Electrophysiological Biomarkers of AV-101

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.

Inclusion criteria

• Age 21-64, inclusive
• US military Veteran
• Healthy volunteer.
• Subject and partner are both using at least 1 medically accepted contraception (double barrier) at randomization until 1 month after single dose

Exclusion criteria

• History of any Axis 1 psychiatric condition
• History of psychosis in first-degree family members
• History of use of psychoactive medication
• Current use of any medication or vitamins except the pill (women)
• History of use of any substances of abuse, except for alcohol, caffeine, and nicotine
• Positive at tests for alcohol and illicit substance at screening and study visits.
• History of epilepsy, head injury, stroke, primary neurological disorder
• Clinically significant abnormal laboratory values, vital signs or ECG placing participants at risk for serious adverse events as determined by the study physician
• Pregnant or nursing
• Serious, unstable illness including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease