Meta-Analysis

. 2022 Jan;43(1):373-384.

doi: 10.1002/hbm.25212. Epub 2020 Oct 5.

Intracranial and subcortical volumes in adolescents with early-onset psychosis: A multisite mega-analysis from the ENIGMA consortium

Tiril P Gurholt^{1

2

3}, Vera Lonning^{2

3}, Stener Nerland^{2

3}, Kjetil N Jørgensen^{2

3}, Unn K Haukvik^{1

4}, Clara Alloza⁵, Celso Arango^{5

6}, Claudia Barth², Carrie E Bearden^{7

8}, Michael Berk^{9

10}, Hannes Bohman^{11

12

13}, Orwa Dandash⁹, Covadonga M Díaz-Caneja^{5

6}, Carl T Edbom¹¹, Theo G M van Erp^{14

15}, Anne-Kathrin J Fett^{16

17

18}, Sophia Frangou¹⁹, Benjamin I Goldstein^{20

21}, Anahit Grigorian²⁰, Neda Jahanshad²², Anthony C James^{23

24}, Joost Janssen^{5

6}, Cecilie Johannessen², Katherine H Karlsgodt^{8

25}, Matthew J Kempton²⁶, Peter Kochunov²⁷, Lydia Krabbendam¹⁸, Marinos Kyriakopoulos^{28

29}, Mathias Lundberg^{11

12

13

30}, Bradley J MacIntosh^{31

32}, Bjørn Rishovd Rund^{33

34}, Runar E Smelror^{2

3}, Alysha Sultan^{19

35}, Christian K Tamnes^{2

3

36}, Sophia I Thomopoulos²¹, Ariana Vajdi⁷, Kirsten Wedervang-Resell¹, Anne M Myhre^{37

38}, Ole A Andreassen^{1

2}, Paul M Thompson²¹, Ingrid Agartz^{2

3

11}; ENIGMA-EOP Working Group

Affiliations

¹ Norwegian Center for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
² Norwegian Center for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³ Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
⁴ Department of Adult Mental Health, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁵ Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, Madrid, Spain.
⁶ School of Medicine, Universidad Complutense, Madrid, Spain.
⁷ Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, California, USA.
⁸ Department of Psychology, UCLA, Los Angeles, California, USA.
⁹ IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Victoria, Australia.
¹⁰ Orygen Youth Health Research Center, The Florey Institute for Neuroscience and Department of Psychiatry, Parkville, Victoria, Australia.
¹¹ Center for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Stockholm Region, Stockholm, Sweden, Stockholm, Sweden.
¹² Department of Neuroscience, Child and Adolescent Psychiatry, Uppsala University, Uppsala, Sweden.
¹³ Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹⁴ Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, California, USA.
¹⁵ Center for the Neurobiology of Learning, University of California Irvine and Memory, Irvine, California, USA.
¹⁶ Department of Psychology, City, University of London, London, UK.
¹⁷ Department of Psychosis Studies, IoPPN, London, UK.
¹⁸ Department of Clinical, Neuro and Developmental Psychology, VU Amsterdam, Amsterdam, Netherlands.
¹⁹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁰ Center for Youth Bipolar Disorder, Sunnybrook Health Science Center, Toronto, Ontario, Canada.
²¹ Department of Psychiatry and Pharmacology, University of Toronto, Canada.
²² Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.
²³ Department of Psychiatry, University of Oxford, Oxford, UK.
²⁴ Oxford Health Foundation NHS Trust, Oxford, UK.
²⁵ Department Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, California, USA.
²⁶ Department of Psychosis Studies, King's College London, London, UK.
²⁷ Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA.
²⁸ Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
²⁹ National and Specialist Children's Inpatient Unit (Acorn Lodge), South London and Maudsley NHS Foundation Trust, Beckenham, UK.
³⁰ The Department of Clinical Science and Education, KI SÖS, Stockholm, Sweden.
³¹ Hurvitz Brain Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
³² Department of Medical Biophysics, University of Toronto, Ontario, Canada.
³³ Department of Psychology, University of Oslo, Oslo, Norway.
³⁴ Department of Research, Vestre Viken Hospital Trust, Drammen, Norway.
³⁵ Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
³⁶ PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway.
³⁷ Child and Adolescent Psychiatry Unit, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³⁸ Department of Psychiatric Research and Development, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

PMID: 33017498
PMCID: PMC8675418
DOI: 10.1002/hbm.25212

Meta-Analysis

Intracranial and subcortical volumes in adolescents with early-onset psychosis: A multisite mega-analysis from the ENIGMA consortium

Tiril P Gurholt et al. Hum Brain Mapp. 2022 Jan.

. 2022 Jan;43(1):373-384.

doi: 10.1002/hbm.25212. Epub 2020 Oct 5.

Authors

Affiliations

¹ Norwegian Center for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
² Norwegian Center for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³ Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
⁴ Department of Adult Mental Health, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁵ Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, Madrid, Spain.
⁶ School of Medicine, Universidad Complutense, Madrid, Spain.
⁷ Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, California, USA.
⁸ Department of Psychology, UCLA, Los Angeles, California, USA.
⁹ IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Victoria, Australia.
¹⁰ Orygen Youth Health Research Center, The Florey Institute for Neuroscience and Department of Psychiatry, Parkville, Victoria, Australia.
¹¹ Center for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Stockholm Region, Stockholm, Sweden, Stockholm, Sweden.
¹² Department of Neuroscience, Child and Adolescent Psychiatry, Uppsala University, Uppsala, Sweden.
¹³ Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹⁴ Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, California, USA.
¹⁵ Center for the Neurobiology of Learning, University of California Irvine and Memory, Irvine, California, USA.
¹⁶ Department of Psychology, City, University of London, London, UK.
¹⁷ Department of Psychosis Studies, IoPPN, London, UK.
¹⁸ Department of Clinical, Neuro and Developmental Psychology, VU Amsterdam, Amsterdam, Netherlands.
¹⁹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁰ Center for Youth Bipolar Disorder, Sunnybrook Health Science Center, Toronto, Ontario, Canada.
²¹ Department of Psychiatry and Pharmacology, University of Toronto, Canada.
²² Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.
²³ Department of Psychiatry, University of Oxford, Oxford, UK.
²⁴ Oxford Health Foundation NHS Trust, Oxford, UK.
²⁵ Department Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, California, USA.
²⁶ Department of Psychosis Studies, King's College London, London, UK.
²⁷ Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA.
²⁸ Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
²⁹ National and Specialist Children's Inpatient Unit (Acorn Lodge), South London and Maudsley NHS Foundation Trust, Beckenham, UK.
³⁰ The Department of Clinical Science and Education, KI SÖS, Stockholm, Sweden.
³¹ Hurvitz Brain Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
³² Department of Medical Biophysics, University of Toronto, Ontario, Canada.
³³ Department of Psychology, University of Oslo, Oslo, Norway.
³⁴ Department of Research, Vestre Viken Hospital Trust, Drammen, Norway.
³⁵ Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
³⁶ PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway.
³⁷ Child and Adolescent Psychiatry Unit, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³⁸ Department of Psychiatric Research and Development, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

PMID: 33017498
PMCID: PMC8675418
DOI: 10.1002/hbm.25212

Abstract

Early-onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early-onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early-onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early-onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed-effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = -0.39) and hippocampal (d = -0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early-onset schizophrenia (d = -0.34) and affective psychosis (d = -0.42), and early-onset schizophrenia showed lower hippocampal (d = -0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = -0.42). The findings demonstrate a similar pattern of brain alterations in early-onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early-onset psychosis.

Keywords: adolescence; antipsychotics; brain structure; early-onset; intracranial volume; psychosis spectrum.

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Conflict of interest statement

Celso Arango: has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, and Takeda; Covadonga M. Díaz‐Caneja: has received honoraria from AbbVie, Sanofi, and Exeltis; Michael Berk: was supported by an unrestricted grant from AstraZeneca; Paul M. Thompson, Neda Jahanshad: MPI of a research grant from Biogen, Inc., for work unrelated to the contents of this manuscript. Ole A. Andreassen: has received speaker's honorarium from Lundbeck, and is a consultant to HealthLytix. Bradley J. MacIntosh: received a NARSAD Independent Investigator award from the Brain Behavior Research Foundation.

Figures

**FIGURE 1**
Regional brain volumes in early‐onset psychosis compared to healthy controls. Notes: Linear mixed‐effects models applied for diagnostic differences between patients with early‐onset psychosis and healthy controls (reference), adjusted for age, sex, and ICV (for subcortical structures) as fixed‐effects variables and scanner as a random‐effects variable. Error bars show pooled effect size ± standard error. Significant differences indicated by *

**FIGURE 2**
Regional brain volumes in early‐onset psychosis patient subgroups compared to healthy controls. Notes: Linear mixed‐effects models applied for diagnostic differences in patient subgroups (EOS/AFP/OTP) with controls (reference), adjusted for age, sex, and ICV (for subcortical structures) as fixed‐effects variables and scanner as a random‐effects variable. Error bars show mean effect size ± standard error. Significant differences indicated by *. AFP, affective psychosis; EOS, early‐onset schizophrenia; OTP, other psychoses

**FIGURE 3**
Regional brain volumes by current antipsychotic medication status in early‐onset psychosis compared to healthy controls. Notes: Linear mixed‐effects models investigating the effect of antipsychotic medication user/non‐user with controls (reference), adjusted for age, sex, and ICV (for subcortical structures) as fixed‐effects variables and scanner as a random‐effects variable. Error bars show mean effect size ± standard error. Significant differences indicated by *

**FIGURE 4**
Effect sizes observed in early‐onset psychosis compared to other neurodevelopmental disorders from prior ENIGMA publications. Notes: Figure compares the effect sizes that we observe in EOP with those from prior ENIGMA publications; In (a) meta‐analysis of adult schizophrenia (van Erp et al., 2016) and bipolar disorder (Hibar et al., 2016), and in (b) mega‐analyses of life‐span ADHD (Hoogman et al., 2017) and ASD (van Rooij et al., 2018). The age‐ranges and healthy control populations differs among the studies, and the ADHD study did not report on the lateral ventricles. ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; BD, bipolar disorder; EOP, early‐onset psychosis; SZ, schizophrenia

See this image and copyright information in PMC

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Intracranial and subcortical volumes in adolescents with early-onset psychosis: A multisite mega-analysis from the ENIGMA consortium

Affiliations

Intracranial and subcortical volumes in adolescents with early-onset psychosis: A multisite mega-analysis from the ENIGMA consortium

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