Depression, Zinc, and an Evolutionary Arms Race

Does it surprise you that major depression is associated with reduced blood levels of zinc?[1] If it doesn’t surprise you, and I asked you why, you might suggest that because zinc is important for health, low levels might set a person up to get depressed. 

Would it surprise you more to learn that the brains of people with major depression (MDD) appear to have reduced expression of a gene essential for zinc transport?[2] Again, you might demur and reply that some people are born with genes that don’t work very well and these people are more likely to get depressed. Isn’t that what we mean when we say that depression is a “genetic disorder”?

These responses reflect the logic of present-day psychiatry in a nutshell. Diseases occur when bodily systems function sub-optimally. Depression is a disease; therefore it might be caused by any bodily system not functioning optimally, including zinc. Low levels of zinc cause depression. So what? Are we saying that lots of things cause depression?

Maybe so, but wouldn’t you agree that this type of answer is a far cry from the types of deep interconnections discovered when science is operating at its cutting edge?

Indeed, although explanations such as “zinc causes depression” are satisfyingly simple, my work as a researcher has made me more and more convinced that we have come to the limit of what this type of “disease-based perspective” can do in terms of unravelling the mysteries of MDD or in discovering new treatments.

Major Depression Doesn’t Fit Typical Disease Models

It’s not that MDD isn’t as terrible as any other disease, or as deadly, but it just doesn’t behave like illnesses for which the disease model is more true to facts on the ground. Most of these illnesses result either from an infectious agent, from the breakdown of the body in old age, or from a mismatch between current conditions and the world in which we evolved (think obesity, type II diabetes, and other conditions of evolutionary mismatch). Moreover, diseases that are purely genetic in origin, such as cystic fibrosis, always remain rare.[3]

In contrast, depression is shockingly common and has no simple genetic cause and tends to hit early in adulthood when the body is in peak physical health.[4] In the vast majority of cases it is not caused by any identifiable infectious agent. Depression may be increased in the modern world due to evolutionary mismatch,[5] but it is prevalent in all cultures and has been described since the beginning of recorded history, so the problems of the modern world can’t be the whole story.

In addition to leaving me dissatisfied with our current way of looking at things in psychiatry, my years as a researcher have also taught me a remarkably generalizable truth about biological systems, and that is that they are very frequently bidirectional. If A causes B, then very often B also causes A.

Turning Depression on Its Head

So let’s return to zinc. If the idea that subtle deficiencies in bioavailable zinc cause depression isn’t particular enlightening, what if we turned things around and asked whether depression might cause zinc deficiency? Or more precisely, might processes in the brain and body that promote depression also lead to reductions in zinc?

This immediately raises two questions. Do such processes exist, and if so, why would they lower zinc availability?

Here is where the pay-off from thinking outside the box comes into play. In fact, there is a process reliably associated with depression that also lowers zinc levels: inflammation.[6]

And inflammation lowers zinc for a good reason and that is to keep it out of the hands of the invading pathogens that need the zinc as badly as we did to survive and prosper. Inflammation-induced reductions in zinc evolved as an antibiotic strategy. Like almost everything else that inflammatory processes set in motion, lowered zinc is not an accident, but plays an important strategic role in our ancient, relentless, and ongoing struggles with the microbial world.

Zinc deficiency doesn’t have much to do with classic explanations for why people get depressed. It’s not a neurotransmitter. It’s not intimately involved in romantic break-ups, or the death of loved ones, or the loss of a job, or the myriad other adversities known to increase the risk for depression.

But it is intimately involved in every aspect of immunity. Without it the immune system can’t function, and the risk of contracting many infectious diseases goes up. On the other hand, when too available in the body, zinc provides key nutritional support to pathogens. Hence the immune system uses multiple complex mechanisms to finely tune zinc availability in various tissues, always trying to balance its own need for zinc against the zinc cravings of the organisms it evolved to fight.

So maybe the fact that depression is associated with lowered levels of zinc is trying to tell us something about at least one place that depression comes from—our endless interactions with viruses, bacteria, and parasites. Maybe lowered zinc is a vestigial reminder that the biology of depression originally evolved, at least in part, to aid our host defense mechanisms against infection.

In fact, my colleagues and I, and others, have made exactly this type of argument,[3,7] and significant data suggest it might have merit. More importantly, however, is the fact that applying this type of evolutionary logic opens up new vistas for thinking about why depression exists, why it is so common, and why the genes that promote it are also so common.

Does Depression Serve a Purpose?

As bad as depression is, to some degree it evolved to serve a purpose. Or because depression is certainly not one unitary thing, perhaps we should say that at least some of the biological bases that promote depression (i.e., “some depressions”) evolved and are maintained by highly prevalent genetic alleles because they served adaptive purposes.

If one truth of scientific discovery is that biological processes are often bidirectional, another is that one knows one is on the right track when a theory makes testable predictions and when it brings together previously unrelated elements into a larger, more unified, and often conceptually simpler schema that provides new ways of intervening in the world.

So let’s go back to zinc. If reduced zinc in MDD reflects the fact that at least some of the biology of depression descends from immune mechanisms that initially evolved to fight infection, we can make a number of logical predictions. First, in patients with MDD, lowered levels of zinc should be associated with increased inflammation. Second, levels of other transition metals, such as iron, that are also essential for pathogen survival and reproduction within the body should also be lowered in MDD. And third, MDD should be associated with other endogenous antibiotic strategies associated with activation of the inflammatory response system.

Evidence supports each of these predictions. Although not widely studied, available data suggest that in depressed populations, lowered levels of zinc are associated with increases in several peripheral inflammatory biomarkers.[8] And a number of studies report that depression is associated with reduced levels of iron.[9-13] Interestingly, even psychological stress—which is a major depressive risk factor—has been shown to lower plasma levels of iron,[14] just as it is known to activate the inflammatory response (we suspect because across evolution stress reliably signaled impending danger of tissue damage with its attendant risk of infectious death).[15]

The Fever and Depression Connection

Finally, it is clear that MDD is associated with other antibiotic strategies promoted by inflammation. One such strategy is fever, which has been shown in countless studies to enhance host survival in the face of infection by denaturing pathogens and by enhancing immune activity.[3] In fact, fever is so central to mammalian host defense systems that were it absent in MDD this would strike a strong blow against the idea that the disorder arose, at least in part, from our evolutionary arms race with the microbial world.

But fortunately for our argument, many studies have observed elevated core body temperature in individuals with depression.[16-22] And interestingly, the amount of increase common in MDD places the body at exactly the temperature range most effective for pathogen killing. Moreover, the successful treatment of depression has been shown to result in normalization of core body temperature.[18]

So back to zinc. It is conceivable that the association between depression and lowered blood levels of zinc may be explained by the fact that reduced zinc availability makes people depressed. But it is hard to believe that the association between elevated body temperature and depression is best explained by the fact that increased body temperature produces depression. And it stretches credulity—at least mine—to believe that the association of depression with reduced zinc, reduced iron, increased body temperature, inflammatory activation, and many other stigmata of anti-pathogen defense reflects a series of disconnected coincidences.

And yet, if we as a field don’t practice turning depression and other psychiatric conditions “on their heads” by viewing them through the lens of evolutionary biology I fear we are likely to continue missing exactly these types of potentially transformative coincidences--coincidences that lie directly in front of us, but remain obscured by our same old way of looking at things. 

References

1. Swardfager W, Herrmann N, Mazereeuw G, Goldberger K, Harimoto T, Lanctot KL. Zinc in depression: a meta-analysis. Biol Psychiatry. Dec 15 2013;74(12):872-878.

2. Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, et al. Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry. May 18 2010.

3. Raison CL, Miller AH. The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D). Mol Psychiatry. Jan 31 2012.

4. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. Nov 9 2013;382(9904):1575-1586.

5. Raison CL, Lowry CA, Rook GA. Inflammation, sanitation, and consternation: loss of contact with coevolved, tolerogenic microorganisms and the pathophysiology and treatment of major depression. Arch Gen Psychiatry. Dec 2010;67(12):1211-1224.

6. Vignesh KS, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS, Jr. Zinc Sequestration: Arming Phagocyte Defense against Fungal Attack. Plos Pathog. Dec 2013;9(12):e1003815.

7. Kinney DK, Tanaka M. An evolutionary hypothesis of depression and its symptoms, adaptive value, and risk factors. J Nerv Ment Dis. Aug 2009;197(8):561-567.

8. Szewczyk B, Kubera M, Nowak G. The role of zinc in neurodegenerative inflammatory pathways in depression. Prog Neuropsychopharmacol Biol Psychiatry. Apr 29 2011;35(3):693-701.

9. Rangan AM, Blight GD, Binns CW. Iron status and non-specific symptoms of female students. J Am Coll Nutr. Aug 1998;17(4):351-355.

10. Maes M, Van de Vyvere J, Vandoolaeghe E, et al. Alterations in iron metabolism and the erythron in major depression: further evidence for a chronic inflammatory process. J Affect Disord. Sep 9 1996;40(1-2):23-33.

11. Maes M, Vandewoude M, Scharpe S, et al. Anthropometric and biochemical assessment of the nutritional state in depression: evidence for lower visceral protein plasma levels in depression. J Affect Disord. Sep 1991;23(1):25-33.

12. Maes M, Scharpe S, Bosmans E, et al. Disturbances in acute phase plasma proteins during melancholia: additional evidence for the presence of an inflammatory process during that illness. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 1992;16(4):501-515.

13. Albacar G, Sans T, Martin-Santos R, et al. An association between plasma ferritin concentrations measured 48h after delivery and postpartum depression. J Affect Disord. Dec 2 2010.

14. Singh A, Smoak BL, Patterson KY, LeMay LG, Veillon C, Deuster PA. Biochemical indices of selected trace minerals in men: effect of stress. Am J Clin Nutr. Jan 1991;53(1):126-131.

15. Raison CL, Miller AH. The evolutionary significance of depression in pathogen host defense (PATHOS-D). Molecular Psychiatry. 2012;Epub.

16. McEnany GW, Lee KA. Effects of light therapy on sleep, mood, and temperature in women with nonseasonal major depression. Issues Ment Health Nurs. Aug-Sep 2005;26(7):781-794.

17. Rausch JL, Johnson ME, Corley KM, et al. Depressed patients have higher body temperature: 5-HT transporter long promoter region effects. Neuropsychobiology. 2003;47(3):120-127.

18. Szuba MP, Guze BH, Baxter LR, Jr. Electroconvulsive therapy increases circadian amplitude and lowers core body temperature in depressed subjects. Biol Psychiat. 1997;42(12):1130-1137.

19. Daimon K, Yamada N, Tsujimoto T, Takahashi S. Circadian rhythm abnormalities of deep body temperature in depressive disorders. J Affect Disord. Nov 1992;26(3):191-198.

20. Persaud R. Nocturnal sweating and temperature in depression. Acta Psychiatr Scand. Mar 2000;101(3):251.

21. Avery DH, Wildschiodtz G, Rafaelsen OJ. Nocturnal temperature in affective disorder. J Affect Disord. Mar 1982;4(1):61-71.

22. Sugahara H, Akamine M, Kondo T, et al. Somatic symptoms most often associated with depression in an urban hospital medical setting in Japan. Psychiatry Res. Oct 30 2004;128(3):305-311.

Charles L. Raison, MD, is an associate professor in the Department of Psychiatry, College of Medicine and the Barry and Janet Lang Associate Professor of Integrative Mental Health in the Norton School of Family and Consumer Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ. He is also the behavioral health expert for CNN.com, and he is a Psych Congress Steering Committee member.

The views expressed on this blog are solely those of the blog post author and do not necessarily reflect the views of Psych Congress Network or other Psych Congress Network authors.