Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2024 Jan 1;81(1):77-88.
doi: 10.1001/jamapsychiatry.2023.3850.

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis

ENIGMA Clinical High Risk for Psychosis Working Group; Shalaila S Haas  1 , Ruiyang Ge  2   3 , Ingrid Agartz  4   5   6   7 , G Paul Amminger  8   9 , Ole A Andreassen  6   10 , Peter Bachman  11 , Inmaculada Baeza  12   13   14   15 , Sunah Choi  16 , Tiziano Colibazzi  17   18 , Vanessa L Cropley  19 , Camilo de la Fuente-Sandoval  20 , Bjørn H Ebdrup  21   22 , Adriana Fortea  12   13   15   23   24 , Paolo Fusar-Poli  25   26 , Birte Yding Glenthøj  21   22 , Louise Birkedal Glenthøj  27 , Kristen M Haut  28 , Rebecca A Hayes  11 , Karsten Heekeren  29   30 , Christine I Hooker  28 , Wu Jeong Hwang  16   31 , Neda Jahanshad  32 , Michael Kaess  33   34 , Kiyoto Kasai  35   36   37 , Naoyuki Katagiri  38 , Minah Kim  39   40 , Jochen Kindler  34 , Shinsuke Koike  36   41 , Tina D Kristensen  42 , Jun Soo Kwon  39   40 , Stephen M Lawrie  43 , Irina Lebedeva  44 , Jimmy Lee  45   46 , Imke L J Lemmers-Jansen  47   48 , Ashleigh Lin  49 , Xiaoqian Ma  50 , Daniel H Mathalon  51   52 , Philip McGuire  53 , Chantal Michel  34 , Romina Mizrahi  54   55 , Masafumi Mizuno  56 , Paul Møller  57 , Ricardo Mora-Durán  58 , Barnaby Nelson  8   9 , Takahiro Nemoto  38 , Merete Nordentoft  27 , Dorte Nordholm  27 , Maria A Omelchenko  59 , Christos Pantelis  19   60 , Jose C Pariente  61 , Jayachandra M Raghava  21   62 , Francisco Reyes-Madrigal  20 , Jan I Røssberg  63 , Wulf Rössler  64   65 , Dean F Salisbury  66 , Daiki Sasabayashi  67   68 , Ulrich Schall  69   70 , Lukasz Smigielski  30   71 , Gisela Sugranyes  12   13   14   15 , Michio Suzuki  67   68 , Tsutomu Takahashi  67   68 , Christian K Tamnes  4   7   72 , Anastasia Theodoridou  30 , Sophia I Thomopoulos  32 , Paul M Thompson  32 , Alexander S Tomyshev  44 , Peter J Uhlhaas  73   74 , Tor G Værnes  7   75 , Therese A M J van Amelsvoort  76 , Theo G M van Erp  77   78 , James A Waltz  79 , Christina Wenneberg  27 , Lars T Westlye  6   10   80 , Stephen J Wood  8   9   81 , Juan H Zhou  82   83 , Dennis Hernaus  76 , Maria Jalbrzikowski  11   84 , René S Kahn  1 , Cheryl M Corcoran  1   85 , Sophia Frangou  1   2   3
Collaborators, Affiliations
Meta-Analysis

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis

ENIGMA Clinical High Risk for Psychosis Working Group et al. JAMA Psychiatry. .

Abstract

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals.

Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder.

Design, setting, and participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022.

Main outcomes and measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores.

Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (β = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (β = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate).

Conclusions and relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Haas reported receiving grants from the National Institute of Mental Health (NIMH) during the conduct of the study. Dr Andreassen reported receiving grants from European Union Horizon 2020 (EU H2020), K. G. Jebsen Stiftelsen, the Research Council of Norway, and the South-Eastern Norway Regional Health Authority during the conduct of the study and personal fees from Cortechs.ai, Janssen Pharmaceuticals, Lundbeck, and Sunovion Pharmaceuticals outside the submitted work. Dr Baeza reported receiving grants from Instituto de Salud Carlos III during the conduct of the study; grants from the Alicia Koplowitz Foundation, Ministerio de Sanidad, and Plan Nacional Sobre Drogas; and personal fees from Angelini Pharma, Janssen Pharmaceuticals, and Otsuka Pharmaceutical-Lundbeck outside the submitted work. Dr Ebdrup reported receiving personal fees from Boehringer Ingelheim, Lundbeck, and Otsuka Pharmaceutical Scandinavia outside the submitted work. Dr Fortea reported receiving educational support from Janssen Pharmaceuticals-Cilag, Otsuka Pharmaceutical-Lundbeck, and ROVI Corporation and travel support from Otsuka Pharmaceutical-Lundbeck outside the submitted work. Dr Fusar-Poli reported receiving personal fees from Angelini Pharma, Boehringer Ingelheim, Lundbeck, Menarini Group, Proxymm Science, and Sunovion Pharmaceuticals outside the submitted work. Dr B. Glenthøj reported receiving grants from the Lundbeck Foundation during the conduct of the study. Dr L. Glenthøj reported receiving grants from the Independent Research Fund Denmark, Mental Health Services in the Capital Region, and TrygFoundation during the conduct of the study and being the leader of a Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research outside the submitted work. Dr Heekeren reported receiving grants from the Zurich Program for Sustainable Development of Mental Health Services during the conduct of the study. Dr Jahanshad reported receiving grants from Biogen outside the submitted work. Dr Kasai reported receiving grants from Amedisys, the Japan Science and Technology Agency, and the Japan Society for the Promotion of Science during the conduct of the study; grants from Daiichi Sankyo, Eli Lilly and Company, Mitsubishi Tanabe Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Shionogi & Co, Sumitomo Pharma, Takeda Pharmaceuticals, and Teijin Limited; and personal fees from FUJIFILM Wako Pure Chemical Corporation, Meiji Seika Pharma, Otsuka Pharmaceutical, Ricoh Company, Sumitomo Pharma, and Takeda Pharmaceuticals outside the submitted work. Dr Katagiri reported receiving grants from the Grants-in-Aid for Scientific Research (KAKENHI) program of the Japan Society for the Promotion of Science during the conduct of the study. Dr Kindler reported receiving grants from the Swiss National Science Foundation outside the submitted work. Dr Lebedeva reported receiving grants from the Russian Foundation for Basic Research during the conduct of the study. Dr Lee reported receiving grants from the Singapore Ministry of Health National Medical Research Council during the conduct of the study and personal fees from Lundbeck Singapore, Otsuka Pharmaceutical, and Sumitomo Pharma outside the submitted work. Dr Mathalon reported receiving personal fees from Neurocrine Biosciences outside the submitted work. Dr Mizuno reported receiving personal fees from Daiichi Sankyo, Eisai, FUJIFILM Pharmaceuticals, Janssen Pharmaceuticals, Kyowa Pharmaceutical Industry, Lundbeck Japan, Mochida Pharmaceutical, Otsuka Pharmaceutical, Sumitomo Pharma, Takeda Pharmaceuticals, and Yoshitomi Pharmaceutical Industries outside the submitted work. Dr Mora-Durán reported speaking for Johnson & Johnson outside the submitted work. Dr Nelson reported receiving grants from the National Health and Medical Research Council (NHMRC) of Australia during the conduct of the study and grants from the National Institutes of Health (NIH), the NHMRC, and Wellcome Trust outside the submitted work. Dr Nemoto reported receiving grants from Mochida Pharmaceutical, Otsuka Pharmaceutical, PDR Pharma, Shionogi & Co-Eisai, and Sumitomo Pharma and personal fees from Boehringer Ingelheim, Eisai, Janssen Pharmaceuticals, Lundbeck, Meiji Seika Pharma, MSD, Otsuka Pharmaceutical, PDR Pharma, Sumitomo Pharma, Takeda Pharmaceuticals, Viatris, and Yoshitomi Pharmaceutical Industries outside the submitted work. Dr Pantelis reported receiving grants from the NHMRC during the conduct of the study; grants from Lundbeck Foundation; and personal fees from Lundbeck Australia outside the submitted work. Dr Reyes-Madrigal reported receiving personal fees from Janssen Pharmaceuticals outside the submitted work. Dr Smigielski reported receiving grants from the Zurich Program for Sustainable Development of Mental Health Services during the conduct of the study. Dr Sugranyes reported receiving grants from Ajut a la Recerca Pons Bartran, the Alicia Koplowitz Foundation, the Brain & Behavior Research Foundation, Fundació Clinic per a la Recerca Biomédica, and Instituto de Salud Carlos III during the conduct of the study and personal fees from Angelini Pharma outside the submitted work. Dr Suzuki reported receiving grants from the Japan Agency for Medical Research and Development and the Japan Society for the Promotion of Science during the conduct of the study; grants from Eisai, FUJIFILM RI Pharma, Otsuka Pharmaceutical, and Sumitomo Pharma; and personal fees from Eisai, Eli Lilly and Company Japan, Igaku-Shoin, Janssen Pharmaceuticals, Meiji Seika Pharma, MSD, Nihon Medi-Physics, Nippon Chemiphar, Otsuka Pharmaceutical, Sumitomo Pharma, Takeda Pharmaceuticals, Viatris Pharmaceuticals Japan, and Yoshitomi Pharmaceutical Industries outside the submitted work. Dr Thompson reported receiving grants from Biogen outside the submitted work. Dr Tomyshev reported receiving grants from the Russian Foundation for Basic Research during the conduct of the study. Dr Westlye reported receiving grants from EU H2020 during the conduct of the study and grants from Norwegian Regional Health Authorities and the Research Council of Norway outside the submitted work. Dr Hernaus reported receiving personal fees from P1vital outside the submitted work. Dr Corcoran reported receiving grants from the NIMH during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Distribution of Hippocampal Subcortical Volume Normative z Scores in the Study Sample
The hippocampus is used as an exemplar because the same pattern was observed for all regions (eFigures 4 and 5 in Supplement 1). The dotted vertical lines represent the cutoffs for infranormal (z < −1.96) and supranormal (z > 1.96) values. CHR-P indicates clinical high risk for psychosis; and CHR-PC, clinical high risk for psychosis converted to a psychotic disorder.
Figure 2.
Figure 2.. Percentage of Participants With Infra- or Supranormal Regional Normative z Scores
Banks STS indicates banks of the superior temporal sulcus; CHR-P, clinical high risk for psychosis; and CHR-PC, clinical high risk for psychosis converted to a psychotic disorder.
Figure 3.
Figure 3.. Distribution of the Total Number of Regions With Infra- or Supranormal Regional Normative z Scores
CHR-P indicates clinical high risk for psychosis; CHR-PC, clinical high risk for psychosis converted to a psychotic disorder.
Figure 4.
Figure 4.. Multivariate Estimation of Group Status Using Normative Deviation Scores and Observed Values for Regional Brain Morphometric Measures
Linear support vector classification was used to estimate group status. AUC indicates area under the curve; CHR-P, clinical high risk for psychosis; CHR-PC, clinical high risk for psychosis converted to a psychotic disorder; and ROC, receiver operating characteristic curve.
See this image and copyright information in PMC

Update of

  • Normative modeling of brain morphometry in Clinical High-Risk for Psychosis.
    Haas SS, Ge R, Agartz I, Amminger GP, Andreassen OA, Bachman P, Baeza I, Choi S, Colibazzi T, Cropley VL, de la Fuente-Sandoval C, Ebdrup BH, Fortea A, Fusar-Poli P, Glenthøj BY, Glenthøj LB, Haut KM, Hayes RA, Heekeren K, Hooker CI, Hwang WJ, Jahanshad N, Kaess M, Kasai K, Katagiri N, Kim M, Kindler J, Koike S, Kristensen TD, Kwon JS, Lawrie SM, Lee J, Lemmers-Jansen IL, Lin A, Ma X, Mathalon DH, McGuire P, Michel C, Mizrahi R, Mizuno M, Møller P, Mora-Durán R, Nelson B, Nemoto T, Nordentoft M, Nordholm D, Omelchenko MA, Pantelis C, Pariente JC, Raghava JM, Reyes-Madrigal F, Røssberg JI, Rössler W, Salisbury DF, Sasabayashi D, Schall U, Smigielski L, Sugranyes G, Suzuki M, Takahashi T, Tamnes CK, Theodoridou A, Thomopoulos SI, Thompson PM, Tomyshev AS, Uhlhaas PJ, Værnes TG, van Amelsvoort TA, van Erp TG, Waltz JA, Wenneberg C, Westlye LT, Wood SJ, Zhou JH, Hernaus D, Jalbrzikowski M, Kahn RS, Corcoran CM, Frangou S; ENIGMA Clinical High Risk for Psychosis Working Group. Haas SS, et al. bioRxiv [Preprint]. 2023 Jan 18:2023.01.17.523348. doi: 10.1101/2023.01.17.523348. bioRxiv. 2023. Update in: JAMA Psychiatry. 2024 Jan 1;81(1):77-88. doi: 10.1001/jamapsychiatry.2023.3850. PMID: 36711551 Free PMC article. Updated. Preprint.

Similar articles

  • Normative modeling of brain morphometry in Clinical High-Risk for Psychosis.
    Haas SS, Ge R, Agartz I, Amminger GP, Andreassen OA, Bachman P, Baeza I, Choi S, Colibazzi T, Cropley VL, de la Fuente-Sandoval C, Ebdrup BH, Fortea A, Fusar-Poli P, Glenthøj BY, Glenthøj LB, Haut KM, Hayes RA, Heekeren K, Hooker CI, Hwang WJ, Jahanshad N, Kaess M, Kasai K, Katagiri N, Kim M, Kindler J, Koike S, Kristensen TD, Kwon JS, Lawrie SM, Lee J, Lemmers-Jansen IL, Lin A, Ma X, Mathalon DH, McGuire P, Michel C, Mizrahi R, Mizuno M, Møller P, Mora-Durán R, Nelson B, Nemoto T, Nordentoft M, Nordholm D, Omelchenko MA, Pantelis C, Pariente JC, Raghava JM, Reyes-Madrigal F, Røssberg JI, Rössler W, Salisbury DF, Sasabayashi D, Schall U, Smigielski L, Sugranyes G, Suzuki M, Takahashi T, Tamnes CK, Theodoridou A, Thomopoulos SI, Thompson PM, Tomyshev AS, Uhlhaas PJ, Værnes TG, van Amelsvoort TA, van Erp TG, Waltz JA, Wenneberg C, Westlye LT, Wood SJ, Zhou JH, Hernaus D, Jalbrzikowski M, Kahn RS, Corcoran CM, Frangou S; ENIGMA Clinical High Risk for Psychosis Working Group. Haas SS, et al. bioRxiv [Preprint]. 2023 Jan 18:2023.01.17.523348. doi: 10.1101/2023.01.17.523348. bioRxiv. 2023. Update in: JAMA Psychiatry. 2024 Jan 1;81(1):77-88. doi: 10.1001/jamapsychiatry.2023.3850. PMID: 36711551 Free PMC article. Updated. Preprint.
  • Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis.
    Baldwin H, Radua J, Antoniades M, Haas SS, Frangou S, Agartz I, Allen P, Andreassen OA, Atkinson K, Bachman P, Baeza I, Bartholomeusz CF, Chee MWL, Colibazzi T, Cooper RE, Corcoran CM, Cropley VL, Ebdrup BH, Fortea A, Glenthøj LB, Hamilton HK, Haut KM, Hayes RA, He Y, Heekeren K, Kaess M, Kasai K, Katagiri N, Kim M, Kindler J, Klaunig MJ, Koike S, Koppel A, Kristensen TD, Bin Kwak Y, Kwon JS, Lawrie SM, Lebedeva I, Lee J, Lin A, Loewy RL, Mathalon DH, Michel C, Mizrahi R, Møller P, Nelson B, Nemoto T, Nordholm D, Omelchenko MA, Pantelis C, Raghava JM, Røssberg JI, Rössler W, Salisbury DF, Sasabayashi D, Schall U, Smigielski L, Sugranyes G, Suzuki M, Takahashi T, Tamnes CK, Tang J, Theodoridou A, Thomopoulos SI, Tomyshev AS, Uhlhaas PJ, Værnes TG, van Amelsvoort TAMJ, Van Erp TGM, Waltz JA, Westlye LT, Wood SJ, Zhou JH, McGuire P, Thompson PM, Jalbrzikowski M, Hernaus D, Fusar-Poli P; ENIGMA Clinical High Risk for Psychosis Working Group. Baldwin H, et al. Transl Psychiatry. 2022 Jul 26;12(1):297. doi: 10.1038/s41398-022-02057-y. Transl Psychiatry. 2022. PMID: 35882855 Free PMC article.
  • Sertindole for schizophrenia.
    Lewis R, Bagnall AM, Leitner M. Lewis R, et al. Cochrane Database Syst Rev. 2005 Jul 20;2005(3):CD001715. doi: 10.1002/14651858.CD001715.pub2. Cochrane Database Syst Rev. 2005. PMID: 16034864 Free PMC article.
  • Extreme deviations from the normative model reveal cortical heterogeneity and associations with negative symptom severity in first-episode psychosis from the OPTiMiSE and GAP studies.
    Worker A, Berthert P, Lawrence AJ, Kia SM, Arango C, Dinga R, Galderisi S, Glenthøj B, Kahn RS, Leslie A, Murray RM, Pariante CM, Pantelis C, Weiser M, Winter-van Rossum I, McGuire P, Dazzan P, Marquand AF. Worker A, et al. Transl Psychiatry. 2023 Dec 2;13(1):373. doi: 10.1038/s41398-023-02661-6. Transl Psychiatry. 2023. PMID: 38042835 Free PMC article.
  • Nutritional interventions for survivors of childhood cancer.
    Cohen JE, Wakefield CE, Cohn RJ. Cohen JE, et al. Cochrane Database Syst Rev. 2016 Aug 22;2016(8):CD009678. doi: 10.1002/14651858.CD009678.pub2. Cochrane Database Syst Rev. 2016. PMID: 27545902 Free PMC article.
See all similar articles

Cited by

See all "Cited by" articles

References

    1. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Publishing; 2013.
    1. GBD 2019 Mental Disorders Collaborators . Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022;9(2):137-150. doi:10.1016/S2215-0366(21)00395-3 - DOI - PMC - PubMed
    1. Fusar-Poli P, Borgwardt S, Bechdolf A, et al. . The psychosis high-risk state: a comprehensive state-of-the-art review. JAMA Psychiatry. 2013;70(1):107-120. doi:10.1001/jamapsychiatry.2013.269 - DOI - PMC - PubMed
    1. Salazar de Pablo G, Radua J, Pereira J, et al. . Probability of transition to psychosis in individuals at clinical high risk: an updated meta-analysis. JAMA Psychiatry. 2021;78(9):970-978. doi:10.1001/jamapsychiatry.2021.0830 - DOI - PMC - PubMed
    1. Fusar-Poli P, Salazar de Pablo G, Correll CU, et al. . Prevention of psychosis: advances in detection, prognosis, and intervention. JAMA Psychiatry. 2020;77(7):755-765. doi:10.1001/jamapsychiatry.2019.4779 - DOI - PubMed

Publication types