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 journalArticlepeer-review

8 Scopus citations


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 languageEnglish (US)
Pages (from-to)1802-1814
Number of pages13
JournalBrain Imaging and Behavior
Issue number4
StatePublished - Aug 2021
Externally publishedYes


  • 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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