Wednesday, 16 September 2015

Sertraline vs Fluoxetine



Steven and others…

I have been considering switching from Sertraline to Prozac.  I would appreciate your thoughts:   

Heres what I know based on what Steven has written on his web site.
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  • When sertraline was added to doxorubicin it resulted in increased chemosensitive over fluoxetine and doxorubicin.  This is apparently due to sertraline’s ability to impact efflux pumps better than fluoxetine.  I do not know if TMZ and doxorubicin are comparable with regards to benefits brought about by inhibiting efflux pumps.

  •    Prozac inhibits MGMT activity, sertraline does not
  •     Disulfiram inhibits MGMT activity

Then from CUSP9*:

  •  Sertraline blocks multiple survival pathways.  No mention of this is made with fluoxetine


So here are my questions:


  • If sertraline inhibits efflux pumps as does disulfiram, how important are PPI’s likely to be if both sertraline and disulfiram are already being utilized?

  • Since disulfiram already inhibits MGMT activity, in theory fluoxetine would not need to be used for this (ignoring the possibility of synergy for now).  And since both sertraline and fluoxetine inhibit efflux pumps, it seems sertraline might be better combined with disulfiram rather than fluoxetine and disulfiram because sertraline has the added benefit of blocking multiple survival pathways.  Do you agree with my thinking on this?
  • Fluoxetine does inhibit MGMT as does disulfiram and I suspect the synergy between the two could be beneficial, but since we are dealing with an IDH1 mutation, presumably most of the cells are MGMT methylated.  There would of course be other cells that are not methylated that could benefit from MGMT inhibition, but with disulfiram in the mix already, do I need to prioritize fluoxetine over sertraline because of this?  Or would the added benefit of blocking survival pathways be of more importance?  I realize there is no known answer to this and I am asking you to offer input lacking any data, but I am wondering if based on what you have read, this makes sense.
  • Jeremy is not willing to add a PDE5 inhibitor to his cocktail.  I think he has had his fill of drugs and supplements.  Does sertraline seem to improve BBB penetration? 


Thanks for the input!

7 comments:

  1. To begin with, I currently favor fluoxetine over sertraline based on the superior evidence. There has been not been even so much as a rodent study published with sertraline for gliomas. There have been two intracranial GBM mouse model studies published for fluoxetine, both showing efficacy.

    Both fluoxetine and sertraline inhibit the drug efflux pumps. We can't assume that sertraline is more effective at doing this based on a single study with doxorubicin. Every drug differs in its affinity for the various efflux pumps. And different cell lines may be more or less prone to using specific pumps than others.

    In my recent contact with one of the CUSP9 authors, he admits there is now a strong case to favor fluoxetine over sertraline. CUSP9 continues to evolve. I wouldn't be surprised to see fluoxetine replace sertraline at some point.

    To your questions:

    There is still no evidence that PPIs cross the blood-brain barrier sufficiently to do anything for brain tumors. But if they do, they have other mechanisms besides influence on the drug efflux pumps. Raising the pH in the tumor environment would be one beneficial effect not shared by the other drugs you mention. The question is whether or not one believes the PPIs can penetrate into the brain sufficiently.
    The jury is still out on PPIs for brain tumors. All the evidence is from non-central nervous system cancers.

    I do differ on the second point. Fluoxetine blocks multiple pathways too, but in vitro evidence tells you very little about how a drug will behave in the body. Sertraline has never been tested in vivo for brain tumors as fluoxetine has.

    The jury is still out on disulfiram as far as how much can get into the brain. I would have more confidence in Keppra and fluoxetine to inhibit MGMT, just due to the fact that they are central nervous system drugs that we know do get into the brain.

    I agree that fluoxetine may not be as beneficial for IDH1 mutant tumors (which are mostly MGMT-methylated) or for MGMT-methylated GBM. However this is not the only in vivo mechanism of action identified for fluoxetine.

    My sense is that you would probably find that fluoxetine inhibits just as many pathways as sertraline in vitro. But this means little until you can show that this is also the case in vivo, at drug doses that don't cause the animal to become sick from drug toxicities.

    See the following study for another possible mechanism of fluoxetine. Note that fluoxetine in this study was almost as effective as TMZ in an intracranial xenograft model with modest oral doses. This is an order of magnitude better evidence than anything we've yet seen for sertraline in GBM studies.

    http://www.ncbi.nlm.nih.gov/pubmed/25671301

    I'm not against sertraline, nor do I think it couldn't be as effective as fluoxetine in vivo. It's just that the evidence for that does not yet exist.

    There is no evidence that sertraline or fluoxetine improve BBB pentration per se, but as both are inhibitors of the drug efflux pumps that are very active at the blood-brain barrier, I speculate that either of these drugs could potentially improve BBB penetration of various drugs that are significant substrates for those pumps. Whether that applies to temozolomide remains to be seen.





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  2. And as always Mike, thank you for asking such pertinent and probing questions!

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  3. "Sertraline has never been tested in vivo for brain tumors as fluoxetine has."

    Or if it has, it was not published.

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  4. Thank you Steven. As always, your input is extremely helpful.

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  5. Steven

    The dosing schedule you have listed is a typical dosing schedule for prozac. Since it takes several weeks for full benefit, the recommendation is to start at 20 mg/d and increase as need in several weeks. Having said that, can you extrapolate from what research there is, whether lower doses look like they are effective, or higher doses are required?

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  6. According to the data that I have, a 10 mg/kg dose of fluoxetine in a mouse would lead to plasma levels equivalent to a ~30 mg per day dose in a human. But that is an approximation. 20-40mg per day would be about right.

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  7. I tried Prozac for a few weeks and started getting rather depressed and generally un-motivated. It might not have been the Prozac as I am aggressively pursuing a multi-drug cocktail. But Prozac was implicated and I switched to sertraline. I’ve been on sertraline for a few weeks now and feel better. In the final analysis, it might not matter much what looks best on paper as you might not like the side effects. But its good to have choices. - Seth

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