Highlights

• Ketamine may work not only by blocking brain receptors but also by forming chemical bonds with brain proteins.  

• The study shows that ketamine and its metabolites can permanently modify proteins in the hippocampus.  

• A total of 21 brain proteins were found to be chemically altered in mice.  

• These protein changes may help explain why ketamine’s antidepressant effects last longer than the drug itself remains in the body.  

Summary

Ketamine is known for its rapid antidepressant effects, often working within hours. However, one puzzling question remains: how can a drug that leaves the body relatively quickly produce effects that last for days?  

This study explores a new explanation. Instead of focusing only on how ketamine blocks certain brain receptors, the researchers investigated whether ketamine forms chemical bonds with proteins inside the brain. When a drug forms a covalent bond—a strong chemical attachment—with a protein, the effect can last much longer than the drug itself.  

Using a technique called chemical proteomics, which combines protein analysis with advanced mass spectrometry, the researchers examined brain tissue from mice after ketamine treatment. They found that ketamine and its metabolites chemically modified 21 different proteins in the hippocampus, a brain region closely linked to mood and memory.  

Importantly, many of these proteins are involved in synaptic transmission—the process by which nerve cells communicate. Some modified proteins are key components of AMPA receptors, which are known to play a major role in ketamine’s antidepressant action. Others are linked to synaptic plasticity, the brain’s ability to reorganize connections.  

The findings suggest that ketamine’s antidepressant effects may result from a combination of rapid receptor activity and longer-lasting chemical modifications of brain proteins. These chemical changes could continue influencing brain signaling even after ketamine has been cleared from the bloodstream.  

This work provides a new perspective on how fast-acting antidepressants function. By identifying specific protein targets that are chemically modified, the study also opens the door to developing safer and longer-lasting treatments for depression.  

Reference

X. Hu, J. Liu, J.-L. Wu, Z.-Q. Xiong, and N. Li, “Chemical proteomics unraveling the contribution of covalent protein modifications to antidepressant effects of ketamine,” Journal of Analysis and Testing, vol. 9, pp. 668–675, 2025, doi: 10.1007/s41664-025-00369-8.