Emergence of Novel Antipsychotic Agents in Schizophrenia - MedPage Today

Dopamine D2‑blocking agents have long been the mainstay of the pharmacological treatment of schizophrenia. But although these agents can reduce hallucinations and delusions, they do come with collateral damage of adverse events. Is there a way to treat schizophrenia without blocking dopamine D2 receptors?

In this second of four exclusive episodes, MedPage Today brought together three expert leaders in the field -- moderator Leslie Citrome, MD, of New York Medical College in Valhalla, is joined by John Kane, MD, of Northwell Health in Long Island, New York, and Jonathan Meyer, MD, of the University of California San Diego -- for a virtual roundtable discussion about two novel mechanisms that were reported at Psych Congress, held virtually and in San Antonio.

Following is a transcript of their remarks:

Citrome: Hello, and welcome to our Psych Congress video roundtable. We'll be talking about hot issues in schizophrenia. Joining me today are doctors John Kane and Jonathan Meyer. Welcome.

Kane: Thanks very much.

Meyer: Thanks for having me, Les -- really appreciate it.

Citrome: Let's talk about new anti-psychotic agents. Like what is TAAR1 [trace amine-associated receptor 1]? What is it and what place do they have in treatment? How do their adverse event profiles differ from what we already have? John?

Kane: Yeah, it's very exciting to have some new compounds that don't rely on dopamine receptor antagonism. What we've seen with the drugs that we have available up until now is that they all share that common mechanism to varying degrees, but those medicines are also associated with a variety of side effects. So extrapyramidal side effects [EPS], weight gain in some cases, prolactin elevation in some cases. We also see that about 30% of patients really don't derive significant benefit from the medicines that we have.

So having alternatives with different mechanisms of action is very exciting. I think the TAAR1 agonism is a very interesting phenomenon because peripherally it reduces appetite and body weight and improves insulin sensitivity, and centrally it can reduce the uptake of dopamine into presynaptic terminals. And so that's a way of reducing presynaptic dopamine levels.

So in effect, we can exert an anti-psychotic effect without the direct dopamine receptor antagonism. And the work that has been done with the first TAAR1 data to be published I think is very exciting, because it showed significant effects -- an effect size of 0.45 on the PANSS [Positive and Negative Syndrome Scale] total in a population of schizophrenia patients who were acutely ill, ages between 18 and 40, with an acute onset within the last couple of months. And they were treated for 4 weeks.

So the results were quite encouraging. And in terms of the adverse effect profile, somnolence was the most common adverse effect. About 6% or 7% in comparison to placebo, which was about 5%. Other side effects: there were no EPS or metabolic effects, so that's very encouraging.

And I think this looks like a promising compound. The first report of the acute study was published in the New England Journal of Medicine. And I think we're very excited about having this as a potential option down the road.

Citrome: Thanks, John. You know, there's another paper in the New England Journal of Medicine about yet another novel mechanism in that of the muscarinic modulation. You want to tell us a few things about that?

Kane: Sure, well so xanomeline is a muscarinic M1/M4 receptor agonist that has some effect on M5 as well. And we had reason to believe that xanomeline would be an effective anti-psychotic because there's a very important balance between dopamine and acetylcholine in key brain areas that appear to be related to schizophrenia.

But the challenge was the peripheral side effects of this kind of agent. So what was done was combining it with trospium, which is a peripheral agent that reduces the adverse effects by about 50%.

So this, as you said, these data were also reported in the New England Journal of Medicine. A study that involved a little under 200 patients who were followed for 5 weeks and showed very good effects on the PANSS-positive and -negative, and also well tolerated. The main side effect was constipation, and some nausea and some dry mouth, but relatively few patients were discontinued. I think the overall results in terms of tolerability were quite good, and superiority over placebo was quite impressive.

So I think here too, another mechanism of action that is distinct from what we've been accustomed to, and the ability to reduce the adverse effects associated with these compounds is, I think, very promising.

Citrome: Well, thanks so much. Jonathan. Anything else to add about can we treat psychosis without blocking D2 receptors?

Meyer: Well, we've had evidence from the Parkinson's disease world from a drug pimavanserin, which really is a very selective serotonin_2A inverse agonist, but with some affinity for serotonin_2C. It worked for Parkinson's disease psychosis; it has nothing to do with D2. It shows anti-psychotic activity.

Now, again, that's not schizophrenia, but I think it did really give us the sense that maybe we can modulate this system without directly doing anything at the D2 receptor. And now these two new mechanisms are very exciting. And as Dr. Kane said, positive phase II data moving into phase III.

Citrome: Terrific.

Watch the first episode of the roundtable: Managing Agitation in Schizophrenia and Bipolar Disorder.

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  Greg Laub is the Senior Director of Video and currently leads the video and podcast production teams. Follow

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