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?
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