Ketamine: long on hype, short on answers

Boston psychiatrist Cristina Cusin, M.D. can’t ignore the dramatic results from treating severely depressed patients with ketamine when traditional antidepressants couldn’t help. She can see it on their faces.

“When it happens, it’s really impressive,” said Cusin, a staff psychiatrist at Massachusetts General Hospital’s Depression Clinical and Research Program. “They look like totally different people. The problem is it doesn’t last very long and the depression goes back to exactly where it started in another few days.”

A fast-acting anesthetic approved more than 40 years ago to treat soldiers during the Vietnam War, ketamine has been shown to relieve depression symptoms within four to 24 hours in about 60 percent of patients given an intravenous infusion of 35 milligrams per kilogram of body weight, according to published data.

At MGH, one of a number of research hospitals around the country studying ketamine’s off-label use for treatment-resistant depression, the response rate is around 45 percent, Cusin said.

That discrepancy could be explained by the small size of the study population thus far, around 200 patients, according to Charles Nemeroff, M.D., Ph.D., chair of an American Psychiatric Association ketamine task force.

There is still much to learn about ketamine even as new clinics open across the country dispensing it to treat depression, bipolar disorder, PTSD, and other mood disorders. The Ketamine Advocacy Network lists two New England clinics: in Lexington and Newburyport, Massachusetts.

A subset of the psychiatric association’s Task Force on Novel Biomarkers and Treatments, the 10-member ketamine task force is working on a draft treatment advisory for its clinical use. A final document should be submitted for publication in the American Journal of Psychiatry by June, Nemeroff said.

Many ketamine clinics are operated by anaesthesiologists and chronic pain specialists, not psychiatrists, raising concerns that patients with depression are not being fully evaluated or given other FDA-approved medication and psychotherapy first.

Ketamine is a popular recreational street drug known as “K” or “Special K” that produces hallucinatory effects and is a Schedule III substance under the U.S. Controlled Substances Act.

“We urgently need new treatments for depression. There’s no question about it,” Nemeroff said. “The last thing we would want is to create a whole new level of abuse.”

Cusin, who is not part of the association’s ketamine task force, said patients typically experience relief from the symptoms of depression for only a few days, although she recalled one case where it lasted a few weeks.

“I don’t really know how to explain why in a few hours they feel lighter, they feel better, and they don’t feel like killing themselves anymore. Nothing is happening except the administration of a drug,” Cusin said.

MGH has four ketamine active studies underway with research participants who are typically considered medically healthy with no history of substance use disorder or bipolar disorder. The fleeting effect of a drug with unknown long-term effects posed a dilemma for Cusin and her colleagues, however.

“We’ve had a lot of patients doing very well doing research studies and after that, we have nothing to offer them,” Cusin said. “You’re in pain, you’re offered a medication that helps you tremendously alleviate the pain and then you hear your doctor say, ‘OK, now we have this drug but we’re not going to give it to you.’ That is really not a good situation.”

So in July 2015, MGH opened a compassionate care clinic for patients with treatment-resistant depression with 14 psychiatrists and eight psychologists on staff.

Patients receive a small intranasal dose of ketamine at the clinic and are not allowed to leave unescorted. They continue to self-administer at home with follow up visits scheduled.

Based on her experience, Cusin said she believes patients treated with ketamine have become more stable and better able to benefit from psychotherapy. She would like to pursue research to measure the effectiveness of psychotherapy treatments in conjunction with ketamine, although she acknowledged the funding climate for such study is challenging.

“The patient does a lot of work to repair the damage caused by years of severe depression, the loss of having to be on disability, the chronic emotional pain, the loss of relationships, the loss of self-esteem or seeing themselves in a very sick way. They have a lot of work,” Cusin said.

Nemeroff, a professor and chairman of the University of Miami Miller School of Medicine Department of Psychiatry and Behavioral Sciences, said ketamine is not being used to treat depression at the clinic there. “We don’t think that there is sufficient evidence yet to administer ketamine here,” he explained.

A case study published online March 1 in the American Journal of Psychiatry is about a 52-year-old man with a long history of depression who received intranasal ketamine from an out-of-state prescriber and later died in a car crash he is believed to have intentionally caused while drunk shows the significant risk involved with a drug still in its experimental phase.

Janssen Pharmaceuticals, Inc., a subsidiary of Johnson & Johnson, is conducting Phase 3 clinical trials of intranasal esketamine for treatment-resistant depression and completing a Phase 2 study of intranasal esketamine in patients with major depression who are at imminent risk for suicide.

Esketamine is a mirror-image of R-ketamine and these two enantiomers comprise ketamine according to Janssen spokesman Greg Panico who said the findings will be presented at the Society for Biological Psychiatry meeting in Atlanta in May. Janssen plans to submit filings to the FDA for these indications by 2019.

For now, many don’t see a role for ketamine to treat depression on an outpatient basis. While some research suggests it can lead to rapid symptom reduction for patients with chronic PTSD, ketamine is not prescribed at the Providence Veterans Affairs Medical Center.

Several large-scale population studies showing its effectiveness would have to happen first, according to Tracie Shea, Ph.D., a staff psychologist at the Posttraumatic Stress Disorders Clinic and director of PTSD Research.

“Typically what you find is that early research tends to be more positive and then over time you get sort of a more realistic view of how things work,” Shea said, a professor in Brown University’s Department of Psychiatry and Human Behavior.

Shea said ketamine’s benefit would be its potential to stabilize someone in a crisis.

“I would see it, based on what I know about it, as a temporary fix,” Shea added. “There’s nothing that shows it can be continued over an indefinite period of time. Depression seems to be very recurrent. So I would see it as an aid to an acute problem rather than a quick fix.”