How to Manage Adverse Effects of Clozapine – Part 1

Last updated: February 22, 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:

  • For sialorrhea, start with local agents like sublingual atropine drops or mouth ipratropium spray. If that fails, systemic agents like glycopyrrolate or terazosin can be used.
  • For constipation, bulk agents can make constipation worse and should be avoided. After docusate, the next agent to add is PEG 3350 and then a stimulant and then lastly, if needed, lubiprostone.
  • For sedation, titrate clozapine slowly, use bedtime dosing and reduce other sedating medications. A trial with modafinil or methylphenidate can be attempted, but the evidence is not strong.
  • Tonic-clonic and myoclonic seizures can occur with clozapine. Titrate down and divide into multiple doses. Divalproex is the drug of choice in preventing clozapine-induced seizures.

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 sialorrhea, constipation, sedation, and seizures. 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.

Before we start though I’d like to challenge you with a case and a question.

A 41-year-old woman has been started on clozapine for treatment-resistant schizophrenia. Within 15 days starting clozapine, she began to develop a fever of 38 degrees Celcius and tachycardia. And she does not have a history of medical problems. What could be the cause of the fever be in this case?

Well, what do you think? Send us your answers at podcast@psychopharmacologyinsitute.com and in the next episode, we will answer the case!

Alright then, let’s get started with our first adverse effect, sialorrhea.

So sialorrhea is common and problematic not only socially but sialorrhea may contribute to the increased incidence of aspiration pneumonia in patients taking clozapine. So, what to do about it?

Dr. Meyer:

Occasionally, you can try dose reduction but often this does not get you much mileage.  We prefer in the state hospital system always starting with locally applied agents. As we will discuss, constipation is an enormous problem in patients with clozapine and one does not wish to add to this anticholinergic burden through the unnecessary use of systemic anticholinergics unless it is absolutely necessary. The starting treatments are either atropine 1% ophthalmic drops administered sublingual. Not in the eye, sublingually. The slides here say one to two drops initially at bedtime and up to t.i.d. and we will certainly go even to three drops as needed up to t.i.d. if that’s what we need to get good control of the sialorrhea. If that doesn’t work, the other option is ipratropium spray. Again, this was developed as a nasal spray but you’re going to spray it in the mouth and use the higher strength which is 0.06%. Again, you can go up to three sprays t.i.d.

OK, so we try local agents like atropine drops or ipratropium spray, orally. What if that works only partially or what if it doesn’t work at all?

Dr. Meyer:

So one option includes glycopyrrolate. We prefer this over other agents such as benztropine simply because glycopyrrolate does not cross the blood-brain barrier. The usual dose is 2 to 4 mg at night. One can go up to slightly higher doses. It is worth knowing though that there is an alternative to glycopyrrolate which can be considered in certain patients if their blood pressure will tolerate it and this is the use of the alpha-1 antagonist terazosin. The doses which have been studied are relatively modest. 1 mg at bedtime would be the starting dose. If this is tolerated, one can after one to two weeks go up to 2 mg.

Right, so if you have to use systemic agents you can try glycopyrrolate 2 to 4 mg or up to 2 mg of terazosin.

If you think about it, sialorrhea is a curious paradox for clozapine. We know that clozapine has some pretty well-established anticholinergic effects which should theoretically cause dryness of mucous membranes. Early in my residency, I was asked about the mechanism of sialorrhea in one clinical round and I was pretty befuddled. Dr. Meyer explains why it happens.

Dr. Meyer:

More likely than not the problem related to clozapine has to do with its metabolite norclozapine which is also called N-desmethylclozapine. This turns out to be a muscarinic M1 agonist and we believe this is responsible for the drooling. So although the parent compound clozapine maybe an antagonist at a number of muscarinic receptors, the metabolite is an agonist. This is why we have people who are both constipated and drool at the same time.

There are additional theories, but this one is probably one of the major contributors. OK so you might be wondering if it’s all related to muscarinic receptor action; why is terazosin suggested as a treatment for sialorrhea? My Psychopharm Institute colleague, Dr. Dana Wang digs deeper.

Dr. Wang:

What is the mechanism of action of how alpha adrenergic agents such as clonidine or terazosin work for sialorrhea?

Dr. Meyer:

The reason why clonidine works is that the salivary nucleus has downstream actions to the parotid and other salivary glands, which are centrally mediated by alpha-2 receptors. So if you can block that action with clonidine, it seems to help treat the sialorrhea. Now, the advantage of this in people who may have failed the locally applied agents is that it’s not an anticholinergic. But the downside, of course, is that it can exacerbate orthostatic hypotension. So it has to be used quite cautiously.

We can all agree that constipation is uncomfortable, to put it mildly. Up to 60% of patients taking clozapine experience constipation. This increases the risk of ileus and possibly transform into a mortal form of the disease. How do you manage constipation in your patients taking clozapine?

Dr. Meyer:

The first step is to minimize the use of systemic anticholinergics. These contribute significantly to the problem and absolutely need to be avoided unless they cannot to the management of sialorrhea. Everybody should start on docusate routinely. If they state it gives them diarrhea, that’s fine. You can stop it. This is rarely a problem. Docusate in and of itself is often not sufficient. And then next, we will add classes of agents in order of increasing, we’ll call this noxiousness.  So the most benign agent next will be an osmotic laxative. And typically, we go to polyethylene glycol 3350 which is also called Miralax in many countries. We prefer this to lactulose as the overall evidence base, it’s a superior agent to lactulose. If the osmotic agent does not work, we will then next add a stimulant either senna or bisacodyl and max dose out as well. The idea is you’re going to continue to add agents and not take away things until you actually get what you need.

So to sum up, we minimize systemic anticholinergics and prescribe docusate routinely. An osmotic laxative can be added like polyethylene glycol or MiraLax. If the patient is still suffering from constipation, add senna or bisacodyl.

Dr. Meyer also mentioned that we encourage patients to drink adequate amounts of water and to educate them or their caregiver to watch out for constipation and to tell their doctor as soon as possible.

OK, can we use bulk-forming laxatives?

Dr. Meyer:

We do not recommend adding bulk-forming laxatives. Often, our patients are already constipated and the addition of psyllium or other bulk-forming laxatives could actually exacerbate the problem especially if a person does not maintain adequate water intake.

So, not a good idea.

Now if all those recommendations don’t work, that is still not a reason to stop clozapine. There are these new and quite expensive agents that Dr. Dana Wang explores further.

Dr. Wang:

Do you mind elaborating more on how the newer agents lubiprostone and linaclotide for treating constipation differ from other laxative agents that are more traditionally used?

Dr. Meyer:

The one we have the most experience with is a drug called lubiprostone, which is a prostaglandin E analog. What this does is bind to chloride channels in the small intestine. It increases chloride rate concentrations and promotes motility through the small and large intestines. There are also two newer classes of agents which both work on guanylate cyclase C; these are called linaclotide and plecanatide. But what we have found, particularly with lubiprostone, is that in patients who have maxed out the combination of docusate plus MiraLAX plus a stimulant, adding lubiprostone not only improves constipation dramatically, sometimes to the extent that we can remove many of the other agents. More importantly, when people have developed ileus, we will often start them on lubiprostone prophylactically when they’re retitrated on clozapine often with great success.

So it seems that there is promise for these newer agents for more resistant and complicated cases.

We are halfway through today’s podcast. The next two side effects we will learn to treat are sedation and seizures.

Excess sedation is one of the reasons patients may stop taking clozapine. It is also quite common. The literature says 40% but Dr. Meyer mentions that it is probably higher. I agree it’s a common side-effect in practice. So what kind of strategies can we try out to reduce this excess sleepiness?

Dr. Meyer:

A couple of strategies that we use. Number one, again, the standard titration. There is data out there about more aggressive clozapine titrations but we try to avoid this.  The other practice which may be somewhat unique to North America more so than Europe and South America is that we always give clozapine at bedtime and we will continue to use clozapine at bedtime up until very high single doses of 500 mg. Of course, you’ll also want to minimize the use of concurrent sedating medications especially those with central anticholinergic properties or other sedating. For people who have persistent problems with sedation, you say, I’m using the lowest effective dose. I am giving it all at bedtime. They are still sleepy during the day. What can we do? There are clinical trials of modafinil. Four double-blind studies were published in the last decade. The nice thing is it didn’t seem to make people worse symptomatically. But the sad thing is it often did not get you what you want. But certainly, I think it’s a place to try at doses starting at 100 a day and maybe going up to 300 mg a day period. There are anecdotal reports of the use of methylphenidate. Again, you have to pick the patients very carefully due to the abuse liability but it certainly can be considered.

So in case YOU were sleepy, let me recap. Titrate clozapine slowly, use bedtime dosing and reduce other sedating medications. A trial with modafinil or methylphenidate can be attempted, but the evidence is not so strong.

Now for seizures. It is a less common side effect of clozapine. Clozapine lowers the seizure threshold and if it elicits a seizure, the experience can be very alarming for everyone involved. But indeed, clozapine-induced seizures are NOT a reason to stop clozapine.  But first what kind of seizures could you observe with clozapine?

Dr. Meyer:

The types of seizures people get on clozapine are predominantly tonic-clonic but the second biggest group is going to be myoclonic.  So again very often, you will see people who will say, I suddenly have been dropping things or I was walking and all of a sudden, my legs went out from under me but I did not have a seizure. I just all of a sudden dropped to the ground. Certainly, you would rule out orthostasis but a lot of these may actually be myoclonic events.

So perhaps you should watch out for those ‘drop attacks’. Typically, seizures develop when the dose has been increased. So keep that in mind when Dr. Meyer talks about how to manage this.

Dr. Meyer:

But if the patient does seize, typically we’ll say we will go back to the prior tolerated dose, try to push most of the medication into divided doses if at all possible because sometimes when you finally got to that one single dose, that high peak plasma level was what actually lowered their seizure threshold significantly. So sometimes, by splitting it up, you keep the Cmax lower and maybe obviate the need for anticonvulsant treatment. But if you cannot do that or they need an anticonvulsant, the drug of choice is always Depakote. And there are a couple of reasons. Number one, it best covers the spectrum of tonic-clonic and myoclonic seizures among all of the anticonvulsants and number two, it will not lower your plasma levels by 50% in a way that Dilantin or Tegretol will.

So besides titrating down and dividing it into multiple doses, Divalproex is the drug of choice in preventing clozapine-induced seizures.

Aaand that’s about it for today’s podcast. We have covered a lot so here come the key points to bring it all together for you.

Key Points

  • For sialorrhea start with local agents like sublingual atropine drops or mouth ipratropium spray. If that fails, systemic agents like glycopyrrolate or terazosin can be used.
  • For constipation, bulk agents can make constipation worse and should be avoided. After docusate, the next agent to add is  PEG 3350 and then a stimulant and then lastly, if needed, lubiprostone.
  • For sedation, titrate clozapine slowly, use bedtime dosing and reduce other sedating medications. A trial with modafinil or methylphenidate can be attempted, but the evidence is not strong.
  • Tonic-clonic and myoclonic seizures can occur with clozapine. Titrate down and divide into multiple doses. Divalproex is the drug of choice in preventing clozapine-induced seizures.

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. Bird, A. M., Smith, T. L., & Walton, A. E. (2011). Current treatment strategies for clozapine-induced sialorrhea. Annals of Pharmacotherapy, 45(5), 667-675.
  2. Meyer, J. M., & Cummings, M. A. (2014). Lubiprostone for treatment‐resistant constipation associated with clozapine use. Acta Psychiatrica Scandinavica, 130(1), 71-72.
  3. Saavedra-Velez, C., Yusim, A., Anbarasan, D., & Lindenmayer, J. P. (2009). Modafinil as an adjunctive treatment of sedation, negative symptoms, and cognition in schizophrenia: a critical review. The Journal of clinical psychiatry, 70(1), 104-112.
  4. Wong, J., & Delva, N. (2007). Clozapine-induced seizures: recognition and treatment. The Canadian Journal of Psychiatry, 52(7), 457-463.
  5. Meyer JM, Stahl SM. The Clozapine Handbook. Cambridge, UK; Cambridge University Press, 342 pp. (release date June 1, 2019)
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