Biomarker Validation to Improve Cognitive and Psychosocial Outcomes in Veterans with Chronic Psychosis

点击翻译按钮获取中文摘要

In response to RX-20-005, this Career Development Award-1 (CDA-1) will provide a mentored research experience and training program for an early career psychiatrist, committed to the care and wellbeing of Veterans, to develop as a VA RR&D Investigator. Cognitive impairment causes significant disability for Veterans with schizophrenia and limits their ability to function independently in the community and enjoy an optimal quality of life. This application aims to improve functional outcomes for Veterans with schizophrenia through the continued development of a promising biomarker linked to a mechanistic model of cortical function in schizophrenia. This biomarker will ultimately be used to predict the response to therapeutic interventions applied within VA rehabilitative settings. Evidence emerging from cognitive remediation suggests that schizophrenia patients can experience clinically meaningful improvement in cognitive functioning; however, a substantial portion of patients show minimal or no response. Biomarkers that could prospectively identify subgroups of patients most “sensitive” to the beneficial effects of cognitive remediation and other pro-cognitive interventions could substantially improve the efficacy of these treatments. Recently, a novel biomarker extracted from spectral properties of electroencephalographic recordings has been proposed as an index of cortical excitation and inhibition balance (“E/I balance”). We reported (Molina et al., 2020) that this measure was abnormal in patients with schizophrenia. We also demonstrated that this E/I balance biomarker was normalized by acute exposure to the NMDA receptor modulator, memantine, which has been shown to improve neurocognition in subgroups of schizophrenia patients. These findings suggest that this novel biomarker may be used to predict therapeutic sensitivity to memantine, and potentially other pro-cognitive interventions. While these preliminary results represent a compelling proof-of-concept, this novel biomarker is not yet ready for large-scale application in prospective rehabilitation trials of pro-cognitive interventions. First, Molina et al. (2020) is the only study to have assessed this E/I biomarker in schizophrenia patients; therefore, replication of this finding – and extending it to Veterans with schizophrenia - is essential. Second, studies have not yet established the stability of this biomarker, nor its suitability for use as a repeated measure in prospective rehabilitative trials. Third, the cognitive and functional consequences of abnormal E/I balance have not yet been determined. In two Specific Aims, this CDA-1 application seeks to address these issues by measuring E/I balance in Veterans with schizophrenia (n=20) and in a nonpsychiatric Veteran comparison group (n=20) recruited from VASDHS rehabilitation settings and outpatient clinics. All participants will undergo comprehensive neurophysiologic, neurocognitive and functional assessments during two test days separated by 1-2 weeks. A third, “Training Aim” will enable the CDA-1 candidate to develop expertise in critical experimental techniques and analytic strategies, and to develop the professional skills necessary for successful career advancement in the VA. In total, this application will conduct a careful psychometric validation of a promising EEG-based biomarker and will characterize its relationships to measures of cognitive and psychosocial functioning in Veterans with schizophrenia. Thus, an important “product” of this application will be a novel biomarker that can be utilized in prospective clinical trials for pro-cognitive therapeutics, to improve quality of life and functional outcomes in a Veteran patient population. Moreover, this CDA-1 will enable the applicant to pursue a robust training plan that will prepare him for a career as a physician-scientist and RR&D Investigator, advancing novel therapeutics for Veterans with severe mental illness.