Why Do You Feel Low When You’re Sick? The Science of Illness and Mood

When we fall sick, our body’s vulnerable and nervous systems suffer complex biochemical changes. Two important factors in this process are histamine and serotonin, which are both biogenic amines involved in so many physiological functions, which include immunity, inflammation, and mood regulation. These two substances interact in complex ways, and it  affects how we feel both physically and mentally during any sickness. 

Dr. Cal, PhD (Genetic Medicine), talks about this on a Instagram reel, here is what she said, ^[4]

"Histamine and Serotonin are more than just neighbors in your brain, they actually directly affect one another. When you are sick your brain is incapable of releasing chemicals that make you happy because a lot of antidepressants also work on these same serotonin releasing neurons, which means if a person deals with chronic inflammation, these antidepressants might not work on them."

They conducted the study by attaching inhibitory receptors to serotonin neurons in mice. Researchers found that the molecule histamine directly inhibits the release of serotonin in the brain of the mice.

Serotonin, often referred to as the ‘feel-good molecule’, is a key target for depression-tackling drugs. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to inhibit the re-absorption of serotonin in the brain, allowing it to circulate for longer period and uplift mood.

However, despite the relief many people find from taking SSRIs, a large number of individuals are resistant to their effects. Researchers believe one reason for this may be related to the unique interactions between chemical messengers, or neurotransmitters, such as serotonin and histamine.

Knowing this, researchers set out to explore the interaction between histamine, serotonin, and SSRIs. They developed serotonin-measuring microelectrodes and inserted them into the hippocampus of live mice, an area known to regulate mood. The technique, known as fast scan cyclic voltammetry (FSCV), this helps to measure brain serotonin levels in real time without causing any harm to the brain.

After implanted microelectrodes, they treated half of the mice with LPS, a toxin which causes inflammation from bacteria; the other half received a saline solution as a control. Serotonin levels in the brain decreased within minutes of the LPS injection while remaining the same in control mice, illustrating how fast inflammatory responses in the body are translated to the brain and impact serotonin. Since LPS cannot penetrate the protective blood-brain barrier, it could not have caused this drop directly.

On closer inspection, they discovered that the histamine in the brain was activated by the inflammatory response and directly inhibited the release of serotonin, by binding to inhibitory receptors on the serotonin neurons. These inhibitory receptors are also found on human serotonin neurons, so this effect may be translatable to humans.

To address this, the researchers treated the mice with SSRIs, but they were much less capable of elevating serotonin levels than in control mice. They hypothesized that this was because the SSRIs directly increased the amount of histamine in the brain, which cancelled out its serotonin boosting action. They followed this by co-administering histamine reducing drugs with the SSRIs and observed serotonin levels return to the control level in the mouse brain. This is consistent with the hypothesis that histamine directly decreases serotonin release.

References:

1. Farnood, Annabel, Bridget Johnston, and Frances S. Mair. 2020. “A Mixed Methods Systematic Review of the Effects of Patient Online Self-diagnosing in the ‘Smart-phone Society’ on the Healthcare Professional-patient Relationship and Medical Authority.” BMC Medical Informatics and Decision Making 20 (1). https://doi.org/10.1186/s12911-020-01243-6.

2. Imperial College London. 2021. “Histamine Could Be a Player in Depression, According to Study.” Imperial News, August 17, 2021. https://www.imperial.ac.uk/news/228353/histamine-could-player-depression-according-study/.

3. Fan, Xin, Liyuan Wu, Yuxi Zhang, and Shuang Zhang. 2022. “A Tale of Two Transmitters: Serotonin and Histamine as In Vivo Biomarkers of Chronic Stress in Mice.” Journal of Neuroinflammation 19 (1): 167. https://pmc.ncbi.nlm.nih.gov/articles/PMC9235270/.

4. Dr. Cal, PhD Genetic Medicine. 2025. “This Video Summarizes the Paper ‘Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal Extracellular Serotonin,’ J. Neurosci. 2021.” Instagram Reels. Accessed February 12, 2025. https://www.instagram.com/reel/DFLyj_sAGIV/?igsh=MTdyMGZoZDdjMHR5Yg%3D%3D.

By Dr Noureen

_MSM