Antidepressant Effects of the Glycine Receptor Antagonist AV-101 (4-chlorokynurenine) in Major Depressive Disorder
Condition: Major Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Intervention: AV 101 (4-Chlorokynurenine); Placebo Comparator
Intervention description: L-4-chlorokynurenine (4-Cl-KYN) was developed as a prodrug that is rapidly converted in vivo to its active metabolite 7-chlorokynurenic acid (7-Cl-KYNA), a well-characterized N-Methyl-D-aspartate receptor (NMDAR) antagonist at the glycine site.; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Major Depression; Glycine Receptor Antagonist; 4-chlorokynurenine; Treatment Resistant; Glutamatergic System

Summary:

      Background:

      - Drugs and talk therapy help treat depression, but these treatments usually take quite a bit
      of time to work. Ketamine is a fast-acting antidepressant, but it has side effects like
      unusual dreams and experiences. The drug AV-101 may have the same antidepressant effects but
      fewer side effects. Researchers want to see if it is effective and safe for people with major
      depressive disorder.

      Objective:

      - To see if the drug, AV-101 is safe and if it treats symptoms of major depressive disorder.

      Eligibility:

      - Adults ages 18-65 with major depression without psychotic features.

      Design:

        -  Participants will be screened under a separate protocol.

        -  Participants will stay in the hospital for 12-14 weeks.

        -  Phase 1 (2-7 weeks): participants will stop taking their medicines then not take any for
           2 weeks. They will have several scans and other procedures.

        -  Phase 2 (6-7 weeks): 2 weeks each of study drug and placebo once a day, with 2 weeks of
           no drugs in between.

        -  Participants will have:

        -  Physical exams

        -  Interviews

        -  Frequent blood collection. A needle will place a small plastic tube in the arm. Some
           blood samples will be taken through this tube.

        -  2 spinal taps (optional). The back will be numbed. A needle will insert a catheter
           between back bones. That will be left in for up to 30 hours. Spinal fluid will be
           collected through it.

        -  5 scans. Participants will lie in a machine with a magnetic field. The machine takes
           pictures of the brain and brain chemicals.

        -  At the end of the study, participants will have medical evaluation, questions, and blood
           tests. Some may continue treatment at the clinic.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  18 to 65 years of age.

          -  Subjects must have a level of understanding sufficient to agree to all required tests
             and examinations, sign an informed consent document and verify understanding. To
             verify this, subjects must score greater than or equal to 80% on the consent quiz.

          -  Subjects must fulfill Diagnostic and Statistical Manual (DSM)-IV or DSM-V criteria for
             MDD, single episode or recurrent without psychotic features, based on clinical
             assessment and confirmed by a structured diagnostic interview (SCID-P). Subjects must
             be experiencing a current major depressive episode of at least 4 weeks duration.

          -  Subjects must have an initial score of at least 18 on the HDRS at screening and at
             baseline of study phase I.

          -  Subjects must have a current or past history of lack of response to one adequate
             antidepressant trial (may be from the same chemical class) operationally defined using
             the modified-Antidepressant Treatment History Form (ATHF).

        EXCLUSION CRITERIA:

          -  Current psychotic features or a diagnosis of schizophrenia or any other psychotic
             disorder as defined in the DSM-IV or DSM-V.

          -  Subjects with a history of DSM-IV drug or alcohol dependency or abuse (or alcohol use
             disorder per DSM-V),except for caffeine or nicotine dependence within the preceding 3
             months.

          -  Head injury that results in loss of consciousness exceeding 5 minutes (for the imaging
             component of the study).

          -  Subjects with a DSM IV or DSM-V Axis II diagnosis of borderline or antisocial
             personality disorder.

          -  Pregnant or nursing women or women of child bearing potential not using at least 1
             medically accepted means of contraception from the time of enrollment in the study
             until 1 month after completion of the second phase. Examples of medically accepted
             means of contraception include oral, injectable, or implant birth control, condom,
             diaphragm with spermicide, intrauterine devices (IUD), tubal ligation, abstinence or
             partner with vasectomy. .

          -  Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory,
             cardiovascular (including ischemic heart disease), endocrinologic, neurologic,
             immunologic, or hematologic disease.

          -  Subjects with clinical hyperthyroidism or hypothyroidism.

          -  Subjects with one or more seizures without a clear and resolved etiology.

          -  Clinically significant abnormal laboratory tests.

          -  Treatment with a reversible monoamine oxidase inhibitor (MAOI) within 4 weeks of study
             phase II.

          -  Treatment with fluoxetine or aripiprazole within 5 weeks of study phase II.

          -  Treatment with any other disallowed concomitant medication or TMS 14 days before
             randomization.

          -  Treatment with clozapine or electroconvulsive therapy (ECT) within 1 month of
             randomization.

          -  Lifetime history of deep brain stimulation.

          -  Subjects who, in the Principal Investigator's judgment, pose a current serious
             suicidal or homicidal risk.

          -  Positive HIV test

          -  Contraindications to MRS (metal in body, claustrophobia, etc for imaging)

          -  No structured psychotherapy will be permitted during the total duration of the study.
             Subjects unable or unwilling to stop psychotherapy will be unable to participate in
             the study.