total Positive and Negative Syndrome Scale (PANSS) scores from baseline using analysis of covariance and categorical treatment response (defined as ≥30% total PANSS score improvement from baseline) in the following age groups: <30, 30-39, 40-49, and 50-69years old. Age and gender did not moderate the treatment response in this study. Both AL 441mg and AL 882mg showed an early and significant improvement of the mean total PANSS scores and categorical treatment responses compared to placebo in all four age groups, including younger patients regardless of gender that was sustained over the 85-day treatment period.

Apathy Is Associated With Ventral Striatum Volume in Schizophrenia Spectrum Disorder.

Apathy is prevalent in schizophrenia, but its etiology has received little investigation. The ventral striatum (VS), a key brain region involved in motivated behavior, has been implicated in studies of apathy. We therefore evaluated whether apathy is associated with volume of the VS on MRI in 23 patients with schizophrenia using voxel-based morphometry. Results indicated that greater self-reported apathy severity was associated with smaller volume of the right VS even when controlling for age, gender, depression, and total gray matter volume. The finding suggests that apathy is related to abnormality of brain circuitry subserving motivated behavior in patients with schizophrenia.

Major depressive disorder with subthreshold hypomania (mixed features): Clinical characteristics of patients entered in a multiregional, placebo-controlled study.

Major depressive disorder (MDD) associated with subthreshold hypomanic symptoms (mixed features), has been identified as a distinct nosological entity in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). We identified the predominant manic symptoms present at baseline in a multiregional, placebo-controlled trial involving 211 patients with MDD with mixed features (Clinicaltrials.govNCT01421134). Patients with 2 or 3 DSM-5 criteria defined manic symptoms were eligible for the study. At study baseline, increased talkativeness (pressure to keep talking) and flight of ideas (racing thoughts) were endorsed by approximately 65% of patients and a decreased need for sleep was endorsed by 40% of patients. Approximately 60% of patients also endorsed irritability and distractibility at baseline although these symptoms are not generally counted as part of the "mixed" depression diagnosis as they may overlap with criteria for MDD. Thus, five clinical symptoms characterized the manic presentation in the majority of patients diagnosed as having MDD with "mixed" features in this first placebo-controlled trial examining the use of a psychotropic medication (lurasidone) in this population. Our findings support the designation of MDD with mixed features specifier and suggest that this subpopulation of depressed patients may warrant additional medication beyond antidepressants.

Audio-digital recordings used for independent confirmation of site-based MADRS interview scores.

Signal detection requires ratings reliability throughout a clinical trial. The confirmation of site-based rater scores by a second, independent and blinded rater is a reasonable metric of ratings reliability. We used audio-digital pens to record site-based interviews of the Montgomery-Asberg Depression Rating Scale (MADRS) in a double-blind, placebo controlled trial of a novel antidepressant in treatment resistant depressed patients. Blinded, site-independent raters generated "dual" scores that revealed high correlations between site-based and site-independent raters (r=0.940 for all ratings) and high sensitivity, specificity, predictive values, and kappa coefficients for treatment response and non-response outcomes using the site-based rater scores as the standard. The blinded raters achieved an 89.4% overall accuracy and 0.786 kappa for matching the treatment response or non-response outcomes of the site-based raters. A limitation of this method is that independent ratings depend on the quality of site-based interviews and patient responses to the site-based interviewers. Nonetheless, this quality assurance strategy may have broad applicability for studies that use subjective measures and wherever ratings reliability is a concern. "Dual" scoring of recorded site-based ratings can be a relatively unobtrusive surveillance strategy to confirm scores and to identify and remediate rater "outliers" during a study.