Your Brain Isn’t “Low on Serotonin”—It’s Low on Energy

Why New Research Is Rewriting the Story of Depression and Brain Health

For decades, most explanations of depression centered on neurotransmitters—serotonin, dopamine, and norepinephrine.

You’ve probably heard the analogy: “Depression is like having low serotonin, just like diabetes is low insulin.”

But today, some of the most exciting neuroscience research is telling a very different story:

The root problem may not be the chemicals that carry messages between brain cells…but the energy required to make those messages happen.

Three recent studies—published in Cell Metabolism, Metabolic Neuropsychiatry, and Advanced Science—are reshaping our understanding of what causes depression, cognitive fog, and stress-related disorders.

Let’s break it down.

1. The Brain Runs on a Razor-Thin Energy Budget

(Rae et al., 2025 — Metabolic Neuropsychiatry)

The first study argues a simple but surprising truth:

Your brain has almost no energy reserve. It must produce the energy it needs—moment to moment—or function begins to fail.

Even small disruptions in:

• sleep

• nutrition

• blood sugar

• oxygen

• inflammation

• chronic stress

…can reduce ATP (the body’s cellular energy) in key brain regions. And because thinking is expensive, the brain adapts by shutting down higher-order functions first:

• memory

• concentration

• emotional regulation

• motivation

• resilience to stress

This explains why brain fog, fatigue, and mood symptoms often appear before physical symptoms.

2. Metabolites Are Not Waste Products—They Are Signals

(Barros et al., 2025 — Cell Metabolism)

The second study shows that molecules like:

• lactate,

• beta-hydroxybutyrate (BHB),

• adenosine,

• succinate,

• and even elements of the TCA cycle

…are more than fuels. They act as messengers that tell brain circuits how much energy is available.

In other words:

Metabolism isn’t just fueling the brain—it’s also communicating with it.

For example:

• Lactate rises during activity and communicates “slow down” or “switch modes.”

• Adenosine builds up during wakefulness and triggers sleepiness.

• BHB (from fasting or exercise) helps protect neurons during metabolic stress.

These “energy signals” shape:

• neural firing

• cognitive performance

• emotional tone

• vulnerability to anxiety or overstimulation

This challenges the old idea that neurotransmitters dominate brain function.

Energy molecules themselves are part of the brain’s communication system.

3. Depression May Begin With Mitochondrial Dysfunction—Not Serotonin

(Ahn et al., 2025 — Advanced Science)

The third study used multi-omics and patient-derived brain organoids (mini-brain models). Their discovery was striking:

People with atypical depression and psychotic symptoms had:

• impaired mitochondrial ATP production

• low metabolic flexibility

• increased oxidative stress

• disrupted stress-response pathways

• downregulated synaptic and plasticity genes

This means:

The neurons in depression are struggling to make energy.And when brain cells run low on energy, neurotransmitters stop working properly—no matter how much serotonin you try to add.

Mitochondrial dysfunction in these patients wasn’t a side-effect.

It was a core driver shaping both mood and cognition.

This helps explain why:

• antidepressants don’t work for everyone

• inflammation worsens depression

• stress makes symptoms worse

• sleep deprivation triggers relapses

• nutrition and metabolic health matter more than we realized

The Big Picture: A Bioenergetic Model of Mental Health

Bringing all three studies together, a new framework emerges.

Traditional View → Neurotransmitter Imbalance

Depression happens because of low serotonin or disrupted neural signaling.

New View → Bioenergetic Strain

Depression happens because the brain cannot meet the energy demands of modern life.

When neural energy supply falters:

• network stability drops

• synapses weaken

• neurotransmitter systems go offline

• emotional circuits become vulnerable

• cognitive performance declines

• inflammatory pathways activate

And the brain adapts by:

• reducing motivation

• reducing cognitive drive

• biasing toward withdrawal

• shifting into "energy-conservation mode"

This is not a weakness.

It’s survival biology.

So What Does This Mean for You?

It means that mental health is deeply connected to your body’s metabolic resilience.

Improving brain energy can involve:

• better sleep rhythm

• stabilizing blood sugar

• exercise (boosts lactate and BHB signaling)

• reducing chronic stress loads

• nutrients that support mitochondrial function

• addressing inflammation

• supporting healthy metabolic flexibility

These approaches don’t replace therapy or medication—but they address the energy foundation on which brain function depends.

Closing Thought

For decades we tried to fix mood by adjusting the messages.

Now science is showing us we also need to support the messengers, the mitochondria, and the entire energy system that powers the brain.

Your brain isn't broken.

It may simply be exhausted.

And with the right support, it can rebuild its resilience.

Barros, L. F., Fernández-Moncada, I., Marsicano, G., Ruminot, I., Saab, A. S., & Weber, B. (2025). Scale-spanning crosstalk between metabolism and information processing. Cell Metabolism, 37(12), Article 100012. https://doi.org/10.1016/j.cmet.2025.10.012

Rae, C. D., Barros, L. F., Behnke, A., Goyal, M. S., Herculano-Houzel, S., Peleg-Raibstein, D., Picard, M., Rothman, D., Vernon, A. C., & Sarnyai, Z. (2025). Brain energy constraints and vulnerability. In D. Öngür & J. M. Ford (Eds.), Metabolic neuropsychiatry (Strüngmann Forum Reports, pp. 29–55). Springer. https://doi.org/10.1007/978-3-032-05630-6_3

Ahn, I., Chang, S., Lee, J., Choi, S.-H., Han, J., & Kim, Y. (2025). Exploration of novel biomarkers through a precision medicine approach using multi-omics and brain organoids in patients with atypical depression and psychotic symptoms. Advanced Science, 12, e08383. https://doi.org/10.1002/advs.202508383