Can interactions occur - even if not pharmacokinetically listed??

[JohnBoy2000]

Might be a silly question - but perhaps the more knowledgeable can give insight, cause I got nothing on this.

The mix is - Mianserin (mirtazapine analogue), desipramine, reboxetine.

Desipramine is one 1/3rd the full dose.
Mianserin, 2/3rds the full dose.
Reboxetine, 1/3rd the full dose.

It's the combination of two NRI's in reboxetine and desipramine that is of concern.

There are no enzyme inhibitions of one to the other that raise plasma levels etc.

But - without the reboxetine, I was okay.

I added 2 mg rebox - and that was okay.

I upped it to four - and on the fourth day, fatigue hit.

To much noradrenaline?

Or a potential combination of desipramine and reboxetine that gives rise to it?

My concern was - on higher levels of desipramine - fatigue was also an issue.
Actually, fatigue with anxiety - like akathisia.

But, being a tricyclic, fatigue is common.
Fatigue plus activation via noradrenaline.

So - reboxetine, fatigue is not common.

Which is why I'm trying to determine how it's addition, with the other two - resulted in it.

 

[jaiho]

Could be, hard to say. But why combine two potent NRIs in the first place?
Either alone is more than potent enough to inhibit the transporter.

It's like combining two SSRIs, it's done sometimes for whatever reason but the better result is combining an SRI & NRI.

 

[Kdem]

It seems more likely that it's a pharmacodynamic interaction.

With those three drugs, it seems hard to say which one is doing what.

 

[sekio]

Are you eating/sleeping properly? NRIs can mess with appetite and sleep, can't they?

I'd take the mianserin at night and the other NRIs in the morning if that's possible. It is after all an antihistamine, and those can negatively impact wakefulness/awareness levels.

 

[checktest]

As Kdem said - hard to say with a wacky combination of moderately dirty drugs. Desipramine is a tricyclic. Mianserin is a tetracyclic. Reboxetine has some serotonergic activity. More specific to your question, perhaps slight p-glycoprotein interactions by reboxetine are enough to increase the relative effects/transport of desipramine?

http://jpet.aspetjournals.org/content/305/1/197

I really hope your psychiatrist has done all the groundwork of EKGs and the like. Desipramine is not a forgiving drug cardiac-wise. And reboxetine something something potassium channels. Watch out for your heart rate with exercise- sometimes the altered perception of exercise, as well as overheating, can occur. I was on fluoxetine and desipramine for some time, which has a listed pharmacologic interaction. Can't say it helped much. Tired from desipramine.

It is probably better to list actual doses rather than relative to a "full" dose, as maximum doses are not always consistent. An example is tranylcypromine (parnate)- NHS has perhaps 30 mg or something as max dose, while many studies did not show benefits until higher doses. [See STAR*D trial]. Personally, I didn't see much of a difference until 50 mg, and only had a major response at 70-80. Limited by side effects, however.

Good luck, though! Polypharmacy is a tricky route.

 

[JohnBoy2000]

I can't access bluelight from Chrome any more.

Anyone else having this trouble?


Combining the two NRI's cause - rebox supposedly has questionable efficacy.
I know desipramine works - but I can't take more than the lowest dose due to akathisia (when I say desipramine, I'm using the UK reference; it's actually lofepramine, 70 mg - the prodrug to desipramine, as that's not licensed here).

In any case - I discontinued the "desipramine" on Sunday - and upped the Reboxetine to 8mg - the standard dose.

Even though they're both NRI's, and I was on one long term - is there still a waiting period for the therapeutic effect of reboxetine to kick in?
Or does one simply, "take over", from the other?


Nice link on the p-glycoproteins - I suppose that would explain the replication of high level desipramine, when low level is combined with reboxetine.

I'm assuming that won't apply in terms of interactions with Mianserin?
Cause I'm on 60 mg Mianserin - not the full 90 mg - as that was excessively sedating there also.
It also made me dizzy - I assume due to it's potent alpha 1 adrenergic blockade.

 

[JohnBoy2000]

I really hope your psychiatrist has done all the groundwork of EKGs and the like. Desipramine is not a forgiving drug cardiac-wise. And reboxetine something something potassium channels. Watch out for your heart rate with exercise- sometimes the altered perception of exercise, as well as overheating, can occur.

When you say the cardiac effects of desipramine - I found that on lofepramine.

Can you comment on that in regards to Nortriptyline - and/ore Maprotaline?
I believe I read they both carry high'ish risks of cardiotoxicity - I don't know what exactly that is relative to arrhythmias and overheating etc.

 

[checktest]

Generally, whenever transitioning from a drug, there usually is a little bit of a lag period. No real direct substitution across different classes- a tricyclic is still quite different from reboxetine. I've heard that NRIs tend to be a bit quicker, though, to get used to. I'm not quite sure what you mean by interactions with mianserin. Reboxetine is a weak CYP2D6 inhibitor as well, and may affect mianserin clearance.

More P-gp
http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2011.01557.x/full#b58

Clinical use of antidepressant therapy and associated cardiovascular risk
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3426258/
http://emj.bmj.com/content/18/4/236

Most of the tricyclic overdoses point toward various ion channels in acute overdose toxicity. A whole bunch of them are HERG blockers (Human ether-a-go-go, fantastic protein name). Relative parasympathetic/sympathetic tone and your "desired" noradrenergic blockade contribute as well. Any anticholinergic properties may lead to possible issues with overheating.

I guess I would just communicate with your doctors carefully about any medication changes, and how you feel. (Not that that is easy sometimes, especially with some psychiatrists.) Tricyclics aren't gentle- there is a reason they went out of favor for SSRIs, even if they had higher efficacy. It may not be best to "aim for a certain dose" or go for the max, especially with drugs with relatively more narrow therapeutic indices.

 

[JohnBoy2000]

I've been trying to find info on cardiac effects of MAPROTILINE specifically - but there's not a lot of material/articles on that drug.

Most that I found, relate it's cardiac implications to it's anti-cholinergic effects - and then claim it's anti-cholinergic effects aren't particularly profound.

Then, Lofepramine supposedly doesn't have severe cardiac effects - but it had hella strong cardiac effects with myself.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1983.tb05872.x/pdf

This was the most specific paper I could find.

It claims: "increased heart rate and PR interval and decreased QTc interval in the maprotiline group."

What does that mean exactly?

As in - "not forgiving", cardiac wise - similar to desipramine??

 

[JK25]

Are you eating/sleeping properly? NRIs can mess with appetite and sleep, can't they?

I'd take the mianserin at night and the other NRIs in the morning if that's possible. It is after all an antihistamine, and those can negatively impact wakefulness/awareness levels.

Agreed.

 

[JohnBoy2000]

Anyone know where to get info as to whether Mianserin clearance is dependant upon p-glycoprotein also??

Can't find anything on google scholar.

 

[JohnBoy2000]

That study relative to potassium channels and human ether a go-go:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055469/


And - in vitro - apparently reboxetine has a mild inhibitory effect on CYP2D6.

Which has not been demonstrated in vivo with DXM.

But - my having to reduce the dose of Mianserin after beginning reboxetine?
There's got to be an explanation for that...

 

[WSH]

Could be, hard to say. But why combine two potent NRIs in the first place?
Either alone is more than potent enough to inhibit the transporter.
.

Yes one is enough to cause the necessary ~80% occupancy and let's say combing the IC50 of one selective NRI with the IC50 of another selective NRI is the same as taking 2x the IC50 of a single one. So why are you taking two, the only reason I can think of are off-NEP-target effects?

 

[JohnBoy2000]

Yes one is enough to cause the necessary ~80% occupancy and let's say combing the IC50 of one selective NRI with the IC50 of another selective NRI is the same as taking 2x the IC50 of a single one. So why are you taking two, the only reason I can think of are off-NEP-target effects?

Well, desipramine didn't interact with mianserin - as tricyclics are not reputed to.

I'm not taking the two together any more but - just currently basically trying to come up with an explanation as to why I had to reduce the miansein dose.

Even at 30 mg - I'm still getting a little of the dizziness i got at 90 mg, without the reboxetine.

In stahls book, the prescribers guide - he has that listed as a possibility.
However, the rebox analogue, Atomoxetine, does not have that listed....

Plus, plenty of case studies show it an effective AD, even if not licensed as such?


Also - is one of you guys updating the wiki page on atomoxetine/strattera?
Keeps becoming more detailed.

 

[WSH]

Well, desipramine didn't interact with mianserin - as tricyclics are not reputed to..

Desipramine is a NRI, whereas mianserin is a norepinephrine autoreceptor (alpha-2) antagonist, so at least theoretically the combination of reuptake inhibition (desipramine) and the simultaneous increase in vesicular exocytosis because of loss of autoreceptor inhibition of locus coeruleus firing (mianserin) should interact.