How to Manage Adverse Effects of Clozapine – Part 2

Last updated: March 8, 2019
 
Host: Wegdan Rashad, MD

Today’s question is: How to manage the non-hematological adverse effects of clozapine?

Here is a summary of this episode:

  • Clozapine can commonly cause a benign fever. If a patient is feverish, do a workup to exclude infections, myocarditis, NMS and inflammatory conditions.
  • For orthostatic hypotension, slowly titrate, encourage fluid intake and avoid other alpha 1 blockers and benzodiazepines. You can consider using 9-fludrocortisone for volume expansion.
  • In cases of tachycardia, manage orthostasis first and if it persists, use atenolol. Keep the resting heart rate under 100 beats per minute.
  • If you suspect myocarditis, measure troponin, and CRP levels. If positive, stop clozapine and cover with an anticholinergic.
  • For the metabolic effects of clozapine, behavioral control techniques are worth a try. You can also start metformin concurrently with clozapine as an effective and safe option.

Transcript

Hello! I’m Dr. Wegdan Rashad and you are listening to the Psychopharmacology Institute podcast. We’ll be discussing topics that matter to you, the mental health clinician, in your practice, sharing expert opinions and the latest research.

Whether you work in an outpatient or inpatient setting surely you have come across clozapine. Most famously known as the gold standard medication for treatment-resistant schizophrenia, clozapine’s repertoire of side effects is daunting. So we thought, why not cover this topic in a two-part podcast?

Today we’ll get some practical tips on managing orthostasis, tachycardia, myocarditis, and metabolic effects. We will do this with snippets from Dr. Jonathan Meyer’s lecture entitled “Managing the Nonhematological Adverse Effects of Clozapine” available on our website. Dr. Meyer is a Clinical Professor of Psychiatry at the University of California San Diego.

In the last episode, I shared with you a case on a 41-year-old woman who began to develop a fever and tachycardia within 15 days of starting clozapine. We received a lot of responses from you, so thank you for that! You guys were right, agranulocytosis associated infection, or a concurrent infection could be a cause, NMS, myocarditis and anticholinergic toxicity could all be causes with varying prevalence. However, there was one answer that a large majority of you missed, which is actually the most likely cause of fever in a patient taking clozapine and that is, benign fever. Let’s listen to Dr. Meyer’s take on this.

Dr. Meyer:
Now, benign fever and flu-like symptoms happen in a large proportion of patients during the first month of clozapine. One case series reported a rate of 55%. Of course, many people worry about there may be an infection or certainly, there may be myocarditis. And so you have to do the appropriate workup. If you do not see evidence of routine source of infection, if the troponin levels are normal which is the diagnostic test for myocarditis and you don’t see any other evidence of inflammatory conditions such as rare drug reactions with eosinophilia or acute interstitial nephritis, the conclusion you will come to is that this is a benign fever.

So, keep in mind that benign fever is a potential culprit and should be suspected after you rule out other potential causes.
At the end of this podcast, I will share another case for you to answer. So, stay tuned.

Clozapine can alter other vital signs, like heart rate and blood pressure. In terms of blood pressure, a good number of patients may experience orthostatic hypotension. It is due to clozapine’s potent alpha 1 receptor blocking abilities. Let’s listen to Dr. Meyer on how to manage it.

Dr. Meyer:
The preferred management strategy is number one, use the slowest dose titration possible. If the person you’re treating cannot tolerate a standard titration, then you need to slow it up. Secondly, always encourage fluid intake. And sometimes, we’ll actually add salt as a way of volume expansion. And lastly, minimize use of other alpha-1 adrenergic antagonists and also benzodiazepine which can exacerbate blood pressure problems. If the person remains symptomatic although it’s not stated here, if they’re on a medicine for hypertension, you might want to consider modifying that. Assuming that’s not the case, we will try volume expansion with Florinef which is also called 9-fludrocortisone. This is a mineralocorticoid which just allows you to reabsorb water and electrolytes. The only contraindication to using this would be in somebody who has congestive heart failure.

For orthostatic hypotension, slowly titrate, encourage fluid intake and avoid other alpha 1 blockers and benzodiazepines. You may also need to adjust antihypertensive medications and consider using 9-fludrocortisone for volume expansion.

What about tachycardia with clozapine? It could be a reflex secondary to orthostasis or even fever. But sometimes clozapine does raise the heart rate independently of those factors.

Dr. Meyer:
So how do you get around tachycardia? Again, sort of like with the orthostasis, use the standard titration, use the lowest effective dose, minimize concurrent agents which may contribute to this problem such as alpha-1 blockers or M1 antagonists. Obviously, manage orthostasis first. If the person is no longer orthostatic, generally, we say beta-blockers are the drugs of choice and we always use atenolol. We do not want to use an agent which crosses the blood-brain barrier. We do not need those additional CNS effects of a medication such as propranolol. So atenolol is our drug of choice starting initially with very small doses such as 12.5 mg in the morning. And then every few days to a week, you can increase it as necessary depending on the tolerability. The goal is to always have a resting heart rate under 100 and perhaps ideally under 90.

Follow similar guidelines to the management of orthostasis and if it persists, you can use atenolol. Keeping the resting heart rate under 100 beats per minute.

So far, we have covered fever, orthostasis, and tachycardia associated with clozapine. What about more sinister side effects like myocarditis and metabolic syndrome? Let’s find out!

Clozapine-induced myocarditis is rare and it occurs relatively early on in the course of clozapine therapy. If not recognized and treated it may have fatal outcomes. So how to do this and what are the next steps?

Dr. Meyer:
What we use in the state hospital, I have called the reasonable protocol which is number one, clinical suspicion. Fevers certainly with tachycardia, dyspnea, flu-like illness and of course, chest pain should prompt a suspicion and immediately you should obtain a troponin I/T and a CRP confirm this. If the above are positive, then you have to stop the clozapine and send to the hospital if they’re not already in the hospital. Most importantly, if you do have to hold the clozapine abruptly, you have to cover them for a cholinergic rebound through an equivalent dose of benztropine. Otherwise, people are both going to have tachycardia and now delirium from cholinergic rebound.

Aha! So clinical suspicion and drawing troponin and CRP levels are important steps. Then if positive, proceed to stop clozapine and cover with an anticholinergic. My Psychopharmacology Institute colleague Dr. Dana Wang ventures further.

Dr. Wang:
If one were to stop clozapine suddenly due to a medical indication, what’s the equivalent dose of benztropine or an anticholinergic agent to use that would correlate with plasma clozapine level in order to prevent cholinergic rebound delirium?

Dr. Meyer:
Depending upon whether the patient is a smoker, at least 1 mg of benztropine is equivalent to maybe 50 mg of clozapine in a nonsmoker or 100 mg of clozapine in a smoker. The idea is to provide a sufficient amount so people do not get both the central effects such as vivid dreams, nightmares, or even delirium as well as the peripheral adverse effects such as diarrhea.

Now here comes the million dollar question.

Dr. Meyer:
The biggest question, of course, is if a troponin is positive, do I rechallenge people? As I mentioned before, 7 of the 12 published cases of rechallenge seemed to work out. But it is certainly a complex decision which should be discussed both with the patient and any other caregivers about the viability of this rechallenge. It is something to consider but there will certainly be instances especially if the patient was extremely ill where it might not be feasible or if the person lives in a remote area where obtaining weekly labs and intensive medical monitoring might also not be feasible.

So yes! Rechallenging is possible but the decision needs to be taken with several factors in mind.

Now we reach the final side effect of today’s podcast and that is the cardiometabolic side effects of clozapine. I am certain you have come across patients who start to gain a lot of weight once they are on clozapine for a few months. First though, how does this happen?

Dr. Meyer:
We recognize that it causes weight gain by H1 blockade which causes both sedation as well as impaired satiety. There may be a role of serotonin 2C antagonism as well. Why it causes dyslipidemia we do not know. We certainly know that many atypicals both cause dyslipidemia as well as problems with glycemic control. There is probably a weight independent mechanism there. We certainly know weight gain will cause these problems but there is often a weight independent mechanism as well.

So it seems still a bit of mystery. More importantly, you might be wondering, how do I tackle this issue, clinically?

Dr. Meyer:
And so if we look at the data on managing clozapine-induced obesity, certainly there is a role for behavioral control, enrolling people on lifestyle management. This may seem like not viable for many patients who are low functioning but it’s worth a try. At least you may help them mitigate the ingestion of a lot of, so let’s say sugared sodas and drinks and other things which are easily avoidable. Medication-related strategies have been studied extensively. Among all of these, the one which has emerged as both the safest and with the best evidence-based is actually metformin. More and more, we will actually consider the use of metformin prophylactically when people start clozapine. Typically, the starting dose is 500 mg once a day for the first week. Then after a week, you can go up to higher doses. And certainly, metformin is both safe as well as showing a lot of efficacy. And we think the efficacy may be greatest when started concurrently with clozapine.

In a nutshell, behavioral control is worth a try and starting metformin concurrently with clozapine could be an efficacious and safe option.

Aaand that’s about it for today’s podcast! I hope that you will now be able to manage more effectively the side effects of this important drug. Now let’s round it all up and go to the key points.

Key Points

  • Clozapine can commonly cause a benign fever. If a patient is feverish do a workup to exclude infection, myocarditis, NMS and inflammatory conditions.
  • For orthostatic hypotension, slowly titrate, encourage fluid intake and avoid other alpha 1 blockers and benzodiazepines. You can also consider using 9-fludrocortisone for volume expansion.
  • In cases of tachycardia, manage orthostasis first and if it persists, use atenolol. Keep the resting heart rate under 100 beats per minute.
  • If you suspect myocarditis, measure troponin, and CRP levels. If positive, stop clozapine and cover with an anticholinergic.
  • For the metabolic effects of clozapine, behavioral control techniques are worth a try. You can also start metformin concurrently with clozapine as an effective, safe option.

Before we go I wanted to share a case with you.

A 35-year-old man is taking sertraline for major depressive disorder. He was introduced by a friend to a herbal remedy (St. John’s wort) that was said to improve his mood in a natural way. So he decided to take it while still on his psychiatric medication. Within a few days, he experienced diarrhea, sweats, and tachycardia. What could explain this?

Do you know?
Send in your answers to podcast@psychopharmacologyinstitute.com.

Liked our podcast? Visit us at psychopharmacologyinstitute.com where you can find more podcasts and some lectures absolutely free. You can also choose to become a premium member to get full access to our content and earn CME credits. If you are a psychiatrist in the US, we also offer SA credits. Sign up today on our website for weekly updates delivered straight to your inbox.

Do you have suggestions, questions or you know the answer to the case? Email us at podcast@psychopharmacologyinstitute.com.

If you are a psychotherapy provider, check out our sister-platform Psychotherapy Academy for lectures and content to help you become a better therapist. Visit psychotherapyacademy.org

The following people participated in this episode: Dr. Flavio Guzman as the general editor, Mark Young as the audio engineer, Pamela Gonzalez as the project manager and myself, Dr. Wegdan Rashad as the host. We’d also like to thank Dr. Jonathan Meyer, and Dr. Dana Wang, for being with us.

Thank you for joining us in today’s podcast until the next episode, goodbye!

References

  1. Testani, M. (1994). Clozapine-induced orthostatic hypotension treated with fludrocortisone. The Journal of clinical psychiatry.
  2. Nielsen, J., Correll, C. U., Manu, P., & Kane, J. M. (2013). Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided?. The Journal of clinical psychiatry, 74(6), 603-13.
  3. Lally, J., Docherty, M. J., & MacCabe, J. H. (2016). Pharmacological interventions for clozapine‐induced sinus tachycardia. Cochrane Database of Systematic Reviews, (6).
  4. Ronaldson, K. J., Fitzgerald, P. B., & McNeil, J. J. (2015). Clozapine‐induced myocarditis, a widely overlooked adverse reaction. Acta Psychiatrica Scandinavica, 132(4), 231-240.
  5. Zimbron, J., Khandaker, G. M., Toschi, C., Jones, P. B., & Fernandez-Egea, E. (2016). A systematic review and meta-analysis of randomised controlled trials of treatments for clozapine-induced obesity and metabolic syndrome. European Neuropsychopharmacology, 26(9), 1353-1365.
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