73: Links Between Antidepressants, Metabolic Health, and Insulin Resistance with Dr. Bikman

Hello and welcome to the Metabolic Classroom. My name is Professor Ben Bickman. I am a biomedical scientist and professor of cell biology. In today's Metabolic Classroom, the topic is the metabolic consequences of medications used for mental health. So this includes antidepressants, but also I want to make sure that the conversation includes some discussion of anti anxiety medications. They're different, but there is of course a tremendous amount of overlap. Speaking of overlap, there is also a great deal of influence or crosstalk between mental health disorders and metabolic health. Mental health disorders like depression and anxiety are closely linked with metabolic conditions like insulin resistance and the eventual manifestation or the end result or the end consequence of insulin resistance, namely type 2 diabetes. Now, over the years this relationship has been known, but not clear in the directionality. And to complicate matters, it seems like it's a bit bi directional that depression can lead to metabolic disturbances. However, existing metabolic disorders can actually also worsen mental health symptoms. And that's certainly the paradigm in the directionality that I'm approaching, approaching with this topic. Now to further complicate this and even give some justification for the time that we're going to spend talking about this, it's very well known that myriad anti anti anxiety and antidepressant depressant medications can themselves lead to significant metabolic side effects like weight gain and insulin resistance. Now as I approach this topic, I do so with a great deal of respect and I want to admit it very openly. I don't like it when scientists claim an expertise across all areas or when someone with some glamorous terminal degree after their name, an MD or a Ph.D. for example, that they then believe that makes them an expert on everything. There's this phenomenon, and it is a very fun word, ultra crepidarianism, which is this term that refers to people giving opinions or advice on matters that are outside of their actual knowledge or their area of competence. You know, this would be like famous physicists who have suddenly become experts on my microbiology and understand viral transmission and vaccine function, you know, for example. So let's just set that stage very, very well and thoroughly. I'm not a clinician, I'm not a psychiatrist, I'm not even a neuroscientist. I'm a metabolic scientist. And that's how I'm, I am approaching this topic now. I'm a professor of physiology, so I can speak about some of this topic comfortably and qualify as your teacher for the next 20 or 30 minutes. So thanks for letting me. Of course, as usual, just be a teacher here. Okay, now to get started. Before we actually describe commonly used anti, anxiety and antidepressant medications, I wanted to start with establishing a foundation, namely by focusing on the key neurotransmitters that are altered. Either altered in a way to create the problem and or altered in a way to help solve the problem. Those aren't necessarily sort of the same thing, but nevertheless, there are a few key neurotransmitters. There are more than I'm going to cover. I'm going to mention three. And I just want you to appreciate that there are more. You would have no trouble finding more, but for the sake of time, I'm just focusing, focusing on the big three. All right, so let's just start with a review of what the neurotransmitters are, their, their general role in mental health. And then I'm going to highlight their role in metabolic health and metabolic function. Then we'll get into some of the specific medications and their influences on, on metabolic health. But having started with review of the neurotransmitters, it'll make that all will make much more sense. So the first neurotransmitter I wanted to discuss is serotonin. You may also see it sometimes indicated as 5ht, and that refers to its more technical chemical name, 5 hydroxytryptamine. But let's just call a serotonin, for goodness sakes. All right, now, serotonin is a key neurotransmitter involved in regulating mood, anxiety, and just overall feeling. Well, low levels of serotonin have been linked to depression, anxiety disorders, and even sleep disturbances, which if you've followed me for some time, you know, that's something I personally struggle with. All right, so that's the general role of serotonin as a neurotransmitter in the central nervous system. Let's particularly with regards to depression and anxiety. However, even if we stick with the central nervous system, in other words, the signaling of serotonin in the brain, it has a metabolic relevance in particular with regards to appetite. And later on, I'm going to revisit this idea of cravings and food addictions, and I'll just touch on that lightly as we go across the three main neurotransmitters. But serotonin is a contributor to appetite suppression. So it is like acting kind of like leptin is in this canonical sense where it is signaling a satiety. It's telling the brain that, hey, we're full, let's not eat anymore. So it's no surprise that high serotonin levels are associated with reduced hunger, while lower levels may increase food cravings. Not cravings for everything, though this appears to be particular to carbohydrates and sugary foods. And again, that's a topic we're going to revisit again at the end. Now, let's go firmly into the metabolic and leave the brain behind and get into the realm of the systemic or peripheral signaling of serotonin. So insulin sensitivity, serotonin impacts insulin regulation in peripheral tissues, especially some key tissues like liver, pancreas, and adipose tissue or fat tissue. We're going to talk more about fat in just a second. But if serotonin isn't signaling well, insulin isn't signaling well either. And so insulin resistance and type 2 diabetes risk goes up. Now, let's talk about the fat cell, in particular, serotonin. So, first of all, there's this promotion of fat accumulation. Serotonin can increase lipid accumulation, and this has been shown to happen in both rodent fat cells and human fat cells. And this is by activating the central regulator of fat storage and adipogenesis, or fat synthesis, fat cell synthesis called ppar g. So that's ppar dash, then the little Greek letter gamma P par gamma. You could look this up for more details, but ppar gamma activators are classes of medication that, among their handful of metabolic effects, are most well known for making a patient gain a lot of weight. So serotonin activates that same thing, so it can lead to greater fat storage and upregulation of the genes that are associated with that process. Okay. At the same time that serotonin is stimulating an increased fat storage, it's also through the receptor that we could just call serotonin receptors, but technically they're the 5 HT2A. So to sail that another way, the serotonin 2A receptors, it can inhibit lipolysis, so that lipolysis is the term for the breakdown of fat. And that, of course, is going to drive the fat cell to continue to store more fat. Also reflective of this general kind of suppressive effect on mobilizing energy and rather storing it, serotonin has been shown to prevent the differentiation or the maturation of brown fat cells. It interferes with this process of the brown fat cells becoming really mature and kind of grown and functioning. And then lastly, serotonin inhibits thermogenesis, and that is very much a brown fat phenomenon. That's something we've talked about previously, this idea of mitochondrial uncoupling, where you have the mitochondria basically like an engine where you are, if you can imagine you're in neutral or you're in park and you're revving the gas pedal so the RPMs are going up and yet you're not moving anywhere. That's this idea of uncoup where the cell is working but not it's burning through nutrients and it's just creating heat. It's not actually getting any work done. Like you pressing on the pedal, the gas pedal and you're not actually moving. Okay, so that's a review of serotonin. Let's move on to the next of the big ones, namely dopamine. Now its role in mental health is that it is, is one of the more famous reward neurotransmitters. So it regulates this degree of motivation and pleasure and behaviors associated with, you know, finding something that makes you feel good. Dopamine imbalances are associated with mental health disorders, including some big ones like depression, bipolar disorder, as well as schizophrenia. All right, now that's the central effect with regards to canonical health, mental.