Amisulpride versus moclobemide in treatment of clozapine-induced hypersalivation
ANATOLY KREININ 1 , CHANOCH MIODOWNIK 2 , SHMUEL SOKOLIK 3 , DIANA SHESTAKOVA 1 , IGOR LIBOV 2 , JOSEPH BERGMAN 1 & VLADIMIR LERNER 2
1 Mental Health Center Tirat Carmel, Bruce Rapaport Faculty of Medicine Technion- Haifa, Israel, 2 Be ' er-Sheva Mental Health Center, Faculty of Health Sciences Ben-Gurion University of the Negev, Be ' er-Sheva, Israel, and 3 Faculty of Health Sciences Ben-Gurion University of the Negev, Be ' er-Sheva, Israel
The World Journal of Biological Psychiatry, 2010; Early Online, 1–7
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Abstract Objectives. Previous publications demonstrated substitute benzamides as effective agents in treatment of clozapine-induced sialorrhea (CIS). The aim of this study was to compare effi cacy of amisulpride and moclobemide (both from the substitute benzamide group) in controlling, or at least minimizing, CIS. Methods. The study was designed as a 6-week, two-center, fi xed-dose, comparison study of 400 mg/day of amisulpride versus 300 mg/day of moclobemide as an adjunctive treatment in 53 schizophrenia and schizoaffective disorder patients (diagnosed according to DSM-IV) suffering from CIS. The patients were treated with each medication during 2 weeks, followed by a washout period of 2 weeks. Primary outcome measures included the reduction in the fi ve-point Nocturnal Hypersalivation Rating Scale (NHRS). Secondary outcomes included the Positive and Negative Syndrome Scale (PANSS), Manic State Assessment Scale, and Extrapyramidal Symp-tom Rating Scale (ESRS). Results. Both amisulpride and moclobemide were very effective in reducing CIS. Almost 74% of patients treated with amisulpride and 83% of patients treated with moclobemide showed some level of improvement on NHRS. Only in one patient treated with amisulpride, CIS worsened. Conclusions. Both medications were safe and effective as treatment of CIS. Although moclobemide exceeded amisulpride in antisalivation activity, treatment of CIS with amisul-pride leads to improvement in psychotic symptoms.
Clozapine is an atypical antipsychotic agent with a proven effi cacy in refractory schizophrenia, but its widespread use is limited due to adverse effects such as agranulocytosis, seizures, sedation, weight gain, and sialorrhea (Miller 2000; Ananth et al. 2004; Praharaj et al. 2006). Hypersalivation, or sialorrhea is a distress-ing adverse effect during the antipsychotic treatment of patients, which leads to noncompliance and can affect quality of life (Praharaj et al. 2006). It occurs in between 10 and 72% of patients treated with clozap-ine (Soler Roibal et al. 1999). with an average rate of 30% (Davydov and Botts 2000; Rogers and Shramko 2000; Sockalingam et al. 2007). Beside the external
Correspondence: Professor Vladimir Lerner, MD, PhD, Be ' er-ShevaFax: � 972 8 6401491. E-mail: [email protected]
(Received 15 June 2010 ; accepted 20 September 2010 )
manifestations related to hypersalivation, additional consequences of hypersalivation include painful parotid gland swelling and parotid duct obstruction due to the formation of calculi (Robinson et al. 1995; Brodkin et al. 1996; Conry et al. 1996). This side effect is usually dose-related (Reinstein et al. 1999; Freudenreich et al. 2004). It may occur during the day, but it is most profound during sleep (Safferman et al. 1991; Ben-Aryeh et al. 1996; Young et al. 1998; Van Kammen and Marder 2005). Patients usually complain of waking with a wet pillow (sometimes called “ wet pillow ” sign) (Praharaj et al. 2006).
Salivation is regulated by sympathetic (adrenergic) and parasympathetic (cholinergic) tones. The
Mental Health Center, PO Box 4600, Be ' er-Sheva, 84170, Israel.
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pathophysiology of clozapine-induced sialorrhea (CIS) is poorly understood, since the drug has potent α 2 -antagonistic, M 4 -muscarinic agonistic, and anti-cholinergic (M 1 , M 2 , M 3 , and M 5 ) activities (Baldes-sarini et al. 1992; Wagstaff and Bryson 1995). Each of these has a different effect on the control of saliva-tion. While α 2 -antagonistic and M 4 -muscarinic ago-nistic effects increase salivation, the anticholinergic effect leads to diminished saliva secretion (Berlan et al. 1992).
The available treatment options are based mostly on case reports and open-label studies. Various phar-macological agents have been used for managing this side effect including anticholinergic agents (Copp et al. 1991; Fritze and Elliger 1995; Spivak et al. 1997; Reinstein et al. 1999; Calderon et al. 2000; Freudenreich et al. 2004; Gaftanyuk and Trestman 2004; Schneider et al. 2004; Sharma et al. 2004; Praharaj and Arora 2007) and α 2 -adrenergic agents (Grabowski 1992; Corrigan et al. 1995; Webber et al. 2004; Praharaj et al. 2005). In case reports and small open-label studies these agents were found to be benefi cial and well-tolerated. However, in some double-blind studies this was not demonstrated (Bai et al. 2001; Sockalingam et al. 2009). Moreover, several agents, including trihexyphenidyl and benz-tropine, can cause additional adverse effects and lead to different somatic and neurological side effects, such as inappropriate antidiuretic hormone secretion (van Laar et al. 1998) and dysfunction of gastric motility (Gurevich et al. 2005), dyskinesia (Hauser and Olanow 1993; Linazasoro 1994). They can even lead to such severe complications as colon perforation secondary to obstruction (Freudenreich and Goff 2000).
Our study and some other publications have dem-onstrated that substitute benzamide derivatives both with higher selective binding to the D 2 /D 3 dopamine receptors (such as sulpiride or amisulpride) and a reversible selective monoamine oxidase inhibitor-A (moclobemide) may be effective as treatment of CIS (Croissant et al. 2005; Kreinin et al. 2005, 2006, 2009; Praharaj et al. 2009).
All these publications also show that CIS might have a different neurobiological basis rather than the proposed mediation by the M 4 -muscarinic receptor.
The aim of our study was to compare the effi cacy and safety of amisulpride and moclobemide in man-agement of CIS.
Subjects and methods
Participants
The study was conducted from November 2008 to December 2009 in two large state referral
institutions: Tirat Carmel Mental Health Center and the Be’er-Sheva Mental Health Center. We screened 58 patients (males and females, 19 – 60 years old) suffering from schizophrenia and schizoaffective dis-orders, treated with clozapine, and suffering from hypersalivation. Of all screened subjects, fi ve patients refused to take part in the study. Thus, 53 patients (40 men and 13 women) were eligible and included in the study. The mean � SD age was 41.6 � 8.4 years (range 19 – 57 years).. The mean duration of illness was 19.7 � 7.8 years (range 2 – 35 years). Forty-fi ve of them suffered from chronic schizophre-nia, and eight subjects suffered from a schizoaffective disorder. All patients had been hospitalized. The clinical and demographic characteristics of subjects are presented in Table I.
Inclusion criteria were: (a) males and females aged 18 – 60 years; (b) met Diagnostic and Statistical Man-ual of Mental Disorders, 4th Edition, Text Revision, criteria for schizophrenia or schizoaffective disorder; (c) clozapine treatment for a minimum of 2 months; (d) constant dose of clozapine and other concomi-tant medications during previous 2 weeks; (e) at least 2 points on the Nocturnal Hypersalivation Rating Scale (NHRS) (Spivak et al. 1997); (f) ability and willingness to sign informed consent for participa-tion in the study.
Study exclusion criteria included: (a) the presence of concurrent medical conditions contributing to hypersalivation (e.g., idiopathic Parkinson ' s disease, cerebral palsy); (b) evidence of mental retardation; (c) alcohol or drug abuse. Patients who had been treated with anticholinergic agents and continued to experience CIS were allowed to participate in the study, provided they continued to suffer from CIS of at least moderate severity.
Complete medical and neurological examinations, including laboratory tests, were performed.
Prior to study entry, all subjects who met the inclusion criteria provided written informed consent after receiving a full explanation regarding the nature of the study and potential risks and benefi ts. The study was approved by both the Tirat Carmel Men-tal Health Center and the Be’er Sheva Mental Health Center Institutional Review Boards.
Study design
This was an open-label trial, which consisted of two phases. In phase I of the study all subjects suffering from CIS were treated with add-on of 400 mg/day amisulpride. The duration of this period was 2 weeks. After that, amisulpride was stopped and washed-out. Those patients who demonstrated re-hypersalivation (score 2 on NHRS) took part in phase II of this study, which lasted for 2 weeks and in which patients
Amisulpride versus moclobemide in treatment of CIS 3
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treated with add-on moclobemide 300 mg/day. Clozapine dose was kept constant during the course of the study.
Assessment
Hypersalivation was diagnosed according to the patient’s report and physician’s assessment. Clinical global impression (CGI) according to the patient ' s self assessment was designated as subjective assess-ment tool and NHRS as objective assessment tool. The NHRS consists of the fi ve points: 0, absent; 1, minimal (signs of saliva on the pillow in the morn-ing); 2, mild (hypersalivation wakes the patient once during the night); 3, moderate (hypersalivation wakes the patient twice during the night), and 4, severe (hypersalivation wakes the patient at least 3 times during the night) (Spivak et al. 1997). Assessment was performed on baseline (entering into the study) and every morning, at the same time by the same physician, during the study period with the add-on medication.
The clinical response was evaluated by comparing the rating scores at baseline, before the amisulpride treatment, at the end of this treatment, after washout before the moclobemide treatment, and after 2 weeks of moclobemide treatment. Clinically signifi cant improvement was defi ned as a reduction of at least 30% on the NHRS from baseline to week 2.
In addition to the NHRS assessment, the subjects were assessed by the Positive and Negative Syndrome Scale (PANSS) (Kay et al. 1987), Manic State
Assessment Scale (Bech et al. 1978), and Extrapy-ramidal Symptom Rating Scale (ESRS) (Chouinard and Margolese 2005) at baseline and at the end of each treatment period.
Statistical analysis
The PASW (Predictive Analytics SoftWare) Statis-tics software was used for all statistical analyses. In particular: construction of the data base and its orga-nization, creation of new parameters and basic sta-tistical analysis. The Wilcoxon signed ranks test for nonparametric consecutive paired variables was applied to measure the fl uctuation of the NHRS and CGI scores at different times. The t -paired samples test was used for comparison between PANSS scores, a quantitative variable.
Results
All patients (53 subjects) enrolled into the study ended it. The mean age was 41.6 � 8.4 years (range 19 – 57 years), and mean dosage of clozapine was 387 � 122 mg/day (range 200 – 600 mg/day). There were no differences in baseline scores of NHRS before treatment with amisulpride and moclobe-mide. Both amisulpride and moclobemide were very effective in reducing CIS.
During treatment with amisulpride, the mean (SD) NHRS score dropped from 3.45 (0.57) on the baseline to 2.55 (0.91) at the end of the second week of treatment ( Z � – 5.653, P � 0.0001). The CGI scores also revealed signifi cant differences ( Z � – 6.401, P � 0.0001). The CGI mean score dropped from 5.45 (0.57) points at baseline to 2.64 (0.81) points at the end of the second week of treatment ( Table II).
Thirty-nine patients (73.6%) demonstrated some kind of improvement. Thirteen patients (24.5%) did not demonstrate any change in condition and only one patient (1.9%) demonstrated a worsening in sia-lorrhea.
Of the 39 patients affected positively, hypersaliva-tion disappeared completely in one patient. Nine patients (23.1%) had signifi cant (more than 50%) improvement in reducing hypersalivation. Seventeen patients (43.6%) showed moderate (from 30 to 50%) reduction of CIS. Thirteen patients (33.3%) had minimal (less than 30%) improvement at the end of the second week of treatment.
During treatment with moclobemide, the mean (SD) NHRS score dropped from 3.49 (0.54) on the baseline to 2.02 (0.89) at the end of the second week of treatment ( Z � – 5.969, P � 0.0001). The CGI mean score dropped from 5.49 (0.54) points at baseline to
Table I. The clinical and demographic characteristics of subjects.
Patients N � 53
SexMale 40Female 13
Age, mean (SD) 41.6 (8.4)Range, years 19 – 57Duration of illness, mean (SD) 9.7 (7.8) Range, years 2 – 35Diagnoses:
Schizophrenia 45Schizoaffective disorders 8
Clozapine dose, mean (SD) 387 (122)Range, mg/day 200 – 600NHRS, mean (SD) 3.45 (0.57)Total PANSS scores, mean (SD) 83.49 (15.245)CGI, mean (SD) 5.45 (0.57)ESRS, mean (SD) 16.3 (2.7)MSAS, mean (SD) 0 (0.0)
NHRS, Nocturnal Hypersalivation Rating Scale; CGI, Clinical Global Impression; PANSS, Positive and Negative Syndrome Scale; MSAS, Manic State Assessment Scale; ESRS, Extra-pyramidal Symptom Rating Scale.
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2.55 (0.85) points at the end of the second week of treatment ( Z � – 6.331, P � 0.0001) ( Table II).
Forty-four patients (83%) demonstrated some kind of improvement. Only nine patients (17%) did not demonstrate any change in condition. None of the patients demonstrated a worsening in hypersali-vation.
Of the 44 patients affected positively to moclobe-mide treatment, hypersalivation disappeared com-pletely in one patient. Thirty patients (68.2%) had signifi cant improvement (more than 50%) in reduc-ing hypersalivation. Ten patients (22.7%) showed moderate (from 30 to 50%) reduction of CIS. Four patients (9.1%) (less than 30%) had only minimal improvement at the end of the second week of treat-ment.
We found that there were signifi cant differences in reducing hypersalivation between treatment with amisulpride versus moclobemide. The mean NHRS score after amisulpride treatment was 2.55 (0.91) and after moclobemide treatment 2.02 (0.89) (Z � – 3.947, P � 0.0001). There was a trend for prefer-ence of moclobemide in the CGI scores but it was not signifi cant.
After changing treatment to moclobemide, six patients (11.3%) demonstrated a relative worsening in hypersalivation symptoms in comparison to the condition during treatment with amisulpride. Eigh-teen patients (34%) demonstrated an equal reaction to both treatments. Twenty-nine patients (54.7%) reacted better to moclobemide treatment. Of these, 13 patients (44.8%) had signifi cant (more than 50%) improvement in reducing hypersalivation. Fourteen patients (48.3%) showed moderate (from 30 to 50%) reduction of CIS, and only two patients (6.9%) had minimal improvement (less than 30%).
During treatment with amisulpride, a drop in the positive and total PANSS scores occurred. The pos-itive subscale scores dropped from 17.74 (4.852) on baseline to 17.04 (4.763) at the end of treatment ( t -paired samples test, t � 2.571, P � 0.013). The total PANSS scores dropped from 83.49 (15.245) on baseline to 81.64 (15.199) at the end of treatment ( t- paired samples test, t � 2.076, P � 0.043). This
improvement continued during the washout period (before moclobemide treatment). During the wash-out period, positive sub scores were 16.62 (4.477) ( t- paired samples test, t � 2.108, P � 0.04) and total PANSS scores 80.75 (14.619) ( t- paired samples test, t � 2.378, P � 0.021). However, moclobemide treat-ment did not produce any signifi cant change in the PANSS scores ( P � 0.05).
Both medications were safe and well tolerated. None of the patients demonstrated any side effect while taking amisulpride or moclobemide accompa-nying clozapine treatment. ESRS score was not dif-ferent between baseline and endpoint measures during amisulpride or moclobemide treatment. No patient had symptoms of mania measured by MSAS before and after treatment with moclobemide.
Discussion
In this report, we present 53 patients suffering from CIS who were treated with substitute benzamide derivatives belonging to different medication groups – antipsychotics and antidepressants. Amisulpride and moclobemide were found as safe and effective agents in treatment of CIS according to measurement by the total NHRS and CGI.
Clozapine is the most effective medication for those schizophrenic patients who have failed to respond to other antipsychotic drugs with minimal risk of extrapyramidal side effects (Kane et al. 1988; Jann 1991; Naber 1999). Unfortunately, clozapine is associated with hypersalivation, a disturbing limiting factor leading to embarrassment and noncompliance. It is a relatively common but quite troubling adverse event, most pronounced at nighttime, occurring in approximately one third of clozapine-treated patients (Rogers and Shramko 2000). CIS can be associated with a risk of choking or aspiration pneumonia. Its management is a crucial element to improve the drug adherence and quality of patients ’ life.
Although the mechanism of CIS is not entirely clear, possibilities include muscarinic agonist effects, α 2 -adrenergic receptor antagonism, a decrease in laryngeal peristalsis, an inhibition of swallowing
Table II. Effi cacy of amisulpride and moclobemide in CIS treatment.
Amisulpride Moclobemide
Bl 2nd week P Bl 2nd week P
NHRS, mean (SD) 3.45 (0.57) 2.55 (0.91) Z � – 5.653 � 0.0001 3.49 (0.54) 2.02 (0.89) Z � – 5.969 � 0.0001CGI, mean (SD) 5.45 (0.57) 2.64 (0.81) Z � – 6.401 � 0.0001 5.49 (0.54) 2.55 (0.85) Z � – 6.331 � 0.0001PANSS (ps), mean(SD) 17.74 (4.85) 17.04 (4.76) t � 2.571 � 0.013 16.62 (4.48) 16.4 (4.68) t � 1.57 � 0.122Total PANSS, mean(SD) 83.49 (15.25) 81.64 (15.19) t � 2.076 � 0.043 80.75 (14.62) 80.62 (15.32) t � 0.449 � 0.655
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refl ex, and/or a disturbance in the circadian rhythm of salivary fl ow (Praharaj et al. 2006).
Several hypotheses have been put forward to explain the etiology of clozapine-induced sialorrhea. According to the response of hypersalivation to clonidine and lofexidine, some researchers have hypothesized that adrenergic α 2 -antagonism may be involved in CIS pathophysiology (Praharaj et al. 2005). Zorn and co-workers have shown that clozap-ine, in a cellular preparation expressing all fi ve sub-types (M 1 – M 5 ) of muscarinic cholinoreceptors, has a potent agonistic effect on the M 4 receptors, while it has antagonistic properties on the other four recep-tor subtypes (Zorn et al. 1994). These authors sug-gest that while M 3 is the predominant muscarinic receptor subtype in salivary glands, there is evidence that M 4 receptors are also expressed in this tissue. It is possible, therefore, that the net effect of clozapine on salivation refl ects the relationship between M 3 receptor blockade, leading to a decrease in salivation, and M 4 receptor stimulation, leading to an increase in salivary output. For some patients taking clozap-ine, the effects of M 4 receptor stimulation may exceed those of M 3 receptor blockade, resulting in hypersalivation. Thus, clozapine-induced hypersali-vation may refl ect the subtype-selective agonist effect of clozapine on the M 4 muscarinic receptor (Zorn et al. 1994).
Previous studies (Kreinin et al. 2005, 2006, 2009) demonstrated effi cacy of three medications from group of substitute benzamide derivatives in treat-ment of CIS. We suggest that the antisalivation activ-ity of this group of medications is most likely related to its peripheral activity for reducing gastric acid secretion.
Substitute benzamide derivatives have higher selective binding for the dopamine D 2 and D 3 recep-tors. Although these agents do not possess α 2 -adren-ergic antagonist, anticholinergic activity they also are not adrenomimetic agents. Its peripheral activity might have reduced salivary secretion via central nervous system dopamine blockade (Caldara et al. 1983). Similar activity is demonstrated in another substitute benzamide derivative – metoclopromide (Kovac 2000). A possible conclusion is that regard-less of its psychotropic activity, each of these chem-ical compounds may lead to reducing CIS. The addition of a second antipsychotic agent may also facilitate a reduction in clozapine dosage, which can reduce CIH symptoms (Croissant et al. 2005).
The patients who were treated with addition of moclobemide demonstrated that this medication is more effective in reducing CIS than additional amisulpride. However, those patients who were treated with additional amisulpride demonstrated signifi cant improvement on the PANSS positive
subscale. In some research studies it is reported that clozapine raised plasma levels of amisulpride (Berge-mann et al. 2004), but it is not clear whether it is effi cient in PANSS reduction (Frick et al. 2003). Moreover, there is no infl uence of amisulpride on clozapine plasma levels (Munro et al. 2004; Berge-mann et al. 2005). Further, several studies have demonstrated improved antipsychotic effi cacy and tolerability with amisulpride augmentation of clo-zapine therapy (Kampf et al. 2003; Zink et al. 2004; George and Cowan 2005; Pani et al. 2008).
This study was an open one, and this is its main limitation. Other double-blind controlled studies are needed in order to replicate the results. Further proof of benzamide derivates ’ effi cacy should give clinicians another tool to overcome this uncomfort-able and distressing side effect.
Acknowledgements
None
Statement of Interest
None to declare.
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