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CME / ABIM MOC

Novel Antipsychotic Therapies: A Review of Non-D2 Mechanisms and Implications for Care

  • Authors: Leslie Citrome, MD, MPH​; Deanna L. Kelly, PharmD, BCPP; Diana O. Perkins, MD, MPH
  • CME / ABIM MOC Released: 1/17/2023
  • Valid for credit through: 1/17/2024
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  • Credits Available

    Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.50 ABIM MOC points

    You Are Eligible For

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    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for psychiatrists, primary care physicians, critical care specialists, nurse practitioners (NPs), physician assistants (PAs), nurses, pharmacists, and other healthcare professionals (HCPs) who provide care to patients with schizophrenia.

The goal of this activity is for learners to be better able to recognize the role of nondopamine mechanisms in the development of emerging and novel therapeutics in schizophrenia and the current status of clinical studies of compounds that target these mechanisms.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Mechanism of trace amine-associated receptor 1 (TAAR1) as a therapeutic target for schizophrenia treatment
    • Involvement of serotonin in psychosis
    • Involvement of acetylcholine and related receptors in psychosis


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Faculty

  • Leslie Citrome, MD, MPH

    Clinical Professor​
    Psychiatry and Behavioral Sciences​
    New York Medical College​
    Valhalla, New York

    Disclosures

    Leslie Citrome, MD, MPH, has the following relevant financial relationships:
    Consultant or advisor for: ​AbbVie, Inc./Allergan; ACADIA Pharmaceuticals Inc.; Adamas Pharmaceuticals, Inc.; Alkermes, Inc.; Angelini; Astellas Pharma, Inc.; Avanir Pharmaceuticals; Axsome Therapeutics, Inc.; BioXcel Therapeutics; Boehringer Ingelheim Pharmaceuticals, Inc.; Cadent Therapeutics; Cerevel; Clinilabs; COMPASS; Eisai, Inc.; Enteris BioPharma; HLS Therapeutics; Impel; Idorsia; INmuneBIO; Intra-Cellular Therapies; Janssen; Karuna; Lundbeck; Lyndra; Medavante-ProPhase; Marvin; Merck; Mitsubishi-Tanabe Pharma; Neurocrine; Neurelis, Inc.; Novartis; Noven; Otsuka; Ovid; Praxis; Recordati; Relmada; Reviva; Sage; Sunovion; Supernus; Teva 
    Speaker or member of speakers bureau for: AbbVie, Inc./Allergan; ACADIA Pharmaceuticals Inc.; Alkermes, Inc.; Angelini; Eisai, Inc.; Intra-Cellular Therapies, Inc.; Janssen; Lundbeck, Inc.; Neurocrine Biosciences, Inc.; Noven Pharmaceuticals, Inc.; Otsuka Pharmaceutical Co., Ltd.; Sage Therapeutics, Inc.; Sunovion Pharmaceuticals Inc.; Takeda; Teva  
    Stock options from: ​Reviva​ Pharmaceuticals Inc. 
    Owns stock (publicly traded) in: Bristol Myers Squibb Company; Eli Lilly; Johnson & Johnson; Merck; Pfizer, Inc.  

  • Deanna L. Kelly, PharmD, BCPP

    MPower Professor of Psychiatry  ​
    University of Maryland Strategic Partnership: MPowering the State  ​
    University of Maryland School of Medicine ​
    Baltimore, Maryland​

    Disclosures

    Deanna L. Kelly, PharmD, BCPP, has the following relevant financial relationships:
    Consultant or advisor for: Alkermes, Inc. (former); Janssen; Sunovion Pharmaceuticals Inc. 
    Research funding from: Saladax Biomedical Inc. 

  • Diana O. Perkins, MD, MPH

    Professor
    Department of Psychiatry ​
    University of North Carolina at Chapel Hill​
    Chapel Hill, North Carolina

    Disclosures

    Diana O. Perkins, MD, MPH, has the following relevant financial relationships:
    Consultant or advisor for: Alkermes, Inc.; Karuna Therapeutics
    Contracted researcher for: Boehringer Ingelheim Pharmaceuticals, Inc. 

Editor

  • Lisette Arnaud-Hevi, PhD

    Medical Education Director, Medscape, LLC

    Disclosures

    Lisette Arnaud-Hevi, PhD, has no relevant financial relationships.

Compliance Reviewer

  • Lisa Simani, APRN, MS, ACNP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Lisa Simani, APRN, MS, ACNP, has no relevant financial relationships.


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CME / ABIM MOC

Novel Antipsychotic Therapies: A Review of Non-D2 Mechanisms and Implications for Care

Authors: Leslie Citrome, MD, MPH​; Deanna L. Kelly, PharmD, BCPP; Diana O. Perkins, MD, MPHFaculty and Disclosures

CME / ABIM MOC Released: 1/17/2023

Valid for credit through: 1/17/2024

processing....

Activity Transcript

Module 1

Dr Citrome: Hello, I am Dr Leslie Citrome, clinical professor of psychiatry and behavioral sciences at New York Medical College in Valhalla, New York. Today, we'll talk about novel antipsychotic therapies, a review of non-D2 mechanisms and implications for care.

I'm going to start off with a discussion of current therapies and clinical limitations, including adverse events, and the ability to effectively manage negative symptoms. So where are we today? Well, now we're stuck with the classic dopamine story, and for over 50 years, psychosis, in particular, auditory hallucinations and delusions, have been thought to be the result of hyperactivation of the dopaminergic mesolimbic pathway. We believed for many years that these psychotic symptoms are due to this mesolimbic pathway abnormality, where excess dopamine is essentially released from the ventral tegmental area to the ventral striatum. It's thought that the dorsal striatum was not affected by this hyperactivity because it's innervated by the nigrostriatal pathway from the substantia nigra and was mainly involved with motor movements. So that's the classical dopamine story. It's gone over through some refinements, though, over the years, and recently we've discovered in humans that actually there is a nigrostriatal pathway that goes to part of the striatum called the associative striatum, which is actually involved in, in psychotic symptoms. But the main story is the same: our treatments block dopamine receptors in the striatum, which results in a reduction in hallucinations and delusions. The first commercially available antipsychotic, chlorpromazine, did exactly that, and all subsequent antipsychotics have proved to date do the same thing. Now, there have been a number of antipsychotics, as you know, from chlorpromazine approved in 1957, haloperidol in 1967, and then the first oral atypical antipsychotic, cclozapine, in 1989. The first first-line second generation or atypical antipsychotic was risperidone in 1993. The most recently approved antipsychotic has been lumateperone in 2019. But basically, all of the antipsychotics that have been approved to date block postsynaptic D2 receptors. So what happens when we block dopamine D2 receptors? Well, this also leads to blockade in the part of the brain where we don't want that. In the dorsal striatum, the motor striatum, this causes drug-induced abnormal movements. This may lead to tardive dyskinesia. So subsequent upregulation of these very same receptors in the dorsal striatum results in another movement disorder that actually worries us quite a bit. Now, we also can see postsynaptic dopamine D2 receptors being blocked in the hypothalamic pituitary pathway causing hyperprolactinemia. There's also other dopamine receptors such as D3, where we believe that antagonism or partial agonism at D3 may potentially improve negative symptoms and cognition. We know that alpha-2 adrenergic receptors, when blocked, may have antidepressant effects, increased alertness. We know that serotonin 5-HT1A partial agonism is associated with anxiolytic effects and antidepressant effects. So there's the potential to block other receptors and gain additional benefit. There's also the possibility of problems with tolerability, though, as well. So we know blockade of D2, as I mentioned, can cause motoric adverse events, such as, let's say, acute dystonia or drug-induced parkinsonism or akathisia, and longer-term effects regarding tardive dyskinesia. And we know that alpha-1 adrenergic blockade can lead to postural hypotension. Histaminergic H1 receptor antagonism can lead to sedation. So there's a trade-off here. Sometimes we get a benefit, sometimes we get a tolerability problem, sometimes both, and we're looking for alternatives that perhaps would be better tolerated and perhaps more efficacious. But let's focus on the side effects first and see how that is kind of an obstacle and a burden for us in selecting treatments. Side effects for treatments of schizophrenia can impose a significant burden on our patients. In one study of close to 2000 participants with psychosis, close to 80% reported medication side effects and 60% reported impairment because of these side effects in their day-to-day life. Thirty percent reported moderate or severe impairment in their daily life as a result of medication side effects. This is not trivial. Side effects can be disabling, markedly affect quality of life, and if not addressed, can cause long-term distress and chronic health complications. We want to improve the functional status of our patients and improve their quality of life. We can't do that if there's a significant burden of adverse events. Unfortunately today, the antipsychotics that we have available are all associated with some degree of a problem, and these problems are kind of the same across the board. Drug-induced motor abnormalities, certainly more common in first-generation than second-generation antipsychotics, but they have not been completely eliminated. Diabetes, obesity, QT prolongation, hyperprolactinemia, orthostasis; these are all not rare problems with the medicines that we have today. A study was done looking at real-world prescriptions in real world people with psychosis, and we can identify in Medicaid and commercial prescription databases those who ran into problems. It turns out they're given those very same antipsychotics that potentially contribute to their problems that are preexisting. So this is an issue here. What do we do with patients with preexisting motor abnormalities? We don't want to make them worse, we don't want to reintroduce them. What do we do with people who are already struggling with diabetes? We certainly don't want to make that worse. So we're looking for other agents that perhaps have a more favorable profile. All this is related to wanting to increase functionality for our patients, their ability to function socially and occupationally, have a good interpersonal relationships, have a job, live independently, all those things that we take for granted. They can't do that if they have positive symptoms, negative symptoms, cognitive deficits, mood symptoms, or motor symptoms. So we want to address all of these aspects in the care of our patients with schizophrenia. I'd like to point out the course of symptoms in schizophrenia so we can put this into perspective as well. We often assume that the problem lies with hallucinations and delusions, the positive symptoms, but actually it's negative symptoms and cognitive deficits which get in the way of ongoing functionality. And did you know that premorbidly before the occurrence of positive symptoms, you could measure negative symptoms and cognitive deficits amongst our patients with schizophrenia? And although we focused a lot on tolerability in our little discussion now, we need to circle back and think also about efficacy in terms of the other symptoms of schizophrenia. So we need medications that treat schizophrenia that are efficacious for all symptom domains. We need medications that have improved or at least different tolerability profiles so we could match up a medicine for our individual patients better than we can today. Perhaps, this can be accomplished with a different mechanism of action other than direct dopamine D2 antagonism.

So in the course of our presentations, we'll go over different ways of doing that. Let me turn this over to Dr Perkins, who will discuss cholinergic pathways involved in schizophrenia.

Module 2

Dr Perkins: Hello, I'm Diana Perkins. I'm a professor of psychiatry at the University of North Carolina at Chapel Hill. And with this segment, I'm going to focus on novel approaches for treating schizophrenia that involve the muscarinic cholinergic system. So the idea that the muscarinic cholinergic system is involved in schizophrenia has been around for decades. For example, clozapine and its active metabolite desmethylclozapine both have potent muscarinic agonist activity. And this activity has been hypothesized to explain clozapine's unique increased efficacy compared to other antipsychotics. Betel nuts, which also have muscarinic cholinergic agonist activity, are chewed in Micronesia as a recreational drug, and observational studies have found that individuals with schizophrenia who chew betel nuts actually have reduced psychosis compared to individuals with schizophrenia who don't chew betel nuts. And more recently, xanomeline, which is also a central muscarinic agonist, was found to improve psychosis in an Alzheimer's clinical trial. In contrast, muscarinic antagonists have been shown to worsen psychosis. For example, in a clinical study, biperiden worsened positive symptoms in persons with schizophrenia. And in addition, there's a lot of preclinical animal studies that indicate that drugs that are muscarinic cholinergic agonists may have antipsychotic effects. However, you may ask, well, if these ideas have been around a long time, why hasn't there been drug development related to muscarinic agonists? And the stumbling block has turned out to be the peripheral side effects because muscarinic agonists activate the parasympathetic nervous system. And so you'll get increased salivation, bladder contraction, increased GI motility, blood vessels will dilate, the heart rate will be slowed, you'll get increased lung secretions and constriction of the bronchials. And these cause side effects such as urinary incontinence, increased salivation, nausea and diarrhea, and could be worsening of asthma. So these side effects really have made drugs like xanomeline alone, just really not possibilities for clinical use, they're just not tolerable. So more recently, a drug has been developed that is a combination of xanomeline with the peripherally acting muscarinic antagonist trospium. And this combination has been shown to greatly reduce the occurrence of such side effects. A published phase 2 clinical trial involved schizophrenia patients hospitalized with psychosis relapse. They were without antipsychotics for at least 2 weeks, and the design was double blind placebo controlled, was flexible dosing. The trial lasted 5 weeks and it involved 182 participants were half got the active drug and half got placebo. The results of this trial were quite interesting and actually quite promising. So in terms of efficacy, the total symptoms, positive symptoms and negative symptoms greatly improved. And while there was a higher rate of GI side effects, this did not appear to lead to increased discontinuation by study participants compared to placebo-treated participants. There's been a phase 3 trial that's been recently presented. This study involves schizophrenia patients hospitalized with psychosis relapse again without antipsychotics for 2 weeks. Very similar design, double-blind placebo controlled, flexible dosing, 5-week trial. But with 252 patients that were randomized, half to placebo and half to a combination of xanomeline and trospium. And the results of this phase 3 study were equally promising and significant improvement in positive and negative symptoms. And again, while there was a higher rate of GI side effects, this did not lead to increased study discontinuation. So the results of these 2 clinical trials are very promising that this drug whose activities involve the muscarinic cholinergic system without direct effects on the dopamine system may actually be efficacious in improving symptoms in patients with schizophrenia. Now, this does not mean that these drugs are devoid of any dopamine system effects because we know that the muscarinic system regulates the dopamine system. These drugs affect 2 subtypes of muscarinic receptors. There's the M1 muscarinic receptor and also the M4 muscarinic receptor. And the muscarinic receptor is thought to regulate dopamine function in a top-down mechanism involving prefrontal cortical regulation of the ventral tegmental area. Now the M4 muscarinic receptors are thought to regulate the dopaminergic system in a bottom-up way where the ventral tegmental system is regulating the dopamine cells that are in the nucleus accumbens.

So I think the evidence is quite promising that drugs that do not directly affect the dopamine system may actually treat the symptoms of schizophrenia possibly through regulation of the dopaminergic system. And I'm looking forward to seeing the results of these type of drugs and perhaps the emergence of use as treatment for our patients. So thank you for listening. Please go ahead and select the next segment where you're going to hear Dr Diana Kelly discussing serotonin system modulation in psychosis.

Module 3

Dr Kelly: Hello, I'm Deanna Kelly. I'm the MPower professor of psychiatry at the University of Maryland strategic partnership, called MPowering the State, and this is at the University of Maryland, School of Medicine in Baltimore, Maryland. I'm also acting director of the Maryland Psychiatric Research Center in Catonsville, Maryland. Welcome today to the segment titled, "Focus on Serotonin in the Management of Psychosis." We'll talk a little bit about the serotonin hypothesis today.

So serotonin we've heard a little bit earlier from Dr Citrome about the different serotonin receptors, but I'll talk a little bit today about the serotonin 2A and the serotonin 2C receptors. So basis of this hypothesis really stimulated because of the hallucinatory effects of lysergic acid, or LSD, and mescaline found in cacti. These are both serotonin partial agonists, but they're both psychedelics. So we know that in small doses these types of substances can cause mild changes in perception, cognitions, and thoughts, and even higher doses we know that they can cause hallucinatory effects. So this is the basis for why serotonin is related to hallucinatory effects or why we believe that it's effective as it relates to psychosis or in schizophrenia. The serotonin 2A receptor is one of the most abundant serotonin receptors in the cortex. So it's particularly found in areas of the prefrontal cortex, the singulate and the posterior singulate cortex. We know serotonin is involved with brain development, regulation of mood, anxiety and cognition, for example. So many second-generation antipsychotics have effects on the serotonin 2A receptors. In fact, we thought the efficacy of the second generation of psychotic was in fact due to, partially, its serotonin antagonist effects. An inverse agonist has the opposite effects of an agonist and an antagonist can block both of these. But for purposes of talking today, we'll use inverse agonism and antagonism somewhat interchangeably. Antipsychotics like olanzapine or risperidone or paliperidone, sertindole, lurasidone, ziprasidone for example, clozapine all are antagonists at the serotonin 2A receptors, and we know that some of these medications are some of the most effective second-generation antipsychotics that we do have. So how does serotonin impact other neurotransmitters? We know that serotonin 2A receptors can modulate the release of dopamine, norepinephrine, glutamate, y-aminobutyric acid (GABA), acetylcholine, and others in the cortex in the limbic region and striatum areas. We know that the stimulation of serotonin 2A receptors can lead to the depolarization of glutamate neurons and can stabilize N-methyl-D-aspartate (NMDA) receptors on postsynaptic neurons. Also, the stimulation of serotonin 2C receptors can lead to the inhibition of cortical and limbic dopamine release. So we do know that serotonin can play a role with other neurotransmitters. We also know that serotonin has some effects on negative symptoms of schizophrenia. There's a meta-analysis that has shown that antidepressant augmentation possibly is beneficial for the treatment of negative symptoms in addition to depressive symptoms in patients who have depression or in schizophrenia, as well. There is some evidence, preclinically, that some of the 2A receptor antagonists and inverse agonists in the pipeline have efficacy for negative symptoms. There is a medication called ritanserin, which is a selective serotonin 2A, 2C inverse agonist and antagonist that has shown specific efficacy in reducing negative symptoms. But keep in mind that not all pure antagonists have been effective. There's been failures along the way, but we do have a vast majority of information that shows us that serotonin is backed involved in the negative symptom process. This then takes us to a newer medication called pimavanserin. Pimavanserin is an inverse agonist and antagonist at the serotonin 2A and somewhat to the 2C receptors. So there's evidence that it's an inverse agonist and antagonist. So I'll lump those together for today. It has no direct action directly on dopamine adrenergic, histaminergic, cholinergic receptors. It's metabolized by the cytochrome P45384. It has a long half-life, steady state's about 12 days with almost a 60-hour halfway. So know that it is approved for Parkinson's disease psychosis. We use doses about 34 milligrams per day, but it's being tested for schizophrenia. I'm going to talk about a study that has come out with the medication pimavanserin around negative symptoms. So there's a study called the ADVANCE study. This was a phase 2, 26-week, double-blind, placebo-controlled study in stable outpatients with patients who had predominantly negative symptoms. This took place in the United States and Europe, as well. The primary endpoint that they looked at over a 26-week period was the change in the Negative Symptom Assessment-16 (NSA-16), which is a negative symptom scale. They also analyzed safety outcomes in patients who had received at least one dose of the study medication. So there was a screening phase of 4 weeks. There was 26 weeks of adjunctive pimavanserin versus placebo treatment for looking at the NSA-16. So there were inclusion, exclusion criteria and really it focused around having some primary negative symptoms. And also the exclusion was around those with high positive symptoms. So it really was about having primary negative symptoms and not primarily positive symptoms. And treatment had to be stable eight weeks prior to randomization. So the advanced primary outcome, as I mentioned, was the NSA-16 and over the 26-week period, you can see here the changes in placebo versus adjunct pimavanserin and at endpoint, it does reach significance. It's a P value of .03, which is about an effect size of 0.21. Other primary endpoints, such as the Personal and Social Performance (PSP) scale or the amount of people who had a 20% improvement in the NSA-16, were not significantly different, but we did have this primary endpoint of a negative symptom change. Just to point out the adverse events seen in the enhanced study. There were about 35% of people on placebo who had adverse events and about 40% in the pimavanserin group. The most common side effect was headache, very, very low though, about 6% in the pimavanserin group and 5% in the placebo group. Less than 5% in both groups discontinued due to adverse effects, which is to be pointed out. Prolactin elevations were seen slightly in the pimavanserin group, not seen in the placebo group, so noting that. There was a follow-up study that's been done called the ENHANCE study, and this study was a phase 3, 6-week study looking at inadequate responders, and the PANSS total score was the primary outcome. They did not meet the primary outcome endpoints; however, there was a trend towards a symptom difference in negative symptoms. Another piece of the evidence suggesting that pimavanserin or the serotonin effects of an antipsychotic medication could be an effective mechanism of action for the treatment of schizophrenia.

Thank you so much for participating in the activity today. Please continue on next segment on TAAR1, presented by Dr Citrome.

Module 4

Dr Citrome: Hello, I'm Dr Leslie Citrome, clinical professor of psychiatry and behavioral sciences at New York Medical College in Valhalla, New York. We're going to be discussing trace amines and trace-amine associated receptors, and how they may be involved in a new avenue of treatment for people with schizophrenia. Let me first define what trace amines are. They're endogenous chemical messengers. They were referred to in the past as false neurotransmitters. They're called that because they're not released from synaptic vesicles when the neuron fires, but they do exist in the neuron itself and they help modulate monoamines, dopamine, norepinephrine, [and] serotonin. They're expressed at levels that are 100-fold lower than those corresponding neurotransmitters. They're trace, that's why they're called trace amines. In 2001, trace amines were found to selectively activate a family of receptors called trace amine-associated receptors, predominantly intracellular in location that modulate neurotransmission. The most studied one is called TAAR1, trace amine-associated receptor 1. Now, as I mentioned, they're predominantly intracellular, but they can move to the membrane and then back in. They're found both pre- and postsynaptically and essentially form heterodimers with other receptors. For example, can interact with dopamine D2 receptors presynaptically and postsynaptically to effect dopamine signaling. This actually can lead to a reduction in dopamine signaling where it is too high and potentially treat schizophrenia without directly blocking dopamine receptors. There are 2 investigational TAAR1 agonists in clinical trials, ralmitaront and ulotaront. Ralmitaront is in phase 2 of clinical development. There was a phase 2 study that was recently terminated where the primary endpoint was negative, but there is an ongoing active phase 2 study in people with schizophrenia or schizoaffective disorder with negative symptoms. It's currently recruiting, and the estimated completion is in May 2023. Further along is ulotaront, a TAAR1 agonist with serotonin 5-HT1A agonist activity. Ulotaront has no affinity to dopamine D2 or serotonin 5-HT2A receptors. It is completely different from any other agent that we have today, and it is in phase 3 of clinical development. Phase 2 studies have been completed in patients with schizophrenia, resulting in the FDA breakthrough therapy designation for the treatment of schizophrenia. There was a 4-week randomized control trial followed by a 26[-week] open-label extension. We'll call these studies 201 and 202. In the 4-week randomized controlled trial, patients were randomized 1 to 1 to either receive ulotaront or placebo. Ulotaront was flexibly dosed [at] 50 or 75 mg a day. The primary outcome measure was a change in the Positive and Negative Syndrome Scale total score. At the end of participation in study 201, patients were invited to participate in an open-label extension where they received ulotaront, initially 50 mg a day, and then flexibly dosed to either 25, 50, or 75 mg a day. This 26-week open-label extension allows us to look at the durability of effect of ulotaront, as well as a variety of safety and tolerability variables. The primary outcome for study 201 was statistically significant, and the effect size was .45, meaning almost a half a standard deviation difference between ulotaront and placebo. We could take a look at the response rate as defined by a total PANSS improvement of at least 20%, and this resulted in response rates of 65% for ulotaront, 44% for placebo, and results in a number needed to treat of 5. This is perfectly respectable and indicates that ulotaront is a potential treatment for schizophrenia. Now, by the end of the flexible-dose period, week 3, about a third of the patients were on 15 mg, but most were on 75 mg. Were these results durable? Well, study 202, the open-label extension, answers that question, and PANSS scores continue to improve over time. What about tolerability? We can take a look at the 4-week randomized control trial and compare ulotaront with placebo in terms of the rate of adverse events. Here's the list of the most commonly encountered adverse events with the frequency of at least 2% for ulotaront and more frequently encountered than placebo. Overall, the discontinuation from the study because of an adverse event was 8.3% for ulotaront, 6.4% for placebo, resulting in a number needed to harm of 52. This basically means for 52 patients randomized to your ulotaront versus placebo, you would expect to encounter 1 additional patient who would discontinue because of an adverse event. This is actually quite uncommon. When we take a look at events such as somnolence, or agitation, or nausea, diarrhea, dyspepsia, in all instances, the number needed to harm is quite large, which means these events are encountered infrequently. The percentage of patients experiencing any adverse motoric event was low for both ulotaront and placebo. Actually, the percentages 3.3% for ulotaront, 3.2% for placebo results in a number needed to harm of 750. That means it took 750 patients to be randomized to ulotaront versus placebo before expecting to encounter 1 additional patient with such a complaint. Now, we can't really make any conclusions here, but we can say we're going in the right direction if we want to avoid these effects. In terms of study 202, the open-label extension, we find no surprises here. No emergence of new adverse events that would make us worry, no increase in rate of any of these adverse events, and close to two-thirds of patients completed the open-label extension. Interestingly, there were little change in weight, body mass index, or metabolic lab values. There's little change in vital signs, and there was an improvement in sleep quality. Treatment with ulotaront resulted in minimal changes in weight, lipids, and glycemic measures. The effect of ulotaront on prolactin levels was minimal and comparable to placebo at week 4. As I mentioned, there was improvement in sleep quality. This persisted throughout the 26th week of the open-label extension. Let me summarize. From phase 2, we see a change in baseline on the PANSS total score that was greater for ulotaront than for placebo, which was statistically significant. The incidence of adverse events was favorable, and discontinuation due to an adverse event was relatively low and comparable for ulotaront and placebo. In the 26-week open-label extension, everything we saw in study 201 seemed to continue. Based on studies 201 and 202, the 4-week randomized control trial and the open-label extension, ulotaront received breakthrough therapy designation from the FDA for the treatment of schizophrenia. Ulotaront is currently in phase 3 of the clinical trial development program in people with schizophrenia. There are two 6-week phase 3 trials of ulotaront in participants ages 13 to 65 [years] who have an acute exacerbation of schizophrenia. There's a 52-week open-label extension in adults and adolescents rolled over from the acute trials, and there's a long term safety study underway comparing ulotaront with quetiapine extended release that lasts about year.

I want to thank you for your participation in this activity. Please complete the posttest questions and evaluation, and I hope to see you again soon.

This transcript has been edited for style and clarity.

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