Ketamine, often associated with street drug "Special-K" and also a hospital-grade anesthetic, could be a breakthrough, fast-acting therapy for major depression in a nasal spray form, according to a new study.
People with depression are 20 times more likely to attempt suicide than the general population. Standard antidepressants prescribed can take four to six weeks to take effect, leaving those with severe depression vulnerable at a time of need. Even worse, those with severe depressive symptoms or judged to be at high immediate suicide risk are often left out of clinical trials for anti-depressant medications.
But a small "proof of concept" study of 66 people, conducted by Yale Department of Psychiatry and Janssen Research at 11 hospitals around the U.S., suggests a possible remedy.
People with severe depression who had been hospitalized for high suicide risk were given esketamine, a nasal spray form of ketamine, along with standard care that included antidepressants and counseling.
Within four hours, the 35 people who received esketamine showed rapid improvement of depressive symptoms and suicidal thoughts, with much better scores on a depression symptom scale than the 31 people who received regular care and a placebo nasal spray. After the first dose, only 29 percent of the esketamine group had "common" or "explicit" suicidal thoughts, compared to 58 percent in the group that had received the placebo.
How esketamine could help bridge the 'efficacy gap'
Esketamine and other ketamine derivatives are attracting interest from many doctors because they could be used to bridge the "efficacy gap" -- the time between the appearance of severe depression and the time standard antidepressant drugs begin to have an effect.
Now that this small study has shown the drug’s potential to rapidly help counteract severe depression faster, larger scale studies can now be done.
Esketamine is probably not a long-term solution for the majority of people with depression; after four weeks, the anti-depressant effect was no different than standard care, and there are side effects. Ketamine is known to cause hallucinations and feelings of "dissociation" -- feeling detached from the immediate surroundings, or even from all physical or emotional experiences.
At the doses used in this study, most patients who got esketamine reported this effect after each dose, though their symptoms were less intense with repeat doses. Five of the 35 patients had to stop taking the drug due to other side effects: Agitation, aggression, dizziness and abnormal heart rhythm.
Ketamine-family medications cause a short-term rise in blood pressure after each dose. While this isn’t an issue when the medication is used for a few days or weeks, this effect may limit its use in the long term and may disqualify those with very high blood pressure from using this medication.
Regulating the use of ketamine to prevent addiction
Prolonged use of ketamine can also lead to addiction. In the world outside the hospital, people abuse ketamine and its derivatives to get high. One of the questions becomes: How can it be safely prescribed to treat depression?
In an editorial published with the study in the American Journal of Psychiatry, Dr. Robert Freedman and several colleagues envisioned a scenario similar to the way oxycodone entered the market. Oxycodone was marketed as a "safe alternative" to the other narcotic painkillers. It then became a major source of addition and abuse, with more than 50,000 admissions per year for addiction to oxycodone alone. Aggressive marketing of prescription narcotics, coupled with an initiative for doctors and nurses to “take pain more seriously,” were key triggers of the current opioid epidemic rippling through the healthcare system.
Like oxycodone, the editorial noted that esketamine could become a drug "whose abuse has outweighed their intended therapeutic effect."
The medication can also be highly beneficial, also like oxycodone and other opioid painkillers, when used for the right person and for the right length of time.
"Just as it is considered irresponsible to ask patients to tolerate pain, it is irresponsible to deny a suicidal patient the fullest range of effective interventions," Freedman added in the editorial.
That’s why, if it receives FDA approval, doctors would need to take steps to ensure ketamine would be used responsibly. The first step would likely be to identify patients who will best benefit from the drug: Those with the most severe and treatment-resistant depression.
Just as importantly, individuals prescribed the drug would need to be re-assessed frequently.
Esketamine has not yet been FDA-approved for depression treatment. But some experts suggest that, if approved, esketamine administration should follow the path of methadone. Methadone, a mild long-acting narcotic, is prescribed for those with chronic pain or opioid use disorder to avoid use or abuse of stronger narcotics. At verified “methadone clinics,” a person’s diagnosis and appropriate methadone dose is carefully documented. At first, individuals have to come to the clinic every day to take their daily dose in a supervised environment. They also get counseling sessions, and eventually many are able to space out their visits and are given enough doses to fill the interim.
Ketamine drugs could be administered in the same fashion. Urine drug screening could be used to ensure that ketamine levels are low enough to actually need a repeat dose. A national registry of esketamine prescriptions could identify those receiving multiple doses from multiple prescribers. Limiting prescriptions to approved facilities might prevent inappropriate use by patients and physicians alike.
Research shows that esketamine could have major potential to help severe depression in people at high risk for suicide or who have not responded to other therapies. With careful study and awareness of its potential downfalls, it may become a valuable component of mental healthcare for people with immediate need.
Dr. Kelly Arps is a resident physician in internal medicine at Johns Hopkins Hospital. Kelly is working with the ABC News Medical Unit.