Anti-depressant for Progressive MS: can mice go to man?

Can we modify the course of progressive MS with anti-depressants? 

Faissner S, Mishra M, Kaushik DK, Wang J, Fan Y, Silva C, Rauw G, Metz L, Koch M, Yong VW. Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic. Nat Commun. 2017 Dec 19;8(1):1990. doi: 10.1038/s41467-017-02119-6.

The treatment of progressive MS is unsatisfactory. One reason is that the drivers of disease, which include iron-mediated neurotoxicity, lymphocyte activity, and oxidative stress, are not simultaneously targeted. Here we present a systematic screen to identify generic, orally available medications that target features of progressive MS. Of 249 medications that cross the blood-brain barrier, 35 prevent iron-mediated neurotoxicity in culture. Of these, several antipsychotics and antidepressants strongly reduce T-cell proliferation and oxidative stress. We focus on the antidepressant clomipramine and found that it additionally inhibits B-lymphocyte activity. In mice with experimental autoimmune encephalomyelitis, a model of MS, clomipramine ameliorates clinical signs of acute and chronic phases. Histologically, clomipramine reduces inflammation and microglial activation, and preserves axonal integrity. In summary, we present a systematic approach to identify generic medications for progressive multiple sclerosis with the potential to advance rapidly into clinical trials, and we highlight clomipramine for further development.

Clomipramine, is a tricyclic antidepressant (TCA) that blocks seratonin re-uptake. Common side effects include dry mouth, constipation, loss of appetite, sleepiness, weight gain, sexual dysfunction, and trouble urinating, which are indicative of an anti-cholinergic (block acetyl-choline nerve transmitter) effects. Serious side effects include an increased risk of suicidal behavior in those under the age of 25, seizures, mania, and liver problems. If stopped suddenly a withdrawal syndrome may occur with headaches, sweating, and dizziness.

Clomipramine is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system. This study took the view that iron deposition and nerve death was a central problem and screened drugs for their potential to block iron-induced nerve death. The compounds could block microglial activity. They searched for things that block T and B cell activity too.

They found effects in excess of the human peak blood concentrations and found doses that completely inhibited EAE, and so stopped one finding cytokines produced by cells that would not be present as there was no disease. 

However the drug accumulated in the CNS, so we will wait and see what happens when it is tried in man.

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  • More evidence of the way MS is viewed by the drug industry establisment:
    "We don't care about the origin of MS, we are blindly testing any substance available, hoping to get a new drug licenced. The cause of MS is irrelevant to us, we don't need it to hold a career or/and get rich. We are forced to make MS-relevant assumptions only because we are supposed to provide a rationale for the way our drugs act on receivers. We are not interested in finding out the real MS-pathology. We are happy with the current theories and their half-knowledge, since they allow unlimited research. In fact, we prefer MS to remain of unknown etiology for a long time in the future."

    • Doubt it. They just volume up their confirmation bias. Drug trials are always done within a predefined set of basic assumptions. These assumptions are never questioned. Surely not by the trial results. Therefore, MS research will beat about the bush for many more decades.

    • Hey MD2, here is another research that fails to find abnormal immune involvement in MS brains:

      "Altogether, our data support the noninflammatory nature of C3d+ microglial clusters, pointing to the possibility that they are involved in the physiological removal of irreversibly damaged axons."

      Doesn't change your views, does it?

    • Hi VV
      Funnily enough I'm putting together a grand theory on this very subject at the moment, tying in B/Plasma cells and microglia so thanks for the link, which certainly fits with my theories on progression. Watch this space!

  • How would anti-cholinergic be related to Alzheimer's development, or is a 3rd generation anti-cholinergic?

    I ask this because the risk of the development of the AD seems to involve the Clemastine.

  • They shown significant T-cell supression .. so is it safe for those with lymphopenia or after alemz or otherwise immunocompromised?

  • Reckon that back in the days BP (before Prozac) so many pwMS would have taken an older tricyclic (eg amitriptyline, clomipramine, imipramine) for depression that it would have surely been noticed if people taking them generally did better than those who didn't. Especially considering high doses needed for antidepressant effect.

    A bit of history for fun on Friday evening:
    Imipramine (Tofranil) was the first tca in 1957. Fluoxetine (Prozac) hit the market (and drug budgets, earning Eli-Lilly a fortune) in 1986. Doctors were loathe to continue with the cheaper (and highly effective) TCAs when SSRIs so much safer in overdose and free from anticholinergic side effects. I remember drug reps scaring the life out of GPs should they continue to Rx TCAs and have a suicide on their hands. Prozac was £30 a box, TCAs were a few pence 😉

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