Major Depressive Disorder (MDD)
A Global Public Health Concern
According to the World Health Organization (WHO), depression is the leading cause of disability worldwide, affecting over 300 million people, or approximately 4.4% of the global population.1 Statistics from the U.S. National Institute of Mental Health (NIMH) indicate that an estimated 17.3 million adults in the U.S., or approximately 7.1% of all adults in the U.S., had at least one major depressive episode in 2017. While most people will experience depressed mood at some point during their lifetime, MDD is different. In typical depressive episodes, the person experiences depressed mood, loss of interest and enjoyment, and reduced energy leading to diminished activity and impaired daily functioning for at least two weeks and often much longer. Symptoms of MDD also may include diminished pleasure in activities, changes in appetite that result in weight changes, insomnia or oversleeping, psychomotor agitation, loss of energy or increased fatigue, feelings of worthlessness or inappropriate guilt, difficulty thinking, concentrating or making decisions, and thoughts of death or suicide and attempts at suicide. MDD is the psychiatric diagnosis most commonly associated with suicide.2
- World Health Organization, https://www.who.int/news-room/fact-sheets/detail/depression
- American Association of Suicidology. Depression and Suicide Risk. Available at: http://www.suicidology.org/Portals/14/docs/Resources/FactSheets/2011/DepressionSuicide2014.pdf
Shortcomings of Currently Available Antidepressants (SSRIs and SNRIs)
For many people, depression cannot be controlled for any length of time without treatment. Current oral antidepressants (ADs) available in the multi-billion-dollar global depression market, including commonly-prescribed oral SSRIs and SNRIs, have modest efficacy, substantial lag of onset of action, and considerable side effects. Approximately two out of every three depression sufferers do not receive adequate therapeutic benefits from their initial treatment with a standard AD, and the likelihood of achieving remission of depressive symptoms declines with each successive AD treatment attempt. Even after multiple treatment attempts, approximately one-third of depression sufferers still fail to find an adequately effective AD. In addition, this trial and error process and the systemic effects of the various ADs involved may increase the risk of patient tolerability issues and serious side effects, including suicidal thoughts and behaviors in certain groups. New generation ADs with different mechanisms of action, faster onset activity and fewer side effects are needed.
Convincing clinical data involving the NMDAR antagonist, ketamine, and its isomer, esketamine, support that the NMDAR complex is involved in improving depressive symptoms faster than current ADs. Ketamine-based therapies block the ion channel of the NMDAR, and this blockade is associated with significant psychological side effects and safety concerns.
We are conducting our ELEVATE Study to evaluate the safety and efficacy of AV-101 as an add-on treatment of MDD in adult patients with an inadequate response to standard, FDA-approved oral ADs. The Principal Investigator of the ELEVATE Study is Dr. Maurizio Fava of Harvard Medical School. Dr. Fava was the co-Principal Investigator with Dr. A. John Rush of the largest clinical trial ever conducted in depression, STAR*D, whose findings were published in journals such the New England Journal of Medicine and the Journal of the American Medical Association. In published preclinical studies, AV-101 has been shown to have rapid, persistent, AMPA-dependent antidepressive effects similar to ketamine controls. Recent nonclinical results also indicate that chronic administration of 4-Cl-KYN induces hippocampal neurogenesis, a hallmark of drugs that have antidepressive effects, and increases endogenous levels of KYNA, which also is a functional NMDAR glycine site antagonist.
The FDA has granted Fast Track designation for development of AV-101 as an add-on treatment for MDD in adult patients with an inadequate response to standard, FDA-approved ADs.