Doctors and medical researchers have spent decades trying to find a solution to treatment-resistant depression, one of the most intractable and challenging problems in mental healthcare. But a series of breakthroughs over the past twenty-five years have suggested the answer could lie in a surprising place: ketamine therapy.
Most patients suffering from depression are prescribed a course of treatment that relies on selective serotonin reuptake inhibitors (SSRIs) and psychotherapy. As many as two thirds of people struggling with depression, however, find that the conventional approach has little effect. Generally, the only other option available is electroconvulsive therapy (ECT) — which doesn’t always work, either.
In their search to find alternative treatments, scientists and medical researchers have become increasingly interested in the potential of psychedelics like ketamine and psilocybin, and evidence suggests they are on to something.
We know that when ketamine works, it works faster, produces fewer side effects and is much cheaper than ECT.
Dr. Pierre Blier, Director of Mood Disorders Research at The Royal Institute of Mental Health in Ottawa, has been studying the effects of ketamine therapy since 2010. He believes that ketamine could become a viable alternative when it comes to treatment-resistant depression.
“We know that when ketamine works, it works faster, produces fewer side effects and is much cheaper than ECT,” Blier said in an interview with The Royal Institute of Mental Health published in 2019.
But what is ketamine therapy, and how did a drug that many still associate with the club scene become the potential key to solving one of the biggest questions in mental health research?
From anesthetic to anti-depressant
The story of ketamine begins in the nineteen fifties, at the Detroit, Michigan-based pharmaceutical company Parke-Davis.
According to a short history of ketamine published in the European Journal of Anaesthesiology, researchers were experimenting with chemical compounds in an attempt to synthesize a new anesthetic agent that would have analgesic properties — something that would suppress sensory stimulation while also helping with pain management.
In 1962, after several attempts to find an agent that would have the desired effects and be safe for human use, Dr. Calvin Stevens, a chemical consultant at Parke-Davis, synthesized a phencyclidine derivative that combined a ketone with an amine. The combination of these two compounds gave the drug the name we know it by today: ketamine.
Ketamine was first patented in Belgium the following year, where it was used as a veterinary anesthetic (the origins of its reputation as a horse tranquilizer), and then patented again by the Parke-Davis team in 1966, after trials proved it could also be safely used to treat humans.
By this point, the U.S. was ramping up its involvement in the Vietnam War, and medical professionals working with U.S. forces were looking for anesthetics that could be used on wounded soldiers undergoing surgery. Because ketamine doesn’t slow breathing or heart rate, patients didn’t need to be hooked up to a ventilator in order to receive it, making it ideal for use in combat situations.
Ketamine saw its first widespread military use during the final years of the sixties, and by the seventies civilian anesthesiologists had adopted it as well. But the effects of ketamine were not particularly well understood. While it could relieve pain and suppress sensory stimulation, it also had other effects — the most famous being the dream-like states of euphoria and dissociation patients reported after using the drug.
It was these ketamine side effects that caused it to be described as a “dissociative anesthetic,” a term coined by Toni Domino, the wife of one of the researchers on the Parke-Davis team.
While ketamine’s dissociative qualities were seen as secondary by researchers trying to synthesize a new anesthetic, they are precisely what caused a new generation of medical researchers to become so interested in the drug’s potential for treating depression and mental illness decades later.
Exploring the potential of ketamine therapy
Ketamine’s potential as an anti-depressant was discovered accidentally. According to Ken Stewart, an emergency doctor who founded the treatment facility Insight Ketamine, first responders started using ketamine to calm down agitated patients after suicide attempts. Over time, reports began to filter in that the drug continued to have positive effects for months following treatment.
When enough stories like that started to pile up, doctors said, ‘Maybe there’s something here.’
“Someone is trying to jump off a bridge and they give him ketamine in the ambulance to calm him down and 9 months later, he says, ‘I haven’t felt suicidal for 9 months,’” Stewart explained, in an interview with WebMD. “When enough stories like that started to pile up, doctors said, ‘Maybe there’s something here.’”
The first major studies into the anti-depressive effects of ketamine were conducted in the late nineties and early two-thousands, with the first esketamine nasal spray reaching the market in 1997. Over the years, researchers have consistently found that while ketamine side effects include abdominal pain, liver injury, spiking blood pressure, and the potential for abuse, its immediate and long-lasting anti-depressant effects are too significant to ignore.
Unlike conventional anti-depressants like SSRIS, which can take weeks or even months to kick in, ketamine can have a noticeable impact within hours. For example, a 2019 study in the Indian Journal of Psychiatry found that subanesthetic doses of ketamine “has a robust and rapid effect on depression, which was seen immediately after the administration of ketamine and sustained at the end of one month.”
It is perhaps ironic, given ketamine’s origins as a battlefield anesthetic, that it could also prove useful in treating post-traumatic stress disorder (PTSD). Though research is still at the preliminary stage, a study published in the American Journal of Psychiatry specifically looking at the effects of ketamine therapy on patients suffering from PTSD found that two-thirds of participants responded to ketamine therapy — compared to one-fifth who responded to the midazolam, the psychoactive control.
The future of ketamine therapy
The growing interest in ketamine therapy is part of a general sea change in attitudes about psychedelics. Where substances like psylocibin and cannabis were once viewed as being primarily recreational and potentially dangerous, researchers are becoming increasingly interested in the medical potential these drugs have for treating mental illness.
Despite all the breakthroughs, ketamine (in the form of esketamine nasal spray) remains a Schedule III non-narcotic substance in the U.S., generally used only for anesthetic and pain management purposes. It was only in 2019 that the U.S. Food and Drug Administration (FDA) cleared it for use for treatment-resistant depression, and it can only be administered through certified doctor’s offices and clinics.
I foresee continued growth in its role in the treatment of depression in the U.S. and around the world.
But for those suffering from forms of depression that have resisted all conventional forms of medical or therapeutic treatment, new research holds out hope that new types of psychotropic drugs based on research into ketamine therapy and psychedelics could succeed where more conventional medication has failed.
“The anti-depressant effects of ketamine are truly remarkable,” John M. Krystal, Chair of Psychiatry at Yale University, noted in an interview with Verywell Health. “I foresee continued growth in its role in the treatment of depression in the U.S. and around the world.”