Low-Dose IV Ketamine Catalyzes New Treatment Paradigm for Major Depressive Disorder

Ketamine hydrochloride (ketamine) is an FDA-approved, rapid-acting general anesthetic administered by intravenous (IV) or intramuscular (IM) injection. However, the use of ketamine, an NMDA receptor antagonist which acts as an NMDA ion channel blocker, to treat MDD has been well-studied in several clinical trials conducted by depression experts at the U.S. National Institute of Mental Health (NIMH) and several leading academic research centers, including Harvard University and Yale University. In multiple clinical trials reported by Dr. Zarate and others at the NIMH, a single IV low dose of ketamine produced robust and rapid antidepressant effects in MDD patients. However, the potential for widespread therapeutic use of ketamine, a Schedule III drug, for the treatment of MDD is limited by its potential for abuse, dissociative and psychosis-like side effects, and by practical challenges associated with the necessity of IV or IM administration in a medical center.

The discovery of ketamine's fast-acting antidepressant effects did, however, revolutionize thinking about the current MDD treatment paradigm involving standard antidepressants and increased interest in the development of a new generation of antidepressants with a fast-acting mechanism of action similar to ketamine's. Our orally administered CNS prodrug candidate, AV-101, is among the new generation of antidepressants with the potential to deliver fast-acting, ketamine-like antidepressant effects, without ketamine's CNS side effects or a required administration in a medical setting.