Experts Remain Enthusiastic About NMDA-Targeting Antidepressants

When the anesthetic ketamine was first shown to have strong and rapid antidepressant properties back in 2000, it triggered a wave of excitement in the psychiatric community. Studies of mood disorders have long focused on serotonin and dopamine signaling in the brain, but ketamine blocks the NMDA receptor and affects glutamate signaling.

Though ketamine has properties that limit its therapeutic potential (it needs to be given intravenously or intranasally for several minutes and induces dissociative anesthesia that can lead to delirium and increase likelihood for abuse), the demonstrated effectiveness of the agent opened the floodgates to new areas of antidepressant research and drug development.

Over the past few years, the waters have appeared to recede. Many existing or newly developed compounds have shown some initial promise only to underperform in larger human studies of depression. Roche’s experimental drug basimglurant failed to improve depressive symptom scores when given as an adjunct in a phase 2 study completed in 2016. AstraZeneca’s lanicemine, which appeared promising in a short-term phase 2 study in 2014, faltered in a replication study, showing no difference over placebo following 12 weeks of treatment.

Despite being one of the lead investigators on the replication study of lanicemine, Gerard Sanacora, M.D., Ph.D., a professor of psychiatry at Yale University School of Medicine and director of Yale’s Depression Research Program remains bullish on NMDA receptors as antidepressant targets.

He said that part of the difficulty in trying to recreate ketamine’s effects is that ketamine is what he calls a “dirty drug.” Ketamine interacts with multiple targets beyond NMDA receptors, and likely alters glutamate activity through both direct and indirect mechanisms. Other drugs that aim to act exclusively on NMDA receptors may have fewer side effects than ketamine but may also suffer from decreased potency.

“I also think an important facet of drug development that gets overlooked in the media is that there are a lot of factors that go into R&D decisions,” Sanacora told Psychiatric News. “Whenever a drug falls off the clinical pipeline, it’s interpreted that the drug doesn’t work, but that is not always the case.”

Sanacora pointed to the decision to abandon traxoprodil—an NMDA-blocking compound that was developed at Pfizer—as an example of the challenges companies face when deciding whether to move forward with development of a drug that shows promise. In 2006, Pfizer conducted a 30-person clinical study testing traxoprodil for treatment-resistant depression. The study found that 60 percent of the patients receiving traxoprodil responded to the medication compared with only 20 percent of the placebo group. Because of concerns that patients taking the medication might experience cardiac problems from QTc prolongation as well as the short patent life of the drug, the company decided not to pursue an antidepressant indication.

In the case of lanicemine, Sanacora noted that in both phase 2 clinical studies the medication showed a robust antidepressant effect; however, in the replication study, patients in the placebo group also experienced a very large, 13.2-point decrease on the MADRS (Montgomery-Asberg Depression Rating Scale) at the six-week primary end point. While patients in the lanicemine group experienced a drop in MADRS of 14.4, the medication did not show superiority to placebo.

“The trial results were discouraging, but this lack of success is not unique to any class of drugs,” Sanacora said. “It’s really hard to conduct clinical trials in depression.”

Sanjay Mathew, M.D., the Marjorie Bintliff Johnson and Raleigh White Johnson, Jr. Chair for Research in Psychiatry at Baylor College of Medicine agreed with Sanacora’s assessment. “Depression is an extremely heterogeneous condition, and without biomarkers, which can be used in clinical trials for diagnostic and prognostic purposes, we are severely handicapped in our ability to identify those patients who might benefit from specific drugs,” he said.

Despite setbacks, Sanacora and Mathew said there is reason to be hopeful about NMDA drug development. Mathew said esketamine—the purified, left-handed version of the ketamine molecule (regular ketamine solutions contain both left- and right-handed molecules)—is particularly worth tracking in the coming year. A phase 3 study of intranasal esketamine sponsored by Johnson & Johnson recently wrapped up and the results from the trial are expected soon.

“The drug has received FDA [Food and Drug Administration] ‘fast track’ status for acute suicidal ideation and behavior, so that would be a first, if successful, to have an antidepressant medication FDA approved for the treatment of suicidality,” Mathew said. “That would be a very big deal, as the only drug we have in psychiatry with a FDA suicide indication is clozapine, for the treatment of suicidality in schizophrenia and schizoaffective disorder.”

Sanacora added that a few other investigational NMDA-receptor modulators such as rapastinel are also being tested in large clinical studies that should be completed in the coming year. Even if these drugs aren’t proven to be effective antidepressants, he said he believes the results will provide important information about glutamate-targeting drugs. “I've done a lot of prognosticating over the years based on relatively limited data,” Sanacora said, “but soon I, along with others, will have much more quality data to consider.” ■