Schizophrenia Podcast

Treatment-Resistant Schizophrenia: Detection, Management, and the Importance of Early Initiation of Treatment

John M. Kane, MD; Jonathan Meyer, MD


March 22, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

John M. Kane, MD: Hi. I'm Dr John Kane, professor of psychiatry and molecular medicine at the Zucker School of Medicine in New York. Welcome to season two of Medscape's InDiscussion series on schizophrenia. Today, we'll discuss treatment-resistant schizophrenia. First, let me introduce my guest, Dr Jonathan Meyer, who is voluntary clinical professor in the Department of Psychiatry at the University of California San Diego. He is also one of our leading educators who, by the way, published an excellent book on clozapine a couple of years ago. Welcome, Jonathan.

Jonathan Meyer, MD: Thank you for having me, John.

Kane: We're going to be talking about treatment-resistant schizophrenia, which is a real clinical challenge for many people. I also think it's often misunderstood as to the epidemiology, what options we have for treating it, and so forth. Are there any new facts about treatment-resistant schizophrenia that you feel we should really emphasize?

Meyer: One of the more important understandings we've come to appreciate in the last few years is that treatment resistance is not just a problem you see in the chronic patient. I know a lot of our audience might work with first-episode psychosis patients, and something we have come to know through large meta-analyses is that while about a third of schizophrenia patients may be treatment resistant, it's not all people with chronic disease. As many as 20%-24% of people who end up being treatment resistant are resistant from day one. And it's important to understand that for those of you who see younger patients, you have to suspect that some of them, in fact, will be treatment resistant. We know, John, that a lot of first-episode patients respond very robustly to antipsychotics. But I think it's clear that if you're working with any schizophrenia patient, you have to be suspicious that the person might be treatment resistant.

Kane: I think that's a very important point. There's been a lot of progress in recent years in introducing early intervention services and coordinated specialty care around the world. But a recent publication from Eric Chen's group in Hong Kong suggested that those services don't really prevent the development of treatment resistance. One thing they might do is reduce the delay in prescribing clozapine, and that's something we'd like to hear more about from you. What else do you want to tell us about treatment resistance?

Meyer: Part of it is the idea that still in 2023, we really only have one effective treatment for resistant schizophrenia, which is clozapine, with response rates of at least 40% and maybe even a bit higher. We want to get our audience to not subject patients to repeated trials of ineffective medications once they have some of that early evidence that a patient really is a nonresponder. What we know is that each successive trial of an ineffective medication pushes the person closer to becoming resistant. Each trial increases this risk by 8%-11%, and each psychiatric hospitalization about half that amount, from 4%-8%. Once patients have failed two trials of antipsychotics, with one of them probably being an antagonist — so we can say we gave them a good shot at responding to D2 blockade — you have to suspect that the patient has been treatment resistant from day one and not continue to pursue other agents with the hope they might work. The point you raise is really germane. One thing we also appreciate is that earlier use of clozapine tends to result in better outcomes. If we can get patients within 3 years of the time they are treatment resistant, they tend to have better outcomes. But you and I have talked about first-episode clinics and clinicians in general, and I know that you've sometimes bemoaned the fact that clinicians may be somewhat reluctant to use clozapine so early in treatment. Is that still the case, in your opinion?

Kane: I think it is. It's a huge challenge, actually. And you mentioned that failing to respond to multiple alternatives reduces the likelihood that someone will eventually respond to clozapine if they do get it. It's interesting that when you talk to a lot of clinicians, they still would rather give a higher dose of the initial medicine, they'll switch to another drug, or they'll even use two drugs in combination with the hope that it will improve the patient's mental state and reduce some of their positive symptoms. But we really don't have data to support those alternatives to clozapine. So, it's a shame when a patient is subjected to multiple failures of different approaches before they actually get clozapine. We should talk a little bit about what makes patients afraid of clozapine. In your book, you talk about all the adverse effects, and unfortunately, many people stop clozapine. Even if they've gotten a trial, they often stop it inappropriately because there's some side effect that hasn't been managed properly. What do you think about that?

Meyer: It is a more complicated medicine than other antipsychotics. We have to be straightforward about that. But again, when the chances of responding to anything else other than clozapine are minuscule — we'd say roughly less than 5% — you're morally incumbent upon learning how to prescribe clozapine. And a big part of it is appreciating two important facts. Number one is that clozapine saves lives. I know some people focus extensively on severe neutropenia, and they worry that their patients are all going to die from sepsis. That's not what happens. Clozapine actually saves lives. It reduces mortality. And some of the highest mortality we see in schizophrenic patients are in those who have been removed from clozapine. And a lot of it is suicide-related mortality. So the risk-benefit is tilted strongly in favor of benefit, and many people only focus on the risk. But the benefit is the stronger part of that equation. The second aspect of this is that, yes, there's a lot of unusual adverse effects with clozapine, but the average practitioner can learn them. Once you've treated maybe 10 people or so with clozapine, you will become an expert at managing the constipation, managing the sialorrhea, and figuring out if they have orthostasis. We now have labs that people can do over the first 6 weeks to look for myocarditis, such as troponin and C-reactive protein. There are a lot of tools out there, and the most important thing is not to deprive your patients when you have no viable alternative. It's hard to justify that in a chart, too. The documentation about why you're not giving somebody clozapine really becomes problematic when you have no viable alternative.

Kane: I think that's a very good point, as well as the comment you made about adverse effects and that we have to be honest about potential side effects. But unfortunately, I think some clinicians will lead with the risks rather than talking about the potential benefits. My advice to our listeners is, if you have a patient who is a candidate for clozapine, you have to explain to them that we can't predict how much somebody is going to benefit from it. They need a trial. It's very hard for them to analyze the benefit-to-risk ratio unless they know what the benefit is. In some patients, it's really life changing, and it would be a shame for somebody to miss that opportunity because they were reluctant to have a 3-month trial of a medicine. Once they have that trial and see how it works, they're in a position to evaluate whether or not it's worth it to them. But without that knowledge there, it's very abstract.

Meyer: I think the important aspect of this is that the likely benefit from anything else other than clozapine is virtually zero. So how can you in good conscience look somebody in the face and say, "Well, why don't we try drug X, whatever it is"? We have zero evidence that anything other than clozapine is going to be effective for treatment-resistant schizophrenia. Perhaps high-dose olanzapine in the well-designed studies has response rates between 7% and 9%. Fair enough. If you want to give people a shot at that, I won't entirely disagree with it. But the idea of, well, let's try the most newly approved drug because it might work — that's just patently false, and engaging in that type of dialogue is not fair to patients. And it's really indefensible if there's a poor outcome. The big part of clozapine's value is reduction in suicide-related mortality. It would be a shame if somebody was deprived of a clozapine trial and ended up ending their life. It would be a shame for them, and it would be a shame for the prescriber who dissuaded them from clozapine. To be honest, they might be on the receiving end of a malpractice suit, and they would have no leg to stand on.

Kane: Even apart from the suicidality question, clozapine seems to reduce mortality, which in a way is a little counterintuitive for some people because they say their patients have a lot of metabolic adverse effects from clozapine. But despite that, the data from large studies still suggest that clozapine is associated with a reduction in premature mortality. I think that is very important. The risk of agranulocytosis is low. The risk of fatality from agranulocytosis is extremely low now. It's been quite a change from what we saw in the 1970s and 1980s. We've learned a lot about how to manage agranulocytosis. So, it's a shame when patients don't get the potential benefit. What are your thoughts about physician training and experience? I wonder sometimes that if people don't have exposure to clozapine during their residency, are they much less likely to use it?

Meyer: I think that's a big issue when I talk to the residents here at University of California San Diego. Very few have the opportunity to initiate clozapine. They sometimes will inherit patients on clozapine. That's not quite the same dynamic in terms of learning because typically, a lot of the adverse effects during the early titration have now been managed and the patient's doing well. I really want to encourage the listeners out there to try to find somebody in their community who has been prescribing clozapine who can mentor them through some of their early cases. From time to time, I get emails from people throughout the country who have issues with clozapine-treated patients. I try to be helpful, but there's usually somebody in every hospital system and every clinic system who's recognized as being comfortable with clozapine. I would try to learn from them because it isn't a mystery. We know how to manage a lot of the adverse effects. And as I mentioned before, once you've treated about 10 people, you generally become an expert in using it. And then you'll also maybe have a sense of pride and accomplishment that you knew what the right thing was to do. And I think most people do. I think those who are depriving patients of clozapine are not necessarily insensitive. I think they're often fearful. And that fear drives a certain type of language when they talk to patients because they are concerned. But I feel like you have a moral obligation to provide clozapine. Getting back to the point of when people are nonresponders — one thing I would encourage people to do is to verify that their patients are taking their drug. As much as I love clozapine, one thing we learned from the literature is that occasionally — not my patients, of course — but I hear stories that patients don't take the oral antipsychotic medication. It's important to verify if this is what is going on while we're thinking about if the individual is treatment resistant. Even if the patient is on a long-acting injectable (LAI), there are variances in drug metabolism and drug clearance such that one patient may not be average in their drug exposure, but at least it helps confirm to you that the patient took this medication, and we pushed it up to the higher end of a therapeutic range — what I call the point of futility — and they didn't get better. It gives you the confidence that pursuing additional strategies beyond those first two agents is not the way to go. And it helps inform your discussion with not only the patient but also caregivers and family because sometimes the patient is on the fence, as you know, John. But if you have the family support, they're like, "Look, Mary, you really struggled. We know there are burdens with this treatment. You have to have blood tests, etc. But, listen to your clinician because what they're saying is that the chances of anything else working are really very low. And this is your best hope."

Kane: I'm glad you raised the issue of adherence and also plasma levels. One study that was done in London found that out of about 100 patients who were referred as treatment resistant did not have therapeutic blood levels. I know you've written about plasma levels, and I think it's very important to check if a patient is really treatment resistant or if they are pseudo–treatment resistant? A trial of an LAI could go a long way. The recent TRRIP guidelines emphasize that we should do a 4-month trial of an LAI before considering someone definitely treatment resistant. And then even with clozapine, plasma levels become very important. You've talked about this in your books. You have also written about plasma levels. And even in managing adverse effects, we found that patients with sialorrhea had higher blood levels than patients without sialorrhea. So there are many reasons to check if patients are having adverse effects. But then you've also recommended a system for monitoring blood levels as we're increasing the dose of clozapine.

Meyer: I think this is important. We do know that the tolerability early on can be an issue and a reason why some patients may not want to persist with clozapine, and also because of differences in drug metabolism based upon heritage. A good colleague of ours, Jose de Leon, wrote a large position paper about being aware of the heritage of patients and the fact that there are variances in drug metabolism throughout the world. If you're treating somebody from Asia, they're going to metabolize clozapine maybe more slowly than a white northern European. So get levels early and be mindful of this, so that patients aren't overexposed and say they're not going to take clozapine before you have a chance to manage the adverse effects. It also helps you when patients aren't getting better to know, as we say — if we are in the ballgame. Most people are unlikely to respond to clozapine if the clozapine level itself is below a level of 350 ng/mL. But just because you're above 350 is no guarantee of response. Maybe the person is not going to respond to a level of 700 or 800, but at least it gives you a relative benchmark for where you're at and helps allow you to make better decisions about dosing. But I really want to encourage clinicians to learn to manage the adverse effects because some patients may need higher levels for response. And the limiting factor for many patients are adverse effects. We've talked about neutropenia, and for a lot of clinicians, neutropenia is the boogeyman. To be honest, the FDA and I think all of us recognize that the bigger source of morbidity and occasionally mortality is actually constipation and ileus. The FDA issued a bulletin in January of 2020 letting clinicians know that this is the one thing to get really good at managing. You want to manage all the adverse effects, but learn how to treat them, so you can help patients not experience severe constipation or ileus, which really can be a source of morbidity.

Kane: Absolutely. It's a shame when someone has a good response to clozapine and then has to discontinue it. Even with patients who do not appear to be having a good response, I would caution our listeners to, whenever possible, work with their families because families often have a very different perspective. In our clinic, we've had situations where the clinical team was about to discontinue the clozapine because they thought it wasn't helping that much. But then when the family heard about it, they were very upset because to them, the patient had benefited to the point where they were now able to be taken out to dinner and to the movies, and do things they hadn't been able to do previously. So it is really important to check with the family, as well.

Meyer: I think that third-party input, to the extent you can gather it, can be helpful. We recognize that clozapine has unique benefits on positive symptoms and for those who are treatment resistant. This doesn't mean the patient will be asymptomatic, and they may still complain from time to time. But considering that their benefit from prior agents was virtually zero, the fact that they might still be moderately symptomatic is a win. The other area where clozapine really shines is in hostility. For those of you who don't know me, for a dozen years, I've consulted with the state hospital system in California. We have 6700 patients there, many of whom are treatment resistant. A big problem for them as a feature of their schizophrenia is aggression. And it's not aggression necessarily motivated by their psychosis, but it's impulsive aggression, which is a separate domain of schizophrenia that a certain fraction of people have. One evidence-based use of clozapine is for schizophrenia patients with persistent aggression, and that's sometimes what the family sees. They say, "Well, she still talks to her voices, but the aspect of hostility we used to see is much better. And to your point, it allows her to be integrated into the family that allows her to do things that couldn't be done in the past — go out to dinner, go to church, do other things, and maybe go to the clubhouse — because now she can get along with her peers in a way that was not possible before." I think it is really critical to appreciate all the domains of the illness. We often focus heavily on positive symptoms. That's often the criterion for getting a patient on clozapine — inadequate, positive symptom response. But it's just one aspect of the whole illness, which clozapine addresses.

Kane: Another question that some listeners might have is what to do if you do prescribe clozapine and the person has an adequate trial and they have a therapeutic blood level, etc., but it doesn't work. There is some evidence that adding electroconvulsive therapy (ECT) can be helpful, but we don't have a lot of alternatives, do we?

Meyer: We don't. Before we go on to that answer, I want to say that what an adequate trial is depends on the person. You really want to try to maximize the levels as much as possible. And the only way you can do that is by managing the adverse effects. There is evidence that there are people who will respond with clozapine plasma levels between the range of 600 and 1000 ng/mL. So, don't be fearful of going up to that higher range. Yes, there are more adverse effects. The rate of seizures is surprisingly low, though. It's under 2%. But make sure you really push the level to the point where either the patient doesn't get better, and the level is 1000 — you say, okay, that's it — or they just can't tolerate it anymore. You say, okay, we pushed the level to 1000 and they still have a lot of positive symptoms. I think ECT is the most evidence-based adjunctive treatment. People have tried antipsychotics that aren't clozapine to add on to it to improve positive symptom response. Sometimes if I suggest this, clinicians will say that's why the patient is on clozapine — because they failed risperidone and haloperidol. But maybe they didn't get zero benefit from those other D2 antagonists. It was just insufficient. Sometimes adding back a little bit of D2 blockade may be helpful because it's the one thing pharmacologically that clozapine doesn't do. It's worth a try. We don't have a lot of other things to offer people at that point. There's a lot of things that have been studied — all sorts of interesting molecules — which I'm not going to mention because I'm not a big endorser of some of those strategies. I would say that most evidence-based strategies are, number one, adding back a bit of D2 blockade. Number two is ECT. And number three is to reassess your diagnosis. Sometimes I'll see people who are billed as being treatment resistant and the problem is they don't have schizophrenia. They actually have schizoaffective disorder, bipolar type, and they're not mood stabilized. We will sometimes recommend an empiric trial of lithium if there's any clinical inkling in the history or the current presentation of something that looks like mania. If a patient just has schizophrenia, lithium doesn't make them a whole lot better. But if they have schizoaffective bipolar type and they aren't mood stabilized, lithium often makes a big difference. If it doesn't work, that's fine. You give it a trial for a couple of months. It's just one thing to think about. Sometimes we miss the more florid aspects of mania when patients are on antipsychotics because they don't have the psychomotor agitation anymore. But that doesn't mean their mania has been fully treated. Mood stabilizers like lithium do something very different than antipsychotics. So that's a clinical pearl. Sometimes people have forgotten about the mania because it's so far in the past. But you go back and look and think maybe that's what we've been missing. And this also means occasionally if you have somebody who you thought was manic in the past, their current antidepressant may be not the best thing for them. The better thing for them may be mood stabilization and the use of a molecule that works for bipolar depression, which could be added on with the clozapine, like cariprazine, lumateperone, or lurasidone.

Kane: Those are very important points. And I want to emphasize that when we are confronted with someone who is not responding the way we hoped, we should go back and review the diagnosis, review adherence, and review prior treatments and concomitant conditions, whether it be substance abuse or what have you. These are very important points. Well, we've covered a lot of territory. This has been a very enlightening discussion. I want to thank Jonathan for highlighting some of these important issues, including how common treatment resistance is, how early it presents, and the fact that if we delay the initiation of clozapine, we're potentially doing the patient a real disservice because their chances of responding to clozapine may decrease over time. And then we also talked about some of the management issues. Thank you so much, everyone, for tuning in. If you haven't done so already, take a moment to download the Medscape app to listen and subscribe to this podcast series on schizophrenia. Again, thank you, Jonathan. This is Dr John Kane for InDiscussion.

Listen to additional seasons of this podcast.


Treatment Resistant Schizophrenia: Clinical, Biological, and Therapeutic Perspectives

Predictors of Treatment-Resistant and Clozapine-Resistant Schizophrenia: A 12-Year Follow-up Study of First-Episode Schizophrenia-Spectrum Disorders

Mortality in People With Schizophrenia: A Systematic Review and Meta-analysis of Relative Risk and Aggravating or Attenuating Factors

Pharmacological Interventions for Clozapine-Induced Hypersalivation

The Effect of Clozapine on Premature Mortality: An Assessment of Clinical Monitoring and Other Potential Confounders

Antipsychotic Plasma Levels in the Assessment of Poor Treatment Response in Schizophrenia

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels

FDA Strengthens Warning That Untreated Constipation Caused by Schizophrenia Medicine Clozapine (Clozaril) Can Lead to Serious Bowel Problems




Follow Medscape on Facebook, Twitter, Instagram, and YouTube


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.