Milnacipran - any reason why this was not approved for MDD??

[JohnBoy2000]

Milnacipran - any reason why this was not approved for MDD??
​

Pharmaco-bureaucracy?

From Wikipedia:

"In a pooled analysis of 7 comparative trials with imipramine,^[1] milnacipran and imipramine were shown to have comparable efficacy while milnacipran was significantly better tolerated. A pooled analysis of studies comparing milnacipran and SSRIs^[2] concluded a superior efficacy for milnacipran with similar tolerability for milnacipran and SSRIs."

https://www.ncbi.nlm.nih.gov/pubmed/12369608

"The pharmacokinetic profile of milnacipran is characterized by rapid absorption, high bioavailability, low protein binding, and rapid elimination, both by hepatic glucuronidation and renal excretion. This gives milnacipran certain pharmacokinetic advantages, such as low inter-individual variation in plasma levels, low potential for drug interactions, and limited impact on hepatic cytochrome P450 systems."​

Seems like a solid SNRI - higher NRI to SRI ratio.

Could it genuinely be competition between newer drugs like Duloxetine?

Or is there any actual reason this drug is not licenced?​

 

[S.J.B.]

The levo enantiomer of milnacipran was approved by the FDA in 2013 for major depressive disorder.

 

[Coolwhip]

Pharmaco-bureaucracy?

Probably so, or adherence to the status quo. At the time Milnacipran was being introduced overseas US pharma was still obsessed with pure SSRI's, and now that SNRI's are in vogue they have gotten the approval of Levomilnacipran which is a stronger NRI than SRI, which sounds perfect for what you are looking for JB. I wonder if they even ever sought the approval of Milnacipran for MDD, I would guess not because I can't see any obvious barriers.

In fact, I am considering going back on an AD and I might give this a shot, I was aware of the existence of Milnacipran but hadn't really studied/considered it, and I didn't even know Levomilnacipran was an option. I am a little worried about insomnia if used twice daily with its strong NRI action though. If its an issue I guess I could try only dosing in the morning, although I'd be wary of effecting its efficacy, or talking my doc into prescribing the racemic off-label and see if the lower NRI action helps, but I hate pure SSRI's and so does my wife if you know what I mean. I'm thinking that could be less of a problem with Levomilnacipran.

 

[Hodor]

Probably so, or adherence to the status quo. At the time Milnacipran was being introduced overseas US pharma was still obsessed with pure SSRI's, and now that SNRI's are in vogue they have gotten the approval of Levomilnacipran which is a stronger NRI than SRI, which sounds perfect for what you are looking for JB. I wonder if they even ever sought the approval of Milnacipran for MDD, I would guess not because I can't see any obvious barriers.

In fact, I am considering going back on an AD and I might give this a shot, I was aware of the existence of Milnacipran but hadn't really studied/considered it, and I didn't even know Levomilnacipran was an option. I am a little worried about insomnia if used twice daily with its strong NRI action though. If its an issue I guess I could try only dosing in the morning, although I'd be wary of effecting its efficacy, or talking my doc into prescribing the racemic off-label and see if the lower NRI action helps, but I hate pure SSRI's and so does my wife if you know what I mean. I'm thinking that could be less of a problem with Levomilnacipran.

IME strong NRI's (like milnacipran or the purely NET-selective reboxetine) are, unfortunately, less well-tolerated than their more serotonergic competitors. Men, in particular, seem to be susceptible to getting side-effects like testicle pain, sensations of incomplete urination, and various other hilarious urological symptoms from them.

Milnacipran was originally introduced in the mid-to-late 90's in a number of European countries, but even there it is nowhere near as popular as more well-tolerated antidepressants like venlafaxine or escitalopram.

 

[Coolwhip]

Well I don't think there is data to back that up(that it is less well tolerated overall, not that they may have a different side effect profile, milnaciprin specifically not reboxetine or atomoxetine), everything I have read about Milnacipran says that it has better tolerability than TCAs and similiar tolerability to SSRI's; and while levomilnacipran is an even stronger NRI it has been approved; and said side effects are hardly dangerous or a reason to stop development.

And even desvenlafaxine has an SET:NE ratio of 10:1(if wikipedia is to believed, they cited a source although I haven't actually checked it) compared to either balanced reuptake or a 1:1.6 ratio depending on the source, so it will obviously work differently and be better suited for certain symptoms/types of depression. And if we know anything it's that popularity has little to do with efficacy, and even if it is better suited for a smaller subset of patients that's not a real reason to prevent it from coming to market, you are basically saying a large group of patients who can benefit from it have to go without because it will be less profitable.

And since SSRI induced sexual dysfunction is often treated with bupropion I wouldn't be surprised to learn that they occur less often, or are less severe with levomilnaciprin. Maybe I'll find out soon because SSRI's absolutely kill my libido and cause anorgasmia(which can be fixed with a dopamine agonist, but that doesn't help libido, which is convenient because they make a great adjunct)

I wish there were more comparisons of the two, because while the consensus is that levomilnaciprin is the stronger NRI, some sources say milnaciprin has a ratio of 1.6:1 while others say it may have up to 3x greater effect as an NRI, while the levo enantiomer's ratio is 2:1...so is it actually a stronger NRI? Are they both balanced reuptake inhibitors? Or could levomilnaciprin have even greater selectivity for NET than we believe?

sensations of incomplete urination

Wanted to add that I have experienced this on certain medications, and it is kind of funny when you think about it, but it feels like there is just a little bit more pee that just won't come out and you end up contracting your kegels repeatedly trying to force it out for fear that when you put your dick away its going to drip into your pants.

 

[Hodor]

And if we know anything it's that popularity has little to do with efficacy, and even if it is better suited for a smaller subset of patients that's not a real reason to prevent it from coming to market, you are basically saying a large group of patients who can benefit from it have to go without because it will be less profitable.

It's not *me* saying that, it is an unfortunate consequence of basic economics. Conducting clinical trials to get FDA approval costs money. Promoting a drug (so doctors will actually consider prescribing it) also costs money.

If milnacipran is actually inferior to an SSRI or venlafaxine for most patients, it's going to be much harder to prove that the minority of patients that actually does better on milnacipran isn't just the result of some statistical fluke.
Also, back in the early 2000's, the market was pretty saturated with novel antidepressants being marketed aggressively by several pharm giants, like GSK's wellbutrin or Lilly's cymbalta, not to mention venlafaxine and various SSRI's that hadn't gone generic yet.
Compared to that, it was probably safer for Pierre Fabre/Forest to focus on the fibromyalgia market, where proving milnacipran's efficacy was easier (pain-killing effects in antidepressants mostly seem to result from the NET action, which milnacipran had lots of), as was showing superior tolerability (as it lacks the sedating and anticholinergic effect of the tricyclics), and there was far less competition.

Now that most blockbuster antidepressants have gone generic or are about to do so soon, the market is once again open to new competitors. Except they obviously wouldn't want to invest money in getting plain racemic milnacipran approved for depression though (as savella and thus racemic milnacipran is also about to go generic), so they're trying it with the levo-isomer which can be protected with a fresh patent.

 

[Hodor]

Expanding on this: IMO, not getting milnacipran approved for depression is a relatively minor loss compared to the fact that in the US, tianeptine is only available from shady nootropics vendors in a powder form that is probably mostly aimed at those using it to get high

That said, OP, I see nothing wrong with asking your doc for an off-label prescription for savella. If you did relatively well on duloxetine, then you might do even better on milnacipran.
Personally, I never experienced libido loss from SSRI's/SNRI's, but did get weird side-effects from reboxetine and to a lesser extent milnacipran. "Weird" feelings like your urethra suddenly constricting during orgasm are probably better than not experiencing orgasms at all. I could really have done without the "blue balls" though - not as in sexual frustration (ok, that too, but it wasn't because of the meds), but actual pain in the testicles.

So there's your dose of TMI for the day, btw

 

[JohnBoy2000]

Great info - cheers.

1st - What DA agonist did you use to alleviate anorgasmia??

2nd - In the UK, I've inquired in several pharmacies - and milnacipran, fetzima etc - doesn't even show up on their system.
I understand it can be purchased online and - that may be a good way to give it a trial run before going through medical channels.
But - a reputable vendor from which one can purchase pharmaceuticals from online - in the UK??
Any pointers?

I haven't tried duloxetine yet but - that's next on the list.

Desvenlafaxine/pristiq - a possibility - some claim is basically identical to Effexor - others claim more efficacious.

Failing them two - something like Levo/milnacipran will be next on the list.

 

[JohnBoy2000]

Oh yeah - I never had a poor response to pure NRI's, rebox and atomoxetine - probably cause my noradrenaline is so "low".

Always - positive in every way, aside from either just not being quite powerful enough.

Both seemed to enhance sexual function; well, maybe slight anorgasmia with atomoxetine.

 

[Hodor]

2nd - In the UK, I've inquired in several pharmacies - and milnacipran, fetzima etc - doesn't even show up on their system.
I understand it can be purchased online and - that may be a good way to give it a trial run before going through medical channels.

Why not go through legit medical channels in the first place, though?
My doc was able to write me a script for tranylcypromine that the local pharmacy would just import from another EU country... maybe your doc could do the same for you?
Unless the tranylcypromine thing only worked because it may actually have been licensed as a pharmaceutical in my country at one point, and was no longer available simply because there was no longer any local manufacturer for it. Not sure if it works for meds that were never approved in your location in the first place.

Can't hurt to ask your doc though. The original and most common brand name of milnacipran is "Ixel", under which it is sold in a number of EU nations, including France, Austria and Finland. Maybe that will help the people at the pharmacy find it.

But - a reputable vendor from which one can purchase pharmaceuticals from online - in the UK??
Any pointers?

Bluelight has a strict "no sourcing" policy.
Plus the unlicensed import of any and all psychoactives into the UK has been made illegal under the Psychoactive Substances Act of 2016.

 

[Coolwhip]

Pramipexole, but be warned you have to titrate your dose up or you will get sick. Knowing that amantadine has been used to treat AD induced anorgasmia I imagine memantine might work as well since it is a d2 agonist, but amantadine has some DRI action as well.

 

[Hodor]

Desvenlafaxine/pristiq - a possibility - some claim is basically identical to Effexor - others claim more efficacious.

Desvenlafaxine's SERT-to-NET affinity ratio is still heavily on the serotonergic side, falling somewhere between plain venlafaxine and duloxetine. However, the difference between venlafaxine and desvenlafaxine effectively shrinks in clinical practice when you consider that most of a patient's venlafaxine dose is eventually metabolized into desvenlafaxine anyway.

So realistically, the main target group for this drug would be patients with decreased liver functionality and/or abnormal CYP2D6 enzymes. Pretty much everyone else is probably going to find effexor just as - if not more - effective, not to mention far cheaper.

 

[JohnBoy2000]

Desvenlafaxine's SERT-to-NET affinity ratio is still heavily on the serotonergic side, falling somewhere between plain venlafaxine and duloxetine. However, the difference between venlafaxine and desvenlafaxine effectively shrinks in clinical practice when you consider that most of a patient's venlafaxine dose is eventually metabolized into desvenlafaxine anyway.

So realistically, the main target group for this drug would be patients with decreased liver functionality and/or abnormal CYP2D6 enzymes. Pretty much everyone else is probably going to find effexor just as - if not more - effective, not to mention far cheaper.

Interesting.

I suppose I would be interested in it specifically as, Effexor did not combine well with Strattera and Mianserin combo - making a triple combo.
It combined horribly.

The only drug I've found to combine thus far is, Sertraline - and not higher than 25 mg.

However - Pristiq's more favourable interaction profile, would be why I would consider it.

And then duloxetine - which doesn't have a great interaction profile but - I guess you can never truly predict these things.

 

[JohnBoy2000]

Just out of curiosity, on the topic of DA agonists - they have the effect of suppressing prolactin via HPA axis downregulation - some such?

But their effect on growth hormone??

Do they administer DA agonists to patients with overactive pituitary dysfunction, to prevent them getting gigantism?

Suppression of growth hormone - could theoretically hinder the healing process if one were say, prone to injury?
Does it work that way?


https://www.ncbi.nlm.nih.gov/pubmed/3108691

This paper seems to suggest - an increase/decrease - kind of a modulation.

 

[Coolwhip]

If significant at all, I highly doubt the effect is so profound enough to illicit such a scenario or even really concern yourself with especially if you are sticking to the lowest effective dose. I mean I don't know a whole lot about it, but if something like this was occuring with DA agonists I think I would have stumbled across it at some point, in the link you shared they weren't even using an exogenous ligand but DA itself, do we even know if typical DA2/3 agaonists like pramipexole, bromocriptine, ropinirole, or cabergoline even bind to and illicit an action similar to dopamine at pituitary cells? And if so does chronic administration of said agonists allow the decreased response from hGRF to even occur and if so how long does said effect last after disassociation of said agonists, or does the relatively constant presence of said agonists cancel out the decreased response from hGRF?

I mean its interesting to think about, and maybe the answer is already established, but I don't think DA agonists are slowing down healing in otherwise normal healthy adults, I definitely wouldn't allow the thought to influence my decision to use DA agonists as medicine.

 

[JohnBoy2000]

Apparently also - there is another analogue of Venlafaxine called, Ansofaxine - just approved for phase 3 trials in the US and Europe.

How long after a drug is approved for phase 3 trials, does it take for a drug to actually come on the market?

It's a triple RI - SER, NE and DA - pretty much equally, from what I understand.

A powerful DRI - without abuse potential?

 

[Hodor]

Apparently also - there is another analogue of Venlafaxine called, Ansofaxine - just approved for phase 3 trials in the US and Europe.

How long after a drug is approved for phase 3 trials, does it take for a drug to actually come on the market?

Phase 3 trials are typically approx 2 or 3 years; the actual FDA approval process takes another 1 or 2 years. Even if a substance reaches Phase 3 trials, there's still a ~40% chance that it will never reach the market, though.

It's a triple RI - SER, NE and DA - pretty much equally, from what I understand.

A powerful DRI - without abuse potential?

If it's a powerful DRI, it sure as hell is going to have abuse potential; however, I'm not sure if an IC of 491nm really constitutes a "powerful" DRI, though.

Also, consider that this drug is the 4-methylbenzoic acid ester of desvenlafaxine. Esters like that tend to be easily cleaved, resulting in a short half-life (see: cocaine); you can thus expect much of the actual pharmacological activity to be the result of its major metabolite, i.e. desvenlafaxine, an SNRI lacking dopaminergic activity.
While this will presumably reduce the abuse potential, it also means that those who do abuse it have a major problem on their hands: If you take enough ansofaxine to achieve a dopaminergic high, you may very well find yourself producing enough desvenlafaxine to send yourself into serotonin syndrome shortly thereafter.

And if that is the case, it does not bode well for this substance's chances of getting approved.

 

[Limpet_Chicken]

Yeah, it sounds like coke that metabolizes into poison. Not that coke is the best thing for you to begin with, but I could see this being trouble.

Why an ester...that seems really a bad idea for a TRI that metabolizes to desvenlafaxine. Would something like an amide be active?

IMO a TRI might not be a bad idea, there seems to be an incredible lack of antidepressant drugs that have any affinity for DAT, at least with any affinity meaningful with respect to affinity for SERT and NET. It almost seems as if DAT-ligands have been left out deliberately. Where some affinity at least would probably be of use in depressive conditions.

Also, just a thought, there seems to be a fair frequency of allergy to PABA, would this potentially crossreact with para-methylbenzoic acid once the ester is cleaved?

 

[JohnBoy2000]

I thought it might be a handy option - to avoid my having to add in a DA agonist like Cabergoline - but yeah - I don't think it'll be available any time soon.

**

To understand this drug a little better (milnacipran), I'm just gonna post a few links and my understanding of its mechanism, as I go.

https://academic.oup.com/ijnp/article/16/5/937/715184

So, receptor occupancy comes in at about 60% for the maximum dose of 200mg - for both 5ht and NE.

Which seems below the standard therapeutic occupancy of 80%

I haven't actually looked at any research/academic info on milnacipran - I'd like to believe it wasn't approved for a reason more than pharmaco-bureaucracy and marketing of alternate agents.

 

[Coolwhip]

Considering it WAS approved for MDD, just not in the US, and has been approved for fibro in the US(so safety isn't a concern) and now levomilnacipran is approved for MDD and there doesn't seem to be that much difference between the two...I think you'll be hard pressed coming up with any data which provides a better explanation. But I find myself becoming more skeptical and cynical which each new day, so perhaps my shit colored glasses are causing my to jump to unjustified conclusions.