Episode 1: The Science of Bipolar Disorder

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Bipolar disorder is more than just mood swings. It’s a journey marked by intense highs of mania and debilitating lows of depression. But within this condition exist millions of people who live unique lives. Today, we're going to talk to three clinical and research experts from the Heinz C. Prechter Bipolar Research Program at Michigan Medicine to learn more about the science of bipolar disorder—diagnostics, genetics, and decision-making. We'll be hearing from Dr. Melvin McInnis, director of the Prechter Program, Dr. Paul Jenkins, associate professor of pharmacology and associate director of the Prechter Program, and Dr. Chandra Sripada, professor of psychiatry and philosophy.

Transcript

Speaker 1:

Welcome to Michigan Medicine Presents, a wide-ranging podcast series that will explore the progress in scientific research and innovation, historic roots, and the current state of conditions that affect us all. Join us for our third series, a three-part look into bipolar disorder.

Bipolar disorder is a mental health condition that is marked by extreme shifts or changes in a person's mood, energy, and behavior. Bipolar disorder affects nearly 11 million Americans at some point in their lives. And despite affecting millions of people, it is still often misunderstood and stigmatized. Throughout this podcast, we're going to hear from clinical, research, and lived experience experts from the Heinz C. Prechter Bipolar Research Program at Michigan Medicine.

The Heinz C. Prechter Bipolar Research Program was established at the University of Michigan in 2004 by Waltraud Wally Prechter, following the death of her husband, Heinz. Heinz Prechter was born in Germany in 1942 and came to the United States in 1963 as an exchange student. By 1965, he opened his own business installing sliding sunroofs in cars. In the late 1960s, Heinz moved his American sunroof company from Los Angeles to Detroit to work with the Ford Motor Company. Prechter became a household name in the Detroit auto industry, and his legacy continues on here in the motor city. Heinz was a successful entrepreneur, philanthropist, and industry leader. Throughout his life, Heinz lived with episodes of depression and hypomania, which was later recognized as bipolar II disorder.

Wally Prechter, Heinz's wife, closest business advisor, and fierce advocate for mental health brought the Prechter program to the University of Michigan for research into the condition. The Prechter Bipolar Research Program focuses its research on the longitudinal study of bipolar disorder, neuropsychology, genetics, cellular and molecular neurobiology and computer, mobile, and AI technologies with the goal of understanding the biological changes that cause bipolar disorder and develop new interventions to treat and prevent the illness. The program enrolled its first research participant in 2006 and now has over 1,500 people participating in its long-term study of bipolar disorder.

Bipolar disorder is more than just mood swings. It's a journey marked by intense highs of mania and debilitating lows of depression. But within this condition exists millions of people who live unique lives. Today, we're going to talk to three Prechter program researchers to learn more about the science of bipolar disorder. We'll be hearing from Dr. Melvin McInnis, Director of the Prechter program, Dr. Paul Jenkins, Associate Professor of Pharmacology and Assistant Director of the Prechter program, and Dr. Chandra Sripada, Professor of Psychiatry and Philosophy.

Speaker 2:

Bipolar disorder is a human condition that was formerly known as manic depressive disorder. It was called manic depressive disorder because exactly what you said, the highs and the lows. So it's characterized by episodes of mania, which are the highs. In that state or condition, the individual has a tremendous amount of energy and needs little sleep. They can go on and on. They have racing thoughts. Ideas come very quickly, and their actions may be impulsive and over-energized. They'll take on many projects and do many things, some of which may not make sense to the average person looking at them. But it's the energy that really characterizes that state, the elevated energy and the ability just to go on and on.

The depressive phase is characterized by a low mood, low energy. The individual has little will to do things, little interest in things, feels very much down on themselves, views the world in a very negative way, views their self in a negative way, and is very pessimistic about the future. In between these states, there are periods of what we refer to as mixed states. These states can have a combination of the manic and the depressive features. For example, one of the most common mixed effective states includes an elevated drive or elevated energy but in the context of a low and irritable mood. And so we have an individual with a lot of energy knocking around inside them in the context of a depressed negative attitude. And so that mixed state can be very dangerous in the sense that they can do untoward things to themselves or to others.

Speaker 1:

What usually leads to a diagnosis? We often hear that people may go many years without being diagnosed with bipolar. Why is it so hard to diagnose?

Speaker 2:

So the research has indicated that there can be upwards of eight or nine, even 10 years, before the diagnosis of bipolar disorder is made from the initial mood symptoms. Now, the initial mood symptoms can be depression and/or anxiety or some irritability or some features like that. The individual lives with that and they may or may not seek treatment or attention for these lower moods or irritable moods. When they do, the clinician at the time probably will diagnose depression because that's what it looks like.

We can't predict the future, and it's very difficult to predict if someone who has a depressed phase is going to develop a manic phase several years down the road. Now, there's research going on to try and identify features that would predict if an individual is going to develop a manic episode or going to develop bipolar disorder. But we're not able to really predict that yet, we're not able to identify those features in the earliest of phases that would definitely say that this individual is going to move into a bipolar diagnosis.

Now, there are many other elements or features that we could take into account. For example, if there is a family history of bipolar disorder and an individual, say 18, 19 years of age, comes to their doctor complaining of depression and it is discovered or found out through the medical history that the parent or a sibling has bipolar disorder. So the wise clinician at that time would be extraordinarily watchful of that individual to determine if he or she is going to develop a bipolar diagnosis. There are factors that can contribute to the instability, contribute to the likelihood that things may go or evolve towards a bipolar disorder. I'm referring here to the use of substances, the use of cannabis, or the use of alcohol, or other intoxicating substances that could lead to instability of mood, that could then accelerate the development of bipolar disorder. The wise clinician is very careful and very observant and vigilant of the pattern that evolves in the individual to be sure that if bipolar disorder is going to emerge or be identified that they're able to identify it very quickly, efficiently, and implement appropriate treatment thereafter.

Speaker 1:

So you touched a little bit on research into bipolar disorder. The Prechter program is the largest bipolar disorder research program in the United States, and the program's largest study is a long-term study that looks at how individuals manage bipolar disorder over their lifetime. Why study bipolar disorder? Why study it over long periods of time?

Speaker 2:

Well, thank you. The Prechter program began almost 20 years ago. Bipolar disorder needs to be studied because it is a human condition that affects probably around 4% of the population. Approximately 1% have the classic form bipolar one disorder, another 1% of the population with the condition known as bipolar II, and another additional 2% of individuals have a form of bipolar disorder that is perhaps less severe, but nevertheless, it impacts the individual's life. So there's a tremendous number of individuals that live with bipolar disorder and also the family members and loved ones, friends and family that live with them that are affected by this illness.

In the Prechter program, we're studying the illness over the lifetime of the individual. We're looking at just at the concept of disease. What does the disease do? How does mania and depression affect the individual? We're looking at cognitive features, how and what kinds of patterns of cognitive functioning are obvious or measurable in individuals that live with bipolar disorder. And so there are a group of individuals who are significantly affected cognitively. In other words, they have difficulties in their executive functioning, in other words, being able to work in a job and make decisions and read and look at data or do and perform tasks.

We look at also the personality and how personality evolves over the time and looking, for example, just that personality styles, maladaptive styles. And so there are certain characteristics in personality that either help or hinder the individual as they go forward. We're also looking at the sleep and circadian patterns over the course of the lifetime of the individual to determine how those patterns affect the course of their illness. We're also looking at the life story. What happens to an individual over their lifetime in living with bipolar disorder? How is this person affected by the average things that happen to people such as marriages, birth of children, educational experiences, difficulties, and so on, these various different life stressors that we all are subjected to and affect individuals with bipolar disorder perhaps in ways that are slightly different comparatively or significantly different comparatively to the average person.

Speaker 1:

So as we go forward, Dr. McInnis, what do you see next for bipolar disorder research? Where do you hope the future lies?

Speaker 2:

I'm very optimistic about the future for research and bipolar disorder. That is really driven to a significant degree by the enthusiasm of the individuals that we are working with in our clinics, in our research programs, and also the researchers worldwide.

In the recent couple of years or so, we've been working with researchers interested in bipolar disorder globally. And so, we've identified individuals that are enthusiastic to contribute to research as scientists or contribute to research as individuals with lived experience or live with bipolar disorder themselves. So I think that we're going to need to identify strategies and ways to enhance the collaborative environment in bipolar disorder. We're interested in learning what we can learn both from the researchers globally and from the individuals who live with bipolar disorder globally and determine how individuals are helped with the illness in different countries. And study, for example, just treatment patterns and cultures as to why a particular medication or class of medications is used in one culture more so than another.

We want to enhance the diversity of our knowledge and determine what we can learn from other cultures and what other cultures can learn from us. And so we've just gone through the pandemic, and every cloud has a silver lining, and what the silver lining for me and for others in bipolar research has been as a consequence of the COVID-19 pandemic has been the realization that we can utilize technology to interact and collaborate globally and work together in a way that I think is going to both enhance the science, enhance the understanding of bipolar disorder, and really bring people together and collaborate, exchange ideas, develop new ones, and implement new strategies for research and new strategies for managing the disorder that will impact our populations both here locally in our hometown, here we're in Ann Arbor, but also in other countries, Nigeria and Hungary, Serbia, England, France, all around the world, Australia, where we're delighted to work with people in Australia, Japan, Taiwan, and that. So we're just so excited to be able to learn from them and to share our ideas and together come up with new ones. And so, this is the exciting part about research.

Speaker 1:

Bipolar disorder is highly heritable. What do we know about genetics' role with bipolar disorder?

Speaker 3:

Yeah, so we know based on family studies that if a patient has bipolar disorder, another family member is 50% likely to have it. But if the gold standard of these sorts of studies is twin studies, where if a twin has bipolar disorder, the identical twin is about 80% likely. And so what this means is that genes play a large role in this disorder. Based on that, there was a large search for decades basically for the causative gene. What has become clear is there is no singular causative gene for bipolar disorder. Instead, there are probably hundreds of genes that are contributing to the disease. And so, we know that the genetics are playing an important role, but we know also that each one of these genes probably only contributes a small amount of risk to disease. But what that means still though is, nevertheless, we have to understand what each one of these genes does so that we can understand how it contributes to disease.

Speaker 1:

Dr. Jenkins, your work with the Prechter program is diving into the biological mechanisms of the disorder. What do we know so far and what do we not know?

Speaker 3:

Yeah, so based on these genetic studies, lots of labs have been looking at individual genes and trying to understand what these genes do. And so for example, one gene that our lab has been studying is the gene ankyrin 3. This gene has been identified through multiple genome-wide association studies as a consistently associated gene with bipolar disorder risk. We know that this gene causes dysfunction of a certain kind of neuron, an inhibitory neuron in the brain. And this is something that is commonly seen in patients with psychiatric disorders that there is dysfunction of this type of neuron. But what it looks like also is that each one of these hundreds of genes that have been identified through these genetic studies, they may all contribute to the disease in a slightly different way. And so the end result may be something similar, but all the underlying mechanisms are different in this case.

Speaker 1:

Your background is in pharmacology too. What are your hopes for the research you do as it relates to bipolar disorder?

Speaker 3:

Being in pharmacology, which is really the original translational science, our goal is always with an eye towards translation. So what we'd really like to do is understand, as we tease apart the sort of nuts and bolts of what is happening in the case of bipolar disorder under the hood, in the brain, if we could find then pathways that we could target to treat this disorder that would actually treat the cause of the disease. So right now, most of the treatments that we use are just treating the symptoms of disease. This is why patients are sort of constantly coming on and going off of these drugs. There are off-target effects that are unpleasant for the patients. But hopefully by diving into these biological mechanisms we can find new therapeutics that lack these off-target effects and are more specific for the cause of the disease and maybe more effective for a larger percentage of patients.

Speaker 1:

What would your ideal study in bipolar disorder look like?

Speaker 3:

Yeah, I think one of the challenges for bipolar disorder is we have different models that we use to study the disease, and each one has strengths and weaknesses. So for example, we can use animal studies, and mice, for example, is what our lab uses. Mice have lots of advantages. We can study an intact organism with an intact brain. We can look at behaviors, try to understand how therapies affect those behaviors. But as the field knows, mice are not small people. And so there are a lot of things that happen in people that don't happen in mice and vice versa.

The other thing we know is that the heritability and the genetics of bipolar disorder is very complex. And so these patients have their own unique genetic background. And so this is the reason that, for example, the Prechter program has been using patient-derived stem cells for many, many years to try to understand what is happening with this patient's exact genetics to neurons and astrocytes and other cell types to their signaling and their activity.

So what an ideal study would look like in my mind is basically one where we could leverage the strengths of these two models and move back and forth between them to sort of in a higher throughput way screen for new therapeutic pathways that might be effective in bipolar disorder. And that takes really the ability to go from genes all the way up to behavior using animal models and then being able to cross between the human-derived samples and the animal models to identify these new pathways.

Speaker 1:

Dr. Sripada, talk to us about the research you do as it relates to bipolar disorder. Do people who live with bipolar disorder have a harder time making decisions? Why is that?

Speaker 4:

Well, the answer is yes. To get there though, we have to back up a little bit. We have to get clear on this term decision. It's used in different ways. I mean, a good example would be a kid at University of Michigan makes a decision about what they'll major in. Well, that's a very complicated procedure they're going through that unfolds over days and weeks. In cognitive science, that's not at all what we mean by decision. What we mean is a very rapid, spontaneous, quick decision made by the mind. We're talking here each one of these decisions lasts about half a second.

Why is this important? Because from the perspective of cognitive science, that's all the mind does. It's just making decisions all the time. It's making decisions about how to move your body. It's making decisions about what thoughts to think with your mind. And it's making decisions about what choices to make and things like that. And so now your question was about decisions in bipolar disorder. We are able to study these decisions in cognitive science with really powerful models. These models use what's called a RACE structure. Every time your mind, and it's hard to wrap your head around, every time your mind is making one of these decisions, there is processes associated with each option that are racing against each other. The process that is the strongest wins out, and that's the choice you make.

You can see that if these decisions are not working perfectly well, then you can start to have problems with decisions. You can have problems with impulsive decisions. You can make rash decisions, decisions that are not in your interest, decisions to stay up all night and things like that. So we're starting to get in the terrain of what may be going on in bipolar disorder.

Speaker 1:

Why do you think it's important to look at decision-making when it comes to mental health conditions like bipolar disorder?

Speaker 4:

Yeah. Great. So now we're really getting into the heart of the matter. What we now know, and I talked about decisions, and again, it's not like the decision what's a major in college, it's going to be these quick decisions happening about... it takes about half a second, happening all the time. We study these decisions with this RACE model. What if these decisions are not quite right? What if they're slightly inaccurate? Then what you would see is the person's behavior would be slightly unpredictable. They would be a little bit less consistent in what they do.

Now imagine that these decisions, not just each individual one but entire sequences of these decisions, are happening differently. It's as if a knob has been turned and some of the options are going to be favored over others. Now you can get more systematic patterns where things are looking different. The person is choosing rewards that come earlier rather than rewards that come later. The person is being rash with their decision-making. Their decisions are directed much more to activity rather than rest. So these are some of the things that are happening, we believe, in bipolar disorder. At baseline, when there aren't acute manic symptoms or depressive symptoms, these decisions are a little bit different. They're a little more inaccurate and a little bit more unpredictable, and we can pick up on that. And, when the person is in a manic phase or a depressed phase, these decisions are now skewed, not just individual ones, but large populations of them are skewed in systematic ways. That's what we think is going on in conditions like bipolar disorder.

Speaker 1:

I know you're still gathering data, but what excites you the most about what you're seeing in your results so far? How will your research ultimately help improve the lives of individuals with bipolar disorder?

Speaker 4:

Great question. In a way, I've kind of saved the best news for last, that is, everything I've said so far is about how cognitive scientists think about decisions, how they think about decisions in conditions like bipolar disorder and so forth. The way to move the field forward is we have to move past these more abstract models and we have to locate these decisions in the brain. That's what my research and the research of my colleagues and the research of the people in my lab, that's what we're making some dramatic progress with.

So we use neuroimaging methods. We use fMRI, which takes a movie of the brain while the brain is engaged in tasks. We understand the brain to be an interconnected network, and with specialized methods, we can image these network patterns. What I and my colleague, especially Alex Weigard, my close colleague who's worked on this research with me in the last four years, what we've identified is a set of network patterns that is very powerfully linked to individual differences in the way that these rapid decisions unfold.

So we can measure special parameters about these rapid decisions behaviorally, and we can link these patterns to configurations of brain networks as an individual goes about a task. So that moves the field forward because now we're talking about a concrete thing, these brain networks, that we can study, quantify and intervene on potentially. So for example, a future line of research could look at these brain networks in young adolescents, kids that are 9, 10, 11 years old. In another study that I'm involved with, the Adolescent Brain Cognitive Development Study, where actually studying 10,000 kids, nine to 10 years old, and following them throughout adolescence. Now that we have these brain imaging network markers of individual differences in these decisions, we can map those over the course of adolescence. It may be possible in the future to identify kids who are going to be vulnerable to bipolar disorder or other mental health conditions.

Speaker 1:

That was Dr. Melvin McInnis, Dr. Paul Jenkins, and Dr. Chandra Sripada in our three-part series, Michigan Medicine Presents: Bipolar Disorder. Educational activities on bipolar disorder, like this podcast, are made possible through generous contributions from people like you. If you're interested in making a gift to support educational materials and events or the vital research of the Prechter program, please send an email to [email protected]. That's [email protected]. You can also learn more about the Prechter program and sign up for e-newsletters at prectorprogram.org. And don't miss the other two episodes in the series. You can find these and other Michigan Medicine podcasts at uofmhealth.org/podcasts or by looking up the Michigan Medicine Podcast Network wherever you stream your podcasts.