Guanfacine for Clozapine-Induced Sialorrhea in Treatment-Resistant Schizophrenia: A Case Report

Guanfacine for Clozapine-Induced Sialorrhea in Treatment-Resistant Schizophrenia: A Case Report | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 22 September 2025 V1 Latest version Share on Guanfacine for Clozapine-Induced Sialorrhea in Treatment-Resistant Schizophrenia: A Case Report Authors : Aynura Shadlinskaya 0009-0005-8051-7337 , Yağmur Kır [email protected] , and Bora Baskak Authors Info & Affiliations https://doi.org/10.22541/au.175854078.88123305/v1 265 views 100 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Clozapine is the gold-standard treatment for treatment-resistant schizophrenia (TRS) but is often limited by adverse effects. Sialorrhea occurs in 30–80% of clozapine users and may cause skin irritation, infections, poor sleep, social isolation, and reduced adherence. First-line treatments include atropine, tropicamide, amitriptyline, and amisulpride. We report the use of guanfacine in a TRS patient with refractory clozapine-induced sialorrhea (CIS). We present a 34-year-old woman with TRS who was successfully managed on clozapine (350 mg/day). However, a few months into therapy, she developed debilitating diurnal and nocturnal sialorrhea. Standard treatments, including sublingual atropine, hyoscine, amitriptyline, and adjunctive amisulpride, failed to alleviate her drooling. Consequently, oral guanfacine at a dose of 1 mg/day (an α2-adrenergic agonist) was initiated. Remarkably, within just 7 days, her sialorrhea completely resolved without any side effects or changes in vital signs. The patient’s quality of life and social functioning improved significantly as drooling stopped. She maintained adherence to clozapine, which allowed further improvement in psychotic symptoms. Low-dose guanfacine may be an alternative treatment approach in CIS. The α2-agonistic effect of guanfacine may have been effective in the treatment of sialorrhea. Case-control studies on the efficacy of guanfacine in CIS are needed. Guanfacine for Clozapine-Induced Sialorrhea in Treatment-Resistant Schizophrenia: A Case Report Authors : Aynura Shadlinskaya a , Yağmur Kır a, * , Bora Baskak a Affiliations : a Ankara University, Faculty of Medicine, Department of Psychiatry, Ankara, Türkiye *Corresponding author. e-mail: [email protected] Funding None. Acknowledgements The authors would like to thank the patient for her participation. Conflict of interest statement The authors have declared no conflicts of interest for this article. Abstract Clozapine is the gold-standard treatment for treatment-resistant schizophrenia (TRS) but is often limited by adverse effects. Sialorrhea occurs in 30–80% of clozapine users and may cause skin irritation, infections, poor sleep, social isolation, and reduced adherence. First-line treatments include atropine, tropicamide, amitriptyline, and amisulpride. We report the use of guanfacine in a TRS patient with refractory clozapine-induced sialorrhea (CIS). We present a 34-year-old woman with TRS who was successfully managed on clozapine (350 mg/day). However, a few months into therapy, she developed debilitating diurnal and nocturnal sialorrhea. Standard treatments, including sublingual atropine, hyoscine, amitriptyline, and adjunctive amisulpride, failed to alleviate her drooling. Consequently, oral guanfacine at a dose of 1 mg/day (an α2-adrenergic agonist) was initiated. Remarkably, within just 7 days, her sialorrhea completely resolved without any side effects or changes in vital signs. The patient’s quality of life and social functioning improved significantly as drooling stopped. She maintained adherence to clozapine, which allowed further improvement in psychotic symptoms. Low-dose guanfacine may be an alternative treatment approach in CIS. The α2-agonistic effect of guanfacine may have been effective in the treatment of sialorrhea. Case-control studies on the efficacy of guanfacine in CIS are needed. Introduction Clozapine is the standard treatment approved for TRS and recommended in various schizophrenia treatment guidelines 1-3 . Despite the effectiveness of clozapine, which is associated with lower mortality rates and better quality of life in patients 4 , serious side effects such as agranulocytosis, lowered seizure threshold, myocarditis, ileus and common side effects such as sedation, constipation, orthostatic hypotension, metabolic syndrome, nighttime enuresis and sialorrhea make psychiatrists reluctant to switch to clozapine 5 . Sialorrhea is one of the most common side effects of clozapine and has been reported in 30-80% of clozapine users 6 . In a recent study, 88.56% of clozapine-treated patients complained of nocturnal, 62.31% diurnal and 65.38% both nocturnal and diurnal sialorrhea. Thirty percent of the patients reported a moderate to severe negative impact of sialorrhea on their quality of life 7 . CIS may lead to skin irritation and infections, parotid gland infection, poor sleep quality, social isolation and deterioration in treatment compliance 8 . CIS can also lead to serious complications such as aspiration pneumonia 9 . Understanding the underlying mechanisms is critical for the treatment of CIS. However, this condition cannot be explained by a single mechanism. Both the mechanisms affecting the salivary production process and the complex binding profiles of clozapine at the receptor level are the main reasons for investigating the efficacy of different pharmacological agents in the treatment of CIS. M3 and M4 muscarinic receptors are highly expressed in salivary gland tissue and stimulation of M3 and M4 receptors leads to excessive saliva production. One of the mechanisms proposed in the pathophysiology of CIS is that the agonistic effect of clozapine on M4 exceeds its weaker antagonistic effect on M3, resulting in CIS 10 . Another theory related to CIS is related to α-adrenoreceptors. Clozapine has an antagonistic effect on α1 and α2 receptors. Blockade of these receptors in the salivary gland may lead to imbalance in adrenergic activity and stimulation of beta receptors, thus increasing saliva production 11 . In addition, an increase in α1 and α2 receptor density may also occur in response to chronic blockade of α-receptors. These changes in receptor density may also play a role in the development of CIS 10 . Non-pharmacological approaches and adjustments in clozapine dosage are recommended in the first instance in CIS, but the effectiveness of these approaches is very limited. Placing a towel on the pillow at night may help absorb excess saliva, but patients may produce so much saliva that it is not limited to the pillow area. The use of sugar-free chewing gum may partially reduce the problems associated with sialorrhea by facilitating swallowing. However, this approach is ineffective in nocturnal sialorrhea. Reducing the dose of clozapine may alleviate the symptoms of CIS. However, there is no consistent evidence in this regard. When clozapine is to be started, slow titration of the dose may reduce the risk of developing sialorrhea 10 . First-line medical treatment in CIS includes mouthwash with 1% atropine sulfate, tropicamide drops, amitriptyline and then second line medication include amisulpride 12 . The results of a recent meta-analysis of the efficacy of agents used to treat sialorrhea due to antipsychotic use suggest that metoclopramide, cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, amitriptyline, atropine and astemizole are superior to placebo, but glycopyrrolate or ipratropium has similar efficacy to placebo; Secondary analyses support that antimuscarinics, benzamides, tricyclic antidepressants and antihistamines are superior to placebo 13 . Considering that one of the mechanisms by which clozapine causes CIS is α-2 adrenergic receptor antagonism, the use of α-2 adrenergic receptor agonists in the treatment of CIS is a possible approach. Guanfacine, a centrally acting α-2 adrenergic receptor agonist primarily used in the treatment of essential hypertension, has also been reported to be effective in managing CIS 14 . Additionally, it is being explored as a potential therapeutic agent in the treatment of attention-deficit/hyperactivity disorder (ADHD) and cognitive deficits associated with schizophrenia 15 . In the present case, the management of CIS was effectively achieved by oral administration of guanfacine 1 mg once daily. This drug is recognized for its role as an α2 adrenergic agonist. This case report discusses the effective use of guanfacine in CIS, a condition that may impair quality of life and treatment compliance. ./tpl/new_commands Case Presentation Our patient was 34 years old, female and single. She had completed high school. She lives with her father in Ankara. She is not working at the moment. Written informed consent was obtained from the patient and her father regarding the case report. The patient’s psychiatric history began in 2019 at the age of 29, marked by the onset of sleep disturbances, self-talk, and escalating aggression, including hostility directed towards her father. Prompted by these concerning developments, her father sought professional help, leading to a referral to the Psychiatry Clinic at Ankara University Faculty of Medicine. Following a thorough anamnesis and psychiatric evaluation, she received a diagnosis of schizophrenia, and a treatment regimen of olanzapine 10 mg/day and escitalopram 10 mg/day was initiated. Initially, the patient demonstrated a positive response to treatment, with a notable regression of her symptoms over a six-month period. However, she subsequently discontinued her medication against medical advice, resulting in a significant exacerbation of her clinical presentation within three months. Once again, her father intervened, bringing her back to the hospital. During this period, her anger towards her father intensified, and she voiced accusations of infidelity towards her mother. She also reported engaging in conversations with angels, claiming to see them and describing these encounters as divine blessings. Her treatment was then adjusted to risperidone 4 mg/day, sertraline 50 mg/day, and paliperidone 100 mg/month injection, which continued for six months. In June 2021, the patient and her mother relocated to Erzurum for a brief period to be closer to family. Unfortunately, her medication adherence faltered, leading to a hospitalization in Erzurum due to the recurrence of self-talk, auditory, and visual hallucinations. During this three-month admission, she received a diagnosis of Non-Organic Psychosis and was treated with clozapine 300 mg/day, aripiprazole 400 mg/month, and haloperidol 10 mg/day. After approximately four months of improved treatment compliance, the patient moved from Erzurum to Ankara in May 2022. Regrettably, in July 2022, her symptoms resurfaced following a decline in medication adherence, necessitating hospitalization at an external facility. Her treatment was modified to include clozapine 450 mg/day, paliperidone 9 mg/day, and biperiden 2 mg/day. The patient continued with follow-up appointments until March 2024. However, consistent medication compliance remained a challenge. The patient expressed reluctance to take clozapine due to the distressing side effect of sialorrhea. Consequently, her medication use was inconsistent. To address the CIS and improve adherence, 1% atropine drops were added to her treatment. While she used the drops for approximately two months, she discontinued them due to a lack of efficacy in reducing salivation. Subsequently, amitriptyline 10 mg/day was introduced, but she stopped this medication after one month due to the absence of benefit and the development of constipation. The patient’s clinical condition deteriorated further following the death of her mother in June 2024. In September 2024, she was admitted to the Ankara University Rehabilitation Service, presenting with a constellation of concerning symptoms, including persistent self-talk, visual hallucinations of soldiers in her home whom she believed intended to harm her, reliance on angels for assistance, debilitating sialorrhea, social withdrawal, and impaired functionality. During the patient’s admission, CIS was prominent. Her clothes were getting wet due to sialorrhea during speech. On mental status examination, she was alert, with adequate orientation to time, place, and person. Attention was adequate. There were no deficits in immediate, recent, or remote memory. Intelligence appeared clinically normal. Visual and auditory hallucinations were present. Speech tempo and rhythm were normal. Her thought content included persecutory and erotomanic delusions. Affect was shallow. Psychomotor activity was assessed as mildly decreased. According to the evaluation, the SAPS score was 35 and the SANS score was 14. Brain MRI and blood tests showed no abnormalities. The patient had no known comorbidities and a negative history of alcohol, smoking, and substance abuse. Her family history revealed a diagnosis of schizophrenia in her mother. After admission, the patient’s medication regimen was adjusted to clozapine 350 mg/day and amisulpride 400 mg/day. Consistent medication adherence was ensured. After one month, the patient’s SAPS score decreased to 20; however, she developed secondary parkinsonism. The CIS score remained unchanged. The patient continued to have significant diurnal and nocturnal sialorrhea. Consequently, amisulpride was discontinued. Quetiapine 400 mg/day was started. Hyoscine butylbromide 3 times daily was added to the treatment regimen to manage persistent CIS symptoms. After two weeks of observation, no improvement in sialorrhea was noted. Therefore, hyoscine butylbromide was discontinued and guanfacine 1 mg/day was started. Four days after the addition of guanfacine 1 mg/day, a significant reduction in diurnal sialorrhea was observed. By the end of one week, both diurnal and nocturnal sialorrhea had completely resolved. Regarding guanfacine’s common cardiovascular side effects, including hypotension and arrhythmias, blood pressure monitoring during the first week of treatment showed no evidence of hypotension. Additionally, two electrocardiograms (ECGs) obtained within the first two weeks of guanfacine treatment revealed no pathological findings. There was no worsening of positive symptoms during follow-up. At the three-month mark, the patient was discharged with a SAPS score of 5 and a SANS score of 7. The improvement in the CIS was accompanied by improved social interactions. The patient is currently attending fortnightly group therapy sessions. With the resolution of sialorrhea, adherence to clozapine is progressing well. ./tpl/new_commands Discussion Clozapine is considered the gold standard for treatment of treatment-resistant schizophrenia. However, its side effects, such as sialorrhea, are common and can affect patients’ comfort and quality of life, but also constitute a significant clinical barrier to the sustainability of clozapine treatment by reducing both adherence and tolerability 16 . Given the psychosocial implications of CIS including sleep disturbances, decreased self-esteem, embarrassment, social withdrawal, and functional impairment—its management is of considerable clinical importance 9 . In the literature, the pathophysiology of clozapine-associated sialorrhea is still not clearly understood and the role of both anticholinergic and adrenergic mechanisms is emphasized. This situation reveals the importance of investigating alternative treatment approaches to manage sialorrhea during the treatment process. A range of pharmacological strategies has been employed in the treatment of CIS, including local and oral anticholinergic agents (e.g., atropine, benztropine, ipratropium bromide, tropicamide, propantheline), alpha-adrenergic agents (e.g., clonidine), clostridium botulinum toxin injections, and benzamide derivatives (e.g., metoclopramide, amisulpride) 12 . The application of centrally acting α-2 adrenergic receptor agonists in the management of CIS is exemplified by clonidine. Clonidine, along with other ’clonidine-like’ pharmaceuticals developed as antihypertensive agents, exerts an inhibitory effect on salivary secretion through the stimulation of alpha-2 adrenoreceptors. Grabowski initially documented the use of clonidine in the context of CIS 17 . In a cohort of patients undergoing clozapine treatment, the administration of 0.1-0.2 mg/day of clonidine, delivered weekly in a sustained-release formulation, resulted in a significant amelioration of sialorrhea in two individuals, a reduction in symptoms in another, and no discernible change in four patients. Lofexidine, another α-2 adrenoceptor agonist employed in the treatment of opioid withdrawal in certain countries, has also been investigated in this context. Corrigan et al. reported a positive response in a single case of CIS following treatment with 0.2 mg twice daily 18 . In comparison to clonidine, guanfacine exhibits a diminished sedative effect due to its relative selectivity for the alpha-2 receptor subgroup. Webber et al. reported efficacious outcomes within a four-day period with the administration of 1 mg of guanfacine in the treatment of CIS 14 . While the current literature on alpha-2 adrenergic agents remains limited, anecdotal reports and uncontrolled open-label studies suggest that such agents may be effective in reducing CIS. Nevertheless, side effects such as hypotension, sedation, dizziness, urinary retention, constipation, and bradycardia may limit their tolerability in certain patients. This case demonstrates the effective use of 1 mg/day guanfacine to treat CIS in a patient with TRS. Guanfacine may represent a promising pharmacological option for the treatment of CIS, which has a detrimental impact on social functioning and medication adherence. To date, its use has been documented in only case reports. 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British Journal of Psychiatry . 1995;167(3):412-412. doi:10.1192/bjp.167.3.412a Information & Authors Information Version history V1 Version 1 22 September 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Aynura Shadlinskaya 0009-0005-8051-7337 Ankara Universitesi Tip Fakultesi View all articles by this author Yağmur Kır [email protected] Ankara Universitesi Tip Fakultesi View all articles by this author Bora Baskak Ankara Universitesi Tip Fakultesi View all articles by this author Metrics & Citations Metrics Article Usage 265 views 100 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Aynura Shadlinskaya, Yağmur Kır, Bora Baskak. Guanfacine for Clozapine-Induced Sialorrhea in Treatment-Resistant Schizophrenia: A Case Report. Authorea . 22 September 2025. 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