Episode 223: Managing Weight Gain from Psychiatric Medications with Dr. Michael Cummings
Dr. Puder and Dr. Cummings have no conflicts of interest.
Transcript edited by Joanie Burns DNP, APRN, PMHNP-BC
In this episode, Dr. Michael Cummings, a renowned expert in psychopharmacology, joins Dr. Puder to discuss the complex relationship between psychiatric medications and weight gain. The conversation explores how medications like antipsychotics (clozapine, olanzapine, risperidone) can lead to metabolic challenges such as obesity and dyslipidemia, especially in patients with chronic mental health conditions. Dr. Cummings delves into the role of GLP-1 agonists, a new class of medications showing promise in managing weight gain and metabolic syndrome. He also covers the mechanisms behind drug-induced weight changes, including how histamine and serotonin receptors influence appetite, metabolism, and overall health. The episode provides listeners with practical strategies for managing medication-induced weight gain, offering insights on diet, exercise, and potential pharmacological interventions.
GLP-1 Agonists In Psychiatry And Weight Management
Dr. Puder (00:02:30):
You recently told me there's this push for GLP-1’s [glucagon-like peptides] to be brought into the state and I know that's a hot topic. There's a lot of expensive medications and so I imagine that's the kind of contract that you're looking at. Is that going to be helpful? What are all the details on that?
Dr. Cummings (00:07:45):
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. We've had an obesity epidemic in the country as a whole, but it's worse among the mentally ill (Goldberg, 2023). 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 probably have a prevalence rate of around 60% of people who meet the criteria for obesity and a slightly lower, somewhere in the 50–55% range who meet the formal criteria for metabolic syndrome. Meaning that, in addition to obesity, they have dyslipidemia, hypertension, central adiposity, and all of the health risks that come with that (Shulman et al., 2014). The GLP-1 agonists at this point are about the only class of medications out there that are very good at actually reversing obesity (Goldberg, 2023). There are a number of medications that can slow weight gain such as metformin, but they're not very good at reversing the weight once the weight is on.
Not all of the GLP-1 agonists are great at reducing weight. However, some of the more recent ones, like liraglutide (Larsen et al., 2017), semaglutide, and, in particular, tirzepatide (trade name Mounjaro) 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 (Flory & Lipska, 2019) . We've also discovered that the GLP-1 [glucagon-like peptide] agonists have some unexpected benefits such as reducing alcohol intake, reducing craving for illicit drugs, and at least tiny amounts of data suggesting they may decrease the number of reward-system driven behaviors. That may include things like self-mutilation, self-cutting and other things that might be of benefit in psychiatric patients. The data on those features are pretty new and still pretty small, but they're enticing in the sense that this class of drugs affects 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.
Challenges And Caveats Of GLP-1 Agonists
Dr. Puder: (00:06:58):
I was excited about these (GLP-1s) at first, and honestly, my excitement has decreased because I see people have gotten on them, and then when they get off, they gain their weight back and often the weight comes back not as the muscle that they lost, but more as fat.
Dr. Cummings:
Well, that's an important element with the GLP-1 agonist 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 shown this all the way down to animal studies. If you put a rat on a starvation diet, make it lose weight, and when you give it access to free feeding the first time it will regain the weight it has lost and it will overshoot slightly by 5-10%. If you do the same experiment again with the same rat, it will lose the weight and then when you refeed it, will regain the weight in about half the time and overshoot by more like 15–20%. So 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.
Dr. Puder:
So, just to give people an idea, if people are not exercising while they take them, they could lose 35% lean muscle mass when they lose weight. That's a lot of muscle. And you know, muscle is very helpful for so many reasons. We've talked about this a lot in the podcast before. It's like a neuroendocrine tissue for the brain. It's a very healthy tissue.
Dr. Cummings:
Indeed. The other thing we've talked about with patients is they need not only to maintain exercise, they need to maintain an adequate diet, even if they don't feel hungry. 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.
Dr. Puder: Right.
Dr. Cummings:
You know, an interesting case example I can think of is a woman who started with a BMI of 38—grade two obesity—and by the time she got taken off of the GLP-1 agonist by her attending physician, she was at a BMI of 19. Because, as she put it, “I have a piece of toast and a 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.
Dr. Puder: So hunger and thirst can be eradicated at a high enough dose.
Dr. Cummings:
Yes. And, this was not so in her case. She was at a standard dose, but she was exquisitely sensitive to the effect of the drug. 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.
Dr. Puder:
Yes. I think it's so fascinating because I've seen other patients where it reduces their drive and motivation in other domains of their life. We talked about decreasing the drive to drink alcohol, the drive to drink water, the drive to eat. It acts on the hypothalamus, the brainstem areas involving appetite regulation, reducing the appetite, slowing gastric emptying, but it also hits the reward centers of the brain–nucleus accumbens, ventral tegmental area [VTA]–influencing reward-driven behaviors. Some of which we may not want to decrease.
Dr. Cummings:
Yes. 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, “I want this behavior to go away, but I want that one to be preserved.” 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.
Dr. Puder:
Right. So this could apply to things like gambling, binge eating, and shopping? Right? Those could decrease. But also you could have decreased motivation to engage in physical activities and exercise. And that's what I've seen from people. I'm pleading with them like, “Hey, try this. We need to keep exercising.” And people who have been exercising for years will say, “I just no longer… 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.”
Dr. Cummings:
Yes. The motivation is gone because it no longer induces the same reward it did, which I think the only way around that, if the person really needs the medication, is to have either external ways of being motivated, such as having a trainer who goes, “Get out there and do your lifting,” or, enough internal sense of, “I need to do this because it's good for me, not because it feels good anymore.” Which is a very difficult position. I think sometimes we don't appreciate how much influence our hypothalamus has over our behavior.
Dr. Puder:
So, you're saying if someone's on this, they may need to be on this for a very long time.
Dr. Cummings:
For a very long time. Otherwise, indeed, of 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. If people stop 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.
Dr. Puder:
To give people context, the positive studies showed that within a year on the medication, with some diet coaching, you could lose about 15–20% of your body weight. And so when people get off of it, they're gaining weight back, is what you're saying?
Dr. Cummings:
Yes. 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.
Dr. Puder:
Do you think there's a rebound? \
Dr. Cummings: Yes.
Dr. Puder: With receptor density? Does that change? Does that rebound? Do we know about that?
Dr. Cummings:
Yes, 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, you know, anything that goes along with that, if you were glucose intolerant, 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.
Dr. Puder:
So what we're talking about then is that one needs to actually change habits and on a very deep, deep level, right? So it's like the basal ganglia, the deep brain structure, is involved in habit formation, motor control and somehow we need to institute habits slowly, maybe one at a time. Or, maybe we only change one habit per month or every two months. The question is, how do you change habits?
Dr. Cummings:
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 and I have talked before about what has happened in modern cultures. Historically, obesity was not such a huge problem. If you had to do hours of manual labor, or you 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.
Dr. Puder:
The problem is that a lot of the medications we give increase weight.
Dr. Cummings: Yes.
Psychiatric Medication And Weight Gain
Dr. Puder (00:18:00):
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 new problem from the medication and I'm trying to figure out how to best help these people. So yes, this is the big sort of overarching problem.
Let's talk about different medications and why they increase weight (Mizuno et al., 2014), starting with the biggest culprits.
Clozapine and Olanzapine and Weight Gain
Dr. Cummings (00:18:45):
Okay. The biggest culprits are clozapine and olanzapine. And they both do a number 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 toward 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 (Goldberg, 2023). 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.
Now, in the case of these two medications, they also have additional effects that promote weight gain. They're pretty good H1 histamine antagonists (Foster et al., 2021). They block histamine receptors. People are very familiar with that in terms of when 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 they do is, in the case of these two drugs, antagonize 5-HT2C receptors. These are serotonin receptors that function in the hypothalamus, in the satiety center, to tell you when you've had enough to eat. If you block 5-HT2C 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, is another great way to gain further weight.
Dr. Puder:
So you have the histamine H1 receptor antagonism, which can cause some nice sedation if they're having difficulty sleeping, but also increases appetite and decreases the metabolic rate. Then you have the serotonin 5-HT2C receptor antagonism. Which they both block in the brain, which leads to…
Dr. Cummings:
… carbohydrate craving. The person wants sugar. I can't tell you how many patients I've seen put on clozapine or olanzapine and they come back and they'll tell me in so many terms, ”I am hungry all the time and what I want is every single sweet thing I see.”
Dr. Puder:
“I'm eating cereal in the middle of the night, sometimes twice.”
What about the M3 receptor antagonism? Do you think that is involved in the insulin secretion?
Dr. Cummings:
Yes. It's involved in insulin secretion, and it probably also does play a role in these people becoming glucose intolerant along with impairment of the functioning of the GLP-1 receptors, which is where the GLP-1 agonists come into the story. They directly oppose the effects of olanzapine and clozapine and similar drugs at the modulation point of that receptor. The change in insulin balance appears to be the most important of the driving forces toward obesity and metabolic syndrome with the antipsychotics. That is likely why olanzapine and clozapine are at the top of the list in terms of producing these effects because they cause the greatest disturbance in those systems.
Dr. Puder:
Okay. Let’s get a little bit deeper into leptin & ghrelin. So leptin promotes satiety. Ghrelin stimulates appetite. Olanzapine and clozapine both disrupt the normal leptin & ghrelin signaling.
Dr. Cummings:
Yes. And they essentially shift the balance of these in the direction of increased calorie intake. Whereas, the GLP-1 agonists shift the same systems in the opposite direction.
Dr. Puder:
So they increase ghrelin levels, which increases the hunger hormone. A blunted leptin response results in decreased satiety hormone. So then increased calorie intake and weight gain result.
Dr. Cummings:
Yes. And at the same time, the antihistamine effects are decreasing calorie output. So, you know, it's the classic story with weight gain. You have increased calorie intake and decreased calorie output, and that extra energy gets stored as adipose tissue.
Insulin and Weight Gain
Dr. Puder: (00:24:52):
I think insulin is gonna be something huge to look at in coming podcasts and just how important it is to be metabolically healthy, you know, in people with increased rates of depression. If out of control, diabetes has much higher rates of depression. Insulin is impaired in these patients. You want to talk more about that?
Dr. Cummings:
Insulin is critically important in human physiology. During active exercise, skeletal muscle 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 an elevated circulating 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. 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.
Dr. Puder:
What I think is the most wild thing about this is the average human, without any glucose regulation issues, they probably have on average about one teaspoon of total sugar, total glucose in their blood at a given time. If you were to drain all of my blood, it might have a teaspoon right now.
Dr. Cummings:
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 [adenosine triphosphate] and essentially provide the energy for the cell. 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.
Dr. Puder:
So imagine someone who is floridly diabetic. Instead of one teaspoon in their blood, total glucose, they have three teaspoons. That's not that much if you think about it, in the big picture of how much sugar we actually drink sometimes. Three teaspoons is not that much, right?
Dr. Cummings:
No, it isn't. But it's the shift in getting it to where it needs to be. 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. In the case of type 2, it's because the person is resistant to the presence of insulin.
Dr. Puder:
And then we also think about steroid use–always increased glucose. And, someone who's in a high stress state, there's a transient fight and flight type of response in you. With hyperglycemia–high blood sugar.
So we have these medications that are great medications for treating psychosis, but do cause weight gain.
Dr. Cummings:
This fits into the discussion of the GLP-1 agonists, the antipsychotics, the 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, the model 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 gonna get more benefit out of this than risk? Obviously, if you don't want to take 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 benefits safely.
Risperidone: Influence on Weight Gain and Prolactin
Dr. Puder: (00:30:40):
Risperidone is another atypical antipsychotic. This one can cause weight gain, as well. There's one mechanism which I think is unique, which is the prolactin elevation, which sometimes occurs (Shimatsu & Hattori, 2012).
Dr. Cummings:
Yes, risperidone, and its metabolite, paliperidone, are both excellent substrates for p-glycoprotein, which is an efflux pump. There are two main places of interest, the blood-brain barrier and the GI tract. The blood-brain barrier is important because it directly pumps these drugs from the brain into the hypophyseal circulation, which 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 take away that tonic inhibition, the person will secrete more. They will synthesize more. And the increased synthesis will also drive division of pituicytes that make prolactin, which may eventually result in microadenoma and may eventually result in a macroadenoma (Pekić et al., 2019). All of which is to say that these drugs are especially good at elevating prolactin, which can promote weight gain. But prolactin's normal role is to promote lactation. 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 weight due to prolactin.
Dr. Puder:
So in men with high prolactin, their testes may not work as well, there is decreased testosterone, they may get gynecomastia (breast tissue development). They may have erectile dysfunction, decreased libido, infertility. So, as we give risperidone, we need to watch out for this. This is not something we want them to live with chronically.
Dr. Cummings:
No. 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 galactorrhea, amenorrhea, or erectile dysfunction.
Dr. Puder:
Also, it can cause osteopenia, osteoporosis.
Dr. Cummings:
Yes. And, in both men and women, it does increase the risk of breast cancer, as well. More so in women, of course, but not unheard of in men exposed to prolactin-elevating drugs.
Dr. Puder:
There have been a couple questions in our Q&A that we haven't gotten to about what we do if someone has high prolactin when they're on risperidone. What's your algorithm for what you would do first?
Dr. Cummings:
If somebody's on risperidone and they have responded, one option to consider would be, might you want to switch them to an alternative dopamine antagonist? Risperidone and paliperidone 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 risperidone and 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 are things like pramipexole, bromocriptine and, you'll see it recurrent in the literature, aripiprazole. The trouble with the last one is it's very easy to switch antipsychotics in that case without meaning to. Basically, the binding of aripiprazole is so high. The binding affinity is so high that, on average, giving somebody two milligrams of aripiprazole means the aripiprazole is going to 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 aripiprazole, whatever antagonist you're giving the person, you have replaced it with aripiprazole. Because the other drug, at that point, has nothing to work with.
Dr. Puder:
What about dose reduction? Could you reduce the dose of risperidone?
Dr. Cummings:
You can. If the person is at a higher dose, you can reduce the dose and thereby reduce the effect of the drug on 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.
Dr. Puder:
Let's say someone has this problem. They know that the patient probably has high prolactin. They figured that out. How fast should they solve this problem? Like, how urgent of an issue is this?
Dr. Cummings:
They should solve it within three to six months.
Dr. Puder:
Okay. That's helpful because that's a different level of a problem than like akathisia.
Dr. Cummings:
Yes, because of 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 has overt galactorrhea or 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 huge cost in terms of destabilizing the person. Again, in the asymptomatic prolactin elevation patient the elevation, per se, is not an emergency.
Dr. Puder:
This is good because we need to know how quickly we need to solve the issue. So you have some time. You can move slowly. You can follow them 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, probably mirtazapine (Remeron). It has some good H2 receptor antagonism.
Dr. Cummings:
It's also a great blocker of 5-HT2C. And indeed, it produces exactly the same response, i.e., the patient will be thinking, “I've never seen a donut that I don't like.”
Dr. Puder:
I've had different responses. Some patients have no issues, very little weight gain. Some people, it's like, “Whoa!” Okay, we're going 15 pounds in a couple months. And we need to think of something else here.
Assessing Side Effects And The Importance Of Early Intervention
Dr. Cummings (00:39:44):
And in that case, the safest thing to do is choose a different antidepressant or anti-akathisia medication–that's its other major use. Like all medications, people vary in terms of how much they respond to blockade to 5-HT2C. 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 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.
In 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 ____” (and usually it's olanzapine or clozapine where I work, but it could be mirtazapine just as easily); and I'll get a call from the psychiatrist, “Well, my patient has 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 are psychiatrists.
Dr. Puder:
Yes. The caveat being risk reward. I have one patient, in particular, I'm thinking of, who gained maybe 50 pounds or so. And he's lost some. He's going down slowly, with lifestyle things, but he doesn't really care. He, and his significant other, are like, “You know, we are in such a better place in terms of our marriage, in terms of the arguments we have in terms of him floridly not being psychotic, it's not our priority.” For other people, it would be…
Dr. Cummings:
…a major priority. But, our job, as the physician in this context, is to spot the problem early. You know, it should never be the case that, “Oh, my patient has gained 120 pounds.” You know, if you are actually weighing them every time they come to 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 it out for them: “These are the risks of gaining too much weight. 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.” That discussion needs to occur early on, not when you finally notice when the patient can't get through your office door.
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 and if they gain 5% above that in the first month, or 7.5% in three months, or 10% in six months. You're looking at somebody who's going to have a long-term weight/metabolic problem with the medication you're giving them.
The advantage, of course, is that if you spot the trend early, it's easier to address. You know, 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 (Chen et al., 2013; Mizuno et al., 2014). You wouldn't have to go to a GLP-1 if you're trying to keep it off, not reverse it. So, there are options out there for dealing with weight gain. But like most problems, better dealt with early than late.
Other Psychotropics Known To Cause Weight Gain
Dr. Puder: (00:44:20):
I want to get through some of the other medications that cause weight gain. Paroxetine (probably the biggest weight gainer of the SSRIs), tricyclic antidepressants like amitriptyline, nortriptyline (have a lot of H2 and serotonin receptor antagonism that causes the weight gain and anticholinergic effects), lithium. Do you want to give any mention of lithium and how that might do it?
Dr. Cummings:
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.
Dr. Puder:
Then we have valproate (Depakote).
Dr. Cummings:
Yes. Also increases weight in a number of ways. Of course, increases overall GABAergic tone in the brain, which also decreases energy expenditure.
Dr. Puder: Gabapentin, pregabalin.
Dr. Cummings: Same thing.
Multimodal Approaches To Address Medication-induced Weight Gain
Dr. Puder (00:45:47):
Now let's try to think through what could be done. What would be some good pathways? Let's go to the most difficult case. You have treatment-resistant schizophrenia. They're finally starting to get stable on clozapine, but they've gained 50 pounds. Where do you go?
Dr. Cummings:
I can tell you that the formal recommendation 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 weight and who look like they're going to continue to gain weight, clozapine is their only viable option to stabilize their mental illness. Until we find things that are better, I suspect that the GLP-1 agonists or combination GLP-1 and GIP [glucose-dependent insulinotropic polypeptide] agonists, like tirzepatide, are likely to be the person's best option.
Dr. Puder:
Just with the caveat that this might be a lifelong journey.
Dr. Cummings:
With the caveat that this might be a lifelong, but, then again, they're suffering from a lifelong mental illness.
Dr. Puder:
The problem I see is, do the insurance companies even pay for these at this point for just plain obesity or just side effects?
Dr. Cummings:
My guess is, over time, the insurance companies will come to the point that 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 healthcare systems. And those systems are already moving in the direction of negotiating for these drugs.
Dr. Puder:
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.
Dr. Cummings:
Yes. 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 happened recently that may help is Eli Lilly announced that they're going to provide their GLP-1 agonist via compounding pharmacy at a substantially reduced cost for selected patients.
Dr. Puder:
Okay. So you have this person, they're on clozapine. They're stable. So, you might consider diet and exercise. 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 were doing it before in a very systematic way, they would have more success. Yes. 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 there's some group. Very varying rates of success.
Dr. Cummings:
The people 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 tended 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. You can see the writing on the wall. If they don't get that under control, their life is going to be shortened 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 (Minuzo et al., 2024).
Dr. Puder:
What about, say they're stable on olanzapine, risperidone, or another one of these bigger weight gainers like quetiapine. Would you ever consider switching to an antipsychotic that's less of a weight gainer?
Dr. Cummings:
For everything except clozapine, yes, I would consider it. Now, it takes 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 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, it's a roll 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 actually weight neutral, lurasidone, is not a bad antipsychotic in 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 lumateperone. 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 effective approach in somebody with a more severe, somewhat more treatment-resistant illness. The new drug that we started out talking about, xanomeline, 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 risperidone and haloperidol and olanzapine. But I never entirely trust pivotal trials, because they're very pristine samples and they are of limited size.
New Medications Being Studied
Dr. Puder: (00:54:26):
Let's back up because that was part of a private conversation. So xanomeline, which is under investigation, targets the M1 and M4 subtypes of the muscarinic and acetylcholine receptors in the brain (Foster et al., 2021; Paul et al., 2022). So it's a unique mechanism.
Dr. Cummings:
Yes. It's unique in that, rather than trying to block dopamine postsynaptically, it regulates, or modulates, the release of dopamine and the ventral tegmental limbic circuits. So that 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, it does not cause extrapyramidal symptoms like dystonia, Parkinsonism, akathisia. It is likely to be approved by the FDA in the late September of this year [2024], 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.
Medication Changes And The Risk of Decompensation
Dr. Puder: (00:56:22):
So let’s say you have a patient and they're stable on an antipsychotic. You could change the medication. 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 95%.
Dr. Cummings:
Yes. It's huge. It's a train wreck.
Dr. Puder:
Which I feel like the anti-psychiatry folks have no idea that's the case. They're like, “Huh, what? No, you just need to take this supplement or just pure psychotherapy.” Which, you know, I'm a fan of psychotherapy.
Dr. Cummings:
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 dementia. And there are things that psychotherapy can change. And there are things that psychotherapy can't change, such as your DNA. Therapy 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.
Dr. Puder:
Yes. So this is where I think people who follow the podcast closely know 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. I would say psychotherapy for someone who's floridly psychotic is mainly aimed at getting them to take the anti-psychotic. And it would be mainly aimed at therapeutic alliance, connecting with them, building trust as much as possible.
Dr. Cummings:
Once they are more stable, meaning positive symptoms of psychosis have either died out or simmered down, at least, then you have the option, you know, and 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. The medications will help decrease the overt symptoms of psychosis, but the medications don't teach people how to live.
Topiramate For Weight Loss: Cognitive Impairments, Renal Risks, And Patient Monitoring
Dr. Puder: (00:59:17):
We haven't really talked about topiramate and if there's any role for a little bit of topiramate for someone?
Dr. Cummings:
There is. Topiramate is another drug that can produce weight loss (Mizuno et al., 2014). Of course, its limitation is most often cognitive and memory impairment. It also, in some people, particularly if they have unstable renal disease, carries their risk of both renal calculi and metabolic acidosis. Things to keep in mind, if you intend to use topiramate, the weight loss is like many things, plus/minus, some people will lose a great deal of weight and 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?
Dr. Puder:
Yes. I've seen an adolescent patient in a psychiatric hospital, when I was a resident, get kidney stones from topiramate.
And I think when I was taking the history, I was like, “Oh, that's interesting. They've had these kidney stones and they've been on topiramate for six months and they've had them for the last three or four months.” Put it together that they were probably related. And then, the cognitive dulling. You know, word finding issues are profound in some patients.
Dr. Cummings:
Yes. It can be very bad when people become anomic. You know you've gone too far with topiramate when you have a conversation [with someone on topiramate] and there are no nouns.
Dr. Puder:
Let me tell you a nightmarish 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 gonna change a couple of the details here. I always protect the patient's identity. 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 he's like, ”I have my wife back. She talks to me now. For years she didn't talk to me.” And so it's a tragic story of these medications that need to be monitored. It just blows my mind that that wasn't caught.
Dr. Cummings:
Yes. Well, you're in trouble if everything becomes a ”thingamajig” or a “whatchamacallit.”
Dr. Puder:
Tell me more about that.
Dr. Cummings:
I've had patients who were on topiramate, when they were trying to describe something, “Well, you know, it's this thingamajig. You know, the whatchamacallit. Well, it 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.
Dr. Puder:
It's a tragic funny. It's an awful funny. I see it mostly beyond the dose of around 50. In some people, going from 50 to a hundred, some people going from a hundred to 150, all of a sudden they have less ability to recall names of things. And then if you push it up even higher than that and it gets even worse.
Dr. Cummings:
Whenever we start a medication with a patient, we need to educate the patient about what the medication's risks and benefits are, including with topiramate. 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.
Integrating Strength Training And Psychiatry: Building Habits For Providers And Patients
Dr. Cummings: (01:03:31):
In 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. It's one we need to pay more attention to, because, again, we're the patient's physician, not just their psychiatrist.
Dr. Puder:
I think my closing remarks would be that, as providers, we need to also develop the habits that we ourselves espouse or desire. I've had a number of listeners reach out and say things like, ”Oh, you know, from listening to your episodes on strength training exercises, I've started a routine and I've been doing it for three years, and it's helped me so much.”
Dr. Cummings: Excellent.
Dr. Puder:
I hope that we can inspire. 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, with eight people, and I've been doing that for years. And then I try to do something every day.
Dr. Cummings:
Very good. 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 gonna go out there and do a full workout. I don't feel like it.” But, you know, that's the point where you have to tell yourself, “Well, I'm gonna do it anyway.”
Dr. Puder:
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. Ideally some of that is in nature. What is the best sport for you as you get older, the one that you enjoy? For some, it's pickleball. And all they can think about is pickleball. I've kind of moved away from thinking that everyone needs to squat and deadlift. Although, I do think everyone needs to squat and deadlift. I think it's great.
Dr. Cummings:
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.
Building Lifelong Healthy Eating Habits: Small Dietary Changes For Sustainable Health
Dr. Puder: (01:06:34):
And then diet. I think diet is another habit that takes time. And how do you eat healthy in a 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 I consider a very healthy food. And less steak and fries, more sushi. So, small changes over time. Right. And trying to do it in a way that's going to be doable; and not just doable for like one week and then you switch back.
Dr. Cummings:
Yes. What I would counsel people is, “Don't do things where you're going to do something drastic for a short period of time, because typically that produces more loss than gain. You may see gains 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.”
Dr. Puder:
Awesome. Okay. We will leave it there for today. Thank you, Dr. Cummings. As always, it’s a 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.
Dr. Cummings: Oh, thanks.
Dr. Puder: Okay. All right. We'll leave it there for today.
References:
Chen, C. H., Huang, M. C., Kao, C. F., Lin, S. K., Kuo, P. H., Chiu, C. C., & Lu, M. L. (2013). Effects of adjunctive metformin on metabolic traits in nondiabetic clozapine-treated patients with schizophrenia and the effect of metformin discontinuation on body weight: a 24-week, randomized, double-blind, placebo-controlled study. The Journal of clinical psychiatry, 74(5), e424–e430. https://doi.org/10.4088/JCP.12m08186
Flory, J., & Lipska, K. (2019). Metformin in 2019. JAMA, 321(19), 1926–1927. https://doi.org/10.1001/jama.2019.3805
Foster, D. J., Bryant, Z. K., & Conn, P. J. (2021). Targeting muscarinic receptors to treat schizophrenia. Behavioural brain research, 405, 113201. https://doi.org/10.1016/j.bbr.2021.113201
Goldberg, J. F. (2023). GLP-1 agonists for weight loss: What you need to know. Current Psychiatry, 22(1), 20–27. https://doi.org/10.12788/cp.0318
Larsen, J. R., Vedtofte, L., Jakobsen, M. S. L., Jespersen, H. R., Jakobsen, M. I., Svensson, C. K., Koyuncu, K., Schjerning, O., Oturai, P. S., Kjaer, A., Nielsen, J., Holst, J. J., Ekstrøm, C. T., Correll, C. U., Vilsbøll, T., & Fink-Jensen, A. (2017). Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder: A Randomized Clinical Trial. JAMA psychiatry, 74(7), 719–728. https://doi.org/10.1001/jamapsychiatry.2017.1220
Mizuno, Y., Suzuki, T., Nakagawa, A., Yoshida, K., Mimura, M., Fleischhacker, W. W., & Uchida, H. (2014). Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis. Schizophrenia bulletin, 40(6), 1385–1403. https://doi.org/10.1093/schbul/sbu030
Paul, S. M., Yohn, S. E., Popiolek, M., Miller, A. C., & Felder, C. C. (2022). Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia. The American journal of psychiatry, 179(9), 611–627. https://doi.org/10.1176/appi.ajp.21101083
Pekić, S., Medic Stojanoska, M., & Popovic, V. (2019). Hyperprolactinemia/Prolactinomas in the Postmenopausal Period: Challenges in Diagnosis and Management. Neuroendocrinology, 109(1), 28–33. https://doi.org/10.1159/000494725
Shimatsu, A., & Hattori, N. (2012). Macroprolactinemia: diagnostic, clinical, and pathogenic significance. Clinical & developmental immunology, 167132. https://doi.org/10.1155/2012/167132
Shulman, M., Miller, A., Misher, J., & Tentler, A. (2014). Managing cardiovascular disease risk in patients treated with antipsychotics: a multidisciplinary approach. Journal of multidisciplinary healthcare, 7, 489–501. https://doi.org/10.2147/JMDH.S49817
Further reading not covered in episode:
Reich, N., & Hölscher, C. (2022). The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review. Frontiers in Neuroscience, 16. https://doi.org/10.3389/fnins.2022.970925
Shetty, R., Basheer, F. T., Poojari, P. G., Thunga, G., Chandran, V. P., & Acharya, L. D. (2022). Adverse drug reactions of GLP-1 agonists: A systematic review of case reports. Diabetes & metabolic syndrome, 16(3), 102427. https://doi.org/10.1016/j.dsx.2022.102427