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Table of Contents
LETTER TO THE EDITOR
Year : 2021  |  Volume : 35  |  Issue : 3  |  Page : 149-150

Paliperidone-induced dose-dependent sialorrhea treated with biperiden: A case report


Department of Psychiatry, Far Eastern Memorial Hospital, New Taipei City, Taiwan

Date of Submission26-Jan-2021
Date of Decision16-Apr-2021
Date of Acceptance27-Apr-2021
Date of Web Publication24-Sep-2021

Correspondence Address:
Pei- Chuan Wu
No. 21, Section 2, Nanya South Road, Banqiao District, New Taipei City 220
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/TPSY.TPSY_29_21

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How to cite this article:
Lin JY, Wu PC. Paliperidone-induced dose-dependent sialorrhea treated with biperiden: A case report. Taiwan J Psychiatry 2021;35:149-50

How to cite this URL:
Lin JY, Wu PC. Paliperidone-induced dose-dependent sialorrhea treated with biperiden: A case report. Taiwan J Psychiatry [serial online] 2021 [cited 2021 Oct 22];35:149-50. Available from: http://www.e-tjp.org/text.asp?2021/35/3/149/326579



Sialorrea as a side effect is commonly reported when treating patients with antipsychotic drugs, notably clozapine. The proposed mechanism of antipsychotic-induced sialorrhea includes the contribution to hypersecretion of saliva and the dysfunction of removing saliva from the mouth [1]. Excessive sialorrhea makes patients socially stigmatized, inconvenient, and can also lead to poor medication adherence. Patients also have higher risk of chocking, contributing to aspiration pneumonia and further physical complications, which should be cautioned in clinical practice. Paliperidone, the primary active metabolite of risperidone, is an often used antipsychotic agent. Paliperidone-induced sialorrhea has been recorded in some experimental research before [2], but few papers exist to discuss further case presentation and possible treatment options.

In this report, we present a case of a patient who developed sialorrhea after paliperidone use, and the side effect was responsive to biperiden treatment. To our knowledge, this is the first case report regarding paliperidone-induced sialorrhea, which serves as a base of further investigation for the adverse effect of paliperidone.


  Case Report Top


A case of 32-year-old female patient had a history of schizophrenia and major depressive disorder (using DSM-5 criteria) with the first onset in October 2016. She was admitted to our acute ward in November 2017 due to persisting psychotic symptoms. Full laboratory examinations of full blood counts, serum chemistry for renal function, liver enzyme, electrolytes, glucose, and thyroid function tests were done to establish the diagnosis. The patient had no previous medical condition and no hospitalization history.

The patient was treated initially with daily escitalopram 10 mg, alprazolam 0.5 mg, and aripiprazole 5 mg. Psychotic symptoms persisted after a three-day treatment, including self-talking, self-laughing, persecutory delusion, and auditory hallucination. Therefore, daily aripiprazole 5 mg was changed to daily paliperidone 6 mg on day 3. The patient manifested with sialorrhea and extrapyramidal symptoms (EPS), including generalized muscle rigidity and akathisia three hours after. Paliperidone treatment was kept, and the psychotic symptoms were improved after the use of paliperidone. She kept complaining about the side effect, such as sialorrhea and EPS. As a result, on day 7, daily paliperidone 6 mg was changed to daily aripiprazole 10 mg, and she also received daily biperiden 4 mg. The sialorrhea and EPS symptoms were improved within one day, and those side effects were never seen again during admission. Her psychotic symptoms were also improved thereafter. Consequently, she was discharged smoothly on day 18. At clinical follow-up, the aripiprazole was increased to daily 15 mg. Moreover, the antipsychotic agent was changed to daily risperidone 4 mg, with long acting injectable (LAI) risperidone 37.5 mg i.m. injection every two weeks. Subsequently, the LAI was changed to paliperidone 150 mg i.m. injection every four weeks. Throughout the outpatient follow-up course, she continuously kept taking daily biperiden 4 mg. Sialorrhea had never been found or been complained of again.


  Comment Top


The contributing factors of sialorrhea may include hypersecretion of saliva, dental malocclusion, and postural problems [1]. Saliva excretion is controlled through parasympathetic system and modified by sympathetic system partly. Currently, three main hypotheses exist to explain the mechanism of antipsychotic-induced sialorrhea:

  • Postsynaptic α2-adrenergic-mediated production of saliva. Such antipsychotic drugs act as α2-adrenergic antagonist, contributing to increased salivation.
  • Parasympathetic muscarinic cholinergic M4 receptor stimulation has been hypothesized to lead to increased saliva secretions. The antipsychotic agents lead to M4 stimulation, causing increased salivation.
  • Antipsychotic agents lead to abnormal regulation by blocking receptors in the pharynx or in the swallowing muscles.


Paliperidone, also known as 9-hydroxyrisperidone, is the primary active metabolite of the older second-generation antipsychotic (SGA), risperidone. Both paliperidone and risperidone are “serotonin, dopamine, and norepinephrine receptor antagonists” as defined in neuroscience-based nomenclature system (www.NbN.ECNP.org). Paliperidone acts mainly as D2 antagonist and 5HT2A antagonist, which is similar to other SGAs. Paliperidone also has effect of α1, α2 adrenergic, and H1 antagonist. It is generally considered that paliperidone has no affinity on cholinergic muscarinic transmission [3].

Antipsychotic-related sialorrhea has been widely reported. Clozapine-induced sialorrhea is most reported and has been treated successfully by several medication including biperiden and antimuscarinic agents such as diphenhydramine [4]. Quetiapine and olanzapine have been reported to lead to sialorrhea [5],[6]. Aripiprazole-induced sialorrhea has also been mentioned before, which is responsive to diphenhydramine treatment [7]. Several cases of risperidone-induced sialorrhea have been reported before, which is dose related and responsive to biperiden and diphenhydramine treatment [8],[9]. The previous reports all suggested that the possible mechanism may be α2-adrenergic receptor antagonism. M4 receptor agonism has been suggested to be the potential mechanism of clozapine and olanzapine. In this case, sialorrhea was found after the use of paliperidone, which is generally considered with little effect on cholinergic muscarinic transmission [10]. Therefore, postsynaptic α2-adrenergic antagonism may be the most likely mechanism to increase the production of saliva in our patient. On the other hand, the EPS found in this patient, including generalized muscle rigidity, may lead to decreased removal of saliva by pharynx and swallowing muscle. Therefore, the EPS-related sialorrhea should be taken into consideration as well.

The paliperidone-induced sialorrhea was not found again when the patient had received paliperidone LAI after biperiden treatment. The most likely mechanism of why biperiden reversed the adverse effect in our patient is that biperiden acts as muscarinic receptor antagonist, resulting in reestablishing the adrenergic–cholinergic balance. Such mechanism may reset the autonomic nervous system effect on the salivary gland, thus reverse the adverse effect [9]. In this patient, sialorrhea was found three hours after her antipsychotic drug was changed from daily aripiprazole 5 mg to daily paliperidone 6 mg. Aripiprazole acts as a long half-life antipsychotic drug with a half-life about 75 h. It did not dissociate the bounded receptors totally when this patient was developing sialorrhea. When our patient's dose of aripiprazole did not reach the recommended treatment dose for an adult patient with schizophrenia, she might still have unoccupied D2 antagonistic receptors while she was receiving daily aripiprazole 5 mg. After paliperidone administration, her unoccupied D2 receptors were then be occupied by paliperidone, resulting in causing side effects, including sialorrhea. But further investigation of precise pharmacokinetic mechanism of aripiprazole–paliperidone interaction is needed.

To our best knowledge, this is the first case report of a paliperidone-induced sialorrhea. Although this case report is limited with only a single case report without other published evidence, we still suggest that sialorrhea is one of the side effects should be mentioned during paliperidone treatment, and that biperiden might be given as a treatment of choice if an early symptom is seen. The institutional review board of Far Eastern Memorial Hospital approved the publication of this case report (IRB protocol number = FEMH No.109198-C and date of approval = January 4, 2021) with the stipulation of obtaining signed informed consent from the patient on November 24, 2020.


  Financial Support and Sponsorship Top


None.


  Conflicts of Interest Top


There are no conflicts of interest.



 
  References Top

1.
Hockstein NG, Samadi DS, Gendron K, et al.: Sialorrhea: a management challenge. Am Fam Physician 2004; 69: 2628-34.  Back to cited text no. 1
    
2.
Savitz AJ, Xu H, Gopal S, et al.: Efficacy and safety of paliperidone palmitate 3-month formulation for patients with schizophrenia: a randomized, multicenter, double-blind, noninferiority study. Int J Neuropsychopharmacol 2016; 19: pyw018.  Back to cited text no. 2
    
3.
Corena-McLeod M: Comparative pharmacology of risperidone and paliperidone. Drugs R D 2015; 15: 163-74.  Back to cited text no. 3
    
4.
Liang CS, Ho PS, Shen LJ, 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: 138-44.  Back to cited text no. 4
    
5.
Allen S, Hoffer Z, Mathews M: Quetiapine-induced hypersalivation. Prim Care Companion J Clin Psychiatry 2007; 9: 233.  Back to cited text no. 5
    
6.
Perkins DO, McClure RK: Hypersalivation coincident with olanzapine treatment. Am J Psychiatry 1998; 155: 993-4.  Back to cited text no. 6
    
7.
Kılınç S, Hergüner A, Hergüner S: Aripiprazole-induced sialorrhea responsive to diphenhydramine treatment. J Child Adolesc Psychopharmacol 2016; 26: 767-8.  Back to cited text no. 7
    
8.
Liang CS, Liao WC, Yang FW, et al.: Risperidone-induced sialorrhea: dose-related? Pharmacopsychiatry 2010; 43: 282-3.  Back to cited text no. 8
    
9.
Panagiotidis PT, Fountoulakis KN, Siamouli M, et al.: Risperidone-induced sialorrhea responsive to biperiden treatment. Schizophr Res 2007; 93: 410-1.  Back to cited text no. 9
    
10.
Jarema M, Bieńkowski P, Heitzman J, et al.: Paliperidone palmitate: effectiveness, safety, and the use for treatment of schizophrenia. Psychiatr Pol 2017; 51: 7-21.  Back to cited text no. 10
    




 

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