2007 — 2010 |
Light, Gregory A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Pathway(S) From Genes to Functional Deficits of Schizophrenia Patients @ University of California San Diego
[unreadable] DESCRIPTION (provided by applicant): This RFA supports studies designed to find genes that relate to functional "behavioral phenotypes of relevance to patients, their families, and policymakers." In response to this RFA, this application will extend the existing body of information regarding the genetics of schizophrenia with a unique focus on understanding the genetic basis for functional deficits in schizophrenia patients. The PI has assembled a team of experts in the areas of schizophrenia research, functional assessment, neurophysiological and neurocognitive assessment, statistical genetics and structural equation modeling. The research team will have access to substantial existing infrastructure and patient resources via two mature and highly productive schizophrenia research programs. Cohorts of 400 schizophrenia patients and 100 nonpsychiatric comparison subjects (NCS) will be characterized by clinical, neurocognitive, neurophysiological, and multi- dimensional functional assessments. From these functional assessments, core and dissociable functional deficits in schizophrenia patients will then be identified via principal components analysis (PCA). PCA will capture the core features of the deficits that are responsible for the difficulties faced by schizophrenia patients as they "navigate" through a maze of functional challenges in real-world day-to-day living. These features will be used as a means of understanding the complex genetic architecture underlying functional impairment in this disorder. The pathways from gene to function, including possible mediating and moderating neurobiological and neuropsychological processes, will then be identified via structural equation modeling. Thus, one key final product of this work will be the identification of core functional deficits in schizophrenia patients and the specification of genes that substantially contribute to those core deficits so that both gene-function and the possible biological pathways by which genes impact behavior and thereby regulate real world functioning will be explicated. [unreadable] [unreadable] [unreadable]
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2012 — 2016 |
Jeste, Dilip V. [⬀] Light, Gregory A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Accelerated Biological Aging in Schizophrenia @ University of California San Diego
DESCRIPTION (provided by applicant): Schizophrenia (SZ) is one of the most disabling mental illnesses. It also is associated with higher medical comorbidity and a 20- to 25-year shorter life span than the general population. There is indirect evidence suggesting that biological aging may be accelerated in SZ; however, this will be the first study of laboratory-based systemic and neurophysiological markers of biological aging comparing persons with SZ to normal subjects during critical periods of the adult lifespan (26-65 years). The study will use a selected panel of systemic biomarkers that track biological aging and may reflect the pathophysiology of aging, especially in SZ, in terms of insulin dysregulation (Homeostatic Model Assessment of Insulin Resistance), inflammation (C-reactive protein), oxidative stress (F2-isoprostanes), and cell aging (telomere length), as well as a validated EEG-based marker of neurophysiological aging (mismatch negativity) that is deficient in SZ patients, has robust associations with both aging and functional outcome, and serves as an intermediate phenotype in genomic association studies. Subjects will include 140 with SZ and 120 normal comparison subjects (NCs) aged 26-65 years. We will recruit more SZ than NC subjects because of expected greater variation in outcomes in the SZ sample, and to maximize power in analyses of illness- and treatment-specific variables in the SZ group. Subjects in each decade (26-35, 36-45, etc.) will be followed annually for up to four years in a Multi-cohort Longitudinal Design, a significant improvement over cross-sectional designs, with balanced recruitment providing 35 subjects with SZ and 30 NCs per decade. While age will be treated primarily as a continuous (if potentially nonlinear) predictor in the hypotheses, age cohort will be entered in preliminary analyses to estimate and test for the possible presence of significant age cohort and/or sampling (e.g., healthy survivor) effects. Baseline values and rates of change in these measures over time in the NC and SZ groups will be compared, after controlling for chronological age. We will examine the extent to which person-related factors such as perceived stress, smoking status, drug use, cognitive function, and physical activity patterns predict individual variation in biomarkers of aging in SZ and NC groups; and whether additional illness- and treatment-related factors (age of onset of illness, current and cumulative antipsychotic use) predict variation in those markers in the SZ sample. A secondary aim of the study will be to examine if everyday functioning is predicted by individual differences in biomarkers of aging. This project is related to the NIMH Strategic Objective # 2: charting mental illness trajectories to determine when, where, and how to intervene. This study is novel in its focus on biological aging in SZ and on putative explanatory variables of this process. Discovering whether accelerated biological aging occurs in SZ and understanding the underlying mechanisms should lead to new ways of predicting, tracking, and treating the serious medical co-morbidities commonly seen in this population. PUBLIC HEALTH RELEVANCE: Schizophrenia is one of the most serious and disabling mental illnesses, and is associated with a greater risk of physical diseases and higher mortality rates and there some indirect evidence suggesting that biological aging may be accelerated in schizophrenia. The goals of this study are to determine if there is more rapid biological aging in schizophrenia, using specific laboratory-based biomarkers, and to assess their relationship with functional outcomes on one hand and behavioral as well as disease- and treatment-related risk factors on the other. Understanding potentially malleable risk and protective factors for biological aging at an individual level may lead to development of new preventive and therapeutic interventions aimed at reducing the excess medical comorbidity and mortality in SZ.
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2021 |
Light, Gregory A |
R33Activity Code Description: The R33 award is to provide a second phase for the support for innovative exploratory and development research activities initiated under the R21 mechanism. Although only R21 awardees are generally eligible to apply for R33 support, specific program initiatives may establish eligibility criteria under which applications could be accepted from applicants demonstrating progress equivalent to that expected under R33. |
Memantine Augmentation of Cognitive Training in Schizophrenia @ University of California, San Diego
In response to RFA-MH-18-705, this application develops and tests a novel treatment strategy for improving cognition in patients with schizophrenia (SZ), via Pharmacologic Augmentation of Cognitive Therapies (PACTs), and directly addresses a critical need for more effective treatments for these disabling impairments. Cognitive benefits in SZ patients can be achieved via ?bottom-up? sensory-based targeted cognitive training (TCT) therapies, but such treatments are time- and resource-intensive, and responses are incomplete and variable. This application tests a rational and empirically supported platform for augmenting the benefits of TCT in antipsychotic medicated SZ patients by adjunctive daily treatment of 20 mg memantine (MEM), an FDA approved medication for the treatment of cognitive dysfunction in Alzheimer's Disease. Recent meta-analyses of MEM augmentation in antipsychotic-medicated SZ patients have demonstrated its safety, tolerability, and effectiveness at improving scores on brief cognitive screening tests. We hypothesize that MEM will augment TCT learning and hence the clinical gains from TCT, and that this PACT approach will be most effective in biomarker-defined subgroups of patients. Preliminary support for these hypotheses comes from our proof-of-concept, randomized, controlled studies of single-dose exposure to MEM relative to placebo. In these studies, we found that MEM significantly enhanced learning in auditory discrimination, the key component of the TCT program which is known to drive the cognitive gains in SZ patients following 30-50h of TCT. We also found that a single dose of MEM significantly enhanced several biomarkers of early sensory information processing in antipsychotic medicated SZ patients. Dose-response and time course studies identified the optimal MEM dose (20 mg) for maximal pro-learning effects. This application conducts a careful assessment of this PACT strategy for SZ: Aim 1) Confirmation of target engagement: 54 SZ patients will be tested to confirm that MEM (20 mg) enhances measures of TCT learning; Aim 2) Efficient pilot testing: Subjects from Aim 1 will be randomized into 2 treatment arms (n=27/arm) for a double-blind placebo-controlled 30-session clinical trial of MEM+TCT vs. placebo+TCT, to determine whether daily dosing of MEM augments the magnitude, rate and/or durability of TCT gains, and whether these gains are associated with target engagement, using specific Go/No-Go criteria and outcome measures of symptoms, cognition and real-life function; Aim 3) Predictive biomarker identification of the PACT response, based on cognitive, electrophysiological, and performance-based measures assessed pre- and post-TCT. This is a highly novel, high-risk high-reward application to develop a PACT-based treatment paradigm that will enhance cognition, improve recovery and enhance outcomes for patients with schizophrenia, and will determine whether a future, fully-powered ?Confirmatory Efficacy trial? of this approach is warranted.
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