Electrophysiological Biomarkers of AV-101
Condition: Healthy
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Suicide is 2-7x higher in Veterans than non-veterans, and may be related to brain kynurenine
      pathway (KP) dysregulation and NMDA receptor (NMDAR) hyperactivation. Experimental drug
      "AV-101" modulates the brain KP, with possible downstream NMDAR deactivation. The
      investigators will examine AV-101 NMDAR modulation by testing dose-response effects on
      resting state EEG, Mismatch Negativity, and P50 gating. Twelve healthy Operation Enduring
      Freedom (OEF) Operation Iraqi Freedom (OIF) and Operation New Dawn (OND) Veterans will be
      administered single dose AV-101 720 mg, 1440 mg, and placebo over 3 weeks in a randomized,
      double-blind, cross-over trial. Repeated measures General Linear Models will test
      dose-response effects. Suicide prevention is an important Veterans Affair (VA) mission. This
      study is a first step to testing anti-suicidal effects of AV-101 in Veterans.
    

Detailed description: 
      Background: Suicide is the 10th leading cause of death in the US, and is 2-7 times higher in
      Veterans than age- and sex-matched civilians. Standard psychiatric medications (such as
      lithium) are anti-suicidal with prolonged use only, and do not impact acute suicidality. A
      priority for suicide prevention is to define novel treatment targets for safe and
      rapidly-acting interventions. Recent studies have associated suicide and medically severe
      suicide attempt (MSSA) with dysregulation of the brain kynurenine pathway (KP), which could
      predispose to excessive NMDAR activation, a molecular target purportedly involved in rapid
      improvement of suicidality with agents such as ketamine. AV-101 (4-chlorokynurenine,
      4-Cl-KYN) is an oral pro-drug that targets KP dysregulation with downstream NMDAR
      deactivation. Phase-1 testing showed that AV-101 is metabolized to 7-Cl-KYN in 1.5 to 2 hours
      after intake.

      Objective: Before testing possible anti-suicidal properties, biomarkers need to be defined to
      show that AV-101 engages the NMDAR. The objective of the current study is to define valid and
      sensitive neurophysiological markers with a dose-response relationship with AV-101 as
      evidence of NMDAR engagement, as well as study safety and tolerability.

      Methods: The investigators will recruit 12 healthy and non-psychiatrically ill OEF/OIF/OND
      Veterans (age 25-64) who will receive two single doses of AV-101 (720 mg, 1440 mg) and
      placebo in a randomized, double-blind, crossover design with one week wash-out between
      conditions. Neurophysiological measures collected at baseline (pre-treatment) and hourly for
      5 hours following medication intake are resting state EEG, Mismatch Negativity amplitude, and
      P50 sensory gating, measures sensitive to modulation of different NMDAR mechanisms. Repeated
      measures General Linear Models will be used to test dose-response relationships.
    

Intervention name(s): Placebo; AV-101 720 mg; AV-101 1440 mg
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Single dose of 4 placebo oral capsules; Single dose of 2 360 mg AV-101 oral capsules + 2 placebo oral capsules; Single dose of 4 360 mg AV-101 oral capsules
Other intervention name(s): Placebo oral dose; L-4-Chlorokynurenine; L-4-Chlorokynurenine
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: placebo-controlled, randomized, double-blind, cross-over
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Suicide; Kynurenine; metabolic pathway; Veterans; OEF/OIF/OND; electrophysiology; NMDA receptor; suicidal ideation