Treatment of clozapine-induced sialorrhea in patients with schizophrenia – a pilot study with an extemporaneously compounded trospium oromucosal suspension

Introduction

Treatment-resistant schizophrenia (TRS) is defined as schizophrenia in which the current symptoms are of at least moderate severity, with moderate or worse functional impairment, and prior treatment with at least two different antipsychotics, each for at least a minimum duration of 4-6 weeks at total daily dose equivalent of at least 600 mg chlorpromazine. The most efficient treatment option in TRS is clozapine, with demonstrated improvement in positive symptoms, reduction of hospitalizations, and reduction in overall mortality^(1,2).

Clozapine-induced sialorrhea (CIS) is a common adverse effect that jeopardizes the efficacy of clozapine in TRS. It can decrease the treatment adherence, increase the irritability of the patients, and it can cause drooling during nighttime, which can lead to halitosis, perioral chapping, salivary glands swelling, and aspiration pneumonia. Currently, there is no authorized treatment for CIS, except for small studies with limited evidence⁽³⁾.

The proposed treatment options included atropine mouthwash 1 mg/10 mL (increased risk of cholinergic rebound), sublingual glycopyrrolate 2 mg/day (too expensive to be extemporaneously prepared), ipratropium nasal spray sublingually administered (poor efficacy), tiotropium (more potent than ipratropium and glycopyrrolate, but never tested in sialorrhea), clonidine 0.1 mg/day p.o. (increased risk of psychosis), trihexyphenidyl 5-15 mg/day p.o., and metoclopramide 10 mg/day p.o. ^(3-5)

Xanomeline/trospium (Cobenfy®) is a novel drug combination for the treatment of schizophrenia, approved by the U.S. Food and Drug Administration (FDA) in October 2024. Xanomeline is a dual M₁ and M₄ central muscarinic agonist, that does not inhibit the D₂ receptors, but showed improvement in both types of symptoms, while trospium is a peripheral anticholinergic used against the cholinergic adverse effects of xanomeline, including sialorrhea. The starting dose for xanomeline/trospium is 100 mg/40 mg/day, which can be titrated up to 300 mg/60 mg/day^(6,7).

Taking into account the potential of trospium to alleviate the cholinergic effects of xanomeline, we considered it may also be a suitable option for CIS since this side effect may be mediated through the activation of M₄ receptors⁽⁸⁾. Therefore, we reported two cases of patients with CIS who showed symptomatic improvement by using an extemporaneously compounded oromucosal suspension of trospium in borax glycerin.

The usage of oromucosal trospium was also motivated by the reduced risk of an increase in the anticholinergic burden (ACB) of these patients, which can lead to confusion, falls, and even death. This is supported by the fact that trospium has a low bioavailability (approximatively 10%), due to its chemical structure and properties^(9,10). Therefore, the ACB for each patient was calculated using the ACB calculator tool⁽¹¹⁾. One more argument that advocated for this route of administration was that some of the previously presented options were also administered sublingual or oromucosal^(3-5).

The extent of sialorrhea was assayed for each patient using two different scales, the Toronto Nocturnal Hypersalivation Rating Scale (TNHR) for nighttime CIS and the Drooling Severity and Frequency Scale (DSF) (Tables 1 and 2) for daytime CIS, before and during trospium treatment^(12,13).
 

Because there are no commercially available formulations, we decided to use an oromucosal suspension compounded in a hospital pharmacy. The oromucosal formulation was prepared first by pulverizing 10 trospium 15 mg film-coated tablets (purchased from a local pharmacy) in a mill. Then, the obtained powder was suspended in 50 g of borax glycerin (already prepared in the hospital pharmacy), resulting in a 3 mg/g trospium oromucosal suspension. The content was orally administered using a cotton swab each evening for seven days.

Case report 1

In January 2024, a 43-year-old male patient with recent history of psychiatric illness (a previous admission in 2020 in the Psychiatric Diagnosis and Treatment Service of Terni and Foligno, Italy, diagnosed with alcohol-induced psychotic disorder and another admission in 2023 in the First Psychiatric Clinic of the Cluj County Emergency Clinical Hospital, Cluj-Napoca, Romania, diagnosed with acute schizophrenia-like psychotic disorder) was brought to the First Psychiatric Clinic of the Cluj County Emergency Clinical Hospital, Cluj-Napoca, Romania, by a police crew and an emergency medical service, for psychomotor agitation, verbal hetero-aggressive behavior against the members of a church community, ideas of reference with a mystical and persecutory character, and delusions of special missions, considered inadequate for the cultural-religious setting. On presentation, the patient was restless, uncooperative, aggressive towards the medical staff, and had a smell of alcohol on his breath. Later, due to aggressiveness and psychomotor restlessness, he was mechanically restrained in four points. The patient’s mental health status at the moment of admission had the following characteristics:

• Dress and attire – inadequate, dirty street clothing.
• Hygiene – poor.
• Facies – flushed face, injected sclerae.
• Mimicry, gestures – hypermobile.
• Attitude – hostile, uncooperative, suspicious (when confronted about his thought content).
• Verbal contact and dialogue – spontaneously initiated and maintained with mild difficulty, coprolalia, high-pitched voice, familiarity.
• Perception – could not be initially assessed; history of subjective depersonalization experiences linked to supernatural powers.
• Attention – hypoprosexia.
• Memory – hypomnesia.
• Thinking – partially coherent flow of thought, circumstantiality, history of paranoid and prejudice delusions (to which the patient does not focus his attention now, but through remembrance they keep their deliriant character), tendency to create superficial associations when supporting his delusions, possible suicidal ideation (denies it, but advocates for the necessity of a ritualic autosacrifice in a mystical context)
• Affect – irascibility, irritability, low tolerance for frustration.
• Activity – hetero-aggressiveness in the context of excessive alcohol use (25 standard drinks/day); alcohol abuse, despite evidence of psychosocial impairment.
• Will – hypobulia, impulsivity.
• Instincts – normal.
• Nocturnal rhythm – transient insomnia episodes and dreams with mystical content to which the patient associates a personal meaning.
• Orientation – oriented to person, place and time.
• Insight – partially present (only for alcohol use disorder).
• Personality – schizotypal personality disorder with emotional instability elements (according to the diagnosis of the previous admission).

The physical examination did not reveal any pathological findings. From a psychiatric point of view and concluding from the clinical presentation, the patient was diagnosed with paranoid schizophrenia (according to the International Classification of Diseases, Tenth Revision – ICD-10) or schizophrenia (according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition – DSM-5)^(14,15).

The initial treatment during admission consisted of diazepam 30 mg/day i.v. (gradually tapered and stopped) risperidone 8 mg/day p.o., tiapride 200 mg/day p.o. (ultimately stopped), valproic acid 1 g/day p.o., trihexyphenidyl 4 mg/day p.o., B group vitamin therapy, and fluids. Additional treatment included multimodal analgesia (sodium metamizole 2 g/day i.v. and acetaminophen 1.50 g/day) and metoprolol 50 mg/day p.o., due to flu-like symptoms and tachycardia. After 12 days, the patient was moved to the chronic psychiatry ward of the clinic for a prolonged treatment period.

During the admission in the chronic compartment, the patient performed paraclinical investigations (laboratory and microbiology tests, abdominal ultrasound and cranial CT scan, which evidenced an absent right frontal sinus) and underwent psychological examination and internal medicine and otorhinolaryngology evaluations. Several additional comorbidities were detected: respiratory infection with Strepotococcus pyogenes, mixed dyslipidemia, gastroesophageal reflux disease (GERD), and increased liver function tests (LFTs).

The psychological examination revealed deficient cognitive functioning with mild hypomnesia (Ray test), hypoprosexia with difficulty in concentration (Praga test), average intellectual potential (QI = 97, according to the Raven test), Positive and Negative Syndrome Scale (PANSS) scores – P = 18, N = 15, G = 26, T = 59, Brief Psychiatric Rating Scale (BPRS) = 31. The patient presented delusions of interpretation, special mission, and mystical delusions and the insight is formally present.

The somatic comorbidities were treated accordingly: antibiotic therapy with amoxicillin/clavulanic acid 3 g/600 mg/day i.v. and acetylcysteine 600 mg/day i.v. for the respiratory infection (stopped when the symptomatology subsided), rosuvastatin 20 mg/day p.o. and fenofibrate 160 mg/day p.o. for the mixed dyslipidemia, omeprazole 20 mg/day p.o. for GERD, silymarin 450 mg/day p.o. for the increased LFTs, and metoprolol 50 mg/day p.o. for tachycardia.

The new psychopharmacologic treatment consisted of risperidone 6 mg/day p.o., followed by long-acting injectable (LAI) risperidone 50 mg i.m. Risperidone was later switched to paliperidone, which was initiated as 12 mg/day p.o., followed by LAI paliperidone 250 mg/week i.m., then maintained at 150 mg/month i.m. Lamotrigine was used as a mood stabilizer in doses of 100 mg/day, but was later stopped due to concerns regarding skin photosensitivity once the patient will be discharged. Trihexyphenidyl 4 mg/day p.o. was administered to prevent the potential extrapyramidal adverse effects of antipsychotics. Lastly, clozapine was initiated at 50 mg/day p.o. and gradually titrated up to 350 mg/day. Weekly blood cell counts were performed to detect potential agranulocytosis, while the clozapine serum levels were tested when the dosage reached 350 mg/day.

During titration of clozapine up to 350 mg/day p.o., the patient developed sialorrhea and complained of it especially at night, which started to affect the treatment adherence. The sialorrhea did not respond to trihexyphenidyl. The ACB score of this patient was 8 points, signifying a high risk of confusion and falls. Before treatment initiation with oromucosal trospium, the patient was assessed for hypersalivation severity using the TNHR and the DSF scales. The scales were repeated during the third and seventh days. Before initiation, the following scores were registered: TNHR = 4 and DSF = 7, underlining a severe sialorrhea that woke the patient up at least three times during the night, with frequent drools that reached onto clothing. On the third day of the treatment, the registered scores were: TNHR = 1 and DSF = 6, underlining that the patient was no longer disturbed by hypersalivation during the nights, but there were still frequent drools reaching on the lips and chin. Finally, on the seventh day, the registered scores were TNHR = 0 and DSF = 3, meaning that nocturnal hypersalivation was absent and there were only mild drools with just wet lips (Figure 1).
 

After 72 admission days, the patient was discharged with improved symptoms. The final treatment regimen consisted of paliperidone 150 mg/month i.m., clozapine 350 mg/day p.o., trihexyphenidyl 2 mg/day p.o., and fenofibrate 160 mg/day p.o.

Case report 2

In September 2024, a 47-year-old male patient with known history of psychiatric illness (diagnosed with paranoid schizophrenia 15 years ago, possibly related to a car accident) presented on his own to the First Psychiatric Clinic of the Cluj County Emergency Clinical Hospital, Cluj-Napoca, Romania, for psychomotor restlessness and multiple somatic complaints in the form of cenesthopathies (abdominal pains, constipation, headaches, muscular pains with multiple localizations, dizziness, hand tremors), in the context of otherwise proper adherence to treatment. The patient’s mental health status in the moment of admission had the following characteristics:

• Dress and attire – adequate, neat street clothing.
• Hygiene – maintained.
• Facies – hypomobile.
• Mimicry, gestures – hypomobile.
• Attitude – cooperative.
• Verbal contact and dialogue – spontaneously initiated and easily maintained.
• Perception – low perceptual threshold, multiple somatic complaints, complex non-commanding auditory hallucinations.
• Attention – hypoprosexia.
• Memory – normomnesia.
• Thinking – partially coherent, slowed flow of thought, thought sonorisation, thought insertion, delusions of interpretation, persecutory delusions.
• Affectivity – anhedonia, irritability, irascibility, low frustration for tolerance, anxiety linked to hallucinations.
• Activity – diminished daily performance.
• Will – hypobulia.
• Instincts – diminished feeding instinct.
• Day-night rhythm – chronic insomnia.
• Insight – partially present.
• Orientation – oriented to person, place and time.
• Underlying personality – cannot be evaluated.

The psychological examination during admission supplementary revealed bradylalia, deficient cognitive functioning with mild hypomnesia (Ray test), hypoprosexia with difficulty concentrating (Praga test), and liminal intellectual potential (QI = 68, according to the Raven test). The patient presented listening attitude (denies the presence of perception disorders) and mental automatisms.

The physical examination did not reveal any pathological findings. The somatic comorbidities of this patient included hypertension, obesity, and rhabdomyolysis (possibly due to psychomotor restlessness).

The issued treatment for somatic comorbidities consisted of perindopril/indapamide 5 mg/1.25 mg/day p.o. and bisoprolol 10 mg/day p.o. for hypertension, ibuprofen 1.20 g/day for the algic complaints, and lactulose 20.01 mg/day (or 30 mL) p.o., until the constipation remitted. The somatized hand tremor was treated using placebo capsules two times per day.

The psychopharmacologic treatment consisted of paliperidone 150 mg/month i.m., clozapine 500 mg/day p.o., and amisulpride 800 mg/day p.o. as antipsychotics. Trihexyphenidyl 6 mg/day p.o. was administered to prevent the potential extrapyramidal adverse effects of antipsychotics. Levomepromazine 12.5 mg/day p.o. and diazepam 10 mg/day i.m. p.r.n. were administered for the treatment of insomnia. The calculated ACB score for this patient was 11, corresponding to a very high risk of confusion, falls and even death. Amisulpride was not available in this tool and the corresponding score was found in literature⁽¹⁶⁾.

Four days after the admission, the patient complained of sialorrhea which we presumed it was induced by the administration of high doses of clozapine. Hence, the same treatment consisting of trospium-based extemporaneously compounded oromucosal suspension 3 mg/g was employed and administered each evening for seven days. Before initiation, the following scores were registered: TNHR = 3 and DSF = 6, underlining moderate sialorrhea that woke up the patient at least two times during the night and frequent drools that reached the lips and chin. On the third day of the treatment, the registered scores were TNHR = 1 and DSF = 6, underlining that the patient was no longer disturbed by hypersalivation during the nights, but the drooling had the same severity and frequency. On the fifth day, the scores were TNHR = 0 and DSF = 4, concluding that nocturnal hypersalivation was no longer present (no wet marks on the pillow, as reported by the patient), with only occasional and mild drools still present. Finally, on the seventh day, the registered scores were TNHR = 0 and DSF = 2, meaning that the patient was no longer drooling (Figure 2).
 

After 24 days, the patient was discharged with improved mental status. The treatment regimen of the patient at discharge consisted of paliperidone 150 mg/month i.m., clozapine 500 mg/day p.o., amisulpride 800 mg/day p.o., levomepromazine 12.5 mg/day p.o., trihexyphenidyl 6 mg/day p.o., bisoprolol 10 mg/day p.o., and perindopril/indapamide 5 mg/1.25 mg/day p.o.

Discussion

The oromucosal usage of trospium against CIS proved to be successful in both cases, with significant improvements during the seven days of treatment. The alleviation of CIS following this trial improved the overall treatment adherence. Possible adverse effects of this treatment may include peripheral anticholinergic side effects if the suspension is swallowed. Therefore, the patients were instructed to let the suspension be absorbed for 2 minutes and spit out the excess. As far as we are concerned, neither of the two patients reported any additional side effects (e.g., constipation, urinary retention).

Moreover, the compounded trospium oromucosal suspension was cheaper to prepare than the available alternatives for hypersalivation on the market. However, the observed results in these two case reports need to be validated through a placebo-controlled study for the efficiency in improving symptoms and maintaining efficacy.

Conclusions

We consider this trospium-based extemporaneously compounded oromucosal formulation as a promising solution for CIS, and we will continue to apply this treatment for future patients complaining of this side effect.

Autori pentru corespondenţă: Adina Popa E-mail: apopa@umfcluj.ro

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

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