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Title: Fluoxetine for Relapsing Multiple Sclerosis: Presented at ECTRIMS

"Fluoxetine for Relapsing Multiple Sclerosis: Presented at ECTRIMS"

By Chris Berrie PRAGUE, CZECH REPUBLIC -- October 18, 2007 --The selective serotonin reuptake inhibitor fluoxetine is well tolerated and shows radiological efficacy in patients with multiple sclerosis (MS), according to a randomized, double-blind, placebo-controlled study presented here on October 13 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Although already frequently prescribed for treatment of depression, obsessive-compulsive disorder, bulimia, and panic disorder, a number of developing lines of evidence have suggested that fluoxetine could be a candidate for treatment of MS. Coinvestigator Jop P. Mostert, MD, Neurologist in Training, Department of Neurology, University Medical Centre, Groningen, The Netherlands, the main hypothesis for efficacy of fluoxetine in MS arises from the depletion of beta2-adrenergic receptors on astrocytes, which results in a reduction in their cyclic adenosine monophosphate (cAMP) signaling. "By increasing the amount of cAMP in the astrocytes, [fluoxetine] reduces the antigen presenting capacity of astrocytes and thus reduces the amount of inflammation in multiple sclerosis," Dr. Mostert said. Fluoxetine has been implicated in other potentially neuroprotective pathways, including decreases in lymphocyte proliferation and suppression of interferon-gamma production in human lymphocyte suspensions; increases in production of neurotrophic factors, increases in glycogenolysis in astrocytes; and blocking of sodium channels. In addition, fluoxetine has been seen to reduce inflammatory activity, and psychiatrists have reported reduced MS activity in patients using fluoxetine. Thus, Dr. Mostert and colleagues investigated more directly fluoxetine's potential in the treatment of MS. The study included patients with confirmed relapsing-remitting (RR) or secondary progressive (SP) MS with exacerbations (one in the last year, or two in the previous 2 years, or one Gd-enhancing lesion on magnetic resonance imaging [MRI] screening). Patients had an Expanded Disability Status Scale (EDSS) score of 0 to 6, and did not receive prior immunomodulating therapy in the previous 24 weeks. Of the 65 patients screened by MRI, 20 patients were randomized to placebo and 20 to fluoxetine 20 mg/day, for 24 weeks. Mean age of patients was 38 and 41 years, respectively (male, 47% and 47%). The primary outcome was for the cumulative number of new Gd-enhancing lesions. Cerebral MRI scans were taken 4 weeks before the start of treatment and at weeks 0, 4, 8, 16, and 24. Clinical evaluations were done at baseline and 24 weeks. Baseline clinical characteristics across the placebo and active treatment groups were not significantly different for: mean disease duration (11 vs 11 years); disease course (RRMS/SPMS, 18/1 vs 16/3); median exacerbations in previous 2 years (2 vs 2); median EDSS (3.0 vs 3.0); mean number of new Gd-enhancing lesions (0.63 vs 0.58); mean T2 lesion load (4761 vs 5521); and scans with enhancements (7 vs 8). Despite a 64% decrease in the cumulative number of new lesions in the fluoxetine group, there was no significant difference between placebo and active treatment (means, 5.16 vs 1.84; [P =.15).

There were trends in favor of fluoxetine for cumulative volume of new Gd-enhancing lesions (median, 77 vs 22 mm³; P =.16), change in T2 lesion load (median, 475 vs 128; P =.10), and scans showing Gd-enhancing lesions (33 vs 22; P =.06). Significant benefit for fluoxetine was reached for scans showing new Gd-enhancing lesions (31 vs 19; P =.04).

"It is interesting to note that it takes several weeks for plasma levels of fluoxetine to stabilize," Dr. Mostert said. This was seen on reanalysis of the last 16 weeks (2 scans) of the secondary outcome trends. Here, the cumulative number of new Gd-enhancing lesions almost reached significance (3.16 vs 1.21; P =.05), and significance was reached for both the number of patients with no new Gd-enhancing lesions (5 vs 12; P =.02) and the scans showing Gd-enhancing lesions (18 vs 9; P =.0).

Thus, while indicating that their small sample size was the main limitation of the study, Dr. Mostert noted the good tolerability of fluoxetine, the beneficial trends associated with its use, and the delay in their significance that matched with the known delay in stabilization of fluoxetine plasma levels.

In considering in particular the characteristics of fluoxetine as an oral agent that is affordable, well tolerated, and not known to have any long-term adverse effects, Dr. Mostert indicated that further studies on this agent are justified.

[Presentation title: A Randomised, Double-Blind, Placebo-Controlled Study of Fluoxetine for Relapsing Multiple Sclerosis. Abstract 86]

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