Abstract
BackgroundCurrently available disease-modifying treatments acting by modifying the immune response are ineffective in progressive multiple sclerosis (MS), which is caused by a widespread axonal degeneration. Mechanisms suspected to be involved in this widespread axonal degeneration are reduced axonal energy metabolism, axonal glutamate toxicity, and reduced cerebral blood flow. Fluoxetine might theoretically reduce axonal degeneration in MS because it stimulates energy metabolism through enhancing glycogenolysis, stimulates the production of brain-derived neurotrophic factor, and dilates cerebral arterioles. The current document presents the protocol of a clinical trial to test the hypothesis that fluoxetine slows down the progressive phase of MS.Methods/DesignThe FLUOX-PMS trial is a multi-center, randomized, controlled and double-blind clinical study. A total of 120 patients with the diagnosis of either secondary or primary progressive MS will be treated either by fluoxetine (40 mg daily) or placebo for a total period of 108 weeks. The primary endpoint is the time to confirmed disease progression defined as either at least a 20% increase in the timed 25-Foot Walk or at least a 20% increase in the 9-Hole Peg Test. Secondary endpoints include the Hauser ambulation index, cognitive changes, fatigue, magnetic resonance imaging of the brain, and in a small subgroup optical coherence tomography.DiscussionThe FLUOX-PMS trial will gives us information as to whether fluoxetine has neuroprotective effects in patients with progressive MS.Trial RegistrationEudra-CT: 2011-003775-11
Highlights
Available disease-modifying treatments acting by modifying the immune response are ineffective in progressive multiple sclerosis (MS), which is caused by a widespread axonal degeneration
Fluoxetine is mainly indicated for the treatment of mild-to-moderate depression, but the drug has potential pleiotropic neuroprotective effects [24]
Some aspects of the trial need clarification. Because it may take several weeks before a steady state of fluoxetine level in blood and brain is achieved [25], progression is measured from the second visit at 12 weeks, and not from start of the trial
Summary
Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease and is considered the most important non-traumatic cause of neurological disability in young adults. Fluoxetine activates PKA in astrocytes [12], and might compensate for the astrocytic ß2 adrenergic receptor deficiency Based on this hypothesis 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 on magnetic resonance imaging (MRI) of the brain [13]. Mechanisms proposed to be involved in the progressive axonal degeneration in MS are reduced axonal energy metabolism, axonal glutamate toxicity, and reduced cerebral blood flow [14,15,16] This might be mediated by astrocytic dysfunction, associated with reduced astrocytic ß2 adrenergic receptors [11]. In addition the difference between the progressive types is not always clear cut and often arbitrary as subjects with primary progressive MS can experience relapses
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