Friday, July 23, 2010

Zinc, Depression, and Everything

Today I will review more specific and up-to-date information about the interplay between zinc and depressive disorders and inflammation. Let's summarize the human evidence thus far (1):

1) Depressed patients in studies have a lower serum zinc level than normal controls.
2) The more depressed the patients are, the lower the zinc level.
3) Low zinc levels in pregnant women are associated with pre- and postpartum depression.
4) Treatment with antidepressants normalizes zinc levels (I've been a little loose with the terminology, I admit, and this finding helps us keep in mind that zinc level can be just a biomarker for depression, not necessarily a cause or effect per se.)
5) Zinc supplementation plus antidepressant therapy can work better for depression than antidepressants alone.
6) Zinc supplementation alone can have antidepressant effects.

Now let's try to clarify a bit more about zinc and the brain. As I noted in my last post, the hippocampus seems to be the most vulnerable to zinc deficiency. The hippocampus is a center of memory, and it also plays a big role in nerve plasticity and repair. Recall that nitric oxide and antidepressants seem to work by increasing the production of brain derived neurotrophic factor in the hippocampus. BDNF is one of many nerve growth factors in the hippocampus, and is part of several different neurochemical pathways which help in nerve recovery, adaptation, and repair.

Scientists have been able to cobble together the following pathway in rat brains: Zinc deficiency leads to decreased zinc in the synapse, which results in an increase in the NMDA receptors (these receptors respond to glutamate, an excitatory neurotransmitter that can be responsible for toxic effects in the brain if there is too much). At the same time, the inhibitory (in this case, neuroprotective) neurotransmitter GABA is decreased, along with BDNF and another nerve growth factor, NGF. The glutamate level in the synapse is higher, so calcium mediated stimulation of the nerves is primed. Do this too much, and you get "excitotoxicity." This same mechanism is thought (in acute vs chronic and in differing areas of the brain) to be responsible for seizures, migraines, dementia, anxiety, depression, and bipolar disorder (and is why pharmaceutical GABA receptor modulators can be effective for certain symptoms of any of those conditions).

Getting down to the real nitty-gritty, Zinc works in conjunction with nearly all of the different membrane signaling and second messenger systems you might have learned about in molecular biology classes. Membrane gated ion channels, p53 signaling, g-proteins, zinc-fingers (obviously) - the whole lot. This is why even though a lot of these different nerve chemicals work via different mechanisms, or multiple mechanisms, zinc can have a hand in all of these up regulating and down regulating events. Zinc is a cog in the machine all along the way.

So there are clear mechanisms by which absolute zinc deficiency can have a hand in all sorts of bad brain syndromes, and vegetarians, dieters, the elderly, those with malabsorption or intestinal issues, and the two billion people on the planet who (due to poverty) pretty much subsist on grains alone (rich in zinc-binding phytates) are all at risk for absolute zinc deficiency.

But robust presumably zinc-replete meat-eaters of a Western diet are at risk for depression, diabetes, dementia, and cardiovascular disease along with the whole diaspora of the Western chronic diseases. I contend (along with many others) that inflammation is the primary driving mechanism behind the whole shebang. Could there be a mechanism by which inflammation could affect brain zinc levels (or vice versa) as a part of the pathway leading from inflammation to bad brain disease?

Wanna put some money on it? Did I mention that pancreatic beta cells in particular run on a lot of zinc-dependent pathways too (2)(3)?

It's common knowledge that zinc supplementation can help ameliorate a cold (at least if you take the zinc within the first day of symptoms (4)), and, as I mentioned in the last post, zinc has a lot to do with mediating our body's immune response. We use zinc to activate the immune pathways that zap viruses (like colds), but zinc can influence the activity of 2000 (yeah, two thousand) different immune transcription factors. The baddest of these factors is NFkappaB. NFkappaB hangs around in the nucleus of immune cells and helps them make all sorts of inflammatory cytokines to fight off the perceived bad guys - good old inflammatory frenemies such as IL-6, IL-2, TNFalpha and many, many more. (Yesterday I noted that zinc deficiency is associated with increased IL-6, and on review of several articles, it seems that high and low zinc is associated high IL-6. It is probably a part of what I discuss in the next paragraph, but I'll look into it more, as a lot of the work is done by the Polish group or Maes, and they seem to cite each other all the time). Zinc not only directly promotes the synthesis of NFkappaB, it helps it get into the nucleus where it can work, and it helps it bind to the DNA to promote inflammation.

It isn't so simple as that. Turns out that zinc also has a hand in down regulating inflammation too! It even activates a protein that helps inactivate NFkappaB. And IL-6, an inflammatory cytokine which needs zinc the be born, will then activate a protein in the liver called metallothionein, a protein that holds on to zinc and keeps it in the liver, so that even if you eat a lot of zinc, it won't be available in your blood or brain for other uses. A lot of biochemical systems are like this - too little zinc (such as in people born without the ability to absorb it (5) and you get immune dysfuntion and vulnerability to infection, as your protective inflammatory response won't work. But if inflammation gets high enough, it has its own down regulating systems (sequestering zinc via IL-6 and metallothionein, for example) that cool things off.

Our inflammatory and fight or flight systems were built for acute insults. Viruses, injury, bacterial invasion, angry lion attacking the camp. When the insults are chronic (unalleviated stress, gallons of inflammatory-promoting omega-6 fatty acids, weird glutens and lectins, chronic depression-causing viral infections such as herpes, borna disease, HIV, or Epstein Barr), the whole system becomes dysregulated. What should be up is down. So zinc ought to be in the central nervous system, helping out with nerve repair and plasticity, and instead it is crusading with NFkappaB or stuck with metallothionein in the liver, and your poor hippocampus is shorting out on glutamate and calcium. Extra zinc might help. As might antidepressants, GABA receptor modulators, and other neuroprotective chemicals. But those are bailing buckets. What we really need is to correct the problem causing the boat to sink. We need to reduce the inflammatory insults in the first place.

There's more. Always more!

11 comments:

  1. "(1) Depressed patients in studies have a lower serum zinc level than normal controls.

    What's the actual differential? And what's considered a normal range?

    "(4) Treatment with antidepressants normalizes zinc levels..."

    What kind of anti-depressants? And were these compared to placebos?

    Best,
    Kevin

    ReplyDelete
  2. Hi Interpolations. The article I got that information from was a review article and did not have that level of detail. However, I'm interested in those answers too, so I'm going to chase down the references over the next couple days.

    I can tell you right now that in a rat study, tricyclic (imipramine), SSRI (citalopram), and electroshock therapy increased zinc levels in the hippocampus by 10%, 20%, and 30% respectively.

    ReplyDelete
  3. From Maes "Hypozincemia in Depression" Journal of Affective Disorders 31:135-40 (1994)-

    80 subjects - 32 controls, 16 minor depression, 14 major depression, 18 melancholia (anyone with zinc absorption issues such as being on thiazides, inflammatory bowel disease, or alchoholism were excluded) -

    Zinc level in controls: 2.02 +/- 0.2 mg/l
    Major depression with melancholia: 1.78 +/- 0.22
    Major depression without melancholia: 1.77 +/- 0.25
    minor depression: 1.89 +/- 0.34

    From Nowak, "Serum Trace Elements in Animal Models and Human Depression. Part 1. Zinc" Hum Psychopharmacol Clin Exp 14: 83-6 (1999)

    19 subjects with major depression, 16 controls, serum zinc level varied linearly with the hamilton D depression ratings (higher the rating, the more depressed, and the lower the serum zinc) Controls had a level of 1.51 +/- 0.15, depressed group 1.22 +/- 0.12 - depressed zinc was 12% lower than control group.

    From Maes et al "Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune inflammatory response in that illness." Biological Psychiatry 1997 42:349-58

    (as a side note - this paper reinforces that clinical depression is characterized by two inflammatory responses, increased IL-6 leading to sequestration of zinc by metallothionein in the liver, and decreased zinc by some sort of cell-mediated immunity response)

    15 controls, 31 depressed inpatients. All inpatients had a 10 day washout period (no one who had been on fluoxetine, which has a 6 week washout, was allowed in the study). Zinc was drawn in the morning on day 10. Then a 5 week treatment period with antidepressants (that's about 6X longer than most admissions to any inpatient unit I ever worked on!) - the antidepressants used were trazodone alone (100mg), trazodone (100mg) + fluoxetine (20mg), and trazodone (100mg) + pindolol (7.5mg) - around 6 patients in each group.

    Controls zinc level = 115 mcg/dl
    MD zinc level = 95
    Treatment resistant MD (did not respond to medication) zinc level = 91
    Treatment responsive MD = 103

    Not that useful clinically as trazodone isn't exactly the antidepressant du jour. Fluoxetine is prozac.

    ReplyDelete
  4. If low zinc levels are due to sequestration in the liver and/or a cell-mediated immune response, it seems as though supplementation might be useless at best or possibly even harmful. Still... hmmmmmm.

    Donna

    ReplyDelete
  5. It seems trendy to implicate chronic inflammation to every / all diseases at the present – kind of like how low serotonin was once implicated in all psychiatric manifestations. Consider how inflammation has been implicated in the demyelination in MS. New work by Moses Rodriguez, suggests that the inflammatory process can also serve to kick-start remyelination (certain omega-6s are involved in the proliferation of oligodendrocyte cells?). Is chronic inflammation really the cause of depression, or rather simply a response to a deeper seated set of imbalances? How is it possible for sleep deprivation, for instance, to result in prompt clinical remission in 65%+ of depressed patients? (sleep deprivation throws the immune system for a loop, elevates synaptic glutamate levels and would probably have no acute effects on zinc status)? The neurotrophic explanation of antidepressant action is also very limited too. In the flinders animal model of depression (in which hippocampal neurogenesis is elevated) nortriptyline or citalopram produces behavioral effects in parallel with an overall decrease in hippocampal neurogenesis. IMHO depression is much simpler than that. Its about bad brain circuitry turned on and good circuitry not functioning too well. All the SSRIs can do is throw brain chemistry for a loop and hope that when the dust settles, more productive brain pathways are somehow functioning. The intracellular bipolar treatments and/or gabaergics (sometimes tried when ADs fail) just indiscriminately slows activity in all brain regions (in the process hopefully taming some of the painful negative circuitry. Things like DBS are the only cure IMHO, just zap the one area that’s causing you problems. As far as every day depression…calm down, eat better, stop overworking, pet your dog, get some exercise (but that’s not a different condition entirely).

    ReplyDelete
  6. I wonder to what extent wheat consumption and industrial seed oils are responsible for the inflammatory assault in the first place.

    ReplyDelete
  7. Wow! This is extremely interesting to me. We came across the zinc connection quite by accident. In a nutshell: My 16 yo ds had always been a bit ADHD; at 13 yo felt "out of focus"; visited neurologist who put him on Concerta which put him into full blown psychosis. Took him to psychiatrist who did blood work and found extremely low ceruloplasmin and copper imbalance. DS was tested to exhaustion for Wilson's Disease which was eliminated. During that time he was placed on a massive amount of zinc (150 mg/day) as well as Symbyax. Symbyax did not help until zinc added. He was taken off Symbyax and did great with just the zinc until doctor tried to reduce zinc dosage. He went back into depression, albeit,not as severe. Doctor increased zinc dosage back up and we are trying to avoid Symbyax. Recent blood work also showed a significant methyltetrahydrafolate deficiency, so he was also put on 5-methyltetrathydrofolate 4000 mg daily. We are awaiting results of celiac disease testing. This is only specific discussion I have seen of questions into depression, zinc, and inflammation connection. Wow!

    ReplyDelete
  8. There are people who encountered problems in terms of their sex life and I heard that people are looking for more information on how to boost testosterone.

    ReplyDelete
  9. These just out studies suggest the mechanism of zinc helping relieve depression is it elevates the GPR39 receptor. Increasing this receptor's activity lowers inflammation as described at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163234/


    Behav Brain Res. 2013 Feb 1;238:30-5. doi: 10.1016/j.bbr.2012.10.020. Epub 2012 Oct 23.
    The role of the GPR39 receptor in zinc deficient-animal model of depression.
    Młyniec K, Budziszewska B, Reczyński W, Sowa-Kućma M, Nowak G.
    Source
    Department of Biochemical Toxicology, Jagiellonian University Medical College, Medyczna 9, PL 30-0688 Kraków, Poland. katarzyna.mlyniec@uj.edu.pl
    Abstract
    During the last decade it has been shown that zinc may activate neural transmissions via the GPR39 Zn(2+)-sensing receptor, which can be involved in the regulation of neuronal plasticity. According to the neurotrophic hypothesis of depression, decreased brain derived neurotrophic factor (BDNF) levels in depressed patients play a key role in the pathogenesis of this disorder. BDNF, similarly as zinc, is known to be involved in the process of neuron survival and the regulation of neuronal plasticity. The aim of the present study was to determine whether the administration of a 6-week diet deficient in zinc would cause depressive-like behaviour and if such behavioural alterations would correlate with changes in the expression of the BDNF protein and GPR39 receptor. In the first part of the present study the animal behaviour after a 6-week zinc-deficient diet, in the forced swim test (FST) was investigated. In the second part expression of the GPR39 and BDNF protein level in the frontal cortex was measured using the Western Blot method. Administration of a zinc-deficient diet for 6 weeks increased immobility time in the FST by 24%, so exerted depression-like behaviour. A biochemical study showed a significant reduction in GPR39 (by 53%) and BDNF (by 49%) protein expression in the frontal cortex in mice receiving the zinc deficient diet for 6 weeks. Our study provides evidence that the GPR39 Zn(2+)-sensing receptor may be responsible for lowering the BDNF protein level and in consequence may be involved in the pathogenesis of depression.
    Copyright © 2012 Elsevier B.V. All rights reserved.
    PMID: 23089648


    Neurochem Int. 2013 Mar 5. pii: S0197-0186(13)00069-7. doi: 10.1016/j.neuint.2013.02.024. [Epub ahead of print]
    GPR39 up-regulation after selective antidepressants.
    Młyniec K, Nowak G.
    Source
    Department of Biochemical Toxicology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland; Institute of Pharmacology, Polish Academy of Sciences and Center of Excellence in Neuropsychopharmacology, Smętna 12, PL 31-343 Kraków, Poland. Electronic address: katarzyna.mlyniec@uj.edu.pl.
    Abstract
    Recent studies indicated that zinc activates neural transmission via the GPR39 Zn2+-sensing receptor. Preclinical and clinical studies demonstrated the antidepressant properties of zinc. To investigate whether the GPR39 receptor is involved in the mechanism of antidepressant action, we measured the expression of the GPR39 receptor (Western Blot) in the frontal cortex of mice treated intraperitoneally with imipramine (30 mg/kg), escitalopram (4 mg/kg), reboxetine (10 mg/kg) or bupropion (15 mg/kg) for 14 days. The present study shows the up-regulation of the GPR39 receptor protein level after escitalopram (by 290%), reboxetine (by 816%) and bupropion (by 272%), but not imipramine treatment. This is the first report to indicate the involvement of the GPR39 Zn2+-sensing receptor in the antidepressant effect of selective monoamine reuptake inhibitors.
    Copyright © 2013. Published by Elsevier Ltd.
    PMID: 23474197

    ReplyDelete
  10. Zinc also inhibits GSK3, quite potently too, it might have a role in its effects.

    ReplyDelete
  11. Hi Emily and Interpolations,

    I only came across this post now, but recently, my colleagues and I conducted a meta-analysis to estimate the magnitude of zinc deficiency in depression (Biol Psychiatry. 2013 Dec 15;74(12):872-8).

    We found that on average, those with depression had blood concentrations that were about 1.85 micromol/L lower than controls. For reference, this is about a quarter of the span of the reference range suggested by Merck (10.1-16.8 micromol/L).

    Best regards,

    Walter Swardfager

    ReplyDelete