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Managing Metabolic Side Effects in Schizophrenia

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Individuals with schizophrenia are at high risk of obesity, elevated lipids, increased insulin resistance, diabetes, and cardiovascular disease. On average, people with schizophrenia die 20–25 years sooner than those without schizophrenia. How can we spot metabolic side effects early in our patients, and what should we be looking for exactly? 

Victoria Hendrick, MD, and Stephen Marder, MD, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.

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Published On: 12/8/2021

Duration: 16 minutes, 42 seconds

Referenced Article:Weight Gain and Metabolic Side Effects,” The Carlat Hospital Psychiatry Report, July/August/September 2021



Dr. Hendrick:  Individuals with schizophrenia are at high risk of obesity, elevated lipids, increased insulin resistance, diabetes, and cardiovascular disease. On average, people with schizophrenia die 20–25 years sooner than those without schizophrenia. It’s important for clinicians to be mindful of the metabolic effects associated with the illness itself, and with the antipsychotic drugs used to treat it. How can we spot metabolic side effects early in our patients, and what should we be looking for exactly? And what should we do after we’ve identified significant and detrimental metabolic changes in our patients? In this podcast, Dr. Marder and I will discuss the metabolic side effects potentially afflicting our patients and how they can best be managed. 

Welcome to The Carlat Psychiatry Podcast

This is an episode from The Carlat Hospital Psychiatry Report.

I’m Dr. Victoria Hendrick, the Editor-in-Chief of The Carlat Hospital Psychiatry Report, and a clinical professor at the David Geffen School of Medicine at UCLA. I’m also the director of inpatient psychiatry at Olive View — UCLA Medical Center.

Joining us in this episode is Dr. Stephen Marder. He is the Daniel X. Freedman Professor of Psychiatry, the Vice-Chair for Education, and the Director of the Section on Psychosis at the UCLA Semel Institute for Neuroscience and Human Behavior. He is also the Director of the VISN 22 Mental Illness Research, Education Clinical Center (MIRECC) for the Department of Veterans Affairs.

Dr. Marder, can you please tell us a little bit about how antipsychotics can induce weight gain in our patients with schizophrenia. 

Dr. Marder: There’s substantial literature about the biology of feeding behavior, and that is that there are peptides from the intestine and the gut that sort of communicate with the hypothalamus that regulates eating behavior. And, in particular, it appears that antipsychotics interfere with satiety experiences; that somehow in this very complex relationship between the gut and the brain that the antipsychotics prevent patients from experiencing satiety.

Dr. Hendrick: Are patients with schizophrenia, regardless of whether they’re treated with an antipsychotic or not, at a higher risk of metabolic complications, such as developing diabetes and obesity, versus the general population? 

Dr. Marder: Well, it’s a good question. If you look at people who are drug naïve (they never had an antipsychotic drug), you find that they have something like three times the risk of developing diabetes, and that’s probably due to shared susceptibility genes between diabetes and schizophrenia. So, as a population they should be viewed as having a greater risk. And then when you add other risk factors such as you know the things that we’ve talked about it increases substantially. And then when you add antipsychotic drugs it takes that hazard ratio of about 3.0 and adds an additional hazard ratio of additional 3.6. So it’s a combination of factors that sort of add up to the diabetes risk.

Dr. Hendrick: Adding on to that, studies have shown that having a lower body mass index (BMI) prior to treatment places people at more risk for weight gain. Also, first-episode patients and younger patients are at greater risk, particularly adolescents. And rapid weight gain in the first month of treatment predicts significant long-term weight gain. Other factors associated with medication-induced weight gain are gender (women being at greater risk) and non-Caucasian ethnicities.

It sounds like we should look out for metabolic changes in all of our patients treated with an antipsychotic, especially those with schizophrenia. How should clinicians monitor and assess metabolic changes in our patients?

Dr. Marder: I believe that picking up relatively early that somebody is at risk is a good sign. So, for example, in Guidelines, that I participated in, we recommend that clinicians weigh patients at every visit, and, if there is not a scale in the office, we should suggest to the patient that they weigh themselves at home. Clinicians should look at early signs of weight gain even during the first weeks of treatment. So, for example, if somebody that is started on an antipsychotic drug gains as little as 1 BMI unit, that should be a concern that they’re at risk for weight gain. 

We have also recommended that very early on in treatment that clinicians look for signs of prediabetes or insulin resistance. So that would include things like ordering either fasting blood glucose or a hemoglobin A1C to look for evidence that the antipsychotic itself is predisposing the person to weight gain and diabetes.

We definitely recommend a lipid panel – you know elevations in triglycerides can indicate that the person is at greater risk for diabetes and weight gain, that it can be early evidence of developing insulin resistance. So yes I would add that as well.

Dr. Hendrick: Okay, so we should definitely check our patient’s weight at every visit to see if their BMI is trending upwards. It’s also a good idea to recommend to your patient that they weigh themselves at home often. This can help your patient take greater ownership of this issue, and allow them to respond more rapidly to and be more mindful of any increases in their weight. And what about the blood tests? How often or when should we do the blood tests that you mentioned?

Dr. Marder: With regard to blood tests, we recommend that if somebody starts a new antipsychotic drug, particularly one associated with weight gain, getting you to know an A1c, a fasting blood glucose or a lipid panel within 6 to 8 weeks is probably a good idea because a lot of these changes occur relatively early in treatment.

Dr. Hendrick: My colleagues and I performed a literature review where we examined whether treatments for antipsychotic-induced weight gain were more effective before or after patients gained weight. Our purpose for investigating this topic was to uncover if better weight gain treatment outcomes resulted from earlier intervention initiation. We reported that the first 3 months of treatment represent a critical period for preventative interventions. Beyond that time, when patients have already gained a significant amount of weight, it’s much harder for them to return to their baseline weight.

So, Dr. Marder, can you tell us about the possible interventions for combating antipsychotic-induced weight gain?

Dr. Marder: The simplest and sometimes the most effective thing is changing the antipsychotic. So what I would emphasize is if you put someone on a drug like olanzapine or quetiapine tell them about the problems with weight gain, and I should add other antipsychotics as well, and then evaluate them early, interact with them, and if that drug is promoting even a little bit of weight gain change the antipsychotic.

Dr. Hendrick: Which antipsychotics are the worst offenders in terms of their risk of weight gain?

Dr. Marder: Oh, clozapine, olanzapine, quetiapine – I would say that they stand out as the medications with the most concerning metabolic profile. But there are patients who certainly gain weight on drugs that are not considered high risk. For example, risperidone, when we began doing some of the phase II trials with risperidone back in the 1990s, I remember a patient every early on developing diabetic ketoacidosis on risperidone. So I mean not all of the antipsychotics, but the majority of them do have at least some metabolic risk.

Dr. Hendrick: What pharmacotherapeutic agents do you recommend that clinicians use for treating the weight gain side effects of antipsychotics?

Dr. Marder: Well, we definitely are predisposed to starting with metformin. It’s the one where there’s the most evidence; it’s relatively easy to prescribe; it’s usually well tolerated. There’s some evidence that topiramate is effective, but because of the cognitive side effects of topiramate, it’s not our first drug of choice. 

There is some evidence recently that liraglutide, or Victoza, might be an effective drug. This is a glucagon-like peptide-1 agonist which seems to be closer to the mechanism of causing weight gain from antipsychotics than other drugs. But that’s a relatively new drug; it needs to be administered subcutaneously, but there is some evidence that that can be effective.

Dr. Hendrick: What about the new combination pill, olanzapine/samidorphan? How does this pill reduce the risk of weight gain with antipsychotic treatment?

Dr. Marder: Right. This is a combination pill where samidorphan, which is an opioid antagonist, is added to olanzapine. And again if you look at the data which is published in a couple of recent articles in The American Journal of Psychiatry, what it does is that it appears to attenuate the weight gain from olanzapine. So it doesn’t prevent it entirely but it substantially decreases weight gain.

Dr. Hendrick: Are there any effective lifestyle changes that have evidence for reducing weight gain and metabolic changes in patients with schizophrenia?

Dr. Marder: Well, you know the first thing I do, and I don’t want to leave this out is if you start someone on a drug like olanzapine or quetiapine to make them aware of how those drugs cause weight gain. 

I think it’s important to tell patients about that effect because sometimes by mere portion control they can prevent weight gain if they are motivated.

The other thing to mention, as you mentioned, lifestyle interventions work, and there are probably dozens of well-controlled studies of different kinds of interventions usually that include nutritional counseling – sort of having people document for themselves what they are eating, and exercise. And all of them work. 

They are not always easy to implement, but it’s really important to dispense with the bias that people with psychotic illnesses aren’t illnesses or motivated to regulate their weight; many of them are, and that’s particularly true early on in the illness. Young people who gain weight are often devastated by it. 

So all of these interventions work; the ones that work better are the ones that include a lot of patient interaction that are longer. You just can’t do this for 8 weeks or 12 weeks; it’s got to be kind of a sustained intervention. And ones that have active monitoring, and that could be by both patients having food diaries that are shared and using you know wearable things to give patients kind of feedback whether they are exercising adequately. So I think there’s a lot of evidence that we should be recommending these things.

The other thing to emphasize is that there are effects of exercise that go beyond just weight control and cardiovascular health. 

Dr. Hendrick: Yeah, I recently read an article that highlighted the benefits of exercise for negative symptoms in schizophrenia. Can you tell us about the relationship between exercise and schizophrenia?

Dr. Marder: Exercise is actually good for managing the illness itself. Exercise promotes neuroplasticity; patients are better able to learn when they exercise. There is actually some evidence from studies done at UCLA that it can actually increase gray matter when you compare people who exercise with people who don’t. 

It improves cognition; you know if you measure people before and after in controlled studies done both at UCLA and elsewhere. 

So the effects of exercise are certainly helpful for physical health, but they have additive effects in helping to manage the schizophrenia itself.

Dr. Hendrick: So to summarize, Dr. Marder, we need to be more aware of the risks of weight gain and diabetes in our patients. When we begin to notice weight gain and metabolic changes in our patients after starting an antipsychotic, it appears that intervening in a preventative manner is more effective for reducing and managing our patient’s weight than starting treatment after the patient has gained a significant amount of weight. Tracking weight at every visit, encouraging exercise, and dietary interventions are important for monitoring and addressing weight gain efficiently and effectively. If your patient has increased their BMI by 1 point or more, consider starting them on metformin, which is so well-tolerated, or switching to another agent that doesn’t cause so much weight gain.

Dr. Marder, is there anything else you’d like to add before we sign off? 

Dr. Marder: You know I think it’s probably a good idea for clinicians if they’re prescribing an antipsychotic to go to some kind of source to look at the risk for weight gain. You know they can go to UpToDate and they can go to other sources to sort of let them know about the relative liabilities of different drugs. And people in practice who don’t prescribe a lot of antipsychotics that’s probably something to consider.

Dr. Hendrick: Thank you so much, Dr. Marder,  for helping us unpack this prevalent side effect, and how we can best tackle it. 

The print version of this interview is available for subscribers to read in The Carlat Hospital Psychiatry Report. This newsletter article also contains a handy table that categorizes antipsychotic agents based on their respective risks of inducing weight gain, glucose abnormalities, and hyperlipidemia. When you’re prescribing or switching antipsychotics, you can use this table as a quick guide for the metabolic risks associated with each antipsychotic. 

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