Wednesday, January 19, 2011

Novel Antidepressant in the Pipeline: NMDA Receptor Antagonists

Author: Brian Gabriel

In a given year, approximately 26.2% of Americans (or roughly 1 in 4 adults) will suffer from a mental disorder. The most prevalent mental disorder, major depressive disorder, strikes anywhere from 6.7% to 9.5% of U.S. adults each year. 15% of these individuals will commit suicide, making depression the second-largest cause of adult mortality in the U.S. following coronary artery disease (furthermore, studies are beginning to illuminate the positive correlation between these two diseases).

Historically, psychopharmaceuticals have putatively targeted the “monoamines” of the brain; namely serotonin, norepinephrine, and dopamine. The first widespread class of antidepressants, monoamine oxidase inhibitors (MAOIs), was serendipitously discovered to benefit those suffering from depression after patients treated with these antihypertensive medications reported elevated moods. MAOIs are fraught with side-effects, however, including the potentially fatal hypertensive crisis. Because of side-effects, MAOIs are less frequently prescribed today. Similarily, tricyclic antidepressants are also characterized by numerous burdensome side effects including fatal cardiotoxicity in overdose. Finally, while safer than MAOIs and tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) present additional difficulties including a delayed onset of action. While subtle variations on SSRIs have developed (including selective serotonin and norepinephrine reuptake inhibitors-SNRIs), truly novel antidepressants outside the paradigm of monoamines are currently lacking. Below is a brief discussion of one such novel class of antidepressant currently in development.

NMDA Receptor Modulators

In August of 2010, researchers at Yale University sparked a media blitz with the publication of a clinical study touting the efficacy of the classic party-drug ketamine in treating treatment-resistant depression. In particular, responses were characterized by rapid onset of action and prolonged duration of therapeutic benefit following a single administration. However, therapeutic doses of ketamine also produced schizophrenia-like side effects in some patients. Combined with the concern for abuse, ketamine is unlikely to be approved as a wide-spread therapy.

Putatively, ketamine acts as a NMDA receptor modulator. NMDA is a glutamate receptor subtype within the brain that changes certain brain activity and is a frequent target for treating a wide variety of CNS disorders. One example of a NMDA receptor modulator is memantine, a drug used to treat Alzheimer’s disease.

Although many purported NMDA receptor modulators are used as recreational drugs (including ketamine) and are associated with intolerable risks, researchers hope to develop selective modulators of the NDMA receptor in order to treat CNS diseases including depression. Ideally, these selective modulators would be free from the intolerable risks associated with ketamine.

This month, Naurex Inc. announced that their Phase I clinical trial for the selective NMDA receptor modulator GLYX-13 succeeded in producing a robust and enduring (up to two weeks post-administration) therapeutic benefit for depression in animal models. GLYX-13 is believed to be a selective modulator of the NMDA receptor specifically acting as a glycine-site partial agonist. Interestingly, administration of GLYX-13 appeared free from the schizophrenia-like side effects and risk for abuse that has impeded more wide-spread usage of many NMDA-modulating agents. Researchers at Naurex hope to begin Phase II clinical trials in early 2011 on patients with inadequate response to antidepressant treatment.

About the author:

Brian is a budding medical writer with a background in medicine and psychology. As an undergraduate studying at Muhlenberg College, Brian pursued a writing and research-intensive psychology and pre-medical curriculum. At Muhlenberg, Brian joined several honors societies including the Phi Beta Kappa Society. As a medical student at Jefferson Medical College, Brian passed both Steps I and II of the USMLE before leaving school to be with his terminally ill father. Brian looks forward to recontributing to the field of medicine as a medical writer. In his free time, Brian enjoys meditating, exercising, and volunteering.

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