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The Psychosis High-Risk State:  A Comprehensive State-of-the-Art Review

Paolo Fusar-Poli, MD, PhD; Stefan Borgwardt, MD, PhD; Andreas Bechdolf, MD; Jean Addington, PhD; Anita Riecher-Rössler, MD, PhD; Frauke Schultze-Lutter, PhD; Matcheri Keshavan, MD; Stephen Wood, MD, PhD; Stephan Ruhrmann, MD, PhD; Larry J. Seidman, MD, PhD; Lucia Valmaggia, MSc, PhD; Tyrone Cannon, PhD; Eva Velthorst, MSc, PhD; Lieuwe De Haan, MD, PhD; Barbara Cornblatt, MBA, PhD; Ilaria Bonoldi, MD; Max Birchwood, DSc; Thomas McGlashan, MD; William Carpenter, MD; Patrick McGorry, MD; Joachim Klosterkötter, MD, PhD; Philip McGuire, MD, PhD; Alison Yung, MD
JAMA Psychiatry. 2013;70(1):107-120. doi:10.1001/jamapsychiatry.2013.269.
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Context During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5.

Objective To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain.

Data Sources Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences.

Study Selection and Data Extraction Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field.

Data Synthesis Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures.

Conclusions The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses.

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Figure 1. Prodromal psychosis items published in each year across the electronic databases. The literature search is updated to December 2011.

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Figure 2. Clinical management (diagnosis and treatment) flowchart of the clinical high-risk state (HR) for psychosis. APS indicates attenuated psychotic symptoms subgroup; BLIP, brief limited intermittent psychotic episode subgroup; BS, basic symptoms subgroup; FEP, first-episode psychosis; GRD, genetic risk and deterioration syndrome subgroup; and UPS, unspecified prodromal symptoms subgroup.

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Figure 3. Model of psychosis onset from the clinical high-risk state. The higher the line on the y-axis, the higher the symptom severity.

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Figure 4. Meta-analysis of transition risks in studies reporting Kaplan-Meier estimates of psychosis transition over time in the high-risk state (n = 984 individuals) (for details of the study, see Fusar-Poli et al75). These risks are based on treated cohorts with no standardized treatment, so transition risk estimates are not for natural course or untreated cases.

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Figure 5. Neurocognitive profiles of individual tasks in high-risk individuals (n = 1188) compared with controls (n = 1029).92 Mean Hedges g scores are shown across cognitive tasks (negative values indicate worse performance in high-risk individuals compared with the control group). Error bars represent 95% CI. C indicates number of controls; CPT, Continuous Performance Test (d prime); CVLT, California Verbal Learning Test; HR, number of high-risk individuals; LNS, Letter Number Sequencing; RAVLT, Rey Auditory Verbal Learning Test; TMT-A, Trail Making Test Part A; TMT-B, Trail Making Test Part B; VF, Verbal Fluency; VRI, Visual Reproduction Index (WMS visual reproduction and Rey complex figures); WCST, Wisconsin Card Sorting Test (perseverative errors); and WMS, Wechsler Memory Scale (verbal recall). Working memory is shown in green, verbal memory in blue, visual memory in violet, attention in orange, processing speed in yellow, verbal fluency in gray, and executive functions in red.

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Figure 6. Structural brain alterations observed in the largest multisite neuroimaging studies of high-risk (HR) individuals (n = 182) and matched controls (n = 167).107 Baseline differences are shown between HR individuals who did (HR-T, n = 48) and did not (HR-NT, n = 134) develop psychosis during the following 2 years. The HR-T individuals had less gray matter volume than did the HR-NT individuals in the left parahippocampal gyrus, bordering the uncus. The plot shows mean gray matter volumes for the 2 HR subgroups at each site (1 indicates London, United Kingdom; 2, Basel, Switzerland; 3, Munich, Germany; and 4, Melbourne, Australia). Error bars represent SD.

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