The Science & Treatment of Bipolar Disorder

**Andrew Huberman** (0:00)
Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life.
I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, we are going to be discussing bipolar disorder, often called bipolar depression. Bipolar depression is a condition in which people undergo massive shifts in their energy, their perception and their mood. However, it is very important to note that the shifts in mood, energy and perception are all maladaptive. They can often cause tremendous damage to the person suffering from bipolar disorder and tremendous damage to the people in their lives. Today, we are going to parse the biology that leads to the shifts in mood, energy and perception. And we are going to talk about the various treatments that exist. Some of those treatments have been around for a very long time. And indeed, one of those treatments, lithium, has an incredible back story about its discovery and in understanding how lithium works and some of the ways in which it does not work well, it reveals a tremendous amount about how the brain works normally in all individuals. So that's a miraculous story that I look forward to sharing with you. As we go forward in this discussion about bipolar disorder, I want everyone to keep in mind that it is a very severe condition. In fact, people suffering from bipolar disorder are at 20 to 30 times greater risk of suicide. So today is a serious discussion and it's certainly one in which people who are suffering from manic bipolar disorder or who know people that are suffering from manic bipolar disorder can benefit from. However, for those of you that might know people or who themselves suffer from major depression, we will also be talking about important treatment developments for major depression. Major depression is a very common thing for many people. In fact, most people will suffer from depression of some sort at some point in their life, although not necessarily a major depressive episode. And yet major depression is very common. As you'll soon learn, up to 20% of people will suffer from major depression. So today's discussion will encompass all of that. And it will also encompass basic brain mechanisms of neuroplasticity, the brain's ability to change in response to experience both for good and for worse. And you'll learn a lot about the basic biology of how the brain regulates mood, energy and perception. Before we dive into the discussion about manic bipolar disorder, I want to highlight some recent findings in an area totally separate from mental health that I think are really important for everyone to know about. This is a paper published in the journal Cell, which is a cell press journal, an excellent journal. In fact, one of the three apex journals. So for those of you that are curious, papers published in the journal Nature, Science and Cell are considered the sort of Super Bowl, Stanley Cup and NBA Championships of publishing. And this paper entitled An Interorgan Neural Circuit for Appetite Suppression illustrates a very important principle that I think everyone should know about. And that's the principle of so-called parallel pathways. Parallel pathways, as the name suggests, are pathways that could be neural pathways or hormonal pathways or otherwise that operate independently of one another to accomplish a common goal. And what this paper really shows is that there's a set of peptides in the body. And the peptide that I'm referring to today is called GLP-1, glucagon-like peptide-1 and some related peptides. I've talked about these on the podcast before for two reasons. First of all, I'm a big proponent and consumer of yerba mate. Yerba mate is a tea that can promote the release of glucagon-like peptide-1.
And there are also new prescription drugs that are now hitting the market and for which there are really impressive clinical trials for diabetes and obesity that are essentially glucagon-like peptide-1 stimulators. So they stimulate the release of that, or they are in fact a synthetic version of glucagon-like peptide-1. What is glucagon-like peptide-1? It is a peptide, which is a small little protein that can dramatically suppress appetite. So that's why these drugs are being explored and are showing quite impressive results for things like treatment of type 2 diabetes and other forms of diabetes as well as obesity. So they lead to weight loss. Now, in terms of the yerba mate stimulation of glucagon-like peptide-1, that's going to be a much lower amount of glucagon-like peptide-1 that's released from drinking yerba mate, as opposed to say taking a drug that stimulates GLP-1 or taking a drug that is GLP-1. Nonetheless, I should also point out that yerba mate comes in a bunch of different forms. There is some concern about certain smoky-flavored forms of yerba mate being carcinogenic. So that's why I avoid those forms of yerba mate. But for me, yerba mate is one of the preferred sources of caffeine for me. I like the way it tastes. It does provide that sort of caffeine kick that I like to have early in the day for focus and for work and for exercise. And yet I actively avoid the smoked varieties of yerba mate because of the potential carcinogenic effects of the smoked varieties. Glucagon-like peptide 1, as I mentioned earlier, can suppress appetite. But what this paper shows is it does that by at least two mechanisms through parallel pathways. What this paper shows is that glucagon-like peptide 1 acts on receptors in the body in a portion of the nervous system called the enteric nervous system, E-N-T-E-R-I-C, enteric nervous system. This is a component of your nervous system that you don't really have control over. It's autonomic or automatic. GLP-1 binds to what are called intestinofugal enteric neurons. You don't need to know the name, but those neurons do two things. First of all, they cause some gut distension. So they actually make you feel full. This is incredible, right? A peptide, not actual physical food, but a peptide that stimulates neurons that cause changes in the so-called mechanoreceptors of the gut of the enteric nervous system and make people feel full. So it can lead to actually mild, or I suppose if levels of GLP-1 are very high, to major gut distension, okay? I think that the levels of GLP-1 that would come from drinking yerba mate and hopefully from appropriate dosaging of the synthetic forms of GLP-1 or drugs that stimulate GLP-1 would cause mild, not major gut distension, because major gut distension would be uncomfortable. So GLP-1 is acting at the level of gut to increase gut distension and by way of a pathway that goes from the gut up to the hypothalamus, this little cluster of neurons about the size of a marble that sits above the roof of your mouth is also suppressing appetite through brain mechanisms. So this is really beautiful, right? You have a peptide, a small little protein that's released in the gut and that release within the gut causes gut distension, which makes you feel full and by way of neural stimulation of the hypothalamus also activates neural pathways within the brain that trigger satiety, the feeling of having had enough food. So to me, GLP-1 is both impressive and important. Why? Because this recent category of drugs that's now hitting the market seems to adjust obesity or can help people with weight loss in order to help their health. And it's doing so by at least two mechanisms. One is within the brain and the other is within the gut and communication through the so-called gut brain access, because again, these enteric neurons are communicating to the brain, the hypothalamus, by way of this, what's called the sympathogastro-spinal-reticular hypothalamic pathway. You absolutely do not need to know all of that. That's a mouthful. That's enough to make your mouth feel distended. But at the same time, things like yerba mate, and I'm sure there are other compounds out there as well, but certainly yerba mate can stimulate the release of GLP-1. So for those of you that are looking for some mild appetite suppression and want to accomplish that while also ingesting caffeine, yerba mate might be a good option for that. And just know that it's operating through two mechanisms, on the body, through mild gut distension to make you feel full, and on the brain to increase satiety or make you feel less hungry. And then for everybody, not just those that are interested in appetite suppression, I think it's important to understand that these parallel pathways are fundamental to how we are organized. Another good example of this would be when we are excited by something, positive or negative. So it could be stressful or we're positively aroused. There is a parallel activation of epinephrine, adrenaline, both from your adrenals and from an area in the brain called the locus coeruleus. So again and again, we see this in biology and in neuroscience, that your brain and your body are acting in concert. They're acting together through mechanisms that either are independent, so separately in the brain and separately in the body, but directed towards a common goal or through communication between brain and body. And almost always that communication is going to be bidirectional, body to brain and brain to body. So I think these results are really interesting and really important for sake of weight loss, for sake of appetite suppression, and just generally for the way that they illustrate this very important theme of the way that we are constructed at a biological level, which is parallel pathways. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Athletic Greens. Athletic Greens is an all-in-one vitamin mineral probiotic drink. I've been taking Athletic Greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking Athletic Greens and the reason I still take Athletic Greens once or twice a day is that it helps me cover all of my basic nutritional needs. It makes up for any deficiencies that I might have. In addition, it has probiotics, which are vital for microbiome health. I've done a couple of episodes now on the so-called gut microbiome and the ways in which the microbiome interacts with your immune system, with your brain to regulate mood, and essentially with every biological system relevant to health throughout your brain and body. With Athletic Greens, I get the vitamins I need, the minerals I need, and the probiotics to support my microbiome. If you'd like to try Athletic Greens, you can go to athleticgreens.com/huberman and claim a special offer. They'll give you five free travel packs plus a year supply of vitamin D3K2. There are a ton of data now showing that vitamin D3 is essential for various aspects of our brain and body health, even if we're getting a lot of sunshine, many of us are still deficient in vitamin D3. And K2 is also important because it regulates things like cardiovascular function, calcium in the body, and so on. Again, go to athleticgreens.com/huberman to claim the special offer of the five free travel packs and the year supply of vitamin D3K2. Today's episode is also brought to us by Element. Element is an electrolyte drink that has everything you need and nothing you don't. That means the exact ratios of electrolytes are an element, and those are sodium, magnesium and potassium, but it has no sugar. I've talked many times before on this podcast about the key role of hydration and electrolytes for nerve cell function, neuron function, as well as the function of all the cells and all the tissues and organ systems of the body. 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