Effects of fingolimod, a sphingosine-1-phosphate (S1P) receptor agonist, on white matter microstructure, cognition and symptoms in schizophrenia

Michael M. Francis; Tom A. Hummer; Emily Liffick; Jenifer L. Vohs; Nikki F. Mehdiyoun; Andrew C. Visco; Ziyi Yang; Richard J. Kovacs; Ying Zhang; Alan Breier

doi:10.1007/s11682-020-00375-7

Effects of fingolimod, a sphingosine-1-phosphate (S1P) receptor agonist, on white matter microstructure, cognition and symptoms in schizophrenia

Michael M. Francis, Tom A. Hummer, Emily Liffick, Jenifer L. Vohs, Nikki F. Mehdiyoun, Andrew C. Visco, Ziyi Yang, Richard J. Kovacs, Ying Zhang, Alan Breier

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1802-1814
Number of pages	13
Journal	Brain Imaging and Behavior
Volume	15
Issue number	4
DOIs	https://doi.org/10.1007/s11682-020-00375-7
State	Published - Aug 2021
Externally published	Yes

Keywords

DTI
Schizophrenia
White matter
fingolimod

ASJC Scopus subject areas

Radiology Nuclear Medicine and imaging
Neurology
Clinical Neurology
Cognitive Neuroscience
Cellular and Molecular Neuroscience
Psychiatry and Mental health
Behavioral Neuroscience

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10.1007/s11682-020-00375-7

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Francis, M. M., Hummer, T. A., Liffick, E., Vohs, J. L., Mehdiyoun, N. F., Visco, A. C., Yang, Z., Kovacs, R. J., Zhang, Y., & Breier, A. (2021). Effects of fingolimod, a sphingosine-1-phosphate (S1P) receptor agonist, on white matter microstructure, cognition and symptoms in schizophrenia. Brain Imaging and Behavior, 15(4), 1802-1814. https://doi.org/10.1007/s11682-020-00375-7

Francis, MM, Hummer, TA, Liffick, E, Vohs, JL, Mehdiyoun, NF, Visco, AC, Yang, Z, Kovacs, RJ, Zhang, Y & Breier, A 2021, 'Effects of fingolimod, a sphingosine-1-phosphate (S1P) receptor agonist, on white matter microstructure, cognition and symptoms in schizophrenia', Brain Imaging and Behavior, vol. 15, no. 4, pp. 1802-1814. https://doi.org/10.1007/s11682-020-00375-7

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title = "Effects of fingolimod, a sphingosine-1-phosphate (S1P) receptor agonist, on white matter microstructure, cognition and symptoms in schizophrenia",

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{\textquoteright}s potential therapeutic effects in schizophrenia.",

keywords = "DTI, Schizophrenia, White matter, fingolimod",

author = "Francis, {Michael M.} and Hummer, {Tom A.} and Emily Liffick and Vohs, {Jenifer L.} and Mehdiyoun, {Nikki F.} and Visco, {Andrew C.} and Ziyi Yang and Kovacs, {Richard J.} and Ying Zhang and Alan Breier",

note = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2020, Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2021",

month = aug,

doi = "10.1007/s11682-020-00375-7",

language = "English (US)",

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AU - Francis, Michael M.

AU - Hummer, Tom A.

AU - Liffick, Emily

AU - Vohs, Jenifer L.

AU - Mehdiyoun, Nikki F.

AU - Visco, Andrew C.

AU - Yang, Ziyi

AU - Kovacs, Richard J.

AU - Zhang, Ying

AU - Breier, Alan

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2021/8

Y1 - 2021/8

N2 - 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.

AB - 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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KW - Schizophrenia

KW - White matter

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Effects of fingolimod, a sphingosine-1-phosphate (S1P) receptor agonist, on white matter microstructure, cognition and symptoms in schizophrenia

Abstract

Keywords

ASJC Scopus subject areas

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