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
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      Objective

      Modulation of the NMDA receptor (NMDAR) complex or other components of glutamatergic
      signaling is likely involved in improvement of depressive symptoms and related
      constructs/dimensions of observable behavior and neurobiological measures. Current standard
      monoaminergic pharmacological approaches for major depressive disorder (MDD) have proven to
      be only modestly effective during acute depressive episodes. We have systematically tested
      different glutamatergic modulators in patients with mood disorders in order to develop
      improved therapeutics. We found that the NMDAR antagonist ketamine produces rapid
      antidepressant effects in patients with treatment-resistant depression (in MDD and Bipolar
      Disorder). However, despite being highly efficacious, the proof of concept ketamine produces
      psychotomimetic effects.

      In the present protocol, we aim to evaluate a new glutamate-mediated mechanism associated
      with antidepressant efficacy by targeting the glycine receptor within the NMDA receptor.
      Targeting the glycine co-agonist site of the (NMDA) receptor may bypass potential adverse
      effects that occur with ketamine without affecting the robust efficacy observed. This may
      then result in the glutamate surge that has been associated with the rapid acting
      antidepressant effects of ketamine.

      The present Phase 2 proof-of-concept study is designed to evaluate the antidepressant effects
      of AV 101 (L-4-chlorokynurenine or 4-Cl- KYN) in MDD; this is a synthetic compound which is
      enzymatically converted into the selective glycine/NMDAR antagonist 7-chlorokynurenine
      (7-Cl-KYNA) after crossing the blood brain barrier (BBB) and then reaching brain glial cells.
      In animal models of depression, 4-Cl-KYNA (AV 101) induced acute and prolonged
      antidepressant-like effects without exhibiting ketamine-like side effects as determined by
      the drug discrimination, conditioned place preference, and pre-pulse inhibition tests.

      We will also evaluate the neurobiological mechanisms involved in the antidepressant response
      to AV 101. We expect that this effect may modulate glutamate transmission and reverse the
      clinical symptoms of depression. The demonstration that a glycine-antagonist produces
      antidepressant effects without psychotomimetic side effects would support the therapeutic
      relevance of the glycine site of the NMDAR and could direct the development of novel drug
      targets for the treatment of depression.

      Study Population

      Twenty-five individuals with treatment-resistant major depressive disorder (MDD) will be
      included.

      Design

      Male and female patients, ages 18 to 65 years, with a diagnosis of MDD, currently in an
      episode of major depression, will be recruited for this study. This study will consist of a
      randomized, double-blind crossover administration of either the glycine receptor antagonist
      AV 101 (1,080 or 1,440 mg/day given orally) or placebo for 2 weeks. The study will assess the
      efficacy in improving overall depressive symptomatology and tolerability of AV 101 in
      treatment-resistant MDD. Other aims of the study include: 1) determining whether changes in
      brain neurochemicals (e.g. glutamate) and peripheral biomarkers obtained via MRS and
      cerebrospinal fluid (CSF) correlate with antidepressant response (decrease in Hamilton
      Depression Rating Scale (HDRS) total scores) to AV 101 in patients with treatment-resistant
      MDD, and 2) examine other potential biomarkers of response.

      Outcome Measures

      Primary: Hamilton Rating Scale (HDRS) total score.

      Secondary: Proportion of subjects achieving remission (HDRS less than or greater than 7) and
      response (greater than or equal to 50% reduction from baseline in HDRS total score); change
      from baseline in Hamilton Anxiety Rating Scale (HAM-A), Montgomery-Asberg Depression Rating
      Scale (MADRS), and the Columbia Suicide Severity Rating Scale (C-SSRS) total scores.
      Surrogate biomarkers of drug effect/response include: changes in prefrontal glutamate levels
      measured with 7T H-MRS.
    

Intervention name(s): AV 101 (4-Chlorokynurenine); Placebo Comparator
Intervention type(s): Drug; Other
Intervention description(s): 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
Other intervention name(s): 4-Cl-KYN
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Major Depression; Glycine Receptor Antagonist; 4-chlorokynurenine; Treatment Resistant; Glutamatergic System