Psychiatric Annals: Please elaborate on why you advocate seeing mental health as primarily neurodevelopmental rather than behavioral.
Thomas R. Insel, MD: We have looked at disorders like autism, schizophrenia, depression, and others through so many different lenses over the last 5 decades, from bad parenting, to chemical imbalance, to social construct. But with the tools we have today, we finally can address these as brain disorders.I think everybody would agree that behavior is the product of one organ, and that is the brain, and that abnormal behavior probably reflects something that is going on with the brain that has to do with abnormal functioning or abnormal circuitry. Up until 4 or 5 years ago, that was just hand waving. Through the power of neuroimaging, and through modern cognitive science, we have the ability to really pin down the circuitry involved with abnormal mood regulation, psychosis, or cognition.For example, we have very good evidence that children with ADHD have about a 2- or 3-year delayed maturation of the cortex compared with kids without ADHD. So, it changes the way we think about a disorder. Instead of it being simply “behavioral,” it is a disorder of cortical maturation, and we can ask, “What increases the rate of maturation?” Once we know that, we can think about developing new diagnostics and therapeutics.Because most of these disorders tend to have onset in the first 20 years of life, we can think of them as neurodevelopmental. That’s important to know, both for understanding the mechanisms and considering the consquences for subsequent development.
Psychiatric Annals: As the neurodevelopmental approach to mental health is in the ascent, what kind of research is the National Institute of Mental Health (NIMH) interested in funding?
Dr. Insel: Probably for readers of Psychiatric Annals, the two most important changes in research are in diagnosis and therapeutics. The idea that diagnosis is based on subjective criteria and that those criteria should fall neatly into a set of categories is not sustainable, especially for diagnosis in children, for whom symptoms are fluid. So we are trying to create a different approach to diagnosis, called the Research Domain Criteria (RDOC). It is essentially saying let’s take a multilevel approach to diagnosis just the way we do in the rest of medicine and include data from cognitive testing, from genetics, from physiology, as well as subjective complaints to try to put together a much broader picture of what any individual is struggling with.We want to make the research diagnosis much more closely aligned with known neural systems, systems linked to emotion, cognition, and behavior. So we’re much more focused on using neural circuits and cognitive domains to complement careful clinical observation of the patient for research today, and potentially in the clinic someday.This is an attempt to build a more valid diagnostic approach than anything that currently exists. It’s a multi-year project that we hope ultimately will introduce to psychiatry what we call ‘precision medicine,’ a term that’s being used in cancer and heart disease and other areas of medicine.So, maybe we won’t be looking so much at funding studies of depression, but studies of many of the aspects that can contribute to what we now call depression, recognizing that depression is probably 10 or 20 different disorders. It’s the same for autism; it is many disorders, and the category we’re using is not really very helpful for understanding either the subtypes of the disease, the mechanisms, or the most targeted treatments.
Psychiatric Annals: Tell us more about the NIMH changes to therapeutics.
Dr. Insel: We’re looking for treatments that are much more targeted, and novel targets for developing new treatments for both medication and nonpharmacologic interventions. Previously, we focused on clinical trials for behavioral intervention or for medication without studying the mechanism of action or even demonstrating that a proposed target was engaged.What we’re trying to do now is clinical trials where we use the drug as a probe to understand much more about the fundamentals of the disorder. This is called “experimental” medicine. It’s done a lot in other fields, but hasn’t really been implemented much in psychiatry. Many of our therapeutic initiatives for the next few years are going to be focused on investigating the targets emerging from an entirely new biology of disease that does not focus on monoamines and may provide a new generation of treatments.
Psychiatric Annals: It sounds like the paradigm is shifting.
Dr. Insel: It’s parallel to the kind of research done in cancer. Previously in psychiatry, we approached every disease as a chemical imbalance. Weirdly enough, the medications are frequently helpful, but we don’t really know yet what the mechanisms of action are of many of the medications used today, so it’s very difficult for us to know how to select a specific medication for any given individual. We don’t yet have personalized medicine for mental disorders.My main stance on all of this is profound humility. We don’t know what the targets should be for developing the next generation of antidepressants, for example. The next step is not to study the drugs, but to study the disorder. The error over the past 3 decades has been that we kept thinking that if we just understood much more about how the drugs worked, we’d be able to better understand depression and we’d come up with better medication. But I think we can now say that that is flawed logic. The entire field has been driven by this idea that you could think of everything as chemical. This might be true in diseases like diabetes where the problem is too little insulin, but it doesn’t translate over to psychosis or mood disorders.
Psychiatric Annals: The notion of a subspecialty called “Immunopsychiatry” is our focus in this issue. What are your thoughts on that?
Dr. Insel: Paul Patterson, PhD, at Cal Tech recently released study results showing that — and this is an amazing claim — that if you take mouse models, in autism, that you could precipitate the disorder through an immune challenge in utero, and that you could treat the disorder subsequently by doing a bone marrow transplant to make the symptoms go away.1So they’re making the case that the maintenance of the symptoms of these diseases really does have to do with the immune system.Our approach to understanding the brain has been so heavily focused on neurons, and yet most of the cells in the brain are not neuronal but are astrocytes. Increasingly we’re learning that astrocytes and another non-neuronal cell, microglia, have enormous roles in neuroplasticity and synaptic efficacy and the way the brain works.The basic science here is just emerging. I think it’s a little premature to jump from those kinds of observations to thinking about Lyme disease and fibromyalgia, but it would be good to look at where some of the basic science is going because it does lay out a pathway for considering how immune factors become highly relevant to how the brain works.
- Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci U S A. 2012;109(31):12776–12781. doi:10.1073/pnas.1202556109 [CrossRef]