Antidepressant Effects of the Glycine Receptor Antagonist AV-101 (4-chlorokynurenine) in Major Depressive Disorder

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.

Timeline

Start

2015-10-14

Primary completion

2019-02-21

Completion

2019-12-03

Publications

• Gorka A, Evans J, Kvarta M, Ballard E, Zarate C. Major depressive disorder is associated with reduced intrinsic connectivity between the bed nucleus of the stria terminalis and ventral striatum. J Psychiatry Neurosci. 2026 Jan 1;51:1-7. doi: 10.1139/jpn-2025-0160.
• Johnston J, Jones G, Peng S, Yuan P, Yavi M, Kadriu B, Henter I, Quintanilla B, Elkahloun AG, Moaddel R, Schulmann A, Akula N, Kvarta M, McMahon F, Zarate C. Time-Dependent Effects of Rapid-Acting Antidepressants in iPSC-Derived Neurons from Treatment-Resistant Depression and Healthy Volunteers. Res Sq [Preprint]. 2026 Feb 12:rs.3.rs-8733841. doi: 10.21203/rs.3.rs-8733841/v1.
• Johnston JN, Yuan P, Kadriu B, Akula N, Quintanilla B, Peng S, Jones GH, Schulmann A, Yavi M, Henter ID, McMahon FJ, Kalynchuk LE, Zarate CA Jr, Caruncho HJ. Response of iPSC-derived neurons from individuals with treatment-resistant depression to (2 R,6 R)-hydroxynorketamine and reelin: an exploratory study. Transl Psychiatry. 2025 Nov 18;15(1):524. doi: 10.1038/s41398-025-03724-6.
• Park LT, Kadriu B, Gould TD, Zanos P, Greenstein D, Evans JW, Yuan P, Farmer CA, Oppenheimer M, George JM, Adeojo LW, Snodgrass HR, Smith MA, Henter ID, Machado-Vieira R, Mannes AJ, Zarate CA. A Randomized Trial of the N-Methyl-d-Aspartate Receptor Glycine Site Antagonist Prodrug 4-Chlorokynurenine in Treatment-Resistant Depression. Int J Neuropsychopharmacol. 2020 Jul 29;23(7):417-425. doi: 10.1093/ijnp/pyaa025.

Drugs

Indications