Mini-Review: A Superior Treatment for Clozapine-induced Sialorrhea

Ai-Li W. Arias^1,2,3,5*, Michael A. Cummings^1,2,3,5, George J. Proctor^1,3,4,5

¹Department of Psychiatry and Neuroscience, University of California, Riverside, CA, USA

²Department of Psychiatry & Human Behavior, University of California, Irvine, Neuropsychiatric Center, Orange, CA, USA

³Psychopharmacology Resource Network, Clinical Operations Division, California Department of State Hospitals (DSH), Sacramento, CA, USA

⁴Department of Psychiatry, Loma Linda University School of Medicine, Loma Linda, CA, USA

⁵Department of State Hospitals - Patton, Patton, CA, USA

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Abstract

Clozapine is the only antipsychotic with demonstrated efficacy for treatment-resistant schizophrenia and mania, and aggression, suicide, or psychogenic polydipsia related to schizophrenia. Sialorrhea, a common adverse effect, is frequently a barrier to clozapine treatment. Anticholinergic agents have limited efficacy and increase risk for constipation, bowel impaction, or ileus. Interval injection of select salivary glands with botulinum neurotoxin (BT) has proven to be a superior alternative treatment for clozapine-induced sialorrhea (CIS). This mini-review describes the viability and logistics for establishing a successful botulinum treatment clinic, including adequate staff, training, educating treatment providers about the availability and effectiveness of botulinum treatment for sialorrhea, and development of a clinic protocol (e.g., procedural elements and relevant rating scales). Finally, botulinum treatment was determined to be cost-effective. Evidence for botulinum treatment of CIS includes Level I data.

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Introduction

This is a narrative mini-review supplemented by real-world clinic protocol experience. Clozapine has been indicated for treatment resistant schizophrenia and mania, and for nonpsychotic aggression, suicidality and primary polydipsia associated with schizophrenia spectrum disorders. Clozapine possesses a gamut of adverse effects, especially sialorrhea which affects up to 90% of clozapine-treated patients¹. Sialorrhea is a barrier to clozapine treatment; this causes social stigmatization leading to patients’ desire to discontinue clozapine and medical comorbidities (e.g., nocturnal aspiration pneumonia)^1,2. Clozapine and its active metabolite norclozapine have muscarinic receptor agonist and antagonist properties. Clozapine is thought to be primarily responsible for constipation, while norclozapine’s M₁ receptor agonism in salivary glands is postulated to cause sialorrhea. Clozapine’s value obliges us to develop sialorrhea management protocols critical to minimizing treatment refusal and patient morbidity³.

Because clozapine can cause obstipation, preferred initial treatments for sialorrhea include topical anticholinergic agents (e.g., atropine drops or ipratropium bromide spray) with minimal systemic absorption. Atropine or ipratropium bromide is applied to the buccal mucosa, swished in the mouth for 15 and 30 seconds, respectively, and rinsed out with 5 ml of water. A systemic agent like glycopyrrolate can be used if topical agents fail, as it does not cross the blood-brain barrier like centrally acting anticholinergics (e.g. benztropine or trihexyphenidyl); however, it can double the risk for potentially fatal ileus⁴.

Evidence Review

Evidence from neurological sialorrhea

More than two decades ago, medical literature described an evidence-based alternative, which involves botulinum toxin injected directly into salivary glands. In 2001, papers noted the use of BT to decrease sialorrhea in patients with neurological conditions such as Parkinson’s disease (PD) or cerebral palsy (CP)⁵. Researchers subsequently examined BT use for CIS as a viable alternative to topical and systemic anticholinergics⁶. In both community and forensic settings, treatment-resistant schizophrenia requiring clozapine therapy compels us to seek an evidence-based treatment for sialorrhea which avoids serious concerns for constipation, ileus, and bowel obstruction observed with systemic anticholinergics used to address CIS^7,8.

In 2001, studies first documented BT injection into salivary glands for Parkinsonian sialorrhea to inhibit release of acetylcholine from synaptic vesicles of post-ganglionic parasympathetic fibers containing cholinergic receptors in the salivary glands^5,9. Subsequent research noted that botulinum injections to the parotid and submandibular glands were highly effective in sialorrhea related to neurological conditions for up to 6 months. Benefits for medication-induced sialorrhea were later published, noting easy administration and no systemic effects^6,10,11. Both BT types have substantial data for sialorrhea, including case reports specifically related to CIS. BT-A and BT-B have been found to have equivalent efficacy¹⁰.

Evidence specific to CIS

CIS may have greater severity due to constant stimulation from norclozapine’s M₁ agonist properties, but the literature demonstrated that BT could reduce sialorrhea from all causes^5,6,9-13. Adverse effects from BT include pain or bruising at the site of inoculation, rare flu-like symptoms, headache, nausea, redness, dry mouth (<5 % of cases), and unlikely possibility of temporary muscle paresis if toxin spreads beyond the injection area. Locally injected BT has virtually no risk of systemic adverse effects (e.g., breathing problems, trouble swallowing, muscle weakness, or slurred speech observed in botulism)^14-17. (Table 1)

Table 1: RimabotulinumtoxinB in sialorrhea: systematic review of clinical trials¹¹

Comparison of toxin types

Seven immunologically distinct BT serotypes use distinct mechanisms to inhibit the SNARE complex resulting in flaccid paralysis of target muscles in dystonia and for cosmetic applications (Figure 1). In the U.S., four type A toxins (onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, prabotulinumtoxinA) and one type B toxin (rimabotulinumtoxinB) are approved for cosmetic purposes, migraine headaches, and muscular dystonia/spasms^14-19. BT provides transient relief of symptoms lasting between 3 to 6 months.

Mechanism of action

Botulinum toxins (BT) disable cholinergic neurotransmission by inhibiting vesicle fusion of presynaptic cholinergic neurons. Type A cleaves synaptosome-associated protein (SNAP-25), while type B targets vesicle-associated membrane protein (VAMP).

Figure 1: Target sites for BT types on SNARE proteins

Adapted from Barr, et al. (2005). Botulinum neurotoxin detection and differentiation by mass spectrometry, Emerging Infectious Diseases, 11, 1578-1583²⁰.

For patients with severe mental illness who may be wary about injections into the face, we considered patient comfort during injection and resistance to BT itself when selecting which BT to use for CIS. Because some literature indicates increased pain with rimabotulinumtoxinB injections compared to BT A, we chose incobotulinumtoxinA which imparts minimal pain when administered with a 30-gauge needle¹⁰. Primary resistance to the toxin itself occurs at a rate of 6.25% in non-cosmetic applications, sometimes appearing after the first treatment^20,21. Secondary resistance can result from the development of antibodies to the toxin if BT is used for conditions with only partial response (e.g., congenital ptosis, myasthenia gravis, etc.) or other treatment variables (i.e., high dosing frequency dosing, improper storage or transport) in about 5 – 10% of non-cosmetic cases, leading to partial or no response to subsequent BT injections.

For the reasons above and its lower risk for immunogenicity (i.e., it is the only BT with no induction of secondary resistance), incobotulinumtoxinA with its FDA approval for sialorrhea was selected^20,21.

Clinic Implementation Protocol

Establishing a BT sialorrhea clinic involves the following, as noted in Table 2.

Table 2: Steps for Establishing a BT Sialorrhea Clinic

Training involving a brief video illustrating the anatomical landmarks and in-person training with an experienced neurologist can be completed in a day (Table 2). Ultrasound guidance, although not necessary for most cases, could be considered for patients with gland atrophy^6,11.

Paperwork could be limited to three forms: referral, informed consent (ICF) and clinic protocol. The ICF is standardized to include what diagnoses BT is FDA-approved to treat, description of the procedure, risks/benefits, and signatures of the patient and administering physician. The clinic protocol details the requisite basic supplies and instructions for handling and administering BT correctly.

Objective and subjective efficacy scales can be used to determine efficacy. Objective measurements of unstimulated salivary flow rate using a digital scale calibrated to the thousandth of a gram and SalivaBio® Oral Swabs is important for clinical research but is not practical for routine treatment of CIS in a clinic (requiring ~1.25 hours). Subjective scales (e.g., Drooling Severity and Frequency Scale and Global Impression of Change Scale) are adequate to measure efficacy of BT for CIS^12,13. (Figures 2 and 3)

Figure 2: Drooling Severity and Frequency Scale (Department of State Hospitals – Patton)

Figure 3: Global Impression of Change Scale (Department of State Hospitals – Patton)

With a nearly 90% efficacy rating, we anticipated a significant lowering of DSFS scores between the pre- and post-injection ratings¹⁰.

Most clinics already have or can easily purchase basic supplies (syringes with smaller gauge needles, straight forceps, rubbing alcohol, cotton/gauze pads, and normal saline solution). The most significant cost is for incobotulinumtoxinA (explained further under cost analysis below).

BT Clinic Protocol

To determine baseline sialorrhea severity, we recommend: discontinuing all systemic anticholinergics for sialorrhea one week prior to initial appointment; all anticoagulants and aspirin 5 days prior to appointment date to reduce injection site bleeding; and all topical medications for sialorrhea 48 hours before initial appointment. Male patients should shave the jawline area prior to the appointment. After injections, patients should resume anticoagulants and aspirin. Because there may be no improvement for up to two weeks, topical/systemic sialorrhea treatments should be resumed for 14 days after the first injection to mitigate risk for aspiration pneumonia during the immediate lag period and then discontinued.

The treating psychiatrist or physician injector should rate the DSFS and GICS prior to injections. After ratings are obtained, the injector administers 30 U (1 U = 0.44 ng of botulinum toxin A) into each parotid gland and 20 U into each submandibular gland (100 U incobotulinumtoxinA per treatment). Initial follow-up visits for ratings are scheduled in 4-week intervals with the first maintenance injection visit scheduled 12 weeks after initial injections. Depending on individual patient response, the interval between injections could be adjusted from every 4 to 20 weeks.

Discussion

This is the first systematic protocol for establishing a BT clinic to treat CIS to circumvent complications from anticholinergic agents. As noted above, injection training could be completed in one day.

Cost Analysis

Sialorrhea treatment with incobotulinumtoxinA is cost-effective. As noted above, no specialized supplies are required for a BT clinic as noted above. The most significant cost for this type of sialorrhea treatment clinic is the medication itself. Based on U.S. wholesale pricing, the annual cost for anticholinergic agents used for sialorrhea approximates $704.10 annually; incobotulinumtoxinA costs approximately USD$2,500 when dosed quarterly (Wholesale Acquisition Price = USD$613.20 per 100 U vial). However, the risk and cost for hospitalization to treat aspiration pneumonia or ileus is significantly higher with ineffective anticholinergic treatment (USD$27,853 with a daily rate of USD$3,979 in California; figures based on information from the 2021 American Hospital Association Annual Survey in the Becker’s Hospital CFO Report)²². Although the annual cost of incobotulinumtoxinA for sialorrhea is 3 to 4 times the cost of anticholinergic agents (only ~10% efficacy), it is 9 times more effective. Hence, treating CIS with BT is cost-effective. Drug cost may vary in other countries based on currency exchange rates and government policies limiting drug pricing. A BT Clinic is fully operational with one physician and one nurse.

All patients were educated about the procedure. All but one underwent the procedure and tolerated it well; this patient could not comprehend the reason for the appointment and refused the injections. None who underwent this procedure reported any discomfort. All injections performed to date were not associated with any complications.

Take-Home Points

• BT offers an evidence-based method to bypass adverse effects of anticholinergics, which may not be effective.
• Physicians can be easily trained to administer BT injections. No severe complications, such as injury to facial nerve, have been observed.
• Bilateral injections into the parotid and submandibular glands are safe and indicated for CIS.

Ethics Approval and Consent to Participate

Not applicable

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