Effects of the potent anti-inflammatory agent fingolimod in schizophrenia

Background: New medications with novel targets are needed for schizophrenia. Several lines of evidence indicate that inflammatory processes including aberrant lymphocytic activity may account for the pathophysiology of this illness. These data suggest that agents with anti‐inflammatory actions including modulation of lymphocytes and their inflammatory substrates may prove to be efficacious for schizophrenia. Fingolimod is a powerful anti‐inflammatory agent that is used in the treatment of relapsing multiple sclerosis. It is a sphingosine‐1‐phosphate (S1P) receptor modulator and decreases circulating lymphocytes through sequestration in lymph tissues. In addition, evidence suggest that it stimulates oligodendrocytes and may enhance white matter integrity. The purpose of this study is to assess the effects of fingolimod in schizophrenia. Methods: Subjects with schizophrenia (N=40) were recruited through the Indiana University Psychotic Disorders Programs and randomized 1:1 in a double‐blind, eight‐week clinical trial of fingolimod 0.5 mg/day and placebo. Circulating total lymphocytes were determined and effects were assessed on symptoms (PANSS), cognition (BACS), plasma cytokines, white matter integrity (MRI DTI) and cortical connectivity (resting fMRI). Results: Results revealed robustly significant decrease in lymphocytes in subjects taking fingolimod versus placebo (treatment x time; F= 61.2, p<0.001). Fingolimod treated subjects had a mean maximal drop in lymphocytes from baseline of 79.2% with all fingolimod treated subjects experiencing decrements greater than 60%. This powerful biological effect did not result in significant improvement (treatment x time) in PANSS total (F=0.66, p = 0.52), any of the PANSS subscales, or BACS composite score (F =0.54, p =0.44). Biomarker data (plasma cytokines, MRI DTI and resting fMRI) will be presented. Serious side effects were not observed and a full safety report will be provided. Conclusions: Fingolimod produced a strong antiinflammatory response with substantial reductions in circulating lymphocytes in all treated subjects. However, this response was not accompanied by improvements in symptoms or cognition. These data suggest that fingolimod's target of S1P modulation and robust anti‐inflammatory actions may not mediate clinical benefits in schizophrenia.