<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02222220</url>
  </required_header>
  <id_info>
    <org_study_id>VLAK-14</org_study_id>
    <nct_id>NCT02222220</nct_id>
  </id_info>
  <brief_title>Metoclopramide as Treatment of Clozapine-induced Hypersalivation</brief_title>
  <official_title>Metoclopramide as Treatment of Clozapine-induced Hypersalivation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Beersheva Mental Health Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Tirat Carmel Mental Health Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Beersheva Mental Health Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hypersalivation (sialorrhea or ptyalism) is known as a frequent, disturbing, uncomfortable&#xD;
      adverse effect of clozapine therapy that can lead to noncompliance. Until now there is no&#xD;
      effective enough treatment for this side effect.&#xD;
&#xD;
      Previous studies demonstrated that different medications from the substitute benzamide&#xD;
      derivatives group: amisulpride, sulpiride (higher selective binding to the D2/D3 dopamine&#xD;
      receptor) and moclobemide (reversible inhibitor of monoamine oxidase A, which inhibits the&#xD;
      deamination of serotonin, norepinephrine and dopamine) may be effective as a treatment of&#xD;
      clozapine-induced hypersalivation (CIH). Moreover, there is another substitute benzamide&#xD;
      derivative: metoclopramide (dopamine D2 antagonist, usually used as antiemetic medication in&#xD;
      general medicine). The investigators hypothesis assumes that anti-salivation effect&#xD;
      characterizes the whole group of benzamide.&#xD;
&#xD;
      The aim of this study was to examine the efficacy of metoclopramide as an optional&#xD;
      possibility for management of CIH.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hypersalivation (sialorrhea or ptyalism) is known as a frequent, disturbing, uncomfortable&#xD;
      adverse effect of clozapine therapy that may persist for several years. This side effect is&#xD;
      usually dose-related. It may occur all over the day, but it is most pronounced during night&#xD;
      sleep, since swallowing reflex is diminished, and patients usually complain of wakening with&#xD;
      a wet pillow (sometimes called as &quot;wet pillow&quot; sign).&#xD;
&#xD;
      Salivation is regulated by sympathetic (adrenergic) and parasympathetic (cholinergic) tones.&#xD;
      The phenomenon of clozapine-induced hypersalivation (CIH) remains mysterious since the drug&#xD;
      has potent α2 antagonistic, M4 - muscarinic agonistic, and anticholinergic (M1, M2, M3, and&#xD;
      M5) activities and each of these has a different effect on the control of salivation. While&#xD;
      α2 antagonistic and M4 - muscarinic agonistic effects increase salivation, the&#xD;
      anticholinergic effect leads to diminished saliva secretion. It has been reported that CIH is&#xD;
      observed from 10 to 80% of patients according to various sources, an average rate is 30% of&#xD;
      clozapine-treated patients. Further to the social embarrassment related to hypersalivation,&#xD;
      additional consequences of CIH include painful parotid gland swelling and parotid duct&#xD;
      obstruction due to the formation of calculi.&#xD;
&#xD;
      Clozapine is a second generation neuroleptic agent whose structure consists of a&#xD;
      dibenzodiazepine derivative with a piperazinyl side chain. It has a unique neuropharmacologic&#xD;
      profile, which is attributed to atypical antipsychotic agents with proven efficacy in&#xD;
      refractory schizophrenia, but its widespread use is limited by adverse effects such as&#xD;
      agranulocytosis, seizures, sedation, weight gain, and sialorrhea. Clozapine has a weak&#xD;
      binding affinity for dopamine D1 and D2 receptors by its slightly greater preference for D1&#xD;
      receptors, as noted with a D1:D2 receptor binding ratio of 1:3. Furthermore the drug has&#xD;
      potent binding affinity for serotonin receptors 5-HT1A and 5-HT2, and also antihistaminic,&#xD;
      anticholinergic, and alpha-adrenergic antagonistic properties.&#xD;
&#xD;
      Sialorrhea is troublesome its stigmatizing nature results for a schizophrenia patient led to&#xD;
      massive compliance problems. For management of this distressing side effect have been&#xD;
      recommended different pharmacological agents such as α2 - adrenoreceptor agonists, including&#xD;
      clonidine, and lofexidine, but these treatments have unwanted side effects, no proved&#xD;
      effectiveness. They are not been routinely used. These publications show that CIH probably&#xD;
      might have a different neurobiological basis rather than the proposed mediation by the M4 -&#xD;
      muscarinic receptor.&#xD;
&#xD;
      Previous studies found that substitute benzamide derivatives with higher selective binding to&#xD;
      the D2/D3 dopamine receptors - amisulpride, sulpiride as well moclobemide (reversible&#xD;
      inhibitor of monoamine oxidase A, which inhibits the deamination of serotonin, norepinephrine&#xD;
      and dopamine) may be effective in treatment of CIH without additional adverse effects.&#xD;
      Unfortunately, these medications are not effective in all patients who suffered from CIH.&#xD;
&#xD;
      Metoclopramide was first described by Dr. Louis Justin-Besançon and C. Laville in 1964. It is&#xD;
      a dopamine D2 receptor antagonist, and a mixed 5-HT3 receptor antagonist. Moreover, it is a&#xD;
      5-HT4 receptor agonist.&#xD;
&#xD;
      Metoclopramide is fairly often used in general medicine as an antiemetic agent. In 1979, FDA&#xD;
      approved it for treatment of nausea and vomiting. This drug also belongs to substitute&#xD;
      benzamide derivatives group. It is assumed that the anti-emetic activity is caused by its D2&#xD;
      receptor antagonism in the chemoreceptor trigger zone in the central nervous system. Dry&#xD;
      mouth is one of its side effects. The investigators hypothesized that antisalivation effect&#xD;
      characterizes the whole group of benzamides, and will be demonstrated also in none&#xD;
      psychotropic agent like metoclopramide.&#xD;
&#xD;
      The aim of our study was to examine efficacy of metoclopramide as an additional agent for&#xD;
      management of CIH and to approve our hypothesis.&#xD;
&#xD;
      Subjects and Methods The study was conducted from January 2012 to May 2014 in two large state&#xD;
      referral institutions: Tirat Carmel Mental Health Center and the Be'er-Sheva Mental Health&#xD;
      Center. The investigators screened 68 patients (males and females, 19-60 years old) suffering&#xD;
      from schizophrenia and schizoaffective disorders, treated with clozapine, and suffering from&#xD;
      hypersalivation. Of all screened subjects, 7 patients refused to take part in the study.&#xD;
&#xD;
      Inclusion criteria were: a) males and females in age 18-60 years old; b) met Diagnostic and&#xD;
      Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for&#xD;
      schizophrenia or schizoaffective disorder; c) Clozapine treatment for a minimum of 2 months;&#xD;
      d) Constant dose of clozapine and other concomitant medications during previous 2 weeks; e)&#xD;
      At least 2 points on the Nocturnal Hypersalivation Rating Scale (NHRS);3 f) Ability and&#xD;
      willingness to sign informed consent for participation in the study.&#xD;
&#xD;
      Study exclusion criteria included: a) the Presence of concurrent medical conditions&#xD;
      contributing to hypersalivation (eg, idiopathic Parkinson's disease, cerebral palsy); b)&#xD;
      Evidence of mental retardation; c) Alcohol or drug abuse. Patients who had been treated with&#xD;
      anticholinergic agents and continued to experience CIH were allowed to participate in the&#xD;
      study, provided they continued to suffer from CIH of at least moderate severity. Complete&#xD;
      medical and neurological examinations, including laboratory tests, were performed. Prior to&#xD;
      study entry, all subjects who met the inclusion criteria provided written informed consent&#xD;
      after receiving a full explanation regarding the nature of the study and potential risks and&#xD;
      benefits. The study was approved by both the Tirat Carmel Mental Health Center and the Be'er&#xD;
      Sheva Mental Health Center Institutional Review Boards.&#xD;
&#xD;
      Study Design The study was conducted in two mental health centers. In order to examine our&#xD;
      hypothesis, the investigators used an add-on design. Sixty-one patients with schizophrenia&#xD;
      and schizoaffective disorder (males and females, 19-60 years old), according to the DSM-IV&#xD;
      criteria, treated with clozapine and suffering from hypersalivation, enrolled into the study&#xD;
      (30 patients in metoclopramide group and 31 in the placebo group).&#xD;
&#xD;
      Procedure and drug administration In order to find a minimal effective dose, all subjects&#xD;
      suffering from CIH (score &gt;2 on Nocturnal Hypersalivation Rating Scale - NHRS) in a double&#xD;
      blind randomized mode were treated during a week with 10 mg/day of metoclopramide or placebo.&#xD;
      The patients without improvement continuing the study with 20 mg/day of metoclopramide or&#xD;
      placebo during the next week. Those patients, who did not respond to this dose, were&#xD;
      continued with 30 mg/day of metoclopramide or placebo for another week.&#xD;
&#xD;
      Hypersalivation will be assessed by subjective and objective tools. Clinical global&#xD;
      impression (CGI) patient's self-assessment will be taken as a subjective tool while NHRS and&#xD;
      Drooling Severity Scale (DSS) as an objective one. NHRS consists of the 5-points: 0-absent;&#xD;
      1-minimal (signs of saliva on the pillow in the morning); 2-mild (hypersalivation wakes the&#xD;
      patient once during the night); 3-moderate (hypersalivation wakes the patient twice during&#xD;
      the night), and 4-severe (hypersalivation wakes the patient at least 3 times during the&#xD;
      night). DSS also consists of the 5-points: 1- never drools, 2 -mild, only wet lips,&#xD;
      3-moderate, wet on lips and chin, 4-severe, clothing becomes wet and 5 - profuse, clothing,&#xD;
      hands, tray, and objects become wet. Assessment was performed on baseline (entering into the&#xD;
      study) and every morning during the study period and two weeks after ceasing the add-on&#xD;
      medications.&#xD;
&#xD;
      Clinically significant improvement was defined as a reduction of at least 30% from baseline&#xD;
      to week 2 on the NHRS and DSS.&#xD;
&#xD;
      Participants Thirty patients from Be'er Sheva Mental Health Center and 31 from Tirat Carmel&#xD;
      Mental Health Center have participated in the study.&#xD;
&#xD;
      The study was approved by the local Institutional Ethics Review Board (&quot;Helsinki Committee&quot;).&#xD;
      Only subjects who will and able to sign a written informed consent form for participation in&#xD;
      the study, were recruited. Confidentially was ensured by means of a number coding system, and&#xD;
      all completed research forms were stored in a secure area.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2012</start_date>
  <completion_date type="Actual">May 2014</completion_date>
  <primary_completion_date type="Actual">May 2014</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Nocturnal Hypersalivation Rating Scale (NHRS)</measure>
    <time_frame>every week, up to 4 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Drooling Severity Scale (DSS)</measure>
    <time_frame>every week, up to 4 weeks</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>The Positive and Negative Syndrome Scale (PANSS)</measure>
    <time_frame>every week, up to 4 weeks</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">61</enrollment>
  <condition>Clozapine-induced Hypersalivation</condition>
  <arm_group>
    <arm_group_label>metoclopramide</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>61 participating subjects were randomized into 2 groups: 30 received metoclopramide up to 30 mg/day and 31 received placebo, each for 4 weeks in a double-blind mode</description>
  </arm_group>
  <arm_group>
    <arm_group_label>metocliopramide</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>61 participating subjects were randomized into 2 groups: 30 received metoclopramide up to 30 mg/day and 31 received placebo, each for 4 weeks in a double-blind mode</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metoclopramide</intervention_name>
    <description>30 mg/day during 4 weeks</description>
    <arm_group_label>metocliopramide</arm_group_label>
    <arm_group_label>metoclopramide</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <arm_group_label>metocliopramide</arm_group_label>
    <arm_group_label>metoclopramide</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18-60 years, male or female&#xD;
&#xD;
          -  DSM-IV criteria for schizophrenia&#xD;
&#xD;
          -  Clozapine treatment&#xD;
&#xD;
          -  At least score &gt;2 on the Nocturnal Hypersalivation Rating Scale (NHRS)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Evidence of organic brain damage, mental retardation, alcohol or drug abuse&#xD;
&#xD;
          -  Patients suffering from pheochromocytoma&#xD;
&#xD;
          -  Patients suffering from Parkinson's disease&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>57 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Vladimir Lerner, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Ben-Gurion University of the Negev</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Be'er Sheva Mental Health Center,</name>
      <address>
        <city>Be'er Sheva</city>
        <zip>8417000</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <reference>
    <citation>Safferman A, Lieberman JA, Kane JM, Szymanski S, Kinon B. Update on the clinical efficacy and side effects of clozapine. Schizophr Bull 1991;17:247-261. Kaplan &amp; Sadock's Comprehensive Textbook of Psychiatry. Philadelphia: Lippincot Williams &amp; Wilkins, 2005. Baldessarini RJ, Huston-Lyons D, Campbell A, Marsh E, Cohen BM. Do central antiadrenergic actions contribute to the atypical properties of clozapine? Br J Psychiatry Suppl 1992:12-16. Kreinin A, Epshtein S, Sheinkman A, Tell E. Sulpiride addition for the treatment of clozapine-induced hypersalivation: preliminary study. Isr J Psychiatry Relat Sci 2005;42:61-63. Kreinin A, Novitski D, Weizman A. Amisulpride treatment of clozapine-induced hypersalivation in schizophrenia patients: a randomized, double-blind, placebo-controlled cross-over study. Int Clin Psychopharmacol 2006;21:99-103. Kreinin A, Miodownik C, Libov I, Shestakova D, Lerner V. Moclobemide treatment of clozapine-induced hypersalivation: pilot open study. Clin Neuropharmacol 2009;32:151-153. Justin-Besancon L, Laville C. [Antiemetic Action of Metoclopramide with Respect to Apomorphine and Hydergine]. C R Seances Soc Biol Fil 1964;158:723-727. Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology. 5th ed. Edinburgh: Churchill Livingstone; 2003. Sweetman S, editor. Martindale: The complete drug reference. 34th ed. London: Pharmaceutical Press; 2004. Tonini M, Candura SM, Messori E, Rizzi CA. Therapeutic potential of drugs with mixed 5-HT4 agonist/5-HT3 antagonist action in the control of emesis. Pharmacol Res 1995;31:257-260. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261-276. Chouinard G, Ross-Chouinard A, Annable L, Jones B. Extrapyramidal Symptom Rating Scale. Can J Neurol Sci (abstract) 1980;7:233.</citation>
  </reference>
  <verification_date>January 2012</verification_date>
  <study_first_submitted>August 17, 2014</study_first_submitted>
  <study_first_submitted_qc>August 20, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 21, 2014</study_first_posted>
  <last_update_submitted>August 20, 2014</last_update_submitted>
  <last_update_submitted_qc>August 20, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 21, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Beersheva Mental Health Center</investigator_affiliation>
    <investigator_full_name>Vladimir Lerner</investigator_full_name>
    <investigator_title>Prof. Vladimir Lerner</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sialorrhea</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metoclopramide</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02222220
org study id: VLAK-14
nct id: NCT02222220
lead sponsor: 
collaborator: 
has dmc: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Nocturnal Hypersalivation Rating Scale (NHRS)
time frame: every week, up to 4 weeks
measure: Drooling Severity Scale (DSS)
time frame: every week, up to 4 weeks
measure: The Positive and Negative Syndrome Scale (PANSS)
time frame: every week, up to 4 weeks
arm group label: metoclopramide
arm group type: Placebo Comparator
description: 61 participating subjects were randomized into 2 groups: 30 received metoclopramide up to 30 mg/day and 31 received placebo, each for 4 weeks in a double-blind mode
arm group label: metocliopramide
arm group type: Experimental
description: 61 participating subjects were randomized into 2 groups: 30 received metoclopramide up to 30 mg/day and 31 received placebo, each for 4 weeks in a double-blind mode
intervention type: Drug
intervention name: Metoclopramide
description: 30 mg/day during 4 weeks
arm group label: metocliopramide
arm group label: metoclopramide
intervention type: Drug
intervention name: placebo
arm group label: metocliopramide
arm group label: metoclopramide
criteria: 
gender: All
minimum age: 19 Years
maximum age: 57 Years
healthy volunteers: No
last name: Vladimir Lerner, MD, PhD
role: Study Director
affiliation: Ben-Gurion University of the Negev
facility: 
country: Israel
citation: Safferman A, Lieberman JA, Kane JM, Szymanski S, Kinon B. Update on the clinical efficacy and side effects of clozapine. Schizophr Bull 1991;17:247-261. Kaplan & Sadock's Comprehensive Textbook of Psychiatry. Philadelphia: Lippincot Williams & Wilkins, 2005. Baldessarini RJ, Huston-Lyons D, Campbell A, Marsh E, Cohen BM. Do central antiadrenergic actions contribute to the atypical properties of clozapine? Br J Psychiatry Suppl 1992:12-16. Kreinin A, Epshtein S, Sheinkman A, Tell E. Sulpiride addition for the treatment of clozapine-induced hypersalivation: preliminary study. Isr J Psychiatry Relat Sci 2005;42:61-63. Kreinin A, Novitski D, Weizman A. Amisulpride treatment of clozapine-induced hypersalivation in schizophrenia patients: a randomized, double-blind, placebo-controlled cross-over study. Int Clin Psychopharmacol 2006;21:99-103. Kreinin A, Miodownik C, Libov I, Shestakova D, Lerner V. Moclobemide treatment of clozapine-induced hypersalivation: pilot open study. Clin Neuropharmacol 2009;32:151-153. Justin-Besancon L, Laville C. [Antiemetic Action of Metoclopramide with Respect to Apomorphine and Hydergine]. C R Seances Soc Biol Fil 1964;158:723-727. Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology. 5th ed. Edinburgh: Churchill Livingstone; 2003. Sweetman S, editor. Martindale: The complete drug reference. 34th ed. London: Pharmaceutical Press; 2004. Tonini M, Candura SM, Messori E, Rizzi CA. Therapeutic potential of drugs with mixed 5-HT4 agonist/5-HT3 antagonist action in the control of emesis. Pharmacol Res 1995;31:257-260. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261-276. Chouinard G, Ross-Chouinard A, Annable L, Jones B. Extrapyramidal Symptom Rating Scale. Can J Neurol Sci (abstract) 1980;7:233.
responsible party type: Principal Investigator
investigator affiliation: Beersheva Mental Health Center
investigator full name: Vladimir Lerner
investigator title: Prof. Vladimir Lerner
mesh term: Sialorrhea
mesh term: Metoclopramide