The Past, Present and Future of Using Ketamine to Treat Depression

The first time Ashley Clayton tried ketamine to treat her depression, it was as if time folded in on itself and there was nothing but the present. Initial responses to doctor-prescribed ketamine run the gamut: some patients enter a dream-like state, while others have been known to tell inappropriate jokes or convince themselves that they’re dead.

Clayton’s experience was mild by comparison, albeit disorienting, and she still searches for the words to explain it even today. The next morning, though, after the fog of fatigue and nausea dissipated, she felt more like herself than she had in years.

At the time, in 2016, Clayton was participating in a Phase II clinical trial to determine the most effective dose of intravenous ketamine for alleviating depression. Trials such as these help determine a drug’s efficacy and dosing, before researchers can move on to the final testing phase and prepare an application for FDA consideration. Clayton had tried psychotherapy and an arsenal of traditional oral antidepressants over the years, but her severe depressive symptoms and suicidal ideations persisted.

Once they began to interfere with her job as a research associate at Yale University, she knew she needed a new approach. Yale is home to a respected ketamine research program, so she began asking around to see if she could enroll in a clinical trial. Today, six years and countless insurance battles later, she’s received nearly 150 ketamine infusions. “It is a lifesaving treatment for me,” she says.

Depression is the third-leading cause of disability worldwide. Even if successfully treated, however, 80 percent of patients will relapse in the five years following remission. Over 30 percent will fail to respond to at least two antidepressant treatments, and be diagnosed with treatment-resistant depression.

Ketamine, meanwhile, was first used in clinical practice in the 1960s as a safer alternative to the anesthetic phencyclidine (PCP), which has been discontinued in the U.S. due to the high incidence of postoperative delirium with hallucinations. In 1970, the FDA approved ketamine as a general anesthetic, and today it resides on the World Health Organization’s Model List of Essential Medicines. But research on ketamine’s antidepressant effects has only taken off in the last couple decades.

In 2000, a team at Yale School of Medicine published the first randomized controlled trial to demonstrate ketamine’s antidepressant effects. Led by John Krystal, now the chair of the school’s psychiatry department, the researchers showed that a single subanesthetic dose (less than what would be given for anesthesia) of ketamine improved depression—and in some cases led to a near complete recovery—in less than 24 hours.

It would take several years and mounting evidence from multiple research groups before ketamine gained traction in the medical community as an effective antidepressant. By 2010, many physicians were so convinced by this series of preliminary studies that they started adopting ketamine—perhaps preemptively—into their clinical practice. And in 2019 the FDA approved a ketamine-based antidepressant (tradename Spravato) for the first and, so far, only time to treat treatment-resistant depression, and later approved it to treat suicidal ideation and behavior in adults with major depression. (Editor’s note: Janssen Pharmaceuticals, the maker of Spravato, is a current advertiser with Smithsonian magazine. The company did not have influence over or provide any direction in the editorial process, including this story.)

Since then, ketamine’s antidepressant potential has captivated researchers, pharmaceutical companies and patients alike. As the pool of clinical and real-world data continues to grow, the treatment appears to be special in more ways than one. While traditional antidepressants take weeks to kick in, even the sickest patients may begin to respond to ketamine as early as a few hours after administration. Researchers also suspect it could help build a more resilient brain in the long-term. However, the U.S. Drug Enforcement Administration classifies ketamine as a Schedule III drug, which means it has a moderate to low potential for physical and psychological dependence (less so than Schedule II drugs such as cocaine, but more so than Schedule IV drugs such as Xanax).

Beyond ketamine’s abuse potential, it can cause other extreme side effects, including a short-lived state of altered consciousness immediately following treatment. This is known medically as a dissociative episode and colloquially as the “K-hole” if the dose is high enough.

Despite warranted trepidation, many herald the discovery of ketamine’s rapid antidepressant effects as the most significant psychiatric development in recent decades—one that is overturning what we thought we knew about the neurobiology of depression. Now, scientists are leveraging the knowledge they’ve gained to reduce ketamine’s less desirable effects, and even inform other unconventional depression treatments, such as the psychedelic psilocybin.

Besides exerting its effects much faster than existing antidepressants, ketamine also affects the brain differently than other popular antidepressant medications that are considered “monoaminergic.” They increase levels of the so-called “monoamine” brain chemicals serotonin, dopamine and norepinephrine to improve mood. However, ketamine seems to primarily impact a different brain chemical called glutamate, which helps stimulate brain cells to communicate.

Researchers have a good sense of where ketamine first binds in the higher brain centers to affect cognitive and emotional functioning. But, as with many drugs, the specific mechanisms by which it exerts its effects remain more mysterious. Researchers also think ketamine may be able to reverse the damage to the connections between brain cells caused by chronic stress. This may be why its antidepressant effects seem to last longer over consecutive doses, and suggests that it could help protect against depression relapse.

Ketamine exists in two different forms that researchers suspect have slightly different properties. They are mirror images of one another, much like your right and left hands. One is called R-ketamine and the other is S-ketamine (sometimes spelled “esketamine”). The version of ketamine that the FDA approved for anesthetic purposes is equal parts R- and S-ketamine. Since then, the patent has expired and it is now a generic drug often called “racemic” ketamine. This treatment is the one that Ashley Clayton has responded to so successfully.

Physicians have been prescribing racemic ketamine off-label to patients with depression for at least two decades. Using an approved drug for unapproved purposes (such as prescribing anti-seizure medications to reduce nerve pain) is perfectly legal with the patient’s informed consent. Medical providers often do this when a suffering patient has exhausted all other options. However, many insurance companies won’t cover the cost of off-label treatments, forcing patients to choose between paying large sums or forgoing a potentially life-saving remedy.

In many cases, a drug that’s widely prescribed for an off-label indication may never be FDA approved for that same treatment, especially if—like racemic ketamine—the drug is generic. Pharmaceutical companies have little financial incentive to fund trials exploring new avenues for generic drugs because they can’t recoup their investment, explains Husseini Manji, who led the team at Janssen—a subsidiary of Johnson & Johnson—that developed Spravato. In addition to being the first ketamine-based FDA-approved antidepressant, Spravato—which is pure S-ketamine—is also the first drug that the FDA has approved that works by modulating glutamate to treat depression.

Before making the switch to industry, Manji served as the director of the mood and anxiety disorders program at the National Institutes of Health, and was a co-author on the first study to replicate Krystal’s findings in 2006. He posited that a nasal spray might be the most practical approach to delivering racemic ketamine to patients, because it wouldn’t require an anesthesiologist to be present. And, entering through the nose would mean reaching the brain faster. However, a spray would deliver much less of the drug, so his team opted to use pure S-ketamine, which they showed was three- to four-times more potent than R-ketamine.

From start to finish, Manji says the entire FDA approval process totaled roughly 25 different studies enrolling thousands of participants. The most common adverse side effects tend to be dissociation, nausea, vertigo, altered sense of taste and dizziness. These appear shortly after dosing and resolve after about an hour and a half. In Phase III trials, many patients with treatment-resistant depression began to see a reduction in depressive symptoms in just 24 hours when given Spravato in conjunction with an oral antidepressant. Manji says many individuals require fewer treatments over time—for example, transitioning from twice-a-week administration to once every several weeks.

The success of Spravato has spurred other pharmaceutical companies to return to antidepressant development and the neuroscience field more broadly after a decades-long hiatus, says Carlos Zarate Jr., chief of experimental therapeutics and pathophysiology at the National Institute of Mental Health and Manji’s former NIH colleague. After President Richard Nixon declared a “war on cancer” in 1971, many pharmaceutical companies shifted their focus and investments to oncology and immunology, which—unlike mental health disorders—had clear therapeutic targets. However, today dozens of companies are cropping up that are devoted to conducting ketamine research and development. Some such companies are working on new delivery systems for the drug—ranging from patches to microneedles.

While some researchers are investigating ways to prolong ketamine’s antidepressant effects using more traditional treatments like psychotherapy, others like Zarate are working to build a better ketamine without the abuse potential and initial dissociative effects. Zarate is studying several of ketamine’s metabolites known as hydroxynorketamines (HNKs), which can offer rapid, sustained antidepressant effects in animal models. Later this year, he and his colleagues plan to begin a clinical trial testing one metabolite called (2R,6R)-HNK in human patients with treatment-resistant depression. He says that new technologies will soon enable treatments that work right away without side effects. “We're not there yet, but we're on the journey.”

Many questions still remain, though, such as which receptors ketamine binds to in the brain. For example, there’s evidence suggesting that ketamine may activate the brain’s opioid system, but it’s still unclear whether this is key to ketamine’s rapid acting antidepressant effects or its misuse potential. “There are concerns about the abuse potential that we should not minimize,” Zarate says. Part of the solution, he explains, is to ensure that standardized procedures are in place to prevent ketamine from being prescribed too “loosely.”

As a patient herself, Clayton frequents online patient forums where individuals recount receiving “cowboy” treatments like ketamine lozenges, which have little to no scientific basis and resemble something from the Wild West of medicine. While providers must follow Spravato’s designated risk evaluation and mitigation strategy protocol, no such standardized, FDA-approved procedure exists for dispensing intravenous racemic ketamine to treat depression. This form of ketamine has been administered by anesthesiologists at independent clinics for years to treat off-label indications such as chronic pain. As more of these clinics begin to treat depression, Clayton worries that patients could be put at risk if the presence of a trained psychiatrist is not required.

To this day, Clayton continues to receive ketamine treatments every other week. She tried participating in Spravato’s clinical trials prior to its FDA approval, but did not respond well to it. She’s opted for intravenous racemic ketamine ever since, but her insurance refuses to cover it. The drug itself is relatively cheap, she explains, but the time and oversight required to administer the infusions raises the out-of-pocket costs to anywhere from $600 to $2,000 per treatment. As a result, she’s been relying on the goodwill of her doctors and hospital administrators to provide care free of charge.

Looking back, the amount of pure luck that saved her life was harrowing; she had access to medical resources and attentive physicians that many others don’t. As a mental health researcher at Yale’s Family Violence Research Program, she’s formally trained in healthcare advocacy and better positioned than most to navigate the complexities of the healthcare system. And yet, she says, “it was almost impossible for me to be able to access this treatment, and I almost died in the process.”

Despite the many hurdles that remain regarding ketamine access, treatment protocols and side effects, with the trepidation comes optimism. Patients and providers alike hope that ketamine will usher in a new era of novel drug treatments, and reveal a clearer picture of depression’s neurological underpinnings.

“These are drugs that have profound effects on consciousness,” Krystal says. “And so we're really learning about the neurobiology and psychopharmacology of the higher aspects of human consciousness as we're learning about these illnesses and their treatment. And that, too, is really exciting.”