The reason antidepressants take time to show effects has been revealed at the molecular level. By utilizing this, there is hope to develop psychiatric medications that can work more quickly and accurately.
A research team from the Icahn School of Medicine at Mount Sinai in the United States reported on the 2nd that they have elucidated the mechanism of the '5-HT1A serotonin receptor,' which is critical for mood regulation, at the molecular level. The research results were published in the international journal 'Science Advances' on the same day.
The 5-HT1A receptor is a protein that detects the chemical serotonin, which is involved in emotions, cognition, and pain in the brain. It acts as a switch that regulates various brain functions such as mood, anxiety, and cognition. When this receptor is stimulated by serotonin, it activates internal proteins to transmit neural signals through various pathways.
Professor Daniel Wacker and his research team analyzed how various drugs activate the 5-HT1A receptor using cultured cells and advanced high-resolution cryo-electron microscopy technology. Cryo-electron microscopy is a state-of-the-art imaging technique that reveals molecular structures at atomic-level resolution.
The research team found that the proteins activated by the receptor vary depending on the drug. The drug asenapine (brand name Saphris) weakly acts on the receptor, activating only one type of protein. In contrast, medications such as the anxiolytic buspirone and the synthetic drug LSD (lysergic acid diethylamide) awakened multiple proteins equally. Drugs that selectively activate specific proteins, like asenapine, tend to have relatively fewer side effects.
The research team also discovered that a type of lipid molecule called phospholipid, present in the cell membrane, plays a crucial role in regulating the receptor's activity as if it were a co-pilot. This presents a new perspective that the receptor does not simply respond to drugs but is also influenced by the cellular membrane environment.
Most currently used antidepressants take several weeks to show effects. Existing drugs also targeted the 5-HT1A receptor, but the operating mechanism of this receptor had not been clearly identified until now.
The research team hopes that this study will help understand why some drugs act quickly while others act slowly, and aid in creating next-generation drugs that work more rapidly. Professor Wacker noted, "By understanding how the 5-HT1A receptor adjusts signals, it will be possible to design medications that can treat psychiatric disorders such as depression, anxiety, and schizophrenia more effectively."
References
Science Advances (2025), DOI: https://doi.org/10.1126/sciadv.adu9851