How Antidepressants Really Work: Beyond the Chemical Imbalance Myth

TL;DR

Antidepressants like SSRIs don’t just fix a chemical imbalance—they work through multiple mechanisms, including promoting neural plasticity, reducing inflammation, and improving brain network function. These effects help many people with depression, even though the “chemical imbalance” theory is scientifically outdated.

Key Takeaways

• SSRIs increase serotonin levels but also influence broader brain and body systems.

• Benefits may come from neuroplasticity, reduced inflammation, and improved metabolism.

• Antidepressants are effective for many, even though the chemical imbalance model is outdated.

Introduction

SSRIs and other antidepressants are prescribed for depression not because depression is simply a “chemical imbalance,” but because these medications can help relieve symptoms through several complex biological effects. Their main action is to increase serotonin levels in the brain, but their benefits likely involve broader changes in brain function, inflammation, and neural plasticity.

How Antidepressants Work

Serotonin Modulation

SSRIs block the reuptake of serotonin, increasing its availability in the brain. This was the original rationale for their use, based on the “monoamine hypothesis” of depression (Edinoff et al., 2021; Vaswani et al., 2003).

Beyond Serotonin

Antidepressants also affect other neurotransmitters (like norepinephrine and dopamine), and newer drugs target multiple systems for broader effects (Blier, 2016; Feighner, 1999; Shelton, 2004).

Neural Plasticity

SSRIs may promote changes in brain connectivity and plasticity, helping the brain adapt and recover from depressive states. These changes take time, which is why antidepressant effects are often delayed (Chottekalapanda et al., 2020; Sharp & Collins, 2023; Hertz et al., 2015; Chen et al., 2021).

Anti-Inflammatory Effects

SSRIs and SNRIs have been shown to reduce inflammation in the brain, which may contribute to their antidepressant effects (Gałecki et al., 2018; Dionisie et al., 2020; Tynan et al., 2012).

Metabolic and Cellular Effects

SSRIs can influence mitochondrial function, energy metabolism, and lipid remodeling, which may also play a role in symptom improvement (Mahmoudiandehkordi et al., 2021).

Why Prescribe Them?

Symptom Relief

Despite the lack of a simple chemical imbalance explanation, SSRIs and related drugs are effective for many people in reducing depressive symptoms (Boschloo et al., 2023; Vaswani et al., 2003; Talaee et al., 2024).

Complex Mechanisms

Their effectiveness likely comes from a combination of effects on neurotransmitters, brain plasticity, inflammation, and cellular health—not just correcting a single imbalance (Blier, 2016; Gałecki et al., 2018; Chottekalapanda et al., 2020; Sharp & Collins, 2023; Hertz et al., 2015; Tynan et al., 2012; Chen et al., 2021).

Mechanism/Effect

Evidence/Citation

Increases serotonin

(Edinoff et al., 2021; Vaswani et al., 2003)

Affects other neurotransmitters

(Blier, 2016; Feighner, 1999; Shelton, 2004)

Promotes neural plasticity

(Chottekalapanda et al., 2020; Sharp & Collins, 2023; Hertz et al., 2015; Chen et al., 2021)

Reduces inflammation

(Gałecki et al., 2018; Dionisie et al., 2020; Tynan et al., 2012)

Alters metabolism/cell health

(Mahmoudiandehkordi et al., 2021)

Addressing the Chemical Imbalance Myth

It’s important to clarify that while SSRIs are prescribed to influence serotonin and other biological systems, this does not confirm the old theory that depression is caused by a “chemical imbalance.”

Modern neuroscience shows that depression involves complex interactions between brain circuits, stress, inflammation, and life experiences. SSRIs can help through multiple mechanisms, but they are not “fixing” a known deficiency like insulin in diabetes. Instead, they can help support the brain’s ability to regulate emotion, process information, and recover from stress.

This distinction matters for how we talk about depression and reduces stigma while promoting more accurate understanding.

Conclusion

Antidepressants are prescribed because they can help many people with depression, but their benefits go far beyond simply fixing a “chemical imbalance.” They work through multiple, interconnected biological pathways that support brain health and emotional recovery.

References

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Boschloo, L., Hieronymus, F., Lisinski, A., Cuijpers, P., & Eriksson, E. (2023). The complex clinical response to selective serotonin reuptake inhibitors in depression: A network perspective. Translational Psychiatry, 13, 6. https://doi.org/10.1038/s41398-022-02285-2

Chen, B., Zhang, M., Ji, M., Gong, W., Chen, B., Zorec, R., Stenovec, M., Verkhratsky, A., & Li, B. (2021). The association between antidepressant effect of SSRIs and astrocytes: Conceptual overview and meta‐analysis of the literature. Neurochemical Research, 46, 2731–2745. https://doi.org/10.1007/s11064-020-03225-6

Chottekalapanda, R., Kalik, S., Gresack, J., Ayala, A., Gao, M., Wang, W., Meller, S., Aly, A., Schaefer, A., & Greengard, P. (2020). AP-1 controls the p11-dependent antidepressant response. Molecular Psychiatry, 25, 1364–1381. https://doi.org/10.1038/s41380-020-0767-8

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