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Translocator Protein Distribution Volume Predicts Reduction of Symptoms During Open-Label Trial of Celecoxib in Major Depressive Disorder

  • Sophia Attwells
    Affiliations
    Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
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  • Elaine Setiawan
    Affiliations
    Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada
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  • Pablo M. Rusjan
    Affiliations
    Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada
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  • Cynthia Xu
    Affiliations
    Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada
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  • Celeste Hutton
    Affiliations
    Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada
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  • Dorsa Rafiei
    Affiliations
    Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada
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  • Benjamin Varughese
    Affiliations
    Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada
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  • Alan Kahn
    Affiliations
    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
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  • Stephen J. Kish
    Affiliations
    Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada

    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
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  • Neil Vasdev
    Affiliations
    Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada
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  • Sylvain Houle
    Affiliations
    Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
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  • Jeffrey H. Meyer
    Correspondence
    Address correspondence to Jeffrey Meyer, M.D., Ph.D., FRCP(C).
    Affiliations
    Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada

    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author

      Abstract

      Background

      Gliosis is common among neuropsychiatric diseases, but the relationship between gliosis and response to therapeutics targeting effects of gliosis is largely unknown. Translocator protein total distribution volume (TSPO VT), measured with positron emission tomography, mainly reflects gliosis in neuropsychiatric disease. Here, the primary objective was to determine whether TSPO VT in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) predicts reduction of depressive symptoms following open-label celecoxib administration in treatment-resistant major depressive disorder.

      Methods

      A total of 41 subjects with treatment-resistant major depressive disorder underwent one [18F]FEPPA positron emission tomography scan to measure PFC and ACC TSPO VT. Open-label oral celecoxib (200 mg, twice daily) was administered for 8 weeks. Change in symptoms was measured with the 17-item Hamilton Depression Rating Scale (HDRS).

      Results

      Cumulative mean change in HDRS scores between 0 and 8 weeks of treatment was plotted against PFC and ACC TSPO VT, showing a significant nonlinear relationship. At low TSPO VT values, there was no reduction in HDRS scores, but as TSPO VT values increased, there was a reduction in HDRS scores that then plateaued. This was modeled with a 4-parameter sigmoidal model in which PFC and ACC TSPO VT accounted for 84% and 92% of the variance, respectively.

      Conclusions

      Celecoxib administration in the presence of gliosis labeled by TSPO VT is associated with greater reduction of symptoms. Given the predictiveness of TSPO VT on symptom reduction, this personalized medicine approach of matching a marker of gliosis to medication targeting effects of gliosis should be applied in early development of novel therapeutics, in particular for treatment-resistant major depressive disorder.

      Keywords

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