Is Depression a Chemical Imbalance?

[Music] Hello and welcome to the Psychiatry and Psychothermic Podcast. I'm here to talk about getting rid of burnout, increasing job satisfaction, and feeling like an expert in what you do. One thing that created a lot of burnout in angst for me was trying to get continued medical education right at the last minute. So why not join the CME membership and do CME while listening to this podcast? Go to Psychiatrypodcast.com, sign up, sign in, take the test, and the certification is emailed to you in seconds. Alright, welcome back to the podcast. I am joined today with Dr. Cummings. Dr. Cummings and I have no conflicts of interest. Dr. Cummings, welcome back to the show. Hello, I'd like to be back. Indeed, it should be an interesting show today. Yeah, today we're going to be talking about a recent paper that came out in Nature magazine. It was titled "The Serotonin Theory of Depression, a Systematic Umbrella Review of the Evidence" by Monzechev at all, just 2022. And in this article, the author concludes the main area of serotonin research provide no consistent evidence of their being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lower serotonin activity or concentrations. Further, he says, "Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentrations." So, Dr. Cummings. Yes, what do you think? I frankly think he is right in some ways. I think the article was intentionally stated provocatively to get people's attention. But frankly, the monoamine, including both serotonin and norbeneffron, hypothesis of depression has been fading into history now for the last 25 years. The monoamine hypothesis arose in the 1950s, first with the discovery of a mipper mean, and then later the other tricyclic antidepressants, as well as the monoamine oxidase inhibitors. Frankly, people saw an improvement in some individuals who were depressed with these medications. They knew what they did. They knew they increased serotonin and norbeneffron. And therefore, they somewhat simplistically made a model which said, "Well, there must be a deficit in these monoamines, and that's the underlying cause of depression." Frankly, that was a relatively simplistic, and it turns out very incomplete model of depression. When I read this paper, I wasn't that shocked or surprised. We've done a number of episodes talking about the complexity of depression, complexity of treatments. And I'm excited in this episode to dive into some articles that you sent me that discussed some of them old, and you'll see from these articles how old this idea that depressed people of low serotonin is. I don't think I've ever, in my professional life, said to a patient, "You have low serotonin levels and you're depressed." I've heard that from commercials maybe, or old psychopharm commercials, but that was something that was before my time. I was not before my time, because I'm old, but indeed, the idea that depression was simply a "chemical imbalance" close quotes, was a vast oversimplification of the pathophysiology of depression. I read some of the articles I sent you were very intentionally older articles that point out that there were other very important elements leading to a much more elaborate model of depression. As the nature article points out, and you can find similar data for Norip and Eufren, there's not really much robust data suggesting that the primary defect that occurs in the brain for major, depressive disorder, or for that matter for bipolar depression, is a result of a loss of synthetic or secretory capacity by neurons in the Raffa nuclei for serotonin. So, you said in an email to me, "Most research suggests the primary pathology underlying depression lies in the limbic system, circuit of papets and associated structures rather than in serotonin or epinephrine or dopamine inputs to the limbic system." Can you tell me more about that? Yes, and in fact, one of the papers I would refer to that I sent to you that you'll post was an article called Synaptic Disfunction 2012, so it's 10 years old now, came out of Yale. And it looked at the data about depression and starts with the recognition of what had become very common in the neurosciences that one of the chief characteristics that occurs in major depression is actually a loss of synaptic connectivity, particularly atrophy of dendritic spines during major depression. That's associated with a decrease in neurotrophic factors as well as a decrease in overall metabolic neuronal activity in the limbic system is on the order of 30 to 40%. Again, pointing to the fact that the changes that are going on are much more centered in the limbic system and its dysfunction. Animal models have suggested that a pretty good replica model for this is essentially chronic stress models and rodents have been able to replicate many of those same changes in rodent brains, leading people to think that perhaps what occurs in major depression is someone who is perhaps genetically vulnerable, meets an ongoing stressor, which gradually leads their limbic system to get further and further out of homeostasis. Until essentially the function of the limbic system deteriorates to the point that the modulatory neurons in the Raffa nuclei and locusts, really is the serotonin and norepinephrine neurons, it's beyond their capacity to push the limbic system back into homeostasis. And that's one clinical symptoms of depression emerge. Okay, so in this 2012 paper by Ronald Duman and George Eganian. Eganian, yeah, it's a difficult name. I've actually met him once. He pronounces it Eganian although the print version might be hard to tell. So they reviewed that depression is associated with reduced size of the prefrontal cortex, hippocampus, with decreased neuronal synapses in these areas. And the damage has been shown to reverse with ketamine as well as other things like antidepressants, exercise, environmental changes. A lot of this, that's like a summary of a lot of things that go on. Anything you would add to that or. Well, and indeed that's one of the reasons I chose this paper is it's a good review of the thinking about depression up to that point. Even though their focus was on ketamine and its rapid response, it goes nicely over most of the things we found that can be beneficial for depression. I think one of the things that's stated in this article that's also repeated in the Nature article is that it's clear that if we're talking about a treatment in which you're trying to fix the limbic system by remotely modulating it with North and Eferin or Serotonin or both, that's an inherently limited approach. It often as they point out takes weeks to months to get a good therapeutic response. A third of people don't respond at all to antidepressants. Another third have what in the literature has been called a response, meaning a 50% reduction in symptoms, but that can still be a long way from recovery. And only about a third actually recover from their depression and response to antidepressants and treatments. Things like ketamine are faster and things like ECT are more effective. What's been associated with them is they seem to be more able to stimulate synaptogenesis. And in particular to turn on rapid response genes that in turn activate structural genes in the limbic system neurons and actually start replacing things like receptors and. transport systems within the cells and so forth. And that may be why those treatments are somewhat either more rapid or more effective than the classic anti-depressants. Yeah. One of the things I've heard as well on social media on TikTok lately is that depression doesn't cause any changes in the brain. And that's simply not true. I know, I think this paper illustrates it well because they talk about how chronic unpredictable stress decreases neurogenesis, dendrite complexity, spine density in the prefrontal cortex, chronic stress leads to hypertrophy in the nucleus accumbens, where we have our motivation, our reward pathways, and the amygdala. So there seems to be a hypertrophy there. Yeah. And those may well be those subsystems attempting to push the rest of the limb existing harder. In other words, trying to push it back into normality. So they high hypertrophy as a result, while things like the prefrontal cortex and the hippocampal complex atrophy. They looked at this one rat study, and seven days of 20 to 30 minutes of restraint. So they restrain the rat in a cage so it can't move, led it to atrophy of the prefrontal cortex permittal neurons. Can you tell me like why do you think the prefrontal cortex specifically is sensitive to seven days of this kind of stress? Basically, the prefrontal cortex, of course, is where, well, certainly we, and very likely rats experience distress in terms of interpreting our environment. Rats are especially sensitive to being restrained. They are used to being able to move freely. For them, being restrained is often associated with the fear of being consumed or eaten. And consequently, it's an exceedingly stressful condition for them to be in it, to be that way for several days. Essentially causes a huge stress response. You know, their HPA axis kicks their ACTH through the roof. Their cortisol levels climb to the point that they're experiencing cortisol feedback that is actually neurotoxic. And as you may recall, one of the things cortisol does is enter cell nuclei and tends to turn off some genes. And that may be the precursor for this sort of atrophy. There are steps in there missing that we still haven't elucidated, but that's at least the thought about what may be the triggering mechanism for stress leading to what has been termed learned helplessness, dysphoria, depression, essentially the stress diathesis model of depression. So glucocorticoids in stress also decrease brain drive, no trophic factor in the prefrontal cortex and hippocampus. Yes. And the autopsies that people with depression show lower BDNF. Yeah, it's clear that you know, brain drive neurotrophic factor as well as glial cell drive neurotrophic factor are both necessary. Our neurons depend essentially on a continuous flow of those peptides to maintain health. One of the characteristics of neurons is that frankly, as cells go, they're pretty limited. They are designed to transmit information, to respond to neurotransmitters. But these are cells that can't even manage to make all of their own internal necessary products. They depend on other cells to do that. They depend on other cells to make trophic factors for them. If those trophic factors go away, you see a fairly rapid evolution of neuronal processes. The dendrites literally start to shrink and disappear, synaptic terminals, atrophy. It doesn't take much of that sort of exposure to loss of neurotrophic factors to start to see atrophy that's big enough to show up in scans as well as if you do pet studies or other metabolic studies, a 30 to 40% reduction in the metabolic rate and places like the prefrontal cortex and hippocampus. What, help me understand like evolutionarily, like how does this have adaptive value for this process, like for this process to take place of chronic stress or what are your thoughts on that? I think this is rather than being something that evolutionarily preserved, it speaks to something that comes up as a question clinically initially. People have sometimes asked me, what's the difference between sadness and depression? Sadness has a characteristic of motivating the individual to either change something in themselves or something in their environment. Person makes the changes, reaches a new equilibrium and is then no longer sad. That's been preserved because I think it has a motivating factor inherent within it to drive us to achieve rewards, achieve goals. I think when that gets out of hand, meaning when it overwhelms the limbic system, that's when things deteriorate into clinical depression because one of the characteristics of depression unlike sadness which motivates people, depression typically has a paralyzing effect on them. Yeah. I have two cats. One is very ambitious and the other one is super anxious and so one likes to go outside all the time, the other one doesn't. I think the one that is super anxious may outlive the one that is very adventurous. That's quite possible. There are risks to going outside all the time. Especially in Florida. Although in a broader sense, for any species, those who adventure and go out, obviously there's always a risk that bad things will happen, but that's also an opportunity to meet goals in the very basic biological sense. It's a potential way to meet mates and reproduce. On the other hand, if you're sort of holed up in your cave all the time, you may live longer, but it's not going to be much of a life. Yeah. So, this article mentions that prior studies have shown that antidepressants exercise enriched environments increase, dendrite complexity and synaptic density. Along with ketamine, they were emphasizing ketamine, but they showed that prior studies had done this as well. The pictures are worth a thousand words, guys. If you have a moment, go to my website, I'll post a picture of this. It's just watching the synapses respr out. Yeah, wonderful. Yeah, one of the most valuable things about this article is beyond the discussion are indeed the images that were included in the article. They're an excellent way of illustrating the difference between the depressed state and the non-depressed state. Frankly, when I'm teaching people about depression, one of the analogies I often use, is that in this context, the limbic system is ill, very much as in somebody with cardiomyopathy. And frankly, we would not blame cardiomyopathy on the person having insufficient vagal activity or insufficient sympathetic activity, but it's when those systems can no longer adequately restart rate and anotropic effect, that's when you start to develop congestive heart failure. Again, the primary defect is not in the modulatory systems. It's in the end organ, in this case, the limbic system. And that doesn't say that the antidepressants have no value. It says, however, that they may have limitations if the depression has gotten beyond their ability to modulate. I think that's a good transition to a 2011 paper in dialogues of clinical neuroscience titled, "Of Sound, Mind, and Body, Depression, Disease, and Accelerated Aging." In this, Owen, Wachowicz and the colleagues discussed how depression is associated with accelerated aging. They looked at it moderating and mediating effects of that. I could list some of them and then maybe we could discuss this a little bit. Some of the moderating effects of this are coping styles, genetic predispositions and epigenetic modifications like childhood adversity. Some of the mediating effects are the limbic hypothalamic pituitary adrenal axis, altercations, alterations, reduced glucocorticoid receptor function, altered glucose, tolerance, and insulin sensitivity. Excidotoxicity increased intracellular calcium, oxidative stress, pro-inflammatory milieu. I'm going to pause there just because there's a list and I'll bring up some of these other ones in the subsequent dialogue that we have. But I'm looking at this and I'm thinking to myself, how can anyone look at depression and not think that depression has like physiologic brain changes and consequences? Like it's all in your mind. It just blows my mind. It's so naive to think that best. In much the way that our initial monomy and hypothesis was well to put a bluntly naive and simplistic, to think that the brain is not involved in depression is sort of like saying, well, the heart's not involved in circulation. And indeed, this article does a very nice job of summarizing those things that seem to be predisposing factors. Why do some people get depressed others don't? Including things like the genetics of the individual, the epigenetics exposure to adverse circumstances, developmental history. And then those things that mediate those episodes of depression, there are a whole host of physiologic changes that occur. And the depressed brain will be on simply the decrease in neurotrophic factors or the atrophy of dendritic spines, their abnormalities in calcium signaling. There's excido neurotoxicity, there's increased inflammatory responses. Many of the things that occur in major depression, particularly if someone is suffering from recurring depression, often promote essentially the development of senescent neurons. People's neurons begin to look as though they have aged beyond the person's calendar age. And that certainly is true just generally physically. I've tweeted a number of patients over the years who unfortunately for them suffered from a current major depression. And frankly, many of them by the time they were in their 50s or 60s looked more likely were in their 70s or 80s. There was one thing that I thought would be worth going over that depressed people have lower counter regulatory neuro steroids like aloe, pregnant, loan and yeah, like most things in biology, the neuro hormones come in opposing camps, the pregnant loans, for example, then to push in a direction opposite that of cortisol. And that's, you know, in essence, the reason biology often uses countervailing molecules from the same group is that it's a way to very fine tune responses at the cellular level steroids among many other things, modulate DNA transcription and translation. And if you wanted to keep that under very tight wraps, ie, exquisitely controlled, you want some molecules that promote transcription and translation and others that tend to dampen it. And that's exactly what you're seeing here. Now in the context of depression, that means that hormones like the pregnant loans will be associated with abortion of depression. And in fact, there, as you may know, there's a pregnant loan and a synthetic analog of it is now commonly infused postpartum to prevent postpartum depression and appears to be effective in doing so. And on the other hand, exposure to excessive chronic cortisol, it seems to be associated not only with promoting depression, but with producing resistance to anti-depressant treatments. How, how, how so if it just just quick tangent, how like, what was the effect size or number needed to treat on that steroid for postpartum depression? Was it really that? Yeah, it was, yeah, it was highly effective. They, they know part of the problem with the study is it was looking at women who had had a previous episode of postpartum depression, so they were assumed to be at risk. They then randomized them to receive placebo infusion or active drug infusion. The response rate in the placebo group was essentially a nil. They still tended to go toward depression. About 80% of those infused with the hormone either reported no depression or very limited depression. I remember it's very expensive as well or something. Oh, yeah, it was very expensive and it's certainly not a treatment that should be used for everyone. But I think if some, you know, frankly, if a patient has a history of severe postpartum depression and they pretty reliably develop it after each delivery, this appears to be an effective preemptive method of preventing it from occurring. The nice thing is the treatment takes place over a few hours and is done only once. So it's not a long-term ongoing treatment, but it is quite expensive. Yeah. They also mentioned in this article how MDD was associated with increased atherosclerosis, heart disease, hypertension, stroke, cognitive decline, dementia, osteoporosis. So there's just this massive link between depression and rapid aging. Do you see those links as the cause of the increased aging from depression or something else? I think they are probably manifestations of the the myriad of physiologic changes that occur during depression. You know, especially well, being a psychiatrist, we tend to focus on the person's mood and how they're feeling, but frankly depression is a not only a brain disease, but given the widespread effects of neuromodulatory systems, it's really a generalized physiologic illness. You know, I think since we've had treatments for depression, we've forgotten in some ways how many people basically just curled up and died when they became severely depressed prior to any antidepressant treatments being available. And a physiologic standpoint, it obviously does, being depressed does very bad things to your inflammatory status, your lipids. So you're basically every organ you have suffers during a major depression episode. Yeah. It's a good article. I recommend I recommend this and we'll link these ones on my website, psychiatrypodcast.com. And in the resource library, you can get it for free. It and Dr. Cummings, is there anything else from this study before we move on that really jumped out at you as like something of value to communicate to the audience here? I think I think of particularly for our audience, one of the things and this has been reflected in a change in treatment guidelines. Frankly, when I was being trained, people would get depressed, they'd receive an antidepressant. If they recovered, the antidepressant was then universally discontinued. And that resulted in fairly high relapse rate. I think psychiatry has gotten much more cautious now so that people have evidence of recurrent depression. You know, their depression is not a one off, not a one time event. We're now much more likely to lean toward this person if they respond to an antidepressant treatment or antidepressant plus exercise plus whatever. They need to be on an antidepressant treatment on an ongoing basis because one of the things that seems to be very clear from the data about depression risk is that each episode of depression makes the next one more likely. Yeah, I have to see the other side of that as well where some people get stuck on a bunch of meds and no one has the courage to change them or decrease them. Do you have any thoughts on that? Well, I always worry a little bit when somebody says a bunch of medications. That's the, yeah, I'm working on an episode. said on polypharmacy. It's like, you know, because I realize there are people who do wind up needing multiple medications. But one of the things I want, I always encourage, is in treating someone, start with your best shot, in terms of what you think will help the person, and actually do a medication trial. Get it up to at least minimum therapeutic dose, plasma concentration. If the person doesn't respond, keep titrating upward until either they reach a point where they're having side effects that you can't manage or they can't tolerate, or you reach the drugs point of futility. One of my major criticisms, somebody walks in the office and says I'm depressed, they should not walk out that day with a prescription for five different medications, all of which are sub therapeutic. Yeah, more on that in the future. I think it'll be, yeah, we need to do more on how to decide which medications to decrease, which ones to increase. There's a lot of thought for us. I mean, a lot of the episodes we did together covered that and sort of start to untangle that drug levels, how to monitor drug levels, how to get someone to do it. Indeed, that's a whole topic on its own, so stay tuned. In another article that you shared, "Backero and Martin wrote depressive symptoms in neurodegenerative diseases published in 2015, which showed how linked depression was with various neurodegenerative diseases. What did this tell us about depression and about treatment that excited you, that made you share it with me?" Well, I think one, it points out that depression is an important issue in the neurocognitive disorders. Given the topic we were talking about today, though, that there's the involvement of the limbic system and the brain as a whole in depression, if you kind of reverse engineer what this is saying, as neural systems deteriorate, that gives rise to depression. Well, in essence, that's what we've been saying is if the limbic system has gotten outside of its homeostatic boundaries, that's the setup for depression, not a primary defect in the model of immune systems. This essentially kind of illustrates that except from the other end where you have a primary degeneration of frontal and limbic neural networks leading to depression as a result. Yeah. So specifically, there is an increased rate of depression in patients with dementia, Alzheimer's disease, being one of the dementia's Parkinson's disease, Louis body disease, vascular dementia, frontal temporal degeneration and many other things. I would say MS as well, when I see. Yeah. And what all of these point to because you're talking about in some ways, very different specific pathologies, but the one thing they have in common is a deterioration in neural networks. That deterioration leads as kind of a common denominator to depression, which again, looking at it from a reverse engineering standpoint argues that it's the limbic system malfunction, if you will, that gives rise to depression. It's not the neuromodulatory systems, which is why the antidepressants have a limit to efficacy. One of these is Parkinson's disease, which is a dopamine issue, is would that say something about the monomine hypothesis that Parkinson's disease might be associated with depression or how would you? Yes. Oh, it does. Certainly. The primary loss in Parkinson's disease is in the part of his compacta. Those cells essentially lose their ability to synthesize dopamine, leading to all of the motor side effects. Dopamine does play a role in depression, albeit most of our antidepressant treatments, have very little direct effect on dopamine. Dopamine is one of the major drivers for the nucleus accumbens, the reward pathway. In Parkinson's disease, it also is a misconception that only dopamine, monochemines, neurons are involved. There is also a decline in other neurotransmitters like serotonin and norepinephrine because of now what is a primary illness in those neurons. Again, underscoring that there is a relationship there between the neuromodulatory systems and depression. In this episode, we're not trying to say that they are not involved clearly. They are, which is why our antidepressants are effective sometimes. But they're not the primary side of pathology for major depressive disorder, but they may be the primary side and some other things like Parkinson's disease. When I treat Parkinson's disease, I usually lean into something with a little bit more in norepinephrine reuptake, Symbalta nor Trip to Lane compared to things like peroxetine, which still seem to help very much at all. Any quick comment on treatment of depression in Parkinson's disease? Yes, indeed. If you were rank ordering what's happening to the monochemines, I remember these are all related molecules. But if you were rank ordering what's being lost most to being what's lost least, dopamine, of course, is at the top of the list. Norepinephrine would be second. And I somewhat more distant third would be serotonin because it's a little bit separate from the other two and that it's an endolamine. It's synthetic pathway is slightly different than that for norepinephrine and dopamine. Okay, getting back into it, there's another article you shared up the grove and colleagues. I hope I'm saying that right. I wrote that down right, published depression and schizophrenia, causes, consequences and transdiagnostic issues in 2016. What did this article teach us about depression? I think the important part of this article was the transdiagnostic issues. That's important for two reasons. One, it suggests that underlying diseases, whether it be schizophrenia or depression that adversely affect frontal temporal circuits can produce symptom complexes that cross current DSM diagnostic boundaries. Because if you look at schizophrenia, one of the points they make is that there's an elevated rate of depression in schizophrenia. Not surprising in that schizophrenia is essentially a very frontally oriented, essentially developmental dementia with loss of neurons and synapses from second trimester onward. It's not surprising that when you have dysfunction of neural circuits that involve the prefrontal cortex in the limbic system, that anything that adversely affects those neural circuits may give rise to depressive symptoms if not to a formal diagnosis of major depressive disorder. The point I was trying to make by including this was that the underlying pathophysiology has to do with frontal temporal systems and that, frankly, some of that cuts across diagnostic boundaries as our current nomenclature works. Because you and I've talked before about the fact that we currently are still dealing with a syndromic diagnostic system in psychiatry. Essentially what we've done is our cluster analyses and said, "Well, if it has symptoms that cluster together, well, that's a disease." That's likely in precise. Most of our clusters are going to turn out to be groups of related diseases when we get down to the underlying causes. Want to talk a little bit about psychotherapy and one of the episodes recently I was having a conversation, we were talking about how long psychotherapy takes. There was a study of 10,000 therapy clients and they were assessed session to session with a validated outcome instrument. They found that it took 21 sessions or about six months of weekly therapy to see clinically significant changes in 50% of the patients. Many after 40 sessions or almost a year of weekly therapy did research to see significant change in 75% of patients. In another study at Emory of 270 experienced psychotherapists, they found that the therapist said that. They agreed that most successful outcomes require about a year to about a year and a half of therapy, like 52 to 75 sessions. And why do you think Dr. Cummings, it takes so long for psychotherapy to work and cause brain changes? And what specific brain changes are we seeing with prolonged psychotherapy? I think we're looking at changes that phenotypically in terms of what happens at the cellular level are very similar to what we see with medications. The medications are faster when they work, they're faster. The psychotherapies tend to be slower, but also tend to produce more permanent change post treatment. I think where they share a common mechanism of action is a model of psychopharmacology that's called initiation and adaptation. Rather than the changes in the neural circuits and dendritic spines and all of those things depending on the continuous presence of the treatment molecule, whether it's an anti-sacrotic grant or a present. What we're doing with the medication is repeatedly perturbing a particular neural network, causing it to then adapt to that perturbation. If you think about psychotherapy, you're essentially doing the same thing via words or activities. You are perturbing those systems and thereby inducing changes. I think the direct chemical exposure to molecules likely is faster because it's a little more. It's a little more proximate to the end target, but then of course when you stop perturbing with medications, the benefits are more likely to be lost sooner. And well done psychotherapy. People have hypothesized that that's because there's a carryover effect in psychotherapy where the last session of psychotherapy really isn't the end of the psychotherapy. The person continues to practice and repeat elements of the psychotherapy that they've learned, which of course is not true with medications. If you take your last pill, five half lives of that medication later, that molecule was gone. Yeah, I think this is why it's like as an outpatient psychiatrist, you know, what I'm trying to do with patients who come to me who are stable on meds, who haven't done therapy is sometimes to get them into therapy, get them exercising. You know, they have to choose to exercise. They have to choose to suffer, so to speak. But if they do choose that and have a meaning in doing that and doing the therapy and doing exercise, sometimes you can decrease the meds over time. Or you could lower the med, wait six weeks, see how they're doing, lower the med, wait six weeks, or simplify the medications. While they're in therapy, if the therapy is going well, I'm always thinking to myself what medications are getting in the way of their work that they're doing, like if they're on a bunch of cognitively doling medications, anticholoneurgic medications, sensory lowering medications of getting them off of those or decreasing them slowly. It's always a slow process in outpatient. Any thoughts on those things? Yes. One, almost every single outcome study out there essentially shows that multimodal treatment, meaning medication plus therapy, plus exercise. Produce more robust results than any modality by itself. And certainly I agree with getting rid of, you know, one of the things I think it surprises people since I work as a psychopharmacology consultant is how many of my consults have recommendations telling people to get rid of most of the things they're prescribing. And indeed, for the reasons you point out, it makes a very little sense to me to introduce somebody to cognitive behavioral therapy while giving them medications that impair cognition and memory. Yeah, I work in the, in the IOP Partial that I am the medical director of, we often are working together, the therapist and myself to try to figure out, how are they processing in group? Or do they have access to their motions? Do they have, are they fall in asleep? And if they are, if they, I mean, if they don't have the ability to stay awake in process, then I might be more quick to decrease the meds. And I've seen them, I'm seeing these patients once a week usually, so it's nice so I can make the changes. One thing I've noticed with my colleagues is sometimes as psychiatrists we want to feel like we're doing something. We want to feel like we are the agent of change and I was just telling my treatment team today, like I'm taking the backseat to you guys. You guys are doing the heavy lifting. I'm here to support you guys and I don't want the patient to think that the medications are causing the change that psychotherapy is causing. And so what I've seen in some patients is that they'll be doing all of the work of like DBT eight hours a day, five days a week, right? And because the meds are being changed, they may put the credit of their change on the medications, which increases their faith in, you know, basically the placebo. If the meds aren't the cause of the change, right? Sometimes the meds are the cause of the change, but sometimes it's the therapy, it's the hard work they're doing. Yeah, my own view of medications is the by and large of the medications we give people in psychiatry are typically not curative. They could be better characterized as tools, which may then help make the person more available to participate in things like therapy and exercise and life changes. You know, as a culture, we tend to be a little too frankly medication centric, which I know is not thing coming from somebody who has devoted decades to working as a pharmacologist. Yeah, it is. It is. Well, I think it's all about the right, the right plan and a plan that the patient will execute. Because I've had patients who, well, I have one patient in particular, I can remember who fired me because I kept recommending partial tour. Obviously, I was pushing too hard. Now, interestingly that the psychiatrist she followed up with also told me that, yeah, I keep telling her about partial as well. So we're going to wear her down eventually. But you know, medication for this patient was life saving when they started it is stabilize them. So they put a lot of trust in it. So they're like thinking, oh, what I really need is medication now. It's like, well, but that's one piece of the puzzle. You know, like if you learn a lot of the tools that you can learn in therapy or you know internalize a loving other person, maybe that you didn't internalize early on. That can be very, that can be very, that actually change your brain in a permanent way. Yeah. Yeah. One of the, one of the things I often tell patients in doing a consult is I tell them the point of this medication is to get you improved and stabilized to the point that you can take advantage of the rest of the treatment that you need. This medication will help in some respects, but it's not going to by itself change your life. That's asking a little bit much of a shot or a pill. I'm coming back to this study that you shared with me the 2012 paper. It talks about how chronic unpredictable stress decreased neurogenesis, dengrade complexity, spine density in the prefrontal cortex. Chronic stress leads to hypertrophy in the nucleus accumbens in the amygdala. It led to atrophy of the prefrontal, per middle neurons. And as I'm looking at that, I'm thinking to myself, sometimes stress is stress for some people and not stress for other people. And like I think, because what we found in, or what I found in following people who do effective therapy is at some point in the midst of the effective therapy, the stress that would have caused them a huge amount of stress. Unraveling maybe for a couple days is like experienced as a mild stress. Yes. Well, as people learn adaptive ways of dealing with distressing events or circumstances, that means those events or circumstances become inherently less stressful for them. because they now have means of dealing with them. You know, people come in a huge array of levels of vulnerability to stress or distressing situations. On one hand, vulnerability on the other hand, resilience. And in many ways, the objective of our type of treatment is to via medication and therapy make the person more resilient. Because I mean, obviously we can't exactly remove stresses or distressing events from someone's life that's just part of living. But we can hopefully make them better able to deal with those circumstances and thereby make them much less stressful. And by saying this, I don't want to negate like traumas near death traumas horrible things that have happened will be stressful probably for every single person that goes through them. One thing that I've realized though is that sometimes that trauma becomes relived every day. And that creates like a chronic stress of sorts that hits the body. And so processing through that in new ways so that you're not constantly thinking about it, constantly tormented by it. That reduces that chronic stress and allows that peace that allows the recovery of, you know, that period of time where the stress is hit you. So I hope that's encouraging to you even if you're like listening to this and you're like, wait, I'm in the midst of this. What do I do? Well, I think the hopeful mode in all of this is that there are things we can do both medication and in terms of psychosocial treatments that will acutely stabilize the situation. But in the long run also make the person more resilient, more able to not live in that nightmare of relivingly stress every day and having it impact them every day. And frankly, being not fearful of the next stressor that may come along. Yeah, I think it's good. I'm also thinking, you know, the sort of the idea of not all stress is bad stress. So sequential stress, that's a good stress can lead to having higher stress reactivity. So for example, I try to do things that are a little bit challenging to my kids and I just did a yesterday we just did a cold plunge. And it's probably about the 10th time that we've done something like this this summer. And so each time we get another extra bag of ice or two bags and so we're up to like, we were up to 80 pounds of ice and we put it in the bathtub. If you're doing this with your kids, don't start with 80 pounds, start with like 10 or just start with the coldest water and see if you can do that. And I'll have my kids hold their breath underwater and they, you know, they're choosing to do this. Okay, like I always say to them like, look, this is your choice. I'm not forcing them to do this. But I'm doing it with them and that makes it fun, right? Because whatever dad's doing at this age, it's like, yeah, if only those years last, right? So, 68 years old, I don't know if I said that right. So, you know, my daughter can go about 20 seconds under the water. My son just submerges completely and then comes up and that's awesome. And we spend about 20 minutes going in and out and we make it fun. But it's like a good stress and it's like, it was interesting because I invited my friend over. And it was the first time he had been in like ice cold water for a while, I think. And so he gets in and his face just like lit up with shock at how cold it was because the kids had been in there, you know, for about 10, 15 minutes before he got in. And anyways, my thought on this is I think as parents, we need to find ways to create good stresses sequentially with for our kids to prepare them for stresses later in life. Yeah, I think one of the things that's important, that's kind of the inverse of childhood adversity is when. In growing up, people are given challenges, which are stresses, but they are also given the means to successfully overcome them, adapt to them. Because from that becomes comes, of course, a better sense of self and a better sense of confidence, self-reliance. So that when an unexpected stress comes along, it is more likely that they'll be able to say, OK, this is tough, but I can deal with it. Yeah, and with my kids, I always try to find that place where it's a little bit difficult, but it's not too difficult that they'll give up. You know, it's not too difficult that it's overwhelming or like I'm asking them to do something which they can't do. Yeah, well, that would put them in the same position as the restrained rat that we were talking about, which we don't want to do to people. But, you know, it's like everything else, there are healthy challenges and unhealthy challenges, and the healthy ones are the ones that help people grow. Yeah. I think about that with like, OK, how does this translate to like patient care? Like let's say you have someone with depression, you've treated them with antidepressant. They're now no longer severely depressed, maybe they're mildly depressed, they're depressed, but they're able to get out of bed. And they're able to, you know, if you say like gently, you know, like, hey, if we could increase the exercise a little bit, you know, start walking every other day or something like that, or you know, progressively increase the exercise, they'll actually do it, right? They'll actually like engage it. And so now they're doing that, and they're taking steps themselves to improve things. And maybe you know, at some point around, you know, in the treatment, they are convinced that psychotherapy could be a part of their long term strategy to combat this. So they've, you've, I want to say seduced them into doing therapy, but it's more like, you've, I don't know, you've, it's like you're trying to convince them to do what's best for themselves. You know, it's like, it's, it's often difficult for people to overcome that initial sense of hopelessness that's associated with depression, no matter what I do, it will never get any better. Well, that is the thought that's associated with the depression, but frankly, it's not true. Now, you know, the first day they get out of bed, they may not go very far, but they got out of bed. Well, maybe the next day a little further and a little further early in my career, I had a very depressed woman who had literally reached the point where the only way she could come to an appointment was for family literally to moral less pluck her out of the bed and bring her. We got her in addition to a good antidepressant regiment, we got her to begin a little bit of physical activity, got the family actually to get her up and take her outside and initially just walk to the end of the block and back. Five years after I started treating her, I saw her again, she was no longer my patient at that point, but she had joined a local running club and was doing six miles a day. At that point, she was frankly more fifth than I was. And I bet you were quite enthusiastic to see her recovery. It was like, oh, yes. And, and, well, and she told me that yes, the antidepressant had sort of started the ball rolling, but it was really the psychotherapy and the increased activity that allowed her to regain control of her life. She still had the occasional dysphoric day, but when that would happen, she could push through it. And for the most part of her life was good. Yeah, when I think about chronic stresses, I think about some of the clinicians I've treated coached over the last couple of years. And some of them are in chronic stress, chronic unpredictable stresses with work situations, working maybe 60 hours a week, maybe commuting in additional hour each way. And sometimes it's hard to overcome the direction that this chronic stress is leading without change. What would you say to a clinician who's kind of stuck in one of the situations? I would encourage them, frankly, to take a very close look at the situation and look at it with them to see what elements can be changed. But, you know, there's almost no situation on the planet that can't be changed in some respects. And that may be the, you know, that part of dealing with it with the environment, as well as getting them perhaps on appropriate medication to help them deal with the stress is very important because. You know, if they're finding the situation intolerable as it is, part of the answer has to be changed the situation in some way. Yeah. Yeah, I think it's, it's very person specific. So if you listen to this, I think you really need a discussion, you know, if you have a colleague you trust, a mentor you trust, I think that's good person to talk to about it. You know, what is a normal amount of stress, right? What is too much? How can you make your work situation more predictable? Because there's something about unpredictable stress. And something clinicians are very bad about is for getting that they need to take care of themselves as well as their patients. You know, burnout is a really bad problem among medical professionals. Because there's always that, well, I'll feel guilty if I don't see, you know, another patient or meet this next demand. It's okay to recognize limits and at some point say, no, that's as much as I can do without damaging myself. Yeah. Very good. Well, I hope this discussion has been helpful to you talking about the complexity of neuroanatomy, neuro changes, the integration of lifestyle, psychotherapy, good medication management. And I'm sure there'll be more episodes in the future where we kind of dig into small aspects of one of these things. And so I hope this has been helpful for you. Dr. Cummings, thank you so much for coming on. Oh, thank you. I enjoyed it. You are now officially retired. I am retired. However, next Monday I come back to the state as a retired anew it and so my retirement lasted six weeks. Well I'm sure I'm sure actually someone reached out to me from patent when they realized that that you were actually at patent and then they knew of you. It was a delight to them. And they said Dr. Cummings is a lifeline to so many psychiatrists here to give very complex cases. So I'm sure that they missed you those last six weeks and have a caseload in front of you to discuss. Yes, indeed. All right. Well we will leave it there for today guys. Thank you so much for staying to the end and I hope this was helpful. Great to care. Thank you. [Music]