By JOE STUMPE
KU School of Medicine-Wichita

WICHITA – The most promising new treatment for depression in decades owes a debt to Wichita and its KU School of Medicine campus.

The drug, called esketamine, is being marketed as a nasal spray under the name Spravato. Approved for use by the FDA in March, esketamine has been shown to help a significant percentage of people who don’t respond to existing antidepressants, which all work on monoamine – also called biogenic amine – neurotransmitters such as serotonin, norepinephrine and dopamine. In contrast, Spravato works via a new mechanism on a new transmitter system, glutamate.

“This medicine works via a different mechanism. That mechanism produces meaningful effects in approximately 60 percent of patients not meaningfully helped by existing antidepressants and within 24 hours,” said Sheldon Preskorn, M.D., a psychiatry professor at KU School of Medicine-Wichita who has helped in the development and now the launch of the drug. “It’s really quite different.”

About a third of the people suffering from depression – several million in the United States alone – aren’t helped by monoamine antidepressants such as Prozac or Zoloft.

“We’ve been working with those (drugs) for 50 years because that is all we’ve had up to the FDA approval of Spravato,” Preskorn said.

Preskorn knows the history, having led or participated in psychopharmacology research since the late 1970s. During a 25-year period, he took part in the development of every antidepressant and antipsychotic drug brought to market in the United States.

“I did one of the earliest studies showing that drugs of (esketamine’s) nature worked,” Preskorn said, referring to a study published in 2008. “It wasn’t esketamine, but it showed that this mechanism of action worked in patients with otherwise treatment-resistant depression.” That study, conducted in Wichita, has been cited more than 400 times in the world’s medical literature.

Preskorn also taught Wayne Drevets, M.D., the physician scientist who led drug development work for Janssen Research & Development, the subsidiary of Johnson & Johnson that won FDA approval to market esketamine. Drevets is a graduate of KU School of Medicine, as is Preskorn.

“He’s a native of Wichita, went to Collegiate High and graduated from medical school at KU in Kansas City,” Preskorn said. “He was a medical student of mine and then a resident of mine when I was on the faculty at KU in Kansas City and then Washington University” in St. Louis.

At Janssen, Drevets, as a vice president of the company, oversees the development of new treatments for depression and other mood and anxiety disorders.

Drevets was motivated to train as a psychiatrist by observing friends who struggled with depression, according to a profile on the Janssen website. He began his research career looking at the effects of existing medicines on the brain. At the time, researchers did not know where in the brain to look for abnormalities that affect emotional behavior. Today, imaging technology allows scientists to see the differences in a person’s brain when they are having symptoms.

The profile quotes Drevets as saying he believes the practice of psychiatry has lagged behind what is now known of the brain, and that’s the main reason he moved into the pharmaceutical industry.

“I wanted to help develop new treatments that would make a difference for patients in the clinic,” he said. Preskorn said he recognized that innovative spirit in Drevets as a medical student and resident.

In addition to Preskorn and Drevets, there is another important KU contributor to the approval of esketamine: Matthew Macaluso, D.O., an associate professor of psychiatry at KU School of Medicine-Wichita and a graduate of its residency program. Macaluso was principal investigator for a portion of the pivotal clinical trials conducted here that led to FDA approval of esketamine. An assistant dean for research and director of the psychiatry residency program, Macaluso also leads the Center for Clinical Research at KU Wichita.

During the course of about three years, Macaluso studied patients whose depression had not responded adequately to at least two therapeutic trials of different existing monoamine antidepressants. The patients were given doses of esketamine twice weekly for one month, and then the frequency of dosing was decreased with some patients receiving the drug only every two weeks.

“We saw good responses to the drug in most but not all the patients,” Macaluso said. “Many of the individuals in the study told us it was a life-changing treatment for them. These were people who had lost interest in life, had less energy and were chronically ill – truly suffering.”

Esketamine has an interesting history. Ketamine – which contains both esketamine and arketamine – was introduced as anesthetic in Germany in 1997. Ketamine showed signs of acting as an antidepressant, leading to research on its use for that purpose. Ketamine is also used by veterinarians as a tranquilizer and has been abused as a party drug nicknamed “Special K.” It is a controlled drug that can only be administered in a medical office.

The same is true of esketamine, which also distinguishes it from other depressants. It works on a chemical in the brain called glutamine, which is a different mechanism of action than drugs such as Prozac and Zoloft.

“Historically, most antidepressant drugs work on what are called biogenic amines – chemicals in the brain like serotonin, norepinephrine and dopamine,” Macaluso said. “Dr. Preskorn earlier studied a novel drug that worked on a different chemical called glutamate. Since then, there has been keen interest in the development of such drugs for patients with depressive illness, which is not responsive to monoamine antidepressants.”

Spravato is now FDA approved to be taken in conjunction with a daily oral monoamine antidepressant, which is how the studies were conducted that led to FDA approval. In addition to reducing depression, a “floating” or tranquilizing sensation is often felt. Some patients have reported dissociation, dizziness and other side effects.

FDA approval was based on research showing that esketamine treated depression where other drugs had not worked and prevented its recurrence. Preskorn said clinical trials are not always representative of how new treatments do in the “real world” of clinical practice, but he is optimistic.

Macaluso said “unfortunately” some psychiatrists may be reluctant to prescribe esketamine because it’s related to a drug “people have abused over the years.” Patients should be screened for a history of substance use disorder or risk for developing the same, he noted.

But Preskorn believes the fact that “it works well for patients who have not benefited from other treatments” will override that concern for many psychiatrists, other health care providers and their patients.

He was one of three psychiatrists picked by Janssen to serve as a panel on the initial broadcast launch presentations about esketamine across the country, reaching over 11,000 health care providers.

“To me, that shows there is a great deal of interest in this treatment,” Preskorn said.