Imagine walking into an emergency room utterly battered. You haven’t slept in weeks, you don’t feel like eating, you have no interest in much of anything, and you can’t stop thinking of death. You feel as though you’re trapped at the bottom of a deep well. After you describe your symptoms, a doctor hands you a prescription. She tells you to take the medication every day and that, in four to six weeks, you might feel better.
Unfortunately, this scenario is not imaginary for many patients suffering from depression. Selective serotonin reuptake inhibitors (SSRIs), the most common medications used to treat the illness, often take weeks to begin working. What’s more, they don’t work for everyone. According to Encyclopedia Britannica, 10 to 30 percent of patients suffering from depression are afflicted with treatment resistant depression—that is, their illness does not respond to existing therapies.
Today, however, a glimmer of hope emerged. Researchers from the pharmaceutical company Naurex announced promising results from a recent trial of their new antidepressant compound. Presenting the findings at the 51st Annual Meeting of the American College of Neuropsyschopharmacology, the researchers noted that, in phase IIa of their clinical trial, GLYX-13 significantly lowered depression levels in subjects whose symptoms had not responded other antidepressants.
The Expert Take
In general, most patients taking antidepressants are prescribed SSRIs. These drugs work by changing the level of the chemical serotonin in the brain, which in turn bolsters their mood. While SSRIs can work well, the drugs may take up to four to six weeks to take effect. In addition, it can take time for the doctor to find the right drug and dose for a given patient. As a result, only one in three depressed patients respond to the first drug they try.
Recently, however, a number of studies, including one highlighted on Healthline.com, point to a potentially powerful alternative drug: ketamine. Unlike SSRIs, the party drug ketamine kicks in quickly, and its effects last longer. Unfortunately, ketamine can also cause serious side effects. These so-called “psychomimetic” effects include auditory and visual hallucinations, paranoia, and delusions.
Ketamine works by blocking a receptor in the brain called NMDA. Ordinarily, this receptor “catches” glutamate, an important brain chemical that stimulates cognition, memory, and learning. When the NMDA receptor is blocked, it can’t catch the glutamate, so there’s more glutamate to go around.
Naurex’s founder, Dr. Joseph R. Moskal, has been working with other compounds block the NMDA receptor since the 1980s. According to Naurex’s Vice President of Corporate Development, Ashish Khanna, “when the research began to coalesce around [the potential therapeutic effects of] ketamine”—about four or five years ago—“we realized that we had a compound that might cause a similar effect.”
But there is one key difference between ketamine and Moskal’s compound, GLYX-13. Like ketamine, GLYX-13, works on the NMDA receptor. However, unlike ketamine, which blocks the receptor entirely, GLYX-13 blocks only part of the receptor. Khanna explains that, if you think of the receptor as a door, while ketamine shuts the door, GLYX-13 “doesn’t close the door entirely.”
The Naurex researchers hope that, because of this difference, GLYX-13 will be able to “dial in the positive aspects of an NMDA blocker”—like ketamine—“without causing negative side effects”—like psychosis.
Their wish seems to be coming true. Within 24 hours of receiving a single dose of GLYX-13, trial participants showed significant improvement in depression symptoms. Better yet, the positive effect of that single dose continued, on average, for seven days. Moreover, the participants did not experience serious side effects.
The researchers could not be happier. “It’s still early in the trial process,” says Khanna, “but it’s exciting…for the first time, we’re seeing [an antidepressant] drug that seems to have rapid effects after a single dose, [and it] appears to do that without creating difficult side effects.”
Psychiatrist Dr. Carole Lieberman, however, warns that it could be “too early to tell whether this drug will be useful for patients…because [the researchers] have not yet tested it in a continuous manner—with repeated doses.”
The Naurex researchers agree. Khanna explains that, building on the success of phase IIa trials, the researchers have “just initiated a phase IIb study, in which [they’ll] test how people react to repeated doses of GLYX-13.” The clinicians hope that those results will be available by December 2013.
Source and Method
Naurex researchers recruited 115 participants, all of whom had tried at least one other antidepressant without success. The participants were divided into five groups: four groups received different doses of GLYX-13, while one group received a placebo. Each participant was given a single dose of the compound intravenously.
The participants’ depression levels were measured according to signs, symptoms, and changes in depression scores as measured by the Bech-6, a modified version of the Hamilton Depression Rating System. The researchers found that those who had been treated with GLYX-13 experienced a significant decrease in depression levels. The change took place with 24 hours of the administration of GLYX-13, and the improvement lasted an average of seven days.
According to clinical psychologist Dr. Raphael Wald, a fast-acting antidepressant could make an immense difference for psychiatrists in the field. He explains that, as it stands, “if you have a patient show up in the ER who’s suicidal and you need to help them [immediately],” you have nothing to give them.
However, if GLYX-13 continues to perform well in clinical trials, the compound could solve that problem. It could, for instance, potentially help people in the throes of suicidal depression.
Wald also notes that the compound “has the potential to help people with treatment resistant depression, [and] it has the potential to be used to complement another [antidepressant] drug.”
Nonetheless, it’s important to note that these trials are still in the early stages. As Lieberman says, “it is way too early to start rushing to the drugstore asking for this. Many more studies need to be done to make sure of the efficacy and the lack of serious side effects.”
Khanna, however, is optimistic. “There really hasn’t been a new mechanism anti-depressant discovery in thirty plus years,” he explains, since the discovery of SSRIs.
As Wald puts it, “if you care…about mental health issues, this is big news. [This compound could] help to solve a problem that has plagued the field of psychology forever.”
In a 2012 article, researchers at Yale University analyzed several studies on ketamine’s effects on the brain. They found that ketamine produces rapid antidepressant responses in patients who are resistant to typical antidepressants.
In a 2009 study, published in the Journal of Experimental and Clinical Psychopharmacology, researchers, including Wald, induced compulsive scratching in rats. They then treated the obsessive-compulsive disorder with fluoxetine (Prozac) and memantine (another drug that works on the NMDA receptor). The researchers found that memantine helped treat the symptoms of OCD.
Finally, in a 2003 study published in the New England Journal of Medicine, researchers studied the effects of memantine on patients with moderate to severe Alzheimer’s. They found that patients treated with memantine experienced reduced clinical deterioration, compared with those taking a placebo.
This research suggests that NMDA receptor blockers show promise in treating a wide variety of psychiatric disorders.