Study sheds new light on promising antidepressant

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Summary: The antidepressant effect of ketamine is the result of enhancement of Kcnq2 potassium channels in a certain subtype of glutamate-sensitive neurons.

Source: Weizmann Institute of Science

Ketamine, a well-known anesthetic used in small doses as a party drug, was hailed as “new hope for depression” in a Time magazine cover story in 2017. Two years later, the arrival of the first antidepressant Ketamine-based – the Esketamine nasal spray, manufactured by Johnson & Johnson, has been hailed as the most exciting development in the treatment of mood disorders in decades.

Yet the United States Food and Drug Administration still limits the use of the spray.

It is mainly given to depressed patients who have not been helped by other therapies, in part because the new drug’s mechanism of action is not sufficiently understood, raising concerns about its safety.

Today, a study published in Neuron reveals new details about how ketamine works, paving the way for the development of safe and effective treatments for depression.

The research was conducted at the Weizmann Institute of Science in Rehovot, Israel, and the Max Planck Institute of Psychiatry in Munich, Germany, in collaboration with the Helmholtz Zentrum, Munich.

Even though depression is on the rise in developed countries, taking a heavy toll in terms of human suffering and economic loss, there has not been a major breakthrough in the treatment of depression since the 1987 approval of the famous antidepressant of all time, Prozac.

Meanwhile, existing medications provide no relief to about a third of depressed patients. Even when the drugs work, they take four to eight weeks to take effect, a delay that can prove fatal in suicidal cases.

This is precisely the reason for much of the excitement around ketamine therapies: they make people feel better within hours. Their antidepressant action then lasts for days after the drug itself has been cleared from the body.

Obviously, it is the body’s response to ketamine, rather than the ketamine itself, that produces the desired effect, but the nature of this response has so far been unclear.

When scientists attempted to clarify ketamine’s mechanism of action in previous studies, they looked at its impact on gene expression in brain tissue, but not in individual brain cells. This approach may miss crucial differences between different cell types.

Recent technological advances, however, have made it possible to assess gene expression at an unprecedented level of resolution: that of the single cell. These technologies were employed in the new study, conducted under the direction of Professor Alon Chen, former director general of the Max Planck Institute of Psychiatry and current president of the Weizmann Institute of Science.

In this study, researchers led by Dr. Juan Pablo Lopez mapped gene expression in thousands of individual neurons in the brains of mice given a dose of ketamine. These neurons belong to networks that convey their signals via the neurotransmitter glutamate.

Ketamine has been known since the 1990s to produce its effects by acting on these neurons, unlike older antidepressants, which primarily affect neurons influenced by serotonin. But since ketamine’s effect persists long after it leaves the body, its action could not be explained by a simple blockade of glutamate receptors on the surface of neurons.

“We wanted to clarify the molecular cascade triggered by ketamine, leading to its long-lasting antidepressant effects,” says Lopez.

To that end, the scientists focused on the ventral hippocampus, a region of the brain that in previous studies had been linked to the antidepressant effects of ketamine.

After mapping gene expression in cells in this area of ​​the mouse brain, the researchers identified a subpopulation of neurons with a characteristic genetic signature. Ketamine had increased the expression by these neurons of a gene called Kcnq2, which codes for a potassium channel, that is to say a tunnel which opens in the cell membrane, allowing the passage of potassium ions.

Potassium channels play a central role in the life of neurons, maintaining their stability and preventing their over-discharge.

In a series of elaborate experiments at the molecular and cellular level, which included electrophysiological, pharmacological, behavioral and functional studies, the scientists confirmed their major finding: ketamine exerts its long-lasting antidepressant effect by enhancing Kcnq2 potassium channels in a certain sub -type of glutamate- sensitive neurons.

“In the past, other researchers used whole tissue samples, made up of different cell types, so the effects of ketamine on specific cell types were averaged,” says Lopez.

The researchers then tested the effects of ketamine in combination with an epilepsy drug, retigabine, known to activate potassium channels in the brain. When the drugs were given together, the antidepressant effects of ketamine were significantly enhanced.

How ketamine works: a schematic representation of the recently discovered and already known mechanisms of action of ketamine. Ketamine molecules directly inhibit a receptor for the neurotransmitter glutamate (top left), generating a cascade of biochemical reactions that increases potassium channel (KCNQ) expression in neurons belonging to the glutamate network in the ventral hippocampus (right ). Credit: Weizmann Institute of Science

“A single dose of retigabine was sufficient to amplify and prolong the antidepressant action of ketamine in mice,” says Lopez.

“Not only that, ketamine produced the same benefits when given in lower doses than usual, which may help reduce its unwanted side effects.” Since both drugs already have FDA approval, the way is open to test their combined action in humans.

According to the World Health Organization, depression affects nearly 300 million people worldwide; more than 700,000 people commit suicide each year. Yet, despite decades of research, there is still much to learn about the neural mechanisms underlying depression and ways to manipulate these mechanisms with medication.

By revealing a new mechanism of action for ketamine, the study could expand the use of ketamine-based drugs. This, in turn, could help these drugs fully deliver on their promise of providing new hope for depression.

See also

This is a cartoon of a head and a man standing behind it, pulling a string from the brain

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

About this psychopharmacology research news

Author: Press office
Source: Weizmann Institute of Science
Contact: Press Service – Weizmann Institute of Science
Image: Image is credited to Weizmann Institute of Science

Original research: Free access.
“Ketamine exerts its sustained antidepressant effects via cell type-specific regulation of Kcnq2” by Juan Pablo Lopez et al. Neuron


Summary

Ketamine exerts its sustained antidepressant effects via cell type-specific regulation of Kcnq2

Strong points

  • scRNA-seq reveals cell type-specific molecular signatures of ketamine treatment
  • The Kcnq2 the gene is identified as an important modulator of ketamine action
  • Adjunctive therapy with retigabine increases the antidepressant effects of ketamine
  • A new mechanism underlying the sustained antidepressant effects of ketamine

Summary

A single subanesthetic dose of ketamine produces a rapid and sustained antidepressant response, but the molecular mechanisms responsible for this remain unclear.

Here, we identified cell type-specific transcriptional signatures associated with a sustained response to ketamine in mice.

More interestingly, we have identified the Kcnq2 gene as an important downstream regulator of ketamine action in ventral hippocampal glutamatergic neurons.

We validated these results by a series of complementary molecular, electrophysiological, cellular, pharmacological, behavioral and functional experiments.

We have demonstrated that adjunctive treatment with retigabine, a KCNQ activator, enhances the antidepressant-like effects of ketamine in mice. Interestingly, these effects are specific to ketamine, as they do not modulate the response to conventional antidepressants, such as escitalopram.

These findings significantly advance our understanding of the mechanisms underlying the sustained antidepressant effects of ketamine, with important clinical implications.

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