Inflammation-Induced CNS Glutamate Changes in Depression
Condition: Depression
MeSH terms: Inflammation; Depression; Depressive Disorder
Intervention: Infliximab; Placebo
Intervention description: Infliximab will be administered intravenously (IV) as 5 mg/kg body weight over a 2 to 2.5 hour period.; Saline solution will be administered intravenously over a 2 to 2.5 hour period.
Intervention MeSH terms: Infliximab
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 22.0
Sex: All
Minimum age: 21 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Psychiatry

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Willing and able to give written informed consent

          -  Primary diagnosis of the Diagnostic and Statistical Manual of Mental Disorders, Fifth
             Edition (DSM-V) MDD, current, or Bipolar, depressed type as diagnosed by the SCID-V

          -  Score of ≥14 on the Quick Inventory of Depressive Symptomatology (QIDS-SR-16) or score
             ≥ 15 on the Patient Health Questionnaire 9 item (PHQ-9)

          -  Absence of significant suicidal ideation defined using the Columbia Suicide Severity
             Rating Scale - Screen Version (CSSRS)

          -  Off all antidepressant or other psychotropic therapy (e.g. mood stabilizers,
             antipsychotics, anxiolytics, and sedative hypnotics) for at least 4 weeks prior to the
             baseline visit (8 weeks for fluoxetine). No patients will be removed from their
             psychotropic medications for the sole purpose of participating in the study.

        Exclusion Criteria:

          -  Autoimmune disorder (as confirmed by laboratory testing)

          -  History of tuberculosis (by history or as discovered by chest X-ray, skin testing or
             blood testing) or high risk of tuberculosis exposure

          -  Hepatitis B or C infection or human immunodeficiency virus infection (as established
             by laboratory testing)

          -  History of fungal infection

          -  History of recurrent viral or bacterial infections

          -  History of any type of cancer

          -  Unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic
             disease (as determined by physical examination and laboratory testing)

          -  History of any (non-mood-related) psychotic disorder; active psychotic symptoms of any
             type; antisocial personality disorder as determined by a clinician; substance
             abuse/dependence within 6 months of study entry (as determined by SCID)

          -  Active suicidal plan as determined by a score >3 on item #3 on the Hamilton Depression
             Rating Scale (HAM-D)

          -  Active eating disorder

          -  History of a cognitive disorder or ≤28 on the Mini-Mental State Exam

          -  Pregnancy or lactation

          -  Women of child bearing potential who are not using a medically accepted means of
             contraception

          -  Heterosexual males and their partners who do not agree to practice appropriate birth
             control

          -  Known allergy to murine products or other biologic therapies

          -  Chronic use of non-steroidal anti-inflammatory agents (NSAIDS), glucocorticoid
             containing medications or statins

          -  Use of NSAIDS, glucocorticoids, or statins at any time during the study

          -  Contraindication to MRI

          -  Previous organ transplant

          -  History of CNS trauma or active seizure disorder

          -  Highly treatment resistant depressed patients who score >5 on the Massachusetts
             General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ) for
             current episode