Iron in Psychiatric Disorders

There's quite a bit of research suggesting that low serum iron or iron deficiency can contribute to symptoms of attention-deficit disorder and can derange the responses to dopaminergic drugs or drugs that indirectly influence dopaminergic transmission, including antidepressants (http://scholar.google.com/scholar?q=iron+%22attention+deficit%22+OR+antidepressant&hl=en&lr=) (Yeragani et al., 1989, in search results). The main idea is that brain iron depletion can reduce D2 dopamine receptor (D2R) density and perhaps also D2 receptor sensitivity, etc. I'm not sure if one can really explain it in terms of agonist-antagonist effects. I mean that one can't necessarily say that the adequate delivery of iron to dopaminergic neurons will increases tonic or phasic D2 dopamine receptor activation, given that an increase in the activation of presynaptic D2 dopamine receptors can decrease the firing rates of dopaminergic neurons and potentially decrease postsynaptic or presynaptic D2 receptor activation. But iron does seem to behave as if it's "weakly-D2-agonist-like."

The no observed adverse effect level (NOAEL) for iron intake, in the long term, is 40 mg or thereabouts (depending on the source of the analysis). That's for nonheme iron, and, in my opinion, iron protein succinylate is superior to the other forms. I don't have any financial stake in anything I've ever discussed or will ever discuss, and my reason for mentioning that form is that it doesn't provide massive amounts of glycine and has been shown to not produce as much GI irritation as other forms. In any case, there's also an article citing some obscure research on the use of iron in treatment resistant depression. Although the research is obscure and in a foreign language journal (I don't have time to cite the article right now), the use of low-dose iron supplementation in ADHD would suggest that the applicability to other psychiatric symptoms, in an adjunctive capacity, might have some validity. In any case, iron supplementation is potentially dangerous, and one would want to discuss it with one's doctor.

The heme iron supplied by a diet high in meat was shown to be equivalent to 50 mg of nonheme iron in at least one study, but I don't know that long-term iron intakes of 30-40 mg would necessarily be "safe" (despite the fact that they're less than the NOAEL). There's research in which researchers have used very large amounts of oral or intravenous iron to treat restless legs syndrome, but I really don't think that's safe in the long term or even short term. Most of that has been done in the short term, and I don't know how that's much of a strategy for treating restless legs syndrome (the high dose approach, if one can only use the approach in the short term). Resistance exercise can put a dramatic strain on iron stores in the long term, and there's research showing that [see Deruisseau et al., 2004, in search results: (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=resistance+exercise+iron)]. The effect of resistance exercise is even greater than the effect of endurance exercise (in terms of potentially accelerating iron turnover), and that study I cited only followed the people for 3 months. So one might want to adjust one's iron intake according to one's activity level.

That said, having a high serum ferritin level is not desirable, in my opinion. When the serum ferritin is higher than something like 100 mcg/L (= 100 ng/mL) or is just high (there's disagreement about the target level, but even 50 mg/day of nonheme iron has generally barely even elevated serum ferritin, over a few weeks, in small trials), the serum transferrin levels start to decrease. That's really bad and tends to increase the fraction of nontransferrin-bound iron, with damaging consequences. When the serum ferritin level is reasonable and not pathologically low and also not high, the delivery of iron by transferrin has the potential to be the most efficient (much more efficient than at high serum ferritin levels, especially). The whole iron transport system falls apart at high serum ferritin levels. Also, iron-loaded ferritin can't bind as much zinc, and zinc binding to tissue ferritin proteins probably serves to buffer intracellular zinc levels and prevent zinc neurotoxicity or hematological toxicity [see Price et al., 1982 and others, in this results list: (http://scholar.google.com/scholar?q=ferritin+zinc&hl=en&lr=)]. The relevant function, in my view, would be the "zinc detoxicant" function of tissue/intracellular ferritin polypeptide chains. I think a lot of people are in no danger of being low in zinc, but that's just my opinion.

In any case, there's a lot of research indicating that low serum iron levels and poor iron uptake into the brain has a lot to do with the excessive release and actions of pro-inflammatory cytokines on the specialized macrophages [the "reticuloendothelial system" (RES) macrophages], in the bone marrow/RES, that export iron and maintain serum iron (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=macrophages+export+iron+TNF+OR+%22IL-6%22); Kemna et al., 2005: (http://bloodjournal.hematologylibrary.org/cgi/content/full/106/5/1864)(http://www.ncbi.nlm.nih.gov/pubmed/15886319?dopt=Abstract)]. Resistance exercise is one example of something that could conceivably reduce pathological pro-inflammatory cytokine production in the long term, even if exercise might tend to worsen it in the short term. Pro-inflammatory cytokines also interfere with iron export and transport in general and with energy metabolism and everything else, essentially.