Bupropion combination with CYP2D6 substrates??

[JohnBoy2000]

In Steve Stahls prescriber's guide, he specifically lists bupropion as an augmentation strategy for Mianserin.

However - bupropion is listed in Stockleys interaction checker, as a potent inhibitor of enzyme CYP2D6, for which Mianserin is also listed as a partial substrate.

In terms of papers examining interaction between these two - there was not much.

However, there is a paper examining the interaction between another potent CYP2D6 inhibitor in Thioridazine, and Mianserin:

http://journals.lww.com/jpharmacoge..._thioridazine,_an_inhibitor_of_CYP2D6,.5.aspx

Now - I don't know the potency of thioridizine relative to bupropion in terms of its potency on that enzyme inhibition but, that paper claims that it significantly affects the plasma levels of mianserin.

And more over - that plasma levels determine the brains response, as oppose to dosage taken.

Which seems of course rather profound.

That being said - Stahls book clearly states on the page for Mianserin - "Combination strategy - Bupropion".


Any insights as to whether that is a feasible combination?

 

[JohnBoy2000]

I did take Bupropion with remeron before - but the response was quite average.

Recently however, whilst taking a combination of mianserin with reboxetine - which was/is quite positive in terms of symptom amelioration - I substituted the mianserin for mirtazapine - and had a response, similar, if not slightly more deficient, to that of the bupropion/remeron combo - in terms of degree of symptom alleviation.

I believe that more recent attempt with remeron, being a step down from mianserin, is attributable to the fact that, serotonergics effectively exacerbate my symptoms.
Remeron in combination with a potent noradrenergic enhancer - due to its a-typical mechanism, increases serotonin, where noradrenaline is concurrently enhanced - if I have that correct?
I believe I do, but my brain is a bit mushy this morning.

That being the case - I believe the enhancement of noradrenergic transmission via bupropion previously, and thus serotonergic transmission via the remeron combination - is what led to a poor response.

In this case however - on paper, due to mianserins lack of serotonergic enhancement, the potency of bupropions effect on NE, should NOT implicated 5HT - and for that reason, should yield a more favorable response.

As I found that to be the case with Reboxetine in combination with either one - as outlined previously.

 

[JohnBoy2000]

See - what is kind of curious regarding my experience with Bupropion is that, it started off so damn well.

But as I got better, I seemed to kind of, simultaneously deteriorate in another regard.

By week 8, it seemed to have stopped working, period.

I chalked that up to the fact that it was considered a substituted amphetamine, and perhaps with similar'ish mechanism - like amphetamine, I had effectively developed a tolerance.

But then I read so many people have been on that for years.

Now I'm thinking, perhaps it was the remeron induced enhancement of 5HT in combination, that kind of eventually, over a period of weeks, outweighed the benefits of bupropion (re: previous explanation of how 5HT exacerbates my symptoms).

 

[JohnBoy2000]

There is conflicting reports but - it would seem that, according to this one at least, the AD effect of Mianserin is yielded primarily from the parent compound, not the metabolites.

https://www.ncbi.nlm.nih.gov/pubmed/1771213

So - If plasma levels are actually raised, it should not necessarily deplete efficacy.
That's my hypothesis at least.


In a far out universe, I'm contemplating throwing 150 SR Bupropion into the Mianserin/Reboxetine mix sinse, there doesn't seem to be rebox interactions - just to see how the mianserin reaction fairs, without tapering of rebox to put my theory to the test.

Opinions are welcome.

 

[JohnBoy2000]

I just sci-hub'ed what seems like a very comprehensive paper on AD drug-drug interactions.
Lots of good links there in.

http://www.sciencedirect.com.sci-hub.cc/science/article/pii/S0033318205700608

Working my way through.

 

[JohnBoy2000]

Pardon me carrying on this conversation with myself:


My sleep improved most profoundly with Bupropion.

Would it be possible, that this was the case, due to it's inhibition of Mirtazapine metabolism via CYP2D6 inhibition, and thus mirtazapines more profound induction of somnolence?

Or is it more likely that the improvement in sleep was a by product of simply improvements related to the bupropion therapy?

 

[Hodor]

I chalked that up to the fact that it was considered a substituted amphetamine, and perhaps with similar'ish mechanism - like amphetamine, I had effectively developed a tolerance.

Bupropion's mechanism of action is less comparable to that of amphetamine (release of dopamine and noradrenaline) than with that of the "bulkier" substituted cathinones (reuptake inhibition of dopamine and noradrenaline). Bupropion, after all, *is* a cathinone - 3-Chloro, N-tert-butyl-Cathinone to be exact. However, unlike the cathinones with the long alpha chains (like Ethyl-Hexedrone or a-PVP), Bupropion's N-tert-butyl group is extremely susceptible to hydroxylation, turning most of the dose into a purely noradrenergic metabolite due to the extensive first-pass-metabolism.

 

[JohnBoy2000]

Bupropion's mechanism of action is less comparable to that of amphetamine (release of dopamine and noradrenaline) than with that of the "bulkier" substituted cathinones (reuptake inhibition of dopamine and noradrenaline). Bupropion, after all, *is* a cathinone - 3-Chloro, N-tert-butyl-Cathinone to be exact. However, unlike the cathinones with the long alpha chains (like Ethyl-Hexedrone or a-PVP), Bupropion's N-tert-butyl group is extremely susceptible to hydroxylation, turning most of the dose into a purely noradrenergic metabolite due to the extensive first-pass-metabolism.

Pardon me I'm not well up on this but - are cathinones clinically classified?

I thought they were basically some shrub.

Are there any specific text books that would cover that?
Nestlers molecular neuropharm didn't really touch on cathinones.

 

[JohnBoy2000]

But - regarding cathinones - are tolerances known to develop?

If not - that would certainly lend some substance to my theory of mirtazapine mediated 5ht enhancement causing bupropions failure in my case (as serotonin exacerbates my primary symptom of chronic fatigue)...

I was surprised at how effective and powerful it was the first couple weeks, then how it went into decline, and by week 8 - seemed to have stopped working.

That kind of a timescale - 8 weeks - I had assumed that would be standard for amphetamine tolerances but - like I said - if tolerances even develop to cathinones, would that establishment take more or less than 8 weeks?
Opinion?

 

[JohnBoy2000]

I've just come across something called, the "Wellbutrin Honeymoon" - where one feels great on the first dose (as I did), and then it tapers off.

Now - it appears, it does establish consistency after a period, unlike for myself, where it was downhill until it flunked out.

Interesting, none the less.

https://www.depressionforums.org/forums/topic/18813-the-wellbutrin-honeymoon/

 

[JohnBoy2000]

I also read a study where wellbutrin raised DXM levels by x35.

Makes me wonder the metabolic ratio between DXM and Mianserin...

 

[Cotcha Yankinov]

Tolerance develops rapidly to releasing agents - they are not sustainable, although amphetamines and opioids are still drugs of last resort for MDD. Some of the cathinones have more serotonergic effects/MDMA-like qualities and those cathinones are even less sustainable.

35x concentration of DXM at some point in time or 35x area under the curve?

 

[JohnBoy2000]

Abstract: The purpose of this study was to assess the effect of bupropion on cytochrome P450 2D6 (CYP2D6) activity. Twenty-one subjects completed this repeated-measures study in which dextromethorphan (30-mg oral dose) was administered to smokers at baseline and after 17 days of treatment with either bupropion sustained-release (150 mg twice daily) or matching placebo. Subjects quit smoking 3 days before the second dextromethorphan administration. To assess CYP2D6 activity, urinary dextromethorphan/dextrorphan metabolic ratios were calculated after an 8-hour urine collection. Thirteen subjects received bupropion, and 8 received placebo. In those receiving active medication, the dextromethorphan/dextrorphan ratio increased significantly at the second assessment relative to the first (0.012 ± 0.012 vs. 0.418 ± 0.302; P < 0.0004). No such change was observed in those randomized to placebo (0.009 ± 0.010 vs. 0.017 ± 0.015; P = NS). At baseline, all subjects were phenotypically extensive CYP2D6 metabolizers (metabolic ratio <0.3); after treatment, 6 of 13 subjects receiving bupropion, but none of those receiving placebo, had metabolic ratios consistent with poor CYP2D6 metabolizers. Bupropion is therefore a potent inhibitor of CYP2D6 activity, and care should be exercised when initiating or discontinuing bupropion use in patients taking drugs metabolized by CYP2D6.

[FONT=Arial, Helvetica Neue, Helvetica, sans-serif]It doesn't seem to state.[/FONT]

[FONT=Arial, Helvetica Neue, Helvetica, sans-serif]Is bupropion a releasing agent?[/FONT]

[FONT=Arial, Helvetica Neue, Helvetica, sans-serif]I'm just trying to find trial data on long term use.[/FONT]
[FONT=Arial, Helvetica Neue, Helvetica, sans-serif]One I've come across seems to state it's long term use is equivalent to amitriptyline? [/FONT]

 

[Cotcha Yankinov]

I would not equate Amitriptyline and Bupropion. As an example, TCAs have been found to reduce the risk of Alzheimer's a bit, I doubt you could say the same for NRIs/DRIs

Burproprion itself acts as a releasing agent when it gets into the brain in appreciable enough amounts but normally it is broken down in first pass metabolism to metabolites which do not possess releasing qualities, these metabolites are just reuptake inhibitors among other things.

But if you were to say inject bupropion into the brain or directly into the blood stream, it can cause some release. Hence why insufflation of bupropion is common in prisons.

 

[cr33py]

Bupropion effectively raises levels of a few meds via CYP2D6 inhibition. I have come across people on venlafaxine, for example, who augment with bupropion partly to extend the time between needed doses. This is where discontinuation symptoms are apparent after a few hours even with the ER version of the drug. Rapid metabolizers perhaps. Sometimes (pretty rare that I have seen) a psychoparm doc will use another drug to slow metabolism and/or raise levels like that. usually the intent with bupropion is to help with the SSRI apathy and residual depressive symptoms, though. Stahl seems to like bupropion. Ive found it kind of a mixed bag where the effects wane over time. Also the tendency for aggression and irritability.

 

[JohnBoy2000]

Wiki tells me the bupropion parent compound occupies the noradrenaline transporter by, 30%
And the DAT by, 100%

But you're saying it's really the metabolites that do the heavy lifting.

So is hydroxybupropion - does is saturate the NET?

"It's a NRI among other things".

If it has other actions - that would suggest that, obviously it's not as selective as say, Reboxetine?

And therefore, assuming it's not as potent at the NET as reboxetine?

Yes/no?

 

[palmanita]

I also read a study where wellbutrin raised DXM levels by x35.

Do you have a link to this study?

Very interesting cause I've experienced this by accident when I was on wellbutrin (just 150mg SR) and single regular cough-suppressant doses of DXM were highly active, duration was extended too... but quite different from DXM on its own, overall a nice experience with powerful hypomanic energy but the norepinephrine overload was too much, tinnitus became worse every day and probably hypertension, don't remember exactly what made me stop but it felt increasingly toxic to the body after a month or so... was a nice time nevertheless.

Do you think the DXM/quinidine combo that is available on prescription might be similar to this but w/o the norepinephrine from wellbutrin?

Wiki tells me the bupropion parent compound occupies the noradrenaline transporter by, 30%
And the DAT by, 100%

Yeah, like Hodor already said the parent compound gets metabolized very quickly..

Looking at the doses, it's not as potent as reboxetine- but this is dosage related I'd say, there's a differency between dosage potency (e.g. fentanyl vs. morphine) and overall potency (buprenorphine vs. morphine) ...

I can't really understand why someone willingly takes pure NET inhibitors like reboxetine, tried that one and it was awful pure tension ... but of course everybody's metabolism is different.

Bupropion is also a nicotinic acetylcholine antagonist (why it's also sold as Zyban to quit smoking) and appears to limit glutamate release (unfortunately lost the links but study is on pubmed).

 

[JohnBoy2000]

Looking at the doses, it's not as potent as reboxetine- but this is dosage related I'd say, there's a differency between dosage potency (e.g. fentanyl vs. morphine) and overall potency (buprenorphine vs. morphine) ...

So - is it possible bupropions potency, non dose related, is stronger??

That DXM study is on the bupropion wiki page.

 

[JohnBoy2000]

And just out of curiosity - how did you deduce that to be the case?

I don't disagree, but just curious, for my own information.

 

[5HT2c]

Pardon me carrying on this conversation with myself:


My sleep improved most profoundly with Bupropion.

Would it be possible, that this was the case, due to it's inhibition of Mirtazapine metabolism via CYP2D6 inhibition, and thus mirtazapines more profound induction of somnolence?



Or is it more likely that the improvement in sleep was a by product of simply improvements related to the bupropion therapy?

Mirtazapine works better as hypnotic at low doses (15mg) than higher ones (30mg), so IMO your sleep improvement was due to other causes.

I don't have a clue but I'd bet Stahl recommends the combination on the basis of combining a stimulant and anxiogenic that can cause insomnia with a hypnotic more frequently anxiolytic agent...