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

https://doi.org/10.1016/j.schres.2010.02.1060Get rights and content

Abstract

Background

Clozapine-induced sialorrhea (CIS) is a subjective distressing adverse effect and occurs in 31%–57% of schizophrenic patients receiving clozapine therapy. Current pharmacotherapy on CIS has focused on anticholinergic agents, even though they may impair cognitive function. Previous case reports have suggested the benefit of glycopyrrolate or biperiden in treating this condition, but no randomized controlled trial has provided evidence. The objective of our study was to evaluate the efficacy and impact on cognition of glycopyrrolate and biperiden treatments for schizophrenic patients suffering from CIS.

Methods

Patients who satisfied the inclusion criteria entered a 12-week, randomized, double-blind, crossover, fixed-dose trial. The study consisted of two 4-week crossover phases, which were separated by a 4-week washout period. Sialorrhea and global cognitive function were assessed by using a Drooling Rating Scale (DRS) and the Mini Mental State Examination (MMSE), respectively.

Results

Throughout the study, patients treated with glycopyrrolate or biperiden had significantly reduced DRS scores. Moreover, the DRS scores were significantly lower with glycopyrrolate treatment than with biperiden. In other respects, there were no significant differences in MMSE scores in patients treated with glycopyrrolate. However, we found a significant reduction in MMSE scores in patients treated with biperiden.

Conclusion

We provide evidence, for the first time, of the efficacy of glycopyrrolate and biperiden in the treatment of CIS. Furthermore, glycopyrrolate displays less impact on cognitive function. Consequently, glycopyrrolate can become a valid option for treating CIS. Observations from our study serve as a springboard for additional large-scale prospective trials.

Introduction

In psychiatry, there is no evidence indicating the definite superiority of any agent as a treatment for major psychiatric disorders. Clozapine, the only exception, has been approved as the gold standard treatment for cases of treatment-resistant schizophrenia (Lewis et al., 2006, McEvoy et al., 2006). Clozapine is an atypical antipsychotic with minimal risk of extrapyramidal side effects; however, its widespread use is limited by its potential adverse effects. Apart from its more serious side effects such as agranulocytosis, seizure, metabolic syndrome, myocarditis, and cardiomyopathy, clozapine may cause sedation, sialorrhea, sexual problems, nocturnal enuresis, tachycardia, constipation and many other significant adverse effects (Iqbal et al., 2003, Yusufi et al., 2007). In one study, up to 17% of schizophrenic patients were required to discontinue treatment with clozapine because of adverse effects (Grohmann et al., 1989). Hence, common side effects emerging early in the treatment course remain an obstacle to treatment adherence and tolerance to clozapine.

Sialorrhea, also referred to as hypersalivation or ptyalism, is the second most common side effect of clozapine. Clozapine-induced sialorrhea (CIS) occurs in 31% to 57% of patients receiving clozapine therapy and usually develops early in the course of treatment (Iqbal et al., 2003, Praharaj et al., 2006, Yusufi et al., 2007). CIS can cause physical and psychosocial complications ranging from mild and inconvenient symptoms to severe problems that may interfere with quality of life. Physical complications include foul odor, skin irritation, skin infection, swelling of salivary glands, parotitis, and aspiration pneumonia (Iqbal et al., 2003, Praharaj et al., 2006). CIS may result in psychosocial complications including sleep disturbance, lowering of self-esteem, embarrassment, isolation and social impairment (Praharaj et al., 2006). Consequently, management of CIS is essential for improving the patient's drug adherence and quality of life, and for the overall effectiveness of clozapine treatment.

Although the actual pathophysiological mechanism of CIS remains unknown, the literature regarding the pharmacological treatment of CIS has focused predominantly on anticholinergic agents (Praharaj et al., 2006). Several lines of evidence support the view that anticholinergic agents may contribute to iatrogenic memory impairment and other cognitive deficits in schizophrenic patients (Brebion et al., 2004, Spohn and Strauss, 1989, Strauss et al., 1990). Cognitive deficits in schizophrenia have been recognized as a critical determinant of functional outcome (Bartels et al., 1997, Dickerson et al., 1996, Green, 1996) and symptomatic outcome (Moritz et al., 2000). Furthermore, central anticholinergic syndrome, also called “the forgotten diagnosis”, is often overlooked in clinical practice because of its wide variety of signs and symptoms (Brown et al., 2004, Moos, 2007). Therefore, clinicians should consider not only the efficacy but also the potential CNS effects of anticholinergic agents in the treatment of CIS.

Glycopyrrolate, a water-soluble quaternary ammonium compound, is an effective and potent anticholinergic agent with poor penetration across the blood-brain barrier (Abboud et al., 1981, Mirakhur and Dundee, 1983, Proakis and Harris, 1978). It is popular as a preanesthetic agent because of its long-lasting ability to decrease salivary secretion and gastric acid (Mirakhur and Dundee, 1983). Glycopyrrolate has been shown to be effective in treating chronic drooling in children and young adults with developmental disabilities (Blasco and Stansbury, 1996, Mier et al., 2000). Two previous case reports have described glycopyrrolate efficacy in the treatment of CIS in one adult and three adolescents (Duggal, 2007, Robb et al., 2008). On the other hand, Richardson et al. (2001) reported a case of excessive sweating caused by clozapine that was reversed by biperiden, a centrally acting anticholinergic agent. This patient's CIS was incidentally eliminated by biperiden. However, until now, no randomized, double-blind, controlled trials have been conducted to validate the efficacy of these two drugs in the management of CIS.

In light of the features of CIS described above, we attempted to evaluate the efficacy and cognitive function of glycopyrrolate and biperiden in the treatment of schizophrenic patients suffering from CIS. To the best of our knowledge, this is the first prospective, randomized, double-blind, crossover, fixed-dose study comparing glycopyrrolate and biperiden for the treatment of CIS. We hypothesized that glycopyrrolate and biperiden would be beneficial in controlling CIS in schizophrenic patients taking clozapine. Moreover, glycopyrrolate would have less impact on cognitive function.

Section snippets

Participants

This study was approved by the Institutional Review Board for the Protection of Human Subjects at the Tri-Service General Hospital, a medical teaching hospital belonging to the National Defense Medical Center in Taipei, Taiwan. Written informed consent was obtained from all participants after they had received a full explanation of the nature of the study. We performed this trial, from July 2009 to September 2009, in the chronic and subacute ward of the Beitou Armed Forces Hospital, Taipei.

Results

The study phases, along with assessment timing, and numbers of subjects recruited and retained, are illustrated in Fig. 1. After screening the 48 patients treated with clozapine, 13 subjects fulfilled the entry criteria and were eligible for the study. One patient later dropped out the trial because of a deteriorating psychiatric condition. Of the patients completing the study, seven patients received biperiden in the first treatment phase and the other five received glycopyrrolate. The

Discussion

This is the first study to compare cognitive function and efficacy for glycopyrrolate and biperiden in schizophrenic patients suffering from CIS in a head-to-head, randomized, double-blind, crossover trial. Congruent with previous case reports (Duggal, 2007, Richardson et al., 2001, Robb et al., 2008), our data provide evidence to support the beneficial effect of glycopyrrolate and biperiden for CIS. It should be noted that a therapeutic response was observed as early as 1 week after treatment,

Role of funding source

Funding for this study was provided by Civilian Administration Division of Beitou Armed Forces Hospital. The Civilian Administration Division had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Liang Chih-Sung contributed to study design, literature review and data collection, and wrote the manuscript. Chiang Kuo-Tung contributed to study design, wrote the protocol and provided overall scientific supervision. Ho Pei-Shen undertook the statistical analysis, interpreted the results, and edited the manuscript. Shen Lih-Jong was involved in the conception and design of the study. Lee Wen-Kuei contributed to the study design and participated in the supervision of clinical data. Yang

Conflict of interest

All authors declare that there is no conflict of interest.

Acknowledgements

We thank Dr. Nancy Thomas-Stonell for her permission to use Drooling Rating Scale in our study.

References (55)

  • P. Michal et al.

    Clozapine interaction with the M2 and M4 subtypes of muscarinic receptors

    Eur. J. Pharmacol.

    (1999)
  • D.D. Moos

    Central anticholinergic syndrome: a case report

    J. Perianesth. Nurs.

    (2007)
  • M.C. Olianas et al.

    Mixed agonist–antagonist properties of clozapine at different human cloned muscarinic receptor subtypes expressed in Chinese hamster ovary cells

    Neuropsychopharmacology

    (1999)
  • G.B. Proctor et al.

    Regulation of salivary gland function by autonomic nerves

    Auton. Neurosci.

    (2007)
  • W.F. Regine et al.

    Neurocognitive outcome in brain metastases patients treated with accelerated-fractionation vs. accelerated-hyperfractionated radiotherapy: an analysis from Radiation Therapy Oncology Group Study 91-04

    Int. J. Radiat. Oncol. Biol. Phys.

    (2001)
  • M.E. Strauss et al.

    Effects of anticholinergic medication on memory in schizophrenia

    Schizophr. Res.

    (1990)
  • T.K. Abboud et al.

    Use of glycopyrrolate in the parturient: effect on the maternal and fetal heart and uterine activity

    Obstet. Gynecol.

    (1981)
  • A. Atri et al.

    Blockade of central cholinergic receptors impairs new learning and increases proactive interference in a word paired-associate memory task

    Behav. Neurosci.

    (2004)
  • Y.M. Bai et al.

    Therapeutic effect of pirenzepine for clozapine-induced hypersalivation: a randomized, double-blind, placebo-controlled, cross-over study

    J. Clin. Psychopharmacol.

    (2001)
  • R.J. Baldessarini et al.

    Clozapine. A novel antipsychotic agent

    N. Engl. J. Med.

    (1991)
  • B.J. Baum

    Principles of saliva secretion

    Ann. N. Y. Acad. Sci.

    (1993)
  • P.A. Blasco et al.

    Glycopyrrolate treatment of chronic drooling

    Arch. Pediatr. Adolesc. Med.

    (1996)
  • T.I. Bonner

    New subtypes of muscarinic acetylcholine receptors

    Trends Pharmacol. Sci.

    (1989)
  • G. Brebion et al.

    Medications and verbal memory impairment in schizophrenia: the role of anticholinergic drugs

    Psychol. Med.

    (2004)
  • D.V. Brown et al.

    Anticholinergic syndrome after anesthesia: a case report and review

    Am. J. Ther.

    (2004)
  • F. Dorje et al.

    Immunological detection of muscarinic receptor subtype proteins (m1–m5) in rabbit peripheral tissues

    Mol. Pharmacol.

    (1991)
  • T. Drimer et al.

    Effects of discontinuation of long-term anticholinergic treatment in elderly schizophrenia patients

    Int. Clin. Psychopharmacol.

    (2004)
  • Cited by (38)

    View all citing articles on Scopus
    View full text