<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/NCT03004443</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00090667</org_study_id>
    <secondary_id>1R01MH112076-01</secondary_id>
    <nct_id>NCT03004443</nct_id>
  </id_info>
  <brief_title>Inflammation-Induced CNS Glutamate Changes in Depression</brief_title>
  <official_title>Inflammation-Induced CNS Glutamate Changes in Depression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Emory University</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>Emory University</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>
      Increased inflammation has been implicated in the pathophysiology of a number of&#xD;
      neuropsychiatric illnesses including mood disorders, which affect almost 30 million adults in&#xD;
      the United States alone. One mechanism by which inflammation may alter behavior is through&#xD;
      increasing brain glutamate, a neurotransmitter that in excess has been implicated in neuronal&#xD;
      toxicity and resistance to conventional antidepressant therapy. The goal of the proposed&#xD;
      research is to test the hypothesis that inflammation alters behavior through increasing&#xD;
      glutamate in specific brain regions, ultimately leading to behavioral changes.&#xD;
&#xD;
      The proposed research is designed to determine the cause and effect relationship between&#xD;
      inflammation and CNS glutamate as well as the relationship between CNS glutamate and specific&#xD;
      symptoms. To accomplish these aims, investigators will administer a single infusion of either&#xD;
      the tumor necrosis factor (TNF) antagonist infliximab or placebo (n=30 per group) to patients&#xD;
      with high inflammation (CRP&gt;3mg/L). A CRP&gt;3mg/L was chosen because it is considered high&#xD;
      inflammation according to guidelines by the American Heart Association. Moreover, a CRP&gt;3mg/L&#xD;
      is associated with significantly increased basal ganglia glutamate and with a clinical&#xD;
      response to infliximab. Inflammatory biomarkers, basal ganglia glutamate as measured by MRS,&#xD;
      and motivation and psychomotor activity will be assessed at baseline and days 1 and 3 and&#xD;
      weeks 1 and 2 following infliximab or placebo administration.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study aims to test the hypothesis that increased inflammation causes increased basal&#xD;
      ganglia glutamate and consequently anhedonia and psychomotor retardation in patients with&#xD;
      major depressive disorder (MDD). Excessive inflammation and glutamate excitotoxicity are two&#xD;
      pathways that have received increasing attention regarding the pathophysiology of&#xD;
      neuropsychiatric disease including mood disorders. Patients with depression exhibit increased&#xD;
      peripheral and central nervous system (CNS) markers of inflammation as well as altered CNS&#xD;
      glutamate as measured by magnetic resonance spectroscopy (MRS). In addition, drugs that block&#xD;
      either inflammation or glutamate signaling can reverse depressive symptoms, especially in&#xD;
      depressed patients with treatment resistance.&#xD;
&#xD;
      Inflammatory cytokines are known to inhibit glutamate reuptake and increase glutamate release&#xD;
      from astrocytes, and glutamate antagonists have been shown to block inflammation-induced&#xD;
      depressive-like behavior in mice. Moreover, using MRS, data has shown that administration of&#xD;
      the inflammatory cytokine interferon (IFN)-alpha significantly increases glutamate in the&#xD;
      basal ganglia in association with IFN-alpha-induced anhedonia and psychomotor slowing. In&#xD;
      addition, increased inflammation as reflected by peripheral blood C-reactive protein (CRP) is&#xD;
      correlated with increased basal ganglia glutamate in association with decreased motivation&#xD;
      and psychomotor speed in patients with MDD. Nevertheless, the data to date has been&#xD;
      correlational, and whether increased inflammation causes increased glutamate in the basal&#xD;
      ganglia, which in turn contributes to behavioral changes in patients with depression has not&#xD;
      been established.&#xD;
&#xD;
      To test this hypothesis, investigators plan to determine the cause and effect relationship&#xD;
      between increased inflammation and increased CNS glutamate by blocking inflammation in&#xD;
      depressed patients with high inflammation (CRP&gt;3mg/L) using the highly specific tumor&#xD;
      necrosis factor (TNF) antagonist infliximab (n=30) versus placebo (n=30). In addition, the&#xD;
      study team will examine whether changes in basal ganglia glutamate are linked to changes in&#xD;
      behaviors related to the basal ganglia including anhedonia and psychomotor retardation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    The study was suspended in March 2020 due to the COVID-19 pandemic and ultimately was&#xD;
    terminated as it is not safe to test a potent anti-inflammatory drug with ongoing surges of&#xD;
    COVID-19.&#xD;
  </why_stopped>
  <start_date type="Actual">May 15, 2017</start_date>
  <completion_date type="Actual">November 27, 2019</completion_date>
  <primary_completion_date type="Actual">November 27, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Central Nervous System (CNS) Glutamate</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>Left basal ganglia glutamate was measured by magnetic resonance spectroscopy (MRS). Left basal ganglia glutamate tends to be increased during inflammation and is also associated with an increase in depressive symptoms.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Snaith-Hamilton Pleasure Scale - Clinician Administered (SHAPS-C) Score</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>The SHAPS-C is a 14-item, clinician-administered instrument assessing pleasure response/hedonic experience. Responses are scored as 1 = lots of pleasure, 2 = average/usual pleasure, 3 = some pleasure, and 4 = no pleasure. Total scores range from 14 to 56 where higher scores indicate increasing severity of anhedonia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mood and Pleasure Scale - Self Report (MAP-SR) Score</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>The Mood and Pleasure Scale is an 18-item self-report inventory that was created to disentangle state-wise motivational and consummatory components of everyday activities over a 24-hour period. Responses are given on a 5-point Likert scale where 0 = no pleasure/not at all and 4 = extreme pleasure/very often. Total scores range from 0 to 72 and higher scores indicate greater motivation and pleasure during everyday activities.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Finger Tapping Task (FTT) Score</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>The FTT uses a specially adapted tapper that the participant taps as fast as possible using the index finger. The participant is given 5 consecutive 10-second trials for the dominant hands. The finger tapping score is the mean of 5 trials. The FTT is designed to assess subtle motor impairment and is altered in subjects with basal ganglia disorders and lesions. A lower score indicates motor impairment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Digit Symbol Substitution Task (DSST) Score</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>The DSST is a subtest of the Wechsler Adult Intelligence Scale (WAIS) and consists of rows of blank squares, each printed with a randomly assigned number. The test involves graphimotor speed, visual scanning and memory, with about half of the variance being accounted for by graphimotor speed, a third by visual scanning and 4-5% by memory. Performance on the DSST has been found to correlate with subcortical atrophy in disorders involving basal ganglia.The DSST is scored as the number of correct responses in 120 seconds, with higher scores indicating better performance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trails Making Test A (TMT-A) Score</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>The scale measures cognitive processing speed using a series of non-sequentially arranged numbers where the participant is asked to sequentially track the numbers occurring to numerical order as quickly as possible. The score is the time time it takes to complete the task, measured in seconds. A longer time to finish may indicate cognitive impairment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Multidimensional Fatigue Inventory (MFI) Score</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to measure motivation and fatigue, covering the dimensions of General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation and Reduced Activity. Participants respond to fatigue related statements using a 5-point scale where 1 = &quot;yes, that is true&quot; and 5 = &quot;no, that is not true&quot;. Total scores range from 20 to 100 and higher scores indicate greater fatigue.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inventory of Depressive Symptoms-Clinician Rating (IDS-SR) Score</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>The Inventory of Depressive Symptomatology-Self-Report (IDS-SR) is a 30-item self-report instrument designed to measure symptom constructs consistent with current Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology and that has been widely used as a self-report outcome measure of depression. Participants complete 28 of the 30 items, depending on if they experienced an increase or decrease in appetite and weight. Each item is scored on a 4-point scale where 0 means that the symptom is absent and 3 means that the symptom is very strongly felt. Total scores can range between 0 and 84 and higher scores indicate more severe symptoms of depression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma C Reactive Protein (CRP)</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>This study is collecting blood samples to assess inflammatory markers. CRP increases when inflammation is present. Changes in plasma CRP will be compared between study arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Tumor Necrosis Factor (TNF)-α</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>This study is collecting blood samples to assess inflammatory markers. TNF-α is elevated in patients experiencing inflammation and a decrease in serum TNF-α is an indication of effective treatment. Changes in plasma TNF-α will be compared between study arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma TNF Receptor 2 (TNFR2)</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>This study is collecting blood samples to assess inflammatory markers. Changes in plasma TNFR2 will be compared between study arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Interleukin (IL)-1ra</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>This study is collecting blood samples to assess inflammatory markers. Changes in plasma IL-1ra will be compared between study arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma IL-6</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>This study is collecting blood samples to assess inflammatory markers. IL-6 is a proinflammatory cytokine that is elevated during times of inflammation, infection, illness, and in patients with mood disorders. IL-6 is not present or is low in healthy individuals and exact reference ranges vary by lab, with an example normal reference range of 0.31 to 5.00 picograms per milliliter (pg/mL). Changes in plasma IL-6 will be compared between study arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Soluble IL-6 Receptor (sIL-6R)</measure>
    <time_frame>Baseline, Day 3, Week 2</time_frame>
    <description>This study is collecting blood samples to assess inflammatory markers. Changes in plasma sIL-6R will be compared between study arms.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Depression</condition>
  <arm_group>
    <arm_group_label>Infliximab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be randomized to receive one intravenous (IV) infusion of infliximab.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will be randomized to receive one intravenous (IV) infusion of placebo.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Infliximab</intervention_name>
    <description>Infliximab will be administered intravenously (IV) as 5 mg/kg body weight over a 2 to 2.5 hour period.</description>
    <arm_group_label>Infliximab</arm_group_label>
    <other_name>Remicade</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Saline solution will be administered intravenously over a 2 to 2.5 hour period.</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Saline solution</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Willing and able to give written informed consent&#xD;
&#xD;
          -  Primary diagnosis of the Diagnostic and Statistical Manual of Mental Disorders, Fifth&#xD;
             Edition (DSM-V) MDD, current, or Bipolar, depressed type as diagnosed by the SCID-V&#xD;
&#xD;
          -  Score of ≥14 on the Quick Inventory of Depressive Symptomatology (QIDS-SR-16) or score&#xD;
             ≥ 15 on the Patient Health Questionnaire 9 item (PHQ-9)&#xD;
&#xD;
          -  Absence of significant suicidal ideation defined using the Columbia Suicide Severity&#xD;
             Rating Scale - Screen Version (CSSRS)&#xD;
&#xD;
          -  Off all antidepressant or other psychotropic therapy (e.g. mood stabilizers,&#xD;
             antipsychotics, anxiolytics, and sedative hypnotics) for at least 4 weeks prior to the&#xD;
             baseline visit (8 weeks for fluoxetine). No patients will be removed from their&#xD;
             psychotropic medications for the sole purpose of participating in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Autoimmune disorder (as confirmed by laboratory testing)&#xD;
&#xD;
          -  History of tuberculosis (by history or as discovered by chest X-ray, skin testing or&#xD;
             blood testing) or high risk of tuberculosis exposure&#xD;
&#xD;
          -  Hepatitis B or C infection or human immunodeficiency virus infection (as established&#xD;
             by laboratory testing)&#xD;
&#xD;
          -  History of fungal infection&#xD;
&#xD;
          -  History of recurrent viral or bacterial infections&#xD;
&#xD;
          -  History of any type of cancer&#xD;
&#xD;
          -  Unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic&#xD;
             disease (as determined by physical examination and laboratory testing)&#xD;
&#xD;
          -  History of any (non-mood-related) psychotic disorder; active psychotic symptoms of any&#xD;
             type; antisocial personality disorder as determined by a clinician; substance&#xD;
             abuse/dependence within 6 months of study entry (as determined by SCID)&#xD;
&#xD;
          -  Active suicidal plan as determined by a score &gt;3 on item #3 on the Hamilton Depression&#xD;
             Rating Scale (HAM-D)&#xD;
&#xD;
          -  Active eating disorder&#xD;
&#xD;
          -  History of a cognitive disorder or ≤28 on the Mini-Mental State Exam&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Women of child bearing potential who are not using a medically accepted means of&#xD;
             contraception&#xD;
&#xD;
          -  Heterosexual males and their partners who do not agree to practice appropriate birth&#xD;
             control&#xD;
&#xD;
          -  Known allergy to murine products or other biologic therapies&#xD;
&#xD;
          -  Chronic use of non-steroidal anti-inflammatory agents (NSAIDS), glucocorticoid&#xD;
             containing medications or statins&#xD;
&#xD;
          -  Use of NSAIDS, glucocorticoids, or statins at any time during the study&#xD;
&#xD;
          -  Contraindication to MRI&#xD;
&#xD;
          -  Previous organ transplant&#xD;
&#xD;
          -  History of CNS trauma or active seizure disorder&#xD;
&#xD;
          -  Highly treatment resistant depressed patients who score &gt;5 on the Massachusetts&#xD;
             General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ) for&#xD;
             current episode&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Andrew H Miller, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Emory University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ebrahim Haroon, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Emory University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Emory University</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>December 8, 2016</study_first_submitted>
  <study_first_submitted_qc>December 27, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 28, 2016</study_first_posted>
  <results_first_submitted>May 10, 2023</results_first_submitted>
  <results_first_submitted_qc>May 10, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">June 7, 2023</results_first_posted>
  <last_update_submitted>July 2, 2023</last_update_submitted>
  <last_update_submitted_qc>July 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 17, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Emory University</investigator_affiliation>
    <investigator_full_name>Andrew H Miller</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Psychiatry</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Inflammation</mesh_term>
    <mesh_term>Depression</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infliximab</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 14, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/43/NCT03004443/Prot_SAP_001.pdf</document_url>
    </provided_document>
    <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>October 23, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/43/NCT03004443/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were recruited from Emory University Hospitals and Clinics in Atlanta, Georgia, USA. Participant enrollment began May 15, 2017 and the final follow-up assessment occurred November 27, 2019. The study was suspended in March 2020 during the coronavirus disease 2019 (COVID-19) pandemic. Due to the intervention being an immune suppressant it was not safe to reopen the study to enrollment and the decision was made to terminate the study in March 2023.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Infliximab</title>
          <description>Participants randomized to receive one intravenous (IV) infusion of infliximab.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Participants will be randomized to receive one intravenous (IV) infusion of placebo.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Pregnancy</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Infliximab</title>
          <description>Participants randomized to receive one intravenous (IV) infusion of infliximab.</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Participants will be randomized to receive one intravenous (IV) infusion of placebo.</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="11"/>
            <count group_id="B2" value="11"/>
            <count group_id="B3" value="22"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="44.6" spread="12.8"/>
                    <measurement group_id="B2" value="33.3" spread="9.9"/>
                    <measurement group_id="B3" value="38.6" spread="12.54"/>
                  </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="9"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </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="4"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="11"/>
                  </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="11"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Central Nervous System (CNS) Glutamate</title>
        <description>Left basal ganglia glutamate was measured by magnetic resonance spectroscopy (MRS). Left basal ganglia glutamate tends to be increased during inflammation and is also associated with an increase in depressive symptoms.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <population>Eleven distinct participants in the placebo study arm were examined at least one time point but some had a poor signal scan resulting in non-usable data. One participant in the placebo study arm was removed from the study following the baseline assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Infliximab</title>
            <description>Participants randomized to receive one intravenous (IV) infusion of infliximab.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants will be randomized to receive one intravenous (IV) infusion of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Central Nervous System (CNS) Glutamate</title>
          <description>Left basal ganglia glutamate was measured by magnetic resonance spectroscopy (MRS). Left basal ganglia glutamate tends to be increased during inflammation and is also associated with an increase in depressive symptoms.</description>
          <population>Eleven distinct participants in the placebo study arm were examined at least one time point but some had a poor signal scan resulting in non-usable data. One participant in the placebo study arm was removed from the study following the baseline assessment.</population>
          <units>mmol/kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.71" spread="0.69"/>
                    <measurement group_id="O2" value="6.73" spread="0.64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.19" spread="0.93"/>
                    <measurement group_id="O2" value="7.81" spread="0.56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.41" spread="0.74"/>
                    <measurement group_id="O2" value="7.17" spread="0.59"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Snaith-Hamilton Pleasure Scale - Clinician Administered (SHAPS-C) Score</title>
        <description>The SHAPS-C is a 14-item, clinician-administered instrument assessing pleasure response/hedonic experience. Responses are scored as 1 = lots of pleasure, 2 = average/usual pleasure, 3 = some pleasure, and 4 = no pleasure. Total scores range from 14 to 56 where higher scores indicate increasing severity of anhedonia.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <population>One participant in the placebo study arm was removed from the study following the baseline assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Infliximab</title>
            <description>Participants randomized to receive one intravenous (IV) infusion of infliximab.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants will be randomized to receive one intravenous (IV) infusion of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Snaith-Hamilton Pleasure Scale - Clinician Administered (SHAPS-C) Score</title>
          <description>The SHAPS-C is a 14-item, clinician-administered instrument assessing pleasure response/hedonic experience. Responses are scored as 1 = lots of pleasure, 2 = average/usual pleasure, 3 = some pleasure, and 4 = no pleasure. Total scores range from 14 to 56 where higher scores indicate increasing severity of anhedonia.</description>
          <population>One participant in the placebo study arm was removed from the study following the baseline assessment.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.9" spread="8.2"/>
                    <measurement group_id="O2" value="41.7" spread="6.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.2" spread="9.4"/>
                    <measurement group_id="O2" value="39.1" spread="7.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32.9" spread="10.9"/>
                    <measurement group_id="O2" value="41.0" spread="6.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mood and Pleasure Scale - Self Report (MAP-SR) Score</title>
        <description>The Mood and Pleasure Scale is an 18-item self-report inventory that was created to disentangle state-wise motivational and consummatory components of everyday activities over a 24-hour period. Responses are given on a 5-point Likert scale where 0 = no pleasure/not at all and 4 = extreme pleasure/very often. Total scores range from 0 to 72 and higher scores indicate greater motivation and pleasure during everyday activities.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <population>One participant in the infliximab study arm did not complete this assessment at the Day 3 time point. One participant in the placebo study arm was removed from the study following the baseline assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Infliximab</title>
            <description>Participants randomized to receive one intravenous (IV) infusion of infliximab.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants will be randomized to receive one intravenous (IV) infusion of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Mood and Pleasure Scale - Self Report (MAP-SR) Score</title>
          <description>The Mood and Pleasure Scale is an 18-item self-report inventory that was created to disentangle state-wise motivational and consummatory components of everyday activities over a 24-hour period. Responses are given on a 5-point Likert scale where 0 = no pleasure/not at all and 4 = extreme pleasure/very often. Total scores range from 0 to 72 and higher scores indicate greater motivation and pleasure during everyday activities.</description>
          <population>One participant in the infliximab study arm did not complete this assessment at the Day 3 time point. One participant in the placebo study arm was removed from the study following the baseline assessment.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29.3" spread="3.9"/>
                    <measurement group_id="O2" value="23.4" spread="11.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29.4" spread="8.5"/>
                    <measurement group_id="O2" value="23.6" spread="9.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30.8" spread="9.6"/>
                    <measurement group_id="O2" value="22.6" spread="10.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Finger Tapping Task (FTT) Score</title>
        <description>The FTT uses a specially adapted tapper that the participant taps as fast as possible using the index finger. The participant is given 5 consecutive 10-second trials for the dominant hands. The finger tapping score is the mean of 5 trials. The FTT is designed to assess subtle motor impairment and is altered in subjects with basal ganglia disorders and lesions. A lower score indicates motor impairment.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <population>One participant in the placebo study arm was removed from the study following the baseline assessment. Some participants did not complete this assessment at the indicated study visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Infliximab</title>
            <description>Participants randomized to receive one intravenous (IV) infusion of infliximab.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants will be randomized to receive one intravenous (IV) infusion of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Finger Tapping Task (FTT) Score</title>
          <description>The FTT uses a specially adapted tapper that the participant taps as fast as possible using the index finger. The participant is given 5 consecutive 10-second trials for the dominant hands. The finger tapping score is the mean of 5 trials. The FTT is designed to assess subtle motor impairment and is altered in subjects with basal ganglia disorders and lesions. A lower score indicates motor impairment.</description>
          <population>One participant in the placebo study arm was removed from the study following the baseline assessment. Some participants did not complete this assessment at the indicated study visits.</population>
          <units>number of taps</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="47.0" spread="7.8"/>
                    <measurement group_id="O2" value="42.4" spread="8.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="48.4" spread="7.2"/>
                    <measurement group_id="O2" value="46.0" spread="9.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="46.1" spread="5.7"/>
                    <measurement group_id="O2" value="46.7" spread="8.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Digit Symbol Substitution Task (DSST) Score</title>
        <description>The DSST is a subtest of the Wechsler Adult Intelligence Scale (WAIS) and consists of rows of blank squares, each printed with a randomly assigned number. The test involves graphimotor speed, visual scanning and memory, with about half of the variance being accounted for by graphimotor speed, a third by visual scanning and 4-5% by memory. Performance on the DSST has been found to correlate with subcortical atrophy in disorders involving basal ganglia.The DSST is scored as the number of correct responses in 120 seconds, with higher scores indicating better performance.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <population>One participant in the placebo study arm was removed from the study following the baseline assessment. Some participants did not complete this assessment at the indicated study visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Infliximab</title>
            <description>Participants randomized to receive one intravenous (IV) infusion of infliximab.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants will be randomized to receive one intravenous (IV) infusion of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Digit Symbol Substitution Task (DSST) Score</title>
          <description>The DSST is a subtest of the Wechsler Adult Intelligence Scale (WAIS) and consists of rows of blank squares, each printed with a randomly assigned number. The test involves graphimotor speed, visual scanning and memory, with about half of the variance being accounted for by graphimotor speed, a third by visual scanning and 4-5% by memory. Performance on the DSST has been found to correlate with subcortical atrophy in disorders involving basal ganglia.The DSST is scored as the number of correct responses in 120 seconds, with higher scores indicating better performance.</description>
          <population>One participant in the placebo study arm was removed from the study following the baseline assessment. Some participants did not complete this assessment at the indicated study visits.</population>
          <units>correct responses</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="55.5" spread="15.0"/>
                    <measurement group_id="O2" value="60.0" spread="16.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="63.8" spread="16.4"/>
                    <measurement group_id="O2" value="67.9" spread="21.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="64.2" spread="17.4"/>
                    <measurement group_id="O2" value="62.9" spread="15.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Trails Making Test A (TMT-A) Score</title>
        <description>The scale measures cognitive processing speed using a series of non-sequentially arranged numbers where the participant is asked to sequentially track the numbers occurring to numerical order as quickly as possible. The score is the time time it takes to complete the task, measured in seconds. A longer time to finish may indicate cognitive impairment.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <population>One participant in the placebo study arm was removed from the study following the baseline assessment. Some participants did not complete this assessment at the indicated study visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Infliximab</title>
            <description>Participants randomized to receive one intravenous (IV) infusion of infliximab.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants will be randomized to receive one intravenous (IV) infusion of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Trails Making Test A (TMT-A) Score</title>
          <description>The scale measures cognitive processing speed using a series of non-sequentially arranged numbers where the participant is asked to sequentially track the numbers occurring to numerical order as quickly as possible. The score is the time time it takes to complete the task, measured in seconds. A longer time to finish may indicate cognitive impairment.</description>
          <population>One participant in the placebo study arm was removed from the study following the baseline assessment. Some participants did not complete this assessment at the indicated study visits.</population>
          <units>seconds</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="28.4" spread="7.6"/>
                    <measurement group_id="O2" value="24.9" spread="7.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23.5" spread="8.0"/>
                    <measurement group_id="O2" value="22.4" spread="8.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.4" spread="3.6"/>
                    <measurement group_id="O2" value="20.9" spread="7.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Multidimensional Fatigue Inventory (MFI) Score</title>
        <description>The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to measure motivation and fatigue, covering the dimensions of General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation and Reduced Activity. Participants respond to fatigue related statements using a 5-point scale where 1 = &quot;yes, that is true&quot; and 5 = &quot;no, that is not true&quot;. Total scores range from 20 to 100 and higher scores indicate greater fatigue.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <population>One participant in the placebo study arm was removed from the study following the baseline assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Infliximab</title>
            <description>Participants randomized to receive one intravenous (IV) infusion of infliximab.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants will be randomized to receive one intravenous (IV) infusion of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Multidimensional Fatigue Inventory (MFI) Score</title>
          <description>The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to measure motivation and fatigue, covering the dimensions of General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation and Reduced Activity. Participants respond to fatigue related statements using a 5-point scale where 1 = &quot;yes, that is true&quot; and 5 = &quot;no, that is not true&quot;. Total scores range from 20 to 100 and higher scores indicate greater fatigue.</description>
          <population>One participant in the placebo study arm was removed from the study following the baseline assessment.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="77.3" spread="11.8"/>
                    <measurement group_id="O2" value="75.8" spread="11.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="71.4" spread="14.4"/>
                    <measurement group_id="O2" value="72.8" spread="16.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="72.3" spread="15.1"/>
                    <measurement group_id="O2" value="71.6" spread="16.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Inventory of Depressive Symptoms-Clinician Rating (IDS-SR) Score</title>
        <description>The Inventory of Depressive Symptomatology-Self-Report (IDS-SR) is a 30-item self-report instrument designed to measure symptom constructs consistent with current Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology and that has been widely used as a self-report outcome measure of depression. Participants complete 28 of the 30 items, depending on if they experienced an increase or decrease in appetite and weight. Each item is scored on a 4-point scale where 0 means that the symptom is absent and 3 means that the symptom is very strongly felt. Total scores can range between 0 and 84 and higher scores indicate more severe symptoms of depression.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <population>One participant in the placebo study arm was removed from the study following the baseline assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Infliximab</title>
            <description>Participants randomized to receive one intravenous (IV) infusion of infliximab.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants will be randomized to receive one intravenous (IV) infusion of placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Inventory of Depressive Symptoms-Clinician Rating (IDS-SR) Score</title>
          <description>The Inventory of Depressive Symptomatology-Self-Report (IDS-SR) is a 30-item self-report instrument designed to measure symptom constructs consistent with current Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology and that has been widely used as a self-report outcome measure of depression. Participants complete 28 of the 30 items, depending on if they experienced an increase or decrease in appetite and weight. Each item is scored on a 4-point scale where 0 means that the symptom is absent and 3 means that the symptom is very strongly felt. Total scores can range between 0 and 84 and higher scores indicate more severe symptoms of depression.</description>
          <population>One participant in the placebo study arm was removed from the study following the baseline assessment.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30.7" spread="8.2"/>
                    <measurement group_id="O2" value="39.7" spread="14.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.4" spread="12.6"/>
                    <measurement group_id="O2" value="32.6" spread="14.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                    <count group_id="O2" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23.5" spread="10.9"/>
                    <measurement group_id="O2" value="32.7" spread="12.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma C Reactive Protein (CRP)</title>
        <description>This study is collecting blood samples to assess inflammatory markers. CRP increases when inflammation is present. Changes in plasma CRP will be compared between study arms.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <posting_date>08/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Tumor Necrosis Factor (TNF)-α</title>
        <description>This study is collecting blood samples to assess inflammatory markers. TNF-α is elevated in patients experiencing inflammation and a decrease in serum TNF-α is an indication of effective treatment. Changes in plasma TNF-α will be compared between study arms.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <posting_date>08/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma TNF Receptor 2 (TNFR2)</title>
        <description>This study is collecting blood samples to assess inflammatory markers. Changes in plasma TNFR2 will be compared between study arms.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <posting_date>08/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Interleukin (IL)-1ra</title>
        <description>This study is collecting blood samples to assess inflammatory markers. Changes in plasma IL-1ra will be compared between study arms.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <posting_date>08/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma IL-6</title>
        <description>This study is collecting blood samples to assess inflammatory markers. IL-6 is a proinflammatory cytokine that is elevated during times of inflammation, infection, illness, and in patients with mood disorders. IL-6 is not present or is low in healthy individuals and exact reference ranges vary by lab, with an example normal reference range of 0.31 to 5.00 picograms per milliliter (pg/mL). Changes in plasma IL-6 will be compared between study arms.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <posting_date>08/2023</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Soluble IL-6 Receptor (sIL-6R)</title>
        <description>This study is collecting blood samples to assess inflammatory markers. Changes in plasma sIL-6R will be compared between study arms.</description>
        <time_frame>Baseline, Day 3, Week 2</time_frame>
        <posting_date>08/2023</posting_date>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Information on adverse events was collected beginning at the baseline assessment and continued through the final assessment at Week 2.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Infliximab</title>
          <description>Participants randomized to receive one intravenous (IV) infusion of infliximab.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Participants will be randomized to receive one intravenous (IV) infusion of placebo.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <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="11"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Product Issues</title>
            <event_list>
              <event>
                <sub_title>Serotonin syndrome after study completion and after receiving escitalopram</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>Andrew H. Miller, MD</name_or_title>
      <organization>Emory University</organization>
      <phone>404-727-8260</phone>
      <email>amill02@emory.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/NCT03004443
org study id: IRB00090667
secondary id: 1R01MH112076-01
nct id: NCT03004443
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Increased inflammation has been implicated in the pathophysiology of a number of
      neuropsychiatric illnesses including mood disorders, which affect almost 30 million adults in
      the United States alone. One mechanism by which inflammation may alter behavior is through
      increasing brain glutamate, a neurotransmitter that in excess has been implicated in neuronal
      toxicity and resistance to conventional antidepressant therapy. The goal of the proposed
      research is to test the hypothesis that inflammation alters behavior through increasing
      glutamate in specific brain regions, ultimately leading to behavioral changes.

      The proposed research is designed to determine the cause and effect relationship between
      inflammation and CNS glutamate as well as the relationship between CNS glutamate and specific
      symptoms. To accomplish these aims, investigators will administer a single infusion of either
      the tumor necrosis factor (TNF) antagonist infliximab or placebo (n=30 per group) to patients
      with high inflammation (CRP>3mg/L). A CRP>3mg/L was chosen because it is considered high
      inflammation according to guidelines by the American Heart Association. Moreover, a CRP>3mg/L
      is associated with significantly increased basal ganglia glutamate and with a clinical
      response to infliximab. Inflammatory biomarkers, basal ganglia glutamate as measured by MRS,
      and motivation and psychomotor activity will be assessed at baseline and days 1 and 3 and
      weeks 1 and 2 following infliximab or placebo administration.
This study aims to test the hypothesis that increased inflammation causes increased basal
      ganglia glutamate and consequently anhedonia and psychomotor retardation in patients with
      major depressive disorder (MDD). Excessive inflammation and glutamate excitotoxicity are two
      pathways that have received increasing attention regarding the pathophysiology of
      neuropsychiatric disease including mood disorders. Patients with depression exhibit increased
      peripheral and central nervous system (CNS) markers of inflammation as well as altered CNS
      glutamate as measured by magnetic resonance spectroscopy (MRS). In addition, drugs that block
      either inflammation or glutamate signaling can reverse depressive symptoms, especially in
      depressed patients with treatment resistance.

      Inflammatory cytokines are known to inhibit glutamate reuptake and increase glutamate release
      from astrocytes, and glutamate antagonists have been shown to block inflammation-induced
      depressive-like behavior in mice. Moreover, using MRS, data has shown that administration of
      the inflammatory cytokine interferon (IFN)-alpha significantly increases glutamate in the
      basal ganglia in association with IFN-alpha-induced anhedonia and psychomotor slowing. In
      addition, increased inflammation as reflected by peripheral blood C-reactive protein (CRP) is
      correlated with increased basal ganglia glutamate in association with decreased motivation
      and psychomotor speed in patients with MDD. Nevertheless, the data to date has been
      correlational, and whether increased inflammation causes increased glutamate in the basal
      ganglia, which in turn contributes to behavioral changes in patients with depression has not
      been established.

      To test this hypothesis, investigators plan to determine the cause and effect relationship
      between increased inflammation and increased CNS glutamate by blocking inflammation in
      depressed patients with high inflammation (CRP>3mg/L) using the highly specific tumor
      necrosis factor (TNF) antagonist infliximab (n=30) versus placebo (n=30). In addition, the
      study team will examine whether changes in basal ganglia glutamate are linked to changes in
      behaviors related to the basal ganglia including anhedonia and psychomotor retardation.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Central Nervous System (CNS) Glutamate
time frame: Baseline, Day 3, Week 2
description: Left basal ganglia glutamate was measured by magnetic resonance spectroscopy (MRS). Left basal ganglia glutamate tends to be increased during inflammation and is also associated with an increase in depressive symptoms.
measure: Snaith-Hamilton Pleasure Scale - Clinician Administered (SHAPS-C) Score
time frame: Baseline, Day 3, Week 2
description: The SHAPS-C is a 14-item, clinician-administered instrument assessing pleasure response/hedonic experience. Responses are scored as 1 = lots of pleasure, 2 = average/usual pleasure, 3 = some pleasure, and 4 = no pleasure. Total scores range from 14 to 56 where higher scores indicate increasing severity of anhedonia.
measure: Mood and Pleasure Scale - Self Report (MAP-SR) Score
time frame: Baseline, Day 3, Week 2
description: The Mood and Pleasure Scale is an 18-item self-report inventory that was created to disentangle state-wise motivational and consummatory components of everyday activities over a 24-hour period. Responses are given on a 5-point Likert scale where 0 = no pleasure/not at all and 4 = extreme pleasure/very often. Total scores range from 0 to 72 and higher scores indicate greater motivation and pleasure during everyday activities.
measure: Finger Tapping Task (FTT) Score
time frame: Baseline, Day 3, Week 2
description: The FTT uses a specially adapted tapper that the participant taps as fast as possible using the index finger. The participant is given 5 consecutive 10-second trials for the dominant hands. The finger tapping score is the mean of 5 trials. The FTT is designed to assess subtle motor impairment and is altered in subjects with basal ganglia disorders and lesions. A lower score indicates motor impairment.
measure: Digit Symbol Substitution Task (DSST) Score
time frame: Baseline, Day 3, Week 2
description: The DSST is a subtest of the Wechsler Adult Intelligence Scale (WAIS) and consists of rows of blank squares, each printed with a randomly assigned number. The test involves graphimotor speed, visual scanning and memory, with about half of the variance being accounted for by graphimotor speed, a third by visual scanning and 4-5% by memory. Performance on the DSST has been found to correlate with subcortical atrophy in disorders involving basal ganglia.The DSST is scored as the number of correct responses in 120 seconds, with higher scores indicating better performance.
measure: Trails Making Test A (TMT-A) Score
time frame: Baseline, Day 3, Week 2
description: The scale measures cognitive processing speed using a series of non-sequentially arranged numbers where the participant is asked to sequentially track the numbers occurring to numerical order as quickly as possible. The score is the time time it takes to complete the task, measured in seconds. A longer time to finish may indicate cognitive impairment.
measure: Multidimensional Fatigue Inventory (MFI) Score
time frame: Baseline, Day 3, Week 2
description: The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to measure motivation and fatigue, covering the dimensions of General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation and Reduced Activity. Participants respond to fatigue related statements using a 5-point scale where 1 = "yes, that is true" and 5 = "no, that is not true". Total scores range from 20 to 100 and higher scores indicate greater fatigue.
measure: Inventory of Depressive Symptoms-Clinician Rating (IDS-SR) Score
time frame: Baseline, Day 3, Week 2
description: The Inventory of Depressive Symptomatology-Self-Report (IDS-SR) is a 30-item self-report instrument designed to measure symptom constructs consistent with current Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology and that has been widely used as a self-report outcome measure of depression. Participants complete 28 of the 30 items, depending on if they experienced an increase or decrease in appetite and weight. Each item is scored on a 4-point scale where 0 means that the symptom is absent and 3 means that the symptom is very strongly felt. Total scores can range between 0 and 84 and higher scores indicate more severe symptoms of depression.
measure: Plasma C Reactive Protein (CRP)
time frame: Baseline, Day 3, Week 2
description: This study is collecting blood samples to assess inflammatory markers. CRP increases when inflammation is present. Changes in plasma CRP will be compared between study arms.
measure: Plasma Tumor Necrosis Factor (TNF)-α
time frame: Baseline, Day 3, Week 2
description: This study is collecting blood samples to assess inflammatory markers. TNF-α is elevated in patients experiencing inflammation and a decrease in serum TNF-α is an indication of effective treatment. Changes in plasma TNF-α will be compared between study arms.
measure: Plasma TNF Receptor 2 (TNFR2)
time frame: Baseline, Day 3, Week 2
description: This study is collecting blood samples to assess inflammatory markers. Changes in plasma TNFR2 will be compared between study arms.
measure: Plasma Interleukin (IL)-1ra
time frame: Baseline, Day 3, Week 2
description: This study is collecting blood samples to assess inflammatory markers. Changes in plasma IL-1ra will be compared between study arms.
measure: Plasma IL-6
time frame: Baseline, Day 3, Week 2
description: This study is collecting blood samples to assess inflammatory markers. IL-6 is a proinflammatory cytokine that is elevated during times of inflammation, infection, illness, and in patients with mood disorders. IL-6 is not present or is low in healthy individuals and exact reference ranges vary by lab, with an example normal reference range of 0.31 to 5.00 picograms per milliliter (pg/mL). Changes in plasma IL-6 will be compared between study arms.
measure: Plasma Soluble IL-6 Receptor (sIL-6R)
time frame: Baseline, Day 3, Week 2
description: This study is collecting blood samples to assess inflammatory markers. Changes in plasma sIL-6R will be compared between study arms.
arm group label: Infliximab
arm group type: Experimental
description: Participants will be randomized to receive one intravenous (IV) infusion of infliximab.
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants will be randomized to receive one intravenous (IV) infusion of placebo.
intervention type: Drug
intervention name: Infliximab
description: Infliximab will be administered intravenously (IV) as 5 mg/kg body weight over a 2 to 2.5 hour period.
arm group label: Infliximab
other name: Remicade
intervention type: Drug
intervention name: Placebo
description: Saline solution will be administered intravenously over a 2 to 2.5 hour period.
arm group label: Placebo
other name: Saline solution
criteria: 
gender: All
minimum age: 21 Years
maximum age: 65 Years
healthy volunteers: No
last name: Andrew H Miller, MD
role: Principal Investigator
affiliation: Emory University
last name: Ebrahim Haroon, MD
role: Principal Investigator
affiliation: Emory University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Emory University
investigator full name: Andrew H Miller
investigator title: Professor
mesh term: Inflammation
mesh term: Depression
mesh term: Depressive Disorder
mesh term: Infliximab
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 