That the drug can treat patients in hours or days, instead of weeks or months, has sent scientists chasing its mechanism of action
When it comes to treating depression, Gerard Sanacora thinks ketamine is a game-changer. A textbook changer, really.
To illustrate his point during lectures, the Yale University neuroscientist likes to include a slide showing an excerpt from a 20-year-old psychiatry textbook. The book “has this whole section about how it’s well known and accepted that recovery from depression takes weeks, if not months, through treatment” with medication, Sanacora says. In contrast, studies run in the past 2 decades have demonstrated that small doses of ketamine can relieve depression symptoms in hours or days.
The drug, originally used in humans as an anesthetic starting in the Vietnam War, not only acts fast but also works in people who don’t respond to other antidepressants. About one-third of people with depression today have treatment-resistant depression (TRD). Ketamine “has changed the expectations in the field,” Sanacora says.
The US Food and Drug Administration showed just how much expectations have changed by approving Janssen Pharmaceuticals’ nasal spray containing Ketamine for sale, the S enantiomer of ketamine, as the first form of ketamine to treat depression, specifically TRD. (The S form of the drug binds to ketamine’s target in the brain more strongly than the R form.) Previously, doctors would administer low doses of a mixture of (R)- and (S)-ketamine to patients off label and through intravenous infusions.
To find molecules that were more effective than these types of drugs, a group of researchers at Yale University in the late 1990s looked beyond the monoamines and zeroed in on another neurotransmitter: glutamate. As the main excitatory neurotransmitter in the brain, it pushes neurons to fire electrically. Research at the time indicated that glutamate somehow regulated brain circuits implicated in depression, says Dennis Charney, one member of the Yale group and currently the dean of the Icahn School of Medicine at Mount Sinai.
The Yale group decided to test ketamine in part because the anesthetic blocks a glutamate receptor in the brain called the N-methyl-d-aspartate (NMDA) receptor. The researchers administered low doses of the drug to patients to avoid their dissociative side effects as much as possible. Charney compares the experience of watching patients unexpectedly feel better just hours after a dose to the movie Awakenings. In that film, a patient stuck in a catatonic state for decades suddenly wakes up when treated with the drug l-dopa.
The Yale team published its results in 2000 (Biol. Psychiatry, DOI: 10.1016/s0006-3223(99)00230-9), but scientists didn’t believe patients could feel better that quickly, Charney says. And, he admits, it was a relatively small trial, with just seven patients. So a few years later, after Charney had moved to the National Institutes of Health, he worked with a new team to replicate the study with 18 patients. Before the trial, the patients had all been diagnosed with TRD and, on average, had tried about six antidepressants without finding relief. But 71% of them responded within hours to a small ketamine dose (Arch. Gen. Psychiatry 2006, DOI: 10.1001/archpsyc.63.8.856).
Since Charney and his colleagues published their results in 2006, other researchers have confirmed ketamine’s rapid antidepressant effect. Scientists have also collected encouraging data showing that ketamine might treat other psychiatric conditions, such as posttraumatic stress disorder, suicidality, and obsessive-compulsive disorder. And they have developed the esketamine nasal spray to provide an easier way for doctors to administer the drug.