Major Depressive Disorder and Current Antidepressants
Depression is a global public health concern. The World Health Organization estimates that “depression is the leading cause of disability worldwide, and is a major contributor to the global burden of disease,” affecting 350 million people globally. According to the U.S. Center for Disease Control and Prevention (CDC), “about one in 10 Americans aged 12 and over takes antidepressant medication.”
While most people will experience depressed mood at some point during their lifetime, Major Depressive Disorder (MDD) is different. MDD is the chronic, pervasive feeling of utter unhappiness and suffering, which impairs daily functioning. Symptoms of MDD include diminished pleasure in activities, weight changes, insomnia or hypersomnia, psychomotor agitation, fatigue, feelings of worthlessness and guilt, poor concentration and suicidal thoughts and behaviors. Suicide is estimated to be the cause of death in up to 15% of individuals with MDD.
Current medications available in the multi-billion dollar global antidepressant market, including commonly-prescribed selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), have limited effectiveness, and because of their mechanism of action, SSRIs and SNRIs must be taken for several weeks to months before patients experience any significant therapeutic benefit and, importantly, most have FDA-required “Black Box” safety warnings due to risk of worsening depression and increased risk of suicidal thoughts and behaviors during treatment. Only about 33% of depression sufferers benefit from initial treatment, and the likelihood of achieving remission of depressive symptoms declines with each successive treatment attempt. Even after many treatment attempts during the course of up to more than a year, about 33% of depression sufferers fail to find an effective therapy. In addition, this trial and error process and the systemic effects of the various antidepressant medications involved increases the risks of patient tolerability issues and serious side effects, including suicidal thoughts and behaviors.
Ketamine and Major Depressive Disorder
In revolutionary randomized, placebo-controlled, double-blind clinical trials conducted by Dr. Carlos Zarate and others at the U.S. National Institute of Mental Health (NIMH), part of the U.S. National Institutes of Health (NIH), ketamine (an NMDA receptor antagonist which acts as an NMDA channel blocker) produced robust and rapid (within hours of intravenous administration of a single dose) antidepressant effects in MDD patients who had not responded to approved antidepressants. The potential for widespread therapeutic use of ketamine is limited by its potential for abuse, dissociative and psychosis-like side effects, and practical challenges associated with its required intravenous administration in a medical center. However, the discovery of ketamine’s fast-acting antidepressant effects revolutionized thinking about the MDD treatment paradigm and the preferred mechanism of action of antidepressant medicines. The discovery also increased interest in development of a new generation of antidepressants with a mechanism of action similar to ketamine’s, including a more rapid therapeutic benefit compared to existing agents. AV-101 is among the new generation of antidepressants with potential to deliver ketamine-like antidepressant effects, without ketamine’s side effects or required intravenous administration.
AV-101 and Major Depressive Disorder
AV-101 is an orally-active prodrug candidate that produces, in the brain, 7-chlorokynurenic acid (7 Cl KYNA), one of the most potent and selective antagonists of the glycine-binding site of the NMDA receptor, resulting in the down-regulation of NMDA signaling. Growing evidence suggests that the glutamatergic system is central to the neurobiology and treatment of MDD and other mood disorders.
AV-101’s mechanism of action is fundamentally different from currently-available antidepressants, placing it among a new generation of glutamatergic antidepressants with breakthrough potential to treat millions of MDD sufferers worldwide who are poorly served by SSRIs, SNRIs and other current depression therapies. AV-101 is functionally similar to ketamine in that both are NMDA receptor antagonists. However, AV-101 modulate (down-regulate) NMDA receptor channel activity and ketamine blocks it. AV-101 accomplishes this NMDA receptor modulation by selectively binding to, and thus blocking, the functionally-required glycine-binding co-agonist site of the NMDA receptor. We believe targeting the glycine-binding co-agonist site of the NMDA receptor and modulating NMDA receptor activity rather than blocking it can bypass potential adverse effects that occur when ketamine blocks the NMDA ion channel, without affecting the robust efficacy observed in previous NIH clinical studies using ketamine to treat MDD. This NMDA receptor modulation by AV-101 may then result in the “glutamate surge” that has been associated with the fast-acting antidepressant effects of ketamine.
The NIH previously awarded VistaGen $8.8 million for preclinical development and Phase 1 clinical development of our AV-101. In preclinical studies, AV-101 has demonstrated the antidepressant-like activity of ketamine, including rapid onset and long duration of effect, without ketamine’s serious side effects. In two NIH-funded randomized, double-blind, placebo-controlled Phase 1 safety studies, AV-101 was safe, well-tolerated and not associated with any severe adverse events. There were no signs of sedation, hallucinations or schizophrenia-like side effects often associated with ketamine and traditional NMDA receptor channel blockers.
In February 2015, we entered a Cooperative Research and Development Agreement (CRADA) with the U.S. National Institute of Mental Health (NIMH). Under this agreement, we will collaborate with the NIH on a Phase 2 clinical study of AV-101 in subjects with Major Depressive Disorder. Pursuant to the CRADA, this study will be conducted and fully-funded by the NIH. For more information, read the following press release: VistaGen and NIH Sign Agreement for NIH-Sponsored Phase 2 Study of Orally-Active AV-101 in Major Depressive Disorder.
World Health Organization Fact Sheet on Depression
To review key facts and a comprehensive overview, visit the following link: World Health Organization Depression Fact Sheet.