Browsing by Author "Francis, Michael"

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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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    Developmental Resting State Functional Connectivity for Clinicians
    (Springer International Publishing, 2014-09-01) Hulvershorn, Leslie A.; Cullen, Kathryn R.; Francis, Michael; Westlund, Mindy; Department of Psychiatry, IU School of Medicine
    Resting state functional magnetic imaging (fMRI) is a novel means to examine functional brain networks. It allows investigators to identify functional networks defined by distinct, spontaneous signal fluctuations. Resting state functional connectivity (RSFC) studies examining child and adolescent psychiatric disorders are being published with increasing frequency, despite concerns about the impact of motion on findings. Here we review important RSFC findings on typical brain development and recent publications of child and adolescent psychiatric disorders. We close with a summary of the major findings and current strengths and limitations of RSFC studies.
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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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    Identifying and treating the prodromal phases of bipolar disorder and schizophrenia
    (Springer, 2018-03) Conroy, Susan; Francis, Michael; Hulvershorn, Leslie A.; Psychiatry, School of Medicine
    Purpose of review: The goal of this paper is to review recent research on the identification and treatment of prodromal periods that precede bipolar and psychotic disorders. We also sought to provide information about current best clinical practices for prodromal youth. Recent findings: Research in the areas of identifying prodromal periods has rapidly advanced. Calculators that can predict risk are now available for use during both bipolar and psychotic disorder prodromes. Cognitive behavior therapies have emerged as the gold standard psychosocial interventions for the psychosis prodrome, while several other types of therapies hold promise for treatment during the bipolar prodrome. Due to safety and efficacy concerns, pharmacologic treatments are not currently recommended during either prodromal period. Summary: While additional research is needed to develop useful clinical tools to screen and diagnose during prodromal phases, existing literature has identified constellations of symptoms that can be reliably identified in research settings. Specialized psychotherapies are currently recommended to treat prodromal symptoms in clinical settings. They may also be useful to curtail future episodes, although further research is needed.
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    O12.3.Effects of Fingolimod, A Potent Anti-Inflammatory Agent, On Brain Structure, Function, And Symptoms in Schizophrenia
    (Oxford University Press, 2019-04) Breier, Alan; Hummer, Tom; Vohs, Jennifer; Mehdyoun, Nicole; Liffick, Emily; Francis, Michael; Medicine, School of Medicine
    Background New medications with novel targets are needed for schizophrenia. Several lines of evidence indicate that inflammatory processes including aberrant lymphocytic activity may be related to the pathophysiology of this illness. These data suggest that agents with anti-inflammatory actions, including modulation of lymphocytes and their inflammatory substrates, may prove to be efficacious for schizophrenia. Fingolimod is a powerful anti-inflammatory agent that is used in the treatment of relapsing multiple sclerosis. It is a sphingosine-1-phosphate (S1P) receptor modulator that decreases circulating lymphocytes through sequestration in lymph tissues. In addition, evidence suggest that it stimulates oligodendrocytes and may enhance white matter integrity. The purpose of this study was to assess the effects of fingolimod in schizophrenia. Methods Subjects with schizophrenia (N=40) were recruited through the Indiana University Psychotic Disorders Programs and randomized 1:1 in a double-blind, eight-week clinical trial of fingolimod 0.5 mg/day and placebo. Circulating total lymphocytes were determined and effects were assessed on symptoms (PANSS), cognition (BACS), plasma cytokines, white matter integrity (DTI) and cortical connectivity (resting fMRI). Results Results revealed a significant decrease in lymphocytes in subjects taking fingolimod versus placebo (treatment x time; F = 61.2, p < 0.001). Fingolimod treated subjects had a mean maximal drop in lymphocytes from baseline of 79.2% with all fingolimod treated subjects experiencing decrements greater than 60%. There was a trend toward higher mean skeletal fractional anisotropy (FA) post-treatment in the fingolimod group. Within the fingolmiod group, there were significant or trend-level correlations between FA increase and decrease in lymphocytes in the genu and body of the corpus collosum and the right superior longitudinal fasciculus. There were also significant group-by-visit interactions in connectivity of left prefrontal cortical (PFC) seeds with clusters in the cerebellum, driven by higher PFC-cerebellum connectivity following fingolimod treatment. There were no improvements (treatment x time) in PANSS total (F = 0.66, p= 0.52), any of the PANSS subscales, or BACS composite score (F = 0.54, p = 0.44). Serious side effects were not observed, and a full safety report will be provided. Discussion Fingolimod produced a strong anti-inflammatory response with substantial reductions in circulating lymphocytes in all treated subjects. Brain effects were observed. However, this response was not accompanied by improvements in symptoms or cognition. These data suggest that fingolimod’s target of S1P modulation and robust anti-inflammatory warrant further investigation in schizophrenia.
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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.