#31 The Underlying Mechanisms of Depression

Depression is one of the most common psychiatric disorders in the world. The World Health Organization estimates that more than 350 million individuals of all ages have depression, and approximately one third of all people with depression fail to respond to conventional antidepressant therapies. To put that into perspective, the that's more people in the world with depression than the entire population of the United States. That's a lot of people when you consider that worldwide there's as many people with depression for which conventional treatment does not work as nearly half of the adult population of the United States. But what causes depression? Mounting evidence suggests that chronic systemic inflammation plays a major role in depression.

In other words, the the overactivity of our own immune systems. Inflammation is a part of a complex biological response to infection or injury that involves the activation of the immune system which produces pro inflammatory cytokines including IL6, interferon gamma, TNF alpha and other inflammatory molecules. While this is a normal and healthy response, an exaggerated and prolonged inflammatory response can come about as a consequence of many lifestyle factors including obesity, poor nutrition and gut health, sedentary lifestyle, poor sleep and social stress. When this occurs, this excessive inflammatory response, resulting in a great number of circulating inflammatory cytokines can promote a state of systemic inflammation.

This has been shown to have a detrimental effect on the brain as well as other tissues. By now you probably see where I'm going with this. Maybe there's a link between depression and systemic inflammation. Evidence seem to suggest this. Take for example the fact that people suffering from clinical depression have higher concentrations of the inflammatory biomarkers C reactive protein in IL6 by up to 50%. In fact, elevated biomarkers of inflammation such as C reactive protein have been shown to predict the risk for major depression. One study showed that the risk of major depression increased by 44% for each standard deviation increase in log C reactive protein. That however, is an association.

More important is the evidence that suggests this relationship between inflammation and depression is actually causal. Several double blinded placebo controlled studies have been conducted in healthy people where they were injected with either lipopolysaccharide or also known as endotoxin which is a component of bacterial cell membranes that elicits an immune response or injected with the pro inflammatory cytokine interferon gamma or with placebo which is saline water. Both the endotoxin and interferon gamma but not the placebo cause people that have an increase in circulating levels of pro inflammatory cytokines including IL6 and TNF alpha and as we might have expected, but very interestingly in both cases they also experienced an acute increase in depressive symptoms, anxiety, feelings of social disconnection and a lack of reactivity to pleasurable stimuli known as anhedonia.

Moreover, this coincided with the peak of the pro inflammatory response. But what if we decide to try to mitigate some of that inflammation? Those people that were injected with the pro inflammatory cytokine but were also given the omega 3 fatty acid known as eicosapentaenoic acid or EPA that I have talked about quite a bit for a variety of reasons and also is renowned for its anti inflammatory properties, did not experience depressive symptoms. It's important to note that some studies have suggested that high EPA fish oil, often in the neighborhood of around 2 grams of EPA per day, may itself have an effect on depression. But why and how might inflammation be affecting depressive symptoms in the first place?

Cytokines and inflammatory molecules such as the E2 Series Prostaglandins Cross the blood brain barrier either by passing through leaky parts of the blood brain barrier or by binding to transport molecules on the blood brain barrier and hitching a ride in or through transport by way of the recently discovered lymphatic vessels in the meninges that surround the brain and spinal cord and thus directly connect the immune system to the brain. Once these pro inflammatory mediators are in the brain, they can affect brain function by a couple of mechanisms. First, they are able to inhibit the release of neurotransmitters from presynaptic neurons. These neurotransmitters play a fundamental role in mood, anxiety and motivation and include serotonin, norepinephrine and dopamine.

Dopamine levels have been shown to decrease in the brain and a reduction in the activation of reward circuitry occurred in people that were injected with the pro inflammatory cytokine interferon gamma but not placebo, in addition to just inhibiting neurotransmitter release. However, in the case of serotonin, the inflammatory cytokines such as TNF alpha actually increase the metabolism or reuptake of serotonin and thus decrease the amount of serotonin that's actively in the synapse where it exerts all of its effects on mood and anxiety.

Inflammatory cytokines also lower the amount of serotonin that is produced by diverting the precursor to serotonin tryptophan into a competing pathway through the activation of an enzyme called indolamine 2,3 dioxygenase or IDO, which is responsible for converting tryptophan into kynurenine instead of serotonin, kynuronine is a compound that can be converted into a metabolite that that is actually neurotoxic and associated with depression, known as quinolinic acid. Interestingly, in humans, exercise has been shown to cause kynurenine to be taken up into muscle and prevent it from becoming this toxic metabolite. So there you have it.

While depression is a complex disorder that is affected by several factors ranging from genetics to nutrition to environmental stress, and emerging research may even reveal many more factors that affect depression. This mechanism, by which the immune system has a direct effect on mood and behavior, may serve as a rich avenue for further exploration for both prevention and treatment of depression, while not necessarily precluding existing therapies. In the future we may see a shift in disease management to include mitigating inflammation as a primary objective and may even go as far as to monitoring inflammatory biomarkers as a marker or measure of therapeutic success.

My prediction is that the ultimate cure for depression will not just be a magic pill, pharmaceutical or otherwise, but instead will be a multi pronged lifestyle intervention that focuses, among other things, on influencing the levels of chronic inflammation. This might include programs targeted at reducing things like visceral fat and making sure all the dietary and nutritional requirements are met for reducing inflammation. If that means getting a whole lot healthier in the process and possibly even living longer, all the better. Dr. Rhonda Patrick over and out. Today's video was a really fun experiment and format. If you like the video, be sure to click like tell your friends, perhaps even share a link with them.

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