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Preliminary Study Shows Prozac®
Holds Promise As A Treatment Option

Ute Traugott, M.D.

(Reprinted from the Multiple Sclerosis Quarterly Report, Volume 17, Number 3, November 1998, a publication of the United Spinal Association).

In the past few years, considerable progress has been made in the treatment of Exacerbating/Remitting Multiple Sclerosis (MS). Betaseron®, Avonex®, and Copaxone® can decrease the exacerbation rate by about one-third.

Encouraged by these results, researchers have looked further to ask whether a combination of two of these new medications or of one of them with another, preferably an oral ImmunoSuppressive drug, could be even more effective in slowing down the progression of the disease.

As of this date, however, no conclusive data are available regarding the effect of such combination regimens.

The approach of combining different medications to increase their beneficial effects and, at the same time, limit their side effects is not new and is routinely used.

The following report indicates that Fluoxetine (Prozac®) might be considered in some sort of combination therapy.


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Why Fluoxetine?

While following MS patients treated with Fluoxetine for Depression, I noticed that some showed not only the expected improvement in their depressive symptoms, but also seemed to stabilize with respect to their MS-related Neurological problems.

Because I had not observed a similar beneficial effect on Neurological signs in patients treated with other AntiDepressive medications.

I considered the possibility that Fluoxetine may have an ImmunoSuppressive effect and, thus, could be of benefit for the treatment of MS.

Fluoxetine belongs to a new class of AntiDepressive medications that are called "Selective Serotonin Re-uptake Inhibitors" (SSRIs).

SSRIs modulate the biologic effect of Serotonin, which is decreased in the Brains of patients suffering from Depression.

Serotonin is also essential for the development of an effective Immune Response. Researchers have shown that depletion of Serotonin in animals leads to ImmunoSuppression.

With MS, changes in Serotonin levels induced by Fluoxetine may interfere with the development of inflammatory lesions and thus, help stabilize the disease process.


Why Animals?

Most new MS medications are first tested in animals, in this case mice, with an MS like disease to see whether they are effective before testing with persons with MS.

The animal model used in this experiment is called Experimental Allergic EncephaloMyelitis (EAE).

EAE can be induced in mice and other animals by injecting an emulsion containing White Matter from the Central Nervous System and complete Freund’s adjuvant (CFA - substance that enhances Immune Responses).

Mice injected with this emulsion develop Neurologic signs that, similar to MS, show spontaneous exacerbations and remissions or Chronic progressive worsening.

Microscopic studies of the CNS have shown considerable similarities between MS and EAE lesions.

With the help of this animal model, researchers have studied in detail how DeMyelinating lesions develop in the CNS and what lesions of different ages look like in MRI scans.

EAE models have also been used to evaluate the therapeutic effects of some drugs.

Thus, the disease-modulating effect of Copaxone® (Glatiramer Acetate for injection) was established in EAE models before it was tested in clinical trials with MS patients.

In animal experiments, there is also no need to test the experimental drug in combination with one of the new medications (Betaseron®, Avonex®, or Copaxone®) against the effect of one of the new drugs alone.

Such combination treatment is appropriate in clinical trials to ensure that MS patients are not deprived of the documented therapeutic effect of an approved drug.

In addition, treatment trials in animals make it possible to examine CNS tissue samples from both treated and untreated groups for differences in numbers of active and inactive lesions.

Thus, testing a new drug in an animal model can provide faster, more detailed, and more reliable information as to its potential ImmunoSuppressive effect and possible side effects than can be obtained from clinical trials with humans.

Although promising results in animal studies do not guarantee a similar beneficial effect in humans, they can serve to screen new medications before they are tested in clinical trials.


How Was the Effect Evaluated?

To study whether Fluoxetine can modulate disease progression, Chronic Relapsing EAE was introduced in 20 mice.

Within one week of onset of Neurologic signs, Fluoxetine treatment was started in 10 of the mice and administered daily thereafter throughout the period of the experiment.

Another group of 10 mice with Chronic EAE was not treated, so that the severity of the clinical signs and spontaneous disease progression could be ascertained.

To determine whether Fluoxetine had a beneficial effect in Chronic EAE, progression of Neurological Signs, inflammatory lesions in the Brain and Spinal Cord.

And, Serum Cytokine levels were studied and the results for the groups of untreated and treated mice with Chronic EAE were compared.


Fluoxetine-Treated Mice Did Better

To evaluate the effect of Fluoxetine on Neurologic signs, disease progression in untreated and treated groups of mice with EAE was compared.

To evaluate disease progression, mean values (averages) were determined for all neurologic scores of untreated and treated groups of mice before and after the day treatment was started.

Then, the differences between the mean values before and during treatment for the experimental group were calculated.

The differences were used to reflect disease progression. Before treatment, disease progression was somewhat more pronounced in the Fluoxetine-treated group (1.96) than in the untreated group (1.63).

During treatment, disease progression was significantly lower in Fluoxetine-treated mice (0.61) than in untreated control mice (1.73).

The beneficial effect of Fluoxetine on disease progression was also reflected in lower numbers of inflammatory lesions in treated mice compared with untreated controls.

While microscopic examination of Brain and Spinal Cord sections showed large inflammatory lesions and considerable Immunologic abnormalities of Glial Cells and Endothelial Cells (inner lining of Blood vessels) in the control mice.

In tissue samples from Fluoxetine-treated mice, only low numbers of Inflammatory cells and minor abnormalities of Glial Cells and Endothelial Cells were observed.

In Serum samples, concentrations of InterLeukin-4 (IL-4) and Transforming Growth Factor-ß (TGF-ß) (soluble factors produced by white blood cells that can suppress inflammation) were higher.

And, concentrations of InterLeukin-2 (IL-2) & Interferon-gamma (IFN-gamma) (soluble factors that can increase inflammation) were lowered in Fluoxetine-treated mice than in untreated mice.

These differences in Cytokine levels showed that Fluoxetine can have an ImmunoSuppressive effect.

The findings from this animal study show that Fluoxetine can slow down disease progression, reduce the number of inflammatory lesions in the Brain and Spinal Cord.

And, promote the production of Cytokines such as IL-4 and TGF-ß over IL-2 and IFN-gamma.

The higher levels of IL-4 and TGF-ß observed in Fluoxetine-treated mice suggest a switch in the Immune Responses from one that favors the development of inflammatory lesions to one that facilitates the production of AntiBodies (Th2), which do not seem to have an adverse effect in this disease.

Ongoing studies are evaluating whether increased levels of IL-4 and TGF-ß can be detected in Serum from MS patients taking Fluoxetine for the treatment of Fatigue or Depression.

Changes in Cytokine levels similar to those observed in Fluoxetine-treated mice, together with the promising results from this study on EAE, would further encourage clinical trials on MS patients.


References:

1. Traugott, U. and Velia Trego:
Fluoxetine greatly inhibits disease progression in Chronic Experimental Allergic EncephaloMyelitis (EAE) in SJL/J mice
Neurology 48: A 422, 1997

2. Ute Traugott:
Detailed analysis of ImmunoModuloatory properties of Fluoxetine (Prozac) in Chronic Experimental Allergic EncephaloMyelitis in SJL/J mice
Neurology 50: A 105, 1998



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