Exploring the Link Between Persistent Infection, Inflammation, and Mood Disorders

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It has been proposed that inflammation stemming from persistent pathogens may influence the development of mood disorders.
It has been proposed that inflammation stemming from persistent pathogens may influence the development of mood disorders.

Mood disorders affect more than 20% of adults in the United States aged 18 to 49 years.1 Extensive research has explored the genetic and behavioral underpinnings of these disorders, and more recently, studies have begun to investigate links between the immune system and mood regulation. Previous findings indicate that inflammation can lead to "sickness behavior" characterized by depressive symptoms such as anhedonia and fatigue.2,3 Inflammation has also been found to play a major role in glutamatergic neurotransmission involved in mood regulation in depression and bipolar disorder.4-6

"Specifically, microglia in the brain are activated by inflammatory cytokines that cross the blood-brain barrier, altering astroglial function such that these cells produce increased levels of cytokines as well as glutamate, contributing to enhanced tryptophan metabolism via the indoleamine 2,3-dioxygenase pathway," wrote the authors of a recent study published in Brain, Behavior, and Immunity.7 "Imbalances in the metabolites of kynurenine which serve as either N-methyl-D aspartate agonists or antagonists and decreased serotonin production, in turn, may contribute to the onset of manic and depressive symptoms."

It has been proposed that inflammation stemming from persistent pathogens may influence the development of mood disorders to a greater extent than inflammation resulting from acute infections. For example, 1 such pathogen is Helicobacter pylori, which has been implicated in gastrointestinal disorders and dysregulation of the gut-brain axis.8 A growing body of evidence also supports the role of interactions at the gut-brain axis in regulation of mood.9-11

In the current study, Dr Simanek and colleagues analyzed data from the National Health and Nutrition Examination Survey III to examine associations between mood disorders and persistent pathogens in individuals aged 15 to 39 years who had been assessed for a lifetime history of major depression, dysthymia, and/or bipolar disorder.

The sample in the present study was limited to participants who had also been tested for seropositivity for cytomegalovirus (CMV; n=6825), herpes simplex virus (n=5618), and/or H pylori (n=3167), as well as for levels of C-reactive protein (n=6792). In addition, CMV immunoglobulin G antibody levels were available for 3358 of the women tested for CMV seropositivity.

The results demonstrate associations between:

  • H pylori seropositivity and increased odds of dysthymia (odds ratio [OR], 2.37; 95% CI, 1.07-5.24) among women;
  • H pylori seropositivity and decreased odds of dysthymia among men (OR, 0.51; 95% CI, 0.28-0.92);
  • CMV seropositivity and lower odds of depression (OR, 0.54; 95% CI, 0.32-0.91) among men; and
  • Elevated CMV immunoglobulin G level and increased odds of mood disorders among women (marginal association)

The findings further show that these associations were not likely mediated by C-reactive protein.

To learn more about the study and its clinical implications, Psychiatry Advisor interviewed study coauthor Amanda Simanek, PhD, MD, assistant professor of epidemiology at the Joseph J. Zilber School of Public Health at the University of Wisconsin-Milwaukee.

Psychiatry Advisor: What is generally known about the link between persistent pathogens and mood disorders, and what do your findings add to this understanding?

Dr Simanek: During the last several decades, evidence has been mounting regarding connections between the immune system and the brain, suggesting that immunologic response to infection might play an important role in the etiology of mood disorders. Herpesviruses or chronic bacterial and parasitic pathogens may be particularly relevant modulators of mood, as once acquired, such infections persist and thus can repeatedly stimulate the immune system over time. Studies examining the role of such pathogens as risk factors for depression and other mood disorders have, however, been primarily carried out in older or clinical populations.

Our study is the first to examine the association between herpesviruses, as well as the chronic bacterial infection H pylori, and multiple mood disorder outcomes including depression, dysthymia, and bipolar disorder among the younger, general US adult population. Moreover, we assessed the role that inflammation may play in explaining these associations and examined, for the first time, whether the effects of such pathogens vary between women and men, potentially explaining the greater prevalence of outcomes such as depression observed among US women.

We found that H pylori seropositivity was associated with 2.5 times higher odds of dysthymia among women, but that seropositivity for this pathogen, as well as the CMV, was associated with decreased odds of mood disorders among men. We did not find evidence for inflammation as a biologic mediator of these associations, suggesting the need to examine mechanisms operating outside of inflammatory pathways.

Psychiatry Advisor: What are your thoughts on why these results were found, including the divergent findings for men and women?

Dr Simanek: Although we hypothesized that the associations between these pathogens and mood disorder outcomes may be stronger among women compared with men, the protective effects observed among men in our study were unexpected, warranting the need for replication of our findings in other study populations. There are, however, several hypothesized mechanisms that may explain our findings, such as differences between women and men in the composition of the gut microbiome or production of endocrine hormones that might serve to modulate the pathogenicity of H pylori, that warrant investigation in future studies.

Psychiatry Advisor: What are the overall clinical implications of these findings?

Dr Simanek: If the association between H pylori and dysthymia observed among young adult women in our study is proven to be causal, our findings suggest that prevention of this infection could serve to lower the burden of chronic, subthreshold depression in this subset of the population.

Psychiatry Advisor: What should be the focus of additional research on this topic?

Dr Simanek: Future studies are needed that examine the association between the persistent pathogens assessed in our study as well as others, and the incidence of mood disorders over time; assess whether these associations differ between men and women across different stages of the life span; and clarify the social and biological pathways by which pathogens may influence mood disorder onset differently in women and men.

References

  1. Kessler RC, Berglund P, Demler OJin RMerikangas KRWalters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593-602.
  2. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008; 9(1)46-56.
  3. McCusker RH, Kelley KW. Immune-neural connections: how the immune system's response to infectious agents influences behavior. J Exp Biol. 2013; 216(Pt 1)84-98.
  4. Dantzer R, O'Connor JC, Lawson MA, Kelley KW. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology. 2011;36(3):426-436.
  5. Machado-Vieira R, Ibrahim L, Henter ID, Zarate CA. Novel glutamatergic agents for major depressive disorder and bipolar disorder. Pharmacol Biochem Behav. 2012;100(4):678-687.
  6. Barbosa IG, Machado-Vieira R, Soares JC, Teixeira AL. The immunology of bipolar disorder. Neuroimmunomodulation. 2014;21:117-122.
  7. Simanek AMParry ADowd JB. Differences in the association between persistent pathogens and mood disorders among young- to middle-aged women and men in the U.S. Brain Behav Immun. 2018;68:56-65.
  8. Ruggiero P. Helicobacter pylori and inflammation. Curr Pharm Des. 2011;16(38)4225-4236.
  9. Budzyński J, Kłopocka M. Brain-gut axis in the pathogenesis of Helicobacter pylori infection. World J Gastroenterol. 2014;20(18)5212-5225.
  10. Deans E. Microbiome and mental health in the modern environment. J Physiol Anthropol. 2017; 36:1.
  11. Evrensel A, Ceylan ME. The gut-brain axis: the missing link in depression. Clin Psychopharmacol Neurosci. 2015;13(3)239-244.       
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