Posted by Marty on July 29, 2008, at 14:54:51
An integral copy of my letter to Dr.Ken Gillman, an expert of the 'Serotonin Syndrome'. I thought it could interest the other 'amateur psychopharmacologist' of PBabble.. When he reply back for the second time I'll post his reply IF he gives me his permission.
------Dr Ken Gillman,
Thank you for your reply. If you don't know very much about the VERY atypical Tianeptine, like the majority of the clinicians and searchers, you're obviously appalled by my question. I'll expose you the rationale behind my hypothesis on the basis that the 5 minutes it will take you to read and digest cannot possibly bore you: Either it will entertain your intellect or will make you laugh out loud. Both outcomes being possibly pleasurable and healthy ...
--- Hypothesis: Tianeptine being consistently demonstrated to ENHANCE 5-HT reuptake rather than INHIBIT it, could it prove itself significantly useful in the treatment of Serotonin Toxicity when co-administrated with known helpful agent?--- Tianeptine primer:
Tianeptine is an atypical TCA which has been demonstrated consistently to -facilitate- rather than retard the SE reuptake. While the mechanism by which it reduce synaptic 5-HT concentration is disputed, no study ever disputed the fact that both acute and chronic administration of Tianeptine increase the concentration of 5-HIAA which is the major metabolite of SE formed by oxidation mediated by MAO-A. This effect can be observed less than an hour after oral administration. Theorized mechanism of action of this effect include increased SERTs and increased VMax (transport capacity) of the SERTs. Other theories and studies dispute any role of SERT in this effect and role of MAOs has been quickly discarded and never revisited. For an interesting primer on Tianeptine may I suggest you Dr.Sheldon Preskorn 2004 paper "Tianeptine: A facilitator of the reuptake of Serotonin and Norepinephrine as an Antidepressant?" published in the Journal of Psychiatric Practice. Full paper URL: http://www.tianeptine.com/stablon-tianeptine.html
Also while Pubmed search engine does a perfect job of referring you paper discussing Tianeptine, http://tianeptine.com/refs/index.html contains a long list of abstracts that are nicely indexed. Also of specific interest:
--- Rationale:1. Tianeptine restore SE reuptake activity level when administered after an SRI and dose-dependently nullify the SRIs synaptic increase of 5-HT concentration and so could be considered an SSRI antidote. This has been consistently demonstrated by an increased 5-HIAA concentration and an abolition of SSRI antidepressant effect.
The majority of Serotonin Toxicity/Syndrome being caused partly by an SSRI taken with another serotonergic agent, it makes sense theorically that by acutely administrating a fast acting agent capable of quickly nullifying the effect of at least one of the drug implicated into the toxicity could be of great help.
In cases where it couldn't nullify the serotonergic effect of one of the culprit, by example Clorgiline + Amphetamine (no SRI), it would reduce the synaptic 5-HT receptors soaking by accelerating recapturing of SE and allow the uninhibited MAO-A to be more efficient in breaking down SE (less 'downtime').2. While Tianeptine significantly reduce 5-HT synaptic concentration even at recommended human dosage of 12.5 mg, Tianeptine can be safely administrated at much higher dosage and so could theorically be acutely administrated for Serotonin Toxicity at a dosage way higher than the common prescription for his currently approved indication. A quick pubmed search about Tianeptine abuse reveal a couple of cases where the usual 12.5 mg TID dosage were greatly exceeded for many months without any significant health issues or sequel. One such report, by example, talk of a 34 year-old patient who took 750 mg per day for a whole year.
Another talk about a 24-year-old patient who also abuse Tianeptine for a year:
"The biological tolerance was excellent, and hepatic parameters were not affected."
This young person escalated to 3000 mg per day without problems. While it hasn't been studied at this dosage in human, we can hypothesize that if the 5-HT reuptake acceleration induced at normal dose of Tianeptine isn't enough to be worthy in the treatment of Serotonin Toxicity such higher dosage could be effective.3. In order to merit any credibility, this hypothesis should address his most profound weakness and evaluate if it nullify any interest one could have in pursuing it into the laboratory: 5-HIAA increased concentration induced by Tianeptine indicate that, while it may or not be dependant somehow of SERTs, it surely depend at some level on MAO-A. Serotonin Toxicity being often induced by irreversible MAOI having potent MAO-A inhibition effect, is his usefulness in MAOI induced toxicity rendered insignificant by this fact ? I think even in those case it could significantly help even if it doesn't help at the same level as, by example, a case of SSRI + high-dose 5-HTP supplements + Dextromethorphan where MAO-A isn't inhibited and ready to breakdown the serotonin transported(reuptaken) more quickly because of Tianeptine. I think an agent capable of optimizing the usage of the working 10% MAO-A Clorgiline didn't inhibited, accelerating the 5-HT breakdown and attenuating the 5-HT toxicity by reducing the serotonin soaking the 5-HT receptors are forced to endure IS of significance. Many drugs in this world have a lesser beneficial effect (and a much higher risk/benefit ratio!) that Tianeptine would have even in those cases and I don't even talk about how way less urgent the health issue they are treated with are compared to a Serotonin Toxicity crisis!
- Details of interest: Heavy MDMA users commonly reports that Tianeptine is the only antidepressant that helped them. Interestingly Tianeptine reduce MDMA toxicity. Would Tianeptine be effective in reducing the neuronal damage/inconvenient plasticity events happening during a Serotonin Toxicity crisis ?
Dr.Gillman, is that hypothesis so stupid that it justify the fact that there is not even
-ONE- study validating/invaliding/evaluating/discussing Tianeptine potential in the treatment of Serotonin Toxicity ? It's -obvious- Tianeptine couldn't be used alone in the treatment but added to a cocktail comprising Chlorpromazine, Cyproheptadine and non-serotonergic benzos may well be an evolution in the treatment of Serotonin Toxicity.I feel this potential has not only been overlooked but, in fact, not looked into at all. There is no other drug known to reverse the 5-HT soaking effect of SSRI and better does it safely, quickly and elegantly (directly and specifically undo what SSRI do without their respective mechanism of action actually 'clashing' in each other), in short the only AND good SSRI antidote AND YET THERE WOULD BE NO PLACE FOR IT IN THE TREATMENT OF, AT LEAST, SSRI IMPLICATED SEROTONIN TOXICITY ?
I think -AT LEAST- a serious, small scale, rodent based (or any good serotonin toxicity non human model) should be warranted.
Again thank you for your time.I wish I had the energy and time to supply you direct references in my quickly drafted exposé of my hypothesis but if you find it interesting I'll be glad to find you all the sources backing the claims. I wish I had keep them all while studying this interesting drug but élas...
If nobody had the audacity and curiosity to check upon Freud shoulder, we wouldn't have cocaine as an ocular anaesthetic today and all it would do for us even in 2008 would be to make sad self-medicated people nose bleed.
If this hypothesis has been overlooked I wish you'd be the one to make sure that all the Freuds of our time didn't pass by that one.
Cordially,
Marty.
poster:Marty
thread:842866
URL: http://www.dr-bob.org/babble/20080727/msgs/842866.html