Psychiatry & Psychotherapy Podcast - Managing Weight Gain from Psychiatric Medications with Dr. Michael Cummings

Episode Date: September 27, 2024

Join Dr. David Puder and renowned psychopharmacologist Dr. Michael Cummings as they dive deep into the complex relationship between psychiatric medications and weight gain. In this episode, they explore the metabolic challenges posed by antipsychotic medications, focusing on cutting-edge solutions like GLP-1 agonists. Whether you're a mental health professional or someone impacted by these medications, this conversation offers practical insights on how to manage medication-induced weight gain through diet, exercise, and pharmacological interventions. Learn how to tackle this growing issue in mental health care with a thoughtful, science-backed approach. By listening to this episode, you can earn 1.25 Psychiatry CME Credits. Link to blog. Link to YouTube video.

All right, welcome back to the podcast. I am joined with Dr. Michael Cummings, the beloved Dr. Cummings, and we are going to be just hitting a bunch of different topics on psychopharmacology. Dr. Cummings has been on multiple episodes and is well known internationally for his encyclopedic memory knowledge of everything, psychopharmacology and psychiatry. So welcome back to the podcast. Thank you. I'm happy to be back for the audience. Dr. Peter is being nice. essentially saying, I don't know when to shut up, but yeah. It's not... We got to work on your punitive internal voice,

if that's what you think I'm saying. Well, yeah, I mean, it's been good to continue to hear from you, and your retiring, I hear is like your retirement is, like, not as successful as you would like. Officially, I'm now working two days a week, however, that somehow has become four. So we'll see if we can reduce that over time. I don't know how successful I'll be.

And then we have no conflicts of interest. It's unusual for someone at your position to have no conflicts of interest. What is the state connection that you're like on the board of? I sit on a couple of advisory boards for the Department of General Services. That's the business slash,

contracting arm of the state of California. And in order to sit on those boards, because I do give the state direct advice about what to spend money on, they want to be sure that I don't have any associations with anyone or anything that may be trying to do business with the state or who might have an interest in influencing any of those decisions. So indeed, once a year they make me sign a non-conflict agreement that basically says that if I do engage in anything outside of a state agency that makes money, I have to have it vetted through their legal department. Okay. Yeah. I really enjoy that you have that connection, and I think that the audience does as well because it's like we don't want to be fed something. just because some drug company is paying us secretively or has us on some council or educational grant. I've stayed away from all of that for that reason. I think people, the serious psychiatrists,

they appreciate that. So thank you for being willing to come on here. Okay. Okay. So let's jump into some questions. Now, you recently told me there's this push for GLP-1s to be sort of brought into the state, and I know that's a hot topic. There's a lot of, those are expensive medications. And so I imagine that's the kind of contract that you're looking at, is like, is that going to be helpful? What are all the details on that? So? Yes, indeed, that's a hot area currently in the California Department of State Hospitals, as you might guess, with a chronically mentally ill population, most of whom are suffering from a psychotic disorder,

rates of obesity and metabolic syndrome are large. I mean, we've had an obesity epidemic in the country as a whole, but it's worse among the mentally ill. I think our average BMI in the state hospital, patient population is 29.9, meaning the average number in our patients is pushing just a hair short of grade one obesity. And we have probably a prevalence rate of around 60% of people who meet the criteria for obesity and a slightly lower, somewhere in the 50 to 55% range, who meet the formal criteria for metabolic syndrome, meaning that in addition to obesity, they have dyslipatemia,

hypertension, central adiposity, and all of the health risks that come with that. So the GOP-1 agonists at this point are about the only class of medications out there that are very good at actually reversing obesity. There are a number of medications that can slow weight gain, things like metformin, but they're not very good at reversing the weight once the weight's on. Not all of the GOP-1 agonists are great at reducing weight. However, some of the more recent ones like Lira glutide, simoglutide, and in particular, teresbitide, trade name Mongero, have shown good research data suggesting that they can produce a substantial amount of weight loss,

in addition to correcting things like glucose tolerance and also assisting with decreasing lipid abnormalities. We've also discovered that the GLP1 agonists have some unexpected benefits, such as reducing alcohol intake, reducing craving for illicit drugs, and at least tiny amounts of data suggesting that they may decrease a number of reward system-driven behaviors that may include things like self-mutilation, self-cutting, other things that might be of a benefit in psychiatric patients. The data on those features are, pretty new and so pretty small, but they're enticing in the sense that this class of drugs affect a lot of the way our hypothalamus functions in terms of modulating drives and impulses,

in addition to the direct anti-obesity and metabolic benefits of the drugs. Okay, let's finish the GOP-1 conversation, but I think where I want to go out, after this is like, let's talk about the meds that increase weight and why they increase weight. Okay. But let's stay with the gLP ones, because I was excited about these at first. And honestly, my excitement has decreased

because I see people have gotten on them, and then when they got off, they gain their weight back, and often the weight comes back, not as the muscle that they lost, but more as fat. So they may, go ahead. That's an important element with the GOP-1 agonists is when you make the decision to start them, this is a case of starting what is likely to be a lifelong medication.

Because indeed, when they are stopped, not only does the weight come back and the metabolic abnormalities come back, they will likely come back in worse form than they were to begin with. In some ways, that parallels the history of weight loss diets. They've all the way down to animal studies if you put a rat on a starvation diet, make it lose weight, and then you give it access to free feeding. The first time, it will regain the weight it lost, and it will overshoot slightly by 5, 10%.

If you do the same experiment again, same rat, it'll lose the weight, and then when you refeat it, it'll regain the weight in about half the time, and it will overshoot by more like 15 to 20%. So that when people either engage in repeated dieting or in use of one of these drugs, it has to be either a lifelong change in diet and exercise habits or a lifelong commitment to take one of these drugs.

Yeah, so just to give people an idea, if people are not exercising while they take them, you could lose 35% lean muscle mass when you lose weight. That's a lot of muscle. And muscle is very, you know, muscle is very, helpful for so many reasons we've talked about this a lot of the podcast for it's like a neuroendocrine tissue it's like a very healthy tissue yeah indeed the other thing we've talked about with patients is they need not only to maintain exercise they need to maintain a an adequate diet even if they

don't feel hungry uh they're rare very rare but we've had a couple of patients that we've had to take off of these drugs because they went from being obese to being anorectic. Right. You know, a case example I can think of. A woman started with a BMI of 38, you know, grade two obesity. By the time she got taken off of the GOP-1 agonist by her attending physician, she was at a BMI of 19. because as she put it, I talked with her.

And as she put it, I have a piece of toast and glass of water in the morning, and I'm not hungry anymore. And, of course, you can't live on a piece of toast and a glass of water. And so hunger and thirst can be eradicated at a high dose. Yes. Yes. Well, it's not even though. In her case, she was at a standard dose, but she was exquisitely sensitive to the effect of the drug.

No, honestly, she was probably, out in the tail of the distribution in terms of sensitivity, but, you know, this was not a class of drugs that she could take. Yeah, and so I think it's so fascinating because I've seen other patients who it reduces their drive and motivation in other domains of their life. We talked about, you know, the drive to drink alcohol, the drive to drink water, the drive to eat. But, you know, it acts on the hypothalamus, the brainstem areas involving appetit.

regulation, reducing the appetite, slowing gastric emptying, but it also hits the reward centers of the brain, nucleus accumbens, ventral tegmental area influencing, you know, reward-driven behaviors, some of which we may not want to decrease, right? Yeah, unfortunately, we've never figured out a way to selectively alter the functioning of the reward pathway. In part, that's because neurologically, it's a fairly simple pathway. The shell of the nucleus accumbens, not even the whole nucleus accumbens, just the outer layer of neurons mediates the reward response and projects forward to both the temporal and frontal lobes, but it's a fairly simple on-off nucleus. And if you alter its modulation, it's not sophisticated

enough that you can say, well, I want to, I want this behavior to go away, but I want that one to be preserved. That the person has to make more of a choice-driven, I'm going to do this because it's good for me and I'd like to continue this, not that it may feel as good as it used to. Right. So this could apply to things like gambling, binge eating, shopping, right? Yes. Those could decrease, but also you could have the decrease motivation to engage in physical activities and exercise. And that's what I've seen from people. It's like I'm pleading with them. Like, hey, as we try this, let's, let's, you know, we need to keep exercising. And people have been exercising for years. They are like, I just no longer, like, I don't know. I can't exercise while I'm on it. I don't know why I can't exercise. But I just have no desire to lift weights anymore. Yeah. Yeah, the motivation is gone.

because it no longer induces the same reward it, which I think the only ways around that, if the person really needs the medication is for them to have either external ways of being motivated, you know, have a trainer who goes, now get out there and do your lifting, or enough sort of internal sense that I need to do this because it's good for me,

not because it feels good anymore, which is a very difficult position. We are, I think sometimes we don't appreciate how much influence our hypothalamus has over our behavior. Okay, so you're saying if someone's on this, they may need to be on this for a very long time. For a very long time, otherwise, indeed, all of the studies that have been done. Now, the longest study I've seen was a two-year follow-up study. but it was the same as all of the one-year follow-up studies that people stopped the medication over about a year to a year and a half all of their weight and dyslipidemia and hypertension and diabetes

would go right back to where they were plus a little bit worse right so okay to give people context the positive studies showed that within a year on the medication with some diet coaching stuff, you could lose about 20%, 15 to 20% of your body weight. And so when people get off of it, they're gaining weight back is what you're saying. Yes. Yeah, that essentially the benefits in terms of correcting metabolic abnormalities and in producing weight loss, if you stop the medication, those benefits go away. In other words, the medication does not produce a positive,

permanent change in the underlying systems, the medications can modulate those systems while the medication is present. Right. Do you think there's a rebound? Is there like a, with receptor density? Does that change? Is that the rebound? Do we know about that?

Yeah, there is a rebound. And as I alluded to, it follows the same thing you see with people who lose weight via strenuous dieting. you can lose weight that way, but if you go from diet back to your usual food intake, you'll regain not only the original weight, but you'll overshoot and gain some additional weight. And anything that goes along with that, if you were glucose intolerance, odds are you'll become glucose intolerant again. If you were dyslipidemic, you're likely to do that again. In other words, if you're just talking about diet and exercise, That's why temporary diet and exercise don't work either.

If people are going to change their metabolic status via diet and exercise, it has to be a permanent change in lifestyle. And I think these medications parallel that in that if you want them to produce a permanent change, then you have to take them permanently. Right. So what we're talking about then is we're talking about one needs to actually change, habits and on a very deep, deep level, right? Yes.

So it's like, you know, the basal ganglia, the deep brain structure is involved in habit formation, motor control. And somehow we need to, we need to kind of institute habits slowly, maybe one at a time over, you know, maybe we only change one habit per month or every two months, you know, but it's like, how can you, the question is like, how do you change habits? With a lot of difficulty, unfortunately, much of this is stuff that occurs well below the conscious level, and much of it is preset by our genetics. You know, you and I have talked before about how a large part of what's happened in modern cultures is obesity was not such a huge problem if you had to do hours of manual labor or you had to do hours of manual labor, or you had to. had to hunt for your food and chase it in order to have an adequate number of calories.

Well, if all you have to do is drive through McDonald's, well, that's a basic change in the environment, but our brain doesn't change very quickly. Yeah. Okay, so, okay, let's go to where the problem is, though, because, like, the problem is a lot of the medications we give increase weight. Yes. It's kind of like a patient will come to me in a crisis. They could be psychotic.

Their life could be completely torturous. You put them on a second generation antipsychotic, and within a couple months, they're no longer psychotic. They're no longer living in this tortured reality, but they have gained some weight. And so now, as an outpatient psychiatrist, I'm managing a problem from the medication.

I'm trying to like, you know, figure out how to best help these people. Yes. This is the big sort of overarching problem. So let's talk about different medications and why they increase weight. Let's start with the biggest culprits, okay? The biggest culprits are clozapine and olanzapine,

and they both do a number of, of things that increase or push the person toward gaining weight. One, they tend to produce glucose intolerance, meaning that the person does not efficiently handle glucose. When you don't efficiently handle glucose, that glucose gets shunted into lipids. And in particular, there's a shift in balance, towards LDL cholesterol as opposed to HDL cholesterol.

There's a tendency toward central adiposity that is gaining fat tissue in the abdomen around organs. That's metabolically active and produces inflammation. That then tends to become a self-reinforcing cycle so that the person gains weight, which worsens the problem, and they gain more weight, which further worsens the problem. further worsens the problem. Now, in the case of these two medications,

they also have additional effects that remote weight gain. They're pretty good H-1 histamine antagonists. They block histamine receptors. Now, people are very familiar with that in terms of you take an antihistamine and you may get drowsy.

But the other effect the histamines have, particularly if you're taking something that's an antihistamine on an ongoing basis is you decrease your basal metabolic rate. You don't burn as many calories. That's another tick in the direction toward weight gain because calories you don't burn get stored. The third thing that they do is they block, in the case of these two drugs, they antagonize 5H2C receptors. These are serotonin receptors that function in the,

the hypothalamus in the satiety center to tell you when you've had enough to eat. If you block 5H2 receptors to see receptors, what you tend to get is carbohydrate craving. The person basically cannot pass up a donut or a cookie or ice cream, which of course are another great way to gain further weight. Yeah, okay, so you have the histamine H1 receptor antagonism, which can cause some nice sedation if they're having difficulty sleeping. It also increases appetite, or decreases the metabolic rate. Then you have the serotonin 5H2C receptor antagonism,

which they both block in the brain, which leads to carbohydrate craving. The person, yeah, the person, the person wants sugar. You know,

I can't tell you how many patients I've seen put on clozapine or lanspine and they come back and they'll tell you in so many terms, I am hungry all the time

and what I want is every single sweet thing I see. Yeah, it's like, I'm eating cereal in the middle of the night, sometimes twice.

What about the M3 receptor antagonism? Do you think that, is that involved in the insulin secretion? And does that impact? Yeah, it's involved in insulin secretion, and it probably also does play a role in these people becoming glucose intolerant, along with impairment of indeed the impairment of the functioning of the GLP1, receptors, which that's where the GLP1

agonists come into the story is they directly oppose the effects of olanzapine and clozapine and similar drugs at the modulation point of that receptor,

which the change in insulin balance appears to be the most important of the driving forces toward obesity. obesity and metabolic syndrome with the antipsychotics, which is likely why olanzapine and chlozapine are at the top of the list in terms of producing these effects, as they are the most, they cause the greatest disturbance in those systems. Okay, so let's get a little bit deeper into leptin, grelin.

So leptin promotes satiety, grilin stimulates appetite. and olanzapine, Clozapine, both disrupt the normal leptin, grelin, signaling. Yeah, and they promote these, they essentially shift the balance of these

in the direction of increased calorie intake, whereas the gLP one agonists shift the same systems in the opposite direction. Right, so they increase Gremlin levels, which increase, it's the hunger hormone,

of a blunted leptin response satiety hormone so then increased calorie intake and weight gain result and at the same time the anahistaminic effects are decreasing calorie output so it's the classic story with a weight gain you have increased calorie intake and decreased calorie output and that extra energy gets stored

as adipose tissue. So then there's also, like with the insulin, I think insulin is going to be something huge to look at in coming podcasts and just how important it is to be half-metabolically healthy. You know, people increase the rates of depression. Mm-hmm. If out-of-control diabetes,

much higher rates of depression. Yeah. So, you know, insulin is, impaired in these patients. You want to talk more about that? And what causes that what leads to that? Essentially, insulin's critically important in human physiology.

During active exercise, skeletal muscle can take up insulin, can take up sugar without insulin being present. But that's about the only tissue that can do that. Everything else requires the presence of insulin in order for glucose to get into cells to be used as fuel. So what you have in the case of somebody who is diabetic, type 2 diabetes, in particular is you have them an elevated circulating a level of insulin that can't bind to its receptor,

can't get the sugar into the cells, so the sugar builds up in the bloodstream. and that's why people have elevated blood sugar and diabetes. Now, in type 1 diabetes, they actually have a lack of insulin. In type 2, they typically have an excess of insulin, but it's ineffective and can't do its job. So literally what's happening to this poor person is most of the cells in their body are starving to death because they can't get fuel because the fuel is stuck outside in the bloodstream. and that leads to a whole host of downstream adverse effects in terms of things like poor healing, blindness, neuropathies, you know, all of the long-term consequences of being diabetic.

You know what I think is the most wild thing about this is like the average human without without any, you know, glucose regulation issues, they probably have on average, average about one teaspoon of total sugar, total glucose in their blood at a given time. Yes. If you were to drain all of my blood, it might have like a teaspoon right now. Well, and that's because if you have normal physiology, the glucose is not supposed to be hanging out in your bloodstream. It's supposed to be getting into the cells where it's oxidized and used to generate ATP

and essentially provide the energy for the cell. You know, this is like being somewhere in the wintertime and freezing to death and all of the firewood is stacked outside, but you can't get it into the fireplace. With people with like insulin resistance. Yes. So imagine, you know, someone who's floridly diabetic, it's like they have, instead of one teaspoon in their blood, total glucose, they have like three teaspoons. You know, like that's not that much.

If you think about it, in the big picture of like how much sugar we actually drink sometimes, when you, you know, like, it's like three teaspoons is not that much, right? No, it isn't. But it's the shift in, is it getting to where it needs to be? Now, you know, in the case of the type 1 diabetic whose beta cells in their pancreas are not producing insulin, of course, they can't get the glucose to where it needs to go either. But that's just because they have. a lack of insulin to get it there.

Case of type 2, it's because the person is resistant to the presence of insulin. Yeah, and then we also think about, like, you know, heavy steroid use, right? Always increased glucose. And so someone who's in a high-stress state, you know, there's like a transient, like a fight-and-flight type of response in your, you know, this hyperglycemia, high-blood sugar. So there's all these things going on. But, okay, back to what we're focused on today is like, yeah, so we have these medications. They're great medications to treating psychosis, but they do cause weight gain.

Yeah. Yeah, you know, and this fits into, in both the discussion of the GOP-1 agonists and the antipsychotics and antidepressants and anything else you care to name, we have yet to discover any medication that does only the thing that we want it to. You know, we divide these into effects and side effects, but that's entirely us. The molecule doesn't make any distinction. It just does what it does. And unfortunately, you know, different drugs have different adverse effects, different risks, which is why you're always hearing physicians talk about risk-benefit analysis, are you going to get more benefit out of this than risk?

Obviously, you don't want to take a medication if there's more risk than benefit, or engage in any other medical procedure where the risk outweighs the benefit. Part of our job, a large part, has become managing the risk profiles of many of these medications so that the patient can derive the benefit. of it safely. So, Resperidone is another atypical antipsychotic. This one can cause weight gain as well. But there's one mechanism, which I think is unique,

which is the prolactin elevation, which sometimes occurs. Yes. Prolactin and, sorry, Resperidone and its metabolite, paloperidone are both excellent substrates for P-glycoprotein, which is an e-flux pump. It occurs largely in two places, well, it occurs more than two places, but the main two places of interest are the blood-brain barrier

and the GI tract. Blood-brain barrier, it's important because it directly pumps these drugs from the brain into the hypophysial circulation, which of course supplies the pituitary. So the concentration of these drugs, both of them, winds up being higher in the pituitary than it is in the brain. And in the pituitary dopamine blockade, D2 blockade, removes tonic inhibition of both prolactin synthesis and prolactin secretion. So if you tonically take away that tonic inhibition, the person will secrete more, they will synthesize more. And the increased synthesis will also drive division of petuocytes that make prolactin,

which may eventually result in microednomas and may eventually result in a macroednomah, all of which is to say that these drugs are especially good at elevating prolactin, which can promote weight gain. Because, of course, prolactin's normal role is to promote lactation, and women who are lactating need more calories because the calories are getting delivered to the infant. If you're not breastfeeding, though, and you're taking something that elevates prolactin,

you're setting other things up in the body to store more calories because your body thinks, oh, well, we're about to try to raise another human being. So we need to store more calories to be ready. and so people will gain way due to prolactin. Right, so in men with high prolactin, their testes may not work as well, decreased testosterone,

they may get gynecomastia, breast tissue development. They may have erectile dysfunction, decreased libido, infertility. So, you know, as we give risperidone, we need to kind of watch out for this. you know, this is not something we want them to live with chronically. No. You know, short-term elevation of prolactin is not a medical emergency,

but it's not something that you want to leave elevated, particularly if the elevation is causing overt symptoms, such as galactaria, amenorrhea, erectile dysfunction. Also, it can cause like osteopenia, osteoporosis. Yes. And in both men and women does increase the risk of breast cancer as well. More so in women, of course, but not unheard of in men exposed to prolactin-elabating drugs. Okay, so like there's been a couple questions in our Q&A that we haven't gotten into about

what can we do if someone has high prolactin their on risperidone? What's your algorithm for like, this is what I would do first? one thing to consider, I mean, if somebody's on Risperidone and they responded well, one option to consider would be might you want to switch them to an alternative dopamine antagonist? Resperidone and Paloperidone are far worse than any of the other D2 antagonists at elevating prolactin. So that's one option. another option would be if the person responds

to Resperidone, it's a beautiful response and they have no side effects and they really don't want to change and you don't want to change because they've had a great antipsychotic response to the drug or great behavioral response, for example, in autism, you can

give them a dopamine agonist to compete with the drug in the pituitary and see if you can bring down their prolactin. The ones that people have used have been things like Pramapexel, bromocryptine,

and you will see it recurrently in the literature Eripeprizole. The trouble with the last one is it's very easy to switch antipsychotics in that case without meaning to basically

the binding of Arapyproprozole is so high. The binding affinity is so high that on average, giving somebody two milligrams of resperidone means that the, sorry, of aeropipiprizole means the aeropiprizole is going to go occupy 72% of their D2 receptors, which may make the antagonist ineffective because it now has nothing to target. By the time you get up to around 10 milligrams of aeropiprizole, whatever antagonist you're giving the person, you have replaced it with aeroproprizole, because the other drug is at that point

got nothing to work with. What about dose reduction? Could you reduce the dose of risperidone? You can. You can. If the person is at a higher dose, you can reduce the dose and thereby reduce the effect of the drug in the pituitary,

the caveat there is you have to proceed carefully so that you don't decrease the dose to the point the person has a psychotic relapse. Okay, so let's say someone has this problem. They know that their patient probably has hyperlactic. They figure that out. How fast should they solve this problem? Like, how urgent of an issue is this? They should solve it within three to six months. Okay, that's helpful, because that's a different level of a problem than like ecsthesia or something. Yeah, because the effects of prolactin, now I'm talking about somebody who's asymptomatic, which frankly, most people are, you have time because the risks of prolactin are slow and long term. Now, if somebody's got overt galactaria, amenorrhea that they don't like or erectile dysfunction, then you may want to proceed more rapidly.

But I've seen people do crazy things with antipsychotics in response to an elevated prolactin that's asymptomatic, like cutting the person's antipsychotic in half, which usually means the person's going to have a psychotic relapse fairly. soon. Will it bring down the prolactin? Yes, but at a, you know, a huge cost in terms of destabilizing the person. Again, in the asymptomatic prolactin elevation patient, the elevation per se is not an emergency. Okay. This is good because it's like we need to know how quickly we need to solve the issue. And so you have some time. You can move slowly. You can follow them. You know, every two to three weeks, try to make some changes. Okay.

I think we're good on that one. Let's talk about the next big weight gainer on the list is probably metazapine, remeron. Yes. You know, this has the good H2 receptor antagonism. Yes. Yeah, it's also a great blocker of 5HT2C. and indeed it produces exactly the same response i.e. the patient will be thinking i've never seen a donut i don't like you know i've had different responses some patients no issues very little weight gain

some people it's like whoa okay we're going 15 pounds in a in a couple months and it's like okay we got to we got to think of something else here yeah oh indeed and in that case you know the safe thing to do is choose a different antidepressant or anti-Akathia medication. That's its other major use. Like all medications, people vary in terms of how much they respond to block A to 5HT2C. Some people have a dramatic response. Some people don't notice much of anything. Most people will notice some increase, if you watch them carefully, some increase in calorie intake, some increase in carbohydrate intake. For some people, it may not be enough to make any difference. They may just adjust their activity level to compensate.

This does give me a chance, though, to say something. I think that should be true for all psychiatric offices. Everybody should own a scale, and everyone should weigh their patients. Dun, dun, duh. You know, my primary work is as a consultant. I can't tell you how many times I've gotten calls. Well, I put this person on, usually it's olanzapine or chlospine where I work,

but it could be metasapine just as easily. And I'll get a call from the psychiatrist. Well, my patients gained 120 pounds. Should I do something about that? And of course, the thought that goes through my mind is, well, yeah, you should have done something about it about a year ago. And, you know, I think people in psychiatry should remember we are physicians first, and then we're psychiatrists.

Yeah. The caveat being risk-reward, and I have one patient in particular I'm thinking of who gained maybe like 50 pounds or so, and he's lost some. He's going down slowly, lifestyle things. but he doesn't really care. Him and his significant other are like, you know, we're in such a better place in terms of our marriage, in terms of the arguments we have, in terms of him, you know,

floridly not being psychotic, that it's like we are not, it's not our priority. For other people, it would be like, a complete. Yeah, a major priority. But our job is the physician in this context is to, one, spot the problem early. It should never be the case that, oh, my patient's gained 120 pounds.

If you are actually weighing them every time they come see you for a visit and you notice that they're gaining weight, then it becomes an issue for clinical discussion. And you can lay out for them, well, you know, these are the risks. of gaining too much weight, and, you know, how would you like to address this? We should talk about ways to modify this if it's something you care about. And maybe you should care about it if it's going to shorten your lifespan. You know, that discussion needs to occur, not, oh, you finally notice when the patient can't get through your office door. Yeah.

You know, in fact, there are nice guidelines out there suggesting that somebody is going to have trouble with a given medication. If you take their baseline weight, if they gain 5% above that in the first month, or 7.5% in three months or 10% in 6 months, you're looking at somebody who's going to have a long-term weight slash metabolic problem with the medication you're giving them. That's good. The advantage, of course, is that if you spot the trend early, it's easier to address. It's far easier to lose five pounds with a little bit of diet and exercise than it is to lose 50 pounds with diet and exercise. It's also easier to prevent weight gain with things like metformin. You wouldn't have to go to a GOP1 if you're trying to keep it off, not reverse it.

So there are options out there for dealing with the weight gain, but like most problems, better dealt with early than late. Okay, so let's, let's, I mean, gosh, I want to get through some of the other meds that cause weight gain. Maybe I'll just mention them and you can jump it and say something, and then let's get to any other solutions we haven't talked about yet. Paroxetine, probably the biggest weight gainer of the SSRIs, tricyclic antidepressants like amatryptylene nortryptylene those have a lot of h2 and serotonin receptor antagonism that caused the weight gain anticholinergic effects lithium which i don't

do you want to give any mention of lithium and how that might do it uh lithium alters a whole host of things including a lot of metabolic parameters in terms of basic energy input and output. You could think of lithium as almost turning down the thermostat on a number of things, including emotions, but also

including a lot of metabolic parameters. Then we have phallproate, depicote. Yes, also increases weight in a number of ways. Of course, increases overall gabber.

urgic tone in the brain, which also decreases energy expenditure. Gabapentin, pre-gabalin. Same thing. Yeah. Okay, so now let's try to think through, like, okay, what could be done? What would be some, like, good pathways? Like, okay, let's go to the most difficult case. You have treatment-resistant schizophrenia.

They're finally starting to get stable on Closopene, but they've gained 50 pounds. Where do you go? I can tell you what the formal recommendations are from nutritionists is to introduce the person to a diet and exercise program. Unfortunately, I can tell you in schizophrenia, that's almost never successful. Even without medications, people with schizophrenia are very difficult to motivate. They often are very prone to poor dietary habits and a sedentary lifestyle. I think for many of those people who've already gained the weight and who look like they're going to continue to gain the weight and close the penis become their only viable option to stabilize their mental illness. Until we find things that are better, I suspect that the GOP-1 agonists or combination GOP-1 and tick agonies.

and it's like Tears but Tide are likely to be the person's best option. Just with the caveat that this might be a lifelong journey. With the caveat that this might be lifelong, but then they're suffering from a lifelong mental illness. See, the problem I see is like, do the insurance companies even pay for these at this point for just plain obesity or just side effects medications? My guess is over time the insurance companies will come to the point

they will pay for these. Frankly, a lot of the schizophrenic population are in the public domain, meaning they're being cared for by public health care systems, and those systems are already moving to in the direction of negotiating for these drugs. I think at this point, I've had a lot of frustration with insurance companies

trying to get them for people unless they have diabetes. Yes, document. Well, their argument, well, insurance companies don't like to pay out money. That's harder for them to argue now that some of these drugs have specific indications for obesity, and it will become harder and harder for them to argue that. My guess is availability will improve with time. One thing that's happened recently that may help is Eli Lilly announced, that they're going to provide their GOP-1 agonist via compounding pharmacy at a substantially

reduced cost for selected patients. Okay. Okay, so you have this person, they're on chlozapine, they're stable, so you might consider the regular diet exercise, you know, if I would say the only success I've had with patients with schizophrenia is if I can get them, well, I've had a couple that go on their own. If they had, if they were doing it before in a very systematic way, I've had more success. I would say to people that, if they weren't, if I could get them to sort of be in some sort of class, you know, at the YMCA or something where it's like there's some group, I don't know,

varying results of success. Yes. The people that I've seen who most often benefit from diet and exercise are those who indeed had a fairly healthy diet and were active exercisers before the onset of their psychosis. It's very difficult to start with somebody who tend to eat a poor diet and was very sedentary prior to the onset of schizophrenia, it's very difficult to get that person up and moving. We have a few recreational therapists

who try their very best to make that happen, but their rates of success are fairly low. Now, granted, where I work, we're not dealing with the younger first-onset psychosis patients. our average patient has been psychotically ill for more than a decade and has often undergone a fair amount of deterioration and is suffering not just from obesity but usually full-blown metabolic syndrome which you can see the writing on the wall

if they don't get that under control their life is going to be foreshortened by things like cardiac disease and liver disease and stroke and everything else that can happen to you if you're diabetic and overweight and have abnormal triglycerides and cholesterol. Yeah. Okay. What about, like let's say they're stable on olanzapine or sparradone or another one of these bigger weight gainers, quatapine. Would you ever consider switching to an antipsychotic that's less of a weight gainer. For everything except Clozapine, yes, I would consider it. Now, it takes a careful consideration

of the person's overall medication history because the big risk, of course, in switching from a successful antipsychotic to something else, is you may lose the psychiatric stability. And I think something people underappreciate is that with every psychotic, psychotic break, there's no guarantee that you're going to recapture stability. Because every time the person has an episode of psychosis, to some extent, their responsiveness to antipsychotic treatment decreases.

Whether it will decrease to a threshold where you just can't recapture them, you know, it's a role of the dice each time. which makes you want to do everything you can to prevent relapse. Those are the elements that you have to weigh while you're wondering, should I switch this person to something that's less prone to weight gain? Unfortunately, many of the medications we have that are either weight neutral or close to it have so far tended not to be our most effective antipsychotics. The one that is probably actually weight neutral,

lorazidone. It is not a bad antipsychotic and relatively new onset psychosis. It has no cardiac effects. It is weight neutral. It doesn't cause metabolic issues. But I can tell you in the more chronically ill, schizophrenic population, it doesn't work very well.

Now, if you're treating bipolar depression, it's a wonderful drug, very potent, very effective. But for chronic schizophrenia, not so much. Same thing is true of drugs like Lomoteperone. No EPS, very little metabolic effect, effect sizes on schizophrenia while they achieve significance. The effect sizes were small,

arguing that it wouldn't be a very likely effective approach in somebody with more severe, somewhat more treatment resistant. illness. Now, the nice thing about the new drug that we started out talking about, Zanolamine, it's not clear how effective it will be compared to other antipsychotics. Some of the pivotal trial data suggests it may be as good as things like Rospatone and haloperidol and olanzapine.

But I never entirely trust pivotal trials because they're very pristine samples and are of limited size. Let's back up because I don't think that was like a private conversation kind of just trying to discuss. So X-A-N-O-M-E-L-I-N-E, which is under investigation, which is a targets the M-1 and M-4 subtypes of the muscular and acetyacetycholine receptors in the brain. Yes.

So it's a unique mechanism. would you just want to say a little bit about it? Yeah, it's unique in that rather than trying to block dopamine post-synaptically, it regulates or modulates the release of dopamine in the ventral-tegmental limbic circuits. So it's more like turning the flow on or off upstream rather than trying to block it downstream. It also stimulates cortical M1 receptors, which may help with cognitive symptoms in schizophrenia. It is metabolically neutral, also does not cause extraparaminal symptoms like dystonia, Parkinsonism, acethesia. It is likely to be approved by the FDA in the late September of this year.

and likely will come to market in early 2025. So it will be an addition to drugs that are not likely to influence metabolic status. Its true efficacy will take time to figure out once we've got more than just the pivotal trial data to work with. Okay, so kind of getting back onto this topic of, okay, So you have a patient, they're stable on an antipsychotic. You could change them. That would risk them decompensating. That's a real risk.

And I think, you know, we had talked about it in another episode how if someone just stops an antipsychotic, the relapse rate is, what, 95%? I think we talked about. Yes. Yes. Which hits huge. It's a train wreck. Which I feel like the anti-psychiatry folks have no idea that that's the case. they're like, huh, what?

No, you just need take this supplementer. Just pure psychotherapy. Which, you know, I'm a fan of psychotherapy. Well, and, you know, people with schizophrenia can benefit from psychotherapy once their psychosis is stabilized.

But as we've talked about, many times, essentially the schizophrenia spectrum disorders are a cluster of developmental dementias. And there are things that psychotherapy can change and there are things that psychotherapy can't change, such as your DNA may be able to make changes in your epigenetic profile to some extent.

But the neuronal loss, synaptic loss, all those things, there's no evidence that psychotherapy reverses those losses. Yeah, so this is where, I think, people who follow the podcast closely know, like there's a good balance between modalities and there's a correct place for medications, there's a correct place for psychotherapy.

There's a correct place for both, ideally both. You know, I would say psychotherapy for someone who's floridly psychotic is mainly aimed at getting them to take the antipsychotic. Yes. It would be mainly aimed at therapeutic alliance, connecting with them, building trust, as much as possible,

so you don't have to, Yeah. And then once they are more stable, meaning their positive symptoms of psychosis have either died out or simmered down at least, then you have the option of, you know, they may very well benefit from things like cognitive rehabilitation, CBT for schizophrenia, things that will help them deal with life as somebody who has a chronic brain disease. because the medications will help decrease the overt symptoms of psychosis. The medications don't teach people how to live. Yep. Okay, so for this topic in particular, I'm wondering if we can kind of like wrap it up in terms of is there anything that you really, that anything else that's floating around your mind that we haven't covered around weight gain, medications, weight loss.

We haven't really talked about, I guess, topiramate, if there's any, you know, any role for a little bit of topiramate on someone? There is. Topiramate is another drug that can produce weight loss. Of course, its limitation is most often cognitive and memory impairment. It also, in some people, particularly if they have unstable renal disease, carries a risk of both renal calculi and metabolic acidosis, things to keep in mind if you intend to use toopirmate.

The weight loss is like many things plus minus. Some people will lose a great deal of weight. Some people it has no effect. With all of these drugs, I think the underlying caveat goes back to the statement I made about everyone having a scale. That includes tracking changes for any treatment intervention you're exploring as well. Is it effective? Yeah. I've seen an adolescent patient in a psychiatric hospital.

hospital when I was a resident, get kidney stones from Topiramate. Yes. And I think when I was taking the history, I was like, huh, that's interesting. They've had these kidney stones, and they've been on Topirmate for six months, and they've had them for the last three or four months, and put it together that they were probably related. And then the cognitive doling, word-finding issues is profound in some patients. Oh, yeah.

It can be very bad. And, you know, when people, when they become anomic, you know you've gone too far with to a pyramid, when you have a conversation and there are no nouns. And let me tell you, let me tell you a nightmareish story of this. I had a patient who was on like 200 twice a day for severe migraines. And she went through a program. I'm going to change a couple of the details here. Not give, you know, always protect the patient's identity.

but she was able to get it down to like 50 once a day over the course of working with me for six months. And her husband came in one day and she's like, I have my wife back. She talks to me now. She was not. For years, she didn't talk to me. And so it's a tragic story of like, you know,

these medications need to be monitored, you know, and figure out like what's, you know, it just blows my mind that that wasn't caught as like, this is the issue. Yes. Yeah, you're in trouble if everything becomes a thing of the jig or what you'll call it. Oh, tell me more about that. Oh, I've had patients who onto pyramid when they were trying to describe something.

Well, you know, it's this thing of a jig. You know, the what you call it? Well, it's sort of, well, it kind of, you know, it did that sort of thing. And of course, I've got no idea what they're talking. about because there are no nouns and no actual verbs that are helpful it's it's like it's a tragic funny it's like a it's like an awful funny um it's some i i see it mostly beyond the dose of around 50 some people some people going from 50 to 100 some people going from 100 to 150 all of a sudden they have less ability to recall names of things um and then if you push it up even

higher than that, it's like, yeah, it gets even worse. Yeah, and it's something certainly, I think that, well, you've heard me advocate this before. Whenever we start a medication with a patient, we need to educate the patient about what the medication's risks and benefits are, including, you know, with toperimate, if you start noticing you can't remember things or you can't find words, I need to know about that sooner rather than later. Yeah. And, yeah,

to pyramid. So, okay, any other things floating in your mind around weight loss? Only, I think as a conclusion, I would say this is an area that psychiatry has

neglected to pay attention to, and in fact, we're actually doing a study in the state hospital system to look at that issue. And it's one we need to pay more attention to because again, we're the patient's physician, not just their psychiatrist.

Yeah. And I think my closing remarks would be, you know, us as providers need to also develop the habits that we ourselves espouse or, you know, desire. And I've had a number of listeners reach out and say, like, oh, you know,

from listening to your episodes on, strength training exercise. I've started a routine and I've been doing it for three years and it's helped me so much. Excellent. And I hope that we can inspire, you know, it takes a while to build a habit. It really does. For me, my habit of strength training is Tuesday and Thursday. I have a group I go to, you know, eight people. And I've been doing that for years and I sometimes posted on Instagram, and then, you know, try to do something everyday exercise, you know, try to do something. Very good.

Yeah, I've got a gymnasium in my garage, which helps because it's convenient. I don't have to go anywhere. And my schedule is Monday, Wednesday, Friday for a full workout, and Tuesday and Thursday for a more minor workout, and then Saturday and Sunday are just more recreational things. is it tough some days to get up and go, yeah, I'm going to go out there and do a full workout. I don't feel like it, but that's the point where you have to tell yourself, well, I'm going to do it anyway. Yeah. In the ideal setting, we find something we can enjoy.

And I would say ideally also we find something that we can do with other people. And, you know, ideally some of that is in nature. but there's a you know it's like what what is the best sport for you as you get older the one that you enjoy you know it's like for some it's pickleball and it's like all they can think about is pickleball it's like great go for it yep don't and i've kind of moved away from thinking like everyone needs to squat and deadlift although i do think everyone needs to squat and deadlift i think it's great i think a little bit of weight training is a very good thing for everyone there's no better form of exercise that will help maintain muscle mass and bone strength.

Now, it doesn't have to be a major amount. If you add just a little bit of weight training to the more aerobic things, it doesn't take all that much to derive the core benefits. In other words, you don't have to become a bodybuilder to get there. But a little bit of weight training goes a long way. Yeah. Very good. And then diet, I think diet is like, you know, it's another habit that takes time. And it's like, how do you eat healthy in community with other people and enjoyable food? For me and my wife, we've improved our habits of eating healthy. And now we do sushi, which is like I consider a very healthy food. and less steak and fries more sushi. So, you know, small changes over time, right?

And trying to do it in a way that's like it's going to be doable and not just doable for like one week and then you switch back to like. Yeah, what I would indeed counsel people is don't do things where you're going to do something drastic for a short period of time because typically it produces more. loss than gain. You may gain in the short term, but in the long term it'll cost you. Small changes that are going to last for the rest of your life are far better for you. Awesome. Okay, we will leave it there for today. Thank you, Dr. Cummys, as always. Pleasure to talk to you. Thank you for your continued mentorship. And I've gotten so much from

this, from you over the years, and I appreciate you. So thank you. Oh, thanks. Okay. All right. We'll leave it there for today.