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Developments in Treating Schizophrenia: New Mechanisms of Action and Methods of Delivery

March 18, 2021

In this podcast, Schizophrenia Section Editor Leslie Citrome, MD, MPH, reviews recent developments and possible upcoming advances in the treatment of schizophrenia.


Read the transcript:

Hello, I'm Dr. Leslie Citrome, Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College. I'd like to talk with you a little bit about what's happening in schizophrenia. What are we doing in terms of developing new ways of treating people with schizophrenia?

Actually, there's a lot of new exciting approaches to the treatment of schizophrenia. They say innovation is dead, but that's really not true at all. We have new molecules that might treat psychosis, we have new ways of delivering these molecules as well as older molecules, and we have a different approach to think about in terms of adherence.

Emerging Mechanisms of Action (0:41)

What are the new mechanisms of action that we're thinking about that may work in people with schizophrenia? We know that today, the treatments that we have at hand are all dopamine receptor blocking agents to varying degrees. They also involve some degree of serotonin 5‑HT2A antagonism, but there are new treatments in development today that don't have any direct effects on the dopamine receptor.

It's pretty exciting, because it represents a new avenue for treatment. Perhaps where the older medicines didn't work for a particular individual, perhaps the newer ones will. That's certainly a possibility.

Now there's 2 agents that are currently in phase 3 that have got a lot of attention lately. One of them is a trace amine‑associated receptor modulator, or TAAR. TAAR is a very interesting receptor. It's an intracellular receptor, and it modulates neurotransmission in monoaminergic neurons.

It's possible that by modulating this receptor, we can treat psychosis. There is an agent—it has only numbers, SEP‑363856—that's being developed to treat people with schizophrenia. It's an agonist at TAAR1 receptors. It also has some affinity to some serotonin receptors.

In a study, comparing it with placebo, it actually reduced the symptom scores of people with schizophrenia, as measured by the Positive and Negative Syndrome Scale. It also decreased negative symptoms. This is pretty exciting, because after all, this does not bind to dopamine receptors, yet it seems to work.

There was a 6‑month open label extension to this study, this double‑blind study that compared SEP‑856 versus placebo. This extension showed that the effect was durable, that reductions in symptoms continued.

And, it did so with a relatively friendly side effect profile with no change in weight, alterations in prolactin, lipids, glucose, or anything like that, as well as not much in the way of extrapyramidal symptoms. This may be a winner. We're going to await phase 3 to tell us more.

There is another mechanism of action that's interesting, and that is through the muscarinic system. Muscarinic modulation of dopamine and glutamate is a therapeutic target in this regard. One of the challenges is developing a drug that doesn't have GI side effects that make it impossible to give.

What we want to do is develop a medicine that affects M1 and M4 muscarinic receptors. By doing that, we may reduce psychotic symptoms. At the same time, we want to make sure that we don't have GI symptoms related to M2, M3 muscarinic receptors.

So a possible solution is providing that M1/M4 agonist in the form of xanomeline and combining it with trospium, a nonspecific muscarinic receptor antagonist. By doing so, you can actually provide this agent, and it's relatively tolerable.

A phase 2 study was published recently in The New England Journal of Medicine which demonstrated this combination drug, administered twice daily, resulted in a reduction in the Positive and Negative Syndrome Scale more so than placebo. This difference was statistically significant.

This is pretty exciting because again, this xanomeline-trospium combination does not bind to dopamine receptors. So here we have 2 new approaches to treat schizophrenia.

We also have some newer agents that have become available to us, such as lumateperone, approved in late 2019. Although it does bind to dopamine D2 receptors, it binds to them somewhat less than other agents that are available in the class. It has 60‑fold higher affinity to serotonin 5‑HT2A receptors.

So it's kind of a twist on the dopamine story. It results in a drug that is efficacious in reducing psychotic symptoms and has a favorable safety profile, actually not much in a way of elevations in prolactin or extrapyramidal side effects, in fact, not much of a difference from placebo at all on those. It seems to be very well tolerated in terms of weight and metabolic issues, but it does have some degree of somnolence or sedation.

There's some other agents that have been explored. They really haven't led us anywhere, phosphodiesterase inhibition and D‑amino acid oxidase inhibition. You'll read about them, but they haven't yielded any tangible results that would make us excited in terms of a phase 3 program today. So apart from the TAAR1 story and the muscarinic story, we're still looking for new possibilities with other mechanisms.

New Approaches to Medicine Delivery (6:08)

Now, the other way that innovation is proceeding at a fast rate is how we deliver medicines. How we deliver medicines include the long‑acting injectables, of which now we have several choices, as well as subcutaneous injection of antipsychotics.

Currently, there is one available, subcutaneous risperidone, that is administered monthly. It's administered in the abdomen.

There is another one that's in development that can be administered in other places in the body, not just in the abdominal skin. So this is exciting. It could also be given every month or every 2 months.

There is a new formulation of paliperidone palmitate that can be given every 6 months. That's in development too.

And there's also the other advances in terms of other risperidone‑containing products. Maybe they'll afford a different way of providing a long‑acting injectable in a way that would be easier to use, so be on the lookout for that.

We also have a patch now of an antipsychotic, an asenapine transdermal system. You remember, asenapine was originally available as a sublingual. Still is available, but it needs to be administered sublingually twice a day, and it could be associated with bad taste and numbing of the tongue.

Well, a once‑a‑day patch is now available. That removes the whole issue of bad taste and numbing of the tongue, of course, and provides a visual verification that a medicine was taken. That's interesting. We haven't had a transdermal patch for an antipsychotic before, and it will be interesting to see where it best fits.

In terms of treatments for agitation, we have a couple of drugs in development. One is that you know already, olanzapine. Olanzapine administered intranasally is the new approach, and that yields blood levels that are high enough to result in a decrease in agitation quickly enough. That's in development.

We also have a drug that's a highly selective α2A‑adrenergic receptor agonist. Its name is actually a tongue twister, dexmedetomidine. I can't even pronounce it, so I prefer to use its experimental name, BXCL501. That's easier to pronounce. That's being developed by BioXcel.

That medicine is a sublingual film administered under the tongue and yields decreases in agitation very rapidly and very safely as well, so it appears. That has completed phase 3 and will be in front of the FDA for them to make a decision about approval. So that's exciting as well.

Also, in front of the FDA is an old drug, olanzapine again, but combined with samidorphan. That's being developed by Alkermes as ALKS 3831, and what that intends to do is make olanzapine easier to use by reducing the amount of weight that is gained.

In studies comparing this combination of olanzapine and samidorphan versus olanzapine alone, there is less weight gain when you compare the 2 groups. It's hoped that people who get into trouble with olanzapine in terms of weight will be able to take this combination drug and avoid that.

So, innovation is not dead in a treatment of schizophrenia. We have new ways of treating the symptoms, new ways of dealing with tolerability issues, and a couple of ways of addressing agitation without the use of a needle.

I hope this has been helpful to you, and I look forward to speaking with you again.


Leslie Citrome, MD, MPH, is Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College, Valhalla, and Schizophrenia Section Editor for the Psychiatry and Behavioral Health Learning Network. He is in private practice in Pomona, New York. Dr. Citrome was the founding Director of the Clinical Research and Evaluation Facility at the Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York, and spent nearly two decades in government service as a researcher in the psychopharmacological treatment of severe mental disorders. He is now engaged as a consultant in clinical trial design and interpretation. Dr. Citrome is a member of the Board of Directors of the American Society of Clinical Psychopharmacology and the current Treasurer and President-Elect. His main areas of interest include schizophrenia, bipolar disorder, and major depressive disorder. Dr. Citrome is the author or co-author of more than 500 research reports, reviews, and book chapters and has lectured extensively throughout the United States, Canada, Europe, and Asia.


More with Dr. Citrome: Using a Multidisciplinary Approach to Improve Outcomes in Schizophrenia


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