How TAAR1 Agonists Might Be Used in Schizophrenia Treatment, With Dr Leslie Citrome

In this podcast recorded at Psych Congress Elevate, Psych Congress Network's Schizophrenia Section Editor Leslie L. Citrome, MD, MPH, Clinical Professor of Psychiatry and Behavioral Sciences, New York Medical College, answers questions about the potential uses of TAAR1 agonists in the treatment of schizophrenia, what implications clinical trial structure and goals have for clinical application, and the medications' effect on the basal ganglia. 

Andrew D. Penn, MS, PMHNP, associate clinical professor, School of Nursing, University of California, San Francisco, moderated the Q&A session that followed the panel entitled "TAAR1 Agonism: A Novel Approach to Schizophrenia Management."

Scroll down to read the transcript of this podcast.

Part 2 coming soon!

Leslie Citrome, MD, MPH, is clinical professor of psychiatry and behavioral sciences at New York Medical College in Valhalla, New York, and adjunct clinical professor of psychiatry, Icahn School of Medicine at Mount Sinai in New York City, New York. In addition to his academic positions, he has a private practice in psychiatry in Pomona, New York. He is a Distinguished Life Fellow of the American Psychiatric Association and a Fellow of the American Society of Clinical Psychopharmacology where he currently serves as President.

Dr Citrome earned his medical degree from McGill University in Montreal, Canada, and his master’s degree in public health from the Columbia University School of Public Health, Division of Health Policy and Management in New York, New York.

Dr Citrome is a consultant in clinical trial design and interpretation. He is a frequent lecturer on the quantitative assessment of clinical trial results and has lectured throughout the United States, Canada, Europe, and Asia. His main interests include schizophrenia, bipolar disorder, and major depressive disorder. He is author or coauthor of over 500 research reports, reviews, and chapters in the scientific literature. Dr Citrome is editor emeritus of the International Journal of Clinical Practice and is on the editorial boards of several publications, including the Journal of Clinical Psychopharmacology, CNS Spectrums, Clinical Psychopharmacology and Neuroscience, and Expert Review of Neurotherapeutics.

Andrew Penn, MS, PMHNP, was trained as an adult nurse practitioner and psychiatric clinical nurse specialist at the University of California, San Francisco. He is board certified as an adult nurse practitioner and psychiatric nurse practitioner by the American Nurses Credentialing Center. He has completed extensive training in Psychedelic Assisted Psychotherapy at the California Institute for Integral Studies and has published in the American Journal of Nursing, Bipolar Disorders, and Frontiers in Psychiatry. He was a study therapist on the MAPS-sponsored Phase 3 study of MDMA assisted psychotherapy for PTSD and is currently a co-investigator on the Usona-sponsored phase 2 study of psilocybin facilitated therapy or major depression.

Currently, he serves as an Associate Clinical Professor at the University of California-San Francisco School of Nursing where he teaches psychopharmacology and is an Attending Nurse Practitioner at the San Francisco Veterans Administration with the joint UCSF/SFVA NP residency program. He has expertise in psychopharmacological treatment for adult patients and specializes in the treatment of affective disorders and PTSD. He has published on the risks and benefits of cannabinoids in psychiatric treatment.

As a steering committee member for Psych Congress, he has been invited to present internationally on improving medication adherence, cannabis pharmacology, psychedelic assisted psychotherapy, grief psychotherapy, treatment-resistant depression, diagnosis and treatment of bipolar disorder, and the art and science of psychopharmacologic practice. In 2021, he was awarded the Distinction in Teaching Award by the UCSF Academic Senate.

Read the Transcript:

Andrew Penn, MS, PMHNP: A number of questions. First question you sort of touched on in [your presentation]. How do you imagine these drugs being used, monotherapy or as adjuncts, at this point? Would you say these are going to be first-line drugs, or are these going to be add-ons to existing medications?

Leslie Citrome, MD, MPH: Yeah, so I'm really wondering about that because access problems have been such a challenge for us when something new comes on. And I'm afraid it may be difficult to access as a first-line agent for someone in their first episode. That may be challenging.

Penn: Mm-hmm.

Dr Citrome: But if it really does demonstrate superiority in terms of overall effectiveness, and that's a combination of efficacy and tolerability and patient acceptance, then it might become a standard. But we just don't know yet. It's a little early. That's why, although I'm enthusiastic about these phase 2 results, I'm still cautious, because I'd like to see how it performs in a larger phase 3 population, with a broader age range and a more diverse population. So I'm hopeful, and we'll see from there.

Also, in order for medicine to be used proactively, adjunctively, and promoted as such, it has to be studied like that. So ulotaront currently, the trials in place are monotherapy trials. So if ulotaront gets approved, it'll be based on those studies as a monotherapy. And anything else that we do in the real world will be off-label. Now that may not be such a big deal, but if we're combining two branded products at the same time, there might be obstacles to doing that. It's often not much of an obstacle to combine a branded product with a generic product. So I'm not worried about that. Ralmitaront on the other hand is being assessed right away as an adjunctive strategy, at least in 1 of the 2 trials. So if that is promising then, and if the label says for adjunctive use with an antipsychotic, then you know, it could be promoted as such commercially, and that'll have a big influence on how a drug is used.

Penn: Okay. Another question here asking how does the novel medication class not affect or modulate the dopaminergic activity in the basal ganglia? Is the concentration of that receptor much diminished there in the basal ganglia. I think I'm understanding the question correctly here. What is the effect of this medication in those movement pathways of the basal ganglia?

Dr Citrome: Yeah, so it's not entirely known. It's thought to perhaps be related to decreasing in dopamine signaling through the regulation within the cell, the dopaminergic cell. Also, through the dimerization between pre- and post-synaptic dopamine receptors and the TAAR1 agonist. This is really kind of mysterious to me, but the animal models certainly point in the direction of the reduction in the psychosis, according to the models. And so that's encouraging. As I've always said, the proof of the pudding, isn't the tasting. So I really don't care really about the mechanism. If the clinical trial actually shows successfully that you can treat someone and it's well tolerated. And then we often come up with a story afterwards to try and explain it in our heads and it makes us feel better about it. But you know, that was the story behind dopamine receptor, partial agonism in aripiprazole. That story wasn't developed until really fully until after the drug was approved.

Penn: Right. Yeah. You know, as you were talking, I was thinking about how so often we kind of reverse engineer the pathophysiology of a disease based on its drug state, which would make headaches, that being caused by ibuprofen shortages in our body, but that this new medication really challenges some of those ideas of dopamine hyperactivity and dopaminergic tracts and are there more subtle ways of modulating them than-

Dr Citrome: Right. So when Rebecca showed her slide of the different neurotransmitters being involved in schizophrenia, there was dopamine, there was serotonin, there's glutamate. And that's fine, but there's more to the story. There's also acetylcholine. And there's also now these trace amine associated receptors. All roads eventually lead to dopamine though, because you have to reduce the dopamine signaling to the ventral striatum to decrease hallucinations and delusions, but you don't have to do it by blocking dopamine D2 receptors. And that's the exciting part for me.