Depression Is Not a Chemical Imbalance - and That Changes Everything

Depression Is Not a Chemical Imbalance — What Science Actually Shows

Depression is not a chemical imbalance, despite decades of messaging that framed it as “low serotonin.” Contemporary neuroscience shows that depression involves dysregulation across multiple brain systems, including neural networks responsible for mood regulation, stress response, motivation, and emotional processing. Rather than reflecting a single neurotransmitter deficiency, depression emerges from the interaction between brain plasticity, chronic stress exposure, inflammation, and individual life experience — which explains why symptoms, severity, and treatment response vary so widely from person to person.

For decades, depression has been described as a chemical imbalance, most often framed as “low serotonin.” While this explanation was well-intentioned and easy to understand, modern neuroscience has shown it to be incomplete and often misleading.

Depression is now understood as a complex brain-based condition involving changes in neural networks, stress hormones, inflammation, and brain plasticity — not simply a shortage of one neurotransmitter (Moncrieff et al., 2022; Malhi & Mann, 2018).

This shift in understanding matters because how we explain depression shapes how people experience it, treat it, and blame themselves for it.

Where the Chemical Imbalance Theory Came From

The chemical imbalance theory gained popularity in the late 20th century alongside the rise of antidepressant medications. Early hypotheses suggested that depression resulted from deficiencies in neurotransmitters such as serotonin, norepinephrine, or dopamine.

However, over time, research failed to consistently demonstrate that people with depression have lower baseline serotonin levels than those without depression (Moncrieff et al., 2022).

Despite this, the narrative persisted — largely because it was:

• Simple

• Stigma-reducing (at the time)

• Easily communicated to patients

But simplicity does not equal accuracy.

What Science Now Shows About Depression

Depression Is a Network Disorder of the Brain

Neuroimaging studies reveal that depression involves altered communication between brain regions, particularly those responsible for:

• Emotion regulation

• Reward processing

• Threat detection

• Self-referential thinking

Key networks affected include the default mode network, salience network, and prefrontal-limbic circuits (Williams, 2016; Kaiser et al., 2019).

Rather than a single “chemical problem,” depression reflects dysregulated brain circuitry.

Stress Hormones and the HPA Axis

Chronic stress plays a central role in depression. Many individuals with major depressive disorder show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to prolonged exposure to cortisol (McEwen & Akil, 2020).

Over time, elevated cortisol:

• Impairs neuroplasticity

• Shrinks hippocampal volume

• Disrupts mood regulation

This explains why depression often follows loss, trauma, illness, or prolonged stress, rather than appearing “out of nowhere.”

Inflammation and Depression

A growing body of research links depression to systemic and neuroinflammation. Elevated inflammatory markers such as C-reactive protein (CRP) and cytokines have been observed in subsets of people with depression (Miller & Raison, 2016; Osimo et al., 2020).

Inflammation can:

• Alter neurotransmitter metabolism

• Reduce dopamine reward signaling

• Increase fatigue and cognitive slowing

This helps explain why depression often includes physical symptoms, not just emotional distress.

Why Antidepressants Still Help (But Not for the Reason You Were Told)

Antidepressants do not simply “replace missing serotonin.” Instead, they:

• Influence neural plasticity

• Modify stress response pathways

• Alter network connectivity over time

Clinical improvement often occurs weeks after neurotransmitter levels change, suggesting downstream brain adaptation — not immediate chemical correction — drives benefit (Duman et al., 2019).

This does not mean antidepressants are ineffective.

It indicates that their mechanism is far more complex and individualized than previously believed.

What Makes Depression Better or Worse

What Worsens Depression

• Chronic stress

• Social isolation

• Poor sleep

• Unresolved trauma

• Invalidation or oversimplified explanations

These factors reinforce maladaptive brain patterns and prolong depressive states (Slavich & Irwin, 2014).

What Improves Depression

• Psychotherapy that targets cognition and emotion regulation

• Trauma-informed care

• Sleep restoration

• Physical activity (graded, not forced)

• Meaningful connection

• In some cases, medication

Effective treatment focuses on supporting brain adaptation rather than “fixing a flaw.”

Clinical Scenario

Two people take the same antidepressant. One improves significantly. The other does not.

This is not because one person’s “chemicals were worse.”

It’s because depression arises from different biological and psychological pathways in different individuals — including stress exposure, inflammation, trauma history, and neural wiring (Malhi et al., 2020).

Why This New Understanding Matters

When depression is framed as a simple chemical imbalance:

• People blame themselves when medication doesn’t work

• Complex suffering is minimized

• Treatment becomes one-dimensional

When depression is understood as a brain-based, stress-responsive condition, something powerful happens:

People stop seeing themselves as broken.

They begin to see depression as a state the brain enters — and can change.

Conclusion

Depression is not a personal failure, a weakness, or a simple chemical defect. It is a biologically real, brain-based condition shaped by stress, experience, and neuroplasticity.

Moving beyond the chemical imbalance myth allows for:

• More accurate education

• More compassionate care

• More individualized treatment

And most importantly, it gives people hope grounded in science, not shame.

References

Duman, R. S., Sanacora, G., & Krystal, J. H. (2019). Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron, 102(1), 75–90. https://doi.org/10.1016/j.neuron.2019.03.013

Kaiser, R. H., Andrews-Hanna, J. R., Wager, T. D., & Pizzagalli, D. A. (2019). Large-scale network dysfunction in major depressive disorder. JAMA Psychiatry, 76(6), 603–611. https://doi.org/10.1001/jamapsychiatry.2018.4055

Malhi, G. S., & Mann, J. J. (2018). Depression. The Lancet, 392(10161), 2299–2312. https://doi.org/10.1016/S0140-6736(18)31948-2

Malhi, G. S., Das, P., Outhred, T., Dobson-Stone, C., Bargh, D. M., Bryant, R. A., … Bell, E. (2020). Cognitive and neuroplastic mechanisms in depression. Molecular Psychiatry, 25, 161–175. https://doi.org/10.1038/s41380-019-0529-1

McEwen, B. S., & Akil, H. (2020). Revisiting the stress concept: Implications for affective disorders. Journal of Neuroscience, 40(1), 12–21. https://doi.org/10.1523/JNEUROSCI.0733-19.2019

Moncrieff, J., Cooper, R. E., Stockmann, T., Amendola, S., Hengartner, M. P., & Horowitz, M. A. (2022). The serotonin theory of depression: A systematic umbrella review of the evidence. Molecular Psychiatry, 27, 240–250. https://doi.org/10.1038/s41380-022-01661-0

Slavich, G. M., & Irwin, M. R. (2014). From stress to inflammation and major depressive disorder. Psychological Bulletin, 140(3), 774–815. https://doi.org/10.1037/a0035302

Williams, L. M. (2016). Precision psychiatry: A neural circuit taxonomy for depression and anxiety. The Lancet Psychiatry, 3(5), 472–480. https://doi.org/10.1016/S2215-0366(15)00579-9