<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/NCT02233556</url>
  </required_header>
  <id_info>
    <org_study_id>201308083MINB</org_study_id>
    <nct_id>NCT02233556</nct_id>
  </id_info>
  <brief_title>Effect of Memantine on ERP in Early Schizophrenia and Healthy Subjects</brief_title>
  <official_title>Effects of Memantine on Event-related Potential in the Comparison of Patients With Early Schizophrenia and Healthy Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Taiwan University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Taiwan University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients with schizophrenia are deeply affected by the positive symptoms, negative symptoms&#xD;
      and cognitive impairment. A generalized cognitive deficit could be frequently observed and&#xD;
      traced back to early stage of the disease. Currently medication intervention significantly&#xD;
      improves positive symptoms through dopamine receptor modification, leaving alone the negative&#xD;
      symptoms and cognitive impairment. Besides dopamine dysregulation, more and more attention&#xD;
      had been paid to the association of N-methyl-D-aspartate (NMDA) type glutamate receptor and&#xD;
      schizophrenia, focusing on the neurobiological and cognitive biomarkers change. Memantine, an&#xD;
      uncompetitive antagonist of NMDA type glutamate receptor approved as cognitive enhancer for&#xD;
      Alzheimer's disease, is a potential candidate for preventing cognitive decline of&#xD;
      schizophrenia. Previous randomized clinical trials failed to demonstrate its efficacy on&#xD;
      chronic schizophrenic patients and it might be related to the chronic and irreversible&#xD;
      disease process. There is also study supporting that memantine induces change in mismatch&#xD;
      negativity (MMN) in frontal cortex of healthy subjects. This study will compare the MMN&#xD;
      change of healthy subjects and the population of early schizophrenia, who has persistent&#xD;
      neurobiological, cognitive biomarkers or negative symptoms despite subsided positive&#xD;
      symptoms. Both male and female aged 20-45 years old outpatients with a length of illness for&#xD;
      less than 5 years since first diagnosed as schizophrenia, currently receiving treatment by&#xD;
      atypical antipsychotics in a relatively stable condition will be recruited. Healthy subjects&#xD;
      will be recruited comparing their age and sex. We plan to recruit 10 subjects for both&#xD;
      patient and healthy subjects with a total of 20 participants. All participants will receive&#xD;
      general clinical, cognitive and event-related potential (ERP) evaluation as baseline before&#xD;
      taking medication. Twenty mg of memantine will be given 4 hours before ERP retest. The&#xD;
      analyses will be performed based on the change of ERP using paired-t sample test. Baseline&#xD;
      clinical and cognitive symptoms will be analyzed as possible confounders.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In this proposal, we use one-dose memantine trial to compare the difference of MMN change&#xD;
      between healthy subjects and early schizophrenia patients. The cognitive and negative&#xD;
      symptoms will be counted as possible confounding variables. We would like to make connection&#xD;
      and association between neurobiological and neurocognitive markers for further treatment&#xD;
      application.&#xD;
&#xD;
      The specific aim of this project is to test if memantine will influence the ERPs change, as&#xD;
      in healthy subjects, in patients with early schizophrenia. The specific study population is&#xD;
      been known of just have their first episode psychosis subsided, conventionally defined by&#xD;
      significantly improved positive symptoms, yet some of them complaining of cognitive decline&#xD;
      or presenting with persistent negative symptoms. Previous study showed improvement in&#xD;
      mismatch negativity was correlated with general function improvement in schizophrenia.&#xD;
      Although a recent study failed to demonstrate positive effects on residual psychopathology of&#xD;
      a group of chronic stable schizophrenic patients. In this study we are targeting at a&#xD;
      specific population of early schizophrenic patients to examine the efficacy of memantine on&#xD;
      neurobiological markers and possible application to general psychopathology. Our objectives&#xD;
      include:&#xD;
&#xD;
        1. Test memantine effects on the change of ERPs, especially focus on mismatch negativity.&#xD;
&#xD;
        2. Compare the ERP difference between healthy subjects and early schizophrenic patients&#xD;
&#xD;
        3. Examine whether the effect of memantine will be affected by any significant baseline&#xD;
           clinical variables or predisposed cognitive deficits.&#xD;
&#xD;
      First if we could replicate the ERP change in healthy subjects influenced by memantine, and&#xD;
      we could further compare the difference between healthy subjects and patient subjects. It may&#xD;
      support the hypothesis of NMDA-type glutamate receptor dysregulation theory in schizophrenia.&#xD;
      If further association is detected through larger scale study between ERP and clinical&#xD;
      symptoms, we could apply memantine in the add-on treatment of schizophrenia. As memantine is&#xD;
      already an approved medicine for treatment of moderate to severe Alzheimer disease in many&#xD;
      countries worldwide, hopefully we can add a new indication to its original clinical&#xD;
      application. Thus it will become the first medicine that can help a condition which has&#xD;
      rendered a lot of schizophrenic patients marked impairments in their social and occupational&#xD;
      functioning from the early stage of their life. We believe this impact will be even bigger&#xD;
      than the original indication of memantine, which is exclusively for patients with dementia.&#xD;
      Rather than delaying deterioration of cognitive functioning in patient's late life, an&#xD;
      adjuvant therapy for early intervention in schizophrenia aiming at improving cognitive&#xD;
      function and hence restoring social and occupational functioning bears greater impact on a&#xD;
      patient's life trajectory and lessen the burden of a society. Furthermore, the results from&#xD;
      this project will provide critical evidence to support or refute the hypoglutaminergic theory&#xD;
      of schizophrenia, which might be an important complement to the hyperdopaminergic theory.&#xD;
      With a better understanding of the pathophysiology of schizophrenia not only focusing on&#xD;
      dopaminergic system-related positive symptoms but also glutamatergic system-related cognitive&#xD;
      and negative symptoms, will provide theoretic base of psychopharmacology in developing agents&#xD;
      targeting at different systems to improve the outcome of schizophrenia from the early stage&#xD;
      or even the putative pre-psychotic stage of the illness.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>February 2014</start_date>
  <completion_date type="Anticipated">December 2016</completion_date>
  <primary_completion_date type="Anticipated">December 2016</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in auditory event-related potentials &quot;MMN&quot;before/after intake of a single dose memantine</measure>
    <time_frame>4 hours after intake of a single dose memantine</time_frame>
    <description>Previous studies revealed deficits in cognition via auditory event-related potential, such as Mismatch Negativity. This study would compare the effect of single dose memantine in MMN.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in auditory event-related potentials &quot;P50&quot; before/after intake of a single dose memantine</measure>
    <time_frame>4 hours after intake of a single dose memantine</time_frame>
    <description>Previous studies revealed deficits in cognition via auditory event-related potential, such as P50. This study would compare the effect of single dose memantine in P50</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Schizophrenia</condition>
  <arm_group>
    <arm_group_label>Memantine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This study has only one arm. i.e. Single dose of memantine 20mg</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Memantine</intervention_name>
    <description>Taking 20mg(2 capsules) of memantine, followed by Event related potential assessments as below:&#xD;
Mismatch negativity(MMN)&#xD;
P50</description>
    <arm_group_label>Memantine</arm_group_label>
    <other_name>Ebixa 10 mg, manufactured by Lunbeck A/S, Denmark</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria for patient subjects:&#xD;
&#xD;
          1. Both male and female outpatients&#xD;
&#xD;
          2. Age 20-45 years old at the time of screening&#xD;
&#xD;
          3. A diagnosis of schizophrenia based on the Structured Clinical Interview for DSM-IV&#xD;
&#xD;
          4. A duration of illness for less than 5 years since initially diagnosed as schizophrenia&#xD;
&#xD;
          5. Currently receiving treatment mainly by an atypical antipsychotic (risperidone,&#xD;
             olanzapine, amisulpiride, aripiprazole, quetiapine, ziprasidone, paliperidone),&#xD;
             including long-acting injectable antipsychotic&#xD;
&#xD;
          6. A first generation antipsychotic agent only for a low-dose, as needed use purpose&#xD;
&#xD;
          7. No revised use of benzodiazepines, antidepressants, anticholinergics, or other&#xD;
             concomitant medications during past 3 months&#xD;
&#xD;
        Inclusion criteria for healthy subjects:&#xD;
&#xD;
          1. Both male and female&#xD;
&#xD;
          2. Age 20-45 years old at the time of screening&#xD;
&#xD;
          3. No psychiatric diagnosis based on the Structured Clinical Interview for DSM-IV&#xD;
&#xD;
          4. No current use of any pharmaceutical agents in past 2 weeks&#xD;
&#xD;
        Exclusion criteria for all participants:&#xD;
&#xD;
          1. A score of 5 or more on any of the 7 positive symptom items of the PANSS rating at&#xD;
             screening&#xD;
&#xD;
          2. Scores of 4 on at least 3 of the 7 positive symptom items of the PANSS rating at&#xD;
             screening&#xD;
&#xD;
          3. A major relapse resulting in readmission or doubling the dosage of previous effective&#xD;
             antipsychotic treatment during the course of illness&#xD;
&#xD;
          4. A change of current antipsychotic medication in recent 3 months&#xD;
&#xD;
          5. Mental retardation known as IQ below 70 prior to the diagnosis of schizophrenia&#xD;
&#xD;
          6. A history of pervasive mental disorder or bipolar disorder&#xD;
&#xD;
          7. A medical condition with significant cognitive sequelae&#xD;
&#xD;
          8. A history of substance dependence&#xD;
&#xD;
          9. A history of hypersensitivity to memantine or other drugs of the same class, such as&#xD;
             amantadine&#xD;
&#xD;
         10. Pregnancy, plan to get pregnant during the study period, or lactating women&#xD;
&#xD;
         11. Abnormal liver function (AST, ALT higher than doubling the upper limits of normal&#xD;
             range) or abnormal renal function (blood creatinine &gt; 1.3 mg/dL)&#xD;
&#xD;
         12. A history of epilepsy&#xD;
&#xD;
         13. A history of myocardial infarction, congestive heart failure, uncontrolled&#xD;
             hypertension, stroke, or severe heart block.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ming-Hsien Hsieh, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Taiwan University Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ming-Hsien Hsieh, MD, PhD</last_name>
    <phone>+886-2-23123456</phone>
    <phone_ext>66790</phone_ext>
    <email>mingh@ntuh.gov.tw</email>
  </overall_contact>
  <location>
    <facility>
      <name>National Taiwan University Hospital</name>
      <address>
        <city>Taipei</city>
        <zip>100</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ming-Hsien Hsieh, MD, PhD</last_name>
      <phone>+886-2-23123456</phone>
      <phone_ext>66790</phone_ext>
      <email>mingh@ntuh.gov.tw</email>
    </contact>
    <investigator>
      <last_name>Cheng-Chung Liu, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Yi-Ting Lin, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>December 2015</verification_date>
  <study_first_submitted>February 26, 2014</study_first_submitted>
  <study_first_submitted_qc>September 3, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 8, 2014</study_first_posted>
  <last_update_submitted>December 10, 2015</last_update_submitted>
  <last_update_submitted_qc>December 10, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 14, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>event-related potential</keyword>
  <keyword>mismatch negativity</keyword>
  <keyword>NMDA</keyword>
  <keyword>Glutamate</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Schizophrenia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Memantine</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/NCT02233556
org study id: 201308083MINB
nct id: NCT02233556
lead sponsor: 
has dmc: Yes
Patients with schizophrenia are deeply affected by the positive symptoms, negative symptoms
      and cognitive impairment. A generalized cognitive deficit could be frequently observed and
      traced back to early stage of the disease. Currently medication intervention significantly
      improves positive symptoms through dopamine receptor modification, leaving alone the negative
      symptoms and cognitive impairment. Besides dopamine dysregulation, more and more attention
      had been paid to the association of N-methyl-D-aspartate (NMDA) type glutamate receptor and
      schizophrenia, focusing on the neurobiological and cognitive biomarkers change. Memantine, an
      uncompetitive antagonist of NMDA type glutamate receptor approved as cognitive enhancer for
      Alzheimer's disease, is a potential candidate for preventing cognitive decline of
      schizophrenia. Previous randomized clinical trials failed to demonstrate its efficacy on
      chronic schizophrenic patients and it might be related to the chronic and irreversible
      disease process. There is also study supporting that memantine induces change in mismatch
      negativity (MMN) in frontal cortex of healthy subjects. This study will compare the MMN
      change of healthy subjects and the population of early schizophrenia, who has persistent
      neurobiological, cognitive biomarkers or negative symptoms despite subsided positive
      symptoms. Both male and female aged 20-45 years old outpatients with a length of illness for
      less than 5 years since first diagnosed as schizophrenia, currently receiving treatment by
      atypical antipsychotics in a relatively stable condition will be recruited. Healthy subjects
      will be recruited comparing their age and sex. We plan to recruit 10 subjects for both
      patient and healthy subjects with a total of 20 participants. All participants will receive
      general clinical, cognitive and event-related potential (ERP) evaluation as baseline before
      taking medication. Twenty mg of memantine will be given 4 hours before ERP retest. The
      analyses will be performed based on the change of ERP using paired-t sample test. Baseline
      clinical and cognitive symptoms will be analyzed as possible confounders.
In this proposal, we use one-dose memantine trial to compare the difference of MMN change
      between healthy subjects and early schizophrenia patients. The cognitive and negative
      symptoms will be counted as possible confounding variables. We would like to make connection
      and association between neurobiological and neurocognitive markers for further treatment
      application.

      The specific aim of this project is to test if memantine will influence the ERPs change, as
      in healthy subjects, in patients with early schizophrenia. The specific study population is
      been known of just have their first episode psychosis subsided, conventionally defined by
      significantly improved positive symptoms, yet some of them complaining of cognitive decline
      or presenting with persistent negative symptoms. Previous study showed improvement in
      mismatch negativity was correlated with general function improvement in schizophrenia.
      Although a recent study failed to demonstrate positive effects on residual psychopathology of
      a group of chronic stable schizophrenic patients. In this study we are targeting at a
      specific population of early schizophrenic patients to examine the efficacy of memantine on
      neurobiological markers and possible application to general psychopathology. Our objectives
      include:

        1. Test memantine effects on the change of ERPs, especially focus on mismatch negativity.

        2. Compare the ERP difference between healthy subjects and early schizophrenic patients

        3. Examine whether the effect of memantine will be affected by any significant baseline
           clinical variables or predisposed cognitive deficits.

      First if we could replicate the ERP change in healthy subjects influenced by memantine, and
      we could further compare the difference between healthy subjects and patient subjects. It may
      support the hypothesis of NMDA-type glutamate receptor dysregulation theory in schizophrenia.
      If further association is detected through larger scale study between ERP and clinical
      symptoms, we could apply memantine in the add-on treatment of schizophrenia. As memantine is
      already an approved medicine for treatment of moderate to severe Alzheimer disease in many
      countries worldwide, hopefully we can add a new indication to its original clinical
      application. Thus it will become the first medicine that can help a condition which has
      rendered a lot of schizophrenic patients marked impairments in their social and occupational
      functioning from the early stage of their life. We believe this impact will be even bigger
      than the original indication of memantine, which is exclusively for patients with dementia.
      Rather than delaying deterioration of cognitive functioning in patient's late life, an
      adjuvant therapy for early intervention in schizophrenia aiming at improving cognitive
      function and hence restoring social and occupational functioning bears greater impact on a
      patient's life trajectory and lessen the burden of a society. Furthermore, the results from
      this project will provide critical evidence to support or refute the hypoglutaminergic theory
      of schizophrenia, which might be an important complement to the hyperdopaminergic theory.
      With a better understanding of the pathophysiology of schizophrenia not only focusing on
      dopaminergic system-related positive symptoms but also glutamatergic system-related cognitive
      and negative symptoms, will provide theoretic base of psychopharmacology in developing agents
      targeting at different systems to improve the outcome of schizophrenia from the early stage
      or even the putative pre-psychotic stage of the illness.
allocation: N/A
intervention model: Single Group Assignment
masking: None (Open Label)
measure: Changes in auditory event-related potentials "MMN"before/after intake of a single dose memantine
time frame: 4 hours after intake of a single dose memantine
description: Previous studies revealed deficits in cognition via auditory event-related potential, such as Mismatch Negativity. This study would compare the effect of single dose memantine in MMN.
measure: Changes in auditory event-related potentials "P50" before/after intake of a single dose memantine
time frame: 4 hours after intake of a single dose memantine
description: Previous studies revealed deficits in cognition via auditory event-related potential, such as P50. This study would compare the effect of single dose memantine in P50
arm group label: Memantine
arm group type: Experimental
description: This study has only one arm. i.e. Single dose of memantine 20mg
intervention type: Drug
intervention name: Memantine
description: Taking 20mg(2 capsules) of memantine, followed by Event related potential assessments as below:
Mismatch negativity(MMN)
P50
arm group label: Memantine
other name: Ebixa 10 mg, manufactured by Lunbeck A/S, Denmark
criteria: 
gender: All
minimum age: 20 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Ming-Hsien Hsieh, MD, PhD
role: Principal Investigator
affiliation: National Taiwan University Hospital
last name: Ming-Hsien Hsieh, MD, PhD
phone: +886-2-23123456
phone ext: 66790
email: mingh@ntuh.gov.tw
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: Taiwan
responsible party type: Sponsor
mesh term: Schizophrenia
mesh term: Memantine