Let me see if I can convince you of this.
Cutting straight to the chase, oxidative and nitrosative stress play a role in depression. Immune system activation and inflammation contribute to depressive symptoms, including anxiety, fatigue, malaise and cognitive impairment.
Several major findings show that depression is is an inflammatory disorder
- Inflammatory cytokines, such as IL-1, IL-6, tumor necrosis factor ( TNF alpha) and interferon (IFN gamma) are consistently increased in the blood or brain of depressives.
- Inflammatory pathways that have recently been discovered in depression include
- Activation of IDO, a tryptophan depleter
- Depleted plasma tryptophan
- Increased tryptophan metabolism byproducts that promote depression
- Bacterial infections that activate immune cell produced inflammatory cytokines
- Oxidative and nitrosative stress
- Decreased synthesis of 5-HT.
The elements of the inflammatory cascade involved in depression seem to be:
- Oxidative and nitrosative stress (O&NS) that causes damage to the brain membrane omega-3 fatty acids, proteins, DNA, mitochondria, and autoimmune responses.
- Decreased levels of omega-3 fatty acids and antioxidants, such as coenzyme Q 10, glutathione peroxidase or zinc, increase inflammatory potential and alter the expression of receptors in the brain.
All these factors lead to neurodegeneration, neuronal apoptosis, lowered neurogenesis and neural plasticity. In short, brain neurons degenerate, die, fewer are regenerated, and the surviving neurons lack energy. The loss of neuroplasticity means you cannot learn new things because you lack the ability to form new networks in the brain.
An underlying cause of the loss of brain neurons suffered in long-term depression is the low level of brain growth factor (BDNF) that depressives show in their blood. The lack of activity in depressives is due to their mood and the low energy level of their brain cells because they lack mitochondrial density and activity. Thus, depressives are not able to engage in the vigorous activities that strongly elevate BDNF.
BDNF is lower in bipolar depression than unipolar depression and is associated with high recurrence and treatment resistance. Neurotics show low BDNF.
These factors suggest that depression is the consequence of a complex interplay between immune system action and inflammation. Depression, anxiety, neurosis, and other maladies may not be consequences of poor thought patterns or stress so much as they are brain states caused by inflammatory processes. In other words, the thoughts of depressives are damaged because their brains are damaged.
Hopelessness, anxiety, and low energy are caused by brain damage and low mitochondrial function. Depressives lose brain neurons in the hippocampus, amygdala, prefrontal cortex, anterior cingulate, and basal ganglia.
These are physiological states not than mental states. Depressive thoughts are the consequence of the loss of brain neurons and defective brain metabolism that are engendered by inflammation
I am suggesting that depression should not be seen as a brain thinking sick thoughts, but of a sick brain thinking depressive thoughts. A depressive brain is a consequences of poor brain metabolism and physiology. These are directly treatable through diet, antioxidant supplements, and activity. Antidepressants that successfully treat depression elevate antioxidant defenses in the brain. Thus, they work by reducing oxidative and inflammatory stress in the brain, as my theory predicts.
Reduced antioxidant status is a key element of depression. Depressives have lower serum levels of zinc, albumin, tryptophan, vitamin E, coenzyme Q10, and glutathione. Treatment with antidepressants restores glutathione peroxidase to almost normal levels. This suggests that antidepressants are successful because they increase oxidative stress capacity.
When taken with the evidence that antioxidants reduce depression, a case can be made that reduced capacity to quench ROS and RNS is a primary element of the depression cascade. Glutathione and Ebselen (a seleno-protein that mimics glutathione peroxidase) are powerful antioxidants and have proven to be helpful in treating depression. The patented Ultrathione contained in Guardian (available at links on this site) is a clinically proven oral source of glutathione that appears in cells within 30 minutes.
Improved nutrition can improve depression. Post-partum depression is associated with low Omega-3 serum levels. EPA has beneficial effects on depression. On the other hand, depressives have high Omega-6 levels. The ratio of Omega-3 to Omega-6 is significantly altered by various Paleo-style diets that limit grain and processed food intake, which are high in Omega-6, and encourage consumption of foods high in Omega-3 fatty acids such as fatty fish. (My diet, The New Evolution Diet, promotes a favorable ratio of these fatty acids and explains the significance of EPA and DHA in human evolution.)
Bacterial infections activate the immune system and inflammatory processes, thus contributing to depression. In addition, the mitochondria of depressive subjects are deficient in energy production and produce excess oxygen free radicals. It is safe to conclude that inflammation, inadequate intake of omega-3 fatty acids and zinc, and decreased levels of antioxidants are involved in depression. Treating these deficiencies may heal your brain so that you may heal your depressive thoughts.
Depression may no more than the firings of damaged neurons As they say in neuropsychiatry, For every twisted thought, a twisted molecule.
Leonard, B. B., & Maes, M. M. (2012). Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neuroscience and Biobehavioral Reviews, 36(2), 22–22. doi:10.1016/j.neubiorev.2011.12.005