Serotonin transporter gene methylation and cortisol reactivity to acute stress: modeling the pathogenetic and therapeutic effects of stress-related disorders?

J Neural Transm (Vienna). 2025 Sep 23. doi: 10.1007/s00702-025-03009-8. Online ahead of print.

ABSTRACT

Mental disorders arise through the interaction of genetic predisposition and environmental influences such as stress. Epigenetic processes, like DNA methylation, could represent a mechanism mediating this interplay in the pathogenesis and maintenance of stress-related mental disorders. Changes in methylation of the serotonin transporter gene (SLC6A4, 5-HTT) are associated with both stress and mental disorders. The present study for the first time longitudinally examines the relationship between the acute stress response and SLC6A4 methylation. For this purpose, 122 healthy adults participated in a standardized acute stress induction paradigm (Maastricht Acute Stress Test; MAST). The stress response was assessed via salivary cortisol collected at seven time points before and after stress induction. SLC6A4 promoter methylation was determined using pyrosequencing of bisulfite-converted DNA from peripheral blood before and 45 min after stress induction. A relative increase in SLC6A4 methylation from before to after the stress test was associated with increased salivary cortisol stress reactivity. Increased SLC6A4 methylation has previously been reported as a potential pathogenetic marker for stress-related mental disorders such as depression and posttraumatic stress disorder (PTSD), and to predict clinical response to both pharmacotherapy and psychotherapy. The present results therefore suggest that acute stress induction may serve as a model paradigm for investigating the potential pathogenetic and treatment mechanisms of stress-related mental disorders.

PMID:40986034 | DOI:10.1007/s00702-025-03009-8