By 2020, depressive disorders are projected to be the 2nd leading cause of worldwide disability. The burden of Mood Disorders is rising both for the individual, the family, and for the society. Currently, most people who are treated for depression are partially responsive or non-responsive. New tools are needed. One of these tools involves a focus on the inflammation, immune dysfunction, and infections that are often associated with depression.

Many immunity-inflammation mediated disorders are co-morbid
with depression: Heart disease, diabetes, Chron's disease, autoimmune
diseases, cancers, HIV, and Multiple Sclerosis.

The brain and the immune system talk to each other, and the communication is bi-directional. This means that inflammation (such as that which occurs due to infection) affects the brain. It also means that changes in brain immunity and inflammation affect the body. A meta-anaysis of several studies on this issue found that several cytokines (hormones of the immune system) and markers of inflammation (C-reactive protein, interleukin 1 and 6) were positively correlated with depression. This means the more depression there is, the more inflammation there is. Cytokines seem to trigger a quick onset of what is called ‘sickness behavior'-meaning malaise and fatigue, as well as a delayed onset of depressed mood. One study found the same very close correlation between certain cytokines, mood, anxiety and memory.

Reducing inflammation may help alleviate depression: In a randomized placebo controlled trial of a COX-2 inhibitor -celebrex-(celecoxib-blocks pro-inflammatory eicosanoids) with reboxetine (a noradrenergic-reuptake inhibitor antidepressant) augmentation with celecoxib was superior to placebo.

A second randomized double blind placebo controlled study showed that etanercept (a TNF-tumor necrosis factor-blocker) reduced depressive symptoms in people with psoriasis, independent of improvement in the psoriasis. This is consistent with elevated levels of plasma TNF elevations found in depressed patients.

Of further relevance is the fact that the core stress response system in the brain activates and regulates the adrenalin-immune connection in the body (this includes the bone marrow and the thymus gland), as well as secondary immune organs (spleen and lymph nodes). Thus, through this pathway (and there are others), stress affects immune function. On the other hand, not only do the brain stress circuits affect the immune system, but the hormones of the immune system-the cytokines referred to above-are know to make the stress circuits of the brain more sensitive.

Another interesting linkage path between the immune system and the brain is the vagus nerve. This nerve system, when activated, opposes the adrenalin system. When it is activated it stimulates the motivational centers in the brain directly, and through the brain's own immune cells (called microglia) increases nor-adrenalin and serotonin.

Chemicals of inflammation, the cytokines I referred to above, can be released by the brain microglia, causing a shift in the balance between helping neurons to grow, and putting them to death. When shifted in the wrong direction, these microglia actually stop the brain from making serotonin, and in that case, any medication that works on serotonin-such as prozac, Zoloft etc-can not work. (This is part of the reason for ‘prozac poop out', and this is why I regularly tell my patients that if an anti-depressant has worked for you for 6 months, and then stops working, something else is going on.) The brain production of serotonin does not return to normal for months after an infection.

How can you know if inflammation, infection or immune dysfunction are playing a role in your depression? Ask yourself these questions: Yes answers imply immune/inflammatory/infectious processes. The more ‘yes' answers the higher the likelihood.
Do I have a physical sense of ‘brain fog'?
Do I have a recent reduction in ‘room-to-room' memory (short term memory)?
Do I have trouble finding words?
Do I sometimes feel confused?
Do I have learning disabilities, or neurodegenerative disorders (e.g.,Alzheimer's is an inflammatory disorder)
Do I feel that if I had plenty of energy my depression would be gone?
Do I have a lot of muscle or joint aches?
Do I feel swollen, puffy?
Do I have a lot of pain?
Do I have gastrointestinal problems?

What to do? Get your doctor to work you up for inflammatory processes, and then try to get to the underlying causes. You will notice an improvement in your depression, if you are on medication it will work better, and many of your symptoms will clear gradually. Remember inflammation is like a smoldering fire. When you treat it, it can take several months for the fire to go out. But the juice is worth the squeeze-you will not only have less depression, but your risk for a host of other diseases will go down.

To Life,

Robert Hedaya, DFAPA

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