David Prietz has struggled with depression for more than 20 years. He's tried a slew of different antidepressants and even electroconvulsive therapy, but, for the most part, nothing much has worked. Nothing, that is, except for an experimental agent he received in the fall of 2011, when he enrolled in a clinical trial of AZD6765, one of a new class of drugs designed to provide rapid symptom relief for people with major depression who don't respond to traditional antidepressants such as selective serotonin reuptake inhibitors (SSRIs).
Prietz, 48, a scheduling supervisor at a sheet-metal manufacturer in Rochester, New York, who has been on disability leave for several years, started to feel his head clear from the fog of depression within days of receiving AZD6765. After his second infusion, he vividly began noticing the fall foliage of the trees outside his doctor's office—something he hadn't previously appreciated in his depressed state. “The greens seemed a lot greener and the blue sky seemed a lot bluer,” he says. Although the lift lasted only a couple months after the three-week trial finished and the drug was taken away, the experience gave Prietz hope that he might one day get better. “I can't recall feeling as well I did at the time,” he says.
AZD6765, an inhibitor of the N-methyl-D-aspartate (NMDA) receptor, a glutamate signaling protein involved in cellular mechanisms for learning and memory, was originally developed as a treatment for stroke. It was shelved in 2000 by the drug's manufacturer, AstraZeneca, after phase 2 trials failed to show signs of efficacy. In the decade that followed, however, small clinical reports started to emerge showing that ketamine, an analgesic that also blocks the NMDA receptor, produced rapid responses in people who didn't benefit from any other antidepressants. And unlike most therapies for major depression, which usually take weeks to kick in, ketamine's mood-lifting effects could be seen within two hours, with a therapeutic boost that often lasted for weeks following a single infusion. Ketamine treatment also came with a number of debilitating side effects, though, including psychosis and detachment from reality. Fortunately for AstraZeneca, the company had a cleaner drug on its shelves that could harness ketamine's benefits with fewer problems.
“We had some clinical evidence for [AZD6765's] different properties from ketamine, and so we wanted to follow up on that and turn this mechanism into a practical antidepressant therapy,” says Timothy Piser, global product director at AstraZeneca's US headquarters in Wilmington, Delaware.
Late last year, the company reported the first clinical data from trials using AZD6765 to treat major depression in people with treatment-resistant disease. On 1 December, Carlos Zarate and his colleagues from the US National Institute of Mental Health in Bethesda, Maryland, published the results of a 22-person, single-infusion trial showing that around a third of participants receiving AZD6765 showed a clinically meaningful antidepressant response at 80 minutes that often lasted for another day or two, compared to a 15% response rate in the placebo group (Biol. Psychiatry doi:10.1016/j.biopsych.2012.10.019, 2012). And the same week, at the American College of Neuropsychopharmacology (ACNP) meeting in Hollywood, Florida, a team led by Gerard Sanacora, director of the Depression Research Program at the Yale School of Medicine in New Haven, Connecticut, presented data from a multidose trial in which 152 people (one of whom was Prietz) received AZD6765 or a saline solution three times a week for three weeks. Although AZD6765's effect wasn't as rapid in all participants in that study, a marked antidepressant effect appeared after a week or two, and that gain persisted for several weeks after the study subjects stopped taking the drug. In both trials, the most serious side effects were mild and transient dizziness and headaches, with no signs of the psychosis.
GLYX-13, a peptide that activates a glycine site on the NMDA receptor that is essential for proper glutamate signaling, has yielded similar antidepressant responses. At the same meeting, Ronald Burch, chief medical officer of Naurex, the Connecticut-based company behind GLYX-13, reported the results of a phase 2, 115-person trial showing that people who received a single infusion of the drug experienced significant improvements in their depression symptoms within 24 hours of treatment, and this bounce persisted for an average of seven days. “It's a very robust effect,” says Burch, “really about twice what an SSRI does, and this is after a single dose of GLYX-13, not several weeks of daily dosing.”
According to Naurex's founder and chief scientific officer Joseph Moskal, a neuroscientist at Northwestern University in Chicago, the company also has an orally bioavailable analog of the drug, called NRX-1074, that it plans to develop as a first-line treatment for people to take instead of SSRIs, rather than just after traditional antidepressants have failed. Phase 1 trials of NRX-1074 are planned for later this year. Larger phase 2 trials involving both GLYX-13 and AZD6765 are ongoing.
Clinical findings like those presented at the December meeting have reinvigorated the field of depression research. “This is really a new generation of drugs for the treatment of depression with a completely different mechanism from the conventional antidepressants,” says Ronald Duman, director of Yale's division of molecular psychiatry. Now, a number of other companies are also working in the ketamine and NMDA receptor research space. Just last month, Janssen Pharmaceuticals, which was already clinically testing new formulations of ketamine, signed a licensing agreement with Germany's Evotec to advance its portfolio of NMDA receptor antagonists.
“I'm encouraged by the fact that we have four or five drugs that all work in somewhat different ways but work through the NMDA receptor,” says Sheldon Preskorn, a psychiatrist at the University of Kansas School of Medicine–Wichita who helped design Naurex's trials. “That gives you a greater level of confidence that where there's smoke, there may be fire.”
Despite the promising results from the newer NMDA receptor–modulating drugs, however, given the more rapid and pronounced effects of ketamine, many psychiatrists aren't ready to write off the older agent quite yet. “For severe depression, sometimes you have to bring out the big guns,” says James Murrough, a psychiatrist at the Mount Sinai School of Medicine in New York.
Murrough recently conducted a randomized trial testing ketamine in 72 people with treatment-resistant depression—the largest such study to date. Notably, that study compared ketamine against midazolam, an antianxiety pill most commonly used to induce relaxation before medical procedures, not saline, as all previous randomized studies have done. Reporting at ACNP, Murrough and his colleagues showed that around 35% of people given ketamine exhibited signs of remission after both one and seven days, compared to 8% and 18% for midazolam at the same time points.
Despite the impressive efficacy data, Sanacora suspects ketamine's days might be numbered. “Ketamine is a drug that requires somebody with quite a bit of experience to administer it and requires some more stringent vital-sign monitoring during infusion. That's going to limit its use,” he says. “The other drugs could easily be given in infusion centers without a tremendous amount of experience. So, if these drugs are equally effective, even if they take a few days more to get to that effect, I think it would be hard to justify using ketamine.”
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Dolgin, E. Rapid antidepressant effects of ketamine ignite drug discovery. Nat Med 19, 8 (2013). https://doi.org/10.1038/nm0113-8