□ A research team led by Professor Oh Yong-Seok of the Department of Brain Sciences at the Daegu Gyeongbuk Institute of Science and Technology (DGIST; President Kunwoo Lee) has, for the first time, identified the key cause of the “treatment delay” phenomenon, in which antidepressant medications often take several weeks or longer to produce therapeutic effects after administration.
□ Selective serotonin reuptake inhibitors (SSRIs), commonly prescribed antidepressants, rapidly increase serotonin levels in the brain. However, patients typically do not experience noticeable mood improvement until weeks to months later. Researchers have long suggested that this delay reflects structural changes in neural circuits, but the underlying molecular mechanisms have remained unclear.
□ Using advanced genomic analysis techniques, Professor Oh’s team examined changes in the brains of mice after long-term antidepressant treatment. The researchers found that when mossy cells [1] in the hippocampus are stimulated by antidepressants, they accelerate the translation of specific genes and produce the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP [2] ).
□ According to the team, the medication-driven rise in serotonin levels functions primarily as a “starting signal,” while the neuropeptide itself plays the central role in brain recovery. Antidepressant effects emerge only after the brain produces sufficient amounts of this peptide and undergo “circuit reprogramming” that rebuilds surrounding neural connections. The team referred to this sequence as “translational reprogramming [3] ” of peptide neural circuits.
□ Notably, the study found that the antidepressant mechanism linked to the PACAP peptide is markedly stronger in female mice. This finding offers an important clue for understanding sex differences in depression onset and treatment response. It may also help advance precision medical treatments tailored for female patients.
□ “We have shed light on why antidepressant treatment takes time to show effects by examining the efficiency of neuropeptide production from a new perspective,” Professor Oh said. “Going forward, we plan to continue research toward developing next-generation rapid-acting antidepressants that can produce immediate effects by directly modulating not only serotonin but also the production and maturation of neuropeptides,” he added.
□ This study was supported by the Ministry of Science and ICT and the National Research Foundation of Korea through the Mid-Career Researcher Program and the Creative Challenge Research Infrastructure Support Program. The findings were published in Molecular Psychiatry , a globally recognized journal in the field of molecular psychiatry.
[1] Mossy Cell: A type of cell located in the hippocampus of the brain that functions as a “gatekeeper” within neural circuits regulating memory and emotion. This study identified it as a key control hub that responds to antidepressant treatment.
[2] Neuropeptide: A protein-based signaling molecule that is larger and more complex than typical neurotransmitters. It finely modulates brain function, and this study confirmed that a peptide known as PACAP plays a decisive role in depression recovery.
[3] Translational Reprogramming: A process in which changes in the efficiency of converting genetic information into proteins within a cell alter the cell’s properties and functions.
Molecular Psychiatry
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