Browsing by Author "Mehdiyoun, Nicole"

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    Are Selective Estrogen Receptor Beta Agonists Potential Therapeutics for Schizophrenia?
    (Oxford University Press, 2020-05-18) Breier, Alan; Liffick, Emily; Hummer, Tom; Vohs, Jennifer; Mehdiyoun, Nicole; Yang, Ziyi; Saykin, Andrew J.; McDonald, Brenna; Francis, Michael; Medicine, School of Medicine
    Background Estrogen therapies, such as estradiol, have shown promise as therapeutics for schizophrenia; however, safety and tolerability concerns, including feminization effects in men and cancer and stroke risk in pre-menopausal women, may limit their broader use. Estradiol binds to both the estrogen alpha (ERA) and beta (ERB) receptors. ERB receptors appear not to mediate many of the concerning side effects of estrogen therapies. In addition, beta receptors have unique localization in cortical regions (i.e., hippocampus), and improve social behaviors and cognition in some animal models, which has led to interests in these compounds for testing in schizophrenia. To our knowledge, there have been no previous clinical trials of selective ERB agonists in schizophrenia. LY500307 is a highly selective agent for beta receptors without effects on estrogen alpha receptors when doses are constrained. Doses that are too high may engage alpha receptors but the alpha engaging threshold dose has not been fully determined in patient groups. The purpose of this dose-response study was to determine: ERB selectivity doses of LY500307 (i.e., without engaging alpha receptors); safety and tolerability; brain target engagement; and effects on cognition and symptoms. Methods A two-staged, double-blind, 8-week, adjunctive to APDs, adaptive phase 1b/2a trial design was conducted in men with schizophrenia (women were not included because of the lack of toxicology, safety, phase 1 and clinical data supporting use in this population). Three LY500307 doses and placebo were evaluated: 25 mg/day, 75 mg/day, and 150 mg/day. The primary markers for estrogen beta receptor selectivity was lack of effects on total testosterone levels (TT) and no feminization signs. Target engagement was assessed with an N-back working memory fMRI task and the electrophysiology measure mismatch negativity (MMN). Cognitive effects were assessed by the MCCB Composite score. Negative and total symptoms were assessed by the NSA-16 and PANSS, respectively. The primary analyses included all subjects and compared the slope from the three LY500307 dosing arms to the placebo slope in order to evaluate the dose responses. The linear mixed model with random intercept was employed and secondary analyses assessed differences between mean changes of the two higher dose arms combined (75 mg and 150 mg) versus placebo. Results Ninety-four patients were randomized across the placebo and three LY500307 dosing arms. There were no effects on plasma TT levels and no evidence of feminization, suggesting all doses were selective for the beta receptor. No significant adverse events were observed. There were no significant differences between the slopes of the three drug doses versus placebo on the brain target engagement variables (fMRI/N-back: F=0.24, p=0.868; MMN (Duration): F=1.08, p=0.358; MMN (Frequency): F=0.89, p=0.446) or on the cognitive/symptom measures (MCCB composite: F=0.87, p=0.458; NSA-16: F=1.79, p=0.148; and PANSS Total: F=0.69, p=0.558.) Secondary analyses also failed to show any significant effects of LY500307 versus placebo on any of the study variables. Discussion Conclusions: This study indicates that the ERB agonist LY500307 was selective, safe, and well tolerated in patients with schizophrenia. This selective ERB agonist, however, failed to demonstrate any significant effects on brain targets, cognition, negative and total symptoms. Potential issues related to dosing and characteristics of the patient population will be discussed. These data suggest that estrogen alpha receptor activation may be necessary to yield positive results in this patient population. Future studies are needed to confirm these findings.
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    A Double-Blind Trial of Adjunctive Valacyclovir to Improve Cognition in Early Phase Schizophrenia
    (Office of the Vice Chancellor for Research, 2015-04-17) Walters, Kamilah; Mehdiyoun, Nicole; Francis, Michael; Breier, Alan
    Schizophrenia is a chronic and debilitating neuropsychiatric disease that occurs in approximately one percent of the population and is characterized by cognitive deficits, including difficulties with abstract thinking, discerning reality from fiction, and communication. Cognitive deficits are a prominent feature of the illness and contribute to significant occupational and social disabilities. Additionally, there are no clinically effective treatments for cognitive deficits in schizophrenia. Although the etiology of these symptoms is unknown, recent studies have shown an association between Herpes Simplex Virus 1 (HSV-1) exposure and the severity of cognitive deficits in the schizophrenic population. Valacyclovir is an oral antiviral medication approved by the United States Food and Drug Administration for treatment of herpes virus infections, including HSV-1. Results from a pilot study at the University of Pittsburgh show that treatment with adjunctive valacyclovir improved working and visual memory in comparison to placebo in a population of older adults with chronic phase schizophrenia. The primary goal of the main study is to determine the efficacy of adjunctive valacyclovir to improve cognition by studying visual and working memory in HSV-1 positive early phase schizophrenia patients in a multi-site clinical trial coordinated by the Indiana University Psychotic Disorders Program. The aim of this research is to present a comprehensive review of recent findings regarding the importance of HSV-1 exposure and inflammatory markers in schizophrenia, and to discuss the methods and expected outcomes of our ongoing study.
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    Social Media Usage and Symptomatology in Patients with First Episode Psychosis
    (Office of the Vice Chancellor for Research, IUPUI, 2016-04-08) Hadley, Abigail; Visco, Andrew; Mehdiyoun, Nicole; Francis, Michael
    Schizophrenia is a severe complex psychiatric disorder characterized by symptoms such as auditory hallucinations, delusional thinking, diminished ability to emote and interact socially, and cognitive impairment. The first episode of schizophrenia manifest in late adolescence or early adulthood, a critical time period for development. Disruption of development frequently leads to psychosocial dysfunction. Early identification and treatment is key. Engagement in treatment is important for patients in the first episode of psychosis (FEP), but is a major challenge for healthcare providers. Concurrent with emerging research on social media usage in the general population, recent literature on the social media usage in patients with psychosis has also expanded. On average, adults in the general population spend about 12 hrs/wk on social media and recent findings have suggested that patients with schizophrenia, despite experiencing significant difficulties in social functioning, utilize social media, as well. Such findings suggests an opportunity for novel interventions that utilize social media to increase treatment engagement. Intervention of this kind is new and has so far shown modest results in increasing patient adherence to treatment, but few studies have specifically analyzed social media usage and symptomatology. Researchers analyzed social media usage of FEP patients in relation to the symptomatology. Data collected at the Prevention and Recovery Center for Early Psychosis (PARC) between 2011 and 2015 was compiled and analyzed. While there were no significant correlations between symptomatology and social media, researchers discovered this patient group spent less time on social media compared to the national average. Therefore, access to electronic devices and social media usage should be considered when developing interventions.