Summary: Fatigue is one of the most debilitating and hardest-to-treat symptoms of major depressive disorder (MDD). New research has identified a biological root for this exhaustion: a breakdown in ATP bioenergetics.
By analyzing the “energy currency” molecules in the brain and blood of young adults, scientists discovered that cells in depressed individuals actually overwork while at rest but lack the capacity to increase energy production under stress. The study suggests that the mitochondria—the cell’s power plants—are pushing themselves to the limit early in the illness, eventually leading to the profound low mood and cognitive slowness associated with depression.
Key Facts
The Resting Overdrive: In young adults with depression, brain and blood cells produce more ATP than healthy peers during rest, suggesting the system is already “redlining” before any actual demand is placed on it.The Stress Failure: Despite higher resting energy, these cells have a significantly reduced capacity to “ramp up” energy production when faced with stress or higher cognitive demand.Universal Biomarker: This is the first time patterns in these “fatigue molecules” have been found simultaneously in both the brain and the bloodstream, offering a potential new way to diagnose MDD via a simple blood test.
Source: University of Queensland
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.
New research 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, contributing to chronic fatigue. Credit: Neuroscience News
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.
Key Questions Answered:Q: Why do I feel so tired if my cells are “overworking”?
A: Think of your cells like a car engine that is idling at a very high RPM. Even when you’re sitting still, your “engine” is burning through fuel and wearing itself out. When you actually try to “drive” (perform a task or handle stress), there’s no extra power left to give. This constant state of overwork leads to the deep, physical fatigue often felt in depression.
Q: Does this mean depression is a “mitochondrial disease”?
A: Researchers are beginning to view it that way. The study shows that the mitochondria have a reduced capacity to cope with energy demands. This biological “energy crisis” contributes directly to low mood, lack of motivation, and that feeling of “brain fog” where your thoughts move slowly.
Q: Can a blood test diagnose depression now?
A: We’re getting closer! Because the study found the same ATP patterns in blood cells as they did in brain scans, it opens the door for a diagnostic tool that measures cellular energy. This would help move depression diagnosis from subjective questionnaires to objective, biological data.
Editorial Notes:This article was edited by a Neuroscience News editor.Journal paper reviewed in full.Additional context added by our staff.About this depression and neuroscience research news
Author: Pam Frost
Source: University of Queensland
Contact: Pam Frost – University of Queensland
Image: The image is credited to Neuroscience News
Original Research: Open access.
“ATP bioenergetics and fatigue in young adults with and without major depression” by Kathryn R. Cullen, Susannah J. Tye, Bonnie Klimes-Dougan, Hannes M. Wiesner, Roger B. Varela, Brooke Morath, Lin Zhang, Wei Chen & Xiao-Hong Zhu. Translational Psychiatry
DOI:10.1038/s41398-026-03904-y
Abstract
ATP bioenergetics and fatigue in young adults with and without major depression
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.