"Why Do Antidepressants Take Weeks to Work?" DGIST Identifies Cause of Delayed Treatment [Reading Science]

Key role lies in neuropeptide production and circuit remodeling in the brain, not serotonin
Findings published in leading psychiatry journal "Molecular Psychiatry"

When patients take antidepressants, serotonin levels rise immediately, but it takes several weeks or longer for their mood to actually improve. A Korean research team has, for the first time in the world, identified the molecular cause of this "delayed therapeutic effect."

On the 26th, a research team led by Professor Oh Yongseok of the Department of Brain and Cognitive Sciences at Daegu Gyeongbuk Institute of Science and Technology (DGIST) announced that they had discovered that the reason the effects of antidepressants appear late lies not in serotonin itself, but in the production of a specific neuropeptide in the brain and the subsequent remodeling of neural circuits. The findings were published online in Molecular Psychiatry, a leading international journal in the field of molecular psychiatry.

(Delayed antidepressant response) Serotonin increases immediately after drug intake, but the actual therapeutic effect appears only after some time. (Peptidergic neural circuit remodeling) In the meantime, PACAP production increases in Mosisepo, and this neuropeptide reorganizes the circuitry to induce recovery from depressive symptoms. Provided by the research team.

Serotonin is a "signal"; the actual treatment is carried out by peptides

Selective serotonin reuptake inhibitors (SSRIs) rapidly increase serotonin levels immediately after ingestion. However, patients do not feel the antidepressant effect for several weeks to several months. Until now, the academic community has assumed that this was due to structural changes in brain neural circuits, but the specific molecular mechanism had not been clearly identified.

The research team tracked the brains of mice that had been given antidepressants for an extended period using state-of-the-art genomic analysis techniques. They found that the translation of specific proteins was selectively activated in mossy cells in the hippocampus, and that, in this process, levels of the neuropeptide PACAP increased.

According to the study, the increase in serotonin serves only as a kind of "signal," and the actual antidepressant effect appears only after sufficient production of neuropeptides and the remodeling of surrounding neuronal circuits. The researchers proposed this as a new mechanism of action, which they termed "translational reprogramming."

Stronger in females...clues to fast-acting therapeutics

In particular, the study also found that the PACAP-based antidepressant mechanism was more pronounced in female mice. This is regarded as an important molecular clue that could explain sex differences observed in the onset of depression and in treatment response.

The team expects that this discovery could lead to the development of biomarkers that predict antidepressant response, as well as the design of next-generation, fast-acting antidepressants that target the regulation of neuropeptide translation.

Professor Oh Yongseok said, "We have explained the delayed therapeutic effect of depression treatment from a new perspective, namely the efficiency of neuropeptide production," adding, "Going forward, we plan to expand our research to develop treatments that exert effects immediately after administration by directly regulating not only serotonin but also the production and maturation of neuropeptides."

This research was supported by the Ministry of Science and ICT and the National Research Foundation of Korea.