Summary: Ketamine has provided rapid relief for many people with treatment-resistant depression, but its brief effect and side effects have limited broader use. Two new studies from Weill Cornell Medicine map how ketamine produces its antidepressant effects and demonstrate ways to reproduce those benefits using combinations of existing, lower-dose drugs that may avoid ketamine’s dissociative and cardiovascular side effects.
By identifying specific opioid receptors on interneurons in the prefrontal cortex and revealing a novel interaction between TrkB and mGluR5 receptors, researchers have replicated ketamine’s initial and sustained antidepressant actions in preclinical models. These findings point to rapid-acting antidepressant strategies that separate therapeutic benefits from unwanted effects.
Key Facts
- Cortical reawakening: Ketamine briefly suppresses inhibitory interneurons through opioid receptors in the medial prefrontal cortex (mPFC), lifting a brake on cortical activity. This transient disinhibition—lasting roughly 15–20 minutes—appears sufficient to trigger a broader program of circuit-level changes linked to antidepressant responses.
- Triple-drug strategy: A Cell study shows that the same brief cortical activation can be reproduced in mice by combining low doses of three drugs that target the same pathway, producing rapid antidepressant-like effects while avoiding the high doses that produce dissociation and blood pressure spikes.
- Maintaining benefit: A Science Advances study found that long-term antidepressant effects depend on cross-talk between two receptors—TrkB and mGluR5—which stabilizes and strengthens synaptic connections after the initial ketamine-triggered reawakening.
- Synaptic strengthening: Brain-derived neurotrophic factor (BDNF) activates TrkB and promotes interaction with mGluR5. This interaction both boosts synaptic potentiation and removes mGluR5 from the cell surface, preventing the receptors from later weakening those same synapses.
- Fast clinical translation: Because these approaches repurpose drugs already known to be safe in humans, clinical trials are being planned to test whether low-dose combinations can reproduce ketamine’s benefits in patients without its problematic side effects.
Source: Weill Cornell Medicine
Weill Cornell Medicine investigators have reverse engineered ketamine’s antidepressant effects to point toward safer, rapid-acting therapies.
Although many effective treatments for depression exist, a substantial fraction of patients do not respond. Roughly one-third require multiple medication trials before improving, and another third meet criteria for treatment-resistant depression. Ketamine, an anesthetic, can deliver fast relief in some of these patients, but benefits are often short-lived and accompanied in some people by elevated blood pressure, dissociation, or addiction risk.
“We really need new treatments,” said Dr. Conor Liston, Robert Michels, M.D. Professor of Psychiatry and professor of neuroscience at the Feil Family Brain and Mind Research Institute. “By understanding how ketamine works, we hoped to find ways to produce rapid antidepressant effects without those side effects.”
Pinpointing the mechanism for ketamine’s rapid effects
Previous work showed that opioid receptor blockers can prevent ketamine’s antidepressant effects, suggesting opioid signaling is involved. In the Cell paper (published April 23), the team led by Drs. Liston and Joshua Levitz identified mu-opioid receptors enriched on somatostatin-expressing interneurons (Sst+ INs) in the mPFC as a key target. Under chronic stress, these interneurons become hyperactive and suppress pyramidal neuron output, contributing to depressive-like circuit states. Ketamine’s action on opioid receptors dampens interneuron activity briefly, reactivating prefrontal circuits and initiating the antidepressant response.
The authors also demonstrated in mice that combining low doses of three drugs that act on the same pathway can reproduce ketamine’s rapid behavioral effects. This synergistic, low-dose approach aims to retain therapeutic benefit while minimizing the doses that produce dissociation or cardiovascular effects.
“This strategy could deliver rapid antidepressant effects using 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 hope to avoid side effects.”
How antidepressant effects are maintained
The second study, published May 1 in Science Advances by teams led by Drs. Levitz and Francis Lee, dissected mechanisms that sustain ketamine’s benefit. Their preclinical work shows that TrkB (the receptor for BDNF) and mGluR5 engage in two complementary modes of cross-talk: signaling cross-talk—where mGluR5 amplifies BDNF-driven TrkB signaling to promote synaptic potentiation—and trafficking cross-talk—where TrkB activation causes mGluR5 internalization, reducing the receptor’s ability to drive synaptic weakening.
Ketamine enhances both modes of cross-talk by increasing TrkB levels at the surface and postsynaptic sites. The net effect is strengthened synapses and reduced capacity for later synaptic depression, which together help sustain antidepressant responses beyond the initial cortical reawakening.
“Drugs that promote these interactions strengthen the brain connections that have been weakened during depression, supporting both immediate and longer-term antidepressant effects,” said Dr. Levitz.
Translating findings into clinical trials
Because the studies identify specific, druggable targets and use compounds already evaluated in humans, the teams are moving quickly toward clinical testing. Dr. Liston and colleagues are launching a clinical trial to evaluate whether low-dose combinations can reproduce the rapid antidepressant effects observed in mice. Drs. Lee and Levitz are also exploring whether combining low doses of mGluR5-targeting drugs with low-dose ketamine can provide durable benefit with fewer side effects, with the goal of initiating human trials.
This research emphasizes a mechanism-guided approach—using molecular and circuit insights to design drug combinations—rather than relying on trial-and-error prescribing. “These two studies reframe how we think about ketamine’s action,” Dr. Lee said. “They show progress toward therapies that preserve rapid relief while reducing adverse effects, and they help clinicians and patients understand the biological basis of treatment.”
Funding: The research received support from the National Institutes of Health (including NIDA, NIMH, and NINDS) under multiple grants, and additional support from the Swedish Research Council, Brain & Behavior Research Foundation, Horizon Europe, the Rohr Family Research Scholar Award, Monique Weill-Caulier Award, the Jake Collective, Hope for Depression Research Foundation, the Pritzker Neuropsychiatric Disorders Research Consortium, and the Burroughs Wellcome Fund.
Key Questions Answered:
A: No. Ketamine is primarily an NMDA receptor antagonist. These studies show ketamine accesses an opioid-receptor pathway—using opioid signaling on specific interneurons as a necessary intermediary for its antidepressant action—which explains why opioid blockers can prevent ketamine’s benefits in some experiments.
A: The goal is to isolate and target the receptors responsible for therapeutic effects at much lower doses, reducing the likelihood of hallucinations, dissociation, or addictive effects associated with higher-dose ketamine.
A: The new research suggests that the initial cortical reawakening is only part of the story. Sustained benefit requires effective TrkB–mGluR5 cross-talk to lock in strengthened synapses. When that handshake is weak, the initial improvement can fade; supplemental drugs that enhance this cross-talk may help “lock in” the benefits.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal papers were reviewed in full by editorial staff.
- Additional context was added by the reporting team.
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,” Cell. DOI: 10.1016/j.cell.2026.04.006. Authors include Hermany Munguba, Anisul Arefin, Joshua Levitz, Conor Liston, and others.
TrkB/mGluR5 cross-talk underlies a synaptic metaplasticity mechanism of ketamine,” Science Advances. DOI: 10.1126/sciadv.aec1444. Authors include Anisul Arefin, Jihye Kim, Manas Pratim Chakraborty, Francis S. Lee, and Joshua Levitz.
Abstract — Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets
Depression arises from dysfunction in specific neural circuits. These studies clarify molecular and synaptic mechanisms underlying ketamine’s fast antidepressant actions to identify G protein–coupled receptor (GPCR) targets. The behavioral effects of ketamine depend on mu-opioid receptors (MORs) enriched in somatostatin-expressing interneurons in the mPFC. Chronic stress causes presynaptic hypertrophy of these interneurons and excessive inhibition of pyramidal neurons, which ketamine reverses. RNA sequencing identified Sst+ IN-enriched GPCRs, and synergistic targeting of multiple GPCRs produced potent antidepressant-like responses with fewer side effects, suggesting a strategy to discover therapeutic GPCR targets for brain disorders.
Abstract — TrkB/mGluR5 cross-talk underlies a synaptic metaplasticity mechanism of ketamine
Neuromodulatory receptors coordinate the synaptic plasticity that drives behavioral state changes. The antidepressant action of ketamine depends on both the receptor tyrosine kinase TrkB and the G protein–coupled receptor mGluR5. mGluR5 amplifies BDNF-driven TrkB signaling to enable synaptic potentiation, while TrkB activation drives mGluR5 endocytosis to impair synaptic depression. Ketamine enhances these cross-talk modes by increasing surface and postsynaptic TrkB; an mGluR5 positive allosteric modulator can further boost cross-talk and enhance ketamine’s effects. These findings reveal that receptor–receptor interplay can drive therapeutic action.