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Serotonin syn. Why high SSRI dose is quite safe but SSRI+DXM is considered dangerous?

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Renald

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SSRIs are known to be not very dangerous in overdose when used alone. Imagine we have a situation, where the patient took 60 mg of paroxetine (maximum recommended dosage) + 120 mg more paroxetine. And now compare the situation with the same amount of paroxetine (60 mg) + 120 mg of DXM. The second situation is considered as more dangerous, despite the fact, that paroxetine is much more potent SSRI comparing to DXM, and SERT inhibition should be higher in first case. Is it based on some scientific researches, or just is stereotypical thinking, that mixing two serotonergic drugs is dangerous due to SS probability. Maybe DXM added to high SSRI dose is more dangerous as adding additional doses of the same potent SSRI due to its action on other receptors?
Lets discuss.
 
I think when you put DXM and paroxetine side by side like you just did, people will regard paroxetine as more dangerous. The advices about using DXM and other serotonergics being reiterated all the time probably comes from the fact that people bring up DXM all the time, and nobody wonders if it's safe to take 300mg of fluoxetine, ever, for example.
 
Part of it might have to do with the matter of some SSRIs inhibiting CYP2D6 and hence increasing Dextromethorphan levels. if I remember correctly normally DXM is metabolized by CYP2D6 to DXO which is not a SRI but is still an NRI, so if you inhibit CYP2D6 you would get more SRI effects because you have mostly DXM.

I'm sure that a fellow bluelighter Dopamimetic would have more to say on this matter but it might also be that DXM does a whole lot of things while SSRIs are typically only selective for the SERT. DXM is also a sigma agonist and sigma is a kinda weird receptor, maybe it would contribute to serotonin syndrome or at least over dose effects. NMDA antagonism could lead to increased excitotoxicity but that would be more with the SSRIs that do not inhibit the CYP2D6 (Dextromethorphan itself is not very strong as an NMDA antagonist, it's DXO that's the real NMDA antagonist, and once again it's the liver enzymes that make the DXO) so you would likely get more NMDA antagonist related toxicity and less SRI related toxicity from combo of DXM with a SSRI that doesn't inhibit 2D6.

I do wonder if DXM is really that bad to combine with SSRIs or if it's just a general opinion going around because there are warnings about serotonin syndrome on the bottles. There are definitely case studies of DXM abuse and SSRIs leading to serotonin syndrome though. But I wonder if that's mostly with the CYP2D6 inhibiting SSRIs.
 
Cotcha Yankinov said:
Part of it might have to do with the matter of some SSRIs inhibiting CYP2D6 and hence increasing Dextromethorphan levels. if I remember correctly normally DXM is metabolized by CYP2D6 to DXO which is not a SRI but is still an NRI, so if you inhibit CYP2D6 you would get more SRI effects because you have mostly DXM.

I'm sure that a fellow bluelighter Dopamimetic would have more to say on this matter but it might also be that DXM does a whole lot of things while SSRIs are typically only selective for the SERT. DXM is also a sigma agonist and sigma is a kinda weird receptor, maybe it would contribute to serotonin syndrome or at least over dose effects. NMDA antagonism could lead to increased excitotoxicity but that would be more with the SSRIs that do not inhibit the CYP2D6 (Dextromethorphan itself is not very strong as an NMDA antagonist, it's DXO that's the real NMDA antagonist, and once again it's the liver enzymes that make the DXO) so you would likely get more NMDA antagonist related toxicity and less SRI related toxicity from combo of DXM with a SSRI that doesn't inhibit 2D6.

I do wonder if DXM is really that bad to combine with SSRIs or if it's just a general opinion going around because there are warnings about serotonin syndrome on the bottles. There are definitely case studies of DXM abuse and SSRIs leading to serotonin syndrome though. But I wonder if that's mostly with the CYP2D6 inhibiting SSRIs.
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I would like to say that NDMA antagonism itself doesn't induce excitotoxicity while the antagonist is active, only as a "rebound overexcitation" when the antagonist has left the system, so in the case of concurrent use of SSRI and DXM that would not be the case. Moreover, I think it is still not clear to what extent NMDA antagonists actually induce excitotoxicity, especially following just one use (correct me if I'm wrong). NMDA antagonism would actually decrease the risk of excitotoxicity while the drugs are active.

I think the more probable reason is, like you said, just stereotypical thinking. Also, is it really considered that SSRIs are safe in overdose? I'm not an expert on SSRIs, but I think regardless of what the substance is, if it inhibits serotonin reuptake, then it has the potential to cause serotonin syndrome. In any case, if anything then I think Cotcha is right about SSRIs inhibiting CYP2D6 and thus indirectly increasing DXM's SRI action. But most likely it's still safe to take them both at the correct dosages (not that I advocate trying that, as always you never know what might happen).

There are many misconceptions about combining drugs. For example, a lot of people believe that drinking alcohol while taking antibiotics is an absolute no-no. It is true for some antibiotics, but in most cases there are few interactions if any. I have drunk while taking antibiotics myself (researched beforehand of course). Another one is alcohol + paracetamol. While it is true that the risk of serious hepatotoxicity increases when combining those two, it's illogical to say that combining them in ANY amounts is dangerous. People tend to over-simplify things that they don't understand very well, so they tend to think that if a certain combination CAN be dangerous (APAP+ethanol; antibiotics+ethanol; opioids+benzos) that it follows that combining the two IS dangerous.

Also, there are probably a lot more cases where persons co-ingested dangerous amounts of DXM and an SSRI compared to overdoses of SSRIs alone, so the latter is just not thought about much when serotonin syndrome is brought up.
 
belligerent drunk said:
Also, there are probably a lot more cases where persons co-ingested dangerous amounts of DXM and an SSRI compared to overdoses of SSRIs alone, so the latter is just not thought about much when serotonin syndrome is brought up.
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exactly what i was trying to say
 
Several endogenous mechanisms exist to prevent serotonin syndrome from developing, including uptake, MAO-A, and autoreceptors. Normally, to induce serotonin syndrome, you have to bypass two of those mechanisms.

For example, SSRIs do not produce serotonin syndrome because their acute administration doesn't produce much of an increase in synaptic serotonin. That is because autoreceptors detect the rise in serotonin produced by transporter blockade, leading to inhibition of firing (5-HT1A) and release (5-HT1B/1D) from serotonergic neurons.

As another example, meperidine (demerol) is a serotonin uptake inhibitor. By itself, it does not induce serotonin syndrome, but it does induce the syndrome when combined with a MAO-A inhibitor.

NMDA receptor antagonists are known to drive the firing of serotonin neurons because they increase glutamate release in prefrontal cortex and other brain regions (which control serotonin neuron firing). They also inhibit GABAergic neurons that normally inhibit serotonergic neurons. So DXM may increase serotonin release, and there is evidence it can block reuptake. These effects are not normally sufficient to induce serotonin syndrome, but in the presence of an SSRI they can be be sufficient.
 
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5-HT2A, SSRIs do need to increase synaptic serotonin to a considerable extent, otherwise they would have no effect, am I wrong? From the rest of your comment it seems that DXM and SSRIs do synergize, but to what extent? Is it additive or multiplicative?
 
I don't think I'm remembering right but doesn't an average dose regimen of SSRI inhibit SERTs by 60% or something? What I'm wondering is if inhibiting the other 40% of SERTs isn't a linear 40% increase in serotonin concentrations because you would think that at 60% inhibition the remaining 40% SERTs would be mopping up more serotonin per SERT than usual, but getting up to 95% SERT inhibition with an OD would result in a massive increase of serotonin (non linear relative to 60% inhibition). I hope this is clear as mud lol. Basically is the relationship between SERT inhibition and serotonin concentrations non linear?
 
belligerent drunk said:
5-HT2A, SSRIs do need to increase synaptic serotonin to a considerable extent, otherwise they would have no effect, am I wrong? From the rest of your comment it seems that DXM and SSRIs do synergize, but to what extent? Is it additive or multiplicative?
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SSRIs don't produce much of an increase if given acutely. It has been argued that the lack of acute effects is why SSRIs take so long to start working. What happens is that with continued treatment the serotonin autoreceptors gradually desensitize and then SSRIs start to increase synaptic serotonin to a much greater degree.

For your second question, the answer probably depends on the doses used. It is probably not simply additive, because neither drug alone can induce as much of an effect as the combination.
 
What you're saying makes sense, but wouldn't SSRIs not be reuptake inhibitors in that case? Because drugs that inhibit reuptake generally do have pronounced acute effects (amphetamines, MDMA etc). According to simple logic it would follow that if reuptake of a neurotransmitter is decreased, thus increasing synaptic concentration of the NT, that the receptor activation would be increased. The mechanism of action you describe begs a different explanation than simple reuptake inhibition. In which case I'm pretty much lost as to the answer to the OP's question.

E: To Cotcha (I apologize if the following text reeks of ignorance and lack of understanding). If we assume that all the serotonin in the synaptic cleft is removed from there by the transporter (not the reality, but it's close to that, right? 90%?), then by simple equilibrium rules the concentration of serotonin vs SERT inibition should be about exponential. If there is absolutely no reuptake, 0% SERT activity, then serotonin concentration should go towards infinity (ideally, obviously; not taking diffusion and other factors into account), and with 100% SERT activity the concentration should be x. Semi-logically, it kind of follows that at 50% SERT activity the concentration should be 2x, right? And with each two-fold decrease in SERT activity, there should be a two-fold increase in serotonin. It's been a late night for me so I apologize if this is illogical, I can't think it through; I'll give it another shot tomorrow.
 
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belligerent drunk said:
What you're saying makes sense, but wouldn't SSRIs not be reuptake inhibitors in that case? Because drugs that inhibit reuptake generally do have pronounced acute effects (amphetamines, MDMA etc).
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Amphetamine and MDMA primarily work as monoamine releasers, not uptake inhibitors. Most DA uptake inhibitors lack psychostimulant activity (e.g., GBR 12909, benztropine). Cocaine and methylphenidate are unusual cases, and they may actually release dopamine through DAT.

belligerent drunk said:
According to simple logic it would follow that if reuptake of a neurotransmitter is decreased, thus increasing synaptic concentration of the NT, that the receptor activation would be increased. The mechanism of action you describe begs a different explanation than simple reuptake inhibition. In which case I'm pretty much lost as to the answer to the OP's question.
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Serotonergic transmission is regulated by autoreceptors to keep it within a very specific range. So if you block reuptake of serotonin, the cells compensate by reducing their firing rate and releasing fewer transmitter molecules per impulse. I'm not saying that there isn't any change in 5-HT transmission after acute administration of SSRIs, but the increase is substantially blunted by reduced firing and transmitter release. Acute paroxetine is certainly not perceived as being similar to MDAI or MBDB.
 
Well, that clears it up for me somewhat, thanks 5-HT2A. I wonder though how SSRIs change the way the serotonergic system works in the long run then. Does DXM work the same way, then? And if SRIs are unable to produce a significant acute effect, then how is acute serotonin syndrome even possible?
 
I too wonder what all happens with long term ssri use, is the goal solely 5-HT2A downregulation or are there other receptors you typically want down regulated as well? Or are there more receptors (5-HT1A?) where you benefit from the increase in synaptic serotonin? Is there more to it than just receptor homeostasis? (BDNF and such aside)

Anywho I think MDMA for one reverses the transporter and is also a 5-HT2B agonist (most of the SSRIs are as well) which has some responsibility for the function of SERT and is also supposedly protective against serotonin syndrome, so maybe SSRIs have that going for them as well and DXM may not https://www.ncbi.nlm.nih.gov/m/pubmed/21277875/
 
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SSRIs do produce an acute effect, it's just not the long term antidepressant one.

The long term picture of SSRI therapy involves a bunch of crazy subtle changes in the brain outside of simple autoreceptor density changes. there are reviews on it, i'm sure.


The main reason to avoid combining DXM and SSRI/SNRI drugs is because you can't tell by how much they will potentiate each other, leading to situations where you can have massive SRI/NRI overdoses leading to SS/hypertension.
 
WRT to DXM and SSRIs, is it the case that risks are primarily present when taking large quantities of DXM, or is it a case of better safe than sorry and DXM should just be avoided in general while on SSRIs?
 
Ended up trying out because I figured dose makes the poison. Started with 5mg or so, nothing happened, upped to 20 (dumb I know, but I was hoping it'd get rid of my cough). Far as I could tell, nothing went wrong, but obviously risks were taken. Didn't help with the cough, either...
 
Psychiatrists sometimes prescribe both SSRI and SNRI at quite large doses, and either they do not know about SS, or the risks are very small. My GF used 60 mg of both paroxetine and duloxetine at one moment, not she is tapering paroxetine and trying to remain on duloxetine.
 
Regular cough dosages shouldn't be harmful as long as you're not in the initial 1-2 weeks of initiating a new SSRI (even then the chance to catch a SS is small, but it exists).

Yeah, some docs prescribe crazy regimens sometimes.. I really don't get it why it should be so hard to get a script for ketamine to alleviate horrid treatment resistant depression and anxiety or pain when they throw out life-threatening scripts from time to time. Remember a colleague who was prescribed 150mg's of d-amphetamine per day, along with duloxetine, propranolol and ropinirole. She's having cognitive problems still now, over a year after stopping the medications. And this was from a professor at the university clinic in Switzerland.
 
dopamimetic said:
Regular cough dosages shouldn't be harmful as long as you're not in the initial 1-2 weeks of initiating a new SSRI (even then the chance to catch a SS is small, but it exists).
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That lines up with experience, I'll keep the second part in mind once I start fluoxetine in a few weeks.
 
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