Schizophrenia and other psychotic disorders are serious and debilitating mental illnesses that incur substantial suffering for patients and major challenges to our health care system. The clinical high-risk (CHR) prodromal phase is the period prior to the onset of psychosis when clinical symptoms gradually emerge and function declines. The presence of a CHR syndrome in young adults is associated with heightened risk (~30%) for the later development of psychosis. The North American Prodrome Longitudinal Study (NAPLS) and other CHR studies have made substantial progress towards predicting psychosis, and in showing an accelerated reduction in prefrontal cortex (PFC) gray matter (GM) density in CHR converters from pre- to post-psychosis onset, but the mechanisms driving conversion remain elusive, partly because no studies include repeated measures prior to the onset of psychosis. In NAPLS2, we found that disrupted resting-state (rs) thalamo- cortical functional connectivity prior to psychosis predicts conversion and correlates with rate of GM decline, but we do not know if rs-dysconnectivity is progressive during the prodrome. Furthermore, in NAPLS2, plasma markers of pro-inflammatory cytokines at baseline predicted the rate of GM loss in converters;these same markers also correlated with rs-dysconnectivity. We do not yet know whether these inflammatory markers drive the changes in brain structure/function or are consequences of these changes. Similarly, higher levels of cortisol, and lower mismatch negativity predicted psychosis and the rate of PFC GM decline and were correlated with each other and with measures of rs-connectivity and cytokines. This application is a competitive renewal for a nine-site, longitudinal study aimed at identifying the brain processes underlying the progression of the clinical syndromes that characterize the psychosis prodrome. The goals are: 1) to determine the pre-onset trajectories of GM decline and disrupted resting-state brain connectivity in CHR individuals who develop psychosis using MRI, and 2) to identify inflammatory and plasticity mechanisms associated with transition to psychosis. Over a two-year period, the study will repeatedly measure these indicators, and at the same time examine changes in physiological indices of brain function, social and cognitive functioning, and symptom progression. The multi-site collaboration will follow large CHR (n= 378) and demographically matched comparison (n= 162) samples that will undergo comprehensive assessments of biological and behavioral changes. This approach will answer important questions about the origins of the brain changes that give rise to psychosis and will provide insights into likely approaches to halting or mitigatig the pathological process and advance our understanding of risk prediction, both critical steps in prevention.

Public Health Relevance

Psychotic disorders typically have their clinical onset in young adulthood, and often derail educational progress and interfere with the acquisition of social skill required for independent adult functioning. There is a broad cost to society that accrues on a personal level in the loss of adult productivity and healthy maturation, and on a socioeconomic level in rising mental health care costs. Elucidating the underlying neurobiological processes in early psychosis will move us closer to targeted preventive interventions that have the potential to halt or ameliorate this neuropathological process and improve the outcome of this vulnerable population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01MH081988-06A1
Application #
8888535
Study Section
Special Emphasis Panel (ZMH1-ERB-D (06))
Program Officer
Rumsey, Judith M
Project Start
2008-01-01
Project End
2019-06-30
Budget Start
2014-09-25
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
$553,684
Indirect Cost
$194,799
Name
Emory University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Cao, Hengyi; McEwen, Sarah C; Chung, Yoonho et al. (2018) Altered Brain Activation During Memory Retrieval Precedes and Predicts Conversion to Psychosis in Individuals at Clinical High Risk. Schizophr Bull :
Stowkowy, Jacqueline; Liu, Lu; Cadenhead, Kristin S et al. (2018) Exploration of clinical high-risk dropouts. Schizophr Res 195:579-580
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
Hampton, Joya N; Trotman, Hanan D; Addington, Jean et al. (2018) The relation of atypical antipsychotic use and stress with weight in individuals at clinical high risk for psychosis. Stress Health 34:591-600
Kline, Emily R; Seidman, Larry J; Cornblatt, Barbara A et al. (2018) Depression and clinical high-risk states: Baseline presentation of depressed vs. non-depressed participants in the NAPLS-2 cohort. Schizophr Res 192:357-363
Woodberry, Kristen A; Seidman, Larry J; Bryant, Caitlin et al. (2018) Treatment Precedes Positive Symptoms in North American Adolescent and Young Adult Clinical High Risk Cohort. J Clin Child Adolesc Psychol 47:69-78
Chung, Yoonho; Haut, Kristen M; He, George et al. (2017) Ventricular enlargement and progressive reduction of cortical gray matter are linked in prodromal youth who develop psychosis. Schizophr Res 189:169-174
Lu, Yun; Marshall, Catherine; Cadenhead, Kristin S et al. (2017) Perceptual abnormalities in clinical high risk youth and the role of trauma, cannabis use and anxiety. Psychiatry Res 258:462-468
Zheutlin, Amanda B; Jeffries, Clark D; Perkins, Diana O et al. (2017) The Role of microRNA Expression in Cortical Development During Conversion to Psychosis. Neuropsychopharmacology 42:2188-2195
Ryan, Arthur T; Addington, Jean; Bearden, Carrie E et al. (2017) Latent class cluster analysis of symptom ratings identifies distinct subgroups within the clinical high risk for psychosis syndrome. Schizophr Res :

Showing the most recent 10 out of 52 publications