November 19, 2024 – Researchers at the University at Buffalo have made significant strides in understanding how low-dose ketamine alleviates symptoms of major depression, often referred to as a “wonder drug.” Their findings, published in Molecular Psychiatry, identify the specific binding site of ketamine, shedding light on its rapid effects, which can manifest within hours and last for several days.
Ketamine, originally developed as an anesthetic in the 1960s, gained attention in 2000 when studies demonstrated its effectiveness at lower doses for treating major depression and suicidal ideation. Dr. Gabriela K. Popescu, senior author of the study and a professor of biochemistry at the Jacobs School of Medicine and Biomedical Sciences, emphasized the drug’s life-saving potential: “Due to its fast and long-lasting effects, low-dose ketamine has proven to be a literally lifesaving medicine.”
Traditional antidepressants often take weeks to show effects, increasing the risk of suicidal thoughts during the initial treatment phase. In contrast, ketamine provides near-instant relief from depressive symptoms, with its effects lasting up to a week. This rapid efficacy has led to the establishment of ketamine clinics across the United States, where the drug is administered intravenously.
Despite its effectiveness, the molecular mechanisms by which ketamine exerts its antidepressant effects have remained largely unclear. The new study reveals that ketamine selectively binds to N-methyl-D-aspartate (NMDA) receptors, a type of neurotransmitter receptor critical for cognitive functions, learning, and memory. Dr. Popescu, an expert in NMDA receptor activity, noted, “We demonstrate how ketamine at very low concentrations can affect the activity of only select populations of NMDA receptors.”
NMDA receptors play a vital role throughout the brain and are crucial for maintaining consciousness. Popescu explained that drugs affecting all NMDA receptors indiscriminately can lead to undesirable psychiatric side effects. “The selectivity we uncovered in our research explains how low-dose ketamine can treat major depression and prevent suicides in people with depression,” she stated.
The research was inspired by an observation made by co-author Sheila Gupta during her undergraduate studies at UB. Gupta noted that ketamine had a stronger inhibitory effect on chronically active NMDA receptors than previously documented. This prompted the team to explore mechanisms beyond the direct blockade of synaptic currents, which had been the primary focus of earlier studies.
Popescu’s lab is among the few worldwide capable of quantifying NMDA receptor activation processes. This expertise allowed the researchers to compare the effects of low and high doses of ketamine on NMDA receptor activity. “By tracking activity from a single receptor molecule over time, we can chart the entire behavioral repertoire of each receptor,” Popescu explained.
The study found that low doses of ketamine primarily affect receptors that have been active for extended periods, leading to an immediate increase in excitatory transmission. This increase not only alleviates depressive symptoms but also promotes the formation of new or stronger synapses, contributing to long-term relief even after the drug has cleared from the body.
The findings suggest that very low concentrations of ketamine can effectively target NMDA receptors without inducing the anesthetic effects associated with higher doses. Popescu noted, “Our results show that low levels of ketamine are sufficient to selectively slow down extra-synaptic receptors, alleviating depression. In contrast, higher doses lead to unwanted side effects by blocking synaptic currents.”
The research team, which included physicists who simulated the NMDA receptor’s three-dimensional structure, identified the specific residues to which ketamine binds. These interactions account for the high affinity of the receptor for low doses of ketamine, providing a foundation for developing ketamine-like drugs that could be administered orally and potentially reduce the risk of addiction.
Looking ahead, the researchers plan to screen existing medications that could target the lateral grooves of NMDA receptors, both through computational models and experimental validation.
The study was led by Jamie A. Abbott, PhD, from the Department of Biochemistry, and Han Wen from the Department of Physics, with contributions from Gupta and others. The research received funding from the National Institutes of Health.
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