A randomized double blind, placebo-controlled study of fluoxetine in progressive multiple sclerosis (FLUOX-PMS)

Based on the hypothesis that fluoxetine might suppress the antigen-presenting
capacity of glial cells we performed a pilot study in patients with relapsing
remitting MS and found that a daily dose of 20 mg tended to reduce the
formation of new inflammatory lesions.

The progressive phase of MS reflects a poorly understood insidious axonal
degeneration that is age related and independent of relapses. Currently
available disease-modifying treatments, which act by modifying the immune
response, are ineffective in progressive MS.

A mechanisms suspected to be involved in the widespread axonal degeneration in
MS is a reduced axonal energy metabolism and axonal glutamate toxicity.Proton
magnetic resonance spectroscopy has shown reduced levels of N-acetyl aspartate
(NAA), which is a marker of axonal mitochondrial metabolism, and enhanced
levels of glutamate 7 throughout the normal appearing white matter of the brain
in MS patients.

Astrocytes in MS are deficient in beta2 adrenergic receptors that are involved
in (1) the release of brain derived neurotrophic factor, and (2) astrocytic
glycogenolysis necessary for maintenance of sodium-dependent glutamate uptake,
and the release of lactate, which is an energy source for axons.

Fluoxetine might reduce axonal loss underlying the progressive phase of MS
because it stimulates glycogenolysis with lactate release and it enhances the
production of brain-derived neurotrophic factor in rodent astrocyte cultures.
We found that 2 weeks of treatment with fluoxetine (first week 20 mg/day and
second week 40 mg/day) significantly improved the cerebral white matter
NAA/creatine ratio, suggesting an improvement in axonal mitochondrial energy
metabolism.

We expect that in people with multiple sclerosis the processing of energy
substances such as sugars (energy metabolism)i n the brains is not optimal . In
our view this could explain the progressive deterioration of the disease.
Currently there are several therapeutic options for multiple sclerosis in which
there are surges (so-called relapsing remitting multiple sclerosis). For the
progressive forms without flares (so-called 'primary and secondary progressive
multiple sclerosis'), there is no treatment that slows the progression.
If we could improve the energy metabolism by administering medication, we
expect that this is a new way that might slow down the progressive
deterioration of multiple sclerosis.
A number of times fluoxetine has been shown to improve this chemical energy
metabolism in multiple sclerosis. With the present study, we will examine
whether this also leads to long term slowing of the progressive phase.

randomized double blind, placebo-controlled study

fluoxetine
placebo

Fluoxetine is a drug that used for over 20 years for the treatment of
depression. However, the body of evidence that fluoxetine could have protective
effects on nerve cellsis growing. As with all medication use, there is a risk
of side effects, but these are well known and usually minor. Most common side
effects include gastrointestinal symptoms, drowsiness and sleepiness at the
beginning of treatment, decreased libido, headache. The MRI brains hold no
radiation burden. There is also no use of radioactive materials or contrast
media.
It is possible that the study medication slows down the pathology of multiple
sclerosis and could therefore be an advantage , but because this that
advantage may not be guaranteed. For patients in the placebo group there is no
direct effect on the expected disease course.