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Original Investigation | Meta-analysis

Heterogeneity of Psychosis Risk Within Individuals at Clinical High Risk A Meta-analytical Stratification

Paolo Fusar-Poli, MD, PhD1,2; Marco Cappucciati, MD1,3; Stefan Borgwardt, MD, PhD4; Scott W. Woods, MD5; Jean Addington, PhD6; Barnaby Nelson, PhD7; Dorien H. Nieman, PhD8; Daniel R. Stahl, PhD1; Grazia Rutigliano, MD1; Anita Riecher-Rössler, MD, PhD4; Andor E. Simon, MD4,9; Masafumi Mizuno, MD, PhD10; Tae Young Lee, MD11; Jun Soo Kwon, MD, PhD11; May M. L. Lam, MBBS12; Jesus Perez, PhD13; Szabolcs Keri, MD, PhD14; Paul Amminger, MD, PhD, FRANZCP7; Sibylle Metzler, PhD15; Wolfram Kawohl, MD15; Wulf Rössler, MSc, MD15; Jimmy Lee, MBBS, MMed(Psychiatry), MCI16; Javier Labad, MD, PhD17; Tim Ziermans, PhD18; Suk Kyoon An, MD, PhD19; Chen-Chung Liu, MD, PhD20; Kristen A. Woodberry, MSW, PhD21,22; Amel Braham, MD23; Cheryl Corcoran, MD24; Patrick McGorry, MD, PhD, FRCP, FRANZCP7; Alison R. Yung, MD25; Philip K. McGuire, MD, PhD1
[+] Author Affiliations
1Institute of Psychiatry, Psychology, and Neuroscience, King’s College, London, United Kingdom
2OASIS Clinic, South London and Maudsley National Health Service Foundation Trust, London, United Kingdom
3Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
4University of Basel Psychiatric Clinics, Basel, Switzerland
5Department of Psychiatry, Yale University, New Haven, Connecticut
6Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada
7Orygen, the National Centre of Excellence in Youth Mental Health, and Centre for Youth Mental Health, the University of Melbourne, Parkville, Australia
8Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
9Specialized Early Psychosis Outpatient Service for Adolescents and Young Adults, Department of Psychiatry, Bruderholz, Switzerland.
10Department of Neuropsychiatry, Toho University School of Medicine, Tokyo, Japan
11Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea
12Kwai Chung Hospital, New Territories, Hong Kong, People’s Republic of China
13Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
14Nyiro Gyula Hospital, National Institute of Psychiatry and Addictions, Budapest, Hungary
15Centre for Social Psychiatry, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry Zurich, Zurich, Switzerland
16Department of General Psychiatry, Institute of Mental Health, Singapore, Singapore
17Department of Psychiatry, Corporacio Sanitaria Parc Tauli Sabadell, Barcelona, Spain
18Department of Clinical Child and Adolescent Studies, Leiden University, Leiden, the Netherlands
19Department of Psychiatry, Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea
20Department of Psychiatry, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
21Center for Psychiatric Research, Maine Medical Center, Portland, Maine
22Departments of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
23Psychiatry Department, University Hospital Farhat Hached, Sousse, Tunisia
24Department of Psychiatry, Columbia University, New York, New York
25Institute of Brain, Behaviour and Mental Health, University of Manchester, and Greater Manchester West National Health Service Mental Health Foundation Trust, Manchester, United Kingdom
JAMA Psychiatry. 2016;73(2):113-120. doi:10.1001/jamapsychiatry.2015.2324.
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Importance  Individuals can be classified as being at clinical high risk (CHR) for psychosis if they meet at least one of the ultra–high-risk (UHR) inclusion criteria (brief limited intermittent psychotic symptoms [BLIPS] and/or attenuated psychotic symptoms [APS] and/or genetic risk and deterioration syndrome [GRD]) and/or basic symptoms [BS]. The meta-analytical risk of psychosis of these different subgroups is still unknown.

Objective  To compare the risk of psychosis in CHR individuals who met at least one of the major inclusion criteria and in individuals not at CHR for psychosis (CHR−).

Data Sources  Electronic databases (Web of Science, MEDLINE, Scopus) were searched until June 18, 2015, along with investigation of citations of previous publications and a manual search of the reference lists of retrieved articles.

Study Selection  We included original follow-up studies of CHR individuals who reported the risk of psychosis classified according to the presence of any BLIPS, APS and GRD, APS alone, GRD alone, BS, and CHR−.

Data Extraction and Synthesis  Independent extraction by multiple observers and random-effects meta-analysis of proportions. Moderators were tested with meta-regression analyses (Bonferroni corrected). Heterogeneity was assessed with the I2 index. Sensitivity analyses tested robustness of results. Publication biases were assessed with funnel plots and the Egger test.

Main Outcomes and Measures  The proportion of each subgroup with any psychotic disorder at 6, 12, 24, 36, and 48 or more months of follow-up.

Results  Thirty-three independent studies comprising up to 4227 individuals were included. The meta-analytical proportion of individuals meeting each UHR subgroup at intake was: 0.85 APS (95%CI, 0.79-0.90), 0.1 BLIPS (95%CI, 0.06-0.14), and 0.05 GRD (95%CI, 0.03-0.07). There were no significant differences in psychosis risk at any time point between the APS and GRD and the APS-alone subgroups. There was a higher risk of psychosis in the any BLIPS greater than APS greater than GRD-alone subgroups at 24, 36, and 48 or more months of follow-up. There was no evidence that the GRD subgroup has a higher risk of psychosis than the CHR− subgroup. There were too few BS or BS and UHR studies to allow robust conclusions.

Conclusions and Relevance  There is meta-analytical evidence that BLIPS represents separate risk subgroup compared with the APS. The GRD subgroup is infrequent and not associated with an increased risk of psychosis. Future studies are advised to stratify their findings across these different subgroups. The CHR guidelines should be updated to reflect these differences.

Figures in this Article

Figures

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Figure 1.
Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Diagram
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Figure 2.
Risk of Psychosis Over Time in the Attenuated Psychotic Symptoms (APS) and Genetic Risk and Deterioration Syndrome (GRD) vs APS-Alone Groups

Test for between-group heterogeneity (P > .05 at all time points).

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Figure 3.
Meta-analytical Stratification of Ultra–High-Risk Individuals

APS indicates attenuated psychosis symptoms; BIPS, brief intermittent psychotic symptoms; BLIPS, brief limited intermittent psychotic symptoms; GRD, genetic risk and deterioration syndrome; CHR−, not at clinical high risk for psychosis. Error bars indicate 95% CI.

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