ATP bioenergetics and fatigue in young adults with and without major depression, 2026, Cullen

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ATP bioenergetics and fatigue in young adults with and without major depression - Translational Psychiatry

Fatigue is a pervasive and difficult-to-treat symptom of major depressive disorder (MDD) that contributes to disability. Understanding this problem in its earlier stages will be critical for averting long-term negative outcomes. To investigate the molecular roots of fatigue in early-stage...
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ATP bioenergetics and fatigue in young adults with and without major depression​

Translational Psychiatry , Article number: (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Abstract​

Fatigue is a pervasive and difficult-to-treat symptom of major depressive disorder (MDD) that contributes to disability.

Understanding this problem in its earlier stages will be critical for averting long-term negative outcomes.

To investigate the molecular roots of fatigue in early-stage depression, the current work measured bioenergetic mechanisms, with a focus on adenosine triphosphate (ATP), in brain and blood cells in young adults with MDD versus healthy controls (HC).

To measure ATP concentration and ATP production rate in the visual cortex, we utilized 31P magnetic resonance spectroscopy imaging with magnetization transfer (31P MRSI-MT) at 7 Tesla, with and without gamma-ATP resonance saturation.

ATP level was also measured in peripheral blood mononuclear cells (PBMCs) at rest and after serial addition of mitochondrial inhibitors.

Out of 25 participants (mean age 21.8 years), usable data were available for 18 participants for imaging (9 per group); 24 for PBMCs (13 HC; 11 MDD).

The MDD group demonstrated higher ATP production rate in the visual cortex than HC, which correlated positively with Fatigue Severity Scale (FSS) scores.

ATP concentrations in PBMCs were higher in MDD than HC, and also correlated with FSS scores.

After mitochondrial uncoupling, PBMCs in the MDD group had a lower capacity for ATP production than HC.

For the first time, we demonstrate an ATP biosignature of fatigue in young adults with MDD that is visible in both brain and peripheral blood.

The findings suggest a compensatory mechanism that occurs early in the disease stage.
 
www.eurekalert.org

Cellular changes linked to depression related fatigue

Researchers may have discovered a new way to diagnose and treat major depression at the earliest stage of the condition, giving patients the best opportunity for recovery.
www.eurekalert.org

News Release 10-Mar-2026

Cellular changes linked to depression related fatigue​

Researchers may have discovered a new way to diagnose and treat major depression at the earliest stage of the condition, giving patients the best opportunity for recovery.

Peer-Reviewed Publication
University of Queensland


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Researchers may have discovered a new way to diagnose and treat major depression at the earliest stage of the condition, giving patients the best opportunity for recovery.

University of Queensland researchers, in collaboration with the University of Minnesota, analysed levels of adenosine triphosphate (ATP) – known as the “energy currency” molecule – in the brain and blood cells of young people with depression.

Associate Professor Susannah Tye from UQ’s Queensland Brain Institute (QBI) said this was the first time patterns in these fatigue molecules had been discovered in both the brain and blood stream of young people with major depressive disorder (MDD).

“This suggests that depression symptoms may be rooted in fundamental changes in the way brain and blood cells use energy,” Dr Tye said.

“Fatigue is a common and hard-to-treat symptom of MDD, and it can take years for people to find the right treatment for the illness.

“There has been limited progress in developing new treatments because of a lack of research and we hope this important breakthrough could potentially lead to early intervention and more targeted treatments.”

During the study, a team at the University of Minnesota collected blood samples and scans from 18 people aged 18-25 years, who had been diagnosed with MDD.

These were then analysed by the QBI team and compared with samples from participants who did not have depression.

QBI researcher, Dr Roger Varela said they found cells in people with depression produced more energy molecules when resting, but had a reduced ability to increase energy production under stress.

“This suggests cells may be overworking early in the illness, which could lead to longer-term problems,” Dr Varela said.

“This was surprising, because you might expect energy production in cells would be lower for people with depression.

“It suggests that in the early stages of depression, the mitochondria in the brain and body have a reduced capacity to cope with higher energy demand, which may contribute to low mood, reduced motivation and slower cognitive function.”

Dr Varela hopes this research will help de-stigmatise depression.

“This shows multiple changes occur in the body, including in the brain and the blood, and that depression impacts energy at a cellular level,” he said.

“It also proves not all depression is the same; every patient has different biology, and each patient is impacted differently.

“We hope this research will help lead to more specific and effective treatment options.”

The study was led by the University of Minnesota’s Katie Cullen MD, and the imaging technique used to measure ATP production in the brain was developed by Professors Xiao Hong Zhu and Wei Chen.

The research is published in Translational Psychiatry.

Journal​

Translational Psychiatry

DOI​

10.1038/s41398-026-03904-y

Method of Research​

Imaging analysis

Subject of Research​

People

Article Title​

ATP bioenergetics and fatigue in young adults with and without major depression

Article Publication Date​

11-Mar-2026

COI Statement​

The authors declare no competing interests.

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