Depression Beyond Neurotransmitters: A Bioenergetic Systems View

For decades, major depressive disorder has often been explained to the public through a simple story: neurotransmitters such as serotonin or dopamine become imbalanced, and antidepressants help restore them.

That explanation was always incomplete.

A growing body of research now places depression within a much broader physiological landscape involving metabolism, insulin signaling, inflammation, stress physiology, mitochondrial function, and neural plasticity. Neurotransmitters remain important, but they may sit further downstream than we once assumed.

A recent mini-review by Palacek and colleagues, published in Frontiers in Psychiatry, brings several of these threads together. The authors examine the interconnected relationships among insulin resistance, obesity, inflammation, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, and major depressive disorder (MDD), while considering whether treatments directed toward insulin signaling might improve depressive symptoms.

From a bioenergetic perspective, these observations allow us to ask a deeper question:

What if depression, in at least some people, is not primarily the consequence of a neurotransmitter deficiency, but the downstream manifestation of an organism struggling to manage energetic pressure?

Depression and Metabolism Are Increasingly Difficult to Separate

The Palacek review summarizes substantial evidence linking MDD with insulin resistance, obesity, metabolic syndrome, type 2 diabetes, chronic inflammation, and dysregulation of the HPA stress axis. These relationships appear to be bidirectional: metabolic dysfunction may increase vulnerability to depression, while depression and chronic stress can worsen metabolic regulation.

One finding is particularly revealing.

The review highlights a meta-analysis of 70 studies involving 240,704 participants. Fasting insulin and HOMA-IR, a marker of insulin resistance, were significantly elevated during acute depressive episodes but not during remission.

This matters because it suggests that insulin resistance may not simply be a permanent background condition that happens to coexist with depression.

In at least some people, it may fluctuate with the depressive state itself.

That moves the discussion away from a simple model of:

metabolic disease → depression

toward something more dynamic:

physiological stress → metabolic adaptation → altered brain function and behavior.

Mendelian-randomization evidence cited by the authors also suggests bidirectional causal relationships between depression and type 2 diabetes, further reinforcing the idea that these systems are biologically intertwined rather than merely coincidental.

Insulin Resistance May Not Begin as a Failure

Conventionally, insulin resistance is described as a metabolic defect.

But physiology is often more interesting than that.

When cells are already exposed to high substrate pressure, continuing to drive glucose and other nutrients into the system may worsen intracellular congestion. Reducing insulin sensitivity can therefore initially function as a form of substrate gating—limiting additional nutrient entry into tissues whose metabolic machinery is already under pressure.

From a bioenergetic viewpoint, this can be interpreted as an adaptive increase in resistance:

substrate pressure rises→ metabolic throughput becomes constrained→ cells reduce insulin responsiveness→ further substrate entry is restricted.

The response may initially protect the cell.

The problem begins when the underlying constraint does not resolve.

The pancreas may compensate by secreting more insulin. Adipose tissue expands to store excess carbon. Metabolic pathways reroute incoming substrates. Stress hormones mobilize additional fuel. Inflammatory signaling reorganizes tissue behavior and communicates distress throughout the organism.

Each response may make sense locally.

Collectively, however, persistent compensation can become increasingly expensive.

Obesity and Inflammation May Also Be Part of the Compensation

This perspective also changes how we think about obesity.

Adipose tissue is not merely unwanted fat. It is one of the body's major energy-buffering compartments.

When more carbon enters the system than can immediately be oxidized, storing that carbon as triglyceride in adipose tissue protects other organs from excessive substrate exposure.

In this sense:

adipose expansion is initially a buffering response.

But buffering capacity is not unlimited.

As adipocytes enlarge and adipose tissue becomes dysfunctional, inflammation, fibrosis, altered hormone signaling, and substrate spillover can develop. The mechanism that initially protected the system can then begin contributing to the very metabolic congestion it was trying to contain.

Inflammation follows a similar pattern.

Inflammatory signaling helps coordinate responses to injury, infection, metabolic stress, and mitochondrial disturbance. It changes substrate allocation, mobilizes immune resources, alters endocrine signaling, and influences behavior.

Again, this is not inherently pathological.

The problem is persistence.

When the initiating stress does not resolve, inflammatory signaling remains active, requiring further energy while interfering with insulin signaling, mitochondrial function, neural plasticity, sleep, and recovery.

A compensatory response can therefore gradually become a source of additional constraint.

The Missing Concept May Be Bioenergetic Impedance

This is where the concept of bioenergetic impedance becomes useful.

Bioenergetic impedance describes a condition in which biological systems become increasingly constrained in their ability to conduct, transform, buffer, and recover from energetic demand.

The key problem is not necessarily lack of calories.

Nor does it necessarily mean that mitochondria stop producing ATP.

The problem is relational:

Energetic demand is exceeding usable throughput and recovery capacity.

A person may therefore have high blood glucose, high insulin, substantial adipose stores, and abundant calories while still experiencing functional energetic insufficiency.

Energy is present.

But its flow, utilization, allocation, and recovery dynamics are impaired.

This distinction helps explain one of the apparent paradoxes of modern metabolic disease: people can simultaneously have energy excess and reduced energetic capacity.

From Cause to Consequence: A Bioenergetic Framework for Depression

Instead of treating serotonin, insulin resistance, inflammation, obesity, cortisol, and mitochondrial dysfunction as competing explanations for depression, we can organize them into a temporal systems framework.

1. Upstream energetic pressure

The process may begin with cumulative stressors such as:

• psychological stress,

• sleep disruption,

• infection or chronic inflammatory burden,

• nutrient excess or deficiency,

• sedentary behavior or excessive physical demand,

• environmental exposures,

• illness,

• repeated psychosocial challenge.

These different exposures share one important feature:

they increase energetic demand, disrupt energetic processing, or reduce recovery capacity.

2. Bioenergetic impedance develops

When energetic pressure exceeds the capacity of cells and tissues to process it efficiently, throughput becomes constrained.

Potential manifestations include:

substrate congestion→ redox backpressure→ impaired oxidative throughput→ mitochondrial stress→ reduced metabolic flexibility.

At this stage, the organism is not necessarily failing.

It is adapting.

3. Compensatory mechanisms are recruited

The body attempts to protect the system and preserve essential function.

Insulin resistance can restrict additional substrate entry.

Adipose expansion increases storage capacity.

Metabolic rerouting diverts carbon away from congested pathways.

Inflammatory signaling coordinates immune and metabolic responses.

HPA-axis and autonomic activation mobilize fuel and redistribute resources.

Behavior can change as well: activity decreases, appetite changes, sleep patterns shift, and motivation may contract.

These should not automatically be interpreted as defects.

They are responses to a problem.

4. Recovery either occurs—or fails

If the stressor resolves and the system has sufficient reserve:

challenge→ transient impedance→ compensation→ recovery→ restoration of baseline.

This is healthy adaptation.

But repeated or prolonged stress can produce:

impedance→ compensation→ incomplete recovery→ persistent compensation→ greater baseline impedance.

The protective responses themselves now add metabolic cost.

This is the transition from adaptation toward maladaptation.

5. Bioenergetic insufficiency emerges

Eventually, the system may reach a point where available energetic throughput and reserve are insufficient relative to competing demands.

This is bioenergetic insufficiency or Exposure-related malnutrition (ERM).

Importantly, it is not synonymous with ATP depletion.

It means:

the organism no longer has sufficient usable energetic capacity to support every physiological function at its previous level while simultaneously meeting current stress demands.

At this point, prioritization becomes necessary.

Allostatic Triage: When the Brain Must Decide What Matters Most

Kelley's allostatic triage model of psychopathology provides an important conceptual bridge here.

When energetic resources become constrained, organisms cannot invest equally in every biological function.

Resources are preferentially allocated toward functions important for immediate survival and stress adaptation, while energetically expensive but less immediately essential activities may be reduced.

These can include:

• exploration,

• motivation,

• reward seeking,

• executive function,

• social engagement,

• reproduction,

• growth,

• maintenance,

• long-term repair.

Seen from this perspective, several characteristic features of depression become biologically understandable.

Fatigue reduces expenditure.

Psychomotor slowing reduces activity.

Anhedonia reduces costly reward-seeking behavior.

Social withdrawal reduces environmental engagement.

Reduced motivation limits investment in uncertain future rewards.

Difficulty concentrating and planning may reflect reduced allocation to metabolically expensive executive networks.

This does not mean depression is simply an adaptive response.

It means the depressive phenotype may have adaptive origins within a system experiencing persistent energetic constraint.

What begins as protection can become pathology when the state cannot be reversed.

Where Do Neurotransmitters Fit?

Neurotransmitters remain important—but their position in the causal chain changes.

The Palacek review emphasizes that insulin receptors are present in brain regions involved in mood and reward regulation, and that insulin resistance can affect serotonin, dopamine, neurogenesis, synaptic plasticity, learning, and reward processing.

Chronic inflammation, cortisol signaling, altered insulin signaling, mitochondrial stress, and impaired metabolic flexibility can all change how neural circuits operate.

The downstream consequences include changes in:

dopamine signaling,serotonin signaling,glutamate regulation,neurotrophic signaling,synaptic plasticity,reward circuitry,stress processing.

Neurotransmitter abnormalities therefore do not disappear from the model.

They become part of the brain's network-level response to altered physiological operating conditions.

Instead of:

low serotonin → depression

we arrive at a more systematic sequence:

cumulative stress and energetic pressure→ bioenergetic impedance→ metabolic, inflammatory, and endocrine compensation→ incomplete recovery→ persistent impedance→ demand-relative bioenergetic insufficiency→ allostatic triage→ altered neural energy allocation and plasticity→ neurotransmitter and circuit reorganization→ depressive symptoms→ persistent network lock-in→ MDD.

Why Antidepressants May Work Without “Correcting a Chemical Imbalance”

This framework also helps reinterpret antidepressant treatment.

Antidepressants certainly modify neurotransmitter signaling. But their clinical effects may extend well beyond the immediate neurotransmitter target.

Changes in neural plasticity, inflammatory signaling, stress-axis regulation, sleep, cognition, behavior, and metabolic state can all influence recovery.

Likewise, the Palacek review finds that drugs targeting insulin resistance—including metformin, PPAR-γ agonists, and GLP-1 receptor agonists—sometimes improve depressive symptoms, but results remain inconsistent. Importantly, improvements in mood do not always parallel improvements in metabolic markers.

This is exactly what we might expect from a systems disorder.

There may be no single intervention capable of correcting every source of impedance.

A treatment will work best when it meaningfully reduces one of the constraints that is actually limiting that person's recovery.

Depression May Be a Downstream Phenotype, Not the Starting Point

The emerging evidence therefore encourages a different question.

Instead of asking only:

Which neurotransmitter is abnormal?

we might ask:

What is preventing this person's physiological system from returning to a lower-cost, higher-capacity state?

That inquiry naturally includes metabolism, mitochondrial function, insulin signaling, inflammation, sleep, stress physiology, nutrient availability, physical activity, recovery, and environmental load.

The Palacek review does not itself propose bioenergetic impedance as the explanation for depression. It documents the increasingly strong relationship between metabolic dysfunction and MDD.

The bioenergetic framework provides an additional organizing layer.

It suggests that insulin resistance, adipose expansion, inflammation, endocrine activation, and eventually neurotransmitter alterations may not be unrelated abnormalities occurring alongside depression.

They may represent different stages and levels of the same adaptive process.

The distinction is important:

Impedance → compensation → recovery is resilience.

Impedance → compensation → incomplete recovery → persistent compensation is maladaptation.

And when this continues:

unresolved impedance → bioenergetic insufficiency → allostatic triage → neural reorganization → depressive phenotype.

Seen this way, major depressive disorder may, in an important subset of patients, represent the downstream neurobehavioral manifestation of an organism that has been adapting for too long without fully recovering.

That is a very different starting point for understanding depression—and potentially a much richer one for understanding how recovery might occur.

Palacek, K., Corbeil, O., Katyal, S., Lo Buglio, G., Zhou, C., Wong, S., & Fabiano, N. (2026). Metabolic dysfunction and insulin resistance in depression: Mechanisms, evidence, and therapeutic implications. Frontiers in Psychiatry, 17, 1930167. https://doi.org/10.3389/fpsyt.2026.1930167

Fernandes, B. S., Salagre, E., Enduru, N., Grande, I., Vieta, E., & Zhao, Z. (2022). Insulin resistance in depression: A large meta-analysis of metabolic parameters and variation. Neuroscience & Biobehavioral Reviews, 139, 104758. https://doi.org/10.1016/j.neubiorev.2022.104758

Kelley, D. P., Singleton, S. P., Venable, K., Sturm, G., Skovgaard, A., Francis, J., Neylan, T. C., Bradley, E. R., Woolley, J., Picard, M., & O’Donovan, A. (2025). The allostatic triage model of psychopathology (ATP Model): How reallocation of brain energetic resources under stress elicits psychiatric symptoms. Neuroscience & Biobehavioral Reviews, 179, 106419. https://doi.org/10.1016/j.neubiorev.2025.106419