<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/NCT01720316</url>
  </required_header>
  <id_info>
    <org_study_id>2012p001597</org_study_id>
    <secondary_id>R21MH097470-01A1</secondary_id>
    <nct_id>NCT01720316</nct_id>
  </id_info>
  <brief_title>Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders</brief_title>
  <official_title>Pilot Study of Glycine Augmentation in Carriers of a Mutation in the Gene Encoding Glycine Decarboxylase</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mclean Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Mental Health (NIMH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Mclean Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to assess the efficacy of oral glycine as an augmentation&#xD;
      strategy in two psychotic patients with a triplication (4 copies) of the gene glycine&#xD;
      decarboxylase (GLDC). Subjects will first undergo a double-blind placebo-controlled clinical&#xD;
      trial in which one 6-week arm will involve glycine (maximum daily dose of 0.8 g/kg,&#xD;
      administered on a TID dosing schedule) and one 6-week arm will involve placebo. A 2-week&#xD;
      period of no treatment will occur between treatment arms. A 6-week period of open-label&#xD;
      glycine (maximum daily dose of 0.8 g/kg, administered on a TID dosing schedule) will follow&#xD;
      the double-blind placebo-controlled clinical trial. Prior to the double-blind&#xD;
      placebo-controlled clinical trial and at the end of the open-label glycine trial, the&#xD;
      following procedures will be carried out: structural MRI (3T), Proton 1H MRS (4T), fMRI (3T),&#xD;
      steady-state visual evoked potentials, and EEG. Positive, negative, and affective symptoms&#xD;
      and neurocognitive function as well as plasma levels of large neutral and large and small&#xD;
      neutral and excitatory amino acids and psychotropic drug levels will be assessed&#xD;
      periodically. In addition, 1H MRS (4T) for 2 hours after a single oral dose of a&#xD;
      glycine-containing drink will be assessed at baseline. Pharmaceutical grade glycine powder&#xD;
      (Ajinomoto) or placebo will be dissolved in 20% solution and prepared by the McLean Hospital&#xD;
      Pharmacy.&#xD;
&#xD;
      Because the results of the double-blind placebo-controlled and open-label glycine treatment&#xD;
      arms showed substantial clinical benefit to the participants, the study has been extended to&#xD;
      include six months of chronic open-label glycine in order to determine 1) whether the&#xD;
      clinical benefits achieved within 6 weeks previously recur, 2) the clinical benefits are&#xD;
      lasting, and 3) additional clinical benefits occur with longer exposure. The glycine for this&#xD;
      extension will be provided by Letco Medical.&#xD;
&#xD;
      The investigators hypothesize that mutation carriers will have reduced endogenous brain&#xD;
      glycine and GABA levels and increased brain glutamate and glutamine levels. Glycine&#xD;
      administration will increase brain glycine in the two carriers, but to a lesser extent than&#xD;
      in non-carrier family members and controls.&#xD;
&#xD;
      The investigators hypothesize reduced activation of magnocellular pathways and abnormal ERPs&#xD;
      modulated by NMDA in mutation carriers compared with non-carrier family members and controls.&#xD;
&#xD;
      The investigators hypothesize that glycine, but not placebo, will improve positive, negative&#xD;
      and affective symptoms as well as neurocognitive function.&#xD;
&#xD;
      The investigators also hypothesize that open-label glycine will improve clinical and&#xD;
      cognitive functioning, will partially normalize decreased baseline glycine and GABA and&#xD;
      increased glutamate and glutamine, and will partially normalize magnocellular pathway&#xD;
      activation and abnormal evoked potentials.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Multiple rare structural variants of relatively recent evolutionary origin are recognized as&#xD;
      important risk factors for schizophrenia (SZ) and other neurodevelopmental disorders (e.g.,&#xD;
      autism spectrum disorders, mental retardation, epilepsy) with odds ratios as high as 7-30&#xD;
      (Sebat et al. 2009; Malhotra et al. 2011; Heinzen et al. 2010; Weiss et al. 2008; McCarthy et&#xD;
      al. 2009). We have found a de novo structural rearrangement on chromosome 9p24.1 in two&#xD;
      psychotic patients. One of the genes in this region is the gene encoding glycine&#xD;
      decarboxylase (GLDC), which affects brain glycine metabolism. GLDC encodes the glycine&#xD;
      decarboxylase or glycine cleavage system P-protein, which is involved in degradation of&#xD;
      glycine in glia cells. Carriers of the GLDC triplication would be expected to have low levels&#xD;
      of brain Gly, resulting in NMDA receptor-mediated hypofunction, which has been strongly&#xD;
      implicated in the pathophysiology of schizophrenia (Olney &amp; Farber, 1995; Coyle, 2006;&#xD;
      Javitt, 2007).&#xD;
&#xD;
      There is an extensive literature on the effects of NMDA enhancing agents on positive,&#xD;
      negative, and depressive symptoms and on neurocognitive function (see Tsai &amp; Lin, 2010; Lin&#xD;
      et al. 2011 for reviews). Although many studies have reported positive results in at least&#xD;
      one symptom domain (Heresco-Levy et al. 1996, 1999, 2004; Tsai et al. 1998, 1999, 2004, 2006;&#xD;
      Javitt et al. 2001; Goff et al. 1996; Lane et al. 2008), the results of other studies have&#xD;
      been negative or ambiguous (Goff et al. 1999; Evins et al. 2000; Duncan et al. 2004; van&#xD;
      Berckel et al. 1999). Factors likely to contribute to this variability include: mechanism of&#xD;
      action of the agent, compliance, concurrent treatment with first- vs second generation&#xD;
      antipsychotic drugs, baseline glycine blood levels, presence/absence of kynurenine pathway&#xD;
      metabolic abnormalities (Wonodi et al. 2010; Erhardt et al. 2007) and individual differences&#xD;
      in brain glycine uptake and metabolism (Kaufman et al. 2009; Buchanan et al. 2007). Genetic&#xD;
      variants that impact the synthesis and breakdown of glycine, glutamate, or other modulators&#xD;
      of NMDA receptor function are also likely to have significant effects. Although glycine&#xD;
      augmentation has shown variable efficacy in patients unselected for having a mutation that&#xD;
      would be expected to lower brain glycine levels, the GLDC triplication in the two carriers in&#xD;
      this study would be expected to result in unusually low brain glycine levels, supporting its&#xD;
      therapeutic potential as an augmentation strategy.&#xD;
&#xD;
      Thus, it is important to evaluate the therapeutic efficacy of glycine augmentation in&#xD;
      individuals in whom there is a high prior probability of therapeutic benefit and to&#xD;
      characterize the neurobiology of this mutation in terms of brain metabolites, brain function,&#xD;
      and the pharmacokinetics of glycine metabolism using well-established methods (Kaufman et al.&#xD;
      2009; Prescot et al. 2006; Martinez et al. 2008; Butler et al. 2001; Jensen et al. 2009;&#xD;
      Ongur et al. 2008).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 10, 2012</start_date>
  <completion_date type="Actual">May 31, 2017</completion_date>
  <primary_completion_date type="Actual">May 31, 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Positive and Negative Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks During Intervention 1 (Glycine or Placebo), Intervention 2 (Glycine or Placebo), and During Open-label Glycine</measure>
    <time_frame>baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period and after each treatment period</time_frame>
    <description>Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms are measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Neurocognitive Function at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine</measure>
    <time_frame>At baseline, during glycine treatment, during placebo treatment and during open-label glycine</time_frame>
    <description>Scores on each of 8 domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, social cognition, overall composite). Scores are T scores ranging from 0-100, with 50 representing the mean for a population based on a normal distribution; standard deviation of 10. Only overall composite score is entered.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Glycine Plasma Amino Acid Levels at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine</measure>
    <time_frame>At baseline, during glycine treatment, during placebo treatment and during open-label glycine</time_frame>
    <description>Plasma glycine levels; normal range is 122-467 nM/mL</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Brief Psychiatric Rating Scale (BPRS) Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Positive and Negative Symptom Scores at Baseline and at 2, 4, and 6 Weeks During Intervention 1, Intervention 2, and During Open-label Glycine</measure>
    <time_frame>baseline and at 2 weeks, 4 weeks, and 6 weeks within and after each treatment period</time_frame>
    <description>Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical Global Impression (CGI) Severity Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period</measure>
    <time_frame>CGI at baseline and at 2 weeks, 4 weeks, and 6 weeks per treatment period</time_frame>
    <description>Clinical Global Impression (CGI) severity scores measure severity of mental illness on a scale of 1-7 where 1 means normal, not at all ill, 2 means borderline mentally ill, 3 means mildly ill, 4 means moderately ill, 5 means markedly ill, 6 means severely ill and 7 means among the most extremely ill patients.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical Global Impression (CGI) Therapeutic Effect Scores at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period</measure>
    <time_frame>at 2 weeks, 4 weeks, and 6 weeks within each treatment period</time_frame>
    <description>Clinical Global Impression (CGI) therapeutic effect scores measure degree of improvement as marked (1), moderate (5), minimal (9) or unchanged/worse (13).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mania Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period</measure>
    <time_frame>baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period</time_frame>
    <description>Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of ratings for 7 symptoms of mania is measured on a scale from 0-4 and the sum of 4 symptoms of mania is measured on a scale from 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Depression Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period</measure>
    <time_frame>baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period</time_frame>
    <description>Hamilton Depression Scale measures severity of depression symptoms. The sum of ratings for 9 depression symptoms are measured on a scale from 0-2 with 0 meaning no symptoms and 2 meaning some level of severity of that specific symptom. The rating for 1 depression symptom is measured on a scale from 0-3 with 0 meaning no symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms are measured on a scale from 0-4 with 0 meaning no symptoms and 4 meaning a severe level of that specific symptom. The three sums are added to produce an overall depression rating scale score ranging from 0-65.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Brain Glycine/CR Ratio</measure>
    <time_frame>baseline (pre-challenge, 60, 80, 100, 120 minutes post-challenge), and week 6 of glycine (pre-dose and 60, 80, 100, 120 minutes post-dose</time_frame>
    <description>magnetic resonance spectroscopy: glycine/creatine ratio. Participants were assessed at 1) BASELINE PRE-GLYCINE TREATMENT: pre-glycine challenge drink, 60 minutes post challenge drink, 80 minutes post challenge drink, 100 minutes post challenge drink, and 120 minutes post challenge drink (0.4 g/kg up to max of 30 g); and 2) IN WEEK 6 OF OPEN-LABEL GLYCINE TREATMENT: pre-glycine dose, and 60 minutes, 80 minutes, 100 minutes and 120 minutes post daily dose of glycine. Measured in posterior occipital cortex</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain Glutamate Metabolite Levels (Glutamate/Creatine Ratio: Glu/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</measure>
    <time_frame>baseline and week 6 of glycine</time_frame>
    <description>magnetic resonance spectroscopy - glutamate metabolite level. Participants were assessed 1) pre-glycine treatment and in week 6 of open-label glycine treatment. Measured in posterior occipital cortex.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain GABA Metabolite Levels (GABA/Creatine Ratio: GABA/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</measure>
    <time_frame>Baseline and week 6 of glycine</time_frame>
    <description>Magnetic resonance spectroscopy GABA/Cr. Participants were assessed 1) pre-glycine treatment (baseline) and 2) in week 6 of open-label glycine treatment measured in posterior occipital cortex.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Auditory Evoked Potentials in Latency (Msec) at BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF TREATMENT WITH GLYCINE</measure>
    <time_frame>Recordings at baseline and week 6 of glycine</time_frame>
    <description>Auditory evoked potentials latency: P300 at fz, cz, and pz); N100 at fz and cz); P200 at fz and cz. Participants were assessed at baseline and in week of open-label glycine treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Magnocellular Pathway Function on Glycine Compared With Baseline. No Data Were Collected.</measure>
    <time_frame>6 weeks per treatment arm</time_frame>
    <description>functional magnetic resonance imaging</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</measure>
    <time_frame>Recordings at baseline and week 6 of glycine</time_frame>
    <description>Auditory evoked potentials amplitude: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz; P50 S1 and S2 amplitude; mismatch negativity (MMN) at fz and cz. Participants were assessed at baseline and in week 6 of open-label glycine treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Auditory Evoked Potentials in Gammas Oscillations (the Power Spectrum is Measured in Microvolts Squared) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</measure>
    <time_frame>Recordings at baseline and week 6 of glycine</time_frame>
    <description>Auditory evoked potentials gamma: G40 hz phase locking at fz and cz; G20 hz phase locking response at fz and cz G30 hz phase locking response at fz and cz. Participants were assessed at baseline and in week 6 of open-label glycine treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Auditory Evoked Potentials - P50 Ratio (P50 S2/P50 S1 Amplitude) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</measure>
    <time_frame>Recordings at baseline and week 6 of glycine</time_frame>
    <description>Auditory evoked potentials amplitude: P50 ratio (S2/S1). Participants were assessed at baseline and in week 6 of open-label glycine treatment.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Schizo-affective Disorder</condition>
  <condition>Bipolar Disorder</condition>
  <arm_group>
    <arm_group_label>glycine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Double-blind</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>placebo, TID dosing, 6 weeks Double-blind</description>
  </arm_group>
  <arm_group>
    <arm_group_label>glycine, open-label</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Glycine</intervention_name>
    <description>Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine</description>
    <arm_group_label>glycine</arm_group_label>
    <arm_group_label>glycine, open-label</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Triplication of glycine decarboxylase gene&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Normal glycine decarboxylase copy number&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Deborah L Levy, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mclean Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>McLean Hospital</name>
      <address>
        <city>Belmont</city>
        <state>Massachusetts</state>
        <zip>02478</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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  <verification_date>September 2017</verification_date>
  <study_first_submitted>October 30, 2012</study_first_submitted>
  <study_first_submitted_qc>October 31, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 2, 2012</study_first_posted>
  <results_first_submitted>April 16, 2017</results_first_submitted>
  <results_first_submitted_qc>April 16, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">April 18, 2017</results_first_posted>
  <last_update_submitted>September 18, 2017</last_update_submitted>
  <last_update_submitted_qc>September 18, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 19, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Mclean Hospital</investigator_affiliation>
    <investigator_full_name>Deborah L. Levy</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Glycine</keyword>
  <keyword>Glycine decarboxylase</keyword>
  <keyword>Psychosis</keyword>
  <keyword>Mutation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bipolar Disorder</mesh_term>
    <mesh_term>Mood Disorders</mesh_term>
    <mesh_term>Psychotic Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glycine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>November 11, 2012</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/16/NCT01720316/ICF_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>October 17, 2012</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/16/NCT01720316/SAP_001.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 2, 2012</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/16/NCT01720316/Prot_002.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Glycine, Then Placebo</title>
          <description>One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then the participant received open-label glycine for 6 weeks.</description>
        </group>
        <group group_id="P2">
          <title>Placebo, Then Glycine</title>
          <description>One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then the participant received open-label glycine for 6 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Double-Blind Glycine Placebo Crossover</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Open-label Glycine</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Glycine, Then Placebo</title>
          <description>One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
        </group>
        <group group_id="B2">
          <title>Placebo, Then Glycine</title>
          <description>One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="1"/>
            <count group_id="B2" value="1"/>
            <count group_id="B3" value="2"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <description>age at beginning of study</description>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <title>age</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59" lower_limit="NA" upper_limit="NA">Single participant in each arm</measurement>
                    <measurement group_id="B2" value="32" lower_limit="NA" upper_limit="NA">Single participant in each arm</measurement>
                    <measurement group_id="B3" value="45.5" lower_limit="32" upper_limit="59"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Positive and Negative Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks During Intervention 1 (Glycine or Placebo), Intervention 2 (Glycine or Placebo), and During Open-label Glycine</title>
        <description>Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms are measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.</description>
        <time_frame>baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period and after each treatment period</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Glycine, Then Placebo</title>
            <description>One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo, Then Glycine</title>
            <description>One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Positive and Negative Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks During Intervention 1 (Glycine or Placebo), Intervention 2 (Glycine or Placebo), and During Open-label Glycine</title>
          <description>Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms are measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.</description>
          <units>units on a scale</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Positive symptoms at baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive symptoms at 2 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12"/>
                    <measurement group_id="O2" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive symptoms at 4 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                    <measurement group_id="O2" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive symptoms at 6 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive symptoms, end of washout1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive symptoms at 2 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12"/>
                    <measurement group_id="O2" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive symptoms at 4 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                    <measurement group_id="O2" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive symptoms at 6 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                    <measurement group_id="O2" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive symptoms, end of washout2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                    <measurement group_id="O2" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive symptoms at 2 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive symptoms at 4 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                    <measurement group_id="O2" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive symptoms at 6 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Positive symptoms, end of washout3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Neurocognitive Function at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine</title>
        <description>Scores on each of 8 domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, social cognition, overall composite). Scores are T scores ranging from 0-100, with 50 representing the mean for a population based on a normal distribution; standard deviation of 10. Only overall composite score is entered.</description>
        <time_frame>At baseline, during glycine treatment, during placebo treatment and during open-label glycine</time_frame>
        <population>Data provided for each participant separately.</population>
        <group_list>
          <group group_id="O1">
            <title>Baseline</title>
            <description>Composite Score at Baseline</description>
          </group>
          <group group_id="O2">
            <title>Composite Score on Glycine, Double-blind</title>
            <description>Glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Double-blind&#xD;
Glycine: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine</description>
          </group>
          <group group_id="O3">
            <title>Composite Score on Placebo</title>
            <description>placebo, TID dosing, 6 weeks Double-blind&#xD;
placebo</description>
          </group>
          <group group_id="O4">
            <title>Composite Score on Glycine, Open-label</title>
            <description>glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks&#xD;
Glycine: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine</description>
          </group>
        </group_list>
        <measure>
          <title>Neurocognitive Function at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine</title>
          <description>Scores on each of 8 domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, social cognition, overall composite). Scores are T scores ranging from 0-100, with 50 representing the mean for a population based on a normal distribution; standard deviation of 10. Only overall composite score is entered.</description>
          <population>Data provided for each participant separately.</population>
          <units>units on a scale</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="2"/>
                <count group_id="O3" value="2"/>
                <count group_id="O4" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Participant 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="1"/>
                    <count group_id="O2" value="1"/>
                    <count group_id="O3" value="1"/>
                    <count group_id="O4" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45"/>
                    <measurement group_id="O2" value="52"/>
                    <measurement group_id="O3" value="52"/>
                    <measurement group_id="O4" value="49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Participant 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="1"/>
                    <count group_id="O2" value="1"/>
                    <count group_id="O3" value="1"/>
                    <count group_id="O4" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="48"/>
                    <measurement group_id="O2" value="52"/>
                    <measurement group_id="O3" value="55"/>
                    <measurement group_id="O4" value="46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Glycine Plasma Amino Acid Levels at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine</title>
        <description>Plasma glycine levels; normal range is 122-467 nM/mL</description>
        <time_frame>At baseline, during glycine treatment, during placebo treatment and during open-label glycine</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Glycine Then Placebo</title>
            <description>Glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Double-blind&#xD;
Glycine: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine</description>
          </group>
          <group group_id="O2">
            <title>Placebo Then Glycine</title>
            <description>placebo, TID dosing, 6 weeks Double-blind&#xD;
placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Glycine Plasma Amino Acid Levels at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine</title>
          <description>Plasma glycine levels; normal range is 122-467 nM/mL</description>
          <units>nM/mL</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="216"/>
                    <measurement group_id="O2" value="271"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Glycine double-blind</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="410"/>
                    <measurement group_id="O2" value="761"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Placebo</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="194"/>
                    <measurement group_id="O2" value="347"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Glycine open-label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="516"/>
                    <measurement group_id="O2" value="634"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Brief Psychiatric Rating Scale (BPRS) Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Positive and Negative Symptom Scores at Baseline and at 2, 4, and 6 Weeks During Intervention 1, Intervention 2, and During Open-label Glycine</title>
        <description>Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms.</description>
        <time_frame>baseline and at 2 weeks, 4 weeks, and 6 weeks within and after each treatment period</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Glycine, Then Placebo</title>
            <description>One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo, Then Glycine</title>
            <description>One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Brief Psychiatric Rating Scale (BPRS) Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Positive and Negative Symptom Scores at Baseline and at 2, 4, and 6 Weeks During Intervention 1, Intervention 2, and During Open-label Glycine</title>
          <description>Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms.</description>
          <units>units on a scale</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>BPRS at baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="39"/>
                    <measurement group_id="O2" value="46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BPRS at 2 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38"/>
                    <measurement group_id="O2" value="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BPRS at 4 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32"/>
                    <measurement group_id="O2" value="39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BPRS at 6 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21"/>
                    <measurement group_id="O2" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BPRS, end of washout1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22"/>
                    <measurement group_id="O2" value="34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BPRS at 2 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37"/>
                    <measurement group_id="O2" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BPRS at 4 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31"/>
                    <measurement group_id="O2" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BPRS at 6 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37"/>
                    <measurement group_id="O2" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BPRS, end of washout2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32"/>
                    <measurement group_id="O2" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BPRS at 2 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23"/>
                    <measurement group_id="O2" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BPRS at 4 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22"/>
                    <measurement group_id="O2" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BPRS at 6 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21"/>
                    <measurement group_id="O2" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BPRS, end of washout3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                    <measurement group_id="O2" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Clinical Global Impression (CGI) Severity Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period</title>
        <description>Clinical Global Impression (CGI) severity scores measure severity of mental illness on a scale of 1-7 where 1 means normal, not at all ill, 2 means borderline mentally ill, 3 means mildly ill, 4 means moderately ill, 5 means markedly ill, 6 means severely ill and 7 means among the most extremely ill patients.</description>
        <time_frame>CGI at baseline and at 2 weeks, 4 weeks, and 6 weeks per treatment period</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Glycine, Then Placebo</title>
            <description>One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo, Then Glycine</title>
            <description>One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Global Impression (CGI) Severity Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period</title>
          <description>Clinical Global Impression (CGI) severity scores measure severity of mental illness on a scale of 1-7 where 1 means normal, not at all ill, 2 means borderline mentally ill, 3 means mildly ill, 4 means moderately ill, 5 means markedly ill, 6 means severely ill and 7 means among the most extremely ill patients.</description>
          <units>units on a scale</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>CGI severity score at baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI severity score at 2 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI severity score at 4 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI severity score at 6 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI severity score, end of washout1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI severity score at 2 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI severity score at 4 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI severity score at 6 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI severity score, end of washout2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI severity score at 2 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI severity score at 4 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI severity score at 6 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI severity score, end of washout3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Clinical Global Impression (CGI) Therapeutic Effect Scores at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period</title>
        <description>Clinical Global Impression (CGI) therapeutic effect scores measure degree of improvement as marked (1), moderate (5), minimal (9) or unchanged/worse (13).</description>
        <time_frame>at 2 weeks, 4 weeks, and 6 weeks within each treatment period</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Glycine, Then Placebo</title>
            <description>One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo, Then Glycine</title>
            <description>One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Global Impression (CGI) Therapeutic Effect Scores at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period</title>
          <description>Clinical Global Impression (CGI) therapeutic effect scores measure degree of improvement as marked (1), moderate (5), minimal (9) or unchanged/worse (13).</description>
          <units>score</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>CGI therapeutic effect at 2 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI therapeutic effect at 4 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI therapeutic effect at 6 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI therapeutic effect, end of washout1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI therapeutic effect at 2 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI therapeutic effect at 4 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI therapeutic effect at 6 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI therapeutic effect, end of washout2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI therapeutic effect at 2 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI therapeutic effect at 4 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI therapeutic effect at 6 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CGI therapeutic effect, end of washout3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Mania Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period</title>
        <description>Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of ratings for 7 symptoms of mania is measured on a scale from 0-4 and the sum of 4 symptoms of mania is measured on a scale from 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms.</description>
        <time_frame>baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Glycine, Then Placebo</title>
            <description>One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo, Then Glycine</title>
            <description>One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Mania Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period</title>
          <description>Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of ratings for 7 symptoms of mania is measured on a scale from 0-4 and the sum of 4 symptoms of mania is measured on a scale from 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms.</description>
          <units>units on a scale</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Manic symptoms at baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manic symptoms at 2 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manic symptoms at 4 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manic symptoms at 6 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manic symptoms, end of washout1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manic symptoms at 2 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manic symptoms at 4 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manic symptoms at 6 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manic symptoms, end of washout2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manic symptoms at 2 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manic symptoms at 4 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manic symptoms at 6 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manic symptoms, end of washout3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Depression Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period</title>
        <description>Hamilton Depression Scale measures severity of depression symptoms. The sum of ratings for 9 depression symptoms are measured on a scale from 0-2 with 0 meaning no symptoms and 2 meaning some level of severity of that specific symptom. The rating for 1 depression symptom is measured on a scale from 0-3 with 0 meaning no symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms are measured on a scale from 0-4 with 0 meaning no symptoms and 4 meaning a severe level of that specific symptom. The three sums are added to produce an overall depression rating scale score ranging from 0-65.</description>
        <time_frame>baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Glycine, Then Placebo</title>
            <description>One participant received glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks, then the participant received placebo TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo, Then Glycine</title>
            <description>One participant received placebo administered with TID dosing for 6 weeks, then the participant received glycine powder, up to 0.8 g/kg, TID dosing for 6 weeks, then open-label glycine for 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Depression Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period</title>
          <description>Hamilton Depression Scale measures severity of depression symptoms. The sum of ratings for 9 depression symptoms are measured on a scale from 0-2 with 0 meaning no symptoms and 2 meaning some level of severity of that specific symptom. The rating for 1 depression symptom is measured on a scale from 0-3 with 0 meaning no symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms are measured on a scale from 0-4 with 0 meaning no symptoms and 4 meaning a severe level of that specific symptom. The three sums are added to produce an overall depression rating scale score ranging from 0-65.</description>
          <units>units on a scale</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Depression symptoms at baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18"/>
                    <measurement group_id="O2" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression symptoms at 2 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression symptoms at 4 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression symptoms at 6 weeks intervention 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression symptoms, end of washout1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression symptoms at 2 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression symptoms at 4 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression symptoms at 6 weeks intervention 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression symptoms, end of washout2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression symptoms at 2 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression symptoms at 4 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression symptoms at 6 weeks open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression symptoms, end of washout3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Brain Glycine/CR Ratio</title>
        <description>magnetic resonance spectroscopy: glycine/creatine ratio. Participants were assessed at 1) BASELINE PRE-GLYCINE TREATMENT: pre-glycine challenge drink, 60 minutes post challenge drink, 80 minutes post challenge drink, 100 minutes post challenge drink, and 120 minutes post challenge drink (0.4 g/kg up to max of 30 g); and 2) IN WEEK 6 OF OPEN-LABEL GLYCINE TREATMENT: pre-glycine dose, and 60 minutes, 80 minutes, 100 minutes and 120 minutes post daily dose of glycine. Measured in posterior occipital cortex</description>
        <time_frame>baseline (pre-challenge, 60, 80, 100, 120 minutes post-challenge), and week 6 of glycine (pre-dose and 60, 80, 100, 120 minutes post-dose</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Subject1: Brain Glycine/CR Ratio at Baseline/Week 6 of Glycine</title>
            <description>Brain glycine/CR ratio at baseline and week 6 of glycine for one participant: Subject 1</description>
          </group>
          <group group_id="O2">
            <title>Subject 2:Brain Glycine/CR Ratio at Baseline/Week 6 of Glycine</title>
            <description>Brain glycine/CR ratio at baseline and week 6 of glycine for one participant</description>
          </group>
        </group_list>
        <measure>
          <title>Brain Glycine/CR Ratio</title>
          <description>magnetic resonance spectroscopy: glycine/creatine ratio. Participants were assessed at 1) BASELINE PRE-GLYCINE TREATMENT: pre-glycine challenge drink, 60 minutes post challenge drink, 80 minutes post challenge drink, 100 minutes post challenge drink, and 120 minutes post challenge drink (0.4 g/kg up to max of 30 g); and 2) IN WEEK 6 OF OPEN-LABEL GLYCINE TREATMENT: pre-glycine dose, and 60 minutes, 80 minutes, 100 minutes and 120 minutes post daily dose of glycine. Measured in posterior occipital cortex</description>
          <units>ratio</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline - pre-challenge drink</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.2558"/>
                    <measurement group_id="O2" value="0.5691"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline 60 minutes post challenge drink</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.6157"/>
                    <measurement group_id="O2" value="0.3918"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline 80 minutes post challenge drink</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.6631"/>
                    <measurement group_id="O2" value="0.6428"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline 100 minutes post challenge drink</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.5938"/>
                    <measurement group_id="O2" value="0.6363"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline 120 minutes post challenge drink</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.6953"/>
                    <measurement group_id="O2" value="0.9559"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6 of glycine - pre-glycine dose</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.6573"/>
                    <measurement group_id="O2" value="0.3235"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6 of glycine - 60 minutes post glycine dose</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.2983"/>
                    <measurement group_id="O2" value="0.3807"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6 of glycine - 80 minutes post glycine dose</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.4577"/>
                    <measurement group_id="O2" value="0.5591"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6 of glycine - 100 minutes post glycine dose</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.5751"/>
                    <measurement group_id="O2" value="0.4142"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6 of glycine - 120 minutes post glycine dose</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.3842"/>
                    <measurement group_id="O2" value="0.3545"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Brain Glutamate Metabolite Levels (Glutamate/Creatine Ratio: Glu/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</title>
        <description>magnetic resonance spectroscopy - glutamate metabolite level. Participants were assessed 1) pre-glycine treatment and in week 6 of open-label glycine treatment. Measured in posterior occipital cortex.</description>
        <time_frame>baseline and week 6 of glycine</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Subject1: Brain Glutamate/CR Ratio- Baseline/Week 6 of Glycine</title>
            <description>Brain glutamate/CR ratio at baseline and week 6 of glycine for one participant: Subject 1</description>
          </group>
          <group group_id="O2">
            <title>Subject2: Brain Glutamate/CR Ratio- Baseline/Week 6 of Glycine</title>
            <description>Brain glutamate/CR ratio at baseline and week 6 of glycine for one participant: Subject 2</description>
          </group>
        </group_list>
        <measure>
          <title>Brain Glutamate Metabolite Levels (Glutamate/Creatine Ratio: Glu/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</title>
          <description>magnetic resonance spectroscopy - glutamate metabolite level. Participants were assessed 1) pre-glycine treatment and in week 6 of open-label glycine treatment. Measured in posterior occipital cortex.</description>
          <units>ratio</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline brain glutamate/Cr ratio</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.98"/>
                    <measurement group_id="O2" value="2.053"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6 brain glutamate/Cr ratio</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.84"/>
                    <measurement group_id="O2" value="1.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Brain GABA Metabolite Levels (GABA/Creatine Ratio: GABA/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</title>
        <description>Magnetic resonance spectroscopy GABA/Cr. Participants were assessed 1) pre-glycine treatment (baseline) and 2) in week 6 of open-label glycine treatment measured in posterior occipital cortex.</description>
        <time_frame>Baseline and week 6 of glycine</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Subject1: Brain GABA/CR Ratio- Baseline/Week 6 of Glycine</title>
            <description>Brain GABA/CR ratio at baseline and week 6 of glycine for one participant: Subject 1</description>
          </group>
          <group group_id="O2">
            <title>Subject2: Brain GABA/CR Ratio- Baseline/Week 6 of Glycine</title>
            <description>Brain GABA/CR ratio at baseline and week 6 of glycine for one participant: Subject 2</description>
          </group>
        </group_list>
        <measure>
          <title>Brain GABA Metabolite Levels (GABA/Creatine Ratio: GABA/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</title>
          <description>Magnetic resonance spectroscopy GABA/Cr. Participants were assessed 1) pre-glycine treatment (baseline) and 2) in week 6 of open-label glycine treatment measured in posterior occipital cortex.</description>
          <units>ratio</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline GABA/Cr</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.16"/>
                    <measurement group_id="O2" value="0.27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6 of glycine tx GABA/Cr</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.22"/>
                    <measurement group_id="O2" value="0.24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Auditory Evoked Potentials in Latency (Msec) at BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF TREATMENT WITH GLYCINE</title>
        <description>Auditory evoked potentials latency: P300 at fz, cz, and pz); N100 at fz and cz); P200 at fz and cz. Participants were assessed at baseline and in week of open-label glycine treatment.</description>
        <time_frame>Recordings at baseline and week 6 of glycine</time_frame>
        <population>Only one subject received these procedures because normal hearing is required.</population>
        <group_list>
          <group group_id="O1">
            <title>Auditory ERPs Latency (ms) Baseline: Subject 1</title>
            <description>Subject1: Auditory ERPs (latency) baseline</description>
          </group>
          <group group_id="O2">
            <title>Auditory ERPs Latency (ms) 6 Weeks of Glycine: Subject 1</title>
            <description>Subject1: Auditory ERPs (latency) week 6 of glycine</description>
          </group>
          <group group_id="O3">
            <title>Auditory ERPs Latency (ms) Baseline: Subject 2</title>
            <description>Subject2: Auditory ERPs (latency) baseline</description>
          </group>
          <group group_id="O4">
            <title>Auditory ERPs Latency (ms) 6 Weeks of Glycine: Subject 2</title>
            <description>Subject2: Auditory ERPs (latency) week 6 of glycine</description>
          </group>
        </group_list>
        <measure>
          <title>Auditory Evoked Potentials in Latency (Msec) at BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF TREATMENT WITH GLYCINE</title>
          <description>Auditory evoked potentials latency: P300 at fz, cz, and pz); N100 at fz and cz); P200 at fz and cz. Participants were assessed at baseline and in week of open-label glycine treatment.</description>
          <population>Only one subject received these procedures because normal hearing is required.</population>
          <units>msec</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="1"/>
                <count group_id="O4" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>P300 latency at fz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="279.3"/>
                    <measurement group_id="O4" value="300.78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P300 latency at cz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="279.3"/>
                    <measurement group_id="O4" value="293"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P300 latency at pz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="279.3"/>
                    <measurement group_id="O4" value="294.92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>N100 latency at fz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="97.66"/>
                    <measurement group_id="O4" value="94"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>N100 latency at cz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="91.8"/>
                    <measurement group_id="O4" value="94"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P200 latency at fz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="197.27"/>
                    <measurement group_id="O4" value="205"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P200 latency at cz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="193.4"/>
                    <measurement group_id="O4" value="203"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Magnocellular Pathway Function on Glycine Compared With Baseline. No Data Were Collected.</title>
        <description>functional magnetic resonance imaging</description>
        <time_frame>6 weeks per treatment arm</time_frame>
        <population>Data not collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Glycine</title>
            <description>Glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks&#xD;
glycine powder: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>placebo, TID dosing, 6 weeks&#xD;
placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Magnocellular Pathway Function on Glycine Compared With Baseline. No Data Were Collected.</title>
          <description>functional magnetic resonance imaging</description>
          <population>Data not collected.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</title>
        <description>Auditory evoked potentials amplitude: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz; P50 S1 and S2 amplitude; mismatch negativity (MMN) at fz and cz. Participants were assessed at baseline and in week 6 of open-label glycine treatment.</description>
        <time_frame>Recordings at baseline and week 6 of glycine</time_frame>
        <population>Only one subject received these procedures because normal hearing is required.</population>
        <group_list>
          <group group_id="O1">
            <title>Auditory ERPs Amplitude (Deg) Baseline: Subject 1</title>
            <description>Subject1: Auditory ERPs (amplitude) baseline</description>
          </group>
          <group group_id="O2">
            <title>Auditory ERPs Amplitude (Deg) 6 Weeks of Glycine: Subject 1</title>
            <description>Subject1: Auditory ERPs (amplitude) week 6 of glycine</description>
          </group>
          <group group_id="O3">
            <title>Auditory ERPs Amplitude (Deg) Baseline: Subject 2</title>
            <description>Subject2: Auditory ERPs (amplitude) baseline</description>
          </group>
          <group group_id="O4">
            <title>Auditory ERPs Amplitude (Deg) 6 Weeks of Glycine: Subject 2</title>
            <description>Subject2: Auditory ERPs (amplitude) week 6 of glycine</description>
          </group>
        </group_list>
        <measure>
          <title>Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</title>
          <description>Auditory evoked potentials amplitude: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz; P50 S1 and S2 amplitude; mismatch negativity (MMN) at fz and cz. Participants were assessed at baseline and in week 6 of open-label glycine treatment.</description>
          <population>Only one subject received these procedures because normal hearing is required.</population>
          <units>microvolts</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="1"/>
                <count group_id="O4" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>P300 amplitude at fz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="-0.635"/>
                    <measurement group_id="O4" value="3.74"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P300 amplitude at cz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="6.53"/>
                    <measurement group_id="O4" value="6.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P300 amplitude at pz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="5.34"/>
                    <measurement group_id="O4" value="5.57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>N100 amplitude at fz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="-3.93"/>
                    <measurement group_id="O4" value="-4.71"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>N100 amplitude at cz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="-3.62"/>
                    <measurement group_id="O4" value="-3.89"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P200 amplitude at fz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="1.662"/>
                    <measurement group_id="O4" value="6.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P200 amplitude at cz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="6.59"/>
                    <measurement group_id="O4" value="7.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P50 S1 amplitude</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="2.76"/>
                    <measurement group_id="O4" value="2.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P50 S2 amplitude</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="1.23"/>
                    <measurement group_id="O4" value="0.78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>MMN amplitude at fz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="-3.356"/>
                    <measurement group_id="O4" value="-1.004"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>MMN amplitude at cz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="-4.13"/>
                    <measurement group_id="O4" value="-1.322"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Auditory Evoked Potentials in Gammas Oscillations (the Power Spectrum is Measured in Microvolts Squared) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</title>
        <description>Auditory evoked potentials gamma: G40 hz phase locking at fz and cz; G20 hz phase locking response at fz and cz G30 hz phase locking response at fz and cz. Participants were assessed at baseline and in week 6 of open-label glycine treatment.</description>
        <time_frame>Recordings at baseline and week 6 of glycine</time_frame>
        <population>Only one subject received these procedures because normal hearing is required.</population>
        <group_list>
          <group group_id="O1">
            <title>Auditory ERPs Gamma Baseline: Subject 1</title>
            <description>Subject1: Auditory ERPs (gamma phase locking) baseline</description>
          </group>
          <group group_id="O2">
            <title>Auditory ERPs Gamma 6 Weeks of Glycine: Subject 1</title>
            <description>Subject1: Auditory ERPs (gamma phase locking) week 6 of glycine</description>
          </group>
          <group group_id="O3">
            <title>Auditory ERPs Gamma Baseline: Subject 2</title>
            <description>Subject2: Auditory ERPs (gamma phase locking) baseline</description>
          </group>
          <group group_id="O4">
            <title>Auditory ERPs Gamma 6 Weeks of Glycine: Subject 2</title>
            <description>Subject2: Auditory ERPs (gamma phase locking) week 6 of glycine</description>
          </group>
        </group_list>
        <measure>
          <title>Auditory Evoked Potentials in Gammas Oscillations (the Power Spectrum is Measured in Microvolts Squared) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</title>
          <description>Auditory evoked potentials gamma: G40 hz phase locking at fz and cz; G20 hz phase locking response at fz and cz G30 hz phase locking response at fz and cz. Participants were assessed at baseline and in week 6 of open-label glycine treatment.</description>
          <population>Only one subject received these procedures because normal hearing is required.</population>
          <units>microvolts squared</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="1"/>
                <count group_id="O4" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>G40 fz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="0.135"/>
                    <measurement group_id="O4" value="0.255"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>G40 cz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="0.168"/>
                    <measurement group_id="O4" value="0.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>G20 fz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="0.023"/>
                    <measurement group_id="O4" value="0.107"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>G20 cz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="0.03"/>
                    <measurement group_id="O4" value="0.108"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>G30 fz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="0.19"/>
                    <measurement group_id="O4" value="0.177"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>G30 cz</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="0.163"/>
                    <measurement group_id="O4" value="0.242"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Auditory Evoked Potentials - P50 Ratio (P50 S2/P50 S1 Amplitude) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</title>
        <description>Auditory evoked potentials amplitude: P50 ratio (S2/S1). Participants were assessed at baseline and in week 6 of open-label glycine treatment.</description>
        <time_frame>Recordings at baseline and week 6 of glycine</time_frame>
        <population>Only one subject received these procedures because normal hearing is required.</population>
        <group_list>
          <group group_id="O1">
            <title>Auditory ERPs Amplitude (Deg) Baseline: Subject 1</title>
            <description>Subject1: Auditory ERPs (amplitude) baseline</description>
          </group>
          <group group_id="O2">
            <title>Auditory ERPs Amplitude (Deg) 6 Weeks of Glycine: Subject 1</title>
            <description>Subject1: Auditory ERPs (amplitude) week 6 of glycine</description>
          </group>
          <group group_id="O3">
            <title>Auditory ERPs Amplitude (Deg) Baseline: Subject 2</title>
            <description>Subject2: Auditory ERPs (amplitude) baseline</description>
          </group>
          <group group_id="O4">
            <title>Auditory ERPs Amplitude (Deg) 6 Weeks of Glycine: Subject 2</title>
            <description>Subject2: Auditory ERPs (amplitude) week 6 of glycine</description>
          </group>
        </group_list>
        <measure>
          <title>Auditory Evoked Potentials - P50 Ratio (P50 S2/P50 S1 Amplitude) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT</title>
          <description>Auditory evoked potentials amplitude: P50 ratio (S2/S1). Participants were assessed at baseline and in week 6 of open-label glycine treatment.</description>
          <population>Only one subject received these procedures because normal hearing is required.</population>
          <units>ratio</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="1"/>
                <count group_id="O4" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="44.51"/>
                    <measurement group_id="O4" value="35.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>26 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Glycine</title>
          <description>Glycine powder, up to 0.8 g/kg, administered with TID dosing for 6 weeks&#xD;
glycine powder: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>placebo, TID dosing, 6 weeks&#xD;
placebo</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>nausea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Deborah L. Levy</name_or_title>
      <organization>McLean Hospital</organization>
      <phone>617-855-2854</phone>
      <email>dlevy@mclean.harvard.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01720316
org study id: 2012p001597
secondary id: R21MH097470-01A1
nct id: NCT01720316
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to assess the efficacy of oral glycine as an augmentation
      strategy in two psychotic patients with a triplication (4 copies) of the gene glycine
      decarboxylase (GLDC). Subjects will first undergo a double-blind placebo-controlled clinical
      trial in which one 6-week arm will involve glycine (maximum daily dose of 0.8 g/kg,
      administered on a TID dosing schedule) and one 6-week arm will involve placebo. A 2-week
      period of no treatment will occur between treatment arms. A 6-week period of open-label
      glycine (maximum daily dose of 0.8 g/kg, administered on a TID dosing schedule) will follow
      the double-blind placebo-controlled clinical trial. Prior to the double-blind
      placebo-controlled clinical trial and at the end of the open-label glycine trial, the
      following procedures will be carried out: structural MRI (3T), Proton 1H MRS (4T), fMRI (3T),
      steady-state visual evoked potentials, and EEG. Positive, negative, and affective symptoms
      and neurocognitive function as well as plasma levels of large neutral and large and small
      neutral and excitatory amino acids and psychotropic drug levels will be assessed
      periodically. In addition, 1H MRS (4T) for 2 hours after a single oral dose of a
      glycine-containing drink will be assessed at baseline. Pharmaceutical grade glycine powder
      (Ajinomoto) or placebo will be dissolved in 20% solution and prepared by the McLean Hospital
      Pharmacy.

      Because the results of the double-blind placebo-controlled and open-label glycine treatment
      arms showed substantial clinical benefit to the participants, the study has been extended to
      include six months of chronic open-label glycine in order to determine 1) whether the
      clinical benefits achieved within 6 weeks previously recur, 2) the clinical benefits are
      lasting, and 3) additional clinical benefits occur with longer exposure. The glycine for this
      extension will be provided by Letco Medical.

      The investigators hypothesize that mutation carriers will have reduced endogenous brain
      glycine and GABA levels and increased brain glutamate and glutamine levels. Glycine
      administration will increase brain glycine in the two carriers, but to a lesser extent than
      in non-carrier family members and controls.

      The investigators hypothesize reduced activation of magnocellular pathways and abnormal ERPs
      modulated by NMDA in mutation carriers compared with non-carrier family members and controls.

      The investigators hypothesize that glycine, but not placebo, will improve positive, negative
      and affective symptoms as well as neurocognitive function.

      The investigators also hypothesize that open-label glycine will improve clinical and
      cognitive functioning, will partially normalize decreased baseline glycine and GABA and
      increased glutamate and glutamine, and will partially normalize magnocellular pathway
      activation and abnormal evoked potentials.
Multiple rare structural variants of relatively recent evolutionary origin are recognized as
      important risk factors for schizophrenia (SZ) and other neurodevelopmental disorders (e.g.,
      autism spectrum disorders, mental retardation, epilepsy) with odds ratios as high as 7-30
      (Sebat et al. 2009; Malhotra et al. 2011; Heinzen et al. 2010; Weiss et al. 2008; McCarthy et
      al. 2009). We have found a de novo structural rearrangement on chromosome 9p24.1 in two
      psychotic patients. One of the genes in this region is the gene encoding glycine
      decarboxylase (GLDC), which affects brain glycine metabolism. GLDC encodes the glycine
      decarboxylase or glycine cleavage system P-protein, which is involved in degradation of
      glycine in glia cells. Carriers of the GLDC triplication would be expected to have low levels
      of brain Gly, resulting in NMDA receptor-mediated hypofunction, which has been strongly
      implicated in the pathophysiology of schizophrenia (Olney & Farber, 1995; Coyle, 2006;
      Javitt, 2007).

      There is an extensive literature on the effects of NMDA enhancing agents on positive,
      negative, and depressive symptoms and on neurocognitive function (see Tsai & Lin, 2010; Lin
      et al. 2011 for reviews). Although many studies have reported positive results in at least
      one symptom domain (Heresco-Levy et al. 1996, 1999, 2004; Tsai et al. 1998, 1999, 2004, 2006;
      Javitt et al. 2001; Goff et al. 1996; Lane et al. 2008), the results of other studies have
      been negative or ambiguous (Goff et al. 1999; Evins et al. 2000; Duncan et al. 2004; van
      Berckel et al. 1999). Factors likely to contribute to this variability include: mechanism of
      action of the agent, compliance, concurrent treatment with first- vs second generation
      antipsychotic drugs, baseline glycine blood levels, presence/absence of kynurenine pathway
      metabolic abnormalities (Wonodi et al. 2010; Erhardt et al. 2007) and individual differences
      in brain glycine uptake and metabolism (Kaufman et al. 2009; Buchanan et al. 2007). Genetic
      variants that impact the synthesis and breakdown of glycine, glutamate, or other modulators
      of NMDA receptor function are also likely to have significant effects. Although glycine
      augmentation has shown variable efficacy in patients unselected for having a mutation that
      would be expected to lower brain glycine levels, the GLDC triplication in the two carriers in
      this study would be expected to result in unusually low brain glycine levels, supporting its
      therapeutic potential as an augmentation strategy.

      Thus, it is important to evaluate the therapeutic efficacy of glycine augmentation in
      individuals in whom there is a high prior probability of therapeutic benefit and to
      characterize the neurobiology of this mutation in terms of brain metabolites, brain function,
      and the pharmacokinetics of glycine metabolism using well-established methods (Kaufman et al.
      2009; Prescot et al. 2006; Martinez et al. 2008; Butler et al. 2001; Jensen et al. 2009;
      Ongur et al. 2008).
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Positive and Negative Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks During Intervention 1 (Glycine or Placebo), Intervention 2 (Glycine or Placebo), and During Open-label Glycine
time frame: baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period and after each treatment period
description: Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms are measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.
measure: Neurocognitive Function at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine
time frame: At baseline, during glycine treatment, during placebo treatment and during open-label glycine
description: Scores on each of 8 domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, social cognition, overall composite). Scores are T scores ranging from 0-100, with 50 representing the mean for a population based on a normal distribution; standard deviation of 10. Only overall composite score is entered.
measure: Glycine Plasma Amino Acid Levels at Baseline, During Glycine Treatment, During Placebo Treatment and During Open-label Glycine
time frame: At baseline, during glycine treatment, during placebo treatment and during open-label glycine
description: Plasma glycine levels; normal range is 122-467 nM/mL
measure: Brief Psychiatric Rating Scale (BPRS) Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Positive and Negative Symptom Scores at Baseline and at 2, 4, and 6 Weeks During Intervention 1, Intervention 2, and During Open-label Glycine
time frame: baseline and at 2 weeks, 4 weeks, and 6 weeks within and after each treatment period
description: Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms.
measure: Clinical Global Impression (CGI) Severity Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period
time frame: CGI at baseline and at 2 weeks, 4 weeks, and 6 weeks per treatment period
description: Clinical Global Impression (CGI) severity scores measure severity of mental illness on a scale of 1-7 where 1 means normal, not at all ill, 2 means borderline mentally ill, 3 means mildly ill, 4 means moderately ill, 5 means markedly ill, 6 means severely ill and 7 means among the most extremely ill patients.
measure: Clinical Global Impression (CGI) Therapeutic Effect Scores at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period
time frame: at 2 weeks, 4 weeks, and 6 weeks within each treatment period
description: Clinical Global Impression (CGI) therapeutic effect scores measure degree of improvement as marked (1), moderate (5), minimal (9) or unchanged/worse (13).
measure: Mania Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period
time frame: baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period
description: Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of ratings for 7 symptoms of mania is measured on a scale from 0-4 and the sum of 4 symptoms of mania is measured on a scale from 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms.
measure: Depression Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks Within Each Treatment Period
time frame: baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period
description: Hamilton Depression Scale measures severity of depression symptoms. The sum of ratings for 9 depression symptoms are measured on a scale from 0-2 with 0 meaning no symptoms and 2 meaning some level of severity of that specific symptom. The rating for 1 depression symptom is measured on a scale from 0-3 with 0 meaning no symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms are measured on a scale from 0-4 with 0 meaning no symptoms and 4 meaning a severe level of that specific symptom. The three sums are added to produce an overall depression rating scale score ranging from 0-65.
measure: Brain Glycine/CR Ratio
time frame: baseline (pre-challenge, 60, 80, 100, 120 minutes post-challenge), and week 6 of glycine (pre-dose and 60, 80, 100, 120 minutes post-dose
description: magnetic resonance spectroscopy: glycine/creatine ratio. Participants were assessed at 1) BASELINE PRE-GLYCINE TREATMENT: pre-glycine challenge drink, 60 minutes post challenge drink, 80 minutes post challenge drink, 100 minutes post challenge drink, and 120 minutes post challenge drink (0.4 g/kg up to max of 30 g); and 2) IN WEEK 6 OF OPEN-LABEL GLYCINE TREATMENT: pre-glycine dose, and 60 minutes, 80 minutes, 100 minutes and 120 minutes post daily dose of glycine. Measured in posterior occipital cortex
measure: Brain Glutamate Metabolite Levels (Glutamate/Creatine Ratio: Glu/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT
time frame: baseline and week 6 of glycine
description: magnetic resonance spectroscopy - glutamate metabolite level. Participants were assessed 1) pre-glycine treatment and in week 6 of open-label glycine treatment. Measured in posterior occipital cortex.
measure: Brain GABA Metabolite Levels (GABA/Creatine Ratio: GABA/Cr) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT
time frame: Baseline and week 6 of glycine
description: Magnetic resonance spectroscopy GABA/Cr. Participants were assessed 1) pre-glycine treatment (baseline) and 2) in week 6 of open-label glycine treatment measured in posterior occipital cortex.
measure: Auditory Evoked Potentials in Latency (Msec) at BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF TREATMENT WITH GLYCINE
time frame: Recordings at baseline and week 6 of glycine
description: Auditory evoked potentials latency: P300 at fz, cz, and pz); N100 at fz and cz); P200 at fz and cz. Participants were assessed at baseline and in week of open-label glycine treatment.
measure: Change in Magnocellular Pathway Function on Glycine Compared With Baseline. No Data Were Collected.
time frame: 6 weeks per treatment arm
description: functional magnetic resonance imaging
measure: Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT
time frame: Recordings at baseline and week 6 of glycine
description: Auditory evoked potentials amplitude: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz; P50 S1 and S2 amplitude; mismatch negativity (MMN) at fz and cz. Participants were assessed at baseline and in week 6 of open-label glycine treatment.
measure: Auditory Evoked Potentials in Gammas Oscillations (the Power Spectrum is Measured in Microvolts Squared) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT
time frame: Recordings at baseline and week 6 of glycine
description: Auditory evoked potentials gamma: G40 hz phase locking at fz and cz; G20 hz phase locking response at fz and cz G30 hz phase locking response at fz and cz. Participants were assessed at baseline and in week 6 of open-label glycine treatment.
measure: Auditory Evoked Potentials - P50 Ratio (P50 S2/P50 S1 Amplitude) at 1) BASELINE - Pre-glycine Treatment and 2) IN WEEK 6 OF GLYCINE TREATMENT
time frame: Recordings at baseline and week 6 of glycine
description: Auditory evoked potentials amplitude: P50 ratio (S2/S1). Participants were assessed at baseline and in week 6 of open-label glycine treatment.
arm group label: glycine
arm group type: Active Comparator
description: Glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks Double-blind
arm group label: Placebo
arm group type: Placebo Comparator
description: placebo, TID dosing, 6 weeks Double-blind
arm group label: glycine, open-label
arm group type: Active Comparator
description: glycine, up to 0.8 g/kg, administered with TID dosing for 6 weeks
intervention type: Drug
intervention name: Glycine
description: Double-blind placebo controlled trial of glycine or placebo, followed by open-label glycine
arm group label: glycine
arm group label: glycine, open-label
intervention type: Drug
intervention name: placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Deborah L Levy, PhD
role: Principal Investigator
affiliation: Mclean Hospital
facility: 
country: United States
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PMID: 20147364
responsible party type: Principal Investigator
investigator affiliation: Mclean Hospital
investigator full name: Deborah L. Levy
investigator title: Associate Professor
mesh term: Bipolar Disorder
mesh term: Mood Disorders
mesh term: Psychotic Disorders
mesh term: Glycine
sharing ipd: No
provided document: 
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 