Clozapine-Induced Sialorrhea: Why Is It Important and How Should You Manage It?

Jonathan Meyer, MD

Clinical Professor of Psychiatry
University of California, San Diego

Last updated: August 3, 2018


Clozapine-induced sialorrhea increases the risk for aspiration pneumonia and is probably linked to norclozapine’s M1 agonism.

  • Management:
    • First-line options: orally applied anticholinergics, they do not increase constipation risk
      • Atropine 1% drops
      • Ipratropium 0.06% spray
    • Consider trying low-dose terazosin before using glycopyrrolate if the orally applied medications are not sufficiently effective




Let’s talk about one of the most significant problems although it’s considered benign but often a reason for treatment discontinuation which is sialorrhea.

Now, many of you understand the pharmacology of salivary glands and know that there are a number of muscarinic receptor subtypes which are expressed there. But what we understand is that 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 may be 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. We’re getting the mixed properties of both the parent compound and the metabolite. The evidence that it’s the M1 effects comes from trials of pirenzepine which is an M1 selective anticholinergic agent available mostly in Europe. But there are case reports and case series of people who were administered pirenzepine and they seemed to block the sialorrhea induced by clozapine.


So what’s the general approach to this? 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. Constipation is an enormous problem in patients with clozapine, 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. 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%. You can go up to three sprays t.i.d.


The reason to manage this is that there is a literature out there about patients on clozapine having increased risk for pneumonia. And we think this has to do with aspiration events which may occur at night. And of course, for people who drool, there’s also the social problem of their appearance in public. So it’s really something to be attentive to and be very aggressive at treating.


If the locally applied agents simply do not work, then one has ample justification for going to the systemic drugs knowing that you are incurring a burden of increased risk of constipation. One option includes glycopyrrolate. We prefer this over other agents such as benztropine simply because glycopyrrolate does not cross the blood-brain barrier. So you are not going to incur the essential anticholinergic effects which one might get from benztropine or other anticholinergic antiparkinsonian medications. 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. 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. The biggest risk of course is going to be orthostasis, but the advantage is that if this works, you avoid all of the peripheral anticholinergic effects of a medication such as glycopyrrolate. If somebody has a partial response to the locally applied agents, these should be kept on board while you’re adding the other agent whether it’s terazosin or then later on glycopyrrolate. But it is important to get on top of this. This may be a reason that the patient will say, “I don’t want to take this medicine”, A. And B, it may present a risk for aspiration pneumonia later on.


To summarize, sialorrhea presents social and medical consequences particularly the risk for aspiration pneumonia. Orally applied medications such as atropine 1% drops or ipratropium 0.06% spray are preferred as they do not increase constipation risk. For the same reason, consider trying low dose terazosin before using glycopyrrolate if the orally applied medications are not sufficiently effective.


  1. Messer W, et al. Evidence for a preferential involvement of m1 muscarinic receptors in representational memory. Neurosci Lett 1990;116: 184-9.
  2. Chew M, et al. A model of anticholinergic activity of atypical antipsychotic medications. Schizophrenia Research 2006;88:63-72
  3. Bird AM, Smith TL, Walton AE. Current treatment strategies for clozapine-induced sialorrhea. Ann Pharmacother. 2011;45:667-75
  4. Gurrera RJ. Aspiration pneumonia an underappreciated risk of clozapine treatment. J Clin Psychopharm 2016; 36(2): 174-176
  5. Liang CS, et al. Comparison of the efficacy and impact on cognition of glycopyrrolate and biperiden for clozapine-induced sialorrhea in schizophrenic patients: a randomized, double-blind, crossover study. Schizophr Res. 2010;119(1-3):138.

Also, you can access to the original version in Spanish: “Sialorrea inducida por clozapina: cómo tratarla”

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