FoundMyFitness - #031 On Depression and Its Underlying Causes

Episode Date: January 25, 2017

The World Health Organization estimates that more than 350 million individuals of all ages have depression and approximately one-third of all patients with depression fail to respond to conventional antidepressant therapies like SSRI's. The good news is that today, good science is starting to illuminate the underlying biological mechanisms of depression. This new understanding may soon help the clinical world develop new and more effective treatments.  In this episode, you'll discover: (00:00) The scope of depression and SSRI use (03:37) How inflammation can cause depression (09:26) But what causes inflammation? (12:03) Treating depression with diet  Join over 300,000 people and get the latest distilled information on depression and it's underlying causes straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Depression is a big problem, whether we're talking about right here in the U.S. where I live or the rest of the world. The World Health Organization estimates that more than 350 million individuals of all ages have depression, and approximately one-third of all patients with depression, fail to respond to conventional antidepressant therapies like SSRIs. According to the CDC, 11% of individuals over the age of 12 in the U.S. are taking some form of an antidepressant. and over 60% that take antidepressants have done so for longer than two years. Clearly, we have a very substantial swath the population now on SSRIs. But how did that happen? To tell the story of how antidepressants ended up as prevalent as they are today,

we need to roll back the clock a few decades. When antidepressants first came onto the scene, people recruited to the trials generally had a form of depression severe enough that they had previously been hospitalized for depression, and about 70% of these depressed patients responded to the antidepressants, but about 30% of the trial participants responded to placebo as well. But what happens when the demographics change? What if our very definition of what depression is gets a little bit looser? That's exactly what happened in the 1970s and 80s. During this time, some big change.

changes were made to the clinical definition of depression in the diagnostic and statistical manual of mental disorders, then known as the DSM-3. Many of the differences between the various subtypes of depression were minimized and now were able to fit into a diagnosis that could be more uniformly applied called major depressive disorder, which ultimately included a broader range of symptoms. This shift ultimately opened up the diagnosis to treat a greater number of to a more standardized agreed-upon treatment protocol. But in changing the population and the criteria for diagnosis, could this not also have an effect on efficacy? In fact, data from FDA reports suggest such a thing might be the case. In the year 2000, a review of the public domain

data from the FDA archive of antidepressants approved during 1985 through 1997 showed something that I think was and still is a bit surprising. That instead a symptom reduction magnitude was closer to 40% instead of the original 70% and still about 30% with placebo. What that means is that based on the new criteria for clinical diagnosis, only 10% more patients are responding to antidepressants than those that would have similar responded to placebo. My goal today isn't actually to try to punch holes in the use of antidepressants. In fact, based on the information we have, it's very clear that there is some effect happening for some people, regardless of the definition of depression that we use, whether this definition

proceeds the changes put forward in the DSM3 or not. But it would seem that it's at least plausible that more people are being prescribed antidepressants than should be. And it's important to point out that the use of these drugs are not without some degree of risk, which is why many, many now come with black box warnings. Today, however, what I would like to do is talk about some of the new understandings that surround depression. I think that it's important because it might give researchers and clinician the tools they need in order to have a better chance at creating treatments that can help a greater number of people.

So let's start with the most basic question of all. What causes depression? To understand that, we should turn our attention to a problem that underpins much of modern disease. Chronic systemic inflammation. In other words, 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 IL-6, 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 detrimental effects 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 seems to suggest this is the case. Take, for example, the fact that people suffer.

from clinical depression have higher concentrations of the inflammatory biomarkers C-reactive protein in IL-6 by up to 50 percent. 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 known as endotoxin,

which is a component of bacterial cell membranes that elicits an immune response, or they were injected with the pro-inflammatory cytokine interferon gamma, or with placebo, which in this case was sailing water. Both the endotoxin or the interferon gamma, but not, the placebo, caused people to have an increase in circulating levels of pro-inflammatory cytokines, including IL-6 and TNF alpha, 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 lack of reactivity to pleasurable stimuli, also known as anhedonia. Moreover,

this coincided with the peak of the pro-inflammatory response. This did not occur, in people that were injected with placebo. But what if we decide to try and 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 icosopentaenoic acid or EPA that I have talked about for a variety of reasons and is known for its renowned 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 vesicles in the meninges that surround the brain and spinal cord, and thus directly connect the immune system to the brain. Once these pro-inflammatory meteors are in the brain, they can affect brain function by a couple of mechanisms. First,

they're able to inhibit the release of neurotransmitters from pre-syneptic neurons. These neurotransmitters play a fundamental role in mood, anxiety, and motivation, including serotonin, norephenephrine, and dopamine. Dopamine levels have been shown to decrease in the brain and a reduction in the activation of reward circuitry incurred 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 re-uptake of serotonin and thus decrease the amount of serotonin that is 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 triptophan into a competing pathway through the activation of an enzyme called endolamine-23 dioxygenase or IDO, which is responsible for converting triptophan into chineeranin instead of serotonin. Cynurin is a compound that can be converted into a metabolite called quinolinic acid that is actually neurotoxic and associated with depressive. Interestingly, in humans, exercise has been shown to cause kineurine to be taken up into muscle and prevents it from becoming this toxic metabolite, which provides yet another possible mechanism by which exercise combats depression. Endurance exercise in humans prevented the formation

of this neurotoxin quinolytic acid that is produced under inflammatory conditions and is associated with depression by increasing enzymes in skeletal muscle that convert the precursor into another metabolite that is not harmful. Not only is quinoletic acid a neurotoxin, but it also deprives the brain of serotonin because it is formed from triptophan during an inflammatory state and thus prevents triptophan from being converted into serotonin. Okay, so I talked quite a bit about causal evidence showing that inflammation can cause depression in normal, healthy individuals. But what causes inflammation? I briefly mentioned many lifestyle factors including obesity, poor nutrition and gut health, sedentary lifestyle, poor sleep, and social stress can all play a role in causing

inflammation. I'm not going to go into detail about how each of these lifestyle factors promote inflammation because that would require a 10-hour podcast. But I will touch on a couple of these. In our conversation about lifestyle factors that can influence inflammation, let's start with stress. Stressful experiences and psychological events, whether we're talking about work-related, financial, or relationship stress, these types of stresses cause us to release stress hormones such as cortisol and a hormone known as corticotropin releasing hormone. Corticotropin releasing hormone, which makes its way into the gut, perhaps the vagus nerve, the direct line between the gut and the brain. Once it's in the gut, the stress hormone activates

immune cells in the gut, specifically called mass cells, and they release pro-inflammatory cytokines like TNF alpha mentioned earlier, as well as proteases, which chew up and degrade some of the proteins that hold the gut epithelium together, and this causes intestinal permeability, leading to more inflammation. Gut inflammation also activates something called the inflammasome, and this is linked to inflammation in the central nervous system and brain. Cortisol has been shown to decrease hippocampal volume. The stress hormone cortisol regulates 20% of the human genome and is part of the normal circadian rhythm, which regulates all of our biological processes according to the day-night cycle. Well, chronic stress increases cortisol,

disregulates that same 20% of the genome, which includes immune function, genes involved in inflammation, metabolism, brain function, and more. If stress hormones remain elevated for months or even years, they can stimulate physiological changes. The hippocampus shrinks and the amygdala grows, for example. Eventually, the complex feedback system that suppresses the excess secretion of cortisol is disturbed. Once this happens, the capacity to discriminate between threat levels falls away. Either everything seems threatening, which is anxiety, or else nothing does, which is depression or burnout. Teenage boys who have depressive symptoms and elevated levels of cortisol are up to 14 times more likely to develop major depression. While this study is not causal, 14-fold

is a pretty high increase. But let's shift gears for a moment. It's one thing to talk about stress hormones in isolation. More practical is when we can tie in diet, since that's something that matters to most of us, health conscious vote. In one randomized control trial, healthy, normal weight young men were given 20 ounces of a sugar-sweetened beverage similar to soda to drink daily for three weeks. They experienced an increase in a well-known biomarker if inflammation known as C-reactive protein by as much as 60% to 100% over their baseline after the extended period of soda consumption. Here too, the link between inflammation and depression pains out when we see that in a separate study looking at a similar relationship, it is observed that people that had four

cups of soda a day were 30% more likely to develop depression than those that did not drink soda. Granted, in this case, this is an association, but within the greater narrative of our story, it does fit very elegantly. Moreover, data from over 70,000 postmenopausal women has shown that consuming refined carbohydrates such as white bread and cookies increases the risk of depression and exacerbates mood changes independent of other lifestyle factors. I could go on and on, but the bottom line is that while depression is a complex disorder that is affected by many components ranging from genetics to nutrition to environmental stress and so much more that will surely only be revealed by emerging research, this mechanism by which the immune system

and inflammation can directly affect our behavior and brains may serve as a rich avenue for further exploration for both prevention and treatment of depression. In the future, we may see a shift in disease management that while not necessarily precluding existing therapies also includes mitigating chronic inflammation as a chief aim, even going so far as to monitor inflammatory biomarkers as an objective measure of therapeutic success. I predict that for us to ever find a cure for depression, that cure will not be a magic pill, but instead an effective, multi-pronged lifestyle intervention

that in addition to everything else influences the levels of systemic inflammation in the body. This might include programs targeted at reducing visceral fat on the body or meeting nutritional needs that robustly affect inflammation and increasing physical activity. If that means also getting a whole lot healthier in the process and maybe even living longer, all the better. Okay, guys, that's it for this podcast.

Time for the wrap up. First, the disclaimer. If you have depression and are currently being treated for it, you should, under no circumstance, use this podcast as a substitute for medical care or as a form of medical advice. Please continue to seek out and abide by the advice of your physician. With that out of the way, I'd like to hit on a few quick reminders that I put out there at the end of every podcast. This podcast has a fabulous newsletter. I send out show notes. I send out details about upcoming events, articles. I've sent out dessert recipes. Go get it. It's great.

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That's FoundMyFitness.com forward slash C-R-O-W-D-S-P-O-N-S-O-R crowd sponsor. Dr. Rhonda Patrick, over and out.