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Schizophrenia: from neurochemistry to circuits, symptoms and treatments

Nature Reviews Neurology volume 20, pages 22–35 (2024)Cite this article

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Abstract

Schizophrenia is a leading cause of global disability. Current pharmacotherapy for the disease predominantly uses one mechanism — dopamine D2 receptor blockade — but often shows limited efficacy and poor tolerability. These limitations highlight the need to better understand the aetiology of the disease to aid the development of alternative therapeutic approaches. Here, we review the latest meta-analyses and other findings on the neurobiology of prodromal, first-episode and chronic schizophrenia, and the link to psychotic symptoms, focusing on imaging evidence from people with the disorder. This evidence demonstrates regionally specific neurotransmitter alterations, including higher glutamate and dopamine measures in the basal ganglia, and lower glutamate, dopamine and γ-aminobutyric acid (GABA) levels in cortical regions, particularly the frontal cortex, relative to healthy individuals. We consider how dysfunction in cortico-thalamo-striatal–midbrain circuits might alter brain information processing to underlie psychotic symptoms. Finally, we discuss the implications of these findings for developing new, mechanistically based treatments and precision medicine for psychotic symptoms, as well as negative and cognitive symptoms.

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Fig. 1: Dopaminergic synapses in healthy individuals and people with schizophrenia.
Fig. 2: The topography of projections from different brain regions to the striatum.
Fig. 3: Neurochemical and other abnormalities in schizophrenia.
Fig. 4: Integrated model of schizophrenia.
Fig. 5: Dopamine dysfunction leads to false associations and misperceptions.

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Acknowledgements

The authors thank E. Dawkins for her contribution in reviewing the literature for the section on the integrated model of the pathophysiology of schizophrenia and implications for developing better treatments. K.B. has received funding from the Royal College of Psychiatrists, Rosetrees Trust and Stoneygate Trust; and O.D.H. has received funding from the Medical Research Council — UK (no. MC_A656_5QD30_2135), Maudsley Charity (no. 666) and Wellcome Trust (no. 094849/Z/10/Z) and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the National Health Service (NHS)/NIHR, the Department of Health or any other organization.

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  1. Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    Oliver D. Howes, Bernard R. Bukala & Katherine Beck

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

    Oliver D. Howes

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O.D.H. was previously a part-time employee of H Lundbeck A/s; has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/Mylan; and has a patent for the use of dopaminergic imaging. The other authors report no competing interests.

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Howes, O.D., Bukala, B.R. & Beck, K. Schizophrenia: from neurochemistry to circuits, symptoms and treatments. Nat Rev Neurol 20, 22–35 (2024). https://doi.org/10.1038/s41582-023-00904-0

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