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Schizophrenia

Nature Reviews Disease Primers volume 11, Article number: 83 (2025) Cite this article

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Abstract

Schizophrenia is a challenging and diverse mental health condition with a lifetime prevalence of 0.4%. Schizophrenia usually manifests in late adolescence or early adulthood and is associated with high disability and a reduced life expectancy. Risk factors include genetic predisposition, prenatal and birth complications, infections and immune dysfunction, and cannabis use as well as psychosocial factors such as childhood trauma or migration. The first psychotic episode is often preceded by a long prodromal phase that can last for several years. No markers are yet available for clinical use that allow prediction of disease development or a diagnosis to be established. A leading theory postulates that excitatory–inhibitory (that is, glutamate–GABA) imbalance in the cortex ultimately leads to dysfunction of the dopaminergic system. Schizophrenia is a heterogeneous disease with different manifestations, including psychotic symptoms as well as negative symptoms and global cognitive deficit, that do not respond to antipsychotic drugs, making management very difficult. Pharmacological treatment coupled with psychotherapeutic interventions, such as cognitive behavioural therapy, cognitive remediation and psychoeducation, remains the mainstay of treatment; however, treatment resistance is frequent. The first medication that targets neurotransmitter systems other than dopamine has been approved for use. Current attempts to use virtual reality and avatars to improve psychotic symptoms and smartphone applications to prevent relapses seem promising.

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Fig. 1: Risk factors, neurobiology and course of schizophrenia.
Fig. 2: The bidirectional association between schizophrenia and other psychiatric disorders.
Fig. 3: Genomic loci related to schizophrenia in a genome-wide association study.
Fig. 4: Pathophysiological mechanisms in schizophrenia.
Fig. 5: Ranking of antipsychotics in efficacy and side effects.
Fig. 6: Dose–response curves pooling all antipsychotic drugs after conversion to risperidone equivalents.

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Acknowledgements

The authors acknowledge A. Rodolico for providing Supplementary Table 3; F. Milosavljević for his work on Fig. 1 and Fig. 4; D. Kim for his work on Box 3; and C. Mei for her help in producing this manuscript. The authors also thank W. Strube, I. Sommer, S. Gangadin and J.m Steiner for reviewing some sections outside the formal review process.

Author information

Authors and Affiliations

  1. Technical University of Munich, TUM School of Medicine and Health, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Munich, Germany

    Stefan Leucht, Spyridon Siafis, Irene Bighelli, Johannes Schneider-Thoma & Josef Priller

  2. German Center for Mental Health (DZPG), Partner site München/Augsburg, Munich, Germany

    Stefan Leucht, Spyridon Siafis, Irene Bighelli, Johannes Schneider-Thoma & Josef Priller

  3. National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark

    John J. McGrath

  4. Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Brisbane, Queensland, Australia

    John J. McGrath

  5. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia

    John J. McGrath

  6. Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, Victoria, Australia

    Patrick McGorry

  7. Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia

    Patrick McGorry

  8. Institute of Psychiatry, Psychology & Neuroscienceo, Kings’s College London, London, UK

    Oliver D. Howes & Richard Carr

  9. Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK

    Oliver D. Howes

  10. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Carol Tamminga

  11. Neuropsychiatry, Charité – Universitätsmedizin Berlin and Deutsches Zentrum für Neurodegenerative Störungen, Berlin, Germany

    Josef Priller

  12. University of Edinburgh and UK DRI, Edinburgh, UK

    Josef Priller

  13. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

    John M. Davis

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Contributions

Introduction (S.L., J.M.D., S.S. and J.P.); Epidemiology (S.L., J.J.M. and J.P.); Mechanisms/pathophysiology (S.L., O.D.H., S.S., C.T., R.C. and J.P.); Diagnosis, screening and prevention (S.L., P.M. and J.P.); Management (S.L., J.M.D., I.B., J.S.-T., S.S. and J.P.); Quality of life (S.L., S.S. and J.P.); Outlook (S.L., J.M.D., J.J.M., O.D.H., P.M., I.B., J.S.-T., S.S., C.T., R.C. and J.P.); overview of Primer (S.L.).

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Correspondence to Stefan Leucht.

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Competing interests

In the last 3 years, S.L. has received honoraria as an adviser and/or for lectures and/or for educational material from Alkermes, Angelini, Apsen, Eisai, Gedeon Richter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Merck Sharp and Dohme, Mitsubishi, Neurotorium, NovoNordisk, Otsuka, Recordati, Roche, Rovi, Sanofi Aventis, and TEVA. C.T. is on the Scientific Advisory Board for Karuna, owns stock and is an adviser for KyNexis, and she reviews for the National Institute of Mental Health. O.D.H. has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Janssen, Karuna, Lundbeck, Merck, Neurocrine, Ontrack/Pangea, Otsuka, Sunovion, Recordati, Roche, Rovi, and Viatris/Mylan. He was previously a part-time employee of Lundbeck A/v. O.D.H. has a patent for the use of dopaminergic imaging. J.P. has a patent on EPO variants and is a member of the SINAPPS2 TSC. All other authors declare no competing interests.

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Nature Reviews Disease Primers thanks S. Lawrie, D. Malaspina, W. Fleischhacker and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Leucht, S., Siafis, S., McGrath, J.J. et al. Schizophrenia. Nat Rev Dis Primers 11, 83 (2025). https://doi.org/10.1038/s41572-025-00667-6

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