Schizophrenia Podcast

What Are the Major Metabolic and Neurologic Risks Associated With Antipsychotic Medications?

John M. Kane, MD; Christoph U. Correll, MD


August 02, 2022

This transcript has been edited for clarity.

John M. Kane, MD: Hi. I'm John Kane, professor and chairman of psychiatry at the Donald and Barbara Zucker School of Medicine in New York and also the Zucker Hillside Hospital. Welcome to Medscape's InDiscussion series on schizophrenia. Today we'll discuss the major metabolic and neurologic risks associated with antipsychotic medications.

First, let me introduce my guest. We're very pleased to have Dr Christoph Correll, who's professor and head of child and adolescent psychiatry at the Charité in Berlin. He's also professor of psychiatry and molecular medicine at the Donald and Barbara Zucker School of Medicine in New York. Dr Correll is one of the most well-published and highly cited experts in all of psychiatry. In fact, we had a hard time choosing a single topic today as he's an expert in so many different areas. Christoph, thanks for joining us.

Christoph U. Correll, MD: Thanks for having me.

Kane: Let me start off with a case that could lead to some discussion about the relevant issues. We have J.S., a 20-year-old man who was attending university when he experienced an acute psychotic episode, resulting in admission to the psychiatric unit at a local hospital, where he received the diagnosis of schizophrenia. He has never received antipsychotic medication, and he and his parents are concerned about side effects — both short-term and long-term side effects. Another relevant point is that his body mass index (BMI) is 28. How would you approach treatment decisions for someone like this?

Correll: Thanks for bringing up this case. First, we need psychoeducation about the illness, but also about the treatment and the need for treatment. Very often, before you can say a second sentence about the risks and benefits, the first question is, how long do I have to be on this? But I would not really address that at that point and say, let's just first get this situation under control and understand the efficacy and the safety. And we obviously want to balance this.

Now, medications can have side effects, whether that's for a medical condition or psychiatric conditions. Often they come early, and often the body gets used to it. And the brain too. Some may stay. We can monitor them and can do something about it. There are very few side effects that would be permanent if we were to stop the medication. So in that sense, we can monitor and address side effects and we can choose some of the side effects that you might be particularly interested in not having. But the first thing is we need efficacy, and let's try this out. Efficacy sometimes takes a little longer than side effects.

What are the general side effects? There can be initial sedation. There can be some problems with bowel movements, whether diarrhea or constipation. That usually goes away. The sedation also. What can be lingering is weight gain. Often people already have an issue that they don't exercise as much or have poor healthy lifestyle and diet behavior, especially when they are revving up to becoming psychotic. This might have happened to this patient. So let's organize this around having healthy lifestyle instruction to begin with, no matter what treatment I would prescribe.

And I see that the patient has a BMI of 28. Basically, for us, medically this means he's in the mid-range between overweight and obese, which goes from 25 to 29.9. So healthy lifestyle is important — diet and moving.

Medications, especially antipsychotics, can be helpful, but they usually cause an increase in appetite. Here again, psychoeducation that the brain counts calories as much as you chew. So even if you have the same caloric intake with a soup or you have something that's more substantive and you chew, the next meal will be larger after liquid meals. So the patient should chew a lot. Satiety signaling is delayed with antipsychotics. People eat and eat. They have an increase in appetite and they feel too late that they should have stopped earlier. This kind of information can help patients to deal with that, and we will monitor weight.

With antipsychotics, we will also have to monitor lipids and glucose, which often are associated with weight gain but can also be independent of this weight gain depending on the medication. Because this is a side effect that can have long-term consequences for morbidity and mortality, people with psychiatric illness and particularly schizophrenia die 15-20 years prematurely. Most of that is due to cardiovascular illness. I would then go on and say, let's review the medications that might have the least risk of causing weight gain and cardiometabolic risk.

Kane: And is he at greater risk of gaining weight and having metabolic side effects because he's already overweight? Would that play a role?

Correll: That's a very interesting question. On the one hand, we know the lower the weight, the more room you have for weight gain. But on the other hand, if this is his natural set point and he's already overeating, in treatment-naive patients, we've seen similar, if not larger, weight gain in people who have already started overweight because they have a tendency to respond to appetite and satiety signaling is not setting in early enough.

Kane: If someone is given a drug that seems to increase their appetite or their potential weight gain, does that level off at some point or does that continue to go on and on?

Correll: Everything in life is somewhat asymptotic, at least biologically, if you are reaching a ceiling at one point. So the weight gain is most prominent in the beginning, but it can go on depending on drug — the "-pines", for example, have a lot of histaminergic blockades and are associated with sedation. [Patients using these drugs] might have weight gain over 12-18 months. Many of the "-dones," on the other hand, that have more type binding to postsynaptic dopamine and can have motor side effects that we haven't yet discussed (and we'll discuss maybe next), they have mid-range weight gain; first-generation "-dones" have generally lower weight gain. And we have some of the newest additions to our armamentarium, the last antipsychotics that are full antagonist or partial agonist, which have lower weight gain. They might level off at 6 months or so. But there seems to be no antipsychotic that is absolutely weight-neutral.

There are some patients who are protected against weight gain even when they're on the most weight-introducing agents. So you can't always say, oh, they must be a nonadherent, but if somebody starts gaining weight and then it suddenly stops rather than slowly leveling off, that's usually an indication that the patient has stopped the antipsychotic.

Kane: I see. And is there a threshold where if somebody gains a certain amount of weight, you would say, I have to do something — I have to change the treatment or add another treatment?

Correll: That's an absolutely important question for our clinicians listening here. I think there are two thresholds. One is in the longer-term, where we know that the FDA would say 7% over baseline body weight is a problem. But from the obesity literature, we know that even a 5% drop is considered a threshold for approving a drug. So if you assume that 5% improvement in baseline body weight in somebody overweight is beneficial, then actually even a 5% increase might be a problem. That's in the longer term.

But I would also focus on the first couple of weeks, because early weight gain clearly predicts later weight gain. If you see, in the first week or two, 4 or 5 lb of weight gain, this is a person who will gain a lot of weight following those initial weeks. You can do two things. Either you intensify healthy lifestyle instruction, maybe start a healthy lifestyle program. But patients are grappling with mental illness. They have a medication, making it harder for them to exercise, and also they might have negative symptoms. So that often fails. You could switch to a potentially lower-risk agent early on, hoping that the same efficacy is maintained, or you could add something that might mitigate against the weight gain. There are some agents that we use in medicine that can mitigate against the antipsychotic-related weight gain.

Kane: And some people have said that the weight gain is somewhat correlated with the clinical response. Is there any truth to that?

Correll: That's another interesting point. I think this comes from the fact that the drug is approved for treatment resistance, so that's clearly stronger than the other antipsychotics, and the very severely ill patients have among the most weight gain of all. But I think that the analyses are somewhat flawed, because who's gaining more weight than the others? It's the people who are more adherent, who stay on the treatment longer. In that sense, I don't think we know exactly what the relationship is and whether there is one. Some analyses have shown that might be some [relationship], even if you control for confounding factors, but the effect is relatively small and if you look at meta analyses, there is really no clear indication that those that cause weight gain are significantly more efficacious than those that cause less weight gain.

Kane: That's been my impression as well. Are patients with schizophrenia more vulnerable to develop type 2 diabetes in general?

Correll: It seems so, because the literature that preceded the first development of antipsychotics was replete with messages or notions that both patients themselves with schizophrenia who might have, again, because of negative symptoms and psychosis, a less healthy life and lifestyle behaviors, and their first-degree family members have a higher rate of diabetes than the general population. There's some feeling and some novel data also coming out that the insulin insufficiency or resistance that we see peripherally might also play a role in psychosis.

Kane: Okay. Are there any other pearls of wisdom that you would offer to the clinicians about weight gain and the management of metabolic side effects?

Correll: Yes. I think first, we shouldn't talk about the body in isolation of the brain, and vice versa, not about the brain in isolation of the body. We know that patients who have metabolic syndrome, hypertension, or diabetes and who are diagnosed with schizophrenia have poorer cognition than those with schizophrenia who don't. So that means by keeping the body weight down, having medications that ideally cause less metabolic syndrome, and not worsening cognition even further.

We also have had several data analyses (study 1, study 2, study 3) showing that patients who have metabolic syndrome or are overweight and obese have a worse outcome in terms of more relapses. Now, could that be because they are sicker than the other patients? But even when you control for baseline variables, this seems to hold and might be related to inflammation and oxidative stress that comes with obesity. And some recent data even suggest that with each BMI point increase in a first-episode patient, you are losing about 1 month of brain age. You're aging prematurely each year by 1 month more because of, again, most likely the inflammatory markers. So that means we need to consider body and mind when treating patients with schizophrenia — both physical and mental health.

Kane: So are you optimistic about getting patients to live healthier lifestyles? Do you have any particular guidance about what works and what doesn't work?

Correll: Yeah, that's difficult. That's even difficult for us, isn't it, to exercise regularly and eat not too much or the right food? And patients who often have little pleasure in life, other than easily accessible calories and indulging and maybe even substance use, have a harder time having a healthy lifestyle. But I think the bottom line is psychoeducation and getting the symptoms under control — both positive but also negative symptoms, because those have clearly been shown to interfere with healthy lifestyle.

Vice versa, even aerobic exercise has been shown, in addition to antipsychotics, to improve positive, cognitive, depressive and especially negative symptoms. So try to get people to exercise at least a little, and that doesn't mean having to go to the gym. It's like 20 minutes of walking per day, and patients generally have time for that and maybe want to do it with someone else who also has an illness. They are in group therapy with them, so that they get some social aspect out of it. It's easier to be silent than sometimes to say something when you walk together, and you have a sense of camaraderie. So I think that would be important to embed in some of our social skills groups and psychotherapy groups.

Kane: It might be a great opportunity for peer counselors to play some role in helping in that process. During the pandemic, we saw so many online exercise groups and things that people did at home. Perhaps we can get our patients involved in some of those things. Some of them are quite engaging.

Let's shift gears now and talk about the neurologic side effects. Starting with the acute patient, what are we concerned about and how do we manage it?

Correll: There are basically four neuromotor side effects we need to be aware of, and they come at different times of treatment. If you treat someone with a strong postsynaptic dopamine blocker or increase the dose too quickly, there can be a dystonic reaction. And we've seen that mostly with first-generation agents. It's very painful and can also be a scary experience for the patient that might interfere with long-term adherence and medication liking. Because if you have torticollis, an oculogyric crisis, or problems with breathing, that can be quite dramatic.

The next one is parkinsonism. It's also dose dependent. Parkinsonism contains three symptoms: ART (akinesia, rigidity, and tremor). And the tremor is usually a resting tremor, a pill-counting tremor that can be seen. We generally want to be below the threshold of parkinsonism. Why? Because parkinsonism doesn't only slow down the body. It also slows down the brain, the basal ganglia, a relay station between the frontal lobe and the cerebellum, which gives us a loop for cognition. And we also have obviously less exercise behavior and less motivation. You can have secondary, cognitive, negative but also depressive symptoms due to too much dopamine blockade.

The third one is akathisia. That can happen alongside early and mid-term. That's a sense of subjective restlessness or objectively seen uncomfortable moving and shifting of the body position. That can be quite uncomfortable and might even lead to suicidal ideas. Again, it's dose-dependent, and we may want to be definitely below the threshold of that. Sometimes with partial agonists, it can be an early rebound effect from prior treatment, and it goes away. But if it's sustained, we need to lower the dose, change the treatment, or give a beta-blocker to counter it. We don't want to use really anticholinergic treatments to treat parkinsonism because that dumbs down the brain and gives you cognitive disability and impairment, and it also enhances the risk for what we are talking about as the fourth neuro motor side effect.

You've done a lot of that very pioneering research, and your name is part of the Schooler-Kane criteria for tardive dyskinesia, which was obviously one of the big limitations of first-generation treatment. But it's not totally gone even with second-generation treatment. It's dose-dependent. It's dependent on extrapyramidal symptoms (EPS) and akathisia, which we want to avoid and also on anticholinergic treatments, but maybe that's also a marker of the increased dose, cumulative dose, and EPS.

Kane: To underscore what you were saying a moment ago, the implication is that if you see somebody who's very vulnerable to the early neurologic side effects, that might indicate that they're at greater risk of developing tardive dyskinesia down the road.

Correll: Absolutely. And even what we discussed before, diabetes, like substance abuse, is also related to a higher risk for tardive dyskinesia. So as we do for weight, we also need to monitor the neuromotor side effects — doing a quick EPS exam, even if it's just wiggling the elbow of the arm, which is a sensitive area or the shoulder for early signs of parkinsonism, or looking at people walking in and if they don't have an arm swing, that could be another indication. We want to scan their face, where most of the tardive dyskinesia symptoms reside — eyes, mouth, tongue — and then also periodically do a systematic assessment with, for example, the abnormal involuntary movement scale, which shouldn't scare clinicians off. Because if you've done it and you've also shown patients how to do it, you can do that in 2-2.5 minutes and get a very good idea of whether there are abnormal involuntary movements.

Kane: Now that so much of treatment is remote or virtual, I guess some clinicians are saying, well, I can't do these assessments. But I would disagree with that. I would say you certainly can do a large proportion of these assessments even remotely. What do you think?

Correll: Yes, I agree. I mean, it's obviously hard to see someone walk, but you can see their facial expression. You can ask them to stretch out their hands, to see whether they have a tremor or abnormal movements. And as we said, most of the tardive dyskinesia symptoms are residing in the face and they are quite obvious.

Kane: How often is tardive dyskinesia irreversible?

Correll: I don't think we have good data on that. Most of the studies looked cross-sectional. They don't give us the severity or a second time point for sustained tardive dyskinesia. But when you look at the studies that were done with the newly approved drugs, we now have, 50-70 years after the first discovery of chlorpromazine, the first set of approved treatments for tardive dyskinesia. These are the so-called VMAT2 inhibitors (vesicular monoamine transporter 2 inhibitors), which are built upon the old drug tetrabenazine. Tetrabenazine is not approved for tardive dyskinesia, doesn't have good data, and has a warning for depression and suicidality, which does not affect the two approved modern VMAT2 inhibitors. When you look at those long-term studies, the symptom reduction of tardive dyskinesia goes on the longer you are on a VMAT2 inhibitor in addition to the antipsychotic. But when they are stopped even 4 weeks later, the symptoms on average almost return back to baseline. That gives you a little bit of an answer that at least those patients who are included in these studies seem to have really persistent symptoms.

Kane: It's a real challenge. Tell me if you agree that what we've seen with these newer medications, the so-called second generation medications, is that the risk for tardive dyskinesia is lower (as you emphasized, it's not gone), but people are perhaps less vigilant about it. And also, the antipsychotic drugs are now used more broadly in patients who are not experiencing schizophrenia. So are we seeing a kind of new wave of tardive dyskinesia in these other populations?

Correll: Yes, I think that's true. We have really broadened use of second-generation agents because they are safer. And there have been also studies showing that they're working for bipolar mania, bipolar depression, and augmentation for unipolar depression; tic disorders; and aggression, including autism, irritability, and kids with autism. But I'm still somewhat impressed that we don't see that many tardive dyskinesia cases because most likely with the second-generation agents and in these non-schizophrenia indications, we do use lower doses and we often stay below the parkinsonian threshold, the neuroleptic threshold.

But you're entirely right: We can't just say, okay it's second-generation, not schizophrenia, therefore I don't need to look for it. We do need to look for it because we believe — although there are again not enough data — that if you catch it early and you can make a treatment adjustment, especially for conditions where an antipsychotic is not indispensable, you might be able to avert the long-term consequence of irreversible tardive dyskinesia.

Kane: And also, tardive dyskinesia may correlate to some extent with treatment response. We have a colleague who did an analysis recently suggesting that those patients who have tardive dyskinesia might be at greater risk for relapse even when they're taking their medicine. What's your take on that?

Correll: You've shown many years ago that early parkinsonian side effects early in an untreated patient or vulnerability to getting early symptoms and signs of EPS or akathisia might be a marker of poor treatment response. Maybe that's just a more vulnerable dopamine system. And if we conceptualize tardive dyskinesia as an upregulation of postsynaptic dopamine receptors — basically an uncoupling from normal brain physiology — that uncoupling could happen in the motor system and also in the system that's responsible for the psychosis. So that goes a little bit in this direction of the not fully proven dopamine hypersensitivity psychosis, but maybe tardive dyskinesia is a marker for that.

Kane: The first thing is to remind everyone that antipsychotic drugs, when used appropriately, are highly effective, but they do have adverse effects. We've learned a lot about the adverse effects and your research has contributed to that, and they are manageable. But the key is clinicians being familiar with them and understanding how to respond to specific side effects. And it's very important that we do psychoeducation to inform patients and families about what to expect, so that they're both not surprised and are also engaged in the management of these conditions.

Correll: Absolutely. I agree with every point. I would just like to underscore two things.

One, we need to monitor [patients in several ways]. Clinicians are aware of it and might even educate patients, but then it slips through the cracks and they rely on patients to proactively say something — but they can't say anything about hypertension, dyslipidemia, or hyperglycemia. And with the tardive dyskinesia symptoms, we might have to ask also family members or caregivers who can tell us something about it.

The second point is, these side effects we've talked about are really core to what we know about the current antipsychotics that are often related to histamine blockade and also are postsynaptic dopamine modulators. So we're very hopeful that the currently developing drugs that are non–postsynaptic dopamine blockers and have other mechanisms of action might be a new generation of treatments that are not associated at all with prolactin elevation (which we haven't talked about). That's also a postsynaptic domain receptor blockade–related side effect, not related to neuromotor side effects, and these drugs also potentially have less weight gain and cardiometabolic side effects.

Kane: Absolutely. Well, thank you so much. We've spoken with Dr Christoph Correll about the metabolic and neurologic side effects of antipsychotic drugs. I want to thank Christoph for joining us. This is John Kane, for Medscape InDiscussion.



Understanding the Effects of Antipsychotics on Appetite Control

Food and Drug Administration's Obesity Drug Guidance Document

Risk of Weight Gain for Specific Antipsychotic Drugs: A Meta-analysis

Diabetes and Schizophrenia

Brain Insulin Action: Implications for the Treatment of Schizophrenia

Obesity as a Risk Factor for Accelerated Brain Ageing in First-Episode Psychosis -- A Longitudinal Study

Body Mass Index Identified as an Independent Predictor of Psychiatric Readmission

Metabolic Syndrome and Illness Severity Predict Relapse at 1-Year Follow-Up in Schizophrenia: The FACE-SZ Cohort

Incidence and Severity of Tardive Dyskinesia Increase With Age

Extrapyramidal Symptoms With Atypical Antipsychotics: Incidence, Prevention and Management

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