The latest clinical trial of esketamine, the nasal-spray form of the club drug ketamine, is boosting confidence among some psychiatrists that it could be a major advance in the treatment of suicidal depression.
In a study published this week in the American Journal of Psychiatry, researchers report that an esketamine trial resulted in a “rapid improvement in depressive symptoms” in people with severe, treatment-resistant depression.
Forty-nine patients completed the four-week trial. Doses were administered twice weekly, and the esketamine quickly showed an effect. Just four hours after the initial dose, people receiving the drug experienced a significant reduction in depressive symptoms. Carla Canuso, who was one of the lead researchers in the study and works with Johnson & Johnson subsidiary Janssen Pharmaceuticals, called the results “robustly significant.”
But a rare editorial signed by the majority of the board of the American Journal of Psychiatry that appeared in the same issue as the study expressed deep concerns about the danger of a drug with a history of abuse.
“We felt it was a problem that really needed particular attention [because] it at least has the potential for causing similar problems to the opioids,” said Robert Freedman, editor of the journal. “That was our single overriding concern.”
Ketamine was approved as a rapid-onset anesthetic decades ago and was an important battlefield tool for medics during the Vietnam War. During the 1970s and '80s, it became better known as Special-K for its psychedelic properties and later, more notoriously, made headlines as a date-rape drug.
The FDA awarded esketamine “breakthrough” status in 2016 and is fast-tracking it through the approval process. The Phase 2 clinical trial reported this week checked the efficacy and safety of the drug and was the first double-blind, randomized, placebo-controlled trial to recruit subjects actively experiencing suicidal ideation. A Phase 3 trial is underway.
In the new trial, the rapid diminishment of symptoms lasted only a short while; at the three-day mark, the initial dramatic improvement had flattened out compared with patients given a placebo spray. And by the end of the trial, at four weeks, there was no difference between the esketamine group and the control group.
Nonetheless, the rapid amelioration of suicidal symptoms within the first few hours was encouraging to the patients, researchers and independent psychiatrists, especially because it can take four to six weeks for traditional antidepressants to be effective.
“There is a desperate need for a better treatment for those who are suicidal,” said Jennifer Vande Voort, a psychiatrist at the Mayo Clinic in Rochester, Minn. “The fact that it's rapid-acting … that type of treatment can save lives.”
“I think we’re in a new generation of antidepressant drug development,” Canuso said. At the very least, she added, “it’s given us the opportunity to look at biochemical pathways that might be important in depression.”
Some mental health experts caution that ketamine is being overhyped, given that its effect seems to fade within days, and sometimes hours.
“Will it give people false hope?” asked Alan Schatzberg, a former president of the American Psychiatric Association. “What do you do afterward? Because these people are often chronically suicidal.”
Researchers also can't say how safe the drug is. Illegal use of ketamine can cause serious side effects, such as bladder ulcers, kidney problems and memory impairment.
“I think it's innovative research,” Vande Voort said. “It may have excellent utility as a short-term antidepressant. ... But using ketamine long-term, we don’t have the evidence for that. We just don’t know.”