How free radicals, oxidative stress, and inflammatory disease cause depression.

It is obvious enough that inflammatory illnesses (those ending in “-itis”), diets low in antioxidants or antioxidant depleting habits such as cigarette smoking or alcoholism, and exposure to sources capable of generating free radicals such as environmental pollutants, high levels of toxic estrogen metabolites or synthetic estrogens, and high-voltage microwave radiation, are associated with disorders of mood, including ADHD, psychosis, bipolar and obsessive compulsive disorders, and depression.

In this essay I intend to focus on depression, and the narrow aspect of depression that is depletion of serotonin and catecholamine neurotransmitters. There are other aspects of depression but this is the aspect that drug treatment exclusively targets, with variable success and the risk of serious side affects including addiction.

The lazy answer is that depression follows a diagnosis of inflammatory disease and is a reaction to illness and poor prognosis. Unfortunately, depression often precedes overt signs of physical illness (for example, in chronic fatigue syndromes). There is nothing mysterious about the role depression plays in inflammatory illness, as will be seen.

Free radicals may be produced by normal process of energy generation in mitochondria, by immune cells fighting disease, from external sources, or by the interaction of ionizing microwave or nuclear radiation entering the body. The latter tends to produce the highly reactive hydroxyl radical, which may react with lipids to form lipid peroxides. These compounds are formed as part of the inflammatory response and high levels are produced in infection. In chronic infection the production of free radicals and lipid peroxides may eventually overwhelm the body’s ability to produce antioxidants such as glutathione and the selenium-containing enzyme glutathione peroxidase, one form of which is capable of neutralizing lipid peroxides. The peroxides made from the omega-6 fatty acid arachidonic acid are particularly pro-inflammatory, and their presence attracts increasing quantities of white blood cells to the site of inflammation.

The inflammatory response itself can result in a chronic depletion of tryptophan, leading to serotonin depletion and depression. This happens because inflammation demands high levels of two compounds made from tryptophan; one is a series of nicotinamide co-enzymes, NAD, NADH, NADP, NADPH, which are used by white blood cells to generate free radicals, and by all cells of the body to quench free radicals, amongst other functions. The other is serotonin itself, which is manufactured by platelets as part of the coagulation cascade, in which it has a different role from its neurotransmitter function in the brain. During inflammation, white blood cells release the enzymes that begin the breakdown of tryptophan in the bloodstream, and as a result total serum tryptophan become depressed, with the eventual depletion of brain serotonin and the sleep hormone melatonin.

Meanwhile, elevated levels of free radical create a condition known as “oxidative stress”, where the body’s antioxidants are insufficient to protect essential metabolic functions, such as enzymes, from damage.
 It is worth pointing out that exposure to prolonged high levels of stress hormones, as in post-traumatic stress disorders, can result in a condition of chronic oxidative stress. A co-enzyme especially vulnerable to oxidative stress is the vitamin B12 molecule in the methionine synthetase enzyme. This vitamin is part of the process that recycles the amino acid methionine to create SAMe, or AdoMet, which donates all methyl groups in the body. Methyl groups from SAMe are required to synthesise many essential compounds, including epinephrine (adrenaline), melatonin, and the choline molecule from which the parasympathetic neurotransmitter acetylcholine is made. Methyl groups from SAMe are not only essential for these mood hormones, they are also required to synthesise energy-generating compounds such as co-enzyme Q10 and (together with vitamin C) carnitine, so that mental depression is often accompanied by quite genuine, non-psychosomatic, physical fatigue.

Oxidative stress may also (depending on intake from diet and supplements) result in the depletion of ascorbic acid (vitamin C), which is required for the synthesis of dopamine and tyrosine, starter chemicals for the synthesis of adrenaline and noradrenaline.

Thus the conditions of oxidative stress and inflammation cause deficiencies of many of the major neurotransmitters; serotonin, adrenaline, acetylcholine; the sleep hormone melatonin; and may, depending on intake of vitamin C, also deplete dopamine.

The connection between inflammation and depression is seen in the way low levels of vitamin D, an anti-inflammatory hormone, cause the form of depression known as seasonal affective disorder (SAD), and the way that a high intake of the anti-inflammatory omega-3 fatty acids EPA and DHA tends to reduce depression as well as inflammation. EPA and DHA are most effective against depression obviously linked to inflammation, such as premenstrual syndrome.

The serotonin precursor 5-HTP and the tryptophan metabolite niacinamide (vitamin B3), together with anti-inflammatory nutrients and antioxidants, can prevent or reduce the low-serotonin type of depression, while the dopamine precursor l-tyrosine and methylcobalamin (B12), folic acid, magnesium and multivitamins, together with antioxidants, with the amino acids l-methionine or SAMe if necessary, can prevent or reduce the low-adrenaline type.

Depression is not one single thing, as will be obvious if you think about happiness, which can take many forms. Serotonin tends to be associated with contented, satisfied forms of happiness, and there is even a high-serotonin depression, which can be due to lead toxicity, and which of course will not respond to SSRI antidepressants, and may be made worse. Adrenaline tends to be associated with thrilling, excited forms of happiness; it is motivating where serotonin is reinforcing. A high adrenaline, low serotonin depression may cause severe anxiety or hypomania. Niacinamide and SAMe can usefully be seen as antidotes; niacinamide helps to soak up methyl groups, lessening the over-production of adrenaline in mania as well as elevating the level of calming serotonin; SAMe (or B12, folate, and lecithin) supplies methyl groups to replace those used in the metabolism of B3 to N-methyl nicotinamide, the form in which it is excreted, preventing the side effect seen at high doses of niacinamide, of jaundice due to a decreased production of phosphatidylcholine (to put this in perspective, many commonly prescribed antidepressant drugs can cause liver and gall-bladder damage). Doses of SAMe surplus to requirements can cause anxiety or hypomania (though these side effects are not seen with B12 and folate), niacinamide surplus to requirements can cause low-adrenaline depression and (at doses above 1,500mg daily) nausea (the first sign of jaundice); it is wise to combine both in an antidepressant regime. Except in the case of lead poisoning, both aspects of depression are usually seen together.