Restarting meds after serotonin syndrome -- What is safe and what isn't?

[SpongeBob DoctorPants]

I have a patient who has had some kind of reaction to medications which is believed to be serotonin syndrome, but this could not be definitively confirmed. All medications (including Prozac, BuSpar, and Adderall) were stopped prior to the patient's hospitalization, but at this time I am wondering... would it be safe to restart a medication with serotonergic effects? Or should I avoid them completely? I at least plan to avoid any combination of medications which may have this potential interaction. I have searched in the literature to get some idea of the risk involved with reintroducing serotonergic medications but haven't found anything yet.

---

Members don't see this ad.

 

[littlefred]

Here I thought that Buspirone had a negative effect on the efficacy of Fluoxetine. Have you given thought to swap to another SSRI that has a shorter half-life and ditch the Buspirone?

 

[clausewitz2]

Here I thought that Buspirone had a negative effect on the efficacy of Fluoxetine.

That's not what STAR*D suggested...

 

[littlefred]

I know, I was talking more on a pharmacological level. Buspirone is an 5-HT1A agonist and Fluoxetine diminishes 5-HT1A activity. 5-HT1A is associated with being more resilient to stress (antidepressant effect?) at least in rat models, hence my comment.

Clinically what I do is that I have prescribed them both together, but give the Buspirone as needed (1-2 hrs) prior to sexual activity but not on a daily basis, due to concerns of lower efficacy of the SRI for mood and serotonin syndrome.

 

[clausewitz2]

I mean, given the profound disconnect between the time scales of maximum blood levels/serotonin release in the cleft and the actual time scales of antidepressant effect, I think it is an inevitable conclusion that fluoxetine's effect on 5-HT1A per se cannot be the proximal mechanism of clinical benefit. This must lie significantly downstream.

 

[ara96]

I have a patient who has had some kind of reaction to medications which is believed to be serotonin syndrome, but this could not be definitively confirmed. All medications (including Prozac, BuSpar, and Adderall) were stopped prior to the patient's hospitalization, but at this time I am wondering... would it be safe to restart a medication with serotonergic effects? Or should I avoid them completely? I at least plan to avoid any combination of medications which may have this potential interaction. I have searched in the literature to get some idea of the risk involved with reintroducing serotonergic medications but haven't found anything yet.

Are you sure that they had serotonin syndrome at all? I have yet to see Serotonin Syndrome

 

[SpongeBob DoctorPants]

Are you sure that they had serotonin syndrome at all? I have yet to see Serotonin Syndrome

Really I am not sure this was a case of serotonin syndrome. There were several symptoms suggesting it, but interestingly conventional treatments for serotonin syndrome didn't help. I have also considered it may have just been delirium.

 

[Dharma]

I have yet to see Serotonin Syndrome

Really? Not even on CL? Subtler presentations of toxicity? Definitely has made me more vigilant. Nothing like tapping on those ankles and watching them beat away a like wind-up toy.

 

[psychattending]

True full blown serotonin syndrome is rare when agents are used at clinical doses. Thus the first step would be to determine if the pt had it, and then what produced it (e.g. did the pt take extra medicine, take an additional offending agent like dextromethoraphan). If in the end it is determined that it occurred solely from the agent at the prescribed dose, then if I had to use that specific agent again, I would use it at a lower dose.

 

[birchswing]

Did they check for carcinoid or pheo?

 

[SpongeBob DoctorPants]

True full blown serotonin syndrome is rare when agents are used at clinical doses. Thus the first step would be to determine if the pt had it, and then what produced it (e.g. did the pt take extra medicine, take an additional offending agent like dextromethoraphan). If in the end it is determined that it occurred solely from the agent at the prescribed dose, then if I had to use that specific agent again, I would use it at a lower dose.

Standard doses of each medication were prescribed, and I do not suspect that higher doses were taken. However, parents did inform me that they began substituting the Adderall with caffeine pills at high doses a few weeks before this happened, which was apparently working well for a while. At the time I sent the patient to the hospital, symptoms included intermittently dilated pupils, large fluctuations in blood pressure, altered mental status, and involuntary movements of the arms and neck.

 

[ara96]

Really? Not even on CL? Subtler presentations of toxicity? Definitely has made me more vigilant. Nothing like tapping on those ankles and watching them beat away a like wind-up toy.

Nope I have never seen it at all.

 

[Dharma]

Nope I have never seen it at all.

Keep on the look out. The subtle (and sometimes not-so-subtle) cases are missed. I'm not sure it's as rare as some believe. I have seen a handful of mild to moderate cases and one that was severe (all met Hunter Criteria). Interestingly enough, clinical doses were utilized however with significant metabolic interactions and in a few of those cases, a component of protein malnutrition, so effectively much higher serum levels than assumed. Granted, most were medically complex cases with other serotonergic agents (mostly pain meds and anti-emetics) on board.

It's definitely out there though. We need to remain aware of potential interactions and screen for use of other serotonergic agents including over-the-counter supplements. Some of our patients may also have variations in 2D6 and 3A4 metabolism as well which could yield a few outliers, especially when there is enzymatic inhibition at play. Also, we should probably break out a good ol' neuro exam every now and again when we have some suspicion.

Really I am not sure this was a case of serotonin syndrome. There were several symptoms suggesting it, but interestingly conventional treatments for serotonin syndrome didn't help. I have also considered it may have just been delirium.

By conventional treatment do you mean cyproheptadine or BZD? They do not always do the trick (especially the former despite its seemingly ubiquitous use).

At the time I sent the patient to the hospital, symptoms included intermittently dilated pupils, large fluctuations in blood pressure, altered mental status, and involuntary movements of the arms and neck.

What did his neuro exam look like? Any hyperreflexia or inducible clonus?

Any other agents on board? How old is this patient? Nutritionally sound? Any thought of gene testing in this case?

 

[clausewitz2]

Keep on the look out. The subtle (and sometimes not-so-subtle) cases are missed. I'm not sure it's as rare as some believe. I have seen a handful of mild to moderate cases and one that was severe (all met Hunter Criteria). Interestingly enough, clinical doses were utilized however with significant metabolic interactions and in a few of those cases, a component of protein malnutrition, so effectively much higher serum levels than assumed. Granted, most were medically complex cases with other serotonergic agents (mostly pain meds and anti-emetics) on board.

It's definitely out there though. We need to remain aware of potential interactions and screen for use of other serotonergic agents including over-the-counter supplements. Some of our patients may also have variations in 2D6 and 3A4 metabolism as well which could yield a few outliers, especially when there is enzymatic inhibition at play. Also, we should probably break out a good ol' neuro exam every now and again when we have some suspicion.



By conventional treatment do you mean cyproheptadine or BZD? They do not always do the trick (especially the former despite its seemingly ubiquitous use).



What did his neuro exam look like? Any hyperreflexia or inducible clonus?

Any other agents on board? How old is this patient? Nutritionally sound? Any thought of gene testing in this case?

Our toxicology service tends to believe that if there is not hyperreflexia or clonus it is probably not serotonin syndrome, to a first approximation. This is not my area of in-depth expertise so I defer to them; I think it is very easy to pin things on serotonergic agents when the clinical picture is unclear. They also simply don't use cyproheptadine and argue that the evidence base for it is distinctly unimpressive. They lean heavily on benzos, and as EM trained people they are very comfortable loading someone with whopping doses of Ativan and letting it be cleared slowly because they're comfortable intubating people if it comes down to it. Obviously less of an option for us...

 

[Dharma]

Our toxicology service tends to believe that if there is not hyperreflexia or clonus it is probably not serotonin syndrome, to a first approximation. This is not my area of in-depth expertise so I defer to them; I think it is very easy to pin things on serotonergic agents when the clinical picture is unclear. They also simply don't use cyproheptadine and argue that the evidence base for it is distinctly unimpressive. They lean heavily on benzos, and as EM trained people they are very comfortable loading someone with whopping doses of Ativan and letting it be cleared slowly because they're comfortable intubating people if it comes down to it. Obviously less of an option for us...

Every case I've seen has had impressive DTR's and inducible clonus, FWIW. Slam dunk IMO.

 

[MBBSMOM]

Only time I have actually seen serotonin syndrome was when the patient overdosed on an SSRI/snri . The IM doctor who I was working with told me it would be safe to restart the meds when heart rate and blood pressure went back to normal .

 

[clausewitz2]

I think the first thing to clarify is the patient had serotonin syndrome. I often get into battles with neurology about this. Did the patient meet hunter criteria for SS? Were they taking serotonergic drugs at the time? You must enter in a risk/benefit analysis too. if the patient has milder mental health problems and there are alternative treatments that might be safer (e.g. psychotherapy) then you may decide not to restart such medications. In starting meds, you start low, go slow, and minimize polypharmacy, as well as providing patient education about milder symptoms of serotonin toxicity to be aware of (e.g. diarrhea, tremor). In more serious illness, the benefits of medications may exceed the risks (for example I have a pt who had fever, AMS, clonus, hyperreflexia and tremor who i'm not convinced really had SS but the pt has a history of psychotic depression and serious suicide attempt so of course will be cautiously restarting appropriate meds). Also this may be one of the few occasions where pharmacogenetic testing to see if they are slow metabolizer of relevant cytochrome enzymes may be indicated, though SS is typically idiosyncratic.

Best not to forget alternative antidepressants that have not been implicated convincingly in SS like mirtazapine or nor/amitriptyline.

 

[SpongeBob DoctorPants]

By conventional treatment do you mean cyproheptadine or BZD? They do not always do the trick (especially the former despite its seemingly ubiquitous use).

What did his neuro exam look like? Any hyperreflexia or inducible clonus?

Any other agents on board? How old is this patient? Nutritionally sound? Any thought of gene testing in this case?

I appreciate your input. Yes, both cyproheptadine and benzodiazepines were used. The benzos only seemed to make things worse (causing irritability), but the cyproheptadine, while it did not appear to be very helpful, at least did not aggravate things. Spontaneous clonus of the leg was documented in the hospital records. Blood pressure was variable, and though it was generally in the normal range, at times it rose to levels as high as 170/90. Patient is an adolescent and other than what I have listed above, was taking Allegra and Zantac. Nutritionally the patient is obese and could probably benefit from dietary improvements. Gene testing was conducted while the patient was hospitalized. With the patient's most recent medications taken into consideration, the results indicated extensive metabolism of 2D6, uncertain status of 3A4, intermediate metabolism of 3A5, altered function of COMT, and no info on 1A2.

 

[SpongeBob DoctorPants]

I think the first thing to clarify is the patient had serotonin syndrome. I often get into battles with neurology about this. Did the patient meet hunter criteria for SS? Were they taking serotonergic drugs at the time?

For reference, I have copied the Hunter Criteria from UpToDate here:

Serotonin syndrome is diagnosed on the basis of clinical findings. We suggest diagnosing serotonin syndrome using the Hunter Toxicity Criteria Decision Rules. To fulfill the Hunter Criteria, a patient must have taken a serotonergic agent and meet ONE of the following conditions:

• Spontaneous clonus
• Inducible clonus PLUS agitation or diaphoresis
• Ocular clonus PLUS agitation or diaphoresis
• Tremor PLUS hyperreflexia
• Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus

Based on this information and the patient's history, I would conclude that serotonin syndrome was present.

 

[Ceke2002]

I have a patient who has had some kind of reaction to medications which is believed to be serotonin syndrome, but this could not be definitively confirmed. All medications (including Prozac, BuSpar, and Adderall) were stopped prior to the patient's hospitalization, but at this time I am wondering... would it be safe to restart a medication with serotonergic effects? Or should I avoid them completely? I at least plan to avoid any combination of medications which may have this potential interaction. I have searched in the literature to get some idea of the risk involved with reintroducing serotonergic medications but haven't found anything yet.

Personal experience only, but happy to share if it helps at all.

I had a single episode of serotonin syndrome around a decade or so ago, which was triggered by taking Venflaxine (75 mgs) on top of a regular dosage of Tramadol (150 mgs bds). And yes it was definitely serotonin syndrome, that is what I was diagnosed with and treated for in the ED and my symptoms were consistent with a number of the Hunter Criteria (spontaneous clonus, hypertonia, tremor, agitation, confusion, ocular clonus, diaphoresis). I can give a more detailed description of my actual experience from onset to treatment if it will add anything useful to the discussion.

Since that singular episode I've obviously been more wary of anti-depressant medication whilst still being on a daily dosage of Tramadol. To this end my former Psychiatrist tended to lean more towards older style ADs (such as Deptran, which I had taken previously with no ill effects, and Mirtazapine), adopted a 'start low, go slow' approach to dosage and titration, and had me come in for a one hour monitoring session (basically a therapy session with an extra 15 minutes and observations being done) for a first time dosage of a new AD. As I said I did tolerate Deptran quite well, even with the addition of another serotonergic agent, and also found no issues with Mirtazapine either. I also found both the in person/in rooms monitoring, and patient education regarding the possibility of anxiety and/or panic attack (due to perhaps hyper vigilance regarding a potential re-occurence of serotonin syndrome - which on a personal level I found to be a rather terrifying experience) to be particular helpful.

 

[clausewitz2]

Personal experience only, but happy to share if it helps at all.

I had a single episode of serotonin syndrome around a decade or so ago, which was triggered by taking Venflaxine (75 mgs) on top of a regular dosage of Tramadol (150 mgs bds). And yes it was definitely serotonin syndrome, that is what I was diagnosed with and treated for in the ED and my symptoms were consistent with a number of the Hunter Criteria (spontaneous clonus, hypertonia, tremor, agitation, confusion, ocular clonus, diaphoresis). I can give a more detailed description of my actual experience from onset to treatment if it will add anything useful to the discussion.

Since that singular episode I've obviously been more wary of anti-depressant medication whilst still being on a daily dosage of Tramadol. To this end my former Psychiatrist tended to lean more towards older style ADs (such as Deptran, which I had taken previously with no ill effects, and Mirtazapine), adopted a 'start low, go slow' approach to dosage and titration, and had me come in for a one hour monitoring session (basically a therapy session with an extra 15 minutes and observations being done) for a first time dosage of a new AD. As I said I did tolerate Deptran quite well, even with the addition of another serotonergic agent, and also found no issues with Mirtazapine either. I also found both the in person/in rooms monitoring, and patient education regarding the possibility of anxiety and/or panic attack (due to perhaps hyper vigilance regarding a potential re-occurence of serotonin syndrome - which on a personal level I found to be a rather terrifying experience) to be particular helpful.

While interacting with with serotonin receptors mirtazapine does not actually increase extracellular serotonin levels and has not ever been convincingly implicated in a case of serotonin syndrome/toxicity. It does not inhibit serotonin reuptake at all, it does not interfere with monoamine oxidase, and indeed you can take it with an MAOI without problems. The fact that psychiatrists sometimes worry about mirtazapine in the setting of serotonin syndrome is largely about the sloppy thinking of some psychiatrists.

 

[Ceke2002]

While interacting with with serotonin receptors mirtazapine does not actually increase extracellular serotonin levels and has not ever been convincingly implicated in a case of serotonin syndrome/toxicity. It does not inhibit serotonin reuptake at all, it does not interfere with monoamine oxidase, and indeed you can take it with an MAOI without problems. The fact that psychiatrists sometimes worry about mirtazapine in the setting of serotonin syndrome is largely about the sloppy thinking of some psychiatrists.

Agreed. I probably should've made it a bit clearer that any off-setting of concerns about Mirtazapine was for my benefit & not actually based on pharmacological necessity. So yes monitoring was unnecessary from that point of view (re Mirtazapine specifically), but I was still so freaked out about a recurrence of what had happened prior that we came to agreement that allowed an extra level of reassurance. I mean yeah if it's not an issue from a pharmacy point of view, then it's not an issue, but if you're dealing with a patient who's had a very negative experience and is perhaps likely to somatise/misinterpret normal parameter reactions etc as being a potential recurrence of serotonin syndrome, then giving them some extra time on top of an already existing appointment schedule to ensure minimisation of the aforementioned might be a good idea.

Sorry for the disjointed rambly-ness of that paragraph as well, 'tis 4.10 am here and I am a tad unwell and sleep deprived.

 

[clausewitz2]

Agreed. I probably should've made it a bit clearer that any off-setting of concerns about Mirtazapine was for my benefit & not actually based on pharmacological necessity. So yes monitoring was unnecessary from that point of view (re Mirtazapine specifically), but I was still so freaked out about a recurrence of what had happened prior that we came to agreement that allowed an extra level of reassurance. I mean yeah if it's not an issue from a pharmacy point of view, then it's not an issue, but if you're dealing with a patient who's had a very negative experience and is perhaps likely to somatise/misinterpret normal parameter reactions etc as being a potential recurrence of serotonin syndrome, then giving them some extra time on top of an already existing appointment schedule to ensure minimisation of the aforementioned might be a good idea.

Sorry for the disjointed rambly-ness of that paragraph as well, 'tis 4.10 am here and I am a tad unwell and sleep deprived.

Oh, for sure. That sounds like very good practice that should be much more standard than it is. I thought perhaps it was your psychiatrist who was freaking out about the idea of mirtazapine in that context.