Developing Novel Treatments for Schizophrenia: Opportunities and Challenges in Personalizing Care

In an interview with Pharmacy Times, Andrew J. Cutler, MD, Clinical Associate Professor of Psychiatry at SUNY Upstate Medical University, Chief Medical Officer of Science Education Institute, discusses his presentation at the 2024 American Association of Psychiatric (AAPP) Conference. Cutler covered factors to consider when selecting treatments for schizophrenia patients, such as balancing efficacy, tolerability and safety. He also explored the need for biomarkers to better match mechanisms of action to individual patient pathology. Cutler highlighted developing novel agents is an opportunity, but challenges include identifying appropriate patient populations and understanding long-term effects. He emphasized combining new drugs with traditional medications may help more patients but also requires understanding potential safety risks.

Pharmacy Times

What factors should clinicians consider when selecting appropriate treatment options for individual patients, particularly in terms of balancing efficacy, tolerability, and safety?

Andrew J. Cutler

Unfortunately, the issue with selecting appropriate treatments or medications for our patients is that we don't have good biomarkers, we're not very good at matching the mechanism of action of the drug to the pathology of the patient. Now, other fields of medicine can do this. For instance, in oncology, if you're selecting chemotherapy, I can do a genetic test and tell you what markers the tumor has, and what type of drug is going to work on that tumor, that particular type of cancer. We're not there yet in psychiatry, what we do know is that some patients do seem to respond better to one medicine than another. We just don't know who and we can't predict that it's only sometimes through trying different medicines that we hit upon one. Our clinical trials don't always give us good advice on this because all they say is on average, on an average group of patients, this drug is likely to work, but buried within averages are individuals. And so, we have individual patients, some of which will do better with one drug than another, some may tolerate one better than the other. So, I think we do pick our drugs to some degree by trying to match the mechanism of action with the symptom complex the patient has maybe some drugs work better at calming a patient, some at activating a patient. And I think we also pick them based on the risks and side effects. If I have a patient who is heavy and has diabetes, I don't want to add to weight gain or metabolic dysregulation, and some do that better than others. The problem is that Schizophrenia is a very heterogeneous disorder not only clinically in the way it presents with symptoms, but also neuro biologically. And so, we it's not reasonable to think that one mechanism is going to work for all of the schizophrenia, as I call them, which are really probably just different forms of the illness.

We're getting closer, it's nice that we're going to have more options. Especially in September of this year, 2024, the FDA is ruling on a medicine called KarXT, from a company called Karuna. It's a combination of xanomeline, which is an M1/M4 muscarinic agonist, and an anti-cholinergic medicine called trospium. That blocks the peripheral cholinergic side effects but doesn't get into the brain and prevent this anomaly from doing its job. So, this would be the first drug approved to treat schizophrenia that does not block these D2 receptors. It's really a paradigm shift. Great phrase would be a game changer, which I know is overused. But it really is great that it offers us a very different mechanism that might help more patients, because our drugs don't work for everybody, and may work importantly on a broader range of symptoms, especially the cognitive impairment and negative symptoms that really affect people's lives.

Pharmacy Times

What are the key challenges or opportunities that lie ahead in the development and implementation of novel agents targeting dopaminergic neurotransmission for the treatment of schizophrenia?

Andrew J. Cutler

I've been doing clinical trials, I've been doing research for 30 years, trying to develop new medicines to treat psychiatric illness, including antipsychotics for schizophrenia. And in that time, I've seen a number of really novel drugs with really cool new mechanisms. And some of them have failed. And I don't think they fail because the drug doesn't work, they fail because they don't have a good biomarker or a good way of matching that drugs mechanism to the exact pathology the patient has. I've had the feeling that in some studies, there's a subset of patients who did very well with the drug. But then because it didn't work for everybody, I'm only targeting a certain sub population, the study fails, because on average, it didn't work. I think one of the challenges here, as we get better at understanding neurobiology and our technology advances, maybe we'll get better markers that will help us to understand how we can match some of these new mechanisms to the right patient.

I think also, there's a lot to learn with respect to how to best deploy the tools we already have. And then certainly, maybe, as these newer medicines come online, such as these muscarinic agonists, figuring out which patients might be especially appropriate for those, we have a number of them in development that have different properties, as I said, either binding to m one, and four, or both. And so maybe those will target different patient types or different symptom complexes. We think that M1 agonism, for instance, is especially helpful for cognitive impairment that may be pro cognitive. And there are some patients who have more cognitive impairment than others. So maybe that's one way to target how the medicine works. And then understanding the long-term safety because Schizophrenia is a chronic illness, and we want people to continue taking the medicine long term. So far, this new class of drugs has not been associated with weight gain, or metabolic disruption, longer term, not terribly sedating, no prolactin elevation, no acute drug induced movement disorders, which may predict virtually no risk of Tardive dyskinesia, which is a chronic condition that usually comes on later. I think these are some of the challenges. Of course, anytime we have a new brand name medication, we have challenges with cost and access and will insurance pay for these drugs or not? Also, I think what's going to happen is because these drugs have such different mechanisms, we're going to combine them with our traditional medications. And so, figuring out who's the best patient to combine them with what is the potential safety or risk of using two drugs at the same time? These are all questions that I think we'll learn more about in the future. I'm very excited because in all my years of doing research, this is one of the most fertile times with some of the most interesting new mechanisms of drug and development and we've learned so much about the neurobiology that I think we just need to stay tuned because there's a lot more to come.