Ketamine, a drug that’s been retooled as a “breakthrough” in depression treatment, is one step closer to becoming mainstream medicine, thanks to the results of a Phase II clinical trial published this week in the American Journal of Psychiatry. But some experts are wary of creating a new drug-abuse crisis by introducing a potentially addictive drug to millions of new users.
Ketamine’s role has shifted plenty since its initial discovery in the 1960s. It was first (and continues to be) used as an anaesthetic, sedative, and painkiller for both animals and people. But by the 1970s, people realised it could also be a recreational drug if snorted in powder form to create a psychedelic high. More recently, doctors have been successfully using low doses of ketamine to treat patients whose depression doesn’t respond to other treatments.
Because ketamine’s effects are much faster-acting than existing antidepressants, which can take four to six weeks to alleviate symptoms, doctors have also theorised that it could quickly help people in the middle of a serious depressive crisis who are experiencing suicidal thoughts.
Currently, though, ketamine isn’t officially approved as a depression treatment. And its beneficial effects are only reliably apparent when given through an IV infusion. Janssen Pharmaceutica, a pharmaceutical company under the umbrella of Johnson and Johnson, has been trying to develop a nasal spray version of ketamine, called esketamine.
In their latest study, Janssen scientists collaborated with the Yale School of Medicine to test out the nasal spray drug in a double-blinded, randomised, placebo-controlled trial.
Across 11 different study sites, researchers recruited 68 severely depressed patients who were at immediate risk of suicide. The patients, admitted to an inpatient psychiatric unit, were given standard antidepressant treatment. But they were also randomised to receive twice-weekly nasal spray doses of esketamine or a placebo for 24 days.
Much like in other trials that involved ketamine infusion, the researchers found that patients who received esketamine experienced a greater reduction of suicidal thoughts and depressive symptoms within four hours of treatment compared to placebo patients. And the difference was largest between the groups within 24 hours.
“These findings may reflect a promising breakthrough in the clinical management of a potentially lethal condition for which there are no approved pharmacotherapies,” the authors wrote.
As the authors themselves point out, however, Phase II trials are only intended as a proof-of-concept. But a Phase III trial of esketamine, which examines safety and efficacy in a larger group of patients and is needed for final FDA approval, is already underway.
But though plenty of doctors and patients are excited about the potential of ketamine, many are also nervous about the unintended consequences of expanding ketamine use.
In an accompanying editorial—co-written by 20 members of the editorial board of the journal—the authors invoked the spectre of the opioid crisis as a worst-case scenario for what could happen.
“The history of pharmacology includes many life-saving drugs. However, it is also replete with examples of drugs whose abuse has outweighed their intended therapeutic effect,” they wrote. “The most recent example is oxycodone, which was developed as an alternative to older abused opioids and then heavily promoted to protect patients from pain after medical and dental procedures.”
As it has now become apparent, the manufacturers of oxycodone, Purdue Pharma, willfully misled doctors and the public about the drug’s addictive potential. The greater availability and access to oxycodone and similar painkillers then helped spark the first wave of the crisis beginning in the late 1990s.
The doses of ketamine given in infusion therapy are less potent than a person would take recreationally to get a high, but the editorial authors noted there have already been reports of depression patients becoming dependent and trying to abuse the drug. Some have shopped around for infusion clinics that will let them dose repeatedly and/or without supervision; others have become addicted to nasal spray formulations of ketamine. And supplies of ketamine used for anesthesia are already being sold illicitly. These risks could only become greater with an easily obtained version like esketamine, they warn.
Adding to that, ketamine isn’t a miracle drug for depression either. About 50 percent to 60 percent of patients respond to it, and even in these individuals, its unique effects don’t last long. In the current study, though esketamine patients felt less depressed and suicidal than they did in the beginning, they ultimately weren’t any better off than the placebo plus standard treatment group by the end of the 24 days. There were no signs of ketamine dependence in their study sample, the researchers said.
Far from shutting the door on ketamine entirely, the editorial authors instead advocate that a framework for safe treatment be established now, before the genie is completely out of the bottle. Doctors and hospitals could be required to only let patients use esketamine under their direct supervision, they suggested. Or, similar to opioid prescriptions now, patients could have their ketamine prescriptions recorded in a nationwide registry, to prevent people from visiting multiple doctors to get more doses.
These steps “would not be intended to deny therapeutic help to patients with significant need,” the authors wrote. “Rather, the aim is to establish the risk for abuse and the framework within which that treatment will continue to be available to those with need, while the population that is at risk for abuse is protected from an epidemic of misuse.”