On the street ketamine is referred to as “Special K,” a drug popular in the party scene because of its hallucinogenic and other psychotomimetic, or psychosis-like, effects. In the operating room, ketamine has long been used for general anesthesia, and a growing body of research also shows ketamine as highly effective at treating depression, especially in patients who are inadequately treated by currently marketed antidepressants – treatment-resistant patients with Major Depressive Disorder. It’s the dangerous chasm between illicit party drug and FDA-approved general anesthetic that raises concern over using ketamine as an antidepressant. The upside is that the continued focus on depression unveils breakthrough alternative treatments currently in development and a changing paradigm for treating Major Depressive Disorder.
Most currently available antidepressant drugs act on serotonin and related neurotransmitter pathways in the brain and require a long lag in onset of antidepressant effects, usually requiring several weeks of administration before therapeutic benefits are achieved. But about 10 years ago, researchers recognized that ketamine has properties that within a matter of hours help alleviate symptoms of patients with Major Depressive Disorder.
A more rapid-acting antidepressant would have a phenomenal impact on the treatment of depression, and the National Institute of Mental Health (NIMH), part of the National Institute of Health (NIH), is among those researching ketamine’s potential for this indication.
Dr. Carlos Zarate, Chief of Experimental Therapeutics and Pathophysiology at the NIMH, is conducting a Phase 2 clinical trial to examine whether ketamine can cause a rapid-next day antidepressant with longer lasting effects. In a previous study, ketamine produced a rapid antidepressant effect within hours, but the effect lasted less than one week.
As highlighted in an article on NPR, Dr. Zarate’s previous study of 30 depressed patients who were dosed with ketamine did in fact demonstrate changes in brainwave activity that indicated the drug is capable of strengthening connections between neurons in areas of the brain associated with depression.
While these studies and others raise new hope for depression patients, especially for treatment-resistant major depression patients, the primary concerns of using the ketamine for this indication remain.
Among those concerns are the requirement of intravenous (IV) administration in a clinical setting, serious psychiatric effects of the drug, risk of abuse, and the lack of long-term studies. While some clinics provide ketamine that patients can self-administer via IV at home, the practice is a rare departure from the standard practice of monitoring patients when they take the drug.
Pharmaceutical companies hope to dissolve many of these challenges by developing drugs that utilize ketamine’s depression-alleviating properties without the side effects. GLYX-13, made by a company called Naurex, is one such drug.
In the company’s recently reported phase 2b study of GLYX-13, the new data confirmed the efficacy and safety results from an earlier phase 2 study, which documented the drug’s rapid onset of antidepressant activity within two hours and lasting for an average of seven days.
Additionally, GLYX-13 was well-tolerated with no sign of the psychosis-like effects associated with ketamine. This is unarguably of incredible clinical significance when it comes to advances in antidepressants. The catch? GLYX-13 is administered intravenously, which for most patients is an inconvenient if not unrealistic method of administration on a weekly basis.
Medical advances are the results of perpetual fine tunings of initial clinical achievements. On that note, Dr. Zarate at the NIMH also has an eye out for new generation antidepressants such as GLYX-13, Cerecor’s CER-301, and VistaGen’s AV-101.
Dr. Zarate has agreed to be the principal investigator of an expected Phase 2 depression study of VistaGen’s AV-101, a novel drug candidate that that might be more potent than GLYX-13, again with out ketamine-like side effects. Furthermore, AV-101 is administered orally by capsule.
In two randomized, double-blind, placebo-controlled phase I clinical studies, AV-101 was well-tolerated and without signs of sedation, hallucinations or the schizophrenia-like side effects often associated with ketamine and other similar channel blockers.
The phase 1 studies were conducted at the University of California, San Diego, by Dr. Mark Wallace, a colleague of psychiatrist Dr. David Feifel, one of only a few academic psychiatrists to offer ketamine treatment. In a recent New York Times article, Dr. Feifel notes that the biggest challenge of ketamine as an antidepressant is that the effect quickly wears off.
VistaGen’s upcoming phase 2 trial will study AV-101’s ability to improve overall depressive symptoms in adult subjects with Major Depressive Disorder. The trial is expected to start in the first quarter of 2015, be conducted by Dr. Carlos Zarate of the NIMH, and funded by the NIH, which previously awarded VistaGen $8.8 million of grant funding for its preclinical and phase 1 clinical development of AV-101.
VistaGen believes its orally-available AV-101 candidate has the potential to deliver the same therapeutic benefits of ketamine and other NMDA receptor modulators, but without IV administration or side effects. AV-101 is also an FDA fast track designation candidate and demonstrates additional potential in epilepsy, pain and Parkinson’s disease.
Depression is a huge, debilitating and global public health concern. The World Health Organization reports that approximately 350 million people worldwide suffer from depression –according to the NIHM, 7% of that number are U.S. adults. Though the FDA has approved antidepressants for decades, the treatments fail to adequately provide rapid-acting and long lasting benefits in treatment-resistant patients with Major Depressive Disorder. As evidenced by the recent suicide of actor Robin Williams, whose long battle with depression was widely publicized, there is tremendous need for a new generation of safe and fast-acting antidepressants.
The paradigm of depression treatment is shifting away from the use of FDA-approved, long-lag onset drugs toward faster-acting treatments like ketamine. Despite the challenges associated with ketamine, its growing acceptance among the psychiatric community and national media continues to spread. How much more so will the world embrace a new generation of antidepressant candidates, like GLYX-13 and AV-101, that are in sync with this new paradigm but void of the typical challenges?
For more information about AV-101, visit www.vistagen.com