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Inflammation: How Depression Can Fuel It

In my link on Testosterone and Depression, I discuss how testosterone can lower depression and depression can lower testosterone. In fact, the latter scenario recently showed up in a study where researchers found that depression was very predictive of low testosterone.  In fact, they found that there were three things that forecasted and thus probably causative of low T and that was a) obesity, b) smoking and c) depression:

“On average, testosterone levels did not decline significantly over five years; rather, they decreased less than 1 percent each year, the authors reported. However, when the investigators analyzed the data by subgroups, they found that certain factors were linked to lower testosterone levels at five years than at the beginning of the study. “Men who had declines in testosterone were more likely to be those who became obese, had stopped smoking or were depressed…” [1]

Basically, what this study did was look at men who were depressed at the start of the study and then followed them five years later.  At five years they found that depression was a major risk factor for low T.  Now why would depression (likely) cause low testosterone?

The answer lies is just what depression does to the brain.  It turns out that depression greatly increases:

  • nitric oxide
  • oxidative load, i.e. free radical production
  • cortisol

Any one of these can do damage, but if you put all three together, it is definitely a dangerous scenario.  (Yes, nitric oxide in moderation is a good thing, but, in excess, can destroy as we will discuss below.)  And this undoubtedly explains why depression hammers the brain and unwires neurons.  Depression has been found in a couple of studies to actually, over time, shrink the hippocampus.  In my page on Testosterone and Depression, I discuss how depression is basically a stressor and stressors generally result in a, b and c above.

Does depression really increase nitric oxide?  Several studies indicate that that is indeed the case:

1. Plasma Nitric Oxide.  One (admittedly small) study found that plasma (blood) nitric oxide levels were significantly higher in depressed patients than in controls. [2]

2. Platelet Nitric Oxide.  Another study found that platelet nitric oxide levels were higher in depressed patients who were untreated when compared to controls. [3]

Isn’t more nitric oxide always better?  Again, not when created in excess and the body does do this sometimes. Remember that nitric oxide is a free radical.  Sure, it is a very important free radical that dilates your arteries, creates erections and acts as a brain neurotransmitter among other things.  But too much of it has been implicated as a root cause in the following brain disorders:

  • suicide [4]
  • schizophrenia [5]
  • ALS (Lou Gehrig/Stephen Hawking Disease) [6]
  • bipolar disorders [9]
  • Parkinson’s [10]

And, sticking to the subject at hand, elevated nitric oxide has been implicated in depression as well. [8] And it is no wonder:  researchers have found that “nitric oxide modulates norepinephrine, serotonin, dopamine, glutamate, the major neurotransmitters involved in the neurobiology of major depression.” [7]  Furthermore, oxidative stress has been coupled with depression as well in a number of studies and reviews.  So it is not just nitric oxide that is getting increased but other free radicals in general as well. [12][13]

Of course, oxidative load and inflammation are intimately linked and one of the most important studies showed that untreated depressed patients were higher in oxidative stress and IL-6, one of the “killer” inflammatory cytokines that is associated with many chronic diseases and conditions. [11] And, most importantly, treatment for depression brought IL-6 and oxidative stress back into line. Of course, the moral of the story is that it is actually dangerous to leave depression untreated for an extended period of time, since it can leave a man exposed to chronic inflammation and oxidation, both of which destroy tissues, trigger nasty metabolic reactions and possibly permanently damage his testosterone.

Now I have some natural solutions that have been shown to help with many types of depression in my page on Depression Cures. But depression should always be taken seriously and, as I hope you see from the above, is every bit as much a medical condition as a psychological one. In other words, depression appears to be a huge stressor that raises inflammation and oxidative stress that can negatively impact the brain and body permanently.  I believe that scientists will soon discover that depression can, if allowed to go on long enough, even lead to lowered testosterone as the initial study I mentioned showed.


1)  https://www.sciencedaily.com/releases/2012/06/120623144944.htm

2) Journal of Affective Disorders, Mar 2001, 63(1-3):221 224, “Elevated plasma nitrate levels in depressive states”

3) Psychiatry Research, Oct 2013, 209(3):447-452, “Increase in nitric oxide levels and mitochondrial membrane potential in platelets of untreated patients with major depression”

4) Progress in Neuro-Psychopharmacology and Biological Psychiatry, Aug 2006, 30(6):1091-1096, “Increased plasma nitric oxide level associated with suicide attempt in depressive patients”

5) https://www.schizophrenia.com/sznews/archives/005764.html#

6) Neurotox Res, 2012 Nov, 22(4):251-64, “Nitric oxide-mediated oxidative damage and the progressive demise of motor neurons in ALS”

7) Nitric Oxide, Apr 30 2011, 24(3):125 131, “Nitric oxide and major depression”

8) Journal of Affective Disorders, Mar 2001, 63(1-3):221-224, “Brief report Elevated plasma nitrate levels in depressive states”

9) Neuropsychobiology, 2002,45:57 61, ” Possible Role of Nitric Oxide and Adrenomedullin in Bipolar Affective Disorder”

10) Nature Medicine, 1999, 5:1403 – 1409, “Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease”

11) Brain Behav Immun, 2013 Jul, 31:143-52, “Dysregulated relationship of inflammation and oxidative stress in major depression”

12) Psychiatry Res, 2013 Apr 30, 206(2-3):213-6, “Increased oxidative stress in patients with depression and its relationship to treatment”

13) Curr Pharm Des, 2012, 18(36):5890-9, “The role of oxidative stress in depressive disorders”

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