What an excellent week it has been for community submissions at This is MS. We started off the week with a great editorial by Finn, and now we have just received an outstanding article from our member Deb, aka "OddDuck." In it, she discusses the possibility that a drug called "desipramine"-- an antidepressant -- could be very useful as a treatment for MS.

She has performed an extensive amount of research and her theories are certainly intriguing. Please take some time to read through her thoughts and just as critically, to share your own. Your participation is crucial if we are to achieve our aim of ending MS, whatever the path. If you find the article far too technical, do not despair-- the main point is that there are people out there dedicated to outsmarting this disease and their work can benefit the entire community.

As always, do NOT begin any treatment without the consent of your doctor-- desipramine has an extensive side effect profile that must be seriously considered, particularly in terms of drug interactions which could cause severe harm.

Enough out of us, here is the article:

"I am on a mission of sorts. I have MS, and I have stumbled onto a medication (desipramine - which is an oral drug) that MAY help MS - not just symptomatically, but possibly via direct disease modification. I have examined literally thousands of individual laboratory research publications. All I can say is that I sincerely hope you will take the time to read my research findings, all of which I believe can be collaborated by medical
experts...

Although there are contradictory theories regarding the role of IL-1B in MS, desipramine appears to have proven mechanisms of action that inhibit IL-1B and TNFa, which thereby turns "off" cPLA2. It has been recently asserted that regulating or "turning off" cPLA2 promotes a preventative process with regard to myelin degradation, thereby possibly
halting MS disease and progression..."

Click "read more" to read the entire article, including her cover letter, the research narrative, and the response from the NMSS (it is actually quite neutral-positive, which we find refreshing given their view on LDN). Be forewarned that it is very technical-- a testament to the time and energy spent on this topic by Deb-- great job!

Full Article Text

Desipramine as a Treatment for Multiple Sclerosis
By Deb, aka OddDuck

I am on a mission of sorts. I have MS, and I have stumbled onto a medication (desipramine - which is an oral drug) that MAY help MS - not just symptomatically, but possibly via direct disease modification. I have examined literally thousands of individual laboratory research publications.

All I can say is that I sincerely hope you will take the time to read my research findings, all of which I believe can be collaborated by medical experts. To date, I have sent my findings to my own former neurologist (who comes from the Mayo Clinic and is a well-known PhD), to John Hopkins University/Hospital, to Aventis Pharmaceuticals, to the National Multiple
Sclerosis Society, and have provided a copy to my primary care physician. Additionally, some MS friends in Wisconsin with medical connections are also pursuing this to get someone's attention. So far, no one can or will tell me that I'm "wrong", which in itself tells me something. And the more research I do, (even to prove myself wrong), the more I find that substantiates my suspicions.

Several other research findings (such as Dr. Moses Rodriguez's findings regarding killer T cells; Sam David's, a McGill University Health Centre neuroscientist, recent article regarding cPLA2; Dr. Fridolin Sulser's recent pharmacological findings with regard to effects on immunotherapy; and recent findings from the University Hospital Groningen, Netherlands regarding norepinephrine and the pathogenesis of MS; to name a few) appear to uncannily back up my hypotheses and findings. A common "theme" appears throughout my research on MS, which brings me back to desipramine time and again.

I am including a copy of my most recent over-simplified narrative on my findings.

My goal is to bring all this to someone's attention to see whether a closer look can be given to mainly desipramine (levetiracetam is still undergoing active research), or for someone to tell me "why not"?

My research narrative and the response from the NMSS (copied directly below)
will explain all this more clearly. I sincerely hope you find the time to read it.

Thanking you in advance,

Deb

*********************
DESIPRAMINE AND MS

My intuition has been working overtime about desipramine and its possible effectiveness for MS. I recently found my personal "eureka" moment. I'm  going to outline what I've found as briefly as possible here. Believe me, I have gone over this a thousand times! I have plenty of substantive documentation for all of what I'm about to say that I have compiled, but I'm
betting you'll get the bottom line with this alone. This is over simplified, but here goes.

EUREKA moment: Although there are contradictory theories regarding the role of IL-1B in MS, desipramine appears to have proven mechanisms of action that inhibit IL-1B and TNFa, which thereby turns "off" cPLA2. It has been recently asserted that regulating or "turning off" cPLA2 promotes a preventative process with regard to myelin degradation, thereby possibly halting MS disease and progression. Norepinephrine interacts with and modulates adrenergic receptors. Inhibiting the reuptake of norepinephrine (via desipramine) helps to increase melatonin synthesis. This in turn also shows evidence of reducing the abnormal activation of cPLA2.

Desipramine also exhibits effects on LPS, again possibly proving beneficial for MS. Another valid hypothesis being that there may also be indication of desipramine's beneficial regulation of COX2. Desipramine exhibits TZD-like effects with regard to astrocyte and mitochondrial functioning (inhibition of IL-1B).

Inhibiting IL-1b helps to inhibit VCAM-1 expression, which in turn inhibits VLA-4 (which is the goal of Antegren). Inhibiting VLA-4 helps with the control of NK cells, which is one of the goals in helping MS. (Vitamin E helps to inhibit IL-6, which also assists in reducing VCAM-1.)

The reduction of IL-1B and TNFa by desipramine also appears to exhibit effects on PTX3. PTX3 is connected to innate immunity and can be a cause of inflammation. Reducing activation of PTX3 appears to assist with the control of NK and/or killer T cells, which might prove to be highly desirable in the treatment of MS.

Desipramine has been proven to enhance GAP-43 expression, which in turn promotes axonal and neuronal regrowth. As a side note, oleic acid is said to promote axonal growth together with the expression of the axonal growth-associated protein, GAP-43.

Desipramine has shown to beneficially modulate the immune system via effects on cellular GRs, T and B cells. Desipramine promotes anti-inflammatory responses via its affects on cytokines, and also enhances IL-10, thereby assisting with immunoregulation, preventing glial activation and neuronal death. Increasing IL-10 may help to reverse the process of
blood/brain permeability.

Desipramine also inhibits 6-OHDA induced apoptosis and detrimental changes and shows evidence of inhibiting CD4 attacks on myelin, via the reduction of IL-4. IL-4 enhances MHC II binding (antigen presenting cells). It has been postulated that reducing MHC II activity in MS could be highly beneficial (which desipramine does). Regulating MHC II, along with GABA, perhaps assists with maintaining cellular and/or neuronal sodium density, thereby
reducing the chances of permanent neurological disability. (See Dr. Samuel F. Hunter's prior research regarding MHC II and maintaining sodium density in MS). MHC II also shows evidence of inducing colitis.

IL-4 tends to be a double-edged sword and fairly complex. My findings indicate that in MS, it might prove preferable to inhibit IL-4, not increase it. IL-4 is an inhibitor of VIP. VIP is important for MS, and inhibiting VIP appears to be detrimental in MS patients. Therefore, the reduction of IL-4 by desipramine not only decreases MHC II (beneficial for MS), but reducing IL-4 in MS also helps to maintain or increase VIP. VIP/PACAP contributes to the initiation of TH2-type immunity, whereas in the presence of a full-blown, inflammatory reaction, VIP/PACAP act as anti-inflammatory agents. Lymphoma is connected to high concentrations of IL-4, also.

Lab results also indicate that desipramine shows distinct evidence of modulating/changing the immune system response from TH1 to TH2 (again possibly desirable for MS treatment).

Desipramine shows beneficial effects on various neurotrophins and BDNF, thereby assisting with remyelination. Desipramine exhibits neuroprotective and anti-inflammatory effectiveness, consequently assisting with neuronal survival. It also is known to improve neuronal communications and synapses.

Symptomatically, desipramine helps with neurological pain, shows effectiveness for adverse bladder symptoms, is proven effective for IBS, narcolepsy, possibly ADHD, fibromyalgia, and is an effective TCA anti-depressant. Due to desipramine's anti-cholinergic properties, its
affect on tremor is not certain at this time. There is some fringe evidence that desipramine may promote retinal improvement.

I could go on and on about desipramine's influence on neuropeptides, nitric oxide, free radicals and oxidative processes, and its known inhibition of the reuptake of serotonin and more importantly NOREPINEPHRINE, but that's all just part of the initial physiological chain reaction and are probably well-known pharmacological properties, so there's no need to go into all that.

Desipramine does metabolize in the liver, but I understand that approximately 70% is excreted in the urine. Desipramine has less anti-cholinergic activity and is cleared more rapidly than its parent compound, though.

Although desipramine works via a slightly different method, it is similar in many ways as the pharmaceutical anti-depressant drug called "Rolipram" and actions with PDE4 (again proving beneficial for MS). Desipramine increases synaptic NA at the spinal level, which binds PDE4 and enhances cAMP. Rolipram binding is significantly enhanced by increasing synaptic NA.
Increasing levels of cAMP prior to lesion promotes axon regeneration. Lab results indicate that increasing intraneuronal cAMP following injury enhances both regeneration and subsequent functional recovery. It is claimed that the drug "Rolipram" basically exerts the same influence, albeit via different pathways. (In my opinion, desipramine appears to be more effective overall.)

The drug "Rolipram" (not yet available in the U.S.) recently completed a clinical trial as a possible effective treatment for MS. The results from the trial have not yet been published. Rolipram's possible beneficial action on MS and the immune system was discovered by accident a couple of years ago in a lab at Schering AG (makers of Interferon), but due to
Rolipram's more extreme side effects of nausea and emesis at the doses necessary for MS treatment, it was not looked at closely until just recently, partially due to decreasing effectiveness of the interferons over time and/or because interferons just don't work for everybody.

Desipramine's side effect profile is fairly extensive, also, but might prove to be more manageable than Rolipram's, because there is reason to believe that beneficial effects for MS from desipramine can be achieved at a lower dosage. Desipramine exhibits modulating effects on PTX3, whereas Rolipram does not.

I also find no indication of desipramine being looked at as an effective treatment for MS, even though there is extensive evidence that it should be (in my humble opinion). I could find no clinical trials in the past nor for the future regarding desipramine and MS. Why not?

I personally see evidence where EXTREME caution should be observed when considering prescribing desipramine in conjunction with the interferons (LPS interactions) or to someone with Lyme's disease.

I could be dead wrong, but at this point in time, I don't foresee any interaction problems with desipramine and levetiracetam, although it certainly has not been examined closely yet, since levetiracetam's exact mechanisms of action are mostly unknown. Off the top of my head, from what I remember reading somewhere, besides its obvious anti-convulsant
properties, levetiracetam has beneficial effects on mitochondria, ATP, and targets the CNS. Hopefully, they will prove to be beneficial adjuncts with each other; desipramine is more "preventative and regenerative", whereas levetiracetam is more "neuro-protective" and is not metabolized in the liver at all.

I can personally attest to levetiracetam's beneficial effects on MS symptomatically (including but not limited to its beneficial effects on cognitive problems due to MS). The only question I have is the fact that desipramine is said to lower the seizure threshold, thereby indicating possible interaction with levetiracetam. This is one of the negatives with desipramine that needs a closer look before combining the two. Perhaps by taking levetiracetam first for a while and calming down convulsant (misfiring) activity BEFORE adding desipramine may prove to negate this potential problem anyway. (NOTE: Since writing this paragraph, I have proven my theory correct by starting on desipramine again, along with levetiracetam, and so far have experienced no interaction problems of any kind. My minor MS hand tremors have now subsided, also.)

The survival of oligodendrocytes is crucial to sustain or repair myelin in MS. Oligodendrocytes contain GABA. Levetiracetam exhibits effects and regulation of GABAa. Desipramine shows affects (secondary message) on GABAb. Might this combination not prove HIGHLY beneficial in MS, as it not only may affect the survival to maturity of oligodendrocytes, but this combination of medications appears to regulate ion channels -
maintains sodium density and reduces potassium? (Also see Dr. Peter Calabresi's recent theory on potassium channels and MS.) There is also evidence of desipramine’s beneficial effects on sulfatide, thereby exhibiting further indication of the drug’s assistance with the survival of oligodendrocytes.

Also, as it pertains to levetiracetam, I ran across something that indicates that levetiracetam helps to increase BDNF (again beneficial for MS). Not to mention how beneficial the "racetam" portion of levetiracetam is for cognitive problems in MS. There appears to yet be NO mention of that fact in any of the ongoing research on levetiracetam. I find that somewhat "odd". To date, there is not much that will help with
cognitive and memory problems in MSers, but I'm living proof that levetiracetam did the trick in reversing my three-year MS cognitive decline! I happened upon that by accident. After about a month to 45 days of taking Keppra (for neurological pain and spasticity), I suddenly realized my cognitive problems were gone. So I wondered how that could be, so again I researched and came across "racetam". All I can say is I am thankful every
day for Keppra for the cognitive benefits alone, nevertheless for its benefits for pain and spasticity!

Apparently, there is recent thought that the antibiotic minocycline exhibits possible efficacy for MS by inhibiting caspase 3 activation. Caspase 3 activation is ALSO stopped in its tracks by BDNF.

Both levetiracetam and desipramine increase BDNF substantially, and this combination may prove to be synergistic for MS treatment similar to minocycline.

Supplementation with anti-histamines and/or high amounts of vitamin C may lead to decreased effectiveness of desipramine, but shouldn't really "interact" too badly. There are some unanswered questions regarding vitamin E’s interactions with desipramine.

And last but not least, I TOOK desipramine back in the mid to late 80s for a period of three years. I took one 50 mg. green tablet of Norpramin at night before I went to bed. I can attest to the fact that I experienced no major adverse side effects or interactions at that time that I can recall (and I have EXTREME trouble with meds and side effects). Upon taking Norpramin, it was the first time in my LIFE that I felt anywhere near "normal" and my numerous various health issues (due to what we now know was MS - it can be sufficiently ascertained that I've had MS since birth) all began to reverse or improve. Due to the facts that I have listed above, is it any wonder why? I had tried everything under the sun.........since I was a child. And lo and behold, desipramine was the ONLY thing that had EVER in my life helped me (no more UTIs, pain stopped, neurological function returned, etc.). I've always called it my "miracle drug". So......if it helped me then, and what I have is MS, then desipramine might prove to be a very effective treatment for MS. And even after I stopped taking it (which I was extremely hesitant to do), I believe I experienced a couple of years (if not longer) of long-lasting effectiveness.

Is there any way that desipramine's effectiveness for actual disease modification and/or neurological regeneration in MS can be clinically measured?

Dosage is something that would need to be closely monitored. I think 50mg might be way too much to start out with. Starting at a lower dose might be more preferable.

I keep getting more and more convinced every day that this combination of medications has a MUCH broader spectrum of beneficial action on MS than any "singular" medication proposed to date!

Thanks for your patience! Call me a fool, and "maybe" this is all a case of extreme coincidence, but unless somebody can tell me why desipramine should NOT be taken a close look at for MS, then I think I might be on to something here. And if I'm wrong, then I'm wrong. No harm done, and perhaps a lot of good.

****************************

RESPONSE FROM NMSS:

Dear Deb,

Thank you for your many interesting messages related to desipramine and your ideas about its broader application to MS.

I have discussed your proposals with my colleagues in the research programs department and we all have concluded that you take an interesting and thoughtful approach to exploring the mysteries of MS and the positive effects the desipramine has had in your battle against MS.

With regards to your proposal, one of the issues that needs to be clarified is what is the specific area that this treatment would be directed towards besides managing symptoms of MS. This is quite important since it would be unlikely that anyone would want to design a clinical trial, let alone try to get it funded, without having a specific non-symptomatic outcome that would be measured in the trial. As you have noted, there is lots of interest in
this compound and their effects on the nervous system and thus I am confident that the scientific community will determine if desipramine or its similar compounds should be examined more closely for their more broader impacts. This is happening with other drugs (i.e. lipitor and the statins as modulators of the immune system) and one could expect a continued reexamination of other drugs used in MS.

Certainly do feel free to keep passing on your thoughts and ideas. I would also encourage you to keep sharing these with your neurologist and encourage him/her to pursue them as we need the researchers in the field to engage in these important questions. Having a champion for your ideas in the research community will be very important to move this forward.

I appreciate your enthusiam and energy and wish you all of the best.

Regards,

Timothy C., Ph.D.
Director
Research Training Programs
National Multiple Sclerosis Society

 <Contact information removed for privacy reasons>

Information on Desipramine can be found here: http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682387.html

This has been an editorial written by a community member of This is MS and does not necessarily reflect the thoughts or opinions of This is MS itself. NEVER begin a course of treatment without first consulting your doctor. The drug described above can have serious side effects, including interactions with other medications and/or supplements.