Is failure of an arm of MS SMART on the cards?

Zhang T, Kingwell E, De Jong HJ, Zhu F, Zhao Y, Carruthers R, Petkau J, Gustafson P, Oger J, Tremlett H. Association between the use of selective serotonin reuptake inhibitors and multiple sclerosis disability progression. Pharmacoepidemiol Drug Saf. 2016 May 23. doi: 10.1002/pds.4031. [Epub ahead of print]

BACKGROUND:Benefits of selective serotonin reuptake inhibitors (SSRIs) in modifying the multiple sclerosis (MS) disease course have been suggested, but their ability to delay disability progression remains unknown. We examined the association between SSRI exposure and MS disability progression.
METHODS: A nested case-control study was conducted using the British Columbia (Canada) Multiple Sclerosis clinical data linked to health administrative data. The primary outcome was a sustained score of 6 (requires a cane to walk) on the Expanded Disability Status Scale (EDSS), and the secondary outcome was the onset of secondary progressive MS (SPMS, an advanced stage of MS). The cases were those who reached a study outcome and were matched with up to four randomly selected controls by sex, age, EDSS and calendar year at study entry using incidence density sampling. The associations between disability worsening and SSRI exposure were assessed with conditional logistic regression models, adjusted for confounders.
RESULTS:A total of 3920 patients were included in the main analyses, of which 272 reached sustained EDSS 6 and 187 reached SPMS. SSRI exposure was significantly different between patients who reached sustained EDSS 6 and controls [adjusted odds ratio (adjOR):1.44; 95% confidence interval (CI):1.03-2.01]. However, SSRI exposure was not significantly different between those who reached SPMS and their controls (adjOR:1.35; 95%CI:0.89-2.04).
CONCLUSION: We found no evidence to suggest that SSRI exposure was associated with a delay in MS disability accumulation or progression.

MS-SMART is a trial of three drugs verses placebo in the hope of slowing secondary progression. This study aimed to study ibudilast but a US group got their hands on it first and so it was dropped in MS-SMART, and replaced with Prozac.

The logic of how this (Fluoxitine) will work in progression has never really been presented by the SMART team.

In this analysis of a cohort of people with MS it indicates that more people with progressive MS take an SSRI (serotonin reuptake inhibitor, so it blocks break-down of serotinin, a neurotransmitter that limits depression). Is it that people take an SSRI to slow progression or is it that more people with progressive MS are depressed, which is more likely. The the data does not support the view that SSRI slows the accumulation for disability. 

Now this is observational rather than a trial and it must be said that the odds ratios of an influence are very large from 0.9 (No effect) to 2 (twice as good). MS-SMART will be the proof in the pudding, but maybe it does not bode well. 

Furthermore, non-use of an SSRI is going to be a condition of participation of MS-SMART, but as the target population is thus more likely to show depression and will be treated, it is going to make it more difficult to recruit to the MS-SMART trial. Therefore fluoxitine may not have been the best third choice.

I don’t wish to put you off the trial and if you are eligible you should consider this.


Even if you end up in the fluoxetine arm your mental health may be be improved and by being in a trial you generally do better due to the strong placebo effect.

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  • It is very important to participate in clinical trials with this.
    My gynecologist already cogitated the use of Fluoxetine as treatment of PMS.
    I know that 04 MSers start using Fluoxetine for treatment of anxiety…

    If Fluoxetine fail, even by analogy, the LDN also fail?

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