Browsing by Author "McDonald, Brenna"

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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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    Indiana Center for Brain Rehabilitation, Advanced Imaging, and Neuroscience (ICBRAIN): An IUPUI Signature Center Initiative
    (Office of the Vice Chancellor for Research, 2012-04-13) Hammond, Flora; Saykin, Andrew J.; Malec, James; Kean, Jacob; Keiski, Michelle; McDonald, Brenna; Neumann, Dawn; Wang, Yang; Yoder, Karmen
    The Mission of the Indiana Center for Brain Rehabilitation, Advanced Imaging, and Neuroscience (ICBRAIN) is: to develop and disseminate techniques and methodologies for advanced neuroimaging and precision behavioral measurement to evaluate novel rehabilitation interventions for people with acquired brain injury. Traumatic and other types of acquired brain injury (ABI) affect millions of U.S. citizens each year, many of whom experience persistent disabilities. For example, among the estimated 1.4 million civilians who sustain a traumatic brain injury (TBI) each year, 50,000 die and a minimum of 80,000 sustain injuries of sufficient severity to require extended rehabilitation. The current conflicts in Iraq and Afghanistan have increased awareness and mobilized interest in medical treatment and rehabilitation for returning soldiers with TBI (designated as the “signature injury” of these conflicts). A 2008 study by the RAND corporation based on a random sample of 1,965 veterans estimated that, among 1.64 million returning veterans, approximately 320,000 experienced a probable TBI (19%). Over the past decade there has been a notable rise in research activities to address serious gaps in the knowledge base of ABI, including neuroimaging, outcome measurement, and intervention studies to change function. However, brain injury researchers have not yet established solid links between these research agendas. Such links are crucial for moving the evidence base forward to improve treatment outcomes. ICBRAIN will fill this gap in neuroscience by bringing together an interdisciplinary team of clinical researchers to (1) advance basic science and clinical knowledge to the next level of integration, (2) translate the knowledge gained directly into clinical care for improved patient outcomes, and (3) use the newly integrated knowledge to drive the leading edge of future research. ICBRAIN represents a unique collaboration among established clinical rehabilitation and measurement researchers in PM&R and at RHI and established researchers at the IU Center for Neuroimaging.
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    Orbitofrontal Cortex and Social Processing in Rodent Models
    (2019-05) Andrews, Katharine DiAnn; Xu, Xiao-Ming; Lamb, Bruce; McAllister, Thomas; McDonald, Brenna; Truitt, William; Wu, Yu-Chien
    Social processing is the reception, interpretation, and reciprocation of social information and is critical for mental health. The neural structures, circuits, and substrates regulating these complex mechanisms are not well understood. Social processing in the form of social safety learning, as measured by a rat model of social familiarity-induced anxiolysis (SoFiA), was impaired following mild blast traumatic brain injury (mbTBI). Initial findings indicated that mbTBI altered resting state network activity in the orbitofrontal cortex (OFC) and was associated with accumulation of neurotoxin marker, acrolein, in lateral prefrontal cortex (PFC) (including OFC), indicating OFC as a brain region of interest that may contribute to social processing. Measuring GABA and Glutamate-related gene expression in OFC of mbTBI or sham-exposed rat brain revealed specific elevations of metabotropic glutamate receptor type 1 and 5 (mGluR1/5) expression in mbTBI but not sham OFC. Exposure-naïve rats intracranially injected with mGluR1/5 agonist demonstrated attenuated SoFiA, and this coincided with an impairment of social recognition (SR) behavior. Additionally, inactivation of OFC by local intracranial injection of GABAA agonist, muscimol, impaired two different measures of SR in which two conspecifics, or members of the same species, one novel and one familiar, were presented and required discrimination. Novelty seeking, decision-making, memory, and gregariousness were tested in isolation to determine OFC contributions to these specific behavioral contributions to SR test performance. OFC inactivation did not impair novelty seeking, non-social decision-making, or non-social memory as measured by novel object recognition (NOR) test, or gregariousness or social decision-making as measure by social preference (SP) test. When measuring SR behavior via consecutive presentation of two different conspecifics, OFC inactivation did not impact SR. Therefore, OFC is not directly responsible for social recognition, but rather the discrimination or ability to act upon discrimination of two simultaneously present conspecifics. These data suggest a novel role for OFC in high order processing or execution of action based on social information.