Clozapine in Schizophrenia Treatment: The Challenges and Best Practices

Dr Andrew Hyatt, a 2023 annual American Psychiatric Association (APA) meeting speaker, shares the key benefits, challenges, best practices, and misconceptions of using clozapine in schizophrenia treatment. Dr Hyatt's upcoming Tuesday session, "Yes, We Can: Increasing Clozapine Uptake at a Safety Net Health System," at the APA annual meeting will also dive into some of the top clozapine prescribing topics for the treatment of schizophrenia.

To stay in the know with the hottest topics from the 2023 Annual Meeting, visit our APA Key Clinical Topics hub.

Transcript:

Dr Andrew Hyatt: Good morning. My name's Dr Andrew Hyatt. I'm a psychiatrist at the Cambridge Health Alliance. I'm an instructor in psychiatry at the Harvard Medical School. I also work in our hospital and health system's Clozapine Clinic, which is what I'm here to talk about today.

Question: What are the key benefits of clozapine use relative to other antipsychotic medications? What are the key risks?

Dr Hyatt: Clozapine is the only antipsychotic that is proven to be beneficial in treatment-resistant schizophrenia. We define treatment-resistant schizophrenia or psychosis as someone who has gone through 2 or more antipsychotic trials and failed them either because they didn't have efficacy or because of certain intolerable side effects. The rates of success with any other antipsychotic after 2 failed trials are in the single digits, whereas with clozapine, you have at least a 50-50 shot, if not more, of getting significant relief or even remission.

We can say that both based on research and clinical experience this leads people who take clozapine to have better functioning, better symptom control, and to get back to the things that really matter to them. So, just controlling symptoms, say, having fewer voices, being less bothered by persecutory delusions or other concerns, but being able to get back to work, being able to live independently, being able to even marry and have children if that's something that's important to them. I think it is important to recognize that it's not just something that is better in the abstract or better for things that doctors care about, but also really beneficial for things that matter to patients, their families, and their communities.

There are a couple significant risks associated with clozapine use that we look to manage to kind of balance the risks and benefits for every person taking this medicine. There are a couple of risks that are shared across all antipsychotic drugs, things like weight gain, risk of diabetes, metabolic syndrome, high cholesterol. There's a couple of specific risks to clozapine itself that we monitor more carefully. The most famous one is something called agranulocytosis, which is a specific kind of bone marrow suppression where the body doesn't produce enough immune cells to fight infections. And there's some evidence that there's an increased risk of this at least in the first year, compared to other antipsychotic medicines.

What this means is that for the first 6 months of treatment, we get a weekly blood test to monitor to make sure the white blood cell counts, the neutrophils to be specific, are not too low in the blood, and if it is, we respond very quickly before any harm reaches the patient. It's notable that there's a regulatory requirement that we continue to monitor people on clozapine forever. It's the first 6 months, it's every week with a blood draw. The next 6 months, it's every two weeks and then monthly thereafter. There's good evidence that this is probably not necessary and is not true in other countries. This is currently an FDA requirement, and this likely discourages the long-term use of clozapine, which is unfortunate. Longer-term studies show that the risks of this bone marrow suppression after 1 year is actually comparable to many other drugs that don't require this kind of monitoring.

The other major life-threatening risk is very confined to the first 6-8 weeks, and that's something called myocarditis, which is a dangerous inflammation of the heart muscles of the myocardium that can cause permanent heart damage. So, that's something that we monitor for very closely in the first 6-8 weeks as well. After that kind of early time, these risks tend to recede. We still monitor for other things that affect people's quality of life like constipation, weight gain, some dizziness, things like that.

Question: What avenues can/need to be taken to improve the prescribing patterns and better align with schizophrenia treatment guidelines?

Dr Hyatt: It is really important that we do everything we can to close a massive gap between the evidence and the practice regarding clozapine. The estimate is that about 30% of people in the United States with schizophrenia meet the definition for treatment-resistance, but the data shows that it's probably about nine or 10% of people who actually get a clozapine trial or are currently prescribed clozapine. This is a huge gap. We're saying one-third of the people who might benefit from this medicine are actually prescribed it. It's important to ask why that's the case.

There's a lot of data on prescriber attitudes, so on psychiatrists or nurse practitioners, and a lot of prescribers are really hesitant to prescribe this medication. I think a lot of that's due to an understandable concern about safety and worries about patient perceptions of this. And what's really interesting is that patient perceptions [he stumbles over his words here and repeats the phrase] and doctor or nurse practitioner perceptions about the risks and benefits of clozapine actually diverge pretty significantly.

Interestingly, it's doctors that tend to overestimate the risks and underestimate the benefits for patients. There've been a couple of really interesting studies on this where they survey doctors, and they say how big a barrier is something like blood monitoring for your patients. And a large proportion will say, "This is a really huge concern. A lot of my patients don't want to do this, and I don't want to prescribe clozapine because of this, because patients are too hesitant." When you survey patients, a much smaller percentage of people identify this as a large barrier to them taking this medicine, and it's interesting. So, when you look at the data, the exact numbers are escaping me, but you have a small minority, maybe a 20-25% of people who say that they don't like the blood draws, and it's annoying that they wish they didn't have to do it, but then 80% of patients say that they prefer clozapine over any other antipsychotic they've been on.

So it's interesting. There's this kind of proportion of people within there who don't like certain things about clozapine, don't like the monitoring, but still prefer it to any other drug they've been on, likely because of the functional benefits and things they're noticing in their lives. What this indicates is it's really important that we give people a chance, that we give everyone who qualifies a trial. I often tell patients that you deserve a trial of this medicine. It may or may not work for you, it may or may not be the right fit, but we deserve to at least try and to see what happens. Better to try it and if it doesn't work, we can stop. Or if you don't like it, we can stop. But what if you're one of those 50-60% of people who has a significant response and can go back to things that are important to you?

So I think one area that's really important is prescriber provider education, bringing out some of this information, letting people know about certainly the real world risk and benefits but to help people educate their patients in a way that's appropriate and that kind of adequately balances the risks and benefits and doesn't let our kind of own fears or our own worries override this. So whenever I do education to our residents, I talk a lot about how you present something to a patient. Do you present clozapine like this? Do you say this is a really last-line treatment? This is something that we only give to people who are really sick. You could get really sick or die if you take this medicine, but we think there's no other option. What do you think about that?

If you or a family member was presented with information like that, you'd probably be pretty worried. You might decline, kind of understandably so, versus presenting it like this. "I see that you have had trouble or have failed these other medicines and I want to offer you something that has shown real significant benefit to people just in your situation. And it's been shown to help people deal with bothersome voices or deal with bothersome kind of beliefs or concerns. It helps people get back to work. It helps people do the things and function the way they want to be as an independent person that wants to get your life back. There's some important risks that we'll talk about and that we monitor really closely to ensure that no harm comes to you as well as some more common but manageable side effects that we will monitor and help you work with."

It is really important to educate providers about that, about how to have a conversation that is a reasonable summary of the risks and benefits and doesn't play into our own fears about that. And then it's really important that health systems set up a system[stumbles over words and repeats the phrase], a support system to help prescribers, doctors, nurse practitioners prescribe this medication effectively. We've talked about some of the regulatory burdens, being to enter blood tests into a database, to make sure that there's adequate and monitoring early on.

I had mentioned earlier that I'm part of something called a Clozapine Clinic which is a multidisciplinary clinic. We have myself, another psychiatrist, we have a nurse, we have a pharmacist, all people who can work together as a team to help support patients as well as providers during the early days and the ongoing prescription of clozapine. We work on a model where we bring people in; we start them, we monitor them really closely through those early days when the risk of side effects is the highest.

Once we get people stable, we transfer them back to their primary psychiatrist. So in that way, we look to really support people, and we're looking to really spread this model. It's shown that in institutions that have a model like this, people are much more likely to prescribe clozapine. They feel more comfortable. Residents and trainees that are training there feel more comfortable in their future careers prescribing this medication. So we have to really intervene early in provider education and development. We have to support people when they prescribe it, and we have to really educate them on the benefits.

Dr Andrew S. Hyatt is a psychiatrist at the Cambridge Health Alliance and also an instructor in psychiatry at Harvard Medical School in Boston, Massachusetts. He also works in the hospital and health systems clozapine clinic. Dr Hyatt received his medical degree from Boston University School of Medicine.