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Linking prolonged childhood and adolescent loneliness to schizophrenia spectrum disorders: results from EU-GEI study

Published online by Cambridge University Press:  16 June 2025

Álvaro Andreu-Bernabeu Open the ORCID record for Álvaro Andreu-Bernabeu [Opens in a new window] ,
Javier González-Peñas ,
Alberto Mora Open the ORCID record for Alberto Mora [Opens in a new window] ,
Miguel Bernardo Open the ORCID record for Miguel Bernardo [Opens in a new window] ,
Gisela Mezquida Open the ORCID record for Gisela Mezquida [Opens in a new window] ,
Silvia Amoretti Open the ORCID record for Silvia Amoretti [Opens in a new window] ,
Julio Bobes Open the ORCID record for Julio Bobes [Opens in a new window] ,
Pilar A. Saiz ,
Maria Paz García-Portilla  and
Julio Sanjuan
...Show all authors
Álvaro Andreu-Bernabeu*
Affiliation:
Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain
Javier González-Peñas
Affiliation:
Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain
Alberto Mora
Affiliation:
Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
Miguel Bernardo
Affiliation:
CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
Gisela Mezquida
Affiliation:
CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain Department of Basic Clinical Practice, University of Barcelona, Barcelona, Spain
Silvia Amoretti
Affiliation:
CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
Julio Bobes
Affiliation:
Department of Psychiatry, School of Medicine, University of Oviedo, Oviedo, Spain Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain Mental Health Services of Principado de Asturias, Oviedo, Spain
Pilar A. Saiz
Affiliation:
CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain Department of Psychiatry, School of Medicine, University of Oviedo, Oviedo, Spain Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain Mental Health Services of Principado de Asturias, Oviedo, Spain
Maria Paz García-Portilla
Affiliation:
CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain Department of Psychiatry, School of Medicine, University of Oviedo, Oviedo, Spain Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain Mental Health Services of Principado de Asturias, Oviedo, Spain
Julio Sanjuan
Affiliation:
CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain Department of Psychiatry, Hospital Clínico Universitario de Valencia, School of Medicine, Universidad de Valencia, Valencia, Spain
José Luis Santos
Affiliation:
CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain Department of Psychiatry, Hospital Virgen de la Luz, Cuenca, Spain
Estela Jiménez-López
Affiliation:
CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain Health and Social Research Centre, Universidad de Castilla-La Mancha, Cuenca, Spain
Manuel Arrojo
Affiliation:
CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain Department of Psychiatry, Instituto de Investigación Sanitaria, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain
Angel Carracedo
Affiliation:
Grupo de Medicina Genómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CIMUS Universidad de Santiago de Compostela, Santiago de Compostela, Spain Fundación Pública Galega de Medicina Xenómica (SERGAS), Foundation Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
Mara Parellada
Affiliation:
Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain
Nadja P. Maric
Affiliation:
Faculty of Medicine, University of Belgrade, Belgrade, Serbia Institute of Mental Health, Belgrade, Serbia
Cem Atbaşoğlu
Affiliation:
Department of Psychiatry, School of Medicine, Ankara University, Ankara, Turkey
Alp Üçok
Affiliation:
Department of Psychiatry, Faculty of Medicine, Istanbul University, Istanbul, Turkey
Köksal Alptekin
Affiliation:
Department of Psychiatry, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey Department of Neuroscience, Graduate School of Health Sciences, Dokuz Eylul University, Izmir, Turkey
Meram Can Saka
Affiliation:
Department of Psychiatry, School of Medicine, Ankara University, Ankara, Turkey
Lotta-Katrin Pries
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands
Michael O’Donovan
Affiliation:
Cardiff University Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
Jim van Os
Affiliation:
Department of Psychiatry, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands Department of Translational Neuroscience, UMC Utrecht Brain Centre, University Medical Centrer Utrecht, Utrecht University, Utrecht, The Netherlands GGNet Mental Health, Apeldoorn, The Netherlands
Bart P. F. Rutten
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands
Philippe Delespaul
Affiliation:
Department of Psychiatry, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
Sinan Guloksuz
Affiliation:
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
Celso Arango
Affiliation:
Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain School of Medicine, Universidad Complutense, Madrid, Spain
Covadonga M. Díaz-Caneja
Affiliation:
Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain CIBER de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain School of Medicine, Universidad Complutense, Madrid, Spain
*
Correspondence: Álvaro Andreu-Bernabeu. Email: a.andreu.bernabeu@gmail.com.
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Abstract

Background

Prolonged childhood and adolescent loneliness (CAL) is linked to various adverse mental health outcomes, yet its impact on schizophrenia spectrum disorders (SSD) has been understudied. While loneliness is associated with psychosis and worsens symptoms in SSD, few studies have explored the long-term effects of early loneliness on SSD risk. Understanding how CAL interacts with genetic liability to schizophrenia is essential for identification of high-risk individuals.

Aims

This study evaluated whether prolonged CAL is associated with increased SSD risk and examined the interaction between CAL and genetic liability for schizophrenia. Gender differences in these associations were also explored.

Method

Data from the European Gene–Environment Interactions in Schizophrenia (EU-GEI) study were analysed, including 1261 individuals with SSD, 1282 unaffected siblings and 1525 healthy controls. CAL was retrospectively assessed for periods before age 12 years and age 12–16 years. Genetic risk was measured using polygenic risk scores for schizophrenia. Logistic regression models and the Relative Excess Risk due to Interaction (RERI) method were used to examine gene–environment interactions, with stratification by gender.

Results

Prolonged CAL was associated with higher odds of SSD (odds ratio [95% CI] = 5.20 [3.85−7.01] for loneliness before age 12; odds ratio [95% CI] = 7.26 [5.63−9.38] for loneliness during adolescence). The interaction between CAL and genetic risk was strongest during adolescence (RERI [95% CI] = 23.46 [10.75−53.53]). Females showed a greater effect (odds ratio [95 %CI] = 10.04 [6.80−14.94]) than males (odds ratio [95% CI] = 5.50 [3.95−7.66]). Incorporating CAL and genetic interaction increased predictive values to 17% for SSD risk − rising to 22.5% in females − compared with 2.6 and 2.8%, respectively, for genetic risk alone.

Conclusions

Prolonged CAL significantly increases SSD risk, particularly in females. The inclusion of CAL alongside genetic risk substantially enhances predictive accuracy. Early identification of CAL could inform preventive strategies, especially in genetically vulnerable populations.

Keywords

Prolonged childhood and adolescent lonelinessschizophrenia spectrum disorderspolygenic risk scoresgene–environment interactiongender differences
Type
Original Article
Information
The British Journal of Psychiatry , First View , pp. 1 - 9
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Copyright
© The Author(s), 2025. Published by Cambridge University Press on behalf of Royal College of Psychiatrists

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Footnotes

*

These authors contributed equally.

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