Dilip Jeste - US grants

A literature review suggests that the onset of schizophrenic symptoms after the age of 45 is not rare. Yet, there have been few systematic studies of neuropsychological, brain-imaging and treatment-response characteristics of late-onset schizophrenia. We postulate that schizophrenia with onset after 45 is a heterogeneous entity with different subtypes. Some of these subtypes may be identifiable with certain clinical, neuropsychological and brain morphological evaluations, and may be associated with differences in neuroleptic response. Our 6- month pilot study of 14 late-onset schizophrenics shows both the feasibility of and the need for the proposed investigation. We will study 90 DSM-III-R late-onset schizophrenics over a period of 5 years. Patients will be assessed with selected psychiatric, neurologic and neuropsychological measures at baseline and then systematically followed at four-month intervals. MRI scans of the brain will be done at the time of study-entry, and will be analyzed with quantitative densitometric and volumetric methods. Normal controls matched for age, gender, level of education and socioeconomic status will be evaluated and followed in a manner similar to late-onset schizophrenics. We will evaluate neuroleptic response in the late-onset schizophrenic patients in terms of therapeutic benefit (comparing "drug-free" psychopathology ratings with those after 6 weeks of haloperidol), and risk of tardive dyskinesia (comparing TD ratings at the end of the study). On the basis of the literature review and our data, we predict that one subset of patients diagnosed as having late-onset schizophrenia will have significant neuropsychological deficits and structural abnormalities in MRI, and poor therapeutic response to neuroleptics with greater risk of tardive dyskinesia. A small proportion of such patients will be found, at follow-up, to have a diagnosable dementing disorder, that initially presented with a schizophrenia-like clinical picture. Another subset of patients will be similar on various measures to age-matched normal controls. We believe that our findings will help improve the understanding of the diagnosis, neurobiological subtyping and neuroleptic treatment of late-onset schizophrenia.

Neuroleptic-induced tardive dyskinesia (TD) is a serious public health problem among chronically mentally ill older patients. There have been very few prospective, long-term studies of the incidence of and risk factors for TD in this population. We propose to evaluate, over a five-year period, 700 psychiatric patients over age 50. At study entry, these patients will have had less than 1 month of total lifetime neuroleptic exposure, and will be neuroleptic-free for at least a month prior to study entry. The initial assessments will include psychiatric and neurologic examinations (with suitable rating scales), a through review of past medical and medication records, a specific clinical evaluation of motor function and of neurologic "soft" signs, a selected neuropsychological test battery, and an instrumental assessment of orofacial and limb motor function (including parkinsonism, involuntary movements and voluntary motor control). Patients will be assigned randomly to either haloperidol or thioridazine, and we will attempt to maintain them on the same neuroleptic throughout the study. The treatment will otherwise be individualized, with the goal always being to treat the patients with the lowest effective dose. Patients will be reexamined one month after initial assessment and that at 3-month intervals for evidence of TD. The neuropsychological and instrumental assessments will be repeated annually. All these evaluations will be done "blind" with respect to the other data (especially treatment). The main goals of our study are: 1) to estimate the incidence of TD in this older patient population, 2) to determine the risk factors for occurrence and precipitation of TD, as well as development of a so-called "malignant" form of TD, and 3) to determine the risk factors for persistence and severity of TD. Statistical methods will include survival analysis with covariates, and stepwise regression analysis. We will perform a quantitative neuropathologic study of the brains of the patients who die. The main strengths of the proposed work are: a large sample size, use of a neuropsychologic test battery, instrumental assessment of orofacial/limb motor function, a comparison of relative risk of TD with two most commonly used neuroleptics, and a neuropathologic study of the brains of TD patients.

Psychoses are among the common and serious psychiatric disorders. With greater longevity, we can expect a progressive increase in the number of older psychotic patients. Antipsychotic or neuroleptic drugs are frequently prescribed for the treatment of psychotic disorders. Yet, in contrast to the large amount of literature on younger adults, there is a dearth of controlled, comprehensive, longitudinal, prospective studies of psychosis and antipsychotics in middle-aged and elderly patients. The main goals of our CRC are to provide infrastructure support to facilitate research on late-life psychosis and antipsychotics, to test hypotheses and generate new ones, and to train young scientists. Since the inception of the CRC in September 1992, we have set up the administrative, clinical, and biostatistics/data management infrastructure for research on late-life psychosis and antipsychotics. We have recruited, evaluated and followed the requisite numbers of patients and normal comparison subjects. We have been responsive to the comments of the previous study section as well as our Scientific Advisory Board. Our work to date has already produced some exciting results-e.g., clinical, neuropsychological, and brain imaging similarities as well as differences between early-onset schizophrenia (with onset before age 45) and late- onset schizophrenia (with onset after age 45). These and other findings have relevance for improving our understanding of psychosis and aging. We have published the CRC-related work in peer-reviewed journals, and generated new R01-type grant support. We are also proud of our record of training quality scientists, including women and ethnic minority candidates. We plan to continue following our current cohort of subjects, and will add 350 new subjects. We will expand our pool of chronic stable outpatients to include schizophrenia patients at two extremes of outcome: chronically institutionalized patients, and subjects with schizophrenia in remission. We will also include patients with other psychoses such as delusional disorder. The four overarching themes of the CRC are: age of onset of schizophrenia, different types of late-onset psychoses, studies of course and outcome, and psychopharmacologic research. The CRC will have seven Cores. (1) Administrative Core for facilitating the proper conductance of research and training in the CRC. (2) Biostatistics/Data Management Core for services, consultation and training in experimental methodology, statistics and data management. (3) Clinical Neuropsychiatry Core for recruitment, diagnosis, psychiatric and medical assessment and follow-up. (4) Neuropsychology Core for a comprehensive neuropsychological assessment. (5) Psychophysiology Core for evaluation of specific psychophysiologic measures. (6) Brain Imaging Core for MRI analysis. (7) Psychosocial Core for evaluating support environment, quality of life, and health-care services utilization. We have a team of experienced, as well as young, dedicated researchers with a commitment to the proposed science. We will pay special attention to the studies of women and minorities. We strongly believe that our CRC will continue to be a national resource for investigations into psychosis and antipsychotics in late life.

A literature review suggests that the onset of schizophrenic symptoms after the age of 45 is not rare. Yet, there have been few systematic studies of neuropsychological, brain-imaging and treatment-response characteristics of late-onset schizophrenia. We postulate that schizophrenia with onset after 45 is a heterogeneous entity with different subtypes. Some of these subtypes may be identifiable with certain clinical, neuropsychological and brain morphological evaluations, and may be associated with differences in neuroleptic response. Our 6- month pilot study of 14 late-onset schizophrenics shows both the feasibility of and the need for the proposed investigation. We will study 90 DSM-III-R late-onset schizophrenics over a period of 5 years. Patients will be assessed with selected psychiatric, neurologic and neuropsychological measures at baseline and then systematically followed at four-month intervals. MRI scans of the brain will be done at the time of study-entry, and will be analyzed with quantitative densitometric and volumetric methods. Normal controls matched for age, gender, level of education and socioeconomic status will be evaluated and followed in a manner similar to late-onset schizophrenics. We will evaluate neuroleptic response in the late-onset schizophrenic patients in terms of therapeutic benefit (comparing "drug-free" psychopathology ratings with those after 6 weeks of haloperidol), and risk of tardive dyskinesia (comparing TD ratings at the end of the study). On the basis of the literature review and our data, we predict that one subset of patients diagnosed as having late-onset schizophrenia will have significant neuropsychological deficits and structural abnormalities in MRI, and poor therapeutic response to neuroleptics with greater risk of tardive dyskinesia. A small proportion of such patients will be found, at follow-up, to have a diagnosable dementing disorder, that initially presented with a schizophrenia-like clinical picture. Another subset of patients will be similar on various measures to age-matched normal controls. We believe that our findings will help improve the understanding of the diagnosis, neurobiological subtyping and neuroleptic treatment of late-onset schizophrenia.

DESCRIPTION: This is a competing renewal of the project on neuroleptic- induced tardive dyskinesia (TD) in older patients. The original study demonstrated that: l) patients older than 45 had a 26% annual incidence of TD: 2) the risk factors for TD among older patients were cumulative neuroleptic exposure, especially to high-potency neuroleptics, history of alcohol abuse or dependence, and subtle motor dysfunction at baseline; 3) the incidence of TD was non-significantly higher in men than in women, and in African Americans than in Caucasians; 4) the course of TD was fluctuating in the early stages. The primary goals of the proposed investigation in middle-aged and elderly patients include: examining the incidence and risk factors for the development and persistence of TD; identifying the clinical, neuropsychological and instrumental motor changes that accompany the course of TD; and determining the predictors of remission vs. persistence of TD. The ongoing study of TD will clarify the relative contributions of individual risk factors to the development and persistence of TD. The study is expected to assist in the understanding of some of the mechanisms underlying TD. Most importantly, it is expected to have clinical implications for the use of neuroleptics in older adults. The proposed continuation research will add neuroleptic-treated psychiatric patients over the age of 45 years who do not have TD at study-entry. The patients will be assessed with clinical, neuropsychological and instrumental motor measures at baseline. The clinical and instrumental motor measures will be repeated one month and three months later, and every three months thereafter. The neuropsychological measures will be completed annually. Patients will be treated with the lowest effective doses of neuroleptics.

DESCRIPTION (provided by applicant): This is an application for a 5-year renewal of the T-32 Fellowship Program in Geriatric Mental Health at the University of California, San Diego (UCSD). As the population ages, the demand for well trained independent investigators in geriatric mental health will continue to increase. Over the last 14 years, we have recruited 67 T-32 trainees including 43 postdoctoral Fellows, and 11 predoctoral and 13 medical students. A majority of the trainees have been women and more than a quarter have come from different ethnic minority groups. Over 90% of the trainees (other than medical students) completed at least 2 years of T-32 Fellowship. This T-32 program is a part of a larger research training program within UCSD's Division of Geriatric Psychiatry. It is affiliated with NIMH-funded Advanced Center for Innovation in Services and Intervention Research (ACISIR), which has a distinct Bioethics Unit and a Latino Studies Unit. On combining the T-32 trainees with those in our three NIH-funded summer research training programs over the past 5 years, 15% of the total trainees have been from Under-Represented Minority ethnic groups. Nine of the 67 T-32 Fellows are still in training;82% of the remaining trainees, who are no longer in the. T32 program, are still continuing full-time academic activities. Most trainees have published multiple peer-reviewed papers. Our trainees have obtained 9 NIMH and 2 VA Career Development Awards, 7 RO1s, 8 R34s/R21s/R03s, 11 NARSAD Young Investigator Awards, 6 NIMH Postdoctoral Minority or Disability Supplements, 4 NIMH Minority Predoctoral Awards, and a number of other competitive grants. We place major emphasis on career development. The Fellowship program includes individual mentoring along with experiential research training, complemented by didactic activities. A personalized training plan is developed for each trainee early in the course of the Fellowship. Training in bioethics, research methodology, cultural competence, laboratory and project management, and writing skills enhancement, along with guidance on balancing personal life and professional career, and exposure to inter-disciplinary mentors are key features of our program. This renewal application proposes to support eight postdoctoral and three predoctoral Fellowship positions, with an additional predoctoral slot to be divided to support four medical students in short-term training annually. We will increase our focus on physician scientists, translational researchers (with both types of translation - from bench to bedside and from bedside to community), and diversity of trainees. We have developed a strong plan for evaluation of the training process as well as short-term, intermediate-term, and long-term outcomes.

Prospective study of 200 psychiatric patients over age 45 with selected psychiatric and neurologic assessments and clinical as well as instrumental evaluation of orofacial/limb motor function.

DESCRIPTION (provided by applicant): The proposed Advanced Center for Interventions and Services Research (ACISR) focuses on community-based research in middle-aged and elderly people with schizophrenia and other chronic psychotic disorders. We will refer to our ACISR as the Center for Community-based Research in Older People with Psychoses (CCROPP). Schizophrenia is one of the most disabling and expensive illnesses, moreover, the total direct cost of schizophrenia in older people is higher than that in other age groups. The number of older adults with psychoses will more than double during next three decades. The biopsychosocial differences between older and younger cohorts of psychotic patients result in major differences in pharmacologic and psychosocial treatment considerations as well as in healthcare service utilization. Our work over the past decade has served to characterize this population, and to optimize pharmacotherapy while developing new psychosocial interventions. We are proud of our record of peer-reviewed publications, community outreach, federal and non-federal grants, a growing pool of junior and senior investigators working in this area, and unique and successful training programs. A number of our findings have had a significant impact on the clinical practice and research in the area of study. We believe that our Center has become a national and international resource for studies of this largely neglected patient population. The goal of the proposed Center is to provide a research infrastructure to promote investigations that improve real-world practice, i.e., provision of evidence-based and clinically useful treatments for the target population. Our primary community partner will be San Diego County's Adult Mental Health Services (AMHS). Additional community partners will include VA San Diego Healthcare System, community-based psychiatrists, homeless shelters, and collaborators from other parts of the country. We will focus on reducing psychopathology (primary deficits, depressive symptoms with suicidality, and functional impairment), reducing physical comorbidity (age-associated and iatrogenic), optimizing health behaviors (mainly substance use and medication adherence), and minimizing healthcare disparities. One major advance in our work as we transition to an ACISR will be a markedly increased involvement and partnership with the community stakeholders (patients, caregivers, care providers, payers, and other critical parties to patient care). Through our Research Partners Council, this partnership will guide and shape our research agenda and activities. We are confident that our work will not only advance scientific knowledge of intervention and services research, but will also have a major impact on the care of people with schizophrenia and other chronic psychotic disorders in the community.

DESCRIPTION (provided by applicant): This innovative training program is designed to expand the pipeline for new researchers in geriatric mental health by providing mentored research opportunities to undergraduate, graduate, and medical students. The Summer Training on Aging Research Topics-Mental Health (START-MH) Program is intended to increase the number and diversity of talented individuals in the "pipeline" of developing investigators in the field of geriatric mental health by increasing trainees' knowledge of what research involves and fostering mentoring relationships between trainees and established investigators. The START-MH Program was piloted in 2003. A number of mechanisms for recruiting applicants to the program were employed including the development of brochures and a program website (http://startmh.ucsd.edu). 85 student applications and 38 mentor applications were solicited in less than six weeks. 30 trainees (13 undergraduate students, 13 graduate students, and 4 medical students) from across the country were selected to participate. 34 mentors were also selected. Each trainee spent 10 weeks in the research lab of an established investigator in geriatric mental health. Each trainee conducted a research project under the supervision of his/her mentor. The trainees also attended a two-day START-MH Conference and presented a poster based on their summer research project. Most of the research projects are now being written up as abstracts and/or manuscripts. 100% of the trainees in the pilot program reported that the START-MH program positively affected their attitude towards a career in the field of geriatric mental health research. 93% reported they were highly likely or likely to pursue a career in geriatric mental health research. The mentors uniformly rated the program and the trainees as excellent. It is notable that all mentors in this program donated their time thus illustrating the importance of career development to leaders in the field of geriatric mental health. The START-MH Program has a number of strengths. It addresses a clear and urgent need for increasing the pipeline of new researchers in geriatric mental health. The PI and the program staff have a long track record of success in research training in geriatric mental health. There is a sense of citizenship among geriatric mental health researchers - they are collectively devoted to career development in the field. The START-MH Program, though administered through UCSD, is a multi-site national program. The trainees, as well as the mentors, are competitively selected by a committee comprised of established investigators and training directors. The focus of the curriculum is on individual mentoring. Lastly, we have specific plans for follow-up of the trainees and for the evaluation of the Program.

DESCRIPTION: (provided by applicant) As the population of middle-aged and elderly persons with schizophrenia increases over the coming decades, more treatment research will be needed in this population. Because of factors such as age-related cognitive impairment, it is important to study methods for evaluating and enhancing consent procedures for treatment research in these patients. The proposed investigation will be a randomized, controlled comparison of an innovative procedure for providing informed consent - a Digital Video Disc DVD)-based, multimedia consent procedure with a routine consent procedure (supplemented with a short "control" DVD). The multimedia consent procedure is based on cognitive models of learning. Participants will be persons 40 years or older with schizophrenia (N=192) and normal comparison subjects (N=192). Each subject will be randomly assigned to receive informed consent for one of two studies, one entailing a relatively lower and lower complexity risk (cognitive training), or one involving substantially higher risk and greater complexity (a randomized, double-blind, placebo-controlled trial of a cognitive-enhancing drug with potential for serious adverse effects). The primary outcome measure will be the subjects' decisional capacity assessed with the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR), at baseline and again at a one-month follow-up. We will also evaluate subject and protocol characteristics associated with usefulness of DVD versus routine consent procedure. The DVD-based consent is not intended to supplant, but rather to supplement, the researcher-participant in-person interaction involved in consent process.

antipsychotic agents; mental disorder chemotherapy; hyperlipidemia; iatrogenic disease; drug adverse effect; longitudinal human study; disease /disorder proneness /risk; diabetes mellitus; human old age (65+); therapy adverse effect; risperidone; thiazoles; serotonin inhibitor; clinical research; human subject;

DESCRIPTION (provided by applicant): This is an application from the University of California, San Diego (UCSD), in conjunction with three neighboring institutions (the Burnham Institute, the Salk Institute;and the Scripps Research Institute), for a Medical Student Summer Aging Research Training Program (MSSARTP). The primary focus of our program will be on Aging Well (or healthy aging) in the context of the aging-associated diseases and disorders. The proposed program will provide support to 18 medical students from across the country selected for training experiences of 8 to 12 consecutive weeks full-time. We will make special efforts to recruit medical students from diverse backgrounds. All the trainees will spend the summer in San Diego working under the supervision of experienced scientists who have outstanding track records in research as well as in research training. Strengths of our faculty range from basic and molecular biology to clinical, epidemiologic, and therapeutic research on aging and age-related disorders such as Alzheimer's disease, cancer, cardiovascular diseases, arthritis, and schizophrenia. The faculty has an excellent track record of NIA and other federal funding and of research training of medical students. The most important aspects of this program will be hands on-research experience and formation of a mentoring relationship. In addition, a combination of didactics and workshops will reinforce the skills learned in the direct research experience. We will pay particular attention to the issues involved in research training of students from ethnic minority groups. The trainees will have a draft of a poster by the end of their summer research, with the goal of presenting a formal poster at the annual meeting of the American Geriatrics Society and a developing a publishable article within a year. An Executive Committee will oversee the recruitment and training of the students. There will be an extensive evaluation of the program from the trainees and the faculty. The students will be followed long-term to determine their career paths. This program would offer a unique opportunity for medical students from across the nation to work with some of the best molecular, translational, and clinical scientists working on aging-related research.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Compare the risk of MCCE associated with four atypical agents: aripiprazole, olanzapine, quetiapine, and risperidone in middle aged and elderly patients. Examine the impact of anitpsychotic induced MCCE on everyday functioning and quality of life.

Project Summary: The aim of the Principal Research Core is to generate and support research that will enhance and expand the Center's capacity to move mental health interventions and services for middle-aged and older people with schizophrenia and other psychotic disorders into community settings. The proposed work builds upon previous studies and an assessment of unmet needs of the various stakeholders. The main objectives are to develop or adapt and test interventions that are effective as well as practical, and to identify approaches to dissemination and implementation of such interventions in the community. We will use different intervention approaches (preventive, treatment, and rehabilitative), with the focus being on the following themes: (I) Optimizing pharmacotherapy, (II) Enhancing recovery and self-efficacy through psychosocia! interventions, and (III) Developing and adapting assessments and interventions for underserved subgroups. A critical component of this Core will be interactive, bi-directional communication with community stakeholders including consumers, caregivers, and care providers throughout the development and execution of research projects. In this application, we propose three exemplar Developmental Research Projects, and five Pilot Projects. These projects were selected and refined through the community partnership, and will be accomplished through close interactions among all the four Center Cores, building sustainable multidisciplinary teams of investigators and community partners. These Research Projects include (I) Ecological Momentary Assessment (EMA) Method Development, (ii) Saludable (A healthy lifestyle intervention for older Latinos), and (iii) Managing Medical Side Effects of Antipsychotics in a Community Mental Health Center. Pilot Projects are single-year projects with budgets of $ 5,000 to $ 10,000 each, and led either by investigators with relatively little research experience or by community partners, who are paired with appropriate faculty nvestigators. Examples of Pilot Projects include studies of a peer support intervention, web-based training for shared decision making, an intervention for suicidality, a qualitative study of remission or successful aging n people with schizophrenia, and an intervention to improve the informed consent process in monolingual Spanish-speaking Latinos. There is a process for regular evaluation of the progress of the projects by the Partners'Council as well as by external reviewers, with a "sunset policy" in place. Relevance: Through close interactions with community stakeholders, the Principal Reserch Core will develop and conduct research on innovative interventions and services for middle-aged and older people with schizophrenia and other psychotic disorders in the community. The ultimate goal is to improve the quality of life of these individuals.

Project Summary: The primary function of the Research Methods Core is to provide the infrastructure for developing innovative research methodology requisite for state-of-the-art community-based practical clinical/behavioral trials for middle-aged and older persons with schizophrenia and other psychotic disorders. This aim will be met through (a) instrument and methods development, testing, and implementation;(b) provision of a pool of Center-affiliated methodologic experts and data management resources to support the needs for innovative methodology of Center projects;and (c) training of Center-affiliated investigators and community partners in innovation and specific tools or methods necessary to meeting the goals of the Principal Research Core. This activity will occur in a multidisciplinary environment representing a broad array of expertise and experiences, including community stakeholders, as well as researchers and clinicians from a variety of relevant professional disciplines. The service goals of this Core overlap with those of the Operations Core, except that the emphasis in the Research Methods Core will be on innovative rather than pre-established methods. The Research Methods Core's service functions will include consultation on all grant submissions;assistance with study design and selection of measures, including advice on the modification of existing measures and development of new measures;and cultural adaptations of measures and interventions. Training / Education functions will include weekly seminars to discuss relevant issues and consultations with center investigators as well as with community stakeholders. A specific Developmental Research Project related to the Research Methods Core is titled "Ecological Momentary Assessment (EMA) Method Development", and is described in the Principal Research Core. Relevance: The Research Methods Core provides the innovative methodology and state-of-the-art services and training that are necessary to develop, implement, and disseminate interventions and services for middle-aged and older persons with schizophrenia and other psychotic disorders in the community. Working closely with other Cores of the Center, the Research Methods Core will contribute to the Center's ultimate goal of improving the quality of life of this important but largely neglected segment of the population.

Project Summary: The Community Network Core is a critical component of the Center's mission to improve the quality of life of middle-aged and older people with schizophrenia and other psychotic disorders through the development, implementation, and dissemination of evidence-based practice through community partnership. The goal of the Community Network Core is to nurture a sustainable collaborative research partnership between the Center and community clinical and services systems, primarily San Diego county's Adult and Older Adult Mental Health Services (AOAMHS), whose infrastructure will promote the research aims of the Center. Based on the models of community-based research and cultural exchange, this Core will partner with the AOAMHS to collaborate in all stages of research: needs assessment, study design, implementation, interpretation, and dissemination of the results. Other community partners will include the San Diego chapter of the National Alliance on Mental Illness (NAMI), the Veterans Affairs San Diego Healthcare System, community-based psychiatrists and clinics, regional homeless shelters, and other collaborators. The Community Network Core will seek to build, sustain, and expand community partnerships, and to mobilize community support and enhance infrastructure for research capacity. Our community partners will benefit by obtaining enhanced tangible resources including money, time, information, and access to technical and scientific expertise;the investigators will benefit by being able to study diverse populations, acquire "real world" information to guide the development of interventions and services, and developing insight and opportunities for improving community practice. The Community Network Core will evaluate the success of the partnerships on a regular basis using quantitative and qualitative procedures that the Center has developed. This Core will work closely with the other Cores to help accomplish the three major themes of the Center: optimizing pharmacotherapy;promoting recovery through psychosocial interventions;and developing and adapting assessments and interventions for underserved subgroups. Relevance: The Community Network Core will be a critical component of the the Center mission of improving the quality of life of middle-aged and older people with schizophrenia and other psychotic disorders in the community, a growing but severely underserved segment of the population.

OPERATIONS CORE The Operations Core serves to coordinate the scientific pursuit, administrative activities, ethical considerations, data issues, and training goals into a cohesive, effective, working system.

[unreadable] DESCRIPTION (provided by applicant): The mission of the proposed Advanced Center for Innovation in Services and Intervention Research (ACISIR) is to improve the quality of life of middle-aged and older people with schizophrenia and other psychotic disorders through the development, implementation, and dissemination of evidence-based practice through community partnerships. The engagement of community stakeholders (consumers, caregivers, and care providers) as well as the expansion of community research capacity will be an important focus of the Center. This will be accomplished under the direction of the Partners' Council, a decision-making group consisting of equal representation from the investigators and community partners, the primary one being a large public mental health system - i.e., San Diego County's Adult and Older Adult Mental Health Services. Additional community partners will include the local chapter of the National Alliance on Mental Illness (NAMI) and VA San Diego Healthcare System. We will seek to build, sustain, and expand community partnerships, and to mobilize community support and enhance infrastructure for research capacity. A critical component of this Core will be interactive, bi-directional communication with community stakeholders throughout the development and execution of research projects. Center infrastructure will foster research and education that address three major themes: (I) Optimizing pharmacotherapy, (II) Enhancing recovery through psychosocial interventions, and III) Developing and adapting assessments and interventions for underserved subgroups. The Operations Core will have five general Units: Administrative Unit; Clinical Trials Management Unit; Methodology, Biostatistics, and Data Management Unit; Community Liaison Unit; and Dissemination Unit; as well as three specialized Units: Bioethics Unit; Latino Studies Unit; and Training and Career Development Unit. In this application, we propose three exemplar Developmental Research Projects, and five Pilot Projects. These projects were selected and refined through the community partnership. These and other research projects will be accomplished through close interactions among all the four Center Cores, building sustainable multidisciplinary teams of investigators and community partners. There will be a regular evaluation of the individual projects, Units, Cores, and the partnership as a whole, conducted by all the partners. Relevance: This proposed Center will address interventions and services for middle-aged and older people with schizophrenia and other psychotic disorders in the community. This group of consumers represents a fast growing yet one of the most disenfranchised and understudied segments of our society. [unreadable] [unreadable] Operations Core [unreadable] [unreadable] DESCRIPTION (provided by applicant): The Operations Core serves to coordinate the scientific pursuit, administrative activities, ethical considerations, data issues, and training goals into a cohesive, effective, working system. These complex, and sometimes competing, tasks will be integrated into five general Units: I. Administrative, II. Clinical Trials Management, III. Methodology, Biostatistics, & Data Management, IV. Community Liaison, and V. Dissemination. There will be three additional specialized Units: VI. Bioethics, VII. Latino Studies, and VIII. Training. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Medical students'Sustained Training and Research Experience in Aging and Mental health (M-STREAM) Abstract This application to the NIMH is for renewal of an innovative national-level research training program designed to expand the pipeline of new physician scientists in geriatric neuropsychiatry by providing sustained mentored research support to medical students. There is a dire need for physician scientists in geriatric mental health. The proposed Medical students'Sustained Training and Research Experience in Aging and Mental health (M- STREAM) program is intended to increase the number and diversity of medical students interested in geriatric mental health research. Though administered through the University of California, San Diego (UCSD), this will be a multi-site national program. Trainees, as well as mentors, will be competitively selected from among national applicants by a Steering Committee of distinguished research mentors. Our previous program included summer research training for undergraduate, graduate, and medical students. Over the last 5 years, the number of medical student applicants has increased exponentially;furthermore, these students have expressed a need for sustained research mentorship and support throughout the medical school career. The new M-STREAM program will recruit 20 medical students annually, while expanding it from one summer of research training to include continued research support during all four years of medical school. The students will be paired with mentors (MDs and/or PhDs) either at their own institution or at another appropriate one. Initially, each trainee will conduct a research project for 10 weeks of summer between the 1st and 2nd years of medical school. The trainees will then attend a 3-day Workshop at UCSD, where they will present their summer research projects. They will also prepare manuscripts with the help of their mentors. During the 2nd year of medical school, these students will participate in an "NIMH-Day", where they will meet with NIMH program officers and intramural scientists. During the 3rd year, the trainees will present their work at a relevant professional conference. Finally, in the 4th year, they will work on a research project in geriatric neuropsychiatry during their elective rotation. We will seek to ensure continued mentoring by the same faculty members throughout the four years. Financial support will be provided to the trainees for all these activities. A password-protected website will be used to facilitate ongoing communication among the trainees and mentors. Rigorous evaluation procedures, including long-term follow-up, will be employed. 1 Public Health Relevance: This is an application for a five-year renewal of an innovative and highly successful program for expanding the pipeline for new physician scientists in geriatric mental health and neuroscience by providing early opportunities and exposure to research for medical students. Medical students'Sustained Training and Research Experience in Aging and Mental health (M-STREAM) will help the students understand what an academic research career may involve, to establish a relationship with mentors, and to build networks that may benefit their academic and career advancement. There will be an emphasis on continued mentorship and research support during later years to enhance the rate of retention of these students in an academic career focusing on NIMH-relevant geriatric mental health research.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Test the preliminary efficacy of a healthy lifestyle intervention for overweight and obese, community-dwelling, Latino patients with schizoprenia or schizoaffective disorders entitled "Interventions to Support Healthy Actions, Porper Nutritions, and Exercise for Latinos with Schizophrenia" (L-In-SHAPE) based on state-of-the-art interventions for the general population that incorporates client and care provider input and is culturally adapted to client needs.

This is a renewal application from the University of California San Diego (UC San Diego), in conjunction with two neighboring institutions (the Sanford-Burnham-Prebys Institute, the Salk Institute), for a 5-year renewal of the Medical Student Training in Aging Research (MSTAR) program, in response to the RFA-AG-20-008. Over the past 15 years we have trained 239 students from across the country, including 66% from ethnic minority groups, with 14% from URM and 59% women. 30% eligible students from the most recent funding period published at least one peer-reviewed article and 74% students gave a poster presentation. After graduation, all our trainees have continued residency in major programs; several are pursuing academic careers in aging research including Alzheimer?s disease and related dementias (ADRD) and geriatrics. The proposed program is designed to expand the pipeline of new physician investigators in the field of aging, especially ADRD. It will provide full-time support for 8-12 consecutive weeks of research and clinical training during summer, provided by faculty to 18 medical students per year from across the country. We will make special efforts to recruit medical students from underrepresented racial or ethnic minority groups, trainees with disabilities, and those from disadvantaged backgrounds. All trainees will spend the summer in San Diego, working under the supervision of some of the finest molecular, translational, and clinical scientists with outstanding track records of NIA- and other federal funding and of research training of medical students. A primary focus of our program will be on aging well in the context of age-associated disorders and disabilities with a major emphasis on prevention, identification, and management of cognitive impairment and ADRD. Strengths of our faculty range from basic and molecular biology to clinical, epidemiologic, and therapeutic research on aging and age-related disorders, especially ADRD and other diseases associated with cognitive impairment like cardiovascular diseases, cancers, and depression. The most important aspects of this program will be hands-on research experience and development of a long-term mentoring relationship. In addition, a combination of didactics and clinical exposure to geriatrics especially patients with ADRD, will reinforce the skills learned in the direct research experience. The trainees will give an oral presentation at a workshop at UCSD held in early August, with the goal of presenting a formal poster at the annual meeting of the American Geriatrics Society and developing a publishable manuscript within a year. An Executive Committee will oversee the recruitment and training of the students. There will be a rigorous and extensive evaluation of the program by trainees, participating faculty, and other stakeholders including long-term follow-up. A website will be used to facilitate continued communication among the trainees and their mentors.

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.

DESCRIPTION (provided by applicant): The life expectancy of adults receiving antiretroviral therapy (ART) has been increasing progressively. By 2015 one-half of HIV+ people in the U.S. will be over age 50, and this number is expected to continue to rise. While there has been a growing interest in aging with HIV, there is a dearth of research on successful aging with HIV. We define successful aging as a multi-dimensional construct with physical, cognitive, and psychosocial domains, with the downstream outcome being self-perceived successful aging. The proposed study will be the first large-scale investigation examining the relationship of positive psychological factors such as resilience, hardiness, optimism, and social engagement along with laboratory-based systemic markers of biological aging and HIV disease severity to the different domains of successful aging in HIV+ individuals as compared to well- matched Non-HIV-infected Comparison subjects (NCs). Subjects will include 120 HIV+ adults and 90 NCs aged 36-65 years. The biomarkers will include: telomere length, F2-isoprostanes, inflammatory markers (high- sensitivity C-reactive protein, IL-6, d-dimer, TNF-alpha, CCL2, d-dimer and sCD14), insulin resistance, and allostatic load, and, among HIV+ individuals, indicators of HIV disease severity (plasma HIV viral load, CD4+ T-cell count, AIDS/nonAIDS). Participants in each decade (36-45, 46-55, 56-65) will be evaluated using a structured Multi-cohort Longitudinal Design (sMLD), with balanced recruitment providing 40 HIV+ and 30 HIV- subjects per decade. The sMLD enables separation of cohort effects from developmental (within-subject) aging effects, allowing us to estimate aging trajectories across the entire age range of 36-65 years. Subjects will be followed for up to 4 years, with in-person bi-annual visits for detailed assessments, and evaluated with follow- up telephone interviews and mail surveys in the years in which they are not seen in person. We will examine the longitudinal trajectories of clinical outcome measures and positive psychological factors as well as biomarkers of aging and HIV disease, and compare them to those in NC subjects. Our first aim is to determine whether and how trajectories of successful aging differ between HIV+ and NC groups. We will also identify predictors of successful aging trajectories in HIV+ and NC groups. This project is related to NIMH Strategic Objective #2: charting illness trajectories to determine when, where, and how to intervene with HIV+ individuals. This study is novel in its focus on multi-dimensional characterization and recognition of predictors of successful aging in HIV+ adults as well as the use of advanced statistical methodology that allows for the distinction of cohort and developmental aging effects. We anticipate that successful aging trajectories will differ between HIV+ and NC groups suggesting that successful aging paradigms established in non-HIV-infected cannot be simply be generalized to HIV-infected persons. Understanding potentially malleable protective versus risk factors at an individual level may lead to development of new interventions aimed at increasing the likelihood of successful aging among people living with HIV.

? DESCRIPTION (provided by applicant): This application aims to develop, implement, and evaluate an innovative research training program designed to expand the number of NIMH-funded new investigators conducting mental health research at the intersection of HIV and aging. Over half of HIV-infected adults in the US are over age 50, and this number is expected to rise. The coexistence of HIV and aging in the context of mental health encompasses a complex relationship with issues of physical and psychiatric comorbidity, polypharmacy, cognitive impairment, and psychosocial stressors on one hand, and positive aspects such as successful aging, resilience, and neuroplasticity on the other. Yet, there is much to be known about pathophysiology, biomarkers, and interventions for enhancing mental health as well as for treating and preventing mental illnesses, including neurocognitive disorders, in older adults with HIV. Fostering the development of researchers with knowledge and expertise in both aging and HIV will be critical for the promotion of urgently needed research in this field. The proposed Sustained Training in Aging and HIV Research (STAHR) program builds on the infrastructure and expertise available at two major research programs at the University of California, San Diego (UCSD): the Sam and Rose Stein Institute for Research on Aging and the HIV Neurobehavioral Research Program. It seeks to address several strategic objectives of the NIMH Division of AIDS Research and the Office of AIDS Research. It will involve faculty from different departments in the UCSD School of Medicine as well as the Schools of Pharmacy and Engineering, along with mentors from other institutions. The program will target clinical and translational post- doctoral fellows and junior faculty from across the country, with previous training in either aging or HIV research, but interested in gaining expertise in the intersection o these two factors. Four new scholars will be selected every year; each will have a primary mentor at her/his home institution and a co-mentor at UCSD. These scholars will attend a 4-week summer institute during their first year and an annual 3-day workshop at UCSD for 3 years. A secondary aim of STAHR is to establish a network of mentors with interest in HIV and aging research to serve as a standing resource for the trainees. Training will aim to increase knowledge and skills on HIV/Aging research, and will also include training in research process and career development. There will be an Individual Development Plan for each scholar, which will outline mentoring activities and research experiences. Innovative distance learning opportunities will be offered in topics such as team science, funding mechanisms, mentorship training, and cultural competence. Other features include active involvement of community stakeholders, group projects, sessions on mentoring, and wide dissemination of STAHR results. There will be rigorous short and long-term evaluation of the scholars' career progress. STAHR will aim to develop high quality independently-funded investigators, who will make lasting contributions to mental health research in HIV/Aging, and sow the seeds for developing a new sub-field of Geriatric HIV Neuropsychiatry.

Project Summary/Abstract Schizophrenia (SZ), one of the most disabling mental illnesses, is also associated with increased medical comorbidity and a 20-year shorter life-span than the general population, which together suggest that SZ is characterized by accelerated aging. To examine that hypothesis, this application for a 5-year renewal of our R01 in SZ represents a unique opportunity to evaluate 10-year trajectories of aging in persons with SZ and healthy comparison subjects (HCs), and to expand the focus to examine serious real world consequences (physical comorbidity and mortality), potentially modifiable risk factors, and inflammatory and cellular markers of aging. Per our original proposal, employing a Multi-Cohort Longitudinal Design (MCLD), we have developed a sex- and age-stratified cohort of 140 subjects with SZ and 120 HCs, aged 26-65 years at baseline. These participants are evaluated clinically every year, and with a panel of selected markers representative of biological aging in alternate years. The biomarkers include systemic measures of inflammatory processes (high-sensitivity C-reactive protein or hs-CRP, along with another cytokine and two chemokines), metabolic dysregulation (Homeostatic Model Assessment of Insulin Resistance; HOMA-IR), oxidative stress (F2- isoprostanes), and cellular aging (telomere length). We are currently in the 49th month of the 5-year project, but are proposing this competitive renewal prior to its completion, to avoid a gap in funding and ensure retention of this invaluable, well-characterized existing cohort. Our retention rate has been excellent (95% annually for SZ). We have preliminary evidence consistent with accelerated biological aging in SZ; however, a 10-year expanded study with additional novel aims and innovative measures is necessary to characterize consequences and risk factors of acceleration, and examine the mechanistic role of gene expression and signaling pathways related to inflammation. The proposed renewal has been designed and informed by our initial findings, and by the evolving literature on inflammation and other biological and cellular mechanisms of aging. During the next five years, we will continue to evaluate trajectories of the current biomarkers, while adding novel measures of inflammatory signaling, and inflammation and cellular aging transcriptomic profiles (?inflammaging?). We will enhance our characterization of physical comorbidity and behaviors, including using mobile assessment of physical activity and everyday functioning, and increase the frequency of biomarker assessments to every 18 months. This project is related to the NIMH Strategic Objective # 2: charting mental illness trajectories to determine when, where, and how to intervene. Demonstrating the presence and characterizing the patterns of accelerated biological aging in SZ will significantly advance understanding of the real-world consequences, risk factors, and underlying mechanisms, which together will inform new ways of predicting, tracking, and treating the serious medical co-morbidities and reducing mortality in SZ. The ultimate goal is to improve the overall health and increase the life-span of people living with SZ.

Project Summary/Abstract Serious mental illnesses (SMI), including schizophrenia, bipolar disorder, and schizoaffective disorder, are associated with increased medical comorbidity and premature mortality from diabetes and cardiovascular disease. Unhealthy lifestyles, including energy-dense (obesogenic) diet, sedentary behavior, and cigarette smoking are important risk factors for diabetes and accelerated biological aging. All of these risk factors are potentially modifiable. There is considerable literature documenting the effectiveness of strategies to prevent and manage diabetes in the general population; yet, these interventions are rarely offered to people with SMI. Residential Care Facilities (RCFs), called Board-and-Care Homes in California, are a common housing modality for patients with SMI; they provide a venue that can maximize efficiency and sustainability of a lifestyle intervention. The goals of the proposed four-year study are to tailor a multi-component intervention to this high-risk group. The study will be a hybrid effectiveness-implementation (Hybrid Type 1) trial of a Multi- component Intervention for Diabetes risk reduction in Adults with SMI (MIDAS) in licensed RCFs in San Diego county. As a Hybrid Type 1 study, the primary emphasis will be on determining the effectiveness of the intervention to achieve desired health outcomes while also systematically collecting data on its implementation within RCFs that will inform implementation strategy refinement. Main components of MIDAS include: (1) Education about diabetes and lifestyle, (2) Dietary intervention at the facility and resident level, (3) Increased physical activity, and (4) Smoking cessation / reduction. We will employ a modified cluster-randomized stepped wedge and adaptive trial design involving 210 residents with SMI and 120 staff members from 12 RCFs. The RCFs will be divided randomly into four cohorts of three RCFs each. Each cohort will be tested over a 15- month period that includes three phases: a three-month initial control phase (no intervention, from baseline month 0 to end of month 3), a six-month intervention phase (months 4 through 9), and a six-month follow-up phase (no intervention, months 10 through 15). All the study participants will be assessed quarterly during the 15-month period. Our investigators will train RCF staff (especially the Activity Director and cook) to increase physical activity and reduce smoking, and to implement healthful dietary modifications among the residents, using evidence-based interventions. During the intervention phase, the RCF Activity Director will conduct twice-weekly manualized group sessions on education about diabetes, nutrition, exercise, and smoking cessation/reduction, to deliver a multi-component group intervention. We will also explore if there are improvements in blood-based research biomarkers of insulin resistance and inflammation in the RCF residents with SMI. This project is responsive to RFA-MH-17-608, and related to NIMH Strategic Objective #3.3B: testing interventions for effectiveness in community practice settings. If successful, MIDAS will be sustained and disseminated, and would lead to reduction in excess medical comorbidity and mortality associated with SMI.