Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02222220 |
| Other study ID # |
VLAK-14 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
August 17, 2014 |
| Last updated |
August 20, 2014 |
| Start date |
January 2012 |
| Est. completion date |
May 2014 |
Study information
| Verified date |
January 2012 |
| Source |
Beersheva Mental Health Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Israel: Ministry of Health |
| Study type |
Interventional
|
Clinical Trial Summary
Hypersalivation (sialorrhea or ptyalism) is known as a frequent, disturbing, uncomfortable
adverse effect of clozapine therapy that can lead to noncompliance. Until now there is no
effective enough treatment for this side effect.
Previous studies demonstrated that different medications from the substitute benzamide
derivatives group: amisulpride, sulpiride (higher selective binding to the D2/D3 dopamine
receptor) and moclobemide (reversible inhibitor of monoamine oxidase A, which inhibits the
deamination of serotonin, norepinephrine and dopamine) may be effective as a treatment of
clozapine-induced hypersalivation (CIH). Moreover, there is another substitute benzamide
derivative: metoclopramide (dopamine D2 antagonist, usually used as antiemetic medication in
general medicine). The investigators hypothesis assumes that anti-salivation effect
characterizes the whole group of benzamide.
The aim of this study was to examine the efficacy of metoclopramide as an optional
possibility for management of CIH.
Description:
Hypersalivation (sialorrhea or ptyalism) is known as a frequent, disturbing, uncomfortable
adverse effect of clozapine therapy that may persist for several years. This side effect is
usually dose-related. It may occur all over the day, but it is most pronounced during night
sleep, since swallowing reflex is diminished, and patients usually complain of wakening with
a wet pillow (sometimes called as "wet pillow" sign).
Salivation is regulated by sympathetic (adrenergic) and parasympathetic (cholinergic) tones.
The phenomenon of clozapine-induced hypersalivation (CIH) remains mysterious since the drug
has potent α2 antagonistic, M4 - muscarinic agonistic, and anticholinergic (M1, M2, M3, and
M5) activities and each of these has a different effect on the control of salivation. While
α2 antagonistic and M4 - muscarinic agonistic effects increase salivation, the
anticholinergic effect leads to diminished saliva secretion. It has been reported that CIH
is observed from 10 to 80% of patients according to various sources, an average rate is 30%
of clozapine-treated patients. Further to the social embarrassment related to
hypersalivation, additional consequences of CIH include painful parotid gland swelling and
parotid duct obstruction due to the formation of calculi.
Clozapine is a second generation neuroleptic agent whose structure consists of a
dibenzodiazepine derivative with a piperazinyl side chain. It has a unique
neuropharmacologic profile, which is attributed to atypical antipsychotic agents with proven
efficacy in refractory schizophrenia, but its widespread use is limited by adverse effects
such as agranulocytosis, seizures, sedation, weight gain, and sialorrhea. Clozapine has a
weak binding affinity for dopamine D1 and D2 receptors by its slightly greater preference
for D1 receptors, as noted with a D1:D2 receptor binding ratio of 1:3. Furthermore the drug
has potent binding affinity for serotonin receptors 5-HT1A and 5-HT2, and also
antihistaminic, anticholinergic, and alpha-adrenergic antagonistic properties.
Sialorrhea is troublesome its stigmatizing nature results for a schizophrenia patient led to
massive compliance problems. For management of this distressing side effect have been
recommended different pharmacological agents such as α2 - adrenoreceptor agonists, including
clonidine, and lofexidine, but these treatments have unwanted side effects, no proved
effectiveness. They are not been routinely used. These publications show that CIH probably
might have a different neurobiological basis rather than the proposed mediation by the M4 -
muscarinic receptor.
Previous studies found that substitute benzamide derivatives with higher selective binding
to the D2/D3 dopamine receptors - amisulpride, sulpiride as well moclobemide (reversible
inhibitor of monoamine oxidase A, which inhibits the deamination of serotonin,
norepinephrine and dopamine) may be effective in treatment of CIH without additional adverse
effects. Unfortunately, these medications are not effective in all patients who suffered
from CIH.
Metoclopramide was first described by Dr. Louis Justin-Besançon and C. Laville in 1964. It
is a dopamine D2 receptor antagonist, and a mixed 5-HT3 receptor antagonist. Moreover, it is
a 5-HT4 receptor agonist.
Metoclopramide is fairly often used in general medicine as an antiemetic agent. In 1979, FDA
approved it for treatment of nausea and vomiting. This drug also belongs to substitute
benzamide derivatives group. It is assumed that the anti-emetic activity is caused by its D2
receptor antagonism in the chemoreceptor trigger zone in the central nervous system. Dry
mouth is one of its side effects. The investigators hypothesized that antisalivation effect
characterizes the whole group of benzamides, and will be demonstrated also in none
psychotropic agent like metoclopramide.
The aim of our study was to examine efficacy of metoclopramide as an additional agent for
management of CIH and to approve our hypothesis.
Subjects and Methods The study was conducted from January 2012 to May 2014 in two large
state referral institutions: Tirat Carmel Mental Health Center and the Be'er-Sheva Mental
Health Center. The investigators screened 68 patients (males and females, 19-60 years old)
suffering from schizophrenia and schizoaffective disorders, treated with clozapine, and
suffering from hypersalivation. Of all screened subjects, 7 patients refused to take part in
the study.
Inclusion criteria were: a) males and females in age 18-60 years old; b) met Diagnostic and
Statistical Manual of Mental Disorders, Fourth 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 concomitant medications during previous 2 weeks; e)
At least 2 points on the Nocturnal Hypersalivation Rating Scale (NHRS);3 f) Ability and
willingness to sign informed consent for participation in the study.
Study exclusion criteria included: a) the Presence of concurrent medical conditions
contributing to hypersalivation (eg, 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 CIH were allowed to participate in the
study, provided they continued to suffer from CIH 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
benefits. The study was approved by both the Tirat Carmel Mental Health Center and the Be'er
Sheva Mental Health Center Institutional Review Boards.
Study Design The study was conducted in two mental health centers. In order to examine our
hypothesis, the investigators used an add-on design. Sixty-one patients with schizophrenia
and schizoaffective disorder (males and females, 19-60 years old), according to the DSM-IV
criteria, treated with clozapine and suffering from hypersalivation, enrolled into the study
(30 patients in metoclopramide group and 31 in the placebo group).
Procedure and drug administration In order to find a minimal effective dose, all subjects
suffering from CIH (score >2 on Nocturnal Hypersalivation Rating Scale - NHRS) in a double
blind randomized mode were treated during a week with 10 mg/day of metoclopramide or
placebo. The patients without improvement continuing the study with 20 mg/day of
metoclopramide or placebo during the next week. Those patients, who did not respond to this
dose, were continued with 30 mg/day of metoclopramide or placebo for another week.
Hypersalivation will be assessed by subjective and objective tools. Clinical global
impression (CGI) patient's self-assessment will be taken as a subjective tool while NHRS and
Drooling Severity Scale (DSS) as an objective one. NHRS consists of the 5-points: 0-absent;
1-minimal (signs of saliva on the pillow in the morning); 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). DSS also consists of the 5-points: 1- never drools, 2 -mild, only wet lips,
3-moderate, wet on lips and chin, 4-severe, clothing becomes wet and 5 - profuse, clothing,
hands, tray, and objects become wet. Assessment was performed on baseline (entering into the
study) and every morning during the study period and two weeks after ceasing the add-on
medications.
Clinically significant improvement was defined as a reduction of at least 30% from baseline
to week 2 on the NHRS and DSS.
Participants Thirty patients from Be'er Sheva Mental Health Center and 31 from Tirat Carmel
Mental Health Center have participated in the study.
The study was approved by the local Institutional Ethics Review Board ("Helsinki
Committee"). Only subjects who will and able to sign a written informed consent form for
participation in the study, were recruited. Confidentially was ensured by means of a number
coding system, and all completed research forms were stored in a secure area.
