Abstract
Several lines of evidence have implicated white matter (WM) deficits in schizophrenia, including microstructural alterations from diffusion tensor (DTI) brain imaging studies. It has been proposed that dysregulated inflammatory processes, including heightened activity of circulating lymphocytes, may contribute to WM pathology in this illness. Fingolimod is a sphingosine-1-phosphate (S1P) receptor agonist that is approved for the treatment of relapsing multiple sclerosis (MS). Fingolimod robustly decreases the number of circulating lymphocytes through sequestration of these cells in lymph tissue. In addition, this agent improved WM microstructure as shown by increases in DTI fractional anisotropy (FA). In this pilot study, we assessed the effects of fingolimod on WM microstructure, cognition and symptoms in an eight-week, double-blind trial. Forty subjects with schizophrenia or schizoaffective disorder were randomized 1:1 to fingolimod (0.5 mg/day) and placebo. Fingolimod caused significant reductions in circulating lymphocytes (p < .001). In addition, there was a statistically non-significant association (p = .089) between DTI-FA change in the WM skeleton and fingolimod. There were significant relationships between the degree of lymphocyte reductions and increases in FA in the corpus collosum (p = .004) and right superior longitudinal fasciculus ( p = .02), and a non-significant correlation with the WM skeleton. There were no significant fingolimod versus placebo interactions on cognitive or symptom measures. There were no serious adverse events related to fingolimod treatment. Future studies with larger samples and treatment durations are needed to further establish fingolimod’s potential therapeutic effects in schizophrenia.
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Acknowledgements
The authors would like to recognize David Spradley and Joan Showalter, whose recruitment efforts were essential for this study. The authors would like to thank Emily Good, Emmalee Metzler and Megan Gaunnac for helping to organize study visits. The authors would thank Dr. Alexander Radnovich for his participation in study visits and study design conceptualization. The authors would like to thank the Eskenazi Health-Midtown Community Mental Health center for their institutional support. The authors would also like to thank Fred Malloy for his work as a study rater. Financial support was provided by a Stanley Medical Research Institute (SMRI) grant (#11T-001, PI: Alan Breier). The SMRI had no further role in study design, data collection and analysis, the writing of the report, and in the decision to submit the paper for publication.
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Drs. Breier, Liffick, Francis, Vohs and Ms. Mehdiyoun conceived and designed the study. Drs. Breier, Liffick, Francis, Vohs, Ms. Mehdiyoun and Mr. Visco were responsible for data acquisition. Drs. Breier, Liffick, Francis, Vohs, and Hummer analyzed and interpreted the data. Drs. Francis, Liffick, Breier, and Hummer supervised the study. Drs. Breier, Liffick, Francis, Vohs, and Hummer drafted the manuscript. All authors contributed to and have approved the final manuscript.
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All procedures performed in this study were in accordance with the ethical standards of the Indiana University School of Medicine Institutional Review Board, the Indiana University Department of Psychiatry Data Safety Monitoring Board, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all patients for being included in the study.
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Dr. Liffick and Ms. Mehdiyoun were employees at Indiana University at the time the research was completed. They are currently employed at Eli Lilly and Company. They are current minor shareholders in the company. All other authors declare that they have no conflicts of interest.
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Francis, M.M., Hummer, T.A., Liffick, E. et al. Effects of fingolimod, a sphingosine-1-phosphate (S1P) receptor agonist, on white matter microstructure, cognition and symptoms in schizophrenia. Brain Imaging and Behavior 15, 1802–1814 (2021). https://doi.org/10.1007/s11682-020-00375-7
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DOI: https://doi.org/10.1007/s11682-020-00375-7