Ketamine is revolutionizing antidepressant research, but we still don’t know how it works

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.

In March 2019, the US Food and Drug Administration showed just how much expectations have changed by approving Janssen Pharmaceuticals’ nasal spray containing esketamine, 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.

The excitement over ketamine among depression researchers and clinicians is clear. They point out that ketamine is the first drug with a new mechanism to treat depression in more than half a century.

But their excitement is tempered with caution. Despite its promise, ketamine comes with side effects such as out-of-body experiences and spikes in blood pressure. Some psychiatrists also worry about its abuse potential and point out that it is taken as a club drug, sometimes known as Special K.

So researchers are now looking for similar molecules that deliver ketamine’s rapid antidepressant effect without its side effects. But to design these molecules properly, the scientists first need to answer one of the field’s biggest questions: How does ketamine do what it does in the brain?

Enter ketamine

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 its 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.

Still, ketamine researchers point out that the field needs to answer some questions when it comes to treating people with the drug. “While I really see ketamine as a game changer that gives hope to patients who are really desperate for help, we need caution,” says Carolyn Rodriguez, a psychiatrist at Stanford University who has studied treating obsessive-compulsive disorder with ketamine.

For example, for how long should a patient receive the drug? Most studies have looked at the effects of just a single dose of ketamine. The clinical trial for esketamine treated patients for over a year. But is it safe to treat patients on a more long-term basis? And what happens when a patient stops taking the drug? In a commentary in the American Journal of Psychiatry, Alan F. Schatzberg, a psychiatrist at Stanford, expressed concern about how people responded when they came off the drug in the esketamine trial (2019, DOI: 10.1176/appi.ajp.2019.19040423). He noted that three patients died by suicide after they stopped taking the drug for between 4 and 21 days, and two of those patients had not been suicidal before stopping the drug.

Researchers think that as more patients start taking ketamine, many of these questions will be answered but that because of the drug’s downsides, patients need to be monitored carefully. In 2017, the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments published a consensus statement on best practices for treating people with ketamine (JAMA Psychiatry 2017, DOI: 10.1001/jamapsychiatry.2017.0080). It suggested that people administering the drug should be trained to monitor for adverse cardiovascular side effects like elevated blood pressure and heart rate. Also, because the drug can cause psychological side effects—like anxiety and out-of-body experiences—the report emphasized that doctors should monitor for these events and be ready to manage them.

Then there’s the abuse issue. While ketamine has a long history of being a safe anesthetic, it has also been abused as a street drug. Because of this abuse potential and the other side effects, the new esketamine nasal spray can be administered only at certified facilities to ensure health-care professionals can monitor these issues.

Finding a better ketamine

All these downsides to ketamine have led researchers to look for other molecules with rapid antidepressant effects but with less baggage. Unfortunately, a complete picture of how ketamine produces its antidepressant effect doesn’t exist, making it hard to know which targets in the brain are the best to go after.

Still, scientists have some hints of the drug’s mechanism, based on studies in people and animals. For example, taking low doses of ketamine produces a sudden burst of glutamate signaling in the brain, followed by rapid increases in the number and strength of synapses in specific brain regions—namely, the medial prefrontal cortex and hippocampus. Research has found that synaptic connections in these regions become weaker in laboratory rodents with depression-like symptoms. Ketamine researchers think the drug’s glutamate-triggered strengthening of these synapses is key to its antidepressant effect. And they think that ketamine acts faster than previous antidepressants because it acts directly on synapses, whereas the older, monoamine drugs act on synapses more indirectly.

One way scientists have tried to replicate ketamine’s effect on synapses is to target a protein complex called mTORC1, which is involved in strengthening those connections between neurons. When neurons form synapses or strengthen existing ones, they need to synthesize proteins and other biomolecules, including lipids and nucleotides. mTORC1 helps cells rev up that synthetic machinery. Experiments in animals have shown that mTORC1 is necessary for synthesizing new synaptic proteins and that inhibiting the complex can block ketamine’s antidepressant effect. Navitor Pharmaceuticals has designed a molecule called NV-5138 to activate mTORC1, says Thomas Hughes, the company’s CEO. NV-5138 completed three Phase I trials during the fall of 2019.

Meanwhile, other scientists looking for ketamine-like antidepressants have focused on sparking glutamate signaling. But so far, those efforts have not been fruitful. “We know glutamate is important, but we are still struggling a bit as to how to target that system in a way that will produce the ketamine response but without the side effect profile,” says Ronald Duman, a neuroscientist at Yale University.

Some scientists have looked at ketamine’s anesthetic target, the NMDA receptor. This receptor is an ion channel that allows calcium and sodium ions to flow into a neuron when opened by a combination of the right electrical conditions and the binding of glutamate and another molecule, sometimes glycine. Ketamine blocks this ion flow by binding inside the ion channel, essentially acting like a plug in a bathtub.

But the question is, How does ketamine trigger glutamate signaling by blocking the NMDA receptor? In the brain, some neurons tell other neurons to fire, while others tell those same neurons to stay quiet. Researchers think that ketamine blocks NMDA receptors on the neurons transmitting that quiet signal. “In the simplest sort of cartoon version, what we think is that ketamine specifically blocks the NMDA receptor on inhibitory neurons and by blocking that, you’re actually increasing activation,” Yale’s Sanacora says. In other words, ketamine stops the inhibitory neurons from putting the brakes on, leading to an increase in glutamate signaling. How ketamine could selectively target inhibitory neurons is not yet clear.

This idea of silencing inhibitory neurons has led some scientists to test other NMDA-receptor blockers and antagonists for antidepressant activity. But blockers like memantine, which is used to treat dementia, and AstraZeneca’s lanicemine have had mixed results in clinical trials. And Cerecor’s rislenemdaz, which indirectly blocks the glutamate-binding site on the NMDA receptor, failed in a Phase II clinical trial for TRD in 2016.

“We still don’t know exactly why these other [NMDA] blockers do not work,” Duman says. He and others wonder if there are subtle differences between how ketamine and these other molecules block the ion channel that scientists don’t fully appreciate.

Meanwhile, other scientists have taken a different approach by developing molecules that enhance NMDA receptor function through so-called partial agonists, which turn on receptors but not to their full extent. Such molecules could activate the excitatory neurons in the brain that tell other neurons to fire. One partial agonist that’s reached clinical trials is rapastinel, originally designed by Joseph Moskal of Northwestern University and then acquired by Allergan. The molecule helps activate the receptor by binding to it in a novel way, separate from how glutamate and glycine bind to it.

The molecule failed to outperform a placebo in Phase III trials in March last year. Moskal still thinks this approach is valid because of promising preclinical and Phase II trial data for rapastinel. Allergan has a similar molecule working its way through clinical trials.

Further complicating the ketamine mechanistic picture is a recent study led by Stanford’s Schatzberg that suggests ketamine may also act outside the NMDA receptor to produce its antidepressant effect. “I’d been struck by the fact that other NMDA antagonists are not particularly antidepressant,” he says. “There’s got to be another mechanism of action.”

Given that ketamine has been a drug of abuse, Schatzberg wondered if the opioid systems in the brain, which are strongly linked to abuse, were involved in ketamine’s mechanism. In 2018, he and his colleagues, including Rodriguez, published the results of a small study demonstrating that giving people naltrexone before giving them ketamine prevented the antidepressant effect (Am. J. Psychiatry, DOI: 10.1176/appi.ajp.2018.18020138). Naltrexone is given to people who are dependent on opioids to help wean them off the drugs. It works by blocking the mu opioid receptor in the brain, which is activated by morphine and its kin.

Schatzberg’s team hasn’t yet determined the molecular mechanism behind its ketamine observation, but this involvement of the opioid system, Schatzberg says, raises questions about whether people may experience withdrawal-like symptoms when they stop taking the drug.

Yet others aren’t convinced that ketamine acts on the opioid system. They point to data published in 2019 on a small group of patients who received naltrexone before ketamine and still experienced an antidepressant effect (JAMA Psychiatry 2019, DOI: 10.1001/jamapsychiatry.2018.3990). Both studies are small, Duman points out, so the experiments have to be replicated for the field to figure out what to think about this mechanism.

Ketamine metabolites

While some researchers have focused on the actions of ketamine in the brain, others have reported data that suggest one of its metabolites may be behind the rapid antidepressant effects. Ketamine’s metabolites had been ignored as biologically inactive because they have a low binding affinity for the NMDA receptor and do not contribute to the drug’s anesthetic effect, says Todd Gould of the University of Maryland School of Medicine. In 2016, a team led by Gould and Carlos Zarate of the NIH, who was the first author of the 2006 ketamine paper, found that the metabolite (2R,6R)-hydroxynorketamine (HNK) had an antidepressant effect in rodents (Nature 2016, DOI: 10.1038/nature17998). (2R,6R)-HNK does not bind to the NMDA receptor, and the scientists have yet to find its molecular target in the brain. Interestingly, in animals, the metabolite doesn’t seem to have the dissociative side effects and abuse potential of ketamine.

Ketamine researchers are intrigued by these findings but caution that the data on (2R,6R)-HNK so far have been collected from animal studies. “It is very exciting, and the preclinical models look very promising, but before we get too carried away with thinking of different mechanisms and changing our thoughts on ketamine, we really have to see some human evidence that this is effective,” Yale’s Sanacora argues. Zarate and Gould don’t disagree, and they say that Phase I trials with the (2R,6R)-HNK metabolite will be starting soon.

Scientists across the antidepressant field agree that the only way to clear up the ketamine picture is to get new molecules into clinical trials. P. Jeffrey Conn, the director of the Vanderbilt Center for Neuroscience Drug Discovery, hopes that the researchers testing these new antidepressants include experiments that allow them to determine if their molecule is having the predicted effects on targeted pathways in the brain. For example, performing positron-emission tomography (PET) scans would allow researchers to observe if a drug is binding to an intended receptor. “Then they can make conclusions about the antidepressant efficacy or lack thereof with that information in hand,” Conn says. “That then helps us to go back and know which aspects of our models are being validated clinically and which are not. It helps us to refine the models.”

Zarate thinks the state of the antidepressant field is in a much better place after ketamine’s antidepressant effect was discovered than it was decades ago. Back then, researchers would look for molecules that improved a particular depression-like behavior in animals they were studying. And as depression researchers repeatedly point out, depression-like behaviors in animals are not the same as depression in people, making translation of a molecule from the lab to the clinic difficult.

With ketamine, the field has been narrowed and refocused as it tries to find new tools to treat depression, which is a major cause of disability worldwide. Scientists, Zarate argues, are essentially reverse engineering ketamine, and that approach limits the number of targets that need to be pursued. “So it’s a more focused research now, and I think all the investigators are working hard together, trying to sort these things out,” he says. “That’s the exciting part.”