Dr. Jair Soares Interview

As laypeople we talk a lot about mental “illness,” but using that term suggests that these conditions, like depression or bipolar disorder, are illnesses in the way the flu, or cancer, are illnesses. Is that right? Does the field of psychiatry like the term mental illness?

We prefer to call them disorders rather than illnesses. To call something a disease, or an illness, implies that we know the mechanisms underlying it, and in the case of mental “illness” we don’t know the mechanisms. So we use the general term “disorder.”

Psychiatry has gotten relatively good at recognizing and classifying these disorders, based on what the patient tells us and through observation of the patient’s behavior. Understanding the causation, however, has been elusive. The tools to unravel that puzzle have gotten dramatically better, but we aren’t there yet.

Let’s talk about one of those tools. You’ve done a lot of research in the area of brain imaging. What have you, and the field more broadly, discovered? Can you literally see schizophrenia, or depression, with an fMRI?

Not quite, but we are getting closer to that. The latest generation of brain imaging studies, primarily done with functional magnetic resonance imaging (fMRI), has shown abnormalities in parts of the brain that are involved in mood regulation. This is in the parts of the brain we call, broadly, frontolimbic—areas like the prefrontal cortex, the amygdala, the hippocampus. Many functional studies have shown abnormalities in these circuits in bipolar disorder and depression. In schizophrenia the difference is often even more pronounced.

For instance, in patients with clinical depression and bipolar disorder there is shrinkage in an area called the anterior cingulate cortex. Most studies show that the hippocampus is diminished in patients with depression, and it seems that when the depression remits the size goes back to close to that of healthy individuals. There is no observable change in the size of the amygdala in patients with major depression, but in bipolar disorder there is sometimes an increase in the size of the amygdala.

Using a technique called Diffusion Tensor Imaging (DTI), we can see that the white matter fiber pathways that interconnect in these regions of the brain have also shown abnormalities in the connectivity patterns, compared to healthy controls.

So we are seeing differences, but even with all this research we can’t look at a scan and deduce a diagnosis from it.

Why not?

It’s not precise enough. We are gradually learning more about specific pathways and mechanisms that are present in these disorders, but none of these abnormalities or patterns are specific enough for us to analyze a scan and say, for instance, you have bipolar disorder rather than borderline personality disorder, or this sub-type of bipolar disorder. There are other conditions, typically mood disorders, that show similar effects, and similar differences in activity patterns and physiology can even show up in people who aren’t exhibiting symptoms of a diagnosable mental disorder.

We did a study in our lab where we used machine learning to develop an algorithm to try to diagnose depression or bipolar disorder based on fMRI scans. We got up to about 70 percent specificity.

We are at least a decade or two away from really understanding how these mental disorders come about, and from diagnosing them in a truly scientific fashion.

That sounds pretty good.

It is, but it’s not necessarily better than what a psychiatrist can diagnose without an fMRI, and it’s much, much more expensive. So there’s a cost-benefit analysis that doesn’t push us, yet, in the direction of using these tools clinically. The hope, however, is that as we continue to refine these tools and analyses, and as we combine them with other types of tests and biomarkers—genetic biomarkers, for instance—we will be able to create a neurobiological profile that offers much higher specificity.

I compare it to the field of oncology, where there has been a major transformation over the last few decades. Now we can not only diagnose specific types of cancer, we can often go even further and identify sub-types of that cancer, and then also the treatments that will be most efficacious.

We are at least a decade or two away from really understanding how these mental disorders come about, and from diagnosing them in a truly scientific fashion. But when we can do that, with mental disorders, that’s what will truly transform the work. Early diagnosis, in particular, will be transformative.

How so?

In a few ways. Early intervention is always better, in terms of improving outcomes. When you’re thinking about bipolar disorder, for example, even if we can help many patients control their mood swings with medication, prolonged experience of depression can produce some level of cognitive impairment that’s permanent. Many of them can’t go back to their prior level of functioning. The brain can heal to some degree, but there are limits. Catching the problem early, in childhood or adolescence, before a lot of damage is done, is going to be key. It’s a lot like in cancer, where early diagnosis and detection has transformed the field.

So early diagnosis and intervention isn’t just about preventing the immediate, near-term suffering, though that’s incredibly important. It’s also about preventing that lasting cognitive and functional impairment.

Better diagnostic tools will also enable precision medicine. I believe many things can cause symptoms of depression. When we get to where we can delineate the mechanisms and the causality, that will also allow us to customize the treatment.

Tell me about some of the work you’re doing in this area.

We are working in the Houston area with a group of adolescents with bipolar disorder. We already have about 200 kids, and we’re doing a really in-depth study that involves not just fMRI scans but genetic analyses, and scans and genetic analyses of their siblings and parents as well, because bipolar disorder does run in families.

In fact, bipolar disorder is one of the most highly heritable psychiatric disorders. We know that from studies of identical and fraternal twins. The concordance is as high as 60-70 percent in some studies among identical twins. Among fraternal twins, it’s more like 20-30 percent, which is still very high, and further validates that there is a genetic component.

The broad hope is to identify biomarkers that will help us understand the risk, and then we can link those biomarkers to attempts to intervene early. And as we know more about which interventions work best with which disorders and individuals, the treatments will improve as well. I believe this could be a very powerful way to prevent this disease from taking hold or from progressing to the point where patients are left with lasting impairment.

If it’s genetic, why is it only 60-70 percent between identical twins? Shouldn’t it be 100 percent?

It’s not just about the genome, which is basically identical between identical twins, but also what’s called the epigenetic expression of genes. The genome stays constant, but all sorts of other factors—like fetal environment, stress, toxins in the air, substance use, and many other environmental factors—can influence which genes are or are not expressed. That’s why identical twins are not in fact identical. In fact, we know now that epigenetic changes in how genes are expressed can even be transmitted across generations.

The good news, with epigenetics, is that even with the most heritable disorders there seems to be a significant epigenetic component, and so it’s not inevitable that they will develop even in people who are predisposed. This, again, is where early intervention may make a difference. If we can identify a predisposition to developing bipolar disorder, we may be able to intervene to make it less likely that the disorder will emerge. But we’re not there yet.

Wait. So what would an early intervention look like, in the case of someone who just shows a predisposition to develop a certain disorder but isn’t symptomatic yet?

We don’t yet know for sure, but we have some evidence of what may work. Stress, for instance, seems to make the development of disorders more likely. So we could work with families in which there is a lot of stress to try to bring that stress level down, including recommending that the patient or the family receive psychotherapy. Substance use often seems to be a contributing factor, so avoiding drugs and alcohol as much as possible is wise. In some cases, we may prescribe medications that bring down the level of stress, or are preventive in other ways.

In general, a healthy lifestyle is a good idea. Exercise, eating well, avoiding too much stress. Those things are good not just for the body but for the brain as well.

Another new avenue that is of great interest is the hypothesis that inflammation and immune system reactions can affect the brain in ways that produce mental disorders. There is some really suggestive evidence in this area. And if that’s true then there may be great promise in approaches that target inflammatory and immune response.

Say more about that.

It’s not that different, conceptually, from auto-immune disorders with which we are more familiar, in which our bodies produce antibodies that end up causing damage. The question is whether there are neuropsychiatric disorders that come from certain type of immune mechanisms that trigger excess response in the brain. Chronic stress, for instance, can lead to some level of neuro-inflammation, which might mediate some of these brain changes and brain damage over time. If we could prevent the inflammation from becoming chronic, that may make a significant difference.

We have a collaborative study we are about to start, with Houston Methodist hospital, in which we are looking at first onset psychosis. We are getting cerebrospinal fluid from patients in order to look for what are called anti-NMDA antibodies, to see if they could be playing a causal role in the psychosis. NMDA receptors play a key role in a lot of cognitive functioning, and there is some evidence that an immuno-response to these receptors in the brain may contribute to psychosis and even mood problems.

In general, I believe that immunology and inflammation are going to become very important avenues for understanding and treating mental disorders.

There is lot of new data suggesting that extreme hardship in childhood ... can wire people in ways that make them more likely to experience serious mental disorders.

As you talk, I’m starting to imagine a future in which we’re taking our kids to the doctor, for routine annual check-ups, and in addition to all the basic tests they get now, they’re also getting genetic screens, and maybe even brain scans, that provide a full neurobiological profile. And then depending on what it shows, they’d get treatment, or a preventive regimen, or at least a plan for what to pay close attention to going forward. Is that how you see it?

I think so. What we have to recognize is that somewhere between 1 in 4 to 1 in 5 people—20-25 percent—will have a diagnosable mental illness over the course of their lives. It’s about 1.5 to 2 percent of the population for bipolar disorder, then another 8 to 10 percent for depression, and then another 5 to 6 percent for anxiety.

That doesn’t mean all of these people will have chronic mental illness. Among the group of clinically depressed people, many have only one or two episodes, and will recover well and function highly, but for some it becomes a recurring, chronic thing. Bipolar disorder is much more likely to be chronic, and to cause lasting damage.

The key in my opinion is going to be childhood and adolescence. There is lot of new data suggesting that extreme hardship in childhood— for example kids who have been sexually or physically abused—can wire people in ways that make them more likely to experience serious mental disorders. Cannabis exposure in teenagers is a risk factor for psychosis. And so on.

It’s not like we can easily go into everyone’s home and effect change. But as the science advances, as we learn more about both protective factors and risk factors, what we may be able to do is help stack the decks where we load up on protective factors, and diminish the effect of risk factors. And as we learn more about the biology, if there are tests we can do to determine the kids who are at highest risk, we can focus more of our resources there.

Right now, in many areas, our treatments are still big sledgehammers. We won’t be able to fix everything. The brain is far too complex an organ. But we will be able to do much better. To go back to the cancer analogy, I’m hopeful that we can follow the trajectory that the field of oncology has traveled over the past few decades, in terms of how precise they’ve gotten in diagnosis and intervention.