Beyond D2 Receptor Manipulation: Novel Agents for Schizophrenia Treatment

In this video, Christoph Correll, MD, professor of psychiatry and molecular medicine, Zucker School of Medicine at Hofstra/Northwell, New York, provides a thorough pharmacological overview of the traditional and novel treatments available for schizophrenia.

To hear more clinical insights from Dr Correll, check out the first interview in this series: Recognizing the Early Indicators of Schizophrenia.

For more expert insights, visit the Schizophrenia Excellence Forum right here on Psych Congress Network.

Save the date for the 2024 Psych Congress, October 29 through November 2 in Boston, MA! For more information and to register, visit the meeting website.

Read the Transcript

Psych Congress Network (PCN): Why has there been some dissatisfaction with the trajectory of schizophrenia therapeutics, particularly those that target the D2 receptor? What are the treatment limitations?

Christoph Correll, MD: For the last seven decades, dopamine receptor antagonism has been the name of the game for psychotic disorders and schizophrenia. We've refined it. It's a foundational treatment for psychosis. We now know that full dopamine blockade may not be necessary. We have also other receptors that are in the mix. We have partial D2 agonists. They have been helpful. We've reduced some of the side effects that were particularly problematic with the first-generation agents. But there are still side effects that are problematic with current D2 antagonists. That is weight gain, metabolic abnormalities, sedation, prolactin elevation, sexual side effects.

Now, not all of the medications have the same side effects, but some do. Some have more of this or another. Generally, we have less extrapyramidal side effects, but there's still the risk of akathisia with some parkinsonism and even tardive dyskinesia. So finding treatments that don't block the postsynaptic dopamine receptor that is responsible for many of these side effects is important, not only to avoid some of the side effects, but also to treat potentially patients that are not helped by postsynaptic dopamine blockade alone, and maybe also have an increase in presynaptic dopamine output because we're also blocking indiscriminately the presynaptic autoreceptor on the dopamine system.

Having medications that target the presynaptic part, where we think there is too much dopamine in certain areas of the brain, is crucial. Then there's also a linkage between EI, excitation inhibition, disturbance and schizophrenia. So reestablishing the balance between GABA, which is the brake in the brain, and glutamate, which is the gas pedal, which might then stimulate dopamine downstream-wise, that's also important. For that, we need different mechanisms of action. We also need different mechanisms of action to have rational polypharmacy.

PCN: Could you provide an overview of the novel agents for schizophrenia treatment? How do they differ from traditional D2 receptor manipulation?

Dr Correll: Current treatments really work postsynaptically on the dopamine receptor. We know that, most likely, the issue is more presynaptically. So we now have some treatments that target this, either approved already for another indication, or also in the making.

Let's start with VMAT2 inhibitors: vesicular monoamine transporter inhibitors. The first prototype that was an irreversible inhibitor was reserpine, was one of the first antipsychotic treatments, but it depleted the presynaptic vesicles of all biogenic amines. So there was no dopamine, no psychosis, but there was also no adrenaline, no serotonin. Patients were depressed, had extrapyramidal side effects for months. So that wasn't viable.

Now we have 2 novel reversible VMAT2 inhibitors: deutetrabenazine and valbenazine. They're currently approved for Huntington's chorea, but also for tardive dyskinesia associated with mental disorders like schizophrenia or bipolar disorder. By reducing the presynaptic dopamine output, they're reducing the stimulation of upregulated postsynaptic dopamine receptors. That is most likely the pathophysiology underlying tardive dyskinesia. But now they can also be studied. They are in phase two to maybe improve the outcome of patients who have residual positive symptoms by reducing the presynaptic dopamine tone.

There are 2 other classes of medications that can potentially also modify the presynaptic dopamine tone. One is the TAAR1 agonism. Ulotaront has been tested. Ralmitaront is another agent that was discontinued. But there's one positive study with Ulotaront, which is a TAAR1 agonist and 5-HT1A agonist. But there was a recent phase three trial program where the drug did have similar improvement in total pens from baseline as in the phase two study, but placebo also increased the response very much, so there was no difference between the two.

But what's a TAAR1 agonist anyway? It's a trace-amine-associated receptor agonist. Trace amines are shorter neurotransmitters than the ones we have. They float around intracellularly. They can reduce both the postsynaptic downstream effect of dopamine, but also reduce presynaptic production and signaling.

Then we have the class of muscarinic agonists. There are M4 and M1. There are either agonists or positive allosteric modulators. Let's start with xanomeline and tropsium. There are 3 positive studies already that have an effect size of 0.75, 0.61, and 0.60. It's both reducing the input into the stray atom from the hindbrain to the midbrain, into the stray atom via M4 agonism. It reduces, also, the glutamatergic input into the stray atom via M1 agonism. M1 can potentially also potentiate cognitive abilities in the frontal lobe. That's xanomeline and tropsium, 3 positive studies. Tropsium is added. It's a peripherally restricted anticholinergic because xanomeline has not only central, but also some peripheral pro-muscarinic effects, which can lead to nausea or vomiting. Then the tropsium has had some side effects on constipation and dyspepsia. These side effects generally emerge in the first one or two weeks and then usually subside within 3 weeks. We have 3 five-week active studies against placebo.

Emraclidine is an M4 muscarinic positive allosteric modulator. So it doesn't sit where the endogenous acetylcholine would sit. It sits at the side, at an allosteric side. Either you can then amplify the signal and make it easier for acetylcholine to bind, and that's a positive allosteric modulator, or you would be able to attenuate it, which would be a negative allosteric modulator. In a phase one B study, with just 27 patients in 2 active arms and in placebo, emraclidine again had an effect size of 0.58 and 0.68 at 6 weeks to treat total positive symptoms.

So it's very exciting that we have now converging data to improve psychosis. Maybe it could also improve psychosis, not only in patients who are acutely exacerbated, which was the study designed for these drugs, but it could also help patients that maybe are not helped enough with the current anti-psychotics, that are partial non-responders or total non-responders.

Christoph Correll, MD, is Professor of Psychiatry at The Zucker School of Medicine at Hofstra/Northwell, New York, USA, and Professor and Chair of the Department of Child and Adolescent Psychiatry, Charité University Medicine, Berlin, Germany. He is board certified in general psychiatry and child and adolescent psychiatry, having completed both residencies at The Zucker Hillside Hospital, NY. Since 1997, he has been working in New York, USA, and since 2017 he is also working in Germany again. Dr. Correll focuses on the early identification and treatment of youth and adults with severe mental illness, clinical trials, epidemiology, psychopharmacology, meta-analyses, and physical health in mental health. Since 2014, the beginning of this metric, he has been listed every year by Clarivate/Web of Science as one of the “most influential scientific minds” and “top 1% cited scientists in the area of psychiatry.”

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