Depression to reduce MS

Sacramento PM, Monteiro C, Dias ASO, Kasahara TM, Ferreira TB, Hygino J, Wing AC, Andrade RM, Rueda F, Sales MC, Vasconcelos CC, Bento CAM. Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4+ T cell subsets in multiple sclerosis patients. Eur J Immunol. 2018 May 2. doi: 10.1002/eji.201847525. [Epub ahead of print

Excessive levels of pro-inflammatory cytokines in the central nervous system (CNS) are associated with reduced serotonin (5-HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5-HT to modulate the T-cell behaviour of patients with multiple sclerosis (MS), a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5-HT attenuated, in vitro, T-cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients. Additionally, 5-HT reduced IFN-γ and IL-17 release by CD8+ T-cells. By contrast, 5-HT increased IL-10 production by CD4+ T-cells from MS patients. A more accurate analysis of these IL-10-secreting CD4+ T-cells revealed that 5-HT favours the expansion of FoxP3+ CD39+ regulatory T cells (Tregs) and type 1 regulatory T cells. Notably, this neurotransmitter also elevated the frequency of Treg17 cells, a novel regulatory T-cell subset. The effect of 5-HT in up-regulating CD39+ Treg and Treg17 cells was inversely correlated with the number of active brain lesions. Finally, in addition to directly reducing cytokine production by purified Th1 and Th17 cells, 5-HT enhanced in vitro Treg function. In summary, our data suggest that serotonin may play a protective role in the pathogenesis of MS.

In this study they found that serotonin (5-HT), which is the “happy” neurotransmitter that stimulates brain areas, may help animals with EAE. If this is true they we should have the answer quite soon as MS SMART has been using fluoxitine, which is also known as a prozac and is an SSRI (selective serotonin reuptake inhibitor) meaning that it induces more serotonin in the system….leading to less depression, but does it mean less Th1/Th17 and less MS.

“The objective of the Fluoxetine for Progressive MS study in Belgium and the Netherlands was to see if fluoxetine could slow the progression of MS. The trial (ECTRIM2016) covered both people with primary progressive MS and secondary progressive MS. Participants were divided into two groups. The 69 people in the first group received a 40 mg-per-day dose of fluoxetine (Prozac) for 108 weeks. The 68 people in the second group received a placebo.
Researchers found no significant difference in disease progression between the two groups”.

So is the idea a bad one or was it that the trial design meant that a sensible answer could not be found.

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  • May be a mixed method approach would work better, such as fluoxetine plus daily mindfulness or exercise.

  • Is it not unethical to do underpowered trials? Why waste the study participants time and the money doing the studies that can't provide a definitive answer?

  • 5-HT upregulates Treg and Treg17 cells and reduces cytokine production from Th1 and Th17 thus reducing active lesions. But the study with fluoxetine, reducing serotonin uptake and increasing its level in the system,failed to show any benefit on progression.

    How many trials will it take before researchers realize that that the pathology behind progression is different from active MS? Limiting pro-inflammatory cytokines leading to new lesions is not enough. Only half of the disease process is being treated. An anti-inflammatory and a molecule to promote restoration or protection from neurodegeneration is needed for progressive trials. It seems that research is repeating the anti-inflammatory trials on progression over and over hoping to get a different result.

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