Rachel L. Loewy - US grants

DESCRIPTION (provided by applicant): Recent findings from epidemiological studies suggest that that there may be a link between the experience of early traumatic events and later development of psychotic symptoms. Animal studies provide a model of "stress sensitization" whereby early stressful events contribute to dopamine dysregulation and a sensitivity to psychosocial stress in young adulthood. "Prodrome" studies provide a unique opportunity to assess stress responsivity prospectively, prior to the onset of full psychosis, by identifying youth with an "ultra-high-risk" syndrome that confers approximately 35 percent risk for conversion to a full psychotic disorder within 2.5 years. In Study 1, we test the hypotheses that 1) UHR participants age 16-25 report a greater number of traumatic life events than healthy controls matched on age, gender and SES;and, 2) UHR participants show dysregulated stress-responsivity compared to healthy controls as exhibited by higher baseline salivary Cortisol levels, a slower return to baseline levels after a laboratory social stressor task, and higher Cortisol levels 16 hours after administration of dexamethasone, which triggers the negative feedback response of the hypothalamic- pituitary-adrenal axis. We will also collect pilot data to demonstrate the feasibility of a longitudinal follow-up to Study 1 by repeating clinical and stress-responsivity assessments with the UHR group 6- and 12-months later. We hypothesize that a greater number of traumatic events and dysregulated stress responsivity in the UHR group will predict later positive symptoms, poor functioning and risk for conversion to full psychosis. Identifying the mechanisms linking early trauma and later psychosis will allow us to identify potential targets for prevention and early intervention in psychosis, while future studies should examine possible gene- environment interactions between early trauma and candidate schizophrenia genes. PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic and debilitating disorder that affects approximately 1 percent of the population and costs society more than depression, dementia and medical illnesses across most of the lifespan. Examining the role of early adverse life events and stress-responsivity in young people at ultra-high-risk for psychosis will help to identify risk factors for the development of schizophrenia and potential targets for prevention and early intervention.

DESCRIPTION (provided by applicant): The purpose of this study is to perform a double-blind randomized controlled trial (RCT) in young patients with recent-onset (RO) schizophrenia to target improvement in cognitive functioning within real-world treatment settings. This multi-site study will be performed in 3 community mental health centers with specialized Early Intervention Services (EIS). We will compare the effects of web-based targeted cognitive training (TCT) vs. web-based general cognitive exercises (GCE), both delivered via portable laptop computers. We will investigate the behavioral and functional changes seen immediately after the intervention as well as at 6-month follow-up, compared to a no-training control group (NTC). This will be the first study to investigate cognitive enhancement for young RO schizophrenia patients in community mental health settings, using scalable interactive neurotechnology, and the first to compare two distinct cognitive training approaches. This study will generate high impact data on the potential for targeted pre-emption of the downward spiral of in cognitive and functional disability that often characterizes psychotic illness. It will also generate valuable daa on the relative effects of two distinct cognitive training approaches in schizophrenia, each derived from a very different theoretical rationale, providing much-needed information on the efficacy of a targeted distributed neural system training model derived from systems neuroscience vs. a general cognitive stimulation training model derived from neuropsychological rehabilitation approaches. The aims of this project are based on the current state of early psychosis research, as well as our own experience successfully applying neuroscience-informed cognitive training in schizophrenia. It is now abundantly clear that cognitive/neural system dysfunction represents a significant risk factor for schizophrenia as well as a poor prognostic indicator. Functional outcome in RO schizophrenia is predicted by level of cognitive impairment and baseline cognitive reserve, and recent findings suggest that specialized EIS programs focusing only on symptom reduction and psychosocial support may not robustly improve long-term outcomes- indicating that critical treatment targets are not being addressed at present in early psychosis interventions. Cognitive dysfunction and underlying neural system inefficiency should therefore be one of the primary targets for pre-emptive intervention in early psychosis. In this study, we will determine whether we can achieve this goal using cognitive training delivered via a portable computer, in order to improve functional outcome in young individuals with RO schizophrenia.

ABSTRACT Among NIMH's top priorities is the continued support of clinical services, interventions, and policy research focused on bridging the dissemination and implementation gap between science and service. For the past 35 years, our training program, called the Clinical Services Research Training Program (CSRTP), has launched the careers of clinical services investigators, many of whom are now leaders in the field, by providing high quality education and support to postdoctoral scholars from a variety of disciplines (including psychology, social work, epidemiology, sociology, medicine, health economics, and nursing) who plan to pursue careers in mental health services research. The graduates of the CSRTP have been extremely successful: eighty-five percent (85%) obtained academic or research positions; of those, 77% received research support from extramural, primarily federal, research funds. Over half (63%) of the graduates are women and a third are racial/ethnic minorities. During the last ten years, 26% of the fellows appointed classify themselves as members of under-represented minorities. Of the women who have graduated from CSRTP, 73% received extramural funding for their research; 88% of the racial/ethnic minority graduates obtained extramural research grant support. CSRTP graduates contributed substantively to the extant literature, producing over 550 peer- reviewed publications to date. Given the success of our program, we seek five additional years to continue providing high quality training to four postdoctoral fellows a year (duration of program tenure is planned for two years each) who promise to be outstanding leaders in the next generation of clinical services researchers. Our training goals are (1) to help postdoctoral fellows acquire sufficient methodological knowledge and research skills to conduct high quality clinical services and interventions research; (2) through study and experiential learning, to help postdoctoral fellows acquire knowledge about the most important pressing and contemporary issues in clinical services research; (3) to assist postdoctoral fellows to attain professional skills essential to career advancement in academic and research settings; and (4) to help postdoctoral fellows develop a national scientific peer network within specific research areas.