Exploring Treatment Options for Patients with Treatment-Resistant Schizophrenia

In an interview with Pharmacy Times, Megan J. Ehret, PharmD, MS, BCPP, Professor and Co-Director of Mental Health Program, University of Maryland, School of Pharmacy Baltimore, MD, discusses her presentation at the 2024 American Association of Psychiatric (AAPP) Conference. Ehret shares the challenges of treating patients with treatment-resistant schizophrenia who have not responded to clozapine monotherapy. She also outlines limited treatment options beyond clozapine and difficulties in understanding patient medication histories. Emerging treatments targeting mechanisms other than dopamine, such as glutamate and muscarinic receptors, are explored. Pharmacists are encouraged to consider adjunctive therapies based on individual patient characteristics and residual symptom domains.

Pharmacy Times

Can you discuss the current landscape of therapeutic options beyond clozapine monotherapy for treatment-resistant schizophrenia, including any emerging treatments of novel approaches?

Megan J. Ehret, PharmD, MS, BCPP

When you think about treatment resistant schizophrenia, typically that's when we think patients who have failed 2 anti-psychotics and then we trial clozapine. Then 40% to 70% of patients who triL to clozapine may not respond to clozapine. Unfortunately, that's typically our last line anti-psychotic. So, when we think about clozapine resistance schizophrenia, that becomes much more challenging. There has been a plethora of studies that have looked at various treatment options, whether that be other anti-psychotics. So, looking at other dopamine 2 blockers, looking at antidepressants, mood stabilizers, non-pharmacologic mechanisms, transcranial magnetic stimulation, electroconvulsive therapy CBT, all of those have been trialed. Many of the trials are small, or underpowered trials. They may lack robust clinical trial criteria. So maybe they're not randomized, maybe they're not blinded. They're very challenging to complete, one to gather that population. So, looking at what treatments might be available is pretty tough. It's hard to say to a patient that we've reached the end of the road. But some of the things that have shown some benefit. There have been some naturalistic studies which have looked at aripiprazole, which has shown some benefit. There are some recent trials with ECT, which have shown benefit. So, when you look at the trip guidelines for clozapine resistance schizophrenia, and look at the various symptom domains, whether it's positive or negative, or suicidal ideation or aggression, they will recommend one not to discontinue clozapine. I think many people think when someone isn't responding that that's the first thing to do— so not discontinuing, and then maybe adding to it. Based on the domain, you might add a particular medication or a non-pharmacologic option to there. Some emerging areas looking at other mechanisms beyond dopamine. So, we're starting to see medications in the pipeline that are looking at glutamate, that are looking at muscarinic receptors and seeing if we can look to see if there are other characteristics of schizophrenia, which we aren't treating, that might be beneficial to this patient population.

Megan J. Ehret, PharmD, MS, BCPP

Many common challenges as where to go to next. As I was thinking about my own practice, and the patients that I particularly see, I always struggle with understanding where the patient has been. We know with patients with mental illness or serious mental illness, gathering previous medications, and trial history is is very difficult because people change practice locations so frequently. One common challenge is just understanding a medication timeline. Has the trials that they've used been adequate in duration and dose. Then once you have a picture, it's trying to select what the next option is going to be. Sometimes I'll wonder, are they taking the meds? Do they have access? How amenable are they going to be to all of these various items that you think about? And I think that for pharmacists, that becomes a big challenge, because we're often asked, what do I do now, I've done everything the guidelines have said, Now helped me. So, it's really for us to discern that very small bit of data and say, This is where I think we might point this particular patient.

Pharmacy Times

What are some common challenges or barriers faced by pharmacists when exploring alternative treatments for patients with treatment-resistant schizophrenia, and how these challenges can be effectively addressed?

Pharmacy Times

Could you elaborate on the mechanisms of action of some of the promising adjunctive or combination thereapies for treatment-resistant schizophrenia, and they complement or differ from clozapine's mode of action?

Megan J. Ehret, PharmD, MS, BCPP

While I'd like to say they're promising, I don't know how often we're going to see great response from some of these newer medications. But we are starting to see investigations into things like zanelonmin and trospium— which has some muscarinic activity, which is completely a new mechanism for us in the treatment of schizophrenia moving outside of dopamine completely. That is going to be a very interesting area to look at. Now, we do know that in combination with clozapine, it's not going to be a great idea to use them adjunctively because they will have additive adverse effects, so some of that might be there. Other medications that are looking at other dopamine receptors, so like D1 or D3 have also started to emerge as new treatment options in schizophrenia. Also looking at partial agonists and dopamine receptors and more serotonin. There are additional studies also, in areas with glutamate, looking at NMDA receptors, and perhaps the excess glutamine that is produced in schizophrenia. So there are some smaller ongoing trials looking at some of these novel mechanismsf or future research. We're starting to move in a direction outside of dopamine, which is exciting. Hopefully we'll begin to think about other things as well, that might affect schizophrenia beyond what we normally think of, at this time.

Megan J. Ehret, PharmD, MS, BCPP

When looking at patient populations, there are some great predictors of what kind of things we should be looking at— looking at the types of symptom domains that are residual. This becomes very important that we use standardized rating scales, I think in many clinical practices, we don't. We seyeball things and assess people clinically, but without a standardized rating scale. It's hard to know those but looking at if it's positive symptoms, then maybe that's when we consider an additional anti-psychotic, if it's a negative symptom that we're still seeing, maybe that's when we consider an antidepressant. If it tends to be more mood instability, that might be a mood stabilizer. Suicidal ideation, we might think ECT. Positive symptoms could also be ECT. I think there are opportunities to look at the specific symptoms and really delve into the patient, versus just thinking about schizophrenia as one option. I think those are the characteristics that I would suggest pharmacists really kind of delve into, it's a little bit outside of what maybe we're normally used to doing, but really homing in on what the patient is suffering from.

Pharmacy Times

What patient characteristics or clinical factors should pharmacists consider when determining the appropriateness of adjunctive therapies for individuals with treatment-resistant schizophrenia?

Pharmacy Times

Can you provide examples of recent clinical trials or real-world studies that have demonstrated the efficiency and safety of adjunctive treatments for treatment-resistant schizophrenia, and how these findings may influence clinical practice?

Megan J. Ehret, PharmD, MS, BCPP

There's been probably a wealth of information. One of the most recent trials in ECT in clozapine resistant schizophrenia, took probably some of the most severe patients that I've seen to date in trials— people that were extremely ill. While ECT didn't show benefit on the primary outcomes later, and some of the secondary outcomes, there was some benefit to it. But this is the first rule sham trial with ECT that we've seen to date, because it's hard to give people sham ECT. It's been interesting to think about other mechanisms that might be beneficial. Although we know ECT tends to be invasive, it might be a treatment option. Things that I also definitely think are important to mention, while you're thinking about treatment resistant schizophrenia, or clozapine resistant schizophrenia, are one, verifying that your clozapine has been adequately trialed. This often gets overlooked. There is great data and information and guidelines on going above the recommended 350 as the level that you're looking for, so really pushing to the point of futility. You might have patients that get up to 900 or 1000 as their level and so really looking at making sure that you've pushed clozapine to the maximum tolerated dose. Then seeking consultation, if needed outside of that. There are a lot of great resources on clozapine dosing and making sure that you're using it right and people are adhering before you abandon the gold standard for schizophrenia.