Experts at the University of Sydney have found that a gene involved in regulating the body’s response to stress switches on more easily in the brains of people who live with schizophrenia. 

The study, published in the American Journal of Psychiatry and carried out in collaboration with researchers at the Max Planck Institute of Psychiatry, looked at the FKBP5 gene and the corresponding FKBP51 protein, which help regulate how strongly the body responds to stress hormones such as cortisol. 

Using donated brain tissue, the researchers found that for people with schizophrenia, the chemical tags that normally keep the FKBP5 gene in check had been stripped away. This change was linked to higher activity of the FKBP5 gene, opening up the possibility of developing new treatments that target it. 

Dr Natalie Matosin, from the School of Medical Sciences, said: “For people who have lost the chemical tags that keep their stress gene in check, it is like having the volume on their speaker stuck on high.

“Responding to stress so strongly can affect the brain over time, making it more vulnerable to serious psychiatric conditions. Understanding what controls this response gives us fresh insights that will help us to develop more effective treatments.” 

How ageing may increase susceptibility  

The researchers also found that changes in the stress-response system become more pronounced with age, potentially affecting the brain’s internal circuitry over time. This means that the system may be switched on more easily and stay on for longer. These changes, in turn, increase vulnerability to developing psychiatric disorders such as schizophrenia later in life.

Dr Matosin, who is also a member of the Charles Perkins Centre and the Brain and Mind Centre, explained: “This altered stress response is particularly concentrated in the brain’s frontal cortex, the area of the brain that supports memory, decision-making and emotional control. 

“Having a persistently heightened stress response may mean that, as the brain ages, the circuits in the frontal cortex becomes more vulnerable to damage, increasing susceptibility to serious psychiatric illness.”

Research:

Matosin, N., Binder, E.B., et al ‘Age-dependent DNA methylation changes at FKBP5 enhancer sites drive increased gene expression in schizophrenia’ (The American Journal of Psychiatry, 2026)

Declaration:

Dr Matosin was supported by a Project Grant and Al & Val Rosenstrauss Fellowship from the Rebecca L. Cooper Medical Research Foundation, as well as an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship, Alexander von Humboldt Foundation Research Fellowship, International Brain Research Organisation (IBRO) Research Fellowship and a NARSAD Young Investigator Grant.