ITI-007 for the Treatment of Schizophrenia: A 4-Week Randomized, Double-Blind, Controlled Trial

BACKGROUND: An urgent need exists for new treatments of schizophrenia that are effective against a broad range of symptoms and free of limiting safety issues. ITI-007 is a new molecular entity with a pharmacologic profile that combines dose-related monoamine modulation with phosphorylation of intracellular signaling proteins. METHODS: A phase II randomized, double-blind, placebo-controlled, and active-controlled trial was conducted at eight sites in the United States with randomization of 335 acutely psychotic adults with schizophrenia. ITI-007 (60 mg and 120 mg), placebo, and risperidone, included for assay sensitivity, were evaluated as monotherapy for 4 weeks. The primary outcome measure was the Positive and Negative Syndrome Scale total score, with secondary analyses conducted on symptom subscales. RESULTS: ITI-007 60 mg (p = .017, effect size = .4) and risperidone (p = .013, effect size = .4) demonstrated antipsychotic efficacy superiority over placebo on the primary end point. The results of secondary analyses reflected improvements in negative and depressive symptoms by ITI-007 60 mg. ITI-007 120 mg did not separate from placebo. However, both doses of ITI-007 were well tolerated in this patient population, as evidenced by low discontinuation and adverse event rates, and were associated with a benign metabolic profile as evidenced by significantly lower levels of prolactin, fasting glucose, total cholesterol, and triglycerides than risperidone. CONCLUSIONS: The mechanistically novel investigational drug ITI-007 was effective for the treatment of schizophrenia and comparable with placebo on safety measures in this trial. Secondary analyses indicated that ITI-007 improved negative and depression symptoms and might have expanded therapeutic efficacy in comparison with current antipsychotic drugs

Molecular imaging reveals a progressive pulmonary inflammation in lower airways in ferrets infected with 2009 H1N1 pandemic influenza virus.

Molecular imaging has gained attention as a possible approach for the study of the progression of inflammation and disease dynamics. Herein we used [(18)F]-2-deoxy-2-fluoro-D-glucose ([(18)F]-FDG) as a radiotracer for PET imaging coupled with CT (FDG-PET/CT) to gain insight into the spatiotemporal progression of the inflammatory response of ferrets infected with a clinical isolate of a pandemic influenza virus, H1N1 (H1N1pdm). The thoracic regions of mock- and H1N1pdm-infected ferrets were imaged prior to infection and at 1, 2, 3 and 6 days post-infection (DPI). On 1 DPI, FDG-PET/CT imaging revealed areas of consolidation in the right caudal lobe which corresponded with elevated [(18)F]-FDG uptake (maximum standardized uptake values (SUVMax), 4.7-7.0). By days 2 and 3, consolidation (CT) and inflammation ([(18)F]-FDG) appeared in the left caudal lobe. By 6 DPI, CT images showed extensive areas of patchy ground-glass opacities (GGO) and consolidations with the largest lesions having high SUVMax (6.0-7.6). Viral shedding and replication were detected in most nasal, throat and rectal swabs and nasal turbinates and lungs on 1, 2 and 3 DPI, but not on day 7, respectively. In conclusion, molecular imaging of infected ferrets revealed a progressive consolidation on CT with corresponding [(18)F]-FDG uptake. Strong positive correlations were measured between SUVMax and bronchiolitis-related pathologic scoring (Spearman's ρ = 0.75). Importantly, the extensive areas of patchy GGO and consolidation seen on CT in the ferret model at 6 DPI are similar to that reported for human H1N1pdm infections. In summary, these first molecular imaging studies of lower respiratory infection with H1N1pdm show that FDG-PET can give insight into the spatiotemporal progression of the inflammation in real-time

Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans

Antiinflammatory drugs achieve their therapeutic actions at least in part by regulation of cytokine formation. A “cytokine hypothesis” of depression is supported by the observation that depressed individuals have elevated plasma levels of certain cytokines compared with healthy controls. Here we investigated a possible interaction between antidepressant agents and antiinflammatory agents on antidepressant-induced behaviors and on p11, a biochemical marker of depressive-like states and antidepressant responses. We found that widely used antiinflammatory drugs antagonize both biochemical and behavioral responses to selective serotonin reuptake inhibitors (SSRIs). In contrast to the levels detected in serum, we found that frontal cortical levels of certain cytokines (e.g., TNFα and IFNγ) were increased by serotonergic antidepressants and that these effects were inhibited by antiinflammatory agents. The antagonistic effect of antiinflammatory agents on antidepressant-induced behaviors was confirmed by analysis of a dataset from a large-scale real-world human study, “sequenced treatment alternatives to relieve depression” (STAR*D), underscoring the clinical significance of our findings. Our data indicate that clinicians should carefully balance the therapeutic benefits of antiinflammatory agents versus the potentially negative consequences of antagonizing the therapeutic efficacy of antidepressant agents in patients suffering from depression

From connection to distance: Using the practice of arts-based research to interpret field work.

This autoethnography describes the process of inquiry that led to the development of a series of ethnodramas that evoke teachers’ experience in the Chicago Public Schools (CPS). I discuss the methods I used to conduct a set of interviews with two groups of elementary school teachers in CPS: beginning teachers who had never worked a classroom as a full-time job and accomplished teachers who spent many years of their lives teaching students of color. I discuss the use of arts-based research methods to engage with these data, and I describe the interpretive journey I undertook as I wrote and produced ethnodramas about CPS teachers’ experience. A major dilemma for my analysis was communicating the structural inequalities that shaped the teachers’ narratives, particularly the Chicago system’s inability to create working conditions necessary to support the retention and professional development of teachers in the city’s high poverty schools. I describe how the conversation and inner dialogue generated by arts-based methods helped me recognize different patterns within the data, and inspired me to reframe my interpretation. In the conclusion, I discuss the limits of my approach as a researcher and an artist. Excerpts from two playscripts are woven throughout the article to convey the commitment that guided the teachers’ work and to evoke the social forces that shaped life in their classrooms

Selective Aerobic Oxidation of 5-Hydroxymethylfurfural in Water Over Solid Ruthenium Hydroxide Catalysts with Magnesium-Based Supports

Solid catalyst systems comprised of ruthenium hydroxide supported on magnesium-based carrier materials (spinel, magnesium oxide and hydrotalcite) were investigated for the selective, aqueous aerobic oxidation of the biomass-derived chemical 5-hydroxymethylfurfural into 2,5-furandicarboxylic acid (FDA), a possible plastics precursor. The novel catalyst systems were characterized by nitrogen physisorption, XRPD, TEM and EDS analysis, and applied for the oxidation with no added base at moderate to high pressures of dioxygen and elevated temperatures. The effects of support, temperature and oxidant pressure were studied and optimized to allow a quantitative yield of FDA to be obtained

Correlations between SUVMax of lung lesions on FDG-PET versus histopathologic severity scores.

<p>A) SUVMax versus cumulative alveolitis severity shows minimal positive correlations in the right (red) and left (blue) lung. B) SUVMax versus cumulative bronchiolitis severity shows high positive correlation in both lungs. C) SUVMax versus cumulative bronchitis severity demonstrates moderate correlation.</p

Distribution of H1N1pdm in right caudal and nasal turbinates^*.

*<p>Numerical values represent log base 10.</p><p>Abbreviation: right caudal or RC, for location of sections A through D illustrated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040094#pone-0040094-g004" target="_blank">figure 4</a>, pone.0040094.g007.tifnasal turbinate or NT.</p