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A path to novel, effective treatments for schizophrenia

Neuropsychopharmacology volume 49, pages 321–322 (2024)Cite this article

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Why do novel treatments for schizophrenia ultimately fail in clinical trials? The heterogeneous underlying biological mechanisms of schizophrenia are likely responsible for these disappointments. Clinical trial designs typically ignore biological heterogeneity, as all patients with a schizophrenia diagnosis are recruited into trials. Instead, we should leverage the heterogeneity of schizophrenia to select patients for clinical trials using biomarkers to identify subgroups with neuropathology consistent with the mechanism of action of the novel treatment. Otherwise, if an effective treatment for a particular biological subtype of schizophrenia was available, then the positive outcome could be missed if patients from non-responsive biological subtypes were included in the trial. The practice of recruiting schizophrenia patients broadly could also explain the difficulty in replicating initial benefits of novel treatments.

It is not clear how many biological subgroups of schizophrenia exist, nor is it clear which factors best characterize the putative subgroups. This uncertainty should not deter us from applying available evidence. Peripheral blood biomarkers have identified subgroups of patients with concurrent cognitive deficits and brain volume reductions [1,2,3]. About half of chronically or acutely ill patients with schizophrenia, first episode psychosis patients, and people at clinical high risk for developing schizophrenia display elevated peripheral blood inflammation markers: C-reactive protein (CRP), neutrophil to lymphocyte ratio, pro-inflammatory cytokines or complement [1,2,3,4,5]. Recruiting only those who display elevated peripheral blood inflammation markers into clinical trials of anti-inflammatories should increase the chance of finding beneficial treatment effects. However, even when biologically based subgroups are identified, not all patients in the relevant subgroup may respond to the treatment to the same extent or in the same time frame. Ideally, we need to collect biologicals during clinical trials as part of discovery driven work identifying biomarkers of responders versus non-responders. To begin, we can use elevated peripheral blood inflammation levels as inclusion criteria for clinical trials of repurposed anti-inflammatories and track each patient’s change in blood markers and symptoms over time.

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References

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Funding

Funding

TWW was supported in part by the Department of Veterans Affairs, Syracuse Veterans Affairs Medical Center Research Service, Syracuse, NY, USA and the SUNY Upstate Medical University, Syracuse, NY, USA; CSW was supported in part by the New South Wales Ministry of Health, Office of Health and Medical Research (Australia), a National Health and Medical Research Council (Australia) Principal Research Fellowship (1117079), and the SUNY Upstate Medical University, Syracuse, NY, USA. The funding sources were not involved in the writing of the paper or in the decision to submit the paper for publication. The views expressed in this paper are those of the authors and do not necessarily represent the official position or policy of the U.S. government, Department of Defense, or Department of Veterans Affairs.

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Authors and Affiliations

  1. Department of Neuroscience and Physiology, State University of New York (SUNY) Upstate Medical University, Syracuse, NY, 13210, USA

    Thomas W. Weickert & Cynthia Shannon Weickert

  2. Neuroscience Research Australia, Sydney, NSW, 2031, Australia

    Thomas W. Weickert & Cynthia Shannon Weickert

  3. Department of Veterans Affairs, Syracuse Veterans Affairs Medical Center, Syracuse, NY, USA

    Thomas W. Weickert & Cynthia Shannon Weickert

  4. School of Clinical Medicine, University of New South Wales, Sydney, NSW, 2031, Australia

    Cynthia Shannon Weickert

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  1. Thomas W. Weickert
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  2. Cynthia Shannon Weickert
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TWW conceptualization, writing and editing. CSW conceptualization, writing and editing.

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Correspondence to Thomas W. Weickert.

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Weickert, T.W., Weickert, C.S. A path to novel, effective treatments for schizophrenia. Neuropsychopharmacol. 49, 321–322 (2024). https://doi.org/10.1038/s41386-023-01705-1

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