How can low-dose ketamine, a “life-saving” drug for major depression, reduce symptoms within hours?

Published in September molecular psychiatryThe UB discovery will also help scientists identify how depression develops in the brain and will facilitate research into the use of ketamine and ketamine-like drugs for other brain disorders.

life-saving medicine

Ketamine has been used as an anesthetic since the 1960s, but the first trials using much lower doses of ketamine in 2000 showed that ketamine was rapidly effective in treating major depression and suicidal thoughts. Proven.

“Low-dose ketamine has literally proven to be a life-saving drug due to its rapid onset and long-lasting effects,” said Gabriela K., senior author of the study and professor of biochemistry at the Jacobs School of Medicine and Biomedical Sciences. Dr. Popescu says. At U.B.

Traditional antidepressants take several months to take effect, increasing the risk that some patients may become suicidal during the early stages of treatment. Ketamine reduces depressive symptoms almost immediately, with effects lasting from a few days to up to a week after administration. Since this observation was published in the early 2000s, clinics administering intravenous ketamine to treat depression have been established in cities across the country.

However, how ketamine achieves such dramatic antidepressant effects so quickly is poorly understood at the molecular level. This information is important not only for understanding how best to use ketamine, but also for developing similar drugs.

Selective effect on NMDA receptors

Ketamine binds to a class of neurotransmitter receptors called N-methyl-D-aspartate (NMDA) receptors. Popescu is an expert on how these receptors generate electrical signals that are essential for cognition, learning and memory, and how dysregulation of these signals can lead to psychiatric symptoms. .

“In this article, we demonstrate how very low concentrations of ketamine affect the activity of only a selected population of NMDA receptors,” Popescu says.

NMDA receptors are found throughout the brain and are essential for maintaining consciousness. Because of this, she explains, drugs that act indiscriminately on all NMDA receptors have unacceptable psychiatric side effects. “We believe the selectivity revealed in our study explains how low-dose ketamine can treat major depression and prevent suicide in depressed patients,” Popescu said. says.

The study was sparked by observations in the lab of co-author Sheila Gupta, then an undergraduate at UB. “Sheila noticed that applying ketamine to chronically active NMDA receptors had a stronger inhibitory effect than expected based on the literature,” Popescu explains. “We were interested in this contradiction.”

When ketamine's antidepressant effects were first known, researchers tried to see how ketamine worked by applying it to synaptic currents generated by NMDA receptors, but the drug had little effect. did not show.

“This observation has led many experts to focus on receptors outside the synapse, which may mediate ketamine's antidepressant effects,” Popescu says. “Sheila's observation that ketamine is a potent inhibitor of longer-active receptors prompted us to look for mechanisms other than DC blockade, which was thought to be the only effect of ketamine on NMDA receptors. I gave it to

Few laboratories have this NMDA expertise

Popescu's lab is one of the few in the world with the expertise to quantify the processes by which NMDA receptors are activated. This allowed Popescu and her colleagues to identify and measure what exactly changed during NMDA activation when ketamine was present at very low doses and when it was present at very low doses. is completed. It was present in high doses (anesthetics).

“Because we track the activity of single receptor molecules over long periods of time, we are able to chart the entire behavioral repertoire of each receptor, and when the receptor binds a drug or “We can identify which parts of the process change when you have a mutation,” Popescu explains.

“The mechanism we have uncovered is that at low doses, ketamine only affects currents carried by receptors that have been active in the background for some time, while synaptic receptors that only experience short, intermittent activation are affected.” “It suggests that there will be no impact,” she continued. “This immediately increases excitatory transmission and improves depressive symptoms. Additionally, increased excitability initiates the formation of new or stronger synapses, making them more effective even after ketamine is removed from the body. It plays a role in maintaining high arousal levels, which explains the long-term relief observed in patients.

UB's research helps explain why such low doses of ketamine are effective.

“Our results show that very low levels of nanoscale ketamine are sufficient to fill the two lateral grooves of NMDA receptors, selectively slowing down extrasynaptic receptors and alleviating depression. As you increase the dose, ketamine spills out of the sulcus and begins to block synaptic currents, starting to have an anesthetic effect.

Popescu's co-authors from the School of Arts and Sciences' Department of Physics simulated the three-dimensional structure of the NMDA receptor and predicted the exact residues to which ketamine binds at the lateral sites. “These interactions are strong and explain the high receptor affinity for low doses of ketamine,” she says.

“Simulations show that at the high concentrations that ketamine is used as an anesthetic, it actually lodges in the central ion-conducting pore of the receptor, where it blocks ionic current from flowing through the receptor,” Popescu said. he says.

In contrast, at low concentrations, ketamine has a very different function: it binds to two symmetrical sites on the sides of the pore, and instead of stopping the current, it slows the receptor's opening, reducing the current only slightly. “Finding the precise binding site on the receptor provides the perfect template for developing ketamine-like drugs that can be administered orally and may not be as addictive as ketamine,” Popescu says.

The logical next step is to screen, first computationally and then ly, existing drugs that fit into the NMDA receptor transverse groove.

The lead authors are Dr. Jamie A. Abbott from the Department of Biochemistry and Han Wen from the Department of Physics. Other co-authors are Gupta, Wenjun Zheng Beiying Liu, and Gary J. Iacobucci. This study was funded by the National Institutes of Health.