Antidepressants in patient with arrhythmias

[Psychresy]

I haven't found much data to suggest which medications might have the best safety profile, with the exception of recommendations to avoid TCAs and possibly celexa. I also see mirtazapine is associated with potential for slight increase in qtc, but nothing concrete in terms of guidelines. How would you handle a patient with history of arrhythmia on rate control?

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[cbrons]

What do you mean "arrhythmia on rate control?"

The issue with most psychotropics is that they cause dose-dependent QTc prolongation which in turn can result in torsades, which can be life-threatening. As far as I know there isn't an association with other types of dysrhythmias.

All SSRIs and TCAs cause QT prolongation but citalopram is probably the worst (that's been my experience as an internist) hence the FDA blackbox warning and recommended upper limit of 20mg in older patients.

btw the best site to lookup a drugs effect on QT and its strength of association with torsades is www.crediblemeds.org.

 

[wolfvgang22]

Concerns about prolonged QTc are overblown. How many torsades due to medications have you seen?

 

[clozareal]

QT changes are typically not seen at clinical doses but can be seen in doses over FDA max for some SSRIs, particularly citalopram and escitalopram (dose related) but even this is hasn't been shown in large studies to have an effect on arrhythmia or cardiac mortality.

I would probably start with sertraline or mirtazapine given that it's been studied pretty extensively in patients with recent MI. The other SSRIs are probably also safe. To be conservative, you can also avoid (es)citalopram although there was one huge study showing that higher doses of citalopram was associated with fewer cardiac adverse outcomes than lower doses.

I would avoid anything noradrenergic (bupropion, SNRIs) and especially TCAs since both can affect blood pressure, heart rate, and cardiac contractility.

Coordinate with the cardiologist/primary care provider to make sure they get an ECG once a patient is on a stable dose.

 

[calvnandhobbs68]

Concerns about prolonged QTc are overblown. How many torsades due to medications have you seen?

Agree...most of the concerns come from the days when people would push IV Haldol over and over when someone was already getting IV Zofran or some other QT prolonging med.

I think if someone's on 3 different QT prolonging meds regularly then probably be careful and grab an EKG every now and then but the incidence of significant dangerous QT prolongation from a single agent is almost nonexistent.

 

[clausewitz2]

A registry analysis of sudden cardiac deaths associated with neuroleptics I read a few months ago broke down excess deaths associated with prescriptions of specific neuroleptics. The idea being you could assess relative risk by actually looking at how many people had to be prescribed the med in question for someone to actually suffer an event in actual practice.

Geodon was least associated with excess sudden cardiac deaths.


I am much less in a tizzy about QTc per se since reading that. It is a sign that something is affecting the heart, but a poor indicator of how much weight if any to put on it. TdP doesn't happen solely as a function of the QT interval reaching a certain length.

 

[Psychresy]

What do you mean "arrhythmia on rate control?"

The issue with most psychotropics is that they cause dose-dependent QTc prolongation which in turn can result in torsades, which can be life-threatening. As far as I know there isn't an association with other types of dysrhythmias.

All SSRIs and TCAs cause QT prolongation but citalopram is probably the worst (that's been my experience as an internist) hence the FDA blackbox warning and recommended upper limit of 20mg in older patients.

btw the best site to lookup a drugs effect on QT and its strength of association with torsades is www.crediblemeds.org.

History of aflutter, currently on diltiazem. Patient also heart disease, CAD.

Thanks for that resource btw

 

[hamstergang]

A registry analysis of sudden cardiac deaths associated with neuroleptics I read a few months ago broke down excess deaths associated with prescriptions of specific neuroleptics. The idea being you could assess relative risk by actually looking at how many people had to be prescribed the med in question for someone to actually suffer an event in actual practice.

Geodon was least associated with excess sudden cardiac deaths.


I am much less in a tizzy about QTc per se since reading that. It is a sign that something is affecting the heart, but a poor indicator of how much weight if any to put on it. TdP doesn't happen solely as a function of the QT interval reaching a certain length.

I made a post about this 5 years ago and didn't get much support:

As mentioned in the study I quoted in my most recent post, "the risk of TdP in patients with LQT is poorly characterized in the literature." There just isn't enough information to be able to say that someone with a QTc in a certain range or a certain QT prolongation from baseline has x% chance of TdP. If drug A prolongs the QT interval more than drug B, it isn't necessarily so that drug A confers a higher risk of TdP. While Geodon prolongs the QTc more than other antipsychotics currently in use, I haven't seen any evidence (and not from a lack of reading, despite what you may believe, Jester) that Geodon is associated with a higher incidence of TdP or sudden death. The prescribing information for Geodon doesn't even recommend an EKG prior to medication initiation.

So the problem is that, while there is a correlation between QT prolongation and TdP, getting the value of the QTc or prolongation of QTc doesn't do much to help you determine if your patient is at appreciably increased risk of TdP. You get the EKG, but then what?

 

[VA Hopeful Dr]

History of aflutter, currently on diltiazem. Patient also heart disease, CAD.

Thanks for that resource btw

Go with whatever in this patient.

 

[cbrons]

QT changes are typically not seen at clinical doses but can be seen in doses over FDA max for some SSRIs, particularly citalopram and escitalopram (dose related) but even this is hasn't been shown in large studies to have an effect on arrhythmia or cardiac mortality.

I would probably start with sertraline or mirtazapine given that it's been studied pretty extensively in patients with recent MI. The other SSRIs are probably also safe. To be conservative, you can also avoid (es)citalopram although there was one huge study showing that higher doses of citalopram was associated with fewer cardiac adverse outcomes than lower doses.

I would avoid anything noradrenergic (bupropion, SNRIs) and especially TCAs since both can affect blood pressure, heart rate, and cardiac contractility.

Coordinate with the cardiologist/primary care provider to make sure they get an ECG once a patient is on a stable dose.

It is seen at clinical doses in patients with acute kidney injury though which is something I've seen a few times now even in my short career. A few months ago in a 80 year old on 20 or 40mg Celexa (cant remember which) but with an AKI had a QTc of 600. Nothing bad happened but still made me nervous. Went away by withholding drug obviously.

Another concern is multiple QT prolonging meds together. And PPIs are QT prolonging btw (which people forget). Honestly this might be a bigger issue in hospital medicine than psychiatry.

 

[wolfvgang22]

Yeah, 40mg of Celexa in an 80 year old with AKI and probable existing polypharmacy sounds like a bad idea. lol

 

[clausewitz2]

Yeah, 40mg of Celexa in an 80 year old with AKI and probable existing polypharmacy sounds like a bad idea. lol

But if they are a bit demented and it makes them less agitated to the point they don't end up getting prescribed a neuroleptic with a very clear increase in risk of all-cause mortality, less clear answer.

 

[Psychresy]

Yeah, 40mg of Celexa in an 80 year old with AKI and probable existing polypharmacy sounds like a bad idea. lol

Why are we particularly concerned with Celexa in AKI? I was under the impression it does not need to be renally dosed, as opposed to lexapro when GFR is sub 30.

 

[cbrons]

Why are we particularly concerned with Celexa in AKI? I was under the impression it does not need to be renally dosed, as opposed to lexapro when GFR is sub 30.

I could be wrong

 

[wolfvgang22]

Why are we particularly concerned with Celexa in AKI? I was under the impression it does not need to be renally dosed, as opposed to lexapro when GFR is sub 30.

I'm not. It's just part of the clinical picture that indicates "one sick hombre" that probably already has polypharmacy and multiple comorbidities I don't want to add to.

 

[Mass Effect]

It is seen at clinical doses in patients with acute kidney injury though which is something I've seen a few times now even in my short career. A few months ago in a 80 year old on 20 or 40mg Celexa (cant remember which) but with an AKI had a QTc of 600. Nothing bad happened but still made me nervous. Went away by withholding drug obviously.

Another concern is multiple QT prolonging meds together. And PPIs are QT prolonging btw (which people forget). Honestly this might be a bigger issue in hospital medicine than psychiatry.

Anyone over 65 should be on a dose of 20 mg Celexa max. I get a lot of people from PCPs and OBs who love Celexa. I don't know why. I rarely use it.

For cardiac patients like the OP's patient, my go-to is usually Zoloft.

I don't tend to worry about QT in most SSRIs unless they're on multiple QT prolonging meds. I did inherit a patient once on 35 mg of Lexapro (OCD), daily hydroxyzine, and Zofran prn which was being used daily and that made me nervous. But I got an EKG and it was fine.

 

[clozareal]

Anyone over 65 should be on a dose of 20 mg Celexa max. I get a lot of people from PCPs and OBs who love Celexa. I don't know why. I rarely use it.

This is probably because they were taught about STAR*D during medical school/residency and then saw that Celexa was the first medication that was used. So they adopted that for themselves.

 

[clausewitz2]

Celexa is somewhat different from Lexapro in that racemate citalopram binds h1 with an order of magnitude affinity higher than the s-enantiomer. Given that one of celexa's claims to fame are the papers that claimed it was as effective as neuroleptics in reducing agitation in elderly people, it is plausible that celexa may accomplish this in a way Lexapro does not. Those papers were also using 40 mg doses of celexa at least, so it is not the go to if you think prolonged QTc is a huge problem in and of itself.

 

[Mass Effect]

Celexa is somewhat different from Lexapro in that racemate citalopram binds h1 with an order of magnitude affinity higher than the s-enantiomer. Given that one of celexa's claims to fame are the papers that claimed it was as effective as neuroleptics in reducing agitation in elderly people, it is plausible that celexa may accomplish this in a way Lexapro does not. Those papers were also using 40 mg doses of celexa at least, so it is not the go to if you think prolylong QTc is a huge problem in and of itself.

Yeah, I don't use it for agitation even in the ICU. I don't feel comfortable dosing it that high in the elderly. I was in med school when the recommendations changed to 40 mg max and then later the elderly dose dropped to 20 mg. Between those two events, one of our attendings presented a case report on a patient of his colleague's who developed TdP because the dose wasn't lowered from 50 mg (or may have been 60 mg, but I think it was 50) following the first recommendation. Patient was 70 though and on other meds too. I know it's rare, but that case stuck with me.

 

[robellis]

Yeah, I don't use it for agitation even in the ICU. I don't feel comfortable dosing it that high in the elderly. I was in med school when the recommendations changed to 40 mg max and then later the elderly dose dropped to 20 mg. Between those two events, one of our attendings presented a case report on a patient of his colleague's who developed TdP because the dose wasn't lowered from 50 mg (or may have been 60 mg, but I think it was 50) following the first recommendation. Patient was 70 though and on other meds too. I know it's rare, but that case stuck with me.

Do you routinely use ssri for agitation in the ICU?

 

[Mass Effect]

Do you routinely use ssri for agitation in the ICU?

Nope. I just meant I don't use it inpatient or outpatient, even if the patient is already on it and on tele or in an intensive care unit where QTc can be monitored. ICU was probably a poor example since it's so acute though. But say I get a 70 yo outpatient on Celexa 20 mg. I wouldn't bump it to treat agitation.

 

[Stagg737]

I haven't found much data to suggest which medications might have the best safety profile, with the exception of recommendations to avoid TCAs and possibly celexa. I also see mirtazapine is associated with potential for slight increase in qtc, but nothing concrete in terms of guidelines. How would you handle a patient with history of arrhythmia on rate control?

Here's the APA guidelines page, the second one from 2018 is on QTc prolongation. This one is a bit useless since most of the "guidelines" are either "use caution" or "generally safe". There is a nice review on QTc calculation and a lot of solid links to studies though, so worth the read from that perspective at least.

Resource Documents

View APA's official resource documents at psychiatry.org

www.psychiatry.org

For this patient, we'd need more info to give decent recs, even knowing the history is A flutter on dilt. How frequently have they gone into A flutter without a stabilizing med? What other meds are they on? What's their current QTc vs. their normal baseline? What's their baseline? How old are they? What's the setting? Medical inpatient? Psych inpatient? Outpatient? Hospice? Substance rehab? What is their substance history? What are you actually treating (I'm assuming depression)?

If you want to be very conservative, use lower doses of Zoloft (Zoloft is generally considered the safest antidepressant in terms of QTc), minimize polypharmacy as much as possible, and monitor frequently. However, depending on the answer to the above questions you may not need to do much outside of the norm (which always includes limiting polypharmacy imo) and regular cardiac monitoring for underlying heart issues.

QT changes are typically not seen at clinical doses but can be seen in doses over FDA max for some SSRIs, particularly citalopram and escitalopram (dose related) but even this is hasn't been shown in large studies to have an effect on arrhythmia or cardiac mortality.

I would probably start with sertraline or mirtazapine given that it's been studied pretty extensively in patients with recent MI. The other SSRIs are probably also safe. To be conservative, you can also avoid (es)citalopram although there was one huge study showing that higher doses of citalopram was associated with fewer cardiac adverse outcomes than lower doses.

I would avoid anything noradrenergic (bupropion, SNRIs) and especially TCAs since both can affect blood pressure, heart rate, and cardiac contractility.

Coordinate with the cardiologist/primary care provider to make sure they get an ECG once a patient is on a stable dose.

I actually use Wellbutrin fairly frequently in patients with QTc risk. There are several studies on it suggesting it is one of the least likely antidepressants to prolong QTc behind Zoloft. There are also several studies suggesting that Duloxetine actually decreases QTc. That being said, most EKGs use Bazette's formula to calculate QTc which underestimates it at higher heart rates, so that needs to be accounted for if using these meds leads to increased HR.

I generally don't care about a single EKG unless the QTc is extremely high (>550 makes me concerned, >600 I'm likely holding the QTc prolonging med regardless of what it is/dose). Imo the value of QTc is in comparison to previous baselines or for ongoing monitoring. A QTc of 490 doesn't mean much to me (and certainly doesn't bother me) if that's the norm for the patient and they don't have a significant cardiac history Despite recommendations that over 450 should be concerning. I honestly don't start paying much attention to QTc unless it's >500, the patient is acutely in critical condition, or they have a significant cardiac history.

Geodon was least associated with excess sudden cardiac deaths.

I made a post about this 5 years ago and didn't get much support:

This is interesting, can one of you link the study if it's not too much trouble? I always find it interesting that our field tends to have several recommendations on meds even though larger studies show conflicting results. It's like the significant concern of death in Clozapine despite FIN11 showing it has the lowest all-cause mortality as well as lowest rate of cardiac related deaths in an N>66,000. I also find it interesting how incongruent the shelf test for psych seems to be with actual data and practices.

 

[clausewitz2]

Here's the APA guidelines page, the second one from 2018 is on QTc prolongation. This one is a bit useless since most of the "guidelines" are either "use caution" or "generally safe". There is a nice review on QTc calculation and a lot of solid links to studies though, so worth the read from that perspective at least.

Resource Documents

View APA's official resource documents at psychiatry.org

www.psychiatry.org

For this patient, we'd need more info to give decent recs, even knowing the history is a flutter on dilt. How frequently have they gone into A flutter without a stabilizing med? What other meds are they on? What's their current QTc vs. their normal baseline? What's their baseline? How old are they? What's the setting? Medical inpatient? Psych inpatient? Outpatient? Hospice? Substance rehab? What is their substance history? What are you actually treating (I'm assuming depression)?

If you want to be very conservative, use lower doses of Zoloft (Zoloft is generally considered the safest antidepressant in terms of QTc), minimize polypharmacy as much as possible, and monitor frequently. However, depending on the answer to the above questions you may not need to do much outside of the norm (which always includes limiting polypharmacy imo) and regular cardiac monitoring for underlying heart issues.



I actually use Wellbutrin fairly frequently in patients with QTc risk. There are several studies on it suggesting it is one of the least likely antidepressants to prolong QTc behind Zoloft. There are also several studies suggesting that Duloxetine actually decreases QTc. That being said, most EKGs use Bazette's formula to calculate QTc which underestimates it at higher heart rates, so that needs to be accounted for if using these meds leads to increased HR.

I generally don't care about a single EKG unless the QTc is extremely high (>550 makes me concerned, >600 I'm likely holding the QTc prolonging med regardless of what it is/dose). Imo the value of QTc is in comparison to previous baselines or for ongoing monitoring. A QTc of 490 doesn't mean much to me (and certainly doesn't bother me) if that's the norm for the patient and they don't have a significant cardiac history Despite recommendations that over 450 should be concerning. I honestly don't start paying much attention to QTc unless it's >500, the patient is acutely in critical condition, or they have a significant cardiac history.





This is interesting, can one of you link the study if it's not too much trouble? I always find it interesting that our field tends to have several recommendations on meds even though larger studies show conflicting results. It's like the significant concern of death in Clozapine despite FIN11 showing it has the lowest all-cause mortality as well as lowest rate of cardiac related deaths in an N>66,000. I also find it interesting how incongruent the shelf test for psych seems to be with actual data and practices.

Clozapine is an interesting example, agranulocytosis happened at a rate three times higher in the Finnish data that led to the temporary withdrawal from the market than any published papers since. Totally wild speculation but given the frequency of hematological and metabolic weirdness in Finnish populations (it seemed like the only time Finland was ever mentioned in med school was because of some rare genetic disease) I wonder if the true rate is much closer to later data than those initial reports if you aren't practicing north of the Baltic.

Re antipsychotics and SCD in a national registry, here you go:

https://www.ahajournals.org/doi/10.1161/JAHA.114.001568

Table 2 is what I was referring to

 

[Stagg737]

Clozapine is an interesting example, agranulocytosis happened at a rate three times higher in the Finnish data that led to the temporary withdrawal from the market than any published papers since. Totally wild speculation but given the frequency of hematological and metabolic weirdness in Finnish populations (it seemed like the only time Finland was ever mentioned in med school was because of some rare genetic disease) I wonder if the true rate is much closer to later data than those initial reports if you aren't practicing north of the Baltic.

Re antipsychotics and SCD in a national registry, here you go:

https://www.ahajournals.org/doi/10.1161/JAHA.114.001568

Table 2 is what I was referring to

Yes, I'm pretty familiar with the h/o Clozapine and that one Scandanavian study that da**ed it int he US in interest of big pharma. I like to use it as a nice segue into discussion of politics' role in medicine and understanding the history of one's chosen field when talking to med students. It's also a good talking point in terms of continued education and reading in terms of understanding what's tested on their shelves often misses other very important facts. For example, agranulocytosis is a must know for shelf exams, but knowing that meds like Bactrim and Sulfasalazine also have a relatively high risk of causing it and that even meds like NSAIDs or Spironolactone can have an increased incidence won't be in study resources for shelf exams (maybe sulfasalazine as a general part of RA treatments).

I know that's a bit of a tangent, but does reinforce the importance of continuing education and understanding where guidelines are actually coming from and what how strictly we should actually be adhering to them.

 

[clozareal]

I actually use Wellbutrin fairly frequently in patients with QTc risk. There are several studies on it suggesting it is one of the least likely antidepressants to prolong QTc behind Zoloft. There are also several studies suggesting that Duloxetine actually decreases QTc. That being said, most EKGs use Bazette's formula to calculate QTc which underestimates it at higher heart rates, so that needs to be accounted for if using these meds leads to increased HR.

I'm not concerned about bupropion's effect on QTc. I'm concerned for the noradrenergic effect on the beta-1 and beta-2 receptors of the heart causing inotropic (QRS amplitude) and chronotropic (RR interval/increasing HR) changes outside of the QTc interval, particularly in someone with atrial fibrillation/flutter. I'm also concerned about the noradrenergic effect on alpha-1 receptors on arterioles (there are no alpha-1 receptors on the heart itself) which can increase systemic vascular resistance and afterload, which would then decrease stroke volume and thus have to compensate by either decreasing heart rate or increasing cardiac output (remember: CO = HR x SV). In any case, I'd rather stay away from all of these adrenergic effects.

 

[hebel]

Some people are mentioning situations when there's multiple QTc prolonging drugs, but have you ever looked at it by the actual K channels affected? I came across this comment on reddit years ago, and found it very interesting. What do you guys think?...

"QTc: First, you have to understand that there is always a risk of Qtc prolongation with zofran. There is no zero risk. That is to say, even if you give it to a completely healthy individual, he might have this effect and depending on the context, it MIGHT lead to a torsade de pointe (might because it increases the risk, it's not 100% sure the individual will have the arrythmia. Other factors can increase the risk. I'll get into that later). That is why the drug is contraindicated in congenital long qt syndrome. However, it is not contraindicated with other drugs known to prolong the qt interval, there is merely a warning to be careful. So how can we be careful? First, you have to understand how two drugs can work together to prolong the qtc interval. Most of the drugs commonly used will prolong the qtc interval by either acting on the Ikr channels or the Iks channels on the heart. These are potassium channels involved in repolarizing the cell membrane. Drugs will compete to bind on these channels, and the one that has the highest affinity will win. Hence, if you have two drugs acting on Ikr and no pharmacokinetic interaction, you will not have additive effects on the Qt interval, because you have a finite number of sites on which the drugs can bind and the one with the highest affinity will always win. So first question you have to ask yourself is, does that drug bind to Ikr or Iks?

Fortunately for us, there are few drugs that act on iks that are commonly used, so it's pretty easy to remember: indapamide, propofol, amiodarone, chloroquine, imipramine, losartan, propafenone, sotalol and triamterene. As you may have noticed, a few of them are antiarrythmics. These are red flags! Because, that means your patient already has arrythmia. Some of them are diuretics. It's also a red flag, because your patient might have electrolytes disturbance! Also, if you have a drug that acts on Iks and you add one that acts on Ikr, it is when it gets a bit more risky, because now you can have an additive effect on the qtc interval! Otherwise, if you have two drugs that act on the same channel, the only time you can have a bigger effect on the qtc interval is if you have a pharmacokinetic interaction. Ex: I have a patient that has a prescription for fluconazole who is already taking a high dose of citalopram. Fluconazole and citalopram both act on Ikr. However, I have to understand that I can have a bigger impact on the Qtc interval because fluconazole inhibits citalopram's metabolism. Thus, there will be higher concentrations of citalopram and we can expect a bigger effect on the qtc interval from the citalopram because we know it's dose dependant!

So back to your question! I can answer the first part. All SSRIs known to prolong the qtc interval act on the Ikr channel. Zofran also acts on the ikr channel. There is no pharmacokinetic interaction between zofran and SSRIs. Hence, there will not be an additive effect from giving zofran to somebody already on a SSRI. So from that standpoint, we're good. Now, there are also other factors to consider. I'm sure most of your patients do not only take SSRIs, so you have to look at other drugs the patient is taking, always asking yourself if one of the drugs acts on a different channel (Iks mostly) or if you have a pharmacokinetic interaction. Once you're done, consider the overall risk of your patient:

• Patient is over 68 years old

• Patient is a woman

• Patient has electrolytes disturbance. Often, you don't have lab results that you can check. So suspect it for patients with renal failure, on diuretics, on PPIs (hypomagnesemia), etc.

• Patient already has prolonged qtc interval. Often, you won't have an EKG! So you can ask the patient some questions to find the highest risk patients. I ask them if they have a family history of sudden death or drowning, because a lot of patients with channelopathies do. A red flag for me also is if they are on nadolol without other drugs for cirrhosis, because nadolol is often used for channelopathies where I live. If you have access to an EKG, know that zofran at most prolongs the Qtc interval by 22 ms, and we consider we might get in trouble if you prolong over 500 ms most of the time. So you can calculate the worst situation!

• Acute MI

• HFrEF

• Sepsis

• Bradycardia

• more than 2 drugs that prolong the Qtc interval (but be smart about that last one, if you only have drugs that act on Ikr and no pharmacokinetic interaction, there is no additivity, so no worries!)"

 

[Stagg737]

I'm not concerned about bupropion's effect on QTc. I'm concerned for the noradrenergic effect on the beta-1 and beta-2 receptors of the heart causing inotropic (QRS amplitude) and chronotropic (RR interval/increasing HR) changes outside of the QTc interval, particularly in someone with atrial fibrillation/flutter. I'm also concerned about the noradrenergic effect on alpha-1 receptors on arterioles (there are no alpha-1 receptors on the heart itself) which can increase systemic vascular resistance and afterload, which would then decrease stroke volume and thus have to compensate by either decreasing heart rate or increasing cardiac output (remember: CO = HR x SV). In any case, I'd rather stay away from all of these adrenergic effects.

I'm still not that concerned with the noradrenergic effects of Bupropion unless they're at max dose given the poor binding affinity for any of those receptors (Ki>10,000). I could see the concern with Duloxetine, but again depends on the patient and what their comorbidities and underlying cardiac status is. I agree with avoiding it for patients with tachycardia or h/o a fib/flutter, but I wouldn’t pull it completely off the table. Duloxetine and SNRIs in general I’m more am cautious about, but purely in terms of QTc Duloxetine isn’t unreasonable.

Some people are mentioning situations when there's multiple QTc prolonging drugs, but have you ever looked at it by the actual K channels affected? I came across this comment on reddit years ago, and found it very interesting. What do you guys think?...

"QTc: First, you have to understand that there is always a risk of Qtc prolongation with zofran. There is no zero risk. That is to say, even if you give it to a completely healthy individual, he might have this effect and depending on the context, it MIGHT lead to a torsade de pointe (might because it increases the risk, it's not 100% sure the individual will have the arrythmia. Other factors can increase the risk. I'll get into that later). That is why the drug is contraindicated in congenital long qt syndrome. However, it is not contraindicated with other drugs known to prolong the qt interval, there is merely a warning to be careful. So how can we be careful? First, you have to understand how two drugs can work together to prolong the qtc interval. Most of the drugs commonly used will prolong the qtc interval by either acting on the Ikr channels or the Iks channels on the heart. These are potassium channels involved in repolarizing the cell membrane. Drugs will compete to bind on these channels, and the one that has the highest affinity will win. Hence, if you have two drugs acting on Ikr and no pharmacokinetic interaction, you will not have additive effects on the Qt interval, because you have a finite number of sites on which the drugs can bind and the one with the highest affinity will always win. So first question you have to ask yourself is, does that drug bind to Ikr or Iks?

Fortunately for us, there are few drugs that act on iks that are commonly used, so it's pretty easy to remember: indapamide, propofol, amiodarone, chloroquine, imipramine, losartan, propafenone, sotalol and triamterene. As you may have noticed, a few of them are antiarrythmics. These are red flags! Because, that means your patient already has arrythmia. Some of them are diuretics. It's also a red flag, because your patient might have electrolytes disturbance! Also, if you have a drug that acts on Iks and you add one that acts on Ikr, it is when it gets a bit more risky, because now you can have an additive effect on the qtc interval! Otherwise, if you have two drugs that act on the same channel, the only time you can have a bigger effect on the qtc interval is if you have a pharmacokinetic interaction. Ex: I have a patient that has a prescription for fluconazole who is already taking a high dose of citalopram. Fluconazole and citalopram both act on Ikr. However, I have to understand that I can have a bigger impact on the Qtc interval because fluconazole inhibits citalopram's metabolism. Thus, there will be higher concentrations of citalopram and we can expect a bigger effect on the qtc interval from the citalopram because we know it's dose dependant!

So back to your question! I can answer the first part. All SSRIs known to prolong the qtc interval act on the Ikr channel. Zofran also acts on the ikr channel. There is no pharmacokinetic interaction between zofran and SSRIs. Hence, there will not be an additive effect from giving zofran to somebody already on a SSRI. So from that standpoint, we're good. Now, there are also other factors to consider. I'm sure most of your patients do not only take SSRIs, so you have to look at other drugs the patient is taking, always asking yourself if one of the drugs acts on a different channel (Iks mostly) or if you have a pharmacokinetic interaction. Once you're done, consider the overall risk of your patient:

• Patient is over 68 years old

• Patient is a woman

• Patient has electrolytes disturbance. Often, you don't have lab results that you can check. So suspect it for patients with renal failure, on diuretics, on PPIs (hypomagnesemia), etc.

• Patient already has prolonged qtc interval. Often, you won't have an EKG! So you can ask the patient some questions to find the highest risk patients. I ask them if they have a family history of sudden death or drowning, because a lot of patients with channelopathies do. A red flag for me also is if they are on nadolol without other drugs for cirrhosis, because nadolol is often used for channelopathies where I live. If you have access to an EKG, know that zofran at most prolongs the Qtc interval by 22 ms, and we consider we might get in trouble if you prolong over 500 ms most of the time. So you can calculate the worst situation!

• Acute MI

• HFrEF

• Sepsis

• Bradycardia

• more than 2 drugs that prolong the Qtc interval (but be smart about that last one, if you only have drugs that act on Ikr and no pharmacokinetic interaction, there is no additivity, so no worries!)"

That's actually a very nice post overall, especially that list of drugs effecting slow potassium channels. The bolded isn't quite right though, as the poster is assuming that maximum saturation has been reached. If you have two drugs and one has a far higher affinity, it only means that it will have priority in terms of binding, not that it will make the other drug completely irrelevant, so there can still be additive effects, especially if the first drug is at lower doses. Clozapine + Abilify is a perfect example of this in terms of D2 receptors. If you've got patient on 400mg of Clozapine and 5-10mg of Abilify, it doesn't mean there won't be any Clozapine bound to D2 receptors if there's not enough Abilify in the system to saturate those receptors (though it may be more likely than with other antipsychotics given that Clozapine is more likely to bind to serotonin receptors than D2 and there is less for Abilify to kick off).

 

[d2305]

Has anyone actually seen a vtach/vfib from a normal recommended dose of a ssri, tca, antihistamine?

 

[NickNaylor]

I haven't once seen a cardiac arrhythmia related to psychotropic use, and like @calvnandhobbs68 I only start to get concerned if there are multiple QT-prolonging drugs on board. The association between TdP and QT-prolonging drugs actually isn't that straightforward... in patients with congenital QT prolongation there is a clear increase in risk between SCD and degree of QT prolongation, but that doesn't relationship is not nearly as strong in otherwise healthy people. And as @hamstergang mentioned, the degree to which a drug causes QT prolongation and the incidence of SCD is decoupled.

I'm not making the argument to be cavalier and ignore QT prolongation altogether, but I agree that the risk is extremely overblown. Manage risk factors, be cautious in acutely ill patients and patients with cardiac risk factors, and monitor closely if there's a significant risk. A couple of months ago, I had an older woman present acutely manic who had been stable for many years on olanzapine but decompensated after she stopped taking it. Her QTc on admission was >600 with no clear cause and no history of QT prolongation in the past. Lithium wasn't an option (I forget why) and she developed hyperammonemia with VPA, so I stuck with the olanzapine, titrated very slowly, regularly checked electrolytes, and checked an EKG every couple of days. She was able to get to a total doe of 30 mg daily and the QT prolongation eventually resolved itself.