BACKGROUND: Suppressing the antigen-presenting capacity of glial cells could represent a novel way of reducing inflammatory activity in multiple sclerosis (MS). AIMS: To evaluate the effects of fluoxetine on new lesion formation in patients with relapsing MS. METHODS: In a double-blind, placebo-controlled exploratory study, 40 non-depressed patients with relapsing remitting or relapsing secondary progressive MS were randomised to oral fluoxetine 20 mg or placebo daily for 24 weeks. New lesion formation was studied by assessing the cumulative number of gadolinium-enhancing lesions on brain MRI performed on weeks 4, 8, 16 and 24. RESULTS: Nineteen patients in both groups completed the study. The mean (SD) cumulative number of new enhancing lesions during the 24 weeks of treatment was 1.84 (2.9) in the fluoxetine group and 5.16 (8.6) in the placebo group (p=0.15). The number of scans showing new enhancing lesions was 25% in the fluoxetine group versus 41% in the placebo group (p
=0.04). Restricting the analysis to the past 16 weeks of treatment showed that the cumulative number of new enhancing lesions was 1.21 (2.6) in the fluoxetine group and 3.16 (5.3) in the placebo group (p=0.05). The number of patients without enhancing lesions was 63% in the fluoxetine group versus 26% in the placebo group (p=0.02). CONCLUSIONS: This proof-of-concept study shows that fluoxetine tends to reduce the formation of new enhancing lesions in patients with MS.