Ketamine has been used since the 1960s as an anesthetic, but in 2000, the first study of much lower doses of ketamine demonstrated its rapid effectiveness in treating major depression and suicidal ideation. Traditional antidepressants take months to take effect, which increases the risk for some patients to act on suicidal thoughts during the initial period of therapy. Ketamine provides almost immediate relief from depressive symptoms and remains effective for several days and up to a week after the first dose. Since this observation was published in the early 2000s, dedicated clinics have been established, where the drug is administered intravenously to treat depression. But how ketamine achieves such a dramatic antidepressant effect so quickly is poorly understood at the molecular level. This information is critical to understanding not only how best to use ketamine, but also to developing similar drugs.
Neuroscientists at the University at Buffalo have identified the binding site of low-dose ketamine, providing key insights into how the drug, often described as a wonder drug, relieves symptoms of major depression in just a few hours with effects that last for days. Published in September in Molecular Psychiatry, the discovery will also help scientists identify how depression begins in the brain and spur research into the use of ketamine and ketamine-like drugs for other brain disorders. Ketamine binds to a class of neurotransmitter receptors called N-methyl-D-aspartate (NMDA) receptors. Popescu is an expert in how these receptors produce electrical signals essential for cognition, learning, and memory, and how those signals, when dysregulated, lead to psychiatric symptoms. But at very low concentrations, the molecule can only affect the activity of select populations of NMDA receptors.
NMDA receptors are found throughout the brain and are essential for maintaining consciousness. For this reason, he explains, drugs that act indiscriminately on all NMDA receptors have unacceptable psychiatric side effects. The researchers believe that the selectivity they discovered in their research explains how low-dose ketamine can treat major depression and prevent suicide in people with depression. The research was sparked by an observation in her lab by co-author Sheila Gupta, who noticed that when applied to NMDA receptors that were chronically active, ketamine had a stronger inhibitory effect than expected based on the literature. So the team became intrigued by this discrepancy. When ketamine’s antidepressant effects were first discovered, researchers tried to figure out how it worked by applying it to the synaptic currents produced by NMDA receptors, but the drug had little to no effect.
Dr. Popescu explained the observations and the underlying hypothesis in depth: “This observation prompted many experts to turn their attention to receptors located outside the synapse, which could mediate the antidepressant effects of ketamine. The observation that ketamine is a stronger inhibitor than receptors that are active for longer periods inspired us to look for mechanisms other than blocking direct current, which was assumed to be the only effect of ketamine on NMDA receptors. Because we monitor the activity of a single receptor molecule over a long period of time, we can track the entire behavioral repertoire of each receptor, and we can identify which part of the process is altered when the receptor binds to a drug or harbors a mutation. The mechanism we discovered suggests that at low doses, ketamine will only affect the current carried by receptors that have been active in the background for a while, but not by synaptic receptors, which experience only brief, intermittent activations.”
“This results in an immediate increase in excitatory transmission, which in turn relieves depressive symptoms. Furthermore, the increased excitatory signal initiates the formation of new or stronger synapses, which serve to maintain higher excitatory levels even after the ketamine has been eliminated from the body, thus explaining the long-term relief observed in patients. Our research helps explain why such low doses of ketamine are effective: our results show that very low levels of ketamine, at the nanoscale, are sufficient to fill two lateral grooves of NMDA receptors to selectively slow down extrasynaptic receptors, relieving depression. Increasing the dose causes ketamine to overflow from the grooves into the pore and begin to block synaptic currents, initiating the anesthetic effect. These interactions are strong and explain the receptor’s high affinity for low doses of ketamine. Simulations show that at high concentrations (as an anesthetic), ketamine instead settles into the central ion-conducting pore, where it blocks the current. ion to flow through the receptor”.
In contrast, at low concentrations, ketamine works very differently, binding to two symmetrical sites on the sides of the pore, so that instead of stopping the current, ketamine slows the opening of the receptors, reducing the current only slightly. Because the team found the exact binding site on the receptor (the critical amino acid residues responsible for the effect), this provides the perfect model for developing ketamine-like drugs that could be administered orally and may not have the addictive potential of ketamine. The natural next step is to screen existing drugs that can fit into the lateral grooves of NMDA receptors, first by computer simulation and then experimentally.
- A cura del Dr. Gianfrancesco Cormaci, PhD, specialista in Biochimica Clinica.
Pubblicazioni scientifiche
Abbott JA et al. Mol Psychiatry 2024 Sep 5; in press.
Tan Y et al. Asian J Psychiatr. 2024 Nov; 101:104246.
Villéga F et al. Neuron. 2024 Oct; 112(19):3311-3328.
Okubo R et al. Biomolecules. 2024 Sep 6; 14(9):1128.