John Krystal, the History of Ketamine, and a New Paradigm for Depression

One of the most anticipated lectures at the annual meeting of the American Psychiatric Association (APA) in 2023 was given by Dr. John H. Krystal, Director of Psychiatry at Yale University. Krystal is one of the pioneers in the study of ketamine for depression, and during the event, he spoke about the 30 years of research on the substance.

Ketamine is a substance that has been used as an anesthetic in surgeries since the 1960s. However, in the 1990s, Krystal and his team began studying the substance, which led to the discovery of its antidepressant effects, offering a better quality of life for many individuals who haven’t found positive responses in conventional treatments.

How ketamine came to be used in depression treatment

Initially, the professor of psychiatry was dedicated to understanding schizophrenia and its relationship with the neurotransmitter glutamate under the influence of ketamine.

After conducting some tests, Krystal soon realized the role of glutamate in treatment-resistant depression as well. This opened up a completely new line of research because, until then, the most accepted hypothesis for the cause of depression was that it was caused by a lack of serotonin or chemical imbalance. It’s no wonder that classical antidepressants modulate the monoaminergic systems (norepinephrine, serotonin, and dopamine).

On the other hand, the hypothesis that emerged from Krystal’s studies suggested that depression could be explained by the action of the neurotransmitter glutamate, which is responsible for the hyperactivation of certain brain areas. The doctor then used ketamine to block the action of glutamate and, in a now classic study published in the 2000s, he concluded that the substance indeed had antidepressant effects.

Thus, a completely new path was born in understanding how depression works in the brain.

Over time, Krystal and his team gained a better understanding of the mechanisms of action of ketamine. In a conversation on “The Tim Ferriss Show” podcast, he explained how they arrived at the conclusion that the doses of the substance should be lower than those used in anesthesia.

“One of the most important things we discovered in the history of the antidepressant effects of ketamine is that if you give a subanesthetic dose, it releases glutamate; if you give an anesthetic dose, it suppresses glutamate (and this does not have an antidepressant effect); but if you give a dose slightly lower than the subanesthetic dose, it doesn’t stimulate glutamate. So, there’s a tight window in which ketamine produces dissociation and other effects we’re interested in,” Krystal said in the conversation, explaining that low doses cause effects lasting around 40 minutes, which are sufficient to achieve improvement in depression.

In 2019, the researcher and his team published the study “Ketam1ne: A Paradigm Shift for Depression Research and Treatment” in the journal Neuron. In the article, they write that “the rapid, profound, and sustained antidepressant effects of ketamine seem ready to transform the treatment of depression.”

Just as antiretrovirals changed the course of HIV/AIDS treatment, researchers argue that ketamine can do the same for depression, while also helping to eliminate the stigma surrounding the disorder.

“Ketamine can be not only a source of hope for patients and their families but also a powerful weapon in the fight against stigma and for parity in supporting the prevention, treatment, and research of depression,” wrote the researchers, demonstrating that following the story of ketamine is a way to understand the future of depression as well.

Image: Reproduction.