Tuesday, May 13, 2008
By John Gever, Staff Writer, MedPage Today
Published: May 01, 2008
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.
GRONINGEN, The Netherlands, May 1 -- The antidepressant drug fluoxetine (Prozac) curbed progression of relapsing-remitting multiple sclerosis in a small placebo-controlled study, but the effect lasted only a few months, researchers here said.
After 16 weeks of double-blind treatment, patients taking 20 mg/day of fluoxetine showed significantly fewer new lesions in MRI scans compared with patients receiving placebo, reported Jop P. Mostert, M.D., of the University of Groningen, and colleagues, online in the Journal of Neurology, Neurosurgery, and Psychiatry.
Twelve of 19 fluoxetine-treated patients had no new gadolinium-enhancing lesions at the 16-week evaluation, compared with five of 19 in the placebo group (P=0.02), they said.
However, the treatment phase lasted 24 weeks, and most measures of disease activity showed no significant differences between the fluoxetine and placebo groups at the study's final evaluation.
Still, the researchers wrote, "the results of our exploratory trial are sufficiently encouraging to justify further studies with fluoxetine in patients with multiple sclerosis."
They recommended that future trials use a higher fluoxetine dose combined with immunomodulating drugs.
The study was prompted by in vitro research and animal experiments suggesting that fluoxetine can modulate the activity of astrocytes, a class of immune cells in the brain, working to elevate cAMP signaling in these cells.
Astrocytes are involved in antigen-presentation and are thought to play a role in multiple sclerosis. They also carry serotonin receptors and reuptake sites, suggesting that serotonin reuptake inhibitors such as fluoxetine could reduce their activity.
Dr. Mostert and colleagues recruited 40 patients with established relapsing-remitting or relapsing secondary progressive multiple sclerosis who did not have a depression diagnosis. The mean time from first MS symptoms was 11 years.
Patients had no contraindications for repeated MRI scans or recent history of corticosteroids or immunomodulating drug therapy.
Participants were evaluated clinically and with MRI scans at baseline and at treatment weeks 4, 8, 16, and 24. One patient in each group discontinued prematurely, leaving 19 in each group for efficacy analysis.
At week 16, the mean cumulative number of new gadolinium-enhancing lesions -- the study's primary endpoint -- was 1.21 among fluoxetine-treated patients and 3.16 in the placebo group (P=0.05).
In addition to the larger number of patients showing no new lesions at 16 weeks, fluoxetine treatment was also associated with a smaller number of total scans showing new lesions (24% versus 47%, P=0.03).
Impressive-seeming numerical differences between groups remained at week 24, but the statistical significance largely vanished.
For example, the mean number of new enhancing lesions at week 24 was 1.84 in the fluoxetine group and 5.16 in the placebo group (P=0.15).
In the fluoxetine group, 32% of patients showed no new enhancing lesions at week 24, versus 21% of the placebo group (P=0.71).
Mean cumulative volume of new lesions at week 24 was 124 mm3 in the fluoxetine patients and 398 mm3 in the placebo group (P=0.16).
The only significant difference at week 24 was in the number of scans showing new lesions (25% in the fluoxetine group, 41% of the placebo group, P=0.04).
The number of patients having exacerbations and the total number of exacerbations did not differ noticeably between the fluoxetine and placebo groups.
Significantly more patients in the fluoxetine group reported nausea (65% versus 30% in the placebo group, P=0.03).
Other adverse effects did not differ significantly between groups, although 55% of fluoxetine patients reported drowsiness compared with 30% of those taking placebo.
The researchers noted that their small sample size limited the study's ability to detect significant treatment effects.
Nevertheless, they concluded, the results support their hypothesis about the role of cAMP signaling in astrocytes and its effect on inflammatory activity in multiple sclerosis.
The researchers added that fluoxetine may have other beneficial effects relevant to multiple sclerosis. For example, other studies have suggested it may help ward off axonal loss by stimulating release of neurotrophic factors.
The study was supported by Multiple Sclerosis anders [sic]. The researchers declared no potential conflicts of interest.
Primary source: Journal of Neurology, Neurosurgery and Psychiatry
Mostert J, et al "Effects of fluoxetine on disease activity in relapsing multiple sclerosis: A double-blind, placebo-controlled, exploratory study" Journal of Neurology, Neurosurgery, and Psychiatry 2008; DOI: 10.1136/jnnp.2007.139345