Researchers Are Closer to Explaining How Ketamine Treats Depression

Ketamine, the anesthetic and pain-relieving drug sometimes used for hallucinogenic effects, could revolutionize mental health care. Yet, how and why the drug relieves depression symptoms is still clouded in mystery.

"Like many advances in psychiatry, the clinical breakthrough occurred before we understood how it worked to alleviate depression," John H. Krystal, MD, chair of the psychiatry department at Yale University, tells Verywell via email.

So, as someone teeters on the edge of a "K-hole"—what exactly is going on inside the brain?

In a new study, researchers at the Karolinska Institutet in Sweden point to a few mechanisms that could explain how the drug provides depression relief. And, they all involve the reduced transmission of the neurotransmitter glutamate.

"Elevated glutamate release has been linked to stress, depression and other mood disorders, so lowered glutamate levels may explain some of the effects of ketamine," Per Svenningsson, MD, PhD, physician, neuroscience professor, and study author said in a press release.

The research was published in Molecular Psychiatry in mid-August.

However, the drug's mechanisms are likely more intricate. Understanding how ketamine alleviates depression is essential to making it a safe and effective option for all who could benefit.

Krystal was not involved in the present study but has researched ketamine's effects on the human brain since 1990. Prior to a landmark study that he and colleagues published in 2000, he says regarding the drug, "we could not have anticipated the remarkably robust and rapid antidepressant effects that we observed."

Understanding How Ketamine Works in the Brain

Ketamine is called a "dissociative anesthetic" because it can make you feel detached from your physical environment and sensations. It can also, depending on the dose, bring about sedation and/or relaxation, immobility, pain relief, and amnesia. 

The drug also works quickly; one dose can relieve depression symptoms within hours and keep them that way for about a week. This is even the case in patients for whom other treatments like antidepressants and/or psychotherapy alone haven't worked before.

"The antidepressant effects of ketamine are truly remarkable," Krystal says.

Yet, the science on how and why ketamine relieves depression is still growing. If we come to understand the drug's effects with more precision, the study authors write, then that might lead us to therapies that more efficiently treat depression.

To get closer to this understanding, the researchers looked at the underlying molecular mechanisms of ketamine’s effects on the brain by experimenting with cells and mouse models.

They already knew that ketamine appeared to act on certain receptors that control the release of the neurotransmitter glutamate, which is widely prevalent in the brain.

Why Glutamate?

Past studies have found that ketamine works to relieve depression by simply increasing glutamate activity. However, the study authors write, it might be more apt to think of the drug as an orchestrator of a glutamatergic crescendo.

In one moment it increases the neurotransmitter, and in the next, sets off a reaction that ultimately decreases its activity.

Ketamine seems to stimulate glutamate's release. If the researchers are correct, then this initial increase enables the activation of neurons that release adenosine, another type of neurotransmitter, in an area of the brain called the hippocampus. The resulting increase in adenosine, then, inhibits further release of glutamate, creating a loop.

"This suggests that the antidepressant action of ketamine can be regulated by a feedback mechanism," Svenningsson said in the press release. "It is new knowledge that can explain some of the rapid effects of ketamine."

But how is glutamate activity interrupted? On a granular level, the authors found, ketamine interferes with glutamate via tiny transporters called synaptic vesicles. These vesicles carry neurotransmitters from one neuron to the next. In both "normal" and "depression-like" mice, the authors write, ketamine "significantly impaired" synaptic vesicle recycling, and primarily in neurons that react to glutamate.

"These effects could contribute to the efficacy of ketamine to instantly alleviate depressive symptoms and suicidal ideations, taking into account that excessive glutamate levels have been linked to [major depressive disorder] and other mood disorders," they write.

More research is needed to confirm the findings' significance. Still, if anything is certain, Krystal says, it's that ketamine "may turn out to produce antidepressant effects via remarkably nuanced effects on glutamate synaptic signaling in ways that may vary over time or differ across brain regions."

Also, Krystal adds, this study is not a comprehensive characterization of ketamine; it produces other effects as well. For example, psychological factors while experiencing the drug's effects may contribute to antidepressant outcomes.

How Ketamine Could Revolutionize Treatment

Although the drug carries a stigma, it certainly is beginning to offer hope to people with treatment-resistant depression.

Major depressive disorder affects about one in five people at some point during their life. Research suggests that, if left untreated, it can contribute to long-term brain damage and put people at higher risk for dementia.

And while treatments such as antidepressants and psychotherapy have much to offer, a third of depression patients will be treatment-resistant.

What's more, even if these treatments work, they take longer. Antidepressants, for example, often don't kick in for 2 to 3 months.

Krystal says that although esketamine and ketamine were initially reserved for the toughest cases of depression, patients' experiences with the drug have "been so positive that it is prescribed increasingly for the broad array of patients with treatment-resistant forms of depression."

Although ketamine isn't likely to become the first line of defense, it can give people the chance to see what it’s like to not be depressed—within the hour, and for weeks.

"I foresee continued growth in its role in the treatment of depression in the U.S. and around the world," Krystal adds.