Stress-Regulating Gene Found More Active in Brains of People With Schizophrenia

Researchers have identified a change in a key stress-response gene in the brains of people with schizophrenia, a finding that could eventually help scientists develop new treatments aimed at the way the brain responds to prolonged stress.

The University of Sydney study, conducted with researchers from the Max Planck Institute of Psychiatry and published in the American Journal of Psychiatry, focused on a gene called FKBP5 and the protein it produces, FKBP51.

Both play an important role in regulating the body’s response to stress hormones such as cortisol.

Using donated human brain tissue, researchers found that in people with schizophrenia, some of the chemical markers that normally help keep the FKBP5 gene under control were reduced.

That was associated with greater activity of the gene.

The finding does not mean FKBP5 has been established as a single cause of schizophrenia. The condition is complex and is believed to involve a combination of genetic, biological and environmental factors.

However, the study gives researchers another potential biological pathway to investigate.

Dr Natalie Matosin from the University of Sydney’s School of Medical Sciences said the findings suggested the brain’s stress-response system may be more easily activated in some people with schizophrenia.

“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,” Matosin said.

“Responding to stress so strongly can affect the brain over time, making it more vulnerable to serious psychiatric conditions.”

What researchers found

The study examined changes around FKBP5, a gene involved in controlling the effects of cortisol and other stress hormones.

Genes are not simply switched permanently on or off.

Their activity can be influenced by chemical markers attached to DNA and surrounding structures. These markers form part of what is known as epigenetic regulation.

They do not change the underlying DNA sequence, but they can affect how active a gene becomes.

Researchers found that some of the chemical control mechanisms around FKBP5 were reduced in brain tissue from people with schizophrenia.

This was associated with higher activity of the gene and increased production of its related protein.

In simple terms, the mechanism that normally helps regulate the stress response appeared to be less restrained.

That could matter because long-term disruption of stress hormones has been associated with changes in brain function.

The researchers believe understanding this process in greater detail could eventually identify new targets for psychiatric medicines.

Study at a glance

Ageing may strengthen the effect

The researchers also found that changes in the stress-response system appeared to become more pronounced with age.

That could be particularly important in the frontal cortex, a region involved in functions including memory, decision-making and emotional regulation.

Matosin said a persistently heightened stress response could make brain circuits in this region more vulnerable over time.

“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,” she said.

The study raises the possibility that stress-related biological changes may interact with ageing in ways that affect vulnerability to psychiatric illness.

However, that does not mean ageing itself causes schizophrenia, nor does it mean everyone with heightened stress responses will develop a psychiatric condition.

The research instead points to a mechanism that may be one part of a much larger picture.

Why FKBP5 is attracting attention

FKBP5 has already been studied in relation to stress and mental health because of its role in regulating the body’s hormonal stress system.

When a person experiences stress, the body releases hormones including cortisol.

Normally, this system activates and then settles down once the immediate pressure has passed.

Problems can arise when the stress response remains elevated for extended periods.

The latest study suggests that in some people with schizophrenia, the biological controls around FKBP5 may make that response easier to activate or harder to turn down.

That makes the gene and its related protein potentially interesting targets for drug development.

But researchers are still some distance from turning the discovery into a treatment.

Any future therapy would need to show that changing FKBP5 activity is both safe and clinically useful.

It would also need to be tested through laboratory studies and clinical trials before being considered for routine patient care.

Schizophrenia remains a complex condition

Schizophrenia is a serious psychiatric disorder that can affect how a person thinks, perceives reality and relates to other people.

Symptoms can include hallucinations, delusions, disorganised thinking, reduced motivation and difficulties with memory or concentration.

Current treatment commonly involves antipsychotic medication alongside psychological, social and community support.

Existing medicines can be highly effective for some symptoms, but they do not work equally well for everyone and can cause significant side effects.

That is one reason researchers continue looking for new biological targets.

A treatment aimed at the stress-response system would represent a different approach from many existing antipsychotic medicines.

The University of Sydney research does not yet establish that such a treatment will work.

Its significance is that it identifies a measurable difference in brain tissue that may help explain how stress biology interacts with schizophrenia.

A possible new direction, but not yet a clinical breakthrough

The study adds to growing research examining how genetics, epigenetics and environmental stress can interact in psychiatric illness.

For patients and families, it is important to distinguish between a promising research finding and an available treatment.

There is currently no FKBP5-based therapy for schizophrenia arising from this study.

The discovery instead provides researchers with a new avenue to investigate.

If future work confirms that excessive FKBP5 activity contributes directly to disease processes, scientists could then explore whether medicines targeting the pathway can reduce symptoms or protect vulnerable brain circuits.

For now, the finding offers another piece of evidence that the brain’s response to stress may play an important role in schizophrenia, and that understanding how this system is regulated could help shape the next generation of psychiatric research.

Source: University of Sydney and Max Planck Institute of Psychiatry. Study published in the American Journal of Psychiatry.