Complex Cases: The State of Precision Psychiatry

To kick off Season 4, Charles Marmar, MD, explains how precision psychiatry is reshaping the way clinicians and researchers think about diagnosis, treatment selection, and the underlying biology of psychiatric disorders. This conversation is a overview of where the field stands today—including emerging molecular markers, biologically informed subtypes, and new translational approaches inspired by oncology and other precision-based specialties.

Dr. Marmar is Chair of Psychiatry at NYU Grossman School of Medicine, and Director of the Center for the Study of Alcohol Use Disorder and Traumatic Stress.

In this episode, he outlines current work on:

• Molecular and genomic signatures that may distinguish patient subtypes
• Clinical trials examining targeted treatments for alcohol use disorder
• The development of proxy “brain biopsy” methods such as exosomal analyses and iPSC-derived organoids
• How converging biological data could eventually support more individualized treatment planning

This discussion reflects ongoing efforts at NYU Langone Health to move psychiatry toward a more mechanism-based, biologically grounded model of care, while acknowledging the complexity and early stage of the work. For clinicians, scientists, and trainees, the episode provides a clear snapshot of the major directions shaping precision psychiatry today.

CHAPTERS

• 00:00 Introduction: The Challenge in Psychiatry
• 00:34 Meet the Experts
• 01:07 Understanding PTSD: Types and Subtypes
• 04:47 Current Research and Innovations
• 06:19 The Future of Psychiatry: Precision Medicine
• 09:34 Case Study: Personalized Treatment Success
• 11:33 Conclusion: The Path Forward

Watch Insights on Psychiatry on YouTube
Executive Producer: Jon Earle

Transcript

[00:00:00] Charles Marmar, MD: What's the number one challenge in the field of psychiatry that has held us back from achieving what has been achieved with such great success in oncology, cardiology, and GI medicine? The answer is those fields can biopsy the organ of illness. So one of the things I'm excited about is to develop a proxy for a brain biopsy.

[00:00:34] Lenard Adler, MD: Welcome to Insights on Psychiatry. I'm Dr. Lenard Adler, the Pottash Professor of Psychiatry and Director of the Adult ADHD Program here in the Department of Psychiatry at the NYU Grossman School of Medicine. It's my pleasure today to be speaking with my chair, Dr. Charles Marmar, the Schub Professor of Psychiatry and Director for the Center for Precision Psychiatry in the Study of Alcohol Use Disorders and Stress Disorders.

[00:01:03] Charlie, it's a pleasure to be talking with you.

[00:01:05] Charles Marmar, MD: Pleasure to have a conversation with you.

[00:01:07] Lenard Adler, MD: Today, I wanted to go over your general sense of PTSD and how we treat it and the types of patients you see. You're an internationally renowned expert in PTSD. Is there one type of patient with PTSD?

[00:01:26] Charles Marmar, MD: Our current research, supported by a now nearly 18-year collaboration of six academic medical centers and the Army's elite molecular biology lab at Walter Reed, colleagues at Harvard and UCSF, and the Institute for Systems Biology and elsewhere, suggests that there are multiple subtypes of PTSD. In the same way that there's not one kind of depression—we have unipolar and bipolar depression, we have typical and atypical depression, we have more endogenous biological and more situationally reactive forms of depression, and other subtypes.

[00:02:14] There are probably at least four or five major subtypes of PTSD. The ones we've been studying, and the ones for which we have the best evidence so far, are the following: a simpler form of PTSD, often following a single traumatic, stressful life event like an accident or a natural disaster, in someone who was previously psychiatrically and medically healthy. They tend to develop a, or someone—a very resilient person—who's deployed to a war zone, comes out of a war zone, experiences some period of being on guard and vigilant because they've come out of great danger, and then quickly accommodates to that. We call that simple or subthreshold PTSD. It usually lasts weeks to months and often spontaneously recovers without treatment, but may require some brief intervention. At the other end of the spectrum is a very complex, very severe, and often very comorbid form of PTSD.

[00:03:27] It's been called Complex PTSD or PTSD with co-occurring problems, and it usually occurs in people who've had very difficult lives, who've been repeatedly exposed to adversity through childhood—sexual abuse, physical abuse, emotional neglect, and repeated trauma exposure—who then experience subsequent adolescent and adult trauma.

[00:03:53] For example, a warfighter who's been deployed on multiple tours of duty to Vietnam or Iraq and Afghanistan, or elsewhere in the world, who had a very difficult childhood and may have chosen to go into the military because they came from a stressed and disadvantaged background and are looking for some structure and safety in their life, and then end up getting very heavy combat exposure.

[00:04:25] And in between those, there are subtypes with PTSD with severe depression and subtypes of PTSD with major cognitive impairment. So at least four: simple, very complex and severe, depressive subtype, cognitive subtype, and maybe a dissociative subtype. Those are the five best well-established ones.

[00:04:47] Lenard Adler, MD: What kind of research are you doing now that you think will have the greatest impact?

[00:04:52] Charles Marmar, MD: We have a number of ongoing projects. A heavy focus is on precision medicine and alcohol use disorder with and without stress disorders. And there what we're doing is we're conducting clinical trials with novel treatments for alcohol use disorder. For example, gabapentin, which is an anticonvulsant drug, which is effective for alcohol use disorder, and we are studying DNA and RNA and other molecular features in each patient to see which molecular pathways are dysregulated and which ones will or will not respond to that treatment. So we're doing genomically informed precision psychiatry trials. We're developing subtypes of PTSD and looking at which molecular pathways and brain circuits are dysregulated in which way in the different subtypes.

[00:05:55] We are planning a new project to study the novel weight loss drug tirzepatide, or one of the other GLP-1 agonists, which are anti-craving, to see if they're effective in alcohol use disorder, and if so, for whom, by studying their genomic variants as well as their imaging patterns. We are developing a very interesting project, Len, to try to address one of the—if I were to say, what's the number one challenge in the field of psychiatry that has held us back from achieving what has been achieved with such great success in oncology, cardiology, and GI medicine? The answer is those fields can biopsy the organ of illness, and they can then study at the single-cell level what the deep nature of the pathology is.

[00:06:58] We know that the amygdala is dysregulated in PTSD and ADHD, but you and I are studying those problems, and we cannot biopsy the amygdala in our living patients. So we are very handicapped in our ability to know precisely what is the nature of the amygdala dysregulation. So one of the things I'm excited about is to develop a proxy for a brain biopsy.

[00:07:26] How do we do that? We study little vesicles called exosomes that are released from neurons in the brain, pass through the blood-brain barrier, and we study them in blood so we can access them to see what's the molecular cargo that's actually dysregulated in our patients. And we can even know where in the brain some of those exosomes came from—the hippocampus or even the hypothalamus. Let's say in the case of the hippocampus, which region? The dentate gyrus of the hippocampus. So we can study exosomes, we can study from brain banks—from people who have generously agreed to donate their brain to science when they pass away. We can study molecular pathways and do single-cell genomics in those brain bank specimens.

[00:08:23] We can harvest peripheral blood cells, reprogram them back to stem cells, and program them forward to create brain organoids, which can reconstruct features of the human brain at an individualized level in a given subject. So, for example, in the topiramate study for AUD and PTSD that we're just completing, where we have an NIH grant pending to grow out brain organelles in those patients who did and did not respond to topiramate, and then we can study those organelles and even challenge those organelles with topiramate to try to understand those differences. The idea would be to triangulate peripheral blood markers, exosomal markers, molecular features from postmortem studies, molecular pathways in brain organelles, and other approaches so that we could approximate a brain biopsy.

[00:09:34] And I could just finish briefly by saying, as a proof of concept of this, we published a paper—so this I can talk about, it's in the public domain. At NYU, psychiatry and neurology collaborated on the care of a patient who was completely refractory to all treatments for depression. They had had electroconvulsive therapy, many medications, many psychotherapies, and other treatments with no benefit over several decades. Concern was raised by neurology that they might have a rare brain disorder, which would warrant a brain biopsy.

[00:10:20] Their brain was biopsied in a silent area in their prefrontal cortex using surgical technique safely. There were no side effects from the biopsy. The biopsy was sent to neuropathology. And it was found the patient's brain, at least in the prefrontal cortex, had massive invasion of inflammatory cells. We gave that patient a novel anti-inflammatory drug, infliximab, that crossed the blood-brain barrier.

[00:10:53] And for the first time in decades, that patient experienced reduction of their depression symptoms. One biopsy, no side effects from it. And you have to also ask, what were the cumulative effects of all the other treatments on their brain and on their life? Obviously, living with severe depression for 20 years would be tremendously disruptive to a person's life.

[00:11:21] While we can't routinely biopsy the brain, if we can develop a proxy for it, that single case provides a proof of concept that we could eventually personalize treatment.

[00:11:33] Lenard Adler, MD: So, Charlie, really the future is bright, and really it's all about trying to get the right treatments for the right patient.

[00:11:39] Charles Marmar, MD: It's all about finding out what's the deep problem that we're trying to solve.

[00:11:48] Then personalizing treatment in relationship to that problem. Let's summarize this way: When you or I were in training, how did we treat breast cancer and prostate cancer? One size fits all, fundamentally. They got some combination of radiation, surgery, and chemotherapy, or all of them. And you did the best you could.

[00:12:13] Now we can treat those disorders in a personalized way with monoclonal antibodies that target their variant of their cancer. I would hope in the future that you and I could collaborate on the care of a warfighter with very complex PTSD and ADHD, and know which molecular and circuit pathways are disrupted and which treatments would help that individual person.

[00:12:43] Lenard Adler, MD: Well, it's been a pleasure talking with you, Charlie, and it's really been exciting to talk about all the new things that are coming. 

[00:12:49] Charles Marmar, MD: Thanks. I enjoyed speaking with you.