This 3-site collaborative R01 aims to improve identification of individuals who will develop schizophrenic psychosis (including brief psychotic disorder, schizophreniform disorder, schizophrenia, or schizoaffective disorder) at the initial prodromal stage of illness, prior to the onset of the full schizophrenic syndrome. Accurate identification of schizophrenic psychosis risk offers what may be the field's best hope for developing more effective treatment strategies, including secondary prevention of this typically devastating disorder. Without sensitive and specific prodromal diagnosis strategies, intervention studies are controversial, and the results of any studies will have limited impact on clinical practice. Identification efforts to date have focused on attenuated positive symptoms, but these criteria do not consider negative symptoms that occur in the prodromal stages of psychosis and are fundamental to schizophrenia. To enhance the potential sensitivity of prodrome evaluation we have developed a modified version of the """"""""Criteria of Prodromal Syndrome"""""""" (COPS) that retains attenuated positive symptoms, but also considers selected negative symptoms in the diagnosis of prodromal state. We propose to develop a schizophrenic psychosis risk prediction model, and our proposed risk factors are selected based on the hypothesis that schizophrenia results from a pathological neurodevelopmental process that occurs during a critical stage of forebrain development in gestation and affects the development of neurons primarily in the thalamic, prefrontal and frontal cortical, and limbic regions of the brain (thalamolimbic- cortical circuitry [TLCC]). These neurodevelopmental abnormalities are likely to be expressed premorbidly by subtle behavioral, cognitive, and structural """"""""vulnerability markers"""""""". In most cases, these abnormalities require specific mamrational processes (i.e., synaptic elimination, myelination), which occur around puberty, to unmask the vulnerability and trigger dysfunction, resulting in the development or worsening of attenuated positive and negative symptoms (clinically defining the """"""""at risk"""""""" state), as well as diverse but specific impairments in social function, social cognition, neurocognitive function, olfaction, and motor function. We hypothesize that as connectivity of the TLCC becomes more dysfunctional, a consequence will be increased severity of measurable impairments with more domains being affected to a greater extent. Thus, the number and severity of symptomatic manifestations of TLCC circuit impairment are indicators of a biologically high-risk state for schizophrenic psychosis. Furthermore, we hypothesize that these vulnerable neural circuits may be further perturbed by environmental events that typically occur during adolescence, such as stressful life events or drug abuse. Such stressors may exceed the adaptive capacity of relevant circuits producing the characteristic symptoms that signal the onset of the illness. To develop the schizophrenic psychosis risk assessment model we propose a 3-site prospective study of 180 individuals meeting modified """"""""Criteria for Prodromal Syndrome"""""""", and 80 help-seeking control subjects who will be prospectively evaluated over 2-5 years for risk of developing schizophrenic psychosis. The collaborative team has developed leading instruments in this field and has substantial expertise in social cognition, neurocognition, developmental psychopathology, statistics, and data management. Each site has proven its ability to recruit prodromal patients in a previous collaboration. ? ?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1-BBBP-5 (01))
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Heinssen, Robert K
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Centre for Addiction and Mental Health
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Velthorst, Eva; Meyer, Eric C; Giuliano, Anthony J et al. (2018) Neurocognitive profiles in the prodrome to psychosis in NAPLS-1. Schizophr Res :
Healey, Kristin M; Penn, David L; Perkins, Diana et al. (2018) Latent Profile Analysis and Conversion to Psychosis: Characterizing Subgroups to Enhance Risk Prediction. Schizophr Bull 44:286-296
Velthorst, Eva; Zinberg, Jamie; Addington, Jean et al. (2018) Potentially important periods of change in the development of social and role functioning in youth at clinical high risk for psychosis. Dev Psychopathol 30:39-47
Cannon, Tyrone D; Yu, Changhong; Addington, Jean et al. (2016) An Individualized Risk Calculator for Research in Prodromal Psychosis. Am J Psychiatry 173:980-988
Auther, A M; Cadenhead, K S; CarriĆ³n, R E et al. (2015) Alcohol confounds relationship between cannabis misuse and psychosis conversion in a high-risk sample. Acta Psychiatr Scand 132:60-8
Stowkowy, Jacqueline; Perkins, Diana O; Woods, Scott W et al. (2015) Personal Beliefs about Experiences in those at Clinical High Risk for Psychosis. Behav Cogn Psychother 43:669-75
Webb, Jadon R; Addington, Jean; Perkins, Diana O et al. (2015) Specificity of Incident Diagnostic Outcomes in Patients at Clinical High Risk for Psychosis. Schizophr Bull 41:1066-75
Lyngberg, Kristina; Buchy, Lisa; Liu, Lu et al. (2015) Patterns of premorbid functioning in individuals at clinical high risk of psychosis. Schizophr Res 169:209-213
Perkins, Diana O; Jeffries, Clark D; Cornblatt, Barbara A et al. (2015) Severity of thought disorder predicts psychosis in persons at clinical high-risk. Schizophr Res 169:169-177
Callaway, Dallas A; Perkins, Diana O; Woods, Scott W et al. (2014) Movement abnormalities predict transitioning to psychosis in individuals at clinical high risk for psychosis. Schizophr Res 159:263-6

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