Recent research is suggesting that reduced serotonin levels due to bodily inflammation may explain the ineffectiveness of antidepressants for some people.

Depression affects about one in ten of the adult population in the United States and is a main cause of disability globally. Many individuals do not respond to pharmaceutical antidepressant therapy, indicating a need for an improved understanding of the development of depression.

Some emerging data points to the immune system, particularly the inflammatory response, as a potential contributor to depression. Stress-induced inflammatory signals can be transmitted to the brain and affect the activity of neurotransmitters.

One neurotransmitter frequently linked to depression is serotonin. Briefly, high levels of serotonin release in the brain are linked to elevated mood, whereas low levels of serotonin are linked to the symptoms of depression.

Many individuals with depression are prescribed selective serotonin reuptake inhibitors (SSRIs), to prevent its reabsorption, meaning more serotonin is available to pass messages between neurons. However, a significant proportion of patients do not find SSRIs beneficial.

A team from Imperial College London, UK, have investigated the link between inflammation, serotonin and the effectiveness of SSRIs.

Dr Parastoo Hashemi and colleagues measured serotonin movement around the brain by placing microelectrodes into the hippocampus of live mice. Then they injected the mice with an inflammation-causing toxin called lipopolysaccharide.

Within minutes, this inflammation led to "robust decreases in extracellular serotonin in the mouse hippocampus," they report in the Journal of Neuroscience.

"There is emerging evidence that inflammation plays a significant role in the clinical variability of SSRIs, though how SSRIs and inflammation intersect with synaptic serotonin modulation remains unknown," they write. "We show that these decreased serotonin levels [because of inflammation] are supported by increased histamine activity."

The team also found that under these conditions, the SSRI drug escitalopram was limited in its ability to increase serotonin, because the drug holds back histamine reuptake, keeping levels of histamine high. Furthermore, when histamine was lowered, the drug escitalopram was able to increase circulating serotonin levels.

"We found that the histamine in the brain was triggered by the inflammatory response and directly inhibited the release of serotonin, by attaching to inhibitory receptors on the serotonin neurons. These inhibitory receptors are also present on human serotonin neurons. So, this effect might translate to people.

"This work reveals a profound effect of inflammation on brain chemistry, specifically the rapidity of inflammation-induced decreased extracellular serotonin, and points the spotlight at a potentially critical player in the pathology of depression, histamine," the researchers write.

"The serotonin/histamine homeostasis thus, may be a crucial new avenue in improving serotonin-based treatments for depression."

Commenting on the work, Dr Hashemi said, “Inflammation could play a huge role in depression, and there is already strong evidence that patients with both depression and severe inflammation are the ones most likely not to respond to antidepressants.

“Our work shines a spotlight on histamine as a potential key player in depression. This, and its interactions with the ‘feel-good molecule’ serotonin, may thus be a crucial new avenue in improving serotonin-based treatments for depression.”

It is important to note that the histamine-reducing drugs used in this study are different to normal antihistamines, which will not boost the efficacy of SSRIs. In addition, more human studies are needed to investigate how inflammation may trigger a chain reaction that increases histamine levels in ways that impair the effectiveness of SSRIs.

Dr Hashemi concluded, "Inflammation is a whole-body response and is therefore hugely complex. Depression is similarly complex, and the chemicals involved are affected in myriad ways by both genetic and environmental factors. Thus, we need to look at more complex models of depression behaviors in both mice and humans to get a fuller picture of both histamine and serotonin's roles in depression."

The role of the brain histamine system on the effectiveness of SSRIs has not yet received a great deal of attention, but in 2015 a team from the University of Florence, Italy, looked at the mechanics behind this mechanism.

Patrizio Blandina, MD, and colleagues explain that the neurobiological changes that prevent antidepressants from working remain poorly understood. They believe that failure to respond to SSRIs may be due to "abnormalities of neurotransmitter systems that excite serotonergic neurons, such as histamine".

Previous experimental studies have shown interactions between the histamine and serotonin systems that share control of functions impaired in depression, such as appetite, cognition, emotion, and sleep.

So the researchers carried out tests on the brains of mice and found that the SSRI drugs citalopram and paroxetine are ineffective in mice that are prevented from synthesizing histamine.

In the International Journal of Neuropsychopharmacology they write, "Here, we report that behavioral and neurochemical responses to SSRIs exclusively, and not to other antidepressants, are abolished in mice genetically or pharmacologically unable to synthesize histamine. Our results demonstrate that SSRIs selectively require the integrity of the brain histamine system to exert their preclinical responses."

They conclude, "The present findings demonstrate that histaminergic neurotransmission is indispensable for behavioral and neurochemical responses to acute administration of SSRIs."

Hence it is likely that individual differences in antidepressant response may be determined partly by genetic variations affecting histamine production, which may prove good predictors of more effective treatments.

Further information on the role of the histamine system in depression comes from studies into the compound oleoylethanolamide, or OEA. This compound regulates the release of different types of neurotransmitters, playing an important physiological and metabolic role. These roles include activating the hedonic dopamine pathway and increasing histamine in the brain.

A study was carried out in 2018 by the same team at the University of Florence, showing that histamine-deficient mice do not respond to the antidepressant-like effects of OEA.

The scientists explain, "It has been suggested that the bioactive lipid mediator OEA possesses anti-depressant-like effects. We recently demonstrated that several of OEA's behavioural actions require the integrity of the brain histaminergic system, and that an intact histaminergic neurotransmission is specifically required for selective serotonin re-uptake inhibitors to exert their anti-depressant-like effect."

The purpose of the 2018 study was to test if OEA requires normally-functioning histaminergic neurotransmission to exert its antidepressant-like effects. They assessed OEA's potential as an antidepressant drug in mice with artificially reduced histamine by testing serotonin release following administration of OEA.

This "revealed a dysregulation of serotonin release induced by OEA mice lacking histamine," they report in the journal Neuropharmacology.

"Our observations corroborate our hypothesis that brain histamine and signals transmitted by OEA interact, and may be the basis for the efficacy of OEA as an antidepressant-like compound."

This work was followed up in 2019 by a team of researchers at Tabriz University of Medical Sciences in Iran. They examined the links between OEA, histamine, and depression, with a focus on satiety and overeating.

Their findings suggest that OEA "can exert satiety-inducing effects by activating the hedonic dopamine pathway and increasing the brain histamine". Hence OEA, together with histamine, are likely to play a role in the management and prevention of obesity.

Furthermore, a group of Spanish researchers in 2019 also found that "the integrity of histamine receptors appears to be indispensable for OEA antidepressant effects to take place". They add, "It is possible that OEA affects cognitive processes associated with the hedonic value of behaviors" such as eating, using tobacco and alcohol.

Interestingly, the University of Florence team explored the mechanisms by which OEA and histamine work together in the brain's amygdala. They tested the role of the brain histaminergic system in the cognitive effect of OEA by depleting rats of brain histamine. They also examined the effect of OEA on histamine release in the animals' amygdalas.

This "showed that OEA increased histamine release from the amygdala", they report. "Our results suggest that activation of the histaminergic system in the amygdala has a 'permissive' role on the memory-enhancing effects of OEA."

The team suggest that targeting histamine receptors "may modify the expression of emotional memory and reduce dysfunctional aversive memories as found in phobias and posttraumatic stress disorder".

Overall, there is compelling evidence from observations in both animal and human experiments that the histamine system is essential for healthy neurotransmission and the effectiveness of antidepressant medications.

Future research will doubtless explore further the mechanisms behind these effects, with results that are likely to improve our understanding of depression and lead to new avenues for pharmacological treatments.

References and Resources

1. Hersey, M. et al. Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal Extracellular Serotonin. Journal of Neuroscience, 28 July 2021 doi: 10.1523/JNEUROSCI.2618-20.2021 https://www.jneurosci.org/content/41/30/6564
2. Miller, A. H. et al. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature Reviews Immunology, January 2016 doi: 10.1038/nri.2015.5 https://www.nature.com/articles/nri.2015.5
3. Munari, L. et al. Brain Histamine Is Crucial for Selective Serotonin Reuptake Inhibitors‘ Behavioral and Neurochemical Effects. International Journal of Neuropsychopharmacology, September 2015 doi: 10.1093/ijnp/pyv045 https://academic.oup.com/ijnp/article/18/10/pyv045/623738
4. Costa, A. et al. Histamine-deficient mice do not respond to the antidepressant-like effects of oleoylethanolamide. Neuropharmacology, June 2018 doi: 10.1016/j.neuropharm.2018.03.033 https://doi.org/10.1016/j.neuropharm.2018.03.033
5. Tutunchi, H. et al. A systematic review of the effects of oleoylethanolamide, a high-affinity endogenous ligand of PPAR-α, on the management and prevention of obesity. Clinical and Experimental Pharmacology and Physiology, 23 December 2019 doi: 10.1111/1440-1681.13238 https://doi.org/10.1111/1440-1681.13238
6. Orio, L. et al. Oleoylethanolamide, Neuroinflammation, and Alcohol Abuse. Frontiers in Molecular Neuroscience, 9 January 2019 doi: 10.3389/fnmol.2018.00490 https://www.frontiersin.org/articles/10.3389/fnmol.2018.00490/full
7. Provensi, G. et al. Histaminergic Neurotransmission as a Gateway for the Cognitive Effect of Oleoylethanolamide in Contextual Fear Conditioning. International Journal of Neuropsychopharmacology, 1 May 2017 doi: 10.1093/ijnp/pyw110 https://academic.oup.com/ijnp/article/20/5/392/2926457

About the Author:

Jane Collingwood is a medical journalist with 17 years experience reporting on all areas of medical research for online and print publications. Jane has also worked on a range of medical studies funded by the UK National Health Service within the University of Bristol in the South West of England. Jane has an academic background in psychology and has authored books on stress management and respiratory infections. Currently she is combining journalism with a national coordinating role on the UK's largest surgical research trial.