Revolutionary New Treatment Strategies for Depression

Foreign welcome everybody to today's presentation on depression prevention and treatment emerging research. I'm your host, Dr. Donnelly Snipes. In this presentation we'll review new types of interventions designed to prevent or treat depression or and or treat depression, including transcranial magnetic stimulation, anti inflammatory approaches, healing the gut, microbiome, ketamine and esketamine, genomic sequencing, oxytocin, chiropractic manipulation, vagus nerve stimulation and acupuncture. So let's start out with tms. That's the one that seems to be just flourishing around here in middle Tennessee. I don't know about in other areas of the country. TMS is a non invasive neuromodulation technique that uses magnetic fields to stimulate nerve cells in the brain, targeting areas involved in mood regulation. TMS devices use an electromagnetic coil placed against the scalp which generates a magnetic field that penetrates the skull without causing discomfort or damage. Now TMS is nothing like electroconvulsive therapy. And that's when people hear about magnetic stimulation brain stuff, they think ECT this is nothing like that. This will not produce the physiological response. It's a very sort of benign sort of thing. People often report feeling a sense of warmth where, where the magnetic field is contacting the scalp, but nothing painful, nothing scary. The magnetic field creates small electrical currents in the brain tissue which depolarize neurons in the left dorsolateral prefrontal cortex. Now we've talked about the prefrontal cortex a lot. That's where we do our executive functioning, our thinking. We take our, our feelings and we can process those feelings to figure out fitcat based on the facts in the current context. Is this a threat to me? People with depression tend to have a disrupted signaling in the dorsolateral prefrontal cortex and that is crucial for mood regulation, decision making and executive functioning. TMS influences not only the targeted area, but interconnected brain networks. And that makes sense. I mean when you have an electrical current going through fluid and tissue, it's going to kind of meander a little bit. They found that it also inter interacts in the subgenual anterior cingulate cortex which is associated with depression related hyperactivity. The default mode network, which we've talked about a bunch, that's your autopilot and your default mode network is involved in rumination and self referential thought processes. So by indirectly targeting the dmn, it can help reduce some rumination and self referential thought. And then the salience network. Remember that's the network that impacts what you pay attention to what is salient in your mind, and then the cognitive control network. All of these are critical for emotion regulation and cognitive processing. So TMS may be targeted towards one particular area, but then it branches out and you can think about it as, as a network. And the network in the brain that typically sends signals to the prefrontal cortex, they're. They're connected. So when the prefrontal cortex is stimulated, those areas are going to be stimulated as well. In terms of effectiveness, atms, or accelerated TMS protocols show significant reductions in depression symptom severity. Now, accelerated TMS and rapid TMS are treatment protocols that use a more intense level of stimulation. Again, nothing like electroconvulsive therapy at all. But they're finding that when they increase the intensity of the magnetic stimulation, there are more rapid results and there is less treatment dropout and there's more patient satisfaction. ATMS protocols can demonstrate symptom improvement within just a few days. Days. A lot of times we've been talking with people about, okay, in the next few weeks, hopefully you're going to start feeling a little bit better. Not with tms, TM, atms specifically. A lot of patients report starting to feel symptom improvement. I mean, it's not, you know, a magic switch, but they start to feel symptom improvement in days. No decline in cognitive functioning has been reported. In fact, some studies have even observed cognitive improvements, such as enhanced attention and executive functioning. Well, let's think about why this might be. If we're rewiring the system, we may be unblocking some blocks. That could be it. But also when people are stressed, when they're depressed, they tend to be in a brain fog. They tend to have difficulty concentrating. So as that fog lifts of, it makes sense that people are going to be able to think more clearly and pay better attention. ATMS does show mixed results for reducing suicidal ideation. And there are other treatments that are being explored for people who are acutely suicidal. But this is an excellent approach or protocol that can be used for people with major depressive disorder with postpartum depression. With and with treatment resistant depression, it has shown effectiveness. And I don't like the term treatment resistant depression, I'll tell you, because that implies that the depression can't be healed. And what it should say is the standard treatment ain't working because what is causing that person's depression has nothing to do with how quickly the serotonin is reuptaken from the synaptic space. There's something else that is causing those depressive symptoms and a lot of times it comes back to systemic inflammation that is throwing all of the HP axes, the HPA axis, the hypothalamic pituitary, adrenal, hypothalamic pituitary, thyroid and hypothalamic pituitary gonadal axis out of whack. And that can even include menopause and andropause. When the gonadal hormones start to go down, it alters the levels of neurotransmitters in the brain and so there can and, and can lead to some systemic inflammation. So it's important to consider, instead of calling it treatment resistant depression, we need to think, well, our standard approach, which only works for about 50% of people anyway, isn't working. We must be missing something. What is causing this particular person's symptoms? Neuroimaging insights Functional MRI and PET studies suggest that changes in the brain correlate with treatment response, indicating potential biomarkers for atms efficacy. So not only are we relying on patient report, which can be affected by the, the placebo effect, they expect it to help them so they're feeling better, but they can actually go into brain imaging studies and they can see changes in the way the brain lights up to different stimuli as a result of atms. TMS is effective for treatment resistant depression. It's also effective for treatment resistant geriatric depression. GD with a clinical response rates ranging from 6.7% to 5.54.3%. And again, you're like, wow, that's a big range. Well, let's think about that again. If the problem is the communication between the neurons in the brain, then TMS could be very effective. If the problem is something else, maybe the person doesn't have any testosterone production anymore, which is throwing the system out of whack. Well, no amount of brain stimulation is going to impact that. We're going to have to balance those hormones somehow. Another thing that impacted the variability in outcomes was differences in the TMS protocols, patient characteristics and dosing strategies. When people get older, they may require higher stimulation intensities due to age related brain atrophy. As we get older and as we're stressed, we start having our brain shrink a little bit. Which is one of the reasons we talk a lot about the importance of cognitive stimulation therapy of, of staying active in older age. Because the more we stay active, the more we've got neurogenesis, the more we prevent the brain from shrinking as quickly and we can even build up some reserves. So we've got, you know, a few Extra neurons that, that we can afford to give up if we have to. At some point when we have age related brain atrophy, the scalp to cortex diff distance is reduced so your skull doesn't change at all. You know that's going to stay the same size, but your brain as it shrinks is further away from the the skull. So it requires increasing the intensity of the TMS in order to get that signal all the way and effectively to the part of the brain that you want it to get to. Many studies apparently underdose TMS compared to FDA approved protocols for younger adults. TMS in older adults has also shown to preserve cognitive functioning and in some cases even improve cognitive functioning, especially in executive fun executive areas. So again they're targeting that prefrontal cortex area which is where we do our executive functioning and by stimulating that it actually can potentially generate some neurogenesis and help the neurons communicate a little bit better. Emerging trends and recommendations Advances in neuroimaging and connectivity mapping with mri, FMRI and EEG can produce individualized TMS targeting. So people can go in and they can have their brain scanned and we know what it should look like. If it's a healthy brain and the the doctors can figure out what areas are not lighting up the way they should and then they can target the TMS for those areas for that particular individual. And that is super helpful not only for people who have history of trauma and other things, but it's also super helpful for people who've had a traumatic brain injury because the problems or the disruption disrupted areas in their brain may be very different as a result of that TBI as well as their body's adaptation and recovery from that tbi. Accelerated TMS protocols are gaining popularity due to their rapid effects and potential for reducing lengthy treatment scale schedules. Integrating TMS with other approaches may improve outcomes, particularly in treatment resistant depress populations. So again, we're going to keep hearing this treatment resistant thing come up because people who respond to SSRIs, we've done that research, these new approaches are pretty much only being used when the first line fails. And I personally have an issue with that. I think we should educate people about all the different options that are available to them. So if they don't want to go with the standard first line treatment that fails 50% of the time, they can opt for other approaches. Combining TMS can also be helpful. As I said, for example, when our hormones get out of whack, it can contribute to systemic inflammation. Inflammation. Now it can also contribute to neural Inflammation as a result, because the brain is a part of the system and TMS can help improve the basically electrical functioning and signaling in the brain. But we still have to address that systemic inflammation. People who've undergone trauma, who are struggling with CPTSD or PTSD are going to have systemic inflammation almost inevitably until that's resolved, until they feel safe and empowered. And as a result, again, we can help the brain communicate, but we've also got to address the underlying issues. What's causing that brain to have trouble communicating. Larger, well controlled trials are needed to standardize TMS protocols, optimize dosing and identify predictors of treatment responses, especially in older adults. This is still a new field. So people are still sort of experimenting, learning. There are a lot of clinics that are available that do provide this service. Now, not all insurance covers it, which can be a bummer for a lot of people. So let's look at another approach. And based on how many times I said inflammation in the last segment, I'm sure it doesn't surprise you that I'm going to say the anti inflammatory approach is actually gaining a lot of traction because we know that when we have inflammation in the body, it correlates very, very strongly with mood disorders. Causes of brain inflammation include immune system dysregulation and plays a central role in the development of depression. Overproduction of pro inflammatory cytokines, your inflammatory markers contribute to this neuro inflammation. Remember, when we're stressed for a long time, cortisol, that hormone that is supposed to suppress inflammation, loses its effectiveness. And when it loses its effectiveness, then those inflammatory cytokines can kind of run wild because it doesn't have the ability to control them anymore. Chronic psychological or physiological stress leads to HPA axis hyperactivity, overactivity of that stress response, increasing cortisol, which paradoxically may induce corticoid glucocorticoid resistance over time promoting inflammation, which is a really fancy way of saying what I just said. Over time cortisol loses its ability to suppress inflammation if it's constantly coursing through your system. And so then we have inflammation increase in the system. All right, well that's not good. Our body registers that is not good. So it turns up the stress response even more and dumps even more cortisol. So it starts sort of spinning out of control. So one of the things we need to focus on is reducing that inflammation and reducing the stress that's causing that inflammation. So the receptors can get a break basically and become more receptive. Systemic infections can trigger Peripheral immune responses that affect the brain via cytokine signaling. Remember, those are some of your inflammatory markers, the vagus nerve, or by crossing a compromised blood brain barrier. So systemic inflamma infections, and I think a lot of us can think of a few that have been, you know, prevalent recently, can actually contribute to neuroinflammation assist and systemic inflammation. Because the immune system's trying to, trying to handle it and is not succeeding. It can also cross that when we get stressed, our blood brain barrier can become more permeable, so those cytotoxins can get into the brain. Trauma during critical developmental periods alters the HPA axis regulation and immune function, increasing lifelong vulnerability to inflammation and depression. Trauma, even in the mother, can impact the fetus because the mother is, you know, doused in cortisol and stress hormones when she experiences chronic stress or trauma. And that little peanut is also being doused in those stress hormones. So we do see infants that are born to parents who were under extreme stress often are born with a dysregulated HPA axis. The beauty is it can heal. We can help them help the parents, help the child feel safe and empowered, reduce the child's unnecessary stress so the brain can heal itself. Trauma induced epigenetic modifications can lead to persistent immune system dysregulation and increased inflammation. If we don't address these changes, we can see persistent inflammation. In some cases, the trauma is long, prolonged enough or severe enough that it actually does cause some genetic changes that can make the person, as I just said, more susceptible to immune system problems and inflammation in the future. Okay, well, we may not be able to change that. We can't rewire that DNA or rna. We need to help the person learn how to adapt so they can mitigate anything that might trigger the immune system dysregulation and inflammation. Gut microbiome alterations increase inflammation through increased gut and blood brain barrier permeability. So the gut takes in food, it breaks it down, and it produces byproducts. You know, there's always waste in a production process. Those byproducts can be toxic. And when the gut becomes more toxic and the blood brain barrier is more toxic, then these endotoxins are able to kind of, you know, filter in to places where they're not supposed to be and we don't want them and cause inflammation. A higher bmi. Now, I don't like bmi. The way we have historically measured it in the articles, they still refer to it as bmi. What we're looking at is a Higher adiposity, a higher percentage of fat or adipose tissue compared to other tissues. Increased levels of fat tissues are associated with increased estrogen and increased inflammation. So when we're talking about anti inflammatory approaches, we need to explore what is causing inflammation for this person. Is it trauma, is it genetic? Is it from their gut microbiome? Is it a result of having too much adipose tissue that's causing estrogen dominance? There's a lot of things that can can cause inflammation. Pro inflammatory cytokines interfere with serotonin, dopamine and glutamate pathways, reducing neuroplasticity and altering mood regulation. So when we have those pro inflammatory cytokines just circulating through our body, it's going to interfere with our body's ability to regulate those neurotransmitters and it's going to interfere with our body's ability to remodel the brain. Neuroplasticity is the, the brain's ability to remodel itself. Well those pro inflammatory cytokines, those are stressors. So we're actually, we've actually got kind of a neurotoxic environment instead of a neurogenesis type environment. Inflammation affects key brain areas involved in mood regulation such as the prefrontal cortex, amygdala and the hippocampus. When we start getting inflammation, it's not real particular, it goes everywhere. And we know the prefrontal cortex, that's our thinking, our reasoning, our attention, the amygdala, that's our mood, emotion, fear processing hippocampus, fear processing sensory. So we've got a lot of very crucial areas of the brain that when they become inflamed are going to cause problems in mood regulation. Reduction of of neurotrophic factors is another issue in the brain. When we have inflammation, inflammatory cyto kindes reduce the level of brain derived neutrophic factors crucial for neuronal survival and plasticity. We need to have those buffers in there to protect our brain against excitotoxic environments. And when we've got inflammation, the buffer can't keep up so it becomes neurotoxic. Now let's talk about how depression causes neuro neuroinflammation. We've talked for a while about different things that can cause inflammation, that can cause the body to have difficulty regulating neurotransmitters and cause depression. But how does depression cause neuroinflammation? Chronic depression maintains HPA axis over activation and you may be scratching your head going when I'm depressed, I got no energy. I don't. The stress response doesn't seem to be there. Ah, but it is. We've talked in other videos about the flat and the furious. When our HPA axis becomes disregulated, the body becomes less responsive to what we'll call minor stressors. But when there's a major stressor then there's a tsunami of stress hormones that pushes us into the frantic or furious. So we go from flat to frantic or flat to furious Underlying all that. When we've got inflammation, even if we're not feeling stressed, our body is stressed. And when our body's stressed, that HPA axis stays turned on and that sustained cortisol secretion and immune system modulation leads to problems and, and perpetuates inflammation. Chronic inflammation leads to that sensitivity of the glucocorticoid receptors impairing cortisol's anti inflammatory effects which exacerbates neuroinflammation and depression. So we're back to the same place we were before. When cortisol can't do its job and we start having inflammation, there's going to be a problem. So when we think of people as depressed, we often miss the fact that that HPA axis is still on overdrive in the background and we need to help them strengthen their vagus nerve, strengthen their, and we'll get there in a few minutes and strengthen their ability to turn on that parasympathetic nervous system that rest and digest which will turn off the fight or flight or the HPA axis. So what can we do? Anti inflammatory medications. Now most of us, I don't know about you, but most people have difficulty tolerating anti inflammatory medications. Yes, it's systemic, yes, it can help a little bit for some people, but it really doesn't do a bunch. Some physicians will use it as an adjunct, especially initially to help the person feel a little bit better, feel less achy, feel less, you know, heavy if you will. But that's not a long term solution. All you're doing is basically doing, trying to do cortisol's job for it and suppress the inflammation. But that cortisol is still running wild. We need to figure out why that HPA axis is dysregulated and help it heal. Moderate aerobic exercise. And I know people hate to hear this, especially when they're depressed. They're like, you're kidding me, right? You expect me to go to the gym? Well, maybe not the gym, but moderate aerobic exercise modulates cyto kind levels and increases anti inflammatory markers. It Reduces systemic inflammation, improves mood and enhances neuroplasticity. All right, so that's a bunch of blah blah, blah, big words. Moderate aerobic exercise. Light to moderate aerobic exercise actually helps reduce cortisol. Actually helps reduce cortisol. Now I'm not talking about going to the gym and you know, lifting three sets of 10 to failure or something. No, number one, that's not aerobic most of the time. What I'm talking about is walking around the, walking around the park, walking around your neighborhood. That actually does increase anti inflammatory markers. We often talk about the parasympathetic nervous system as rest and digest, right? But really it's rest, digest and repair. When the HPA axis is active, when we're under stress, our body is not repairing on the fly. Our body's saying, okay, let's suppress that inflammation until we can have devote our energy to repair. So when we are triggering that relaxation response, we're triggering the repair response and we're telling the inflammatory cytokines, we got this, you know, go back to your, go back to where you need to be. So we start to see a reduction in inflammation. Anti inflammatory diets are huge, rich in omega 3 fatty acids. Fruits, vegetables and whole grains have been reduced to depressive, linked to reduced depressive symptoms. Mediterranean style diets, what they're talking about, lots of olive oil, lots of walnuts for example, and lots of colors. The darker, the richer and the more numerous the colors that you're eating, the more antioxidants and anti inflammatory chemicals you're getting into your body. Probiotics and gut microbiome repair with probiotics or prebiotics may also help reduce systemic inflammation and improve depressive symptoms by modulating the gut brain axis. A lot of our neurotransmitters are made in our gut. Up to 90% of your serotonin is made in your gut. And if your gut microbiome, if the workers in your gut are not healthy, you may not have the, or you don't have the right workers to make serotonin, then you're going to have a problem. So by healing the gut microbiome and healing the positive or the beneficial microbes in your gut, it allows your gut to take in the food that needs to be broken down, break it down effectively and send it to where it needs to be. Stress reduction in each piece of life. And the book that I wrote and I, I distributed the other day, well not the other day, it's been a few weeks on healing your nervous system has a lot of suggestions for stress reductions in each piece of life. Ultimately, your stress response, your HPA axis is going to be activated when you are under stress. Physical stress, sleep deprivation, poor nutrition, pain, illness, all of those are stressors. And when those are going on, you're going to have increased HPA axis activation. Interpersonal stress, emotional stress, mental stress. We talked a few a couple months ago about how people with hearing loss actually have more inflammation as a result of excess HPA axis activity because they're straining to hear. They have such a high cognitive effort to try to hear and understand what's being said that it actually contributes to increased HPA axis activation, inflammation and neurodegeneration. So physical, interpersonal, emotional, cognitive, and we can't forget environmental stress. Those are your toxins as well as your sensory environment. If it's too hot, it's stressful. If it's too cold, it's stressful. We want Goldilocks. If it's too bright or not bright enough, you know, we're again, we're looking for Goldilocks, but everybody's just right is not the same. My husband and I are very different as far as temperature is concerned. I'm about 15 degrees. I wanted about 15 degrees cooler than he actually likes it. And at any given time. So we've had to compromise over the years. But knowing what works for you and reduces stress is important. I remember when my son was little, he used to overheat really easily and he would get so angry. I mean, he was when he was an infant and the first thing we would do is pull off his little socks and try to help him get cool. And as soon as he'd cool down, he would calm down. And so you could see that HPA axis just, you know, right in front of your eyes. Transcript Transcranial magnetic stimulation, like we talked about earlier, also reduces neuroinflammation by modulating brain excitability and altering cytokine production. A lot of these, you're hearing me talk about things that overlap. Why do they overlap? Because they're trying to basically accomplish the same thing. They're trying to reset the nervous system. But we need to figure out what's causing the inflammation and what's going to work for this person to help reduce that inflammation. Vagus nerve stimulation is another approach to reducing inflammation because as the vagus nerve activates, as that parasympathetic nervous system rest, digest and repair activates, we start seeing cortisol go down and the nervous system start to heal and become more responsive to cortisol again, if you will. We want cortisol to be able to suppress inflammation, but, but ul first we've got to get rid of our tolerance to it. We've got to get rid of our tolerance to it. And we've talked in other videos and I've made the analogy before about alcohol and alcohol, the first couple times you drink it, you may be able, may, may be able to get buzzed off one or two drinks. If you're drinking regularly, over time your body becomes tolerant to it, your body becomes resistant to it. It, your body doesn't even pay attention to the stimulation from the first couple of drinks. It's not until your blood alcohol level gets up to like, you know, 0.1215 that you start feeling buzzed. The same sort of thing is true with insulin. It's true with cortisol, it's true with all of the chemicals in our body. If the receptors are constantly being bombarded by it, eventually they're going to ignore it. They're going to say, no, you know, go away, you bother me. Until the intensity of those of that chemical is turned up and the receptors just can't ignore it anymore. So Vegas nerve stimulation is really good because it helps the person develop better vagal tone and helps the person basically manually override that stress response and say, you know what, this is not something we need to be stressed out about right now. We're not in objective danger. And so you're reducing the cortisol in the body and you're giving those receptors a break. The gut microbiome consists of trillions of microorganisms, including bacteria, viruses, fungi, protozoa, which primarily reside in the gastrointestinal tract. These microbes significantly influen digestion, immune modulation and brain function. Who knew all that stuff going on in your gut affected everything? Now wonder when you get, why when you get the flu, you have a hard time thinking clearly. When your gut gets out of whack, it can be a problem. Now, I didn't put a bunch of research in here on it, but it's also important to remember when you take antibiotics, antibiotics are going to go in and they're just going to wipe things out. It's not that the antibiotic is going to specifically target streptococcus or staphylococcus or something. It goes in and at best wipes out all gram negative or gram positive bacteria. Or you take one of the, you know, really strong antibiotics and it goes in and wipes out everything. Well, what are we wiping out? We're Wiping out a bunch of that bacteria in our microbiome, a lot of it good. We're taking out the good guys with the bad guys. And that can be problematic. They find people may have more mood symptoms for up to six months. And after taking antibiotics and some people's microbiome two years later still hasn't restored to the same balance it was prior to taking the antibiotics. The gut microbiome regulates digestion and immune responses, synthesizes vitamins and interacts with the brain through the gut brain axis. We have that vagus nerve that wanders through our body and is attached to most of our major organs, but especially our gut. And the vagus nerve communicates to the brain what the status of things down here is. And if it's getting toxic down there, the vagus nerve says, hey, this is no good, we're under stress, we're under attack, we got a problem. Or it sends the all clear signal. The vagus nerve acts as a communication superhighway between the gut and the brain, influencing immune responses, gut motility and neurotransmitter production. Think about when you get really stressed and to not get too graphic. A lot of times when we get really stressed, our vagus nerve is not kicking in because our, our HPA axis is kind of taking over because we're really stressed. What happens to your gut motility and, and for a lot of people it speeds up significantly. For some people who have irritable bowel syndrome, it may actually go the other way and slow way down, but it changes dramatically. And that is partly because the vagus nerve is communicating to the brain that we need to alter, basically alter the crew that's in the gut making hormones and neurotransmitters. I said earlier 90% of serotonin is produced in the gut, modulated by gut microbes like enterococcus and Streptococcus. I know Streptococcus strep bacteria a little bit can be useful, especially in that anaerobic environment. GABA is produced by Lactobacillus and Bifidobacterium series species influencing stress and anxiety responses. Well, we know GABA is our sort of internal volume and it's important to recognize that it is produced partly in the gut and part of if we don't have those microbes in our gut, then they're not going to be able to break down the food to make GABA and then we're going to have a problem. Over 50% of dopamine is synthesized in the gut and influenced by bacteria like Staphylococcus, your staph bacteria. Again, I know it sounds really gross, but really in that anaerobic environment those microbes can thrive and actually be beneficial. But obviously it's in very, very small amounts compared to, you know, other situations in terms of the microbiome and its influence on depression. When the microbiome gets out of whack, we call it dysbiosis. And dysbiosis leads to something we call leaky gut, which I talk a lot about it in the, in the video on, on gut health. So if you want to know all the nitty gritty details, you can go watch that video. But ultimately the mucus that lines our gut becomes much more permeable, becomes and, and the junction between the cells in our GI system become looser. So your toxic material, your waste products can actually kind of seep out. Which, you know, I think is gross too. But this, when that happens, your body says, oh, toxins are here. Systemic inflammation starts to happen. This also leads to disrupted neurotransmitter synthesis contributing to depression. If we've got a bunch of ickies leaking out and we don't have the right bacteria able to in the, in the gut able to make the serotonin, then we can start having problems with balancing neurotransmitters in terms of depression in the microbiome. Chronic stress alters gut composition, reduces microbial diversity and increases pro inflammatory cytokines. Now remember, even when somebody's depressed, they're in that flat stage. They're, they feel hopeless, helpless, no energy in the background. The HPA axis is still often turned up because there's systemic inflammation, because there is something wrong in the system. And that chronic stress of the depression is going to increase inflammation and reduce the microbial diversity. It act we actually start seeing the number of good microbes drastically decrease. They quit. They're like, hey, you know, I'm not needed here, no need to make serotonin right now. Ain't nobody happy, so I'm going on strike. The fetal microbiota can also be transplanted. Now this is a very new technique, but it has been shown to be useful in people who are particularly struggling with, with treating the depression. So trans transmitting the microbiome of somebody who is healthy in, into the microbiome of somebody who is depressed has shown to help in improve mood and do not do that at home, do not do your own, do not. And I know there are videos out there, don't know it has to be done very specifically, very carefully and very surgically in order to do it effectively and not harm yourself. So short chain fatty acids produced by the gut bacteria are anti inflammatory. The good gut bacteria, when that is flourishing, you're, it's producing as a, as a side effect these short chain fatty acids. These short chain fatty acids are anti inflammatory. So that's great. We just, you know, extra bonus. And it influences brain function by modulating the immune responses. If there's not as much inflammation, then the immune system doesn't have to be nearly as active. It maintains the blood brain barrier and helps regulate neurotransmitter synthesis. Dysbiosis or disruption of that microbiome causes tryptophan, one of the proteins, amino acids that we eat, to be broken down into neurotoxic metabolites which are implicated in depression. Now that's really interesting because tryptophan can be broken down into positive metabolites, but under stress, the microbes that act on the tryptophan actually turn it into a toxin. Yikes. Probiotics are beneficial bacteria that can improve mood, regulate the HPA axis and reduce inflammation. They did do a study and you know, poor mouse, I'm. Or rats, I'm sorry, breaks my heart. But they did do a study with some rats where in half the rats they cut their vagus nerve in their gut and half the rats they didn't. And in that they gave them both probiotics. The rats that had their vagus nerve cut showed absolutely no change in response to the probiotics. The rats that did not have their vagus nerve cut showed improved mood, improved activity, improved attention. So there was a huge change in the intact rats, if you will. Obviously it's not ethical to do that on humans, but we can extrapolate that. Healing, you know, healing the gut microbiome, getting the right probiotics in there can be very beneficial. I will say like everything else, Goldilocks principle, you actually can overdo it on probiotics too. You can eat, I found out the hard way at one point, you can eat too much yogurt and you know that's not going to have super long lasting consequences, but it can be unpleasant for a short period of time. So in our, in our society where we think if one is good, two must be better and three must be great, that ain't it. You want to start with a low dose and if it works great, maybe increase it a little bit, but don't go, don't go bananas with it. Prebiotics are non digestible fibers that Promote beneficial bacteria growth, enhancing mental health. Inulin is a prebiotic that is prevalent in chicory root. So if you drink chicory tea, you're getting some inulin. There are a lot of other prebiotics that are out there. Again they're non digestible fibers but they get down into the gut and they can be consumed, if you will by the Ben. Beneficial bacteria. Diets rich in fiber from prebiotics and whole grains and those things, polyphenols, those are the basically colorful foods. And fermented foods support microbial diversity and reduce inflammation. When we're talking about fermented foods, we're talking about everything from sauerkraut to kefir. Whatever it is that you like, fermented foods, if you can incorporate it in your diet can really help the microbiome. As I mentioned earlier, fecal microbi microbiota transplantation can in extreme circumstances restore a healthy microbiome and improve mood disorders and vagus nerve stimulation. Now we've talked a lot in other classes as well as this one about vagus nerve strengthening but vagus nerve stimulation is actually also can be done and we're going to talk about it in a few minutes through implantation of a device kind of like a pacemaker that regularly stimulates the vagus nerve. They've done studies with that and found it to be super helpful. We'll get to that. Phytopharma therapy for depression Basically using herbal remedies and plant derived compounds to manage depression. These phytochemicals modulate neurotransmitter path pathways, reduce oxidative stress and inflammation and address both neurochemical and inflammatory inflammatory contributors to depression. If you are taking an over the counter supplement, recognize that it is not quote harmless. If you're taking an SSRI, recognize that it can and probably will interact with these things. So you need to be very, very careful not to trigger serotonin syndrome. Saffron modulates serotonin, dopamine and norepinephrine reuptake. It has anti inflammatory actions and anti antioxidant properties. Lemon balm enhances GABA receptor activity, reduces anxiety and promotes relaxation. Lavender modulates the serotonin system and enhances parasympathetic or your rest and digest activity and reduces cortisol levels. Well if you're enhancing parasympathetic you're going to reduce cortisol. Gingo biloba improves mood through antioxidant effects, enhancement of blood flow to the brain and modulation of the HPA axis. It also influences monoamine Neurotransmission monoamines are your neurotransmitters. So it improves communication and, and transmission of signals from your as a result of your neurotransmitters. Helps with inflammation, helps with blood flow. All of these things have very similar characteristics. Panax ginseng regular. Regulates HPA X's activity, reduces inflammation, promotes neurogenesis, the creation of new brain cells and modulates dopamine, serotonin and norepinephrine systems. Now, how much you take, how often you take it, whether it's even safe to take, that's something you need to talk about with your doctor. Ketamine and esketamine are two more things that are coming on the market or have been on the market in, in terms of ketamine for quite a while right now. Ketamine was originally developed as an anesthetic and oftentimes it was used in veterinary medicine. It produced rapid antidepressant effects and they found that it could be administered through, through an IV to, to address acute depressive and acute suicidal ideation in, in people. Well, that's great, but it's not a resolution. It is an acute thing. Sort of like you use naran for something. For somebody who's OD'd on opioids, this using ketamine to address suicidal ideation, it's a very, very short term intervention. I won't even say fix. Esketamine is more potent with fewer dissociative effects and administered as a nasal spray, it is actually approved for use with treatment resistant depression. So esketamine is out there, but it's very regulated, you have to get it by prescription and there are only a few places that actually are able to dispense it. Both drugs show significant improvement in depressive symptoms within hours to days, unlike traditional antidepressants which take weeks. One thing you need to be aware of with ketamine though is a lot of people who are going to these clinics where they can get ketamine to feel better. Ketamine for depression. If it's not very, very tightly controlled and regulated and ethically prescribed, people can become dependent on the ketamine. I've had a couple of patients come to me who had been taking ketamine regularly for months and they're like, I can't function if I'm not getting my ketamine dose. And I'm like, well that, that's, that's a problem here. So we do need to be careful with that. Esketamine doesn't have nearly the Same dissociative effects and, and problematic effects, which I think is why that one has become available for and approved for treatment. Resistant depression. Another issue that both contributes to depression as well as systemic inflammation is the disruption of sleep and circadian rhythms. I know, right? It's amazing that sleep in your, your sleep and circadian rhythms can actually cause depression. The circadian rhythm or the circadian system coordinated. Can't speak anymore, sorry. The circadian system coordinates sleep, wake cycles, hormone releases and mood regulation. So when your circadian rhythms get out of whack, all of those things are going to get out of whack. Disruptions in circadian rhythms, often due to irregular light exposure, shift work or sleep disorders, can lead to desynchronization between your internal clock and the external environment. Light, temperature and activity all work together to help set your circadian rhythm and provide clues to your body about when cortisol is supposed to be high and when it's supposed to be low. Sleep disturbances can worsen emotional dysregulation and cognitive impairments, increasing vulnerability to chronic stress, which will further impair sleep and circadian rhythms, inflammation and depression. So I've said it before, I'll say it again. If your patients are willing to do only one thing. Focus on sleep and circadian rhythms at first, because a lot of people find huge amounts of relief when all of their hormones and neurotransmitters and signaling actually gets into into a rhythm. Chronic sleep deprivation activates the HPA axis, leading to elevated cortisol. Dysregulation of the cortisol leads to glucocorticoid resistance, which increases inflammation, disrupts feedback mechanisms that regulate the stress response. So we've heard this three times already. In this presentation, inflammation influences the gut microbiome, neurotransmitter metabolism, neuroendocrine function and neuroplasticity, all of which are critical in mood regulation. When you've got inflammation, a lot of times you've got pain. It may just be general aches, but it's pain. And pain keeps us from getting good sleep. And when we don't get good sleep, it throws the circadian rhythms out of whack, which is triggers a stress response and increased cortisol. And so it's a cascade effect, which is why I harp on the fact that we look at a symptom, but we don't want to just put a band aid on the symptom. We want to say what is causing this symptom? What is causing this sleep disruption? What is causing this person's circadian rhythm to be out of whack. In terms of addressing things. A sleep routine. A sleep routine with the same activities every day, the same temperature at night, and turning down the lights when it's time to start getting sleepy is really important. Getting rid of that blue light, having very dim lights in the evening and is super important to reducing cortisol and triggering melatonin release. Light therapy, which includes bright light in the day, dim light at night, blue light reduction, especially two to four hours before bed. All three of these can work together synergistically to help reset those circadian rhythms. Melatonin supplementation is often used. Talk with your doctor before taking any supplements. And vagus nerve activation activities, I. E. Relaxation activities, are also helpful. Why? Because as the vagus nerve is activated, cortisol is going to go down. As cortisol goes down, melatonin can go up. So we see how these things can work together. Not everybody likes yoga or stretching or whatever. Whatever works for them to start slowing their breathing and triggering that vagus nerve and can be really helpful. Progressive muscular relaxation for people who don't have trauma histories can be really helpful at triggering that vagus nerve and helping people get to sleep. Genomic sequencing looks at DNA to find genes that affect how your body processes antidepressants and responds to them. It identifies gene variations that influence how well you produce, transport or respond to mood related chemicals. The information on this is really promising. A lot of people are finding that. They get this test done and it comes back and it says, well, Zoloft isn't going to work for you. And they're like, yeah, it didn't. I was on it and it was awful. This, though, over here may work better. And everybody I've talked to who's had it done, literally everybody has said that it really helped them find an antidepressant. They that was more effective. It may not have done everything, but it was much more effective. So they didn't have to try. 4, 5, 6 different antidepressants. Oxytocin helps regulate emotions and stress hormone levels. Like cortisol. Oxytocin goes up, cortisol goes down. This can help reduce feelings of anxiety and emotional distress. Also, as cortisol goes up, serotonin and GABA go down. So as oxytocin goes up, serotonin and GABA also tend to go up. Oxytocin strengthens the connection between the amygdala, our fear processing area, and the prefrontal cortex, leading to better mood stability and less emotional Reactivity, so they're talking more. And the amygdala sends a signal to the prefrontal cortex. The prefrontal cortex says, nah, this is nothing to worry about and it's all good. Instead of getting stuck in that auto loop where the person feels anxious and starts to panic. Oxytocin nasal sprays have shown mixed results for use in humans with depression. It's shown great results with some other things. Depression, not so much. Chiropractics is also a new field that we're looking at that can help restore proper alignment and movement in the spine, reducing tension, which reduces pain and helps us sleep, and improves communication in the nervous system by improving spinal alignment. Chiropractic care may improve the function of the vagus nerve, which is responsible for helping to trigger that relaxation response. Limited evidence exists for the use of chiropractics at this point. Some people love it, some people hate it, but there's not a lot of really good quality evidence. But it is something we're talking about. Vagus nerve stimulation, as I mentioned before, can be done via an implanted device that sends periodic signals to the vagus nerve. The electro electrical stimulation increases activity in brain areas related to mood regulation, such as the amygdala and prefrontal cortex. It boosts the release of neurotransmitters and reduces inflammation by decreasing the production of inflammatory cytokines and reduces the stress response. So again, the cortisol is not constantly circulating and the body can start to become less resistant to the to to cortisol when it's released. Over time, vagus nerve stimulation helps retrain the brain's neural circuits to respond more positively to stress, improving emotional regulation. Strong evidence exists for using the implanted VNs for treatment resistant depression. Lots of clinical trials have shown good evidence. Other methods of vagus nerve stimulation can also be used through vagus nerve activation activities like yoga, deep breathing, meditation, biofeedback, and auricular vagus nerve stimulation, where you're stimulating the vagus nerve that comes out through the trigeminal nerve and like right around your ear. Acupuncture stimulates nerves, muscles and connective tissues that promote natural healing processes. The needle insertion activates the body's pain relief mechanisms, leading to the release of endorphins, which improve mood and reduce the perception of pain. As endorphins go up, dopamine goes up and we also see serotonin start to go up. So by triggering one, you're increasing some of his buddies. The needle insertion also reduces levels of cortisol as the endorphins go up, cortisol tends to go down, increases levels of serotonin and dopamine and reduces inflammation, lowering the levels of pro inflammatory cytokines. Research has shown that acupuncture can be as effective as some antidepressants for mild to moderate depression, especially when combined with other treatments. Acupuncture is going to work sort of in the moment to help release that release those neurotransmitters. But in the long haul we need to address the underlying cause of that inflammation. Evidence for acupuncture in the treatment of mood disorders is growing, but more large high quality studies are needed. Terms of oldies but goodies. These are not new treatments, but things we need to rule out. If somebody has depression, we need to have their gonadal hormones tested, their thyroid hormones tested, their blood tested for nutrient deficiencies like anemia, B12, D well iron B12 and D we need to screen them for irritable bowel syndrome, Crohn's disease or colitis. Inflammation in the gut is going to lead to systemic inflammation and alcohol consumption, which causes inflammation in the gut. Diabetes, chronic pain, hyperparathyroid, chronic fatigue syndrome, long C and hearing loss are also all things that can contribute to symptoms of exhaustion and depression and systemic inflammation. Depression results when the hormones and neurotransmitters get out of balance. We need to figure out why are they out of balance. One of the main causes of this imbalance is inflammation caused by stress in one or more pieces of life. Typical pharmacotherapy does not address inflammation or sympathetic dominance, it does not strengthen the vagus nerve, and it does not reduce inflammation. Standard CBT therapists often fail to address non cognitive sources of inflammation like sleep deprivation or chronic pain. Whatever's going on. For many, treatment resistant depression simply means the professionals did not identify the right cause of the problem. I don't want people to feel hopeless by calling it treatment resistant depression. That sounds like we can't fix it. Well, the old way ain't going to work, but it doesn't mean it's not fixable. It needs means. We need to figure out what's causing your depression. Treatment must be holistic and individualized to be effective. All righty, back to questions. Can TMS be used to treat alcohol related brain changes? Yes, it can. TMS can be used for just about anything. And let me see if I can pull something up for you. I'll just send you this search that shows some of the ways that TMS is being explored in relation to recovery from substance Use repetitive deep TMS and alcohol dependent patients. Halts the progression of white matter changes and early abstinence. That's super important. That, that's mind blowing. So there's a lot of stuff that TMS actually can be really helpful for. Great question. I agree with you, Dr. Darlene. The recommendation for keto must be made very carefully. I can't handle it. When I try to go, go keto, I start having all kinds of increased issues with my heart and it's, it's very problematic. Um, I can do, you know, a Mediterranean diet with no problem. But we do need to consider the individual and make sure that they're consulting their physician and or a dietitian before they start making sweeping nutrient changes like that. Thank you so much, Oliver, for your support of the channel. You have been such a godsend and a great supporter for many years and I really appreciate you. In terms of a protocol for working with clients who are receiving tms, obviously working in conjunction with the TMS provider, having them log monitor their baseline symptoms can be really helpful. But just like any other treatment, helping them identify if they're using TMS for depression, help them identify their triggers for depression and things that have been different when they weren't depressed and what they can do in order to start making small changes. I typically will go through the pieces mnemonic with people to try to identify sources of stress in their life. And I'll say, where do you want to start? Any change you make in any of these areas is going to have a positive effect, most likely. So where do you want to start? And that. And if they wonder why, then I explain the whole stress and inflammation connection and everything. But ultimately a lot of it has to do with the client having faith in the process and being motivated. They're not going to continue to do things that they're not motivated to do or they, you know, like journaling. For me, I'm not a journaler, so I was never effective at being compliant with regular journaling. But exercise, yeah, I'll do that. Not a problem. Finding things that people are willing to stick with, especially in those early days of treatment when their depression is just oppressive can be huge. Because as they start to feel improvements, they're going to have more energy, they're going to have more, more motivation. And I typically, with depressive patients, unless they really want to go there, I typically want them to get a little more energy and start feeling better before we dive into intense trauma processing, that kind of stuff, because that's exhausting and that will trigger stress reactions. So I want them to try to heal their nervous system a little bit and feel somewhat recuperated before we start trying to run that marathon. And Adriana's right. This presentation was specifically about depression. Bipolar is a whole different presentation. And bipolar depression is by no means the same as unipolar depression. And I agree with you, Enola. Exercise comes in many different forms. I will go out and garden, and you'd be surprised at how high you can get your heart rate up. Hoe in a garden, playing with your dog, playing with your kids, cleaning the house, you know, mopping. Actually, I can work up a sweat when I'm mopping. Whatever it takes, especially if you put on your headphones and you're rocking out while you're cleaning the house, you can usually, you know, hit that level of moderate activity. So that's a great point that we need to find something that the individual is willing to do and even maybe looking forward to doing. There is a lot of. Andrew, there is a lot of research coming out about different alternative drugs that can be used to treat depression, from mushrooms to LSD and. And a lot of other different chemicals. So there is a lot of research or research being done, but there really isn't a lot out there that I would consider a. A best practice, especially not one that's really accepted widely in the US at this point. I hope that some of that is going to change rapidly, but we shall see. Alrighty, everybody. Thank you very much for being here. I appreciate your attention, I appreciate your questions, and I will see you next week, same time, same station.