Building a Shared Scientific Understanding of Psychopathology: Q&A with Dost Öngür
The editor of JAMA Psychiatry reflects on the state of psychiatric science
Dost Öngür, MD, PhD, is the William P. and Henry B. Test Professor of Psychiatry at Harvard Medical School and Chief of the Psychotic Disorders Division at McLean Hospital. He is also the Editor-in-Chief of JAMA Psychiatry, a premier journal in the field. A native of Istanbul, Turkey, Dr. Öngür obtained his M.D./Ph.D. degree from Washington University in St. Louis and psychiatric residency training at the MGH/McLean Adult Psychiatry program. His research uses brain imaging approaches to probe brain abnormalities in psychotic disorders as well as clinical studies to understand the trajectories of illness in the early phases of these disorders. He is currently the principal investigator of a P50 Center grant from the NIMH focused on early psychosis research. He is also an active clinician and an administrator responsible for all clinical services serving patients with psychotic disorders at McLean. Dr. Öngür has won awards from McLean Hospital, Harvard Medical School, and the Kempf Award from the American Psychiatric Association for his teaching and mentoring. He is past president of the American Psychopathological Association and serves on the Council for the Society of Biological Psychiatry and the Schizophrenia International Research Society, as well as the NARSAD/BBRF Scientific Council.
Awais Aftab, MD, is a clinical assistant professor of psychiatry at Case Western Reserve University. He is interested in critical and conceptual issues in psychiatry and is the author of this Substack newsletter.
Aftab: What are some important, formative influences that have shaped your career as a psychiatrist and researcher?
Öngür: There were several threads running through the early stages of my career. Foremost was neuroscience. I finished my university education and went to graduate school in the 1990s (the Decade of the Brain) when basic neuroscience research was exploding. I was enamored and inspired by how much we could now understand about the most complex organization of matter, the human brain, and I felt deeply that studying the brain would be the royal road to understanding human behavior. Although I no longer consider myself a practicing neuroscientist, I try to follow the literature as much as I can, and I have deep respect for what the field has accomplished. As I finished my MD/PhD and moved on to clinical training in psychiatry in 2000, I entered a world where the psychopharmacology era was peaking. It is hard to imagine this in our current era of me-too drugs and distrust in the pharmaceutical industry, but there was a time in our field when new medications were anticipated with hope and occasionally made significant positive impacts on the lives of our patients and their families. Reasonable experts could hope that a new antipsychotic could be as good as clozapine but easier to tolerate and stay on, for example. Although I have not done much work in psychopharmacology per se, this melioristic attitude has propelled my own interest in patient-oriented research. Finally, I discovered quickly that I loved clinical psychiatry. I was affected by the suffering of our patients, fascinated by their mental content, and challenged by clinicians’ divergent opinions and formulations of their problems.
I was fortunate to learn from experts with very different clinical orientations – from training psychoanalysts to psychopharmacology clinical trialists. This diversity of experience strongly influenced my current thinking about the problems in our field – allowing room for various levels of description and analysis, the need for humility in trusting our own conclusions, and open-mindedness to new ideas. I am still taken aback when I see workers in the field cling so tightly to their own conclusions about one or another topic, even though we are all continuously humbled by the real world. I chose to pursue a career in clinical and translational psychiatric research where reductionism and linear thinking are necessary evils, but I strive to place all of my thinking in a broader context of psychiatry in the real world.
Aftab: Schizophrenia and Bipolar Disorder Research Program at McLean has been at the forefront of neurobiological research into psychotic disorders, using multiple different approaches such as functional and structural neuroimaging, genetics, cell biology, neuropsychology, and computational methods. What are some of the most salient findings that this research effort has generated over the past 10-15 years?
Öngür: Our program was founded by my mentor Stephan Heckers in 2003. I took over from him while still a junior faculty member in 2006 when he left to become department chair at Vanderbilt. The program has grown significantly over the years and now includes 10 Principal Investigators each with their own expertise and funded research projects. I serve as Division Chief, overseeing the work, and I also conduct my own research. I can highlight a few topics we work on.
My early work using Proton Magnetic Resonance Spectroscopy (MRS) in brain levels of glutamate (the principal neurotransmitter) showed that neurochemical abnormalities in schizophrenia and bipolar disorder are not static but rather strongly state-dependent. Glutamate turnover is upregulated in manic episodes as well as psychosis exacerbations but can be normal in clinically stable individuals.
More recently, we added Phosphorus MRS to our imaging modalities. This approach allows us to quantify energy metabolism in the brain, and we have discovered significant abnormalities in this process in people with schizophrenia spectrum disorders. We find that there is a significant reduction in ATP synthesis in the brain, accompanied by an imbalance in critical redox reactions, starting with the first episode of psychosis. This reduction is partially attenuated in chronic illness by a switch from highly efficient oxidative phosphorylation in mitochondria to less efficient glycolysis in the cytosol. The brain in schizophrenia appears to compensate for the original problem in energy production by switching to a less desirable mechanism that can still meet the demand.
In the past several years, I have expanded my focus from these in vivo neuroimaging studies to more clinically oriented research. We have a consortium of first-episode psychosis clinics in Massachusetts that are collecting standardized clinical data that can also be linked to other large datasets, such as electronic health records or state administrative databases. These approaches can identify patterns in disease and treatment trajectories to inform future care system design and decision-making. Early findings from this work indicate, for example, that a first episode of psychosis is almost universally preceded by episodes of medical and psychiatric care of escalating intensity as the onset of psychosis approaches. Our consortium is part of NIMH’s EPINET initiative, which is forming a learning healthcare system from these first-episode psychosis data analysis efforts.
Aftab: The nature and validity of the distinction between schizophrenia and bipolar disorder remains contested as ever, yet it also refuses to die. What do you make of this Kraepelinian dichotomy and its legacy? How well does it serve us in the 21st century?
Öngür: Let me start where Kraepelin left off the dichotomy that bears his name towards the end of his career in 1920: “It is becoming increasingly clear that we cannot distinguish satisfactorily between these two illnesses, and this brings home the suspicion that our formulation of the problem may be incorrect.” We have well over a century of work on the heterogeneity of psychotic disorders and have not been able to produce conclusive evidence either to support or refute clear distinctions between affective and nonaffective psychotic disorders. It’s unlikely that new data will settle the issue. We have all we need to learn the requisite lessons.
Wittgenstein remarked that “classifications made by philosophers and psychologists are as if one were to classify clouds by their shape.” There are clearly different kinds of clouds; two clouds can be distinct from one another, but they can also merge. It depends on where you are in the life cycle of a cloud, many environmental parameters, and stochastic processes. So it is with psychiatric disorders: there are useful categories of disorders, but these only reflect the confluence of relevant factors in occasionally recognizable patterns and not immutable natural kinds that inexorably manifest themselves. In our clinical services at McLean, we occasionally see a textbook case of bipolar disorder or schizophrenia, but those patients are a minority of all cases with psychosis. This is, to me, the primary lesson of the Kraepelinian journey in the 21st century: instead of trying to determine whether reality aligns with one or another preconceived notion, we must reconceptualize our approach to psychiatric nosology.
Öngür: There are useful categories of disorders, but these only reflect the confluence of relevant factors in occasionally recognizable patterns and not immutable natural kinds… Instead of trying to determine whether reality aligns with one or another preconceived notion, we must reconceptualize our approach to psychiatric nosology.
Aftab: You are the current editor-in-chief of JAMA Psychiatry, a leading journal in this field. In a sense, you have a front-row seat to the scientific evolution of psychiatry, and as an editor, you have some degree of influence on the trajectory as well. In your role as the editor, have you gained any particular insights about the state of psychiatric science and the direction in which it might be headed?
Öngür: My role in JAMA Psychiatry has been the privilege of a lifetime. I have learned more about many corners of our field than I imagined could even exist—from ADHD and motor vehicle crashes to grip strength in people with dementia. My goal in the journal is always to prioritize the best original research, as that will make the most meaningful difference in our field. I will share a couple of related observations from this work.
First, our field is in what Thomas Kuhn called a pre-paradigmatic state. There is no single ruling paradigm that allows us to make sense of most scientific observations in the field, and different workers can produce good science without consensus on what to study and how to study it. This manifests itself in the journal as waves of papers using specific approaches or focusing on specific topics such as network analysis, neuroinflammation, machine learning, or mendelian randomization. The findings from these studies are often interesting and probably useful, but they come in a burst of interest where many groups in the field adopt the new focus and analyze their data but then everyone moves on to the next topic. This, to me, indicates a huge unmet need. Many in the field seem to share the hope that some new topic or method will provide a deep insight into the nature of psychopathology that we have been missing so far. When that insight fails to materialize, the field moves on to the next hope. This is what Stephan Heckers calls the “better microscopy hypothesis”—if only we had the right tool to apply to the problem, a new world of mechanisms would emerge into view.
The second observation is that there is a lack of imagination in our field. It was probably necessary for psychiatric science to mature by becoming institutional, developing its own dictionaries (such as the DSM), and establishing shared terms and references. But these do not amount to a scientific paradigm; they are simply a set of concepts and practices that we inculcate in each new generation of researchers. And these concepts and practices narrow the scope of questions that are asked and explored. No need to get philosophical about this; suffice it to say that it is rare for me to read a newly submitted manuscript and think, “This is clever!” That happens perhaps once or twice a year, and I feel excited that someone out there is thinking originally about our field. The constant parade of fashions without genuine creativity makes me think that our field needs, like Proust, not to seek new landscapes but to have new eyes.
Öngür: Many in the field seem to share the hope that some new topic or method will provide a deep insight into the nature of psychopathology that we have been missing so far. When that insight fails to materialize, the field moves on to the next hope… The constant parade of fashions without genuine creativity makes me think that our field needs, like Proust, not to seek new landscapes but to have new eyes.
Aftab: There is a lot of current enthusiasm around mitochondrial and metabolic dysfunction in psychiatric disorders. Some of the popular discussion on this topic can get a bit reductive (for instance, see my review of Brain Energy). What’s your assessment of the role mitochondrial processes may play in psychopathology?
Öngür: I myself have been surprised by the resurgence of interest in bioenergetics in psychiatry based on relatively thin evidence, even though this is one of my own areas of inquiry. It is good to realize that the notion of brain metabolism abnormalities in psychiatric disorders goes back to the earliest days of biological psychiatry with Louis Sokoloff and others conducting heroic studies on human subjects to quantify cerebral glucose metabolism. This line of inquiry quickly took a backseat to research on biogenic amines because of the success of psychopharmacology, but has come in and out of focus over the decades. The most recent enthusiasm stems from the observation that dietary interventions stimulating mitochondrial function have positive effects on some patients with psychotic disorders. Large-scale definitive clinical trials on those interventions have not yet been completed, so it is still early days. The advent of GLP-1 agonists and other interventions improving metabolic status may further fuel interest in this domain.
My own assessment is that there is no doubt there are metabolic abnormalities in the brain in psychotic disorders; our own imaging work supports this notion. Some of the details are quite interesting and suggest that metabolism is not a bystander but rather a key factor in the evolution of the brain changes seen in these conditions. On the other hand, this work is essentially a “promising observation” and not much more at the moment. Some of the unanswered questions are: what exactly is the nature of brain bioenergetic abnormalities in psychosis, e.g., ATP availability at subcellular locations where it is needed? Are there different kinds of energetic problems that manifest across biochemical networks? How do these abnormalities affect neuronal activity? How do neuronal activity disturbances relate to circuit and system-level activity and ultimately to symptom formation? Another way of putting it is that there is a large black box interposed between “bioenergetic abnormalities” on the one hand and “psychosis” on the other. Another issue is the relationship between bioenergetics and the diversity of psychiatric problems; are all disorders characterized by such abnormalities? If so, how do they relate to each other? In the other direction, maybe some people with psychosis have brain bioenergetic abnormalities but others do not? That might determine who benefits from metabolic interventions.
Perhaps this will turn out to be a subfield where pragmatic clinical interventions outpace scientific progress, much like happened with the development of antipsychotic and antidepressant medications. But much more clinical research needs to be done before we can make that statement.
Öngür: My own assessment is that there is no doubt there are metabolic abnormalities in the brain in psychotic disorders; our own imaging work supports this notion. Some of the details are quite interesting and suggest that metabolism is not a bystander but rather a key factor in the evolution of the brain changes seen in these conditions. On the other hand, this work is essentially a “promising observation” and not much more at the moment.
Aftab: Let's talk about the nature of evidence in modern psychiatric research. Scientific evidence is always incomplete and imperfect, and its interpretation is subject to a wide variety of auxiliary hypotheses and methodological issues. There is greater uncertainty and a lot more unknowns in psychiatry, but the nature of scientific evidence is not fundamentally different from other domains of scientific inquiry. Nonetheless, there is a lot more skepticism about psychiatry and distrust in psychiatric science. There is also a sentiment that the standards of evidence are so different in different psy-communities that no shared scientific framework is possible. What’s your take on all this? How can we best navigate this situation?
Öngür: I was surprised by this absence of shared standards of evidence when I went to my first psychiatric research conference in the early 2000s. I was accustomed to attending neuroscience conferences where discrepant results were viewed as an opportunity to deepen insights; now I observed very senior psychiatric researchers voicing distrust in data from other groups without any clear rationale. It appeared that many senior investigators only believed in their own work and thought there must surely be something wrong with what others were doing. This micro-scale observation is amplified across the different psy-communities as you say.
There is no single solution to this thorny problem in the sociology of science that arises from the nature of scientific evidence itself. But establishment psychiatric science does carry the responsibility to get it more right than wrong because workers in this field benefit from the reputation, social capital, and income that come with their work. I believe there is a great need for humility in our field. I cannot think of any statement in psychiatric science that is universally correct—one can find exceptions to the rule for anything a psychiatric researcher can say about patients, treatments, and biology. When psychiatric research is criticized, it is not useful to engage in fruitless debates by “pulling rank,” resorting to the superiority of the scientific method or consensus statements from professional organizations. When we do that, it invites others to look for exceptions to the asserted truth and gotcha moments going back and forth. I am much more satisfied when I see people in the field say something like, “No study is perfect, and we cannot cling too tightly to our own preconceived notions. Instead, let’s try to identify areas of convergent evidence, placing what we know in the context of patient outcomes.” We want to reach a shared understanding that captures the lived experience of suffering people, their families, and the treaters who accompany them on their journeys.
Öngür: I believe there is a great need for humility in our field. I cannot think of any statement in psychiatric science that is universally correct—one can find exceptions to the rule for anything a psychiatric researcher can say about patients, treatments, and biology.
Aftab: You and Bruce Cohen write in a recent article for Molecular Psychiatry: “There is growing evidence that these primarily categorical structures of both ICD and DSM do not fit either the clinical presentations of patients, recent discoveries from genetics and neurobiology, nor therapeutic choices well.” To a lot of people, that sounds like a pretty damning assessment of the psychiatric diagnostic enterprise (I discussed this in an earlier post). DSM and ICD are clearly inadequate clinically and scientifically, and yet it isn't clear if we can give them up because nothing else seems clinically and scientifically adequate either. We are in this twilight zone where we need to juggle multiple schemas to carry out clinical and scientific work, and we have to do this in a context of ignorance of the fundamental mechanisms of psychopathology and with different ideological factions vying for dominance. What a quandary!
Öngür: A common thread in my responses to you has been the continuity of themes from my early days in the field to now. When I first started learning clinical psychiatry, I quickly noticed that the DSM system does not capture the vibrant and bewildering complexity of psychiatric disorders. It’s almost as though we tolerate the DSM, but we all know it’s not really describing reality as we find it every day. I believe most trainees who enter the field today experience this kind of cognitive dissonance: they have studied and memorized the DSM system, then they go out to the field and they learn that it is not particularly relevant. As I became older and had more discussions with others in the field, I also realized that I do not know any academic psychiatrist who respects the DSM, is proud of it, and thinks that the DSM gets psychiatric diagnosis just right. In fact, we all know intuitively that the DSM’s answer to the question “What kind of thing is a psychiatric disorder?” is plain wrong. The DSM framework is about discrete illnesses which one recognizes from lists of symptoms that are either present or absent. Symptoms don’t work that way; symptoms don’t form regular lists, and the illnesses are not discrete. But I do know many academic psychiatrists who think the DSM system was necessary to make progress and that it is better than all current alternatives. I would list some of my own mentors and others who worked on the DSM in that group—all brilliant people committed to improving our understanding of psychiatric disorders. It is instructive to talk with some of those folks who describe the chaos in the field prior to DSM-III and be reminded that the DSM enterprise played a positive role in standardizing how clinicians think and communicate.
Let’s also not forget that these debates on nosology take place in a sociological context. The DSM enterprise has influenced society in so many ways that it is now too big to fail. Most stakeholders in the process cannot afford to walk away and say, “Let’s scrap this system and come up with something better.” Insurance companies, healthcare administrators, the legal system, journalists, and many others who are not directly involved in mental healthcare delivery nevertheless need the DSM to continue in recognizable form as long as possible for their smooth operation. This was not at all the intention of the originators of the DSM enterprise or of its current leaders, but it is a reality that we need to reckon with.
Öngür: The DSM enterprise has influenced society in so many ways that it is now too big to fail. Most stakeholders in the process cannot afford to walk away.
Given this landscape, I don’t see a rapid abandonment of the DSM in our near future. But its conceptual dominance has certainly waned, and there is fertile ground for developing new ways of thinking about the problem. We may live in this twilight zone you are alluding to for a while longer, with multiple simultaneous drafts of psychiatric nosology without a clear resolution. That’s probably just fine, and in fact, that’s where clinicians typically reside in their day-to-day work. When surveyors ask clinicians what factors they consider in formulating the problems a patient presents with and deciding on a course of treatment, DSM diagnosis is not high on the list. Clinicians know they have to list a DSM diagnosis in their paperwork, but that’s where the DSM typically ends, and the presenting problems, course of illness, functional impairment, response to past treatments, patient and family characteristics, social determinants, cultural context, and other factors begin.
Aftab: What frustrates you the most about the current state of affairs in mental healthcare, and what gives you hope?
Öngür: The unmet need to alleviate the suffering of our patients and their families is too great. Any mental health care provider is familiar with the imperative and hope to do better for future generations. I sometimes feel that we have been conditioned to not demand better outcomes, and this leads many in the field to accept the given situation as the only possible one. But other times, I see this “learned helplessness” start to break down in places, and people start to imagine a world in which individuals with mental illness lead dignified and productive lives that they are happy with. That is my hope.
Aftab: Thank you!
This post is part of a series featuring in-depth interviews and discussions intended to foster a re-examination of philosophical and scientific debates in the psy-sciences. See prior discussions with Diane O’Leary, Richard Gipps, David Mordecai, Emily Deans, Nicole Rust, Rob Wipond, Martin Plöderl, Peter Kramer, Dinah Miller, Kirk Schneider, Robert Chapman, and Owen Scott Muir.
Such a fun read. I'd be so burnt out without this newsletter and the exposure to thoughtful commentary on the field I think about (and am part of) daily.
Fantastic interview and many rich points. The issue of the social roles making the DSM being "too big to fail" is interesting and ripe for more discussion. Speaking as someone who's done forensic training and continues to do some legal work, I'm not sure the DSM is actually essential for the law. The law is very clearly not bound to psychiatric nosology. This was shown quite sadly and firmly by Kansas v Hendricks (and I was just lecturing about this yesterday to the Columbia fellows), which showed that a state can make up its own shaky definition of "mental abnormality" and not be bound to the opinion of the psychiatric community. On a smaller scale there have always been forensic experts opining on unconventional diagnoses (e.g., "battered woman syndrome"). So I'd imagine is that without the DSM, what you would have is a range of more ideosyncratic opinions, some "rogue" and low-quality, but others probably perfectly reasonable, and perhaps some enhanced by being less bound to the DSM. Would that be a net positive or negative? Hard to say, but cynically I do tend toward the latter.
All that said, re: insurance reimbursement, billing, also policy issues like parity, I do think the "too big to fail" idea is correct!