Weill Cornell Medicine researchers have “reverse engineered” the antidepressant effects of ketamine and identified a potential new strategy for treating depression.
There are many effective treatments for depression, but not all patients respond to them. Approximately one-third of patients must try multiple medications before their symptoms finally subside, and the remaining one-third have treatment-resistant depression.
An anesthetic called ketamine provides immediate symptom relief for some patients with treatment-resistant depression, but its effects are often short-lived. Ketamine also causes serious side effects for some patients, including changes in heart rate and blood pressure, feeling disconnected from one’s thoughts and self, and addiction.
“We really need new treatments,” says Dr. Conor Liston, Robert Michels, M.D., professor of psychiatry at Weill Cornell Medical College and professor of neuroscience in the Feil Family Brain and Mind Institute at Weill Cornell Medical College. “By understanding how ketamine works, we hoped to find new ways to quickly achieve similar antidepressant effects without the side effects.”
Pinpointing the mechanism behind ketamine’s initial benefits
Previous studies have shown that drugs that block opioid receptors in the brain interfere with ketamine’s antidepressant effects, indicating that these receptors play a role in ketamine’s activity. So Dr. Liston teamed up with Dr. Joshua Levitz, a professor of biochemistry and biophysics at Weill Cornell Medical College, to pinpoint which ones are key.
In a study published on April 23, 2026, cellThey showed that ketamine targets a specific subset of opioid receptors on specialized brain cells called interneurons in the prefrontal cortex, a brain region that plays a central role in emotion, attention, and behavior. Interneurons function as master regulators of cellular activity in this brain region, Dr. Levitz explained.
However, excessive stress causes hyperactivity of these cells, which excessively suppresses overall brain cell activity in the prefrontal cortex, contributing to depression. Ketamine can reverse this effect by stimulating opioid receptors and suppressing interneuron activity.
Ketamine targets these opioid receptors, relieves interneuron inhibition, and reactivates prefrontal cortex cells for only a very short time, perhaps 15 to 20 minutes. That alone seems to be enough to start the entire cortical awakening program. ”
Dr. Joshua Levitz, Professor of Chemistry, Weill Cornell University
The researchers also showed that combining small doses of three drugs that target the same pathway could reproduce the antidepressant effects of ketamine in mice, potentially providing an effective alternative to ketamine with fewer side effects.
“This synergistic strategy has the potential to produce rapid antidepressant effects at much lower doses of each compound,” said Dr. Liston, who is also a psychiatrist at NewYork-Presbyterian/Weill Cornell Medical Center. “You can avoid side effects by avoiding high doses.”
Dr. Hermany Mnguba, Postdoctoral Researcher. Liston and Levitz at the time of the study, as well as Anisul Arefin, a doctoral candidate in Levitz’s lab, were co-lead authors on the study.
Maintenance of antidepressant effects requires multiple signals within brain cells
The second study, a collaboration between Dr. Levitz and the lab of Dr. Francis Lee, Jack D. Barkas, M.D., professor of psychiatry at Weill Cornell Medical College, provided new insight into the long-term antidepressant effects of ketamine. Published on May 1st scientific progressBuilding on previous cell and tissue studies by the research team, this study confirmed in preclinical models that crosstalk in brain cells between a receptor called TrkB and a receptor called mGluR5 is essential for maintaining ketamine’s antidepressant effects.
“Ketamine has always been known to target different receptors in the brain called NMDA receptors,” said Dr. Lee, who is also chief psychiatrist at NewYork-Presbyterian/Weill Cornell Medical Center. “The discovery that mGluR5 receptors are involved in the antidepressant effects of ketamine is novel.”
Previous studies have shown that ketamine and other antidepressants cause the release of brain-derived neurotrophic factor (BDNF), a protein that promotes brain cell survival, growth, and function. Digging deeper into the mechanism by which BDNF exerts its effects, the research team showed that BDNF stimulates the tyrosine kinase receptor TrkB, promoting its interaction with mGluR5 receptors. This interaction strengthens connections between brain cells and improves communication.
This interaction also leads to the removal of a portion of the mGluR5 receptor from the cell membrane. This prevents excessive communication between cells from causing weakening of synapses by receptors.
“Drugs that promote these interactions can help strengthen all the brain connections that were weakened during depression and promote early and long-term antidepressant effects,” Dr. Levitz said. “It strengthens brain connections and at the same time removes the ability to weaken brain connections.”
Anisul Arefin, assistant professor of psychiatry at Weill Cornell University, and Dr. Jihye Kim. The study’s co-lead author is Dr. Manas Pratim Chakraborty, a former postdoctoral fellow in Levitz’s lab.
Applying research results to clinical practice
Dr. Liston and his colleagues are preparing to begin a clinical trial to test whether the antidepressant effects seen in the Cell study can be replicated in patients by combining small doses of existing drugs that have already been shown to be safe and effective in humans.
“If that’s true, we could bring these new treatments to patients on a more rapid schedule,” Dr. Liston said.
Dr. Lee and Dr. Levitz are continuing to study whether combining low-dose existing drugs that target mGluR5 receptors with low-dose ketamine can produce long-lasting antidepressant effects with fewer side effects, with the goal of eventually starting clinical trials. This rapid translation of their findings was facilitated by the team’s interdisciplinary expertise in clinical psychiatry, molecular signaling, and biochemistry, Dr. Lee said.
Overall, efforts to better understand existing drugs will improve their use and help clinicians develop evidence-based drug combinations rather than using a trial-and-error approach.
“Together, these two studies reshape the way we think about how ketamine works in patients,” Dr. Lee said. “This shows patients that we are making progress toward innovative treatments and helps them understand the treatments they are receiving.”
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References:
Mnguba, H. others (2026). Mechanism-based identification of antidepressant G protein-coupled receptor drug targets. cell. DOI: 10.1016/j.cell.2026.04.006. https://www.cell.com/cell/abstract/S0092-8674(26)00395-8.
Arefin, A. others (2026). TrkB/mGluR5 crosstalk underlies the synaptic metaplasia mechanism of ketamine. scientific progress. DOI: 10.1126/sciadv.aec1444. https://www.science.org/doi/10.1126/sciadv.aec1444.
