Summary: Ketamine has been a “miracle” for many with treatment-resistant depression, but its side effects and short duration have limited its use. Two new studies have “reverse engineered” exactly how the drug works.
By identifying specific opioid receptors in the prefrontal cortex and a unique “cross-talk” between cell receptors, researchers have successfully recreated ketamine’s benefits in mice using a combination of lower-dose, safer drugs. This breakthrough paves the way for rapid-acting antidepressants that skip the “trip” and the side effects.
Key Facts
- The “Cortical Reawakening”: Ketamine works by targeting opioid receptors on “interneurons”, cells that normally act as brakes on the brain. By briefly silencing these brakes for just 15–20 minutes, ketamine “reawakens” the prefrontal cortex, kickstarting the antidepressant effect.
- The Triple-Drug Strategy: In the Cell study, researchers proved they could achieve the same “reawakening” by combining low doses of three existing drugs. This synergistic approach avoids the high doses that cause dissociation and blood pressure spikes.
- Maintaining the Glow: While the initial “kick” comes from interneurons, the Science Advances study found that long-term relief depends on a “handshake” between two receptors: TrkB and mGluR5.
- Synaptic Strengthening: This receptor interaction, triggered by the protein BDNF, strengthens weakened brain connections and simultaneously removes the cell’s ability to weaken those connections again.
- Accelerated Clinical Trials: Because the researchers are using drugs already proven safe in humans, a clinical trial is being launched immediately to see if these combinations can treat patients on an accelerated timeline.
Source: Weill Cornell University
Weill Cornell Medicine investigators have “reverse engineered” ketamine’s antidepressant effects to identify potential new strategies for treating depression.
While there are many effective treatments available for depression, not all patients respond to them. About one-third of patients must try multiple medications before eventually finding relief, and another third have treatment-resistant depression.
An anesthetic called ketamine can provide immediate relief to some patients with treatment-resistant depression, but the effects are often short-lived. Ketamine also has serious side effects for some patients, including changes in heart rate or blood pressure, feelings of being disconnected from one’s thoughts or self and addiction.
“We really need new treatments,” said Dr. Conor Liston, the Robert Michels, M.D. Professor of Psychiatry at Weill Cornell Medicine and a professor of neuroscience at the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. “By understanding how ketamine works, we hoped to find new ways of achieving similar antidepressant effects rapidly, without some of those side effects.”
Pinpointing the mechanism behind ketamine’s initial benefits
Previous studies had shown that drugs that block opioid receptors in the brain interfere with ketamine’s antidepressant effects, showing these receptors play a role in its activity. So, Dr. Liston teamed up with Dr. Joshua Levitz, a professor of biochemistry and biophysics at Weill Cornell Medicine, to identify precisely which ones were key.
In a study published April 23 in Cell, they 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.
The interneurons act as a master regulator of cell activity in this brain region, Dr. Levitz explained. But excessive stress causes these cells to become hyperactive and unduly suppress overall brain cell activity in the prefrontal cortex, contributing to depression. Ketamine can reverse this effect by stimulating the opioid receptors to tamp down the interneurons’ activity.
“Ketamine targets these opioid receptors, relieving inhibition by the interneurons and reactivating prefrontal cortex cells for a very brief period of time—maybe only for 15 or 20 minutes,” said Dr. Levitz, who is also a professor of biochemistry in psychiatry at Weill Cornell Medicine. “That seems to be enough to kickstart this whole program of cortical reawakening.”
The team also showed that it could recreate ketamine’s antidepressant effects in mice by combining small doses of three drugs that target the same pathway, which may provide an effective alternative to ketamine with fewer side effects.
“This synergistic strategy could 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. “By avoiding higher doses, we can avoid side effects.”
Dr. Hermany Munguba, a postdoctoral associate with Drs. Liston and Levitz at the time of the study, and Anisul Arefin, a doctoral candidate in the Levitz lab, were co-first authors of this study.
Maintenance of antidepressant effects requires multiple signals in brain cells
The second study, a collaboration between the laboratories of Dr. Levitz and Dr. Francis Lee, chair of psychiatry and the Jack D. Barchas, M.D. Professor of Psychiatry at Weill Cornell Medicine, provided new insights into ketamine’s longer-term antidepressant effects.
Published May 1 in Science Advances, the study confirmed in a preclinical model that cross-talk in the brain cells between a receptor called TrkB and a receptor called mGluR5 is essential to maintaining ketamine’s antidepressant effects, building on previous cell and tissue studies by the team.
“Ketamine was always known to target different receptors, called NMDA receptors, in the brain,” said Dr. Lee, who is also psychiatrist-in-chief at NewYork-Presbyterian/Weill Cornell Medical Center. “Finding that mGluR5 receptors are involved in ketamine’s antidepressant effects is novel.”
Previous studies have shown that ketamine and other antidepressants trigger the release of brain-derived neurotrophic factor (BDNF), a protein that promotes the survival, growth and function of brain cells. Delving deeper into the mechanism by which it exerts its effects, the team showed that BDNF stimulates the tyrosine kinase receptor TrkB and promotes interaction with the mGluR5 receptor, an interaction that strengthens connections and improves communication between brain cells.
This interaction also leads to the removal of some of the mGluR5 receptors from the cell membrane. This prevents excessive communication between the cells from triggering a weakening of the synapses by the receptors.
“Drugs that drive these interactions strengthen all the brain connections that have been weakened during depression, which helps promote initial and longer-term antidepressant effects,” Dr. Levitz said. “It both makes the brain connections stronger and removes the ability to weaken brain connections.”
Anisul Arefin, Dr. Jihye Kim, an assistant professor of psychiatry at Weill Cornell Medicine; and Dr. Manas Pratim Chakraborty, a former postdoctoral associate in the Levitz lab, were co-first authors of the study.
Moving the findings into the clinic
Dr. Liston and his colleagues are preparing to launch a clinical trial testing whether combining small doses of existing drugs, which have already been shown to be safe and effective in humans, may recreate in patients the antidepressant effects seen in the Cell study.
“If that’s true, we could get these new therapies to patients on an accelerated timeline,” Dr. Liston said.
Dr. Lee and Dr. Levitz are continuing to study whether combining low doses of existing drugs that target mGluR5 receptors with low doses of ketamine may also deliver lasting antidepressant effects with fewer side effects, with the goal of eventually launching a clinical trial. This rapid translation of their findings has been facilitated by the teams’ multidisciplinary expertise in clinical psychiatry, molecular signaling and biochemistry, said Dr. Lee.
Overall, efforts to better understand existing drugs will help improve their use and help clinicians develop evidence-based drug combinations rather than using a trial-and-error approach.
“These two studies together reframe how we think about how ketamine works for our patients,” Dr. Lee said. “It shows patients that we are making progress towards innovative therapies and will help them understand the treatments they are receiving.”
Funding: The research reported in this story was supported in part by the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke, all part of the National Institutes of Health, through grant numbers R33DA051529, R01MH129693, R01MH118451, R01NS126073, R01MH123154, F31MH123130, R01NS126590, K08MH127383 and T32DA039080. Additional support was provided by the Swedish Research Council (VR2020-06395), the Brain & Behavior Research Foundation, the Horizon Europe Framework Programme, the Rohr Family Research Scholar Award, the Monique Weill-Caulier Award, the Jake Collective, the Hope for Depression Research Foundation and the Pritzker Neuropsychiatric Disorders Research Consortium and The Burroughs Welcome Fund.
Key Questions Answered:
A: Not exactly. Ketamine is an NMDA antagonist, but these studies show it uses the opioid receptor pathway as a critical middleman to achieve its antidepressant effects. This explains why previous studies found that opioid-blocking drugs also blocked ketamine’s benefits.
A: That’s the goal of “reverse engineering.” By identifying the specific receptors responsible for healing versus those responsible for side effects, scientists can target the “healing” ones with much lower doses, ideally eliminating the hallucinations and addictive potential.
A: It likely comes down to the “handshake” mentioned in the second study. If the communication between the TrkB and mGluR5 receptors is weak, the initial “reawakening” happens, but the brain connections don’t stay strengthened. The new research suggests we can use supplemental drugs to “lock in” those connections.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Ketamine and Depression research news
Author: Krystle Lopez
Source: Weill Cornell Medicine
Contact: Krystle Lopez – Weill Cornell Medicine
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets” by Hermany Munguba, Anisul Arefin, Ryota Hasegawa, Luca Posa, Giovanna R. Romano, Teja N. Peddada, Alexander Donatelle, Ashna Singh, Vanessa A. Gutzeit, Akshara Vijay, Prerana Vaddi, Melanie Kristt, Daniel Shaver, Shanjida Hoque, Johannes Broichhagen, Joseph M. Stujenske, Francis S. Lee, Evan O’Brien, Joshua Levitz, and Conor Liston. Cell
DOI:10.1016/j.cell.2026.04.006
Open access:
“TrkB/mGluR5 cross-talk underlies a synaptic metaplasticity mechanism of ketamine” by Anisul Arefin, Jihye Kim, Manas Pratim Chakraborty, Silvia Martinelli, Betty Bai, Francis S. Lee, and Joshua Levitz. Science Advances
DOI:10.1126/sciadv.aec1444
Abstract
Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets
Depression is driven by dysfunction in discrete neural circuits, but a deeper understanding of the underlying molecular and synaptic mechanisms is needed to guide the development of therapeutics.
Here, we decipher the mechanisms of action of the fast-acting antidepressant ketamine to enable the identification of G protein-coupled receptor (GPCR) antidepressant targets. We find that the behavioral effects of ketamine rely on mu-opioid receptors (MORs), which are enriched in somatostatin-expressing interneurons (Sst+ INs) in the medial prefrontal cortex (mPFC).
Chronic stress drives presynaptic hypertrophy of mPFC Sst+ INs and excessive inhibition of pyramidal neurons, which is rescued by ketamine. Motivated by these findings, we use RNA sequencing to identify mPFC Sst+ IN-enriched GPCRs and validate the antidepressant potential of promising targets.
Synergistic targeting of multiple GPCRs enables potent antidepressant-like responses with reduced side effects. Together, these findings reveal a general approach to identifying therapeutic GPCR targets for brain disorders.
Abstract
TrkB/mGluR5 cross-talk underlies a synaptic metaplasticity mechanism of ketamine
A complex ensemble of neuromodulatory receptors orchestrates the many forms of synaptic plasticity that drive behavioral state changes, but an understanding of how such receptors functionally interact is limited.
Here, we find that the antidepressant action of ketamine is dependent on both the receptor tyrosine kinase, tropomyosin-related kinase B (TrkB), and the G protein–coupled receptor, metabotropic glutamate receptor 5 (mGluR5).
mGluR5 amplifies brain-derived neurotrophic factor (BDNF)–driven signaling of TrkB, enabling synaptic potentiation via “signaling cross-talk,” while BDNF activation of TrkB drives mGluR5 endocytosis via “trafficking cross-talk,” impairing synaptic depression.
These modes of cross-talk are enhanced by ketamine, which increases surface and postsynaptic levels of TrkB. Last, we find that an mGluR5 positive allosteric modulator can enhance both modes of cross-talk and boost the effects of ketamine.
Together, these data unravel the intimate relationship between different classes of neuromodulatory receptors, revealing that receptor-receptor interplay can drive therapeutic action.
