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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Think herbal supplements are safe?

People are mixing supplements, herbs and over-the-counter medications and prescription drugs to cure themselves of ills, unaware that they could be making themselves sicker, says George Grossberg, M.D., director of the division of geriatric psychiatry at Saint Louis University.

Dr. Grossberg is about to change all that. He is the co-author of a new book, "The Essential Herb-Drug-Vitamin Interaction Guide," which is a comprehensive listing of what various herbs and supplements do, possible side effects and how they might interact with other medications and foods.

"People think if it doesn't require a prescription, it's got to be safe, and that's not true. There could be life-thr eatening effects."

Dr. Grossberg first became interested in the topic after a routine six-month visit with a patient he had successfully treated for depression. He had been seeing the patient for four or five years, and asked if the man was dealing with any new health problems.

The patient mentioned that he was scheduled to go in for cystoscopy in a couple weeks because there had been blood in his urine. The procedure involves inserting the pencil-thin tip of a probe through the urethra, up to the bladder to detect the cause of the problem.

The patient had undergone thousands of dollars of MRIs and CAT scans of his lower abdomen and pelvis, which had not revealed the reason for the bleeding, and the test was the next diagnostic step.

Dr. Grossberg asked if the patient had changed anything – perhaps had started taking a new medication.

No new medicine. Then the patient's wife pulled from her purse a vial containing a supplement she had purchased from the health food store to enhance memory. Both husband and wife had started taking the herbal memory enhancer, which largely contained ginkgo biloba.

"One of the side effects of ginkgo biloba is an increased risk of bleeding. He had no awareness of this. I told him to stop taking the herb and get rechecked before having cystoscopy. The bleeding stopped, and he didn't need the test."

Dr. Grossberg ticks off other common herbs that people take without realizing their side effects or how they might interact with medications.

St. John's wort sometimes is taken for anxiety and depression. Those who also are taking antidepressants or anti-anxiety medications, such as Prozac, Zoloft or Paxil, should beware. Mixing St. John's wort with these medicines can cause serotonin syndrome -- with symptoms that may include agitation, rapid heart beat, flushing and heavy sweating -- that may be fatal.

Dong quai, which some women take for menstrual disorders and to ease symptoms of menopause, has been linked to cardiovascular problems, such as irregular heart rhythm and low blood pressure. If a patient takes the herb along with an antihypertensive drug, her blood pressure could plummet, putting her at risk of stroke.

Some people take echinacea, which enhances the immune system, for the common cold. However, those who also take Lipitor, Celebrex and Aleve face an increased risk of liver damage. Echinacea also can be harmful for those who have multiple sclerosis, diabetes, HIV infections or allergies.

Dr. Grossberg and his co-author Barry Fox make it clear that they're not anti-herb or anti-medicine.

"There just are a lot of things people can take that have a lot of bad interactions. And on some level it makes sense for them to think that what they're doing is safe. They associate natural remedies with nature and think if the supplement wasn't safe, they couldn't pick it up without a prescription.

"Hopefully this will get them to think more about it so they look before they leap. People can look up what they're thinking of taking and see if there's efficacy. And they should always talk to their doctor about everything they're taking."

Many doctors don't know much about herbal remedies, which have been used as medications for thousands of years.

"When I trained, there was nothing like this in our medical education," says Dr. Grossberg, who graduated from medical school in 1975. "The younger doctors are more likely to know this than older doctors."

Elderly people, he says, use herbal remedies and don't always tell their doctors and pharmacists. They should.

"A lot of our older patients are buying herbals and botanicals. In addition, while those over 65 represent about 14 percent of the population, they consumer 40 percent of over-the-counter medications," he says.

The book, published by Broadway Books, a subsidiary of Random House, is being released in mid-April.