Expert: New Schizophrenia Treatments Targeting Muscarinic Receptors

In an interview with Pharmacy Times, Jose Rey, MS, PharmD, BCPPDirector, Psychopharmacology Residency Program Professor, Nova Southeastern University, discusses his presentation at the 2024 American Association of Psychiatric (AAPP) Conference. Rey shares gaps in current schizophrenia treatments such as limited efficacy for positive symptoms, poor response in negative symptoms, and lack of effect on cognitive problems. He explained that new muscarinic receptor-targeting drugs work differently than dopamine receptor-blocking antipsychotics. Clinical trials show these new drugs effectively treat psychotic symptoms. Rey believes they could be used as monotherapy or adjuncts to improve responses and side effect profiles compared to existing antipsychotics.

What gaps in current schizophrenia treatments are prompting exploration of therapeutics targeting muscarinic acetylcholine receptors?

Key Takeaways

Current schizophrenia treatments have gaps in efficacy, especially for negative and cognitive symptoms, leaving room for improvement.
New drugs targeting muscarinic receptors work differently than existing antipsychotics by modulating dopamine upstream rather than directly blocking dopamine receptors.
Clinical trials demonstrate muscarinic receptor-targeting drugs effectively treat psychotic symptoms and have potential to be integrated into care as monotherapy or adjuncts to optimize outcomes and side effect profiles.

So, what gaps exist. I would say the important gaps are that we haven't cured the disorder of schizophrenia. Our treatments are, I want to say, sometimes that they've hit a wall, we have limited efficacy. Even when we're trying to treat problems like hallucinations and delusions of paranoia, agitation, hostility, a lot of the things that we associate with schizophrenia, we still have residual symptoms leftover. The other domains of schizophrenia, sometimes when we break down schizophrenia, we break it down into positive symptoms, negative symptoms, and cognitive symptoms. Now, the positive symptoms are the common ones that people associate with psychosis. The negative symptoms like amotivation and anhedonia — these symptoms, they don't respond very well to our medications. Some of our newer atypical antipsychotics, they have efficacy, but even their efficacy is a little limited, but it's better than what we had before with the older medications. Then the cognitive area — attention, executive functioning memory, these are still not being treated as well as we would like. Some of our older medications, again, might even make the cognitive problems worse. These are the gaps—some efficacy and reliable efficacy but not perfect efficacy in positive symptoms, limited efficacy and negative symptoms, and practically no efficacy in the cognitive areas. So, we have a lot of room for improvement with our treatments.

Timestamps

0:00:00 - Start of interview discussing gaps in current schizophrenia treatments
0:01:56 - Question about how new therapeutics work differently than existing drugs
0:02:01 - Response explaining how new drugs target muscarinic receptors instead of dopamine
0:02:19 - Question about evidence of effectiveness from clinical trials
0:03:48 - Response summarizing positive results from Phase 1-3 trials
0:04:45 - Question about potential integration of new treatments into care approaches

How do these new therapeutics work differently from existing drugs for schizophrenia?

For almost the last 70 years, our anti psychotics have targeted essentially the dopamine receptor, the D2 receptor. Our older agents, chlorpromazine, old brand name, Thorazine, all the way through to our newest anti-psychotic, is on that D2 receptor in one way, shape or form. We even have D2 partial agonist but they're still on the dopamine receptor. That works well with the dopamine hypothesis of schizophrenia. However, that is probably a problem that may be related to another neurotransmitter dysregulation. And so, it's probably time to move on to other treatment targets, in this case, the muscarinic receptors. But we can't say that the glutamate receptors and activity is not important. We can't say GABA isn't important. Our newer atypicals are also serotonin receptor antagonist. So, it's a heterogeneous problem — probably more than one way to approach the problem. But these newer agents are finally going to leave the dopamine receptor. They're still going to modulate dopamine. Maybe downstream, I consider these agents one or two steps upstream in the pathophysiology of schizophrenia. Our anti psychotics of today are handling the problem of schizophrenia and psychosis a little bit closer to the dopamine hypothesis a little bit farther downstream. That's how I look at it, upstream and downstream problems. In the end, there's dopamine dysfunction. But now I think we're getting better at approaching it from different directions.

What evidence suggests effectiveness of these therapeutics in managing schizophrenia symptoms?

Well, that's the good news, especially with the muscarinic receptor activators, whether they're agonist or allosteric modulators. The phase 1 and phase 2, and now even phase 3 research trials, they're showing evidence that they work. Even if we didn't know the pharmacology of these medications, we can't deny the signal that they have an anti-psychotic effect. But now we have evidence in these trials, and these trials are getting in larger numbers, that they are starting to even reliably work for psychotic symptoms. We've had that signal for many years. But these phase 2 and phase 3 trials are very encouraging. I'm not guaranteeing that they're going to be FDA approved or something. But we finally have a really good look and signal for efficacy. And the data is backing it up.

How might these new treatments be integrated into current schizophrenia treatment approaches?

We're not going to throw away these dopamine receptor blockers or antagonist. We're not going to stop using older or newer agents. But these newer agents that we're talking about in the research pipelines, they can work by themselves as monotherapy. We don't need the older or newer antipsychotics of the day. I think they will also be used as adjuncts. Since they're approaching the problem from another direction, I think we may be able to use them synergistically to perhaps even acquire a better response overall, whether it's those positive symptoms or negative symptoms, and in a very meaningful way, change that side effect profile. The older medications, even the newer ones have these movement disorders — extra pyramidal symptoms. We have problems with metabolic, like weight gain and lipid problems and glucose problems. And therefore, these newer agents don't have the same side effect profile. We may be able to improve the patient's not just efficacy or response and therefore the treatment of the disease. But that side effect burden is going to be different.

What future advancements do you anticipate in this field and their potential impact on patient care?

The future advancements are going to be continued research. We're not done. We haven't figured out schizophrenia. These newer treatments that are fairly close to possibly FDA approval, like the muscarinic receptor activators, they are offering another treatment approach, but we are looking at glutamate. We're looking at tar 1 receptor agonist. We were excited for those agents a couple of years ago. I will say the data is inconsistent with those, and therefore I think we're going to entertain any idea that will perhaps improve a patient's treatment. Therefore, I think we're going to not walk away from glutamate or GABA or serotonin or other targets that maybe we have yet to even discover. So, I don't want us to stop doing research. I want us to keep trying to help our patients achieve the quality of life that we want them to achieve.