Schizophrenia Therapies: All Roads Lead to Dopamine

In this video, Leslie Citrome, MD, MPH, Clinical Professor of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, New York, expands on his recent Psych Congress session and discusses new treatments for patients with schizophrenia, including the TAAR1 agonist currently in phase 3 clinical trials. Dr Citrome talks about what is on the horizon and reiterates that “all roads lead to dopamine” when talking about schizophrenia therapies.

Dr Citrome presented his session, “Managing Agitation in Schizophrenia and Bipolar Disorder: What’s Available, What’s New, What’s Next,” in San Antonio at the 2021 Psych Congress.

Read the transcript:

Dr. Leslie Citrome:  Hello. I'm Dr. Leslie Citrome, Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College in Valhalla, New York. Let's talk about new advances in schizophrenia treatment. Up to now, we've been used to using dopamine D2-blocking agents.

What that means is that we block dopamine receptors, actually, postsynaptic dopamine receptors, in the part of the brain called the ventral striatum. By doing so, we reduce hallucinations and delusions. However, this comes with some collateral damage.

We'll also block those dopamine D2 receptors in the dorsal striatum, which causes motor abnormalities, like drug-induced Parkinsonism and dystonia. We also block dopamine receptors and cause hyperprolactinemia. Is there a way to treat psychosis, to treat schizophrenia without blocking dopamine D2 receptors?

There very well may be. In phase III of clinical development are agents that work on TAAR1 receptors, trace amine receptors, and by doing so, will involve the downstream regulation of dopamine in a different way.

TAAR1 agonists will interact with dopamine receptors and serotonin receptors to decrease excessive dopamine that occurs in the ventral striatum and also, at the same time, possibly increase dopamine where we need it, such as the dorsolateral prefrontal cortex.

We may be able to treat the symptoms of schizophrenia without directly blocking dopamine D2 receptors. However, all roads lead to dopamine. By altering TAAR1, by using a TAAR1 agonist for those receptors, we may be able to alter dopamine neurotransmission in a way that we want.

Another way of dealing with psychosis that differs from what we have today is through the use of muscarinic agonists. There is an agent that is currently in phase III of clinical investigation that's a combination of xanomeline...xanomeline, I should say, and trospium.

What this combination does is alter the regulation of glutamate and dopamine through activity at muscarinic receptors. That too is a promising area of treating psychosis in the absence of directly blocking dopamine D2 receptors.

Both the TAAR1 agonist that I was referring to—it's actually called ulotarant—and the treatment involving xanomeline combined with trospium called KarXT in phase III of clinical development, both have phase II studies that were successful. These studies were published in The New England Journal of Medicine. We can look forward to a new approach to treat schizophrenia.

Also on the horizon is the development of an agent to help with the cognitive impairment associated with schizophrenia using a glycine transporter inhibitor. This is being developed by Boehringer Ingelheim, also in phase III, but it is limited to the cognitive impairment associated with schizophrenia.

The other 2 drugs I mentioned are for the routine use in the treatment of schizophrenia in adults. I look forward to these developments, and I'm crossing my fingers that they will be successful.