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
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