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The neurobiology of duration of untreated psychosis: a comprehensive review

Molecular Psychiatry volume 28, pages 168–190 (2023)Cite this article

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Abstract

Duration of untreated psychosis (DUP) is defined as the time from the onset of psychotic symptoms until the first treatment. Studies have shown that longer DUP is associated with poorer response rates to antipsychotic medications and impaired cognition, yet the neurobiologic correlates of DUP are poorly understood. Moreover, it has been hypothesized that untreated psychosis may be neurotoxic. Here, we conducted a comprehensive review of studies that have examined the neurobiology of DUP. Specifically, we included studies that evaluated DUP using a range of neurobiologic and imaging techniques and identified 83 articles that met inclusion and exclusion criteria. Overall, 27 out of the total 83 studies (32.5%) reported a significant neurobiological correlate with DUP. These results provide evidence against the notion of psychosis as structurally or functionally neurotoxic on a global scale and suggest that specific regions of the brain, such as temporal regions, may be more vulnerable to the effects of DUP. It is also possible that current methodologies lack the resolution needed to more accurately examine the effects of DUP on the brain, such as effects on synaptic density. Newer methodologies, such as MR scanners with stronger magnets, PET imaging with newer ligands capable of measuring subcellular structures (e.g., the PET ligand [11C]UCB-J) may be better able to capture these limited neuropathologic processes. Lastly, to ensure robust and replicable results, future studies of DUP should be adequately powered and specifically designed to test for the effects of DUP on localized brain structure and function with careful attention paid to potential confounds and methodological issues.

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Article 12 November 2020

Jo Ellen Wilson, Matthew F. Mart, … E. Wesley Ely

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Authors and Affiliations

  1. Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, 77030, USA

    Anthony W. Zoghbi

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    Anthony W. Zoghbi

  3. Institute of Genomic Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA

    Anthony W. Zoghbi

  4. Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, 10032, USA

    Anthony W. Zoghbi, Jeffrey A. Lieberman & Ragy R. Girgis

  5. Office of Mental Health, New York State Psychiatric Institute, New York, NY, 10032, USA

    Anthony W. Zoghbi & Ragy R. Girgis

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Contributions

AWZ and RRG performed the literature search and developed the first draft of the article. All authors contributed to conceptualizing the project and drafting the final version of the article.

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Correspondence to Anthony W. Zoghbi or Ragy R. Girgis.

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Competing interests

Within the last 3 years, RRG has received research support from Allergan, consulted for Noble Insights, and received royalties from books published by Wipf and Stock and Routledge/Taylor and Francis. JAL has received support administered through his institution in the form of funding or medication supplies for investigator-initiated research from Lilly, Denovo, Biomarin, Novartis, Taisho, Teva, Alkermes, and Boehringer Ingelheim, and is a member of the advisory board of Intracellular Therapies and Pierre Fabre. He neither accepts nor receives any personal financial remuneration for consulting, advisory board, or research activities. He holds a patent from Repligen and receives royalty payments from SHRINKS: The Untold Story of Psychiatry. AWZ is a paid consultant for AstraZeneca. The project described was supported by K23MH121669 (AWZ) and R01MH113861 (RRG).

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Zoghbi, A.W., Lieberman, J.A. & Girgis, R.R. The neurobiology of duration of untreated psychosis: a comprehensive review. Mol Psychiatry 28, 168–190 (2023). https://doi.org/10.1038/s41380-022-01718-0

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