Ketamine for Depression: Key Efficacy, Safety Questions Remain

Ketamine and other glutamate-modulating agents may represent the first major advance in treating major depressive disorder (MDD) in years, but key questions remain regarding safety, tolerability, and efficacy, experts say.

“The ongoing clinical trial research focusing on the glutamate system may lead to a completely new class of antidepressants that may significantly change the way patients with depression, and in particular, treatment-resistant depression, are treated,” ketamine researcher James W. Murrough, MD, director of the mood and anxiety disorders program at Icahn School of Medicine at Mount Sinai in New York City, noted in a statement.

Dr Murrough and two coauthors review progress in treating glutamate signaling in depression in a review published online March 17 in Nature Reviews Drug Discovery.

Next-Gen Treatment

Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS). Studies have shown changes in glutamate receptors, as well as elevated glutamate levels, in patients with MDD. Drugs such as ketamine that block glutamate receptors in the CNS or that lower glutamate levels in the brain may be the next generation of antidepressant medications and offer potential advantages over current drug treatments.

Dr Murrough’s team and several other groups around the United States are conducting studies on ketamine and other agents that modulate the glutamate system. No glutamate modulator has been approved for the treatment of depression.

“There are key questions right now concerning both the scientific understanding of ketamine and the potential future use of ketamine or ketamine-like drugs for depression,” Dr Murrough told.

One question is how ketamine triggers an antidepressant response within 1 day, whereas conventional antidepressants require 2 weeks or longer to take effect. “What is the biological basis of ketamine’s antidepressant mechanism of action?” he asked.

It also remains a mystery why ketamine is successful in treating symptoms of depression in patients who have not responded to conventional treatments. “What can ketamine do in the brain that is relevant to the treatment of depression, that current antidepressant drugs do not do?” asked Dr Murrough.

“Although substantial progress has been made over the past decade in identifying ketamine as a prototype rapid-acting antidepressant, there is a large gap in the literature, which represents a crucial unmet research need to examine its safety and efficacy beyond a single treatment administration,” said Dr Murrough.

Another important unknown, he said, concerns the relationship between glutamate modulation and conventional therapeutic approaches for depression, “which may shed light on the strengths and limitations of this approach.”

The depression field continues to be challenged by a lack of definitive diagnostic and treatment-related biomarkers, as well as an exclusive reliance on the Diagnostic and Statistical Manual of Mental Disorders for case identification, Dr Murrough and colleagues note in their article.

Regarding clinician practice, “there are many unanswered questions, and both clinicians and patients should remember that ketamine is not approved for the treatment of depression, and large-scale clinical trials in patients have not been completed,” Dr Murrough told.

“Therefore, we do not know the optimal way to dose ketamine, how long it should be given, or if it is safe to give over longer periods, for example, months or years. Ketamine can work quickly, but depression tends to be a chronic condition,” he explained. “Therefore, after a patient responds to a short course of ketamine, there is a lack of data to guide next-step decision making in the patient’s treatment.”

Beyond Ketamine

In their article, Dr Murrough and colleagues review other glutamate modulators that are in development for depressive disorders (as of June 15, 2016). These agents include the following:

• D-Cycloserine (DCS), an antibiotic used to treat tuberculosis, has been shown to have antidepressant effects. At low doses, DCS acts as a partial agonist at the glycine site of the N-methyl-D-aspartate receptor (NMDAR). At high doses, it appears to behave as a functional NMDAR antagonist. In a recent single-center 6-week trial, gradually titrated high-dose DCS was used as an adjunct to standard antidepressant medication in patients with treatment-resistant depression. The researcehrs reported superior benefit with DCS in comparision with placebo.
• Rapastinel (formerly GLYX-13, Allergan), a partial NMDAR agonist, demonstrated antidepressant efficacy 1 day after administration of a single dose in a phase 2 clinical trial in patients with MDD who had experienced an inadequate response to one or more antidepressants. No psychotomimetic or hallucinogenic side effects were observed with rapastinel. The drug was granted fast-track status by the US Food and Drug Administration (FDA) for the treatment of MDD in 2014 and breakthrough therapy designation in 2016.
• NRX-1074 (Allergan), a glycine-site partial NMDAR agonist, is in phase 2 testing.
• AXS-05 (dextromethorphan plus bupropion, Axsome Therapeutics), an oral nonselective NMDAR antagonist (dextromethorphan component), is in phase 3 testing. No human studies have been published to date.
• CERC-301 (Cerecor), an oral NR2B-selective antagonist, is currently being tested in a randomized, double-blind, placebo-controlled trial for adjunctive antidepressant effects. CERC-301 received fast-track designation from the FDA in 2013. The trial is designed such that two doses of the drug will be intermittently administered 7 days apart. This will test the hypothesis that NMDAR antagonism is more effective for depression when administered intermittently, rather than on a daily basis.
• AVP-786 is an oral nonselective NMDAR antagonist from Avanir Pharmaceuticals/Otsuka Pharmaceuticals. No human studies have been published to date.
• AV-101 (4-chlorokynurenine) is an oral glycine-site NMDAR antagonist from VistaGen Therapeutics. No human studies have been published yet.
• Diazoxide is a vasodilator that is being tested in a phase 2 study sponsored by the National Institutes of Mental Health.
• Basimglurant (Hoffmann-LaRoche) is an mGluR5 negative allosteric modulator that is in phase 1b testing.

The Icahn School of Medicine at Mount Sinai is a co-owner of a patent covering the use of ketamine for the treatment of treatment-resistant depression, has entered into a licensing agreement with a pharmaceutical company for rights to the patent, and will receive payments related to the use of ketamine if it is approved for the treatment of treatment-resistant depression. Dr Murrough is not named as an inventor on the patent and will not receive any payments

Nat Rev Drug Discov. Published online March 17, 2017.