A newly uncovered mechanism of ketamine’s influence on potassium channels in neurons could lead to more effective treatments for depression, says new research.

In a Time magazine cover story in 2017, ketamine, a well-known anesthetic used in smaller quantities as a party drug, was praised as a “new hope for depression.” Two years later, the introduction of the first ketamine-based antidepressant – Johnson & Johnson’s nasal spray esketamine – was hailed as the most significant advancement in the treatment of mood disorders in decades.

Despite this, the spray’s use is still restricted by the US Food and Drug Administration. It’s mostly given to depressive patients who haven’t responded to conventional treatments, in part because the new drug’s mechanism of action isn’t well understood, raising safety concerns.

A new study published in Neuron sheds fresh light on how ketamine works, paving the way for the creation of safe and effective depression treatments. The study was carried out in partnership with the Helmholtz Zentrum Munich at the Weizmann Institute of Science in Rehovot, Israel, and the Max Planck Institute of Psychiatry in Munich, Germany.

Despite the fact that depression is on the rise in industrialized countries, causing significant human suffering and economic loss, there have been no substantial advances in the treatment of depression since the introduction of Prozac, the world’s most well-known antidepressant, in 1987.

Meanwhile, nearly a third of depressive people are not helped by present medications. Even when the meds work, it takes four to eight weeks for them to take action, which can be fatal in suicidal situations.

That is precisely why ketamine-based medicines have generated so much interest: They improve people’s moods within hours. After the medicine is gone from the body, their antidepressant effect lasts for days. The body’s response to ketamine, rather than ketamine itself, appears to be what causes the intended effect, although the nature of this response has remained unknown until now.

In prior studies, scientists looked at ketamine’s effect on gene expression in brain tissues, but not in individual brain cells, to try to figure out how it works.

This method may overlook important differences between cell types. Recent technical advancements, on the other hand, have enabled researchers to examine gene expression at a previously unheard-of level of granularity: that of a single cell. Prof. Alon Chen, former managing director of the Max Planck Institute of Psychiatry and current president of the Weizmann Institute of Science, led the new study, which used these technologies.

Gene expression research

Researchers led by Dr. Juan Pablo Lopez studied gene expression in hundreds of individual neurons in the brains of mice who had received a ketamine dose.

These neurons are part of networks that communicate via the neurotransmitter glutamate. In contrast to previous antidepressants, which primarily impact neurons controlled by serotonin, ketamine has been known since the 1990s to achieve its effects by acting on such neurons.

However, because ketamine’s effect lasts long after it leaves the body, it can’t be explained by just blocking glutamate receptors on neuron surfaces. “We wanted to clarify the molecular cascade that is triggered by ketamine, leading to its sustained antidepressant effects,” says Lopez.

The researchers concentrated their efforts on the ventral hippocampus, a brain region previously linked to ketamine’s antidepressant effects in studies.

The researchers discovered a subpopulation of neurons with a distinct genetic signature after assessing gene expression in cells from this part of the mouse brain. Ketamine enhanced the expression of a gene called Kcnq2, which codes for a potassium channel, or a tunnel that opens up in the cell membrane to allow potassium ions to pass through. Potassium channels are important in the life of neurons because they keep them stable and prevent them from firing excessively.

The scientists validated their primary conclusion in a series of extensive investigations on the molecular and cellular levels, which included electrophysiological, pharmacological, behavioral, and functional research. Ketamine increases the Kcnq2 potassium channels in glutamate-sensitive neurons, which has a long-lasting antidepressant effect.

“In the past, other researchers used whole tissue samples, which are composed of different cell types, so ketamine’s effects on specific cell types were averaged out,” explains Lopez.

The effects of ketamine were then examined in combination with retigabine, an epileptic medication that is known to stimulate potassium channels in the brain. The antidepressant effects of ketamine were greatly boosted when the medications were given concurrently.

“A single dose of retigabine was enough to amplify and prolong ketamine’s antidepressant action in mice,” Lopez adds. “Not only that, ketamine produced the same benefits when given in smaller doses than usual, which may help reduce its unwanted side effects.” Since both medications have already received FDA approval, it is possible to examine their combined effect on humans.

Dr. Juan Pablo Lopez explains, “Ketamine produced the same benefits when given in smaller doses than usual, which may help reduce its unwanted side effects.”

According to the World Health Organization, about 300 million people worldwide suffer from depression, with more than 700,000 individuals committing suicide each year. Despite decades of research, there is still much to learn about the neural systems that underpin depression and how to manipulate those pathways using medications.

The discovery may make it possible to increase the use of ketamine-based medications by identifying a novel mechanism of ketamine activity. As a result, these medications may be able to completely deliver on their promise of bringing new hope for depression sufferers.

“In-depth knowledge of how antidepressants work might lead to a better understanding of depression and help improve existing treatments,” Chen concludes.

Image Credit: Getty

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