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
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.
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