Fluoxetine (Prozac) Temporarily Slows MS Progression

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

Source reference:
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

Fluoxetine Shows Promise in Multiple Sclerosis

News Author: Thomas S. May
CME Author: Laurie Barclay, MD

October 16, 2007 (Prague, Czech Republic) — Fluoxetine (Prozac) may help reduce the number of new brain lesions in patients with multiple sclerosis (MS), according to a study presented here at the ECTRIMS 2007: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis.

The study, which was conducted by Jop P. Mostert, MD, and colleagues at the University of Groningen, the Netherlands, shows a trend toward a reduction in new enhancing lesions with fluoxetine treatment in patients with relapsing-remitting or relapsing secondary progressive MS.

Why Fluoxetine?

Fluoxetine, a selective serotonin reuptake inhibitor, was approved by the US Food and Drug Administration in 1987 and is frequently prescribed for the treatment of various psychiatric disorders, including major depression. However, fluoxetine also has a number of immunomodulatory effects, and previous studies have indicated that it might be beneficial for patients with MS, Dr. Mostert said in his presentation.

One of these earlier studies, which was first presented at the 1997 Annual Meeting of the American Association of Neurology, showed that fluoxetine reduced disease activity in experimental autoimmune encephalomyelitis, the animal model of MS, Dr. Mostert noted. "Furthermore, psychiatrists already reported in 1991 reduced MS in patients using fluoxetine," he added.

Previous research has also found that astrocytes in patients with MS lack beta-2 adrenergic receptors, and this leads to decreased cyclic adenosine monophosphate (cAMP) production, which in turn contributes to the initiation of the inflammatory cascade that eventually results in demyelination, Dr. Mostert explained. Because fluoxetine is able to increase the amount of cAMP in the astrocyte, the researchers hypothesized that the drug could help compensate for the loss of beta-2 adrenergic receptors and thus, reduce the amount of inflammation in MS.

Fewer New Lesions

To test their hypothesis, Dr. Mostert's team enrolled 40 patients (age 18 - 65 years) with relapsing-remitting or relapsing secondary progressive MS in a randomized, double-blind, placebo-controlled trial, with a duration of 24 weeks. Half of the patients were given fluoxetine (20 mg/day), whereas the remaining subjects received placebo.

The primary end point was the cumulative number of new gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (MRI) of the brain performed at weeks 4, 8, 16, and 24. Secondary outcome measures included changes in the Expanded Disability Status Scale (EDSS) and in the Multiple Sclerosis Self-Efficacy Scale (MSSE) from baseline to week 24.

The investigators found that the study drug was generally well tolerated, with only 1 patient dropping out because of adverse effects (nausea) in the treatment group. One patient also dropped out from the placebo group, leaving 19 completers in each group.

Regarding the primary end point, the results show that there was a trend toward a reduction in the number of new enhancing lesions in patients treated with fluoxetine. The mean (SD) cumulative number of new enhancing lesions during the 24 weeks of treatment was 1.84 (2.9) in the fluoxetine-treated patients and 5.16 (8.6) in the control subjects (P = .15).

At week 4, the cumulative number of new enhancing lesions was "quite comparable" in the two 2 groups, pointed out Dr. Mostert. He emphasized, however, that in the latter part of the trial, there was a steady increase in new lesions in the placebo group, while the number of lesions in the fluoxetine-treated patients remained relatively stable. Restricting the analysis to the last 16 weeks showed a "nearly significant" reduction in the cumulative number of new enhancing lesions and a higher number of patients without new enhancing lesions (63% vs 26%; P = .02).

Commenting on the study, session cochair Roland Liblau, MD, PhD, from Toulouse University Hospital in France, noted that the researchers used "a very interesting approach," because fluoxetine has a very good safety profile.

"It has been used in hundreds of thousands of patients, so we know it's safe," he told Medscape Neurology and Neurosurgery. "The possibility that it has even a slight effect in multiple sclerosis would be very interesting," he added. "The data showed a trend toward efficacy in MS, and I would strongly encourage further trials involving more patients."

This study was an investigator-initiated trial, with no pharmaceutical industry funding.

Medscape Medical News 2007. ©2007 Medscape


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Antidepressants Appear Ineffective in Relieving Depression in MS

Jacquelyn K. Beals

June 6, 2007 (Washington, DC) — A study of multiple sclerosis (MS) patients diagnosed with major depressive disorder (MDD) and/or dysthymia shows no relation between antidepressant use and improved outcomes.

A poster presentation here at the 21st annual meeting of the Consortium of Multiple Sclerosis Centers reported the results of a University of Washington study involving 96 MS patients enrolled in a trial investigating the value of exercise as a treatment for depression. Inclusion criteria for the study were a diagnosis of MDD and/or dysthymia based on the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV).

Investigators became aware that some subjects in the primary study were being treated with antidepressants and some were not. This offshoot study investigated the proportion of people with MS and MDD and/or dysthymia taking antidepressants and assessed behavioral variables associated with antidepressant use.

Celeste Hunter, from the Multiple Sclerosis Rehabilitation Research and Training Center, University of Washington, in Seattle, and an author of the poster, explained to Medscape that 1 of her colleagues noticed that although all patients in the study suffered from clinical depression, there appeared to be no discernible difference in terms of affect between patients who took antidepressants and those who did not.

"Depression is harder to pin down in patients with MS," Ms. Hunter said. "I see the MS patients as being more emotionally reactive in a given situation than if they didn't have MS. The unpredictability factor is so important — they don't know, if they have a really bad exacerbation, whether they'll get the same function back as before."

Almost half of the patients in this group (44%) were not taking antidepressants. Those on treatment were receiving various agents.

Patient-Reported Antidepressant Use

Treatment (%)
None 44.0
Fluoxetine 5.0
Citalopram 6.0
Bupropion 14.0
Venlafaxine 11.0
Sertraline 6.0
Other 14.0

Subjects were 85% female, 42.7% employed, and 91.7% white. Their Expanded Disability Status Scale scores were 4 or less in 52.1%, 4.5 to 6.0 in 45.8%, and 6.5 or more in 2.1%.

The researchers compared patients taking antidepressants (n = 54) with those not taking antidepressants (n = 42) — using the Hamilton Rating Scale for Depression, the Hopkins Symptom Checklist, the Modified Fatigue Impact Scale, item 8 of the Brief Pain Inventory, and the Expanded Disability Status Scale — and found no significant difference between the outcome scores of the 2 groups on any of these scales.

The authors concluded, "Because the study did not include people who were on antidepressants and not suffering from current MDD, our results may have been biased against finding improved outcomes associated with antidepressant use." Further studies in this area of MS treatment are needed, they added.

Kurt Johnson, PhD, a professor in the department of rehabilitation medicine at the University of Washington, but not an author of this study, commented to Medscape that there has not been much evidence in the MS literature that antidepressants are useful in treating depression. "We found the same thing in another study with a larger group of people. A lot of people in our sample were taking antidepressants when they weren't depressed, and a lot were depressed but were not taking antidepressants."

Higher Incidence of Depression

Medscape also talked with Stephen Kirzinger, MD, from the Multiple Sclerosis Care Center Program, Department of Neurology, University of Louisville, in Kentucky, about this poster. "Certainly we feel that patients who have a chronic disease can develop a reactive depression, but in the MS population the incidence is much greater than what you would expect, comparing it with other chronic-disease processes," said Dr. Kirzinger. "So we feel it is a manifestation of the disease that our patients, because of their MS activity, actually have a chemical change that leads to depression."

The antidepressants listed by patients participating in this study are serotonin reuptake inhibitors. Dr. Kirzinger noted that some preliminary data have indicated that serotonin itself has a beneficial effect on the immune system. "I think the present study flies in the face of most of our clinical experience [in which] the patients who have depression seem to respond to antidepressants. The fact that they did not see a dramatic difference between those on antidepressants and those not taking antidepressants is a little surprising."

This study was funded by the National Rehabilitation Research and Training Center on Multiple Sclerosis from the US Department of Education, National Institute on Disability and Rehabilitation Research.

Consortium of Multiple Sclerosis Centers 21st annual meeting: Abstract S110. Presented June 1, 2007.



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