The chemist who designed ketamine wasn’t looking for an antidepressant. Parke-Davis consultant Calvin Stevens first synthesized the drug in 1962 as a safer alternative to phencyclidine (PCP), a common street drug then in development for use as an anesthetic (1). At high enough doses, both PCP and ketamine cause patients to dissociate from the sensations in their bodies, creating an anesthetic effect. But because PCP lingers in the body, it can leave patients experiencing hallucinations and psychosis for hours after administration. In contrast, the body metabolizes and clears ketamine much more quickly.
Even as ketamine became a popular anesthetic in veterinary and human medicine,
Since that accidental discovery, many neuroscientists hoping to better understand depression and effective antidepressants have spent the last quarter century studying the cascading molecular interactions that occur after ketamine enters the brain. They proposed theories to explain how the drug can rewire neurons and help patients overcome depression-linked loss of synaptic connections in the mood-regulating regions of the brain. But the complex, intertwined nature of the brain’s molecular pathways makes it incredibly difficult to draw a straight line from cause to effect. While knowledge about the drug continues to accumulate, scientists in the field don’t agree on where they’ll find the key to unlock its remarkable antidepressant effects.
A surprising result and a compelling explanation
Around the time ketamine came onto the scene in the 1960s, neuroscientists were learning more about the neurotransmitter glutamate, which activates a variety of receptors and plays a role in learning, memory, and cognition (2). A few decades later, in the 1990s, Yale psychiatrist John Krystal was investigating the role of glutamate in the neurobiology of schizophrenia. Because ketamine blocks NMDA glutamate receptors, he decided to administer low doses of the drug to healthy participants to see if it would induce schizophrenia-like symptoms (3). The doses were too low to anesthetize them; instead, the drug induced aberrant cognitive symptoms like those experienced by patients with schizophrenia, indicating an important role for the glutamate system in the disorder.
While he was conducting that study, Krystal regularly met with his mentor and colleague Dennis Charney, who was studying the neurobiology of depression. “His office was upstairs from mine, and we both worked late,” said Krystal. At first, Charney talked about his work with serotonin and norepinephrine, which are monoamine neurotransmitters that bind to different receptors than glutamate. But as time went on, he and Krystal became aware of a growing body of research suggesting a role for NMDA glutamate receptors in the neurobiology of depression. Since Krystal was already working with ketamine to study schizophrenia, he suggested that they use it to study depression as well.
Together, Krystal and Charney administered ketamine to a group of patients with depression (4). “We really didn’t expect to see anything therapeutic with a single dose of ketamine,” said Krystal. “We were shocked.” Patients reported relief from their symptoms within hours of administration. In contrast, antidepressants that target monoamine systems, like selective serotonin reuptake inhibitors (SSRIs), typically take weeks to produce an effect.
Charney moved away from Yale around the time that he and Krystal published the results of their study in 2000, but after settling in, Charney was able to replicate their results with his colleagues at the National Institute of Mental Health (NIMH) (5). Not only did they confirm that ketamine provided rapid relief from the symptoms of depression, but they also showed that ketamine was effective in patients with treatment-resistant forms of depression. Furthermore, a third of the patients in the study continued to report relief from their symptoms a week after treatment, suggesting that a single dose of ketamine could have a more durable effect than SSRIs, which most patients take daily. With ketamine’s effects being both fast-acting and long-lasting, researchers turned their attention to investigating the underlying molecular biology.
Ron Duman, another Yale psychiatrist, was particularly intrigued by the findings. Duman had previously claimed that mood disorders like depression arise when chronic stress reduces the expression of proteins that promote synaptic growth, leading to atrophy in large, mood-regulating regions of the brain like the hippocampus (6). To explore how ketamine fit into this picture, Duman administered the drug to rats in 2010 (7). In line with his model, he found that ketamine promoted rapid synaptic growth, which coincided with similarly rapid relief from the symptoms of depression.
These results amazed Krystal, who has spent the ensuing years trying to understand the precise mechanism that enables ketamine to treat depression (8-10).
A tangled web of molecular interactions
Today, many scientists who study ketamine agree with Krystal and Duman’s conclusions regarding its antidepressant effects. “Most folks in the field, including myself, have converged with this idea that ketamine is inducing synaptic changes,” said Todd Gould, a psychiatrist at the University of Maryland.
However, there’s less consensus on the precise molecular interactions that enable those changes.
No one disputes the fact that ketamine inhibits NMDA glutamate receptors. However, some researchers think the drug may have additional molecular interactions that are more important for treating depression. Ketamine is a mixture of two distinct molecules with different chemical properties, and there is evidence that the molecule that interacts less strongly with NMDA receptors has stronger antidepressant effects (11).
On top of that, the human body starts to break down both molecules when they enter the brain, and some of the metabolites interact with the brain’s molecular receptors. In 2016, Gould showed that one metabolite in particular reproduced the antidepressant effects of ketamine in mice, despite the fact that it did not interact with NMDA glutamate receptors (12).
Mike Michaelides, a neuroscientist at the National Institute on Drug Abuse (NIDA), became fascinated by the results of Gould’s paper. It was no longer just the two ketamine molecules producing antidepressant effects. Now, a ketamine metabolite that does not even interact with NMDA receptors was producing those effects as well. “That means that there may be a completely unknown target that all three of these interact with,” said Michaelides.
As a NIDA researcher who also investigates the abuse potential of drugs, Michaelides is particularly interested in ketamine’s interactions with the opioid system. Ketamine is not an opioid, but it induces activity in the same types of neuronal receptors that respond to pleasure-inducing opioids, such as the brain’s own endorphins and synthetic substances like heroin. Shortly after Gould published his study on ketamine’s metabolite, researchers found evidence that activation of the opioid system may be necessary for ketamine’s antidepressant effects to occur (13). In January, Michaelides contributed to a study corroborating that theory, at least in male rats (14).
Michaelides knows that the involvement of the opioid system in ketamine’s antidepressant action is controversial, but it makes sense to him. “If you look back in history, the first antidepressants are [opiates],” he said.
A controversial bid for simplicity
While research on alternative mechanisms of action continues to grow, many scientists still focus on NMDA glutamate receptors to reveal ketamine’s antidepressant effects. Over a decade ago, Hailan Hu, a neuroscientist at Zhejiang University, became interested in the lateral habenula, a small region of the brain that primarily inhibits activity in the brain’s reward system (15). When glutamate activates NMDA receptors on the lateral habenula, the nerves inhibit the release of dopamine, which ordinarily helps reinforce rewarding behaviors. “This region is now considered the anti-reward center in the brain,” said Hu.
In 2018, she presented evidence that overly active lateral habenula neurons are a hallmark of depression, and that ketamine blocks activity in the lateral habenula in mice for an hour after treatment (16). This drop in activity caused by ketamine coincided with reductions in mice’s symptoms of depression. Thus, Hu’s team proposed that ketamine treats depression by reversing overactivity in the lateral habenula.
Other researchers indicated that Hu made a compelling case for a connection between the lateral habenula and ketamine’s rapid antidepressant effects but left some questions unanswered. For instance, Gould wondered why her team hadn’t also checked lateral habenula activity after more than an hour had elapsed, given that ketamine has sustained antidepressant effects as well. In response to a similar question from a reviewer, Hu decided to compare the effects of ketamine and memantine, a medication currently prescribed to slow the progression of Alzheimer’s disease. Like ketamine, memantine physically interacts with NMDA receptors, but it abandons the receptors much more quickly.
Hu and her team administered each drug to mice, which quickly cleared both substances from their bodies (17). That was the end of the story for the mice that received memantine, but ketamine continued to suppress lateral habenula activity for a whole day after treatment — long after the drug had fallen to immeasurable levels. Hu concluded that ketamine molecules had become physically trapped in NMDA receptors on the lateral habenula and that this phenomenon sufficiently explained both the fast-acting and the long-lasting antidepressant effects of the drug.
Yet, when Hu’s study came out last year, her central claim that ketamine molecules become physically trapped proved to be highly controversial. “There aren’t very many other drugs that are known to work like that,” said Gould. To accept such a bold claim, Gould said that he would need to see direct evidence that ketamine molecules remain present in NMDA receptors. But Michaelides, who often conducts experiments to visualize molecules as they interact with neurons, doesn’t think that evidence exists. “I haven’t seen any evidence of ketamine staying there for extended periods of time,” he said.
Neither Michaelides nor Gould, however, disputes the fact that Hu measured sustained suppression of electrical activity in the lateral habenula after ketamine administration. For her part, Hu has continued to explore the connection between the antidepressant effects of ketamine and the anti-reward center. In August, she and her team presented evidence that ketamine specifically inhibits NMDA receptors on lateral habenula neurons of mice exhibiting symptoms of depression, but not receptors on hippocampal neurons (18). These results do not address Michaelides and Gould’s concerns about the conclusions of her previous paper, but they provide further evidence that researchers trying to make sense of ketamine’s antidepressant effects should consider the role of the lateral habenula.
The tools available to today’s neuroscientists allow researchers like Krystal, Gould, Michaelides, and Hu to investigate the effects of ketamine with unprecedented precision. The ongoing challenge is figuring out which specific molecular interactions enable the drug’s therapeutic benefits.
“We’re continuing to probe that with the idea that we could make a better ketamine,” said Krystal.
Correction: This article was updated on November 11, 2024 to note that ketamine is currently used as an anesthetic in human medicine.
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