Back in July, I wrote a number of posts about zinc. There was Zinc! (which remains one of my most popular posts - perhaps it was the exclamation point?), Zinc, Depression, and Everything, and the optimistically titled Zinc Clarity. By all means go back and dig in, but the summary here: rather like magnesium, zinc is wasted and sequestered during periods of inflammation, but zinc is also necessary for our brains to work properly. Low serum levels of zinc have been measured in ADHD, depression, and anorexia, and zinc repletion has been shown to help the symptoms of those illnesses, at least in small studies (though for anorexia with need for weight gain, zinc supplementation should really be standard of care, as the data is good). Hunter gatherers averaged 43 mg daily (above the RDA safety zone "upper tolerable limit" of 40mg daily, but below the lowest level where there begins to be issues with copper absorption, which is around 60mg daily, but is likely not a serious problem until 150mg daily). A Standard American averages much, much less than all those numbers, somewhat below the RDA of 11-15mg daily, and as zinc is available mostly in egg yolks and other animal foods, a vegetarian has a serious risk of being deficient, as does anyone on a thiazide diuretic medication.
Cool. Well, as always, it is not quite that simple. As I mentioned in Zinc, Depression, and Everything, zinc deficiency doesn't necessarily cause depression (though it might play a role). In fact, depression (inflammation) will cause low serum zinc. Low serum levels of zinc are a biomarker for depression, rather like high C reactive protein is a biomarker for inflammation. (Please, please, please do not take Crestor for the sole purpose of lowering your C reactive protein. Don't do it!)
On Wednesday when I was tooling through the Journal of Affective Disorders, I found this new study from the same zinc-obsessed Polish group who have produced a slew of papers over the last several years, "Serum zinc level in depressed patients during zinc supplementation of imipramine treatment."
The researchers took 60 patients diagnosed with Major Depressive Disorder from inpatient units and outpatient clinics, and also recruited 25 healthy age- and sex-matched controls with no mental illness (and, interestingly, no family history of depression or mania). The healthy controls had their serum zinc measured once, the depressed subjects four times (before, and 2, 6, and 12 weeks after starting antidepressant medication treatment).
All the depressed patients were treated with an antidepressant (imipramine), but the 60 patients were divided into receiving placebo + imipramine or zinc + imipramine. During the data analysis after the experiment, "resistant" and "non-resistant" groups were established by how the patients responded to the treatment (it also happened to line up with now long they had been depressed). Got it? So in the end, you have four groups of depressed patients:
Treatment resistant receiving imipramine + zinc
Treatment resistant receiving imipramine + placebo
"Non-resistant" receiving imipramine + zinc
"Non-resistant" receiving imipramine + placebo
Some results (all of these are statistically significant unless I note otherwise). Serum zinc levels were 22% lower on average at baseline in the depressed individuals than in the healthy controls. The serum zinc levels of the long-term "resistant" depressed patients were lowest of all. Serum zinc over the twelve weeks increased in all the depressed patients except the treatment-resistant imipramine + placebo group. Yes, that means that anyone who felt better by depression rating scales at the end of the 12 weeks had a higher zinc level, whether they were given placebo or zinc supplementation. The treatment resistant group who received zinc also had a higher zinc level at the end of the treatment than at the beginning, but it was still much lower than both non-resistant groups. Everyone remained lower than the normal controls, but the treatment responsive groups were fairly close.
Based on review of other zinc studies and the results of this study, the researchers concluded the following: It is unlikely that low blood zinc level in depression is due to lack of appetite or from HPA axis hyper-stimulation that occur with depression. They felt it was specifically due to inflammation (as zinc levels are negatively correlated with inflammatory markers, like IL-6 and neopterin), and even more specifically due to either a decrease in the protein that carries zinc around in the blood, or the increase in IL-6 leading to metallothionein sequestering zinc in the liver. Therefore, "it can be inferred that normalization of the serum zinc level in treatment non-resistant patients was the result of the abatement of inflammatory processes during remission of the depressive episode." (The entire paper reads like that. It is thankfully quite short.) In other words, inflammation causes depression and low zinc levels. Successfully treat the inflammation and your depression gets better and your zinc levels rise.
Why did I call this post "Zinc Revolution?" Well, here we have something heretofore unknown in psychiatry -- a simple blood test that could, if all this pans out in more studies, monitor treatment resistance and treatment response. In the old days they would do tedious dexamethasone suppression tests and even, sometimes, in research, spinal taps to measure serotonin levels and the like. Certain features of depression would correlate with some of the measures, but there was nothing found that would give you a real physiologic clue for most patients with depression.
Not to mention here we have real proof that depression isn't all in your head. It's in your blood, too, right there in the inflammation, measured by the biomarker zinc.
We can measure treatment resistance and response already, via diagnostic interviews and symptom scales. All these are subjective, but similar to how a neurologist would measure treatment response to migraine medication. An objective blood test could be a nice addition to the psychiatric armament, but it is the principle that matters, and I'll repeat it here:
Depression is not all in your head.