KATHLEEN R. MERIKANGAS: Hello, everybody. And welcome to World Bipolar Day. I’m Kathleen Merikangas from the Intramural Program at the National Institute of Mental Health. And our work in the Intramural Program involves studying the familial patterns of bipolar disorder so that we can understand what runs in families and identify early signs of the manifestations of bipolar disorder so that we can identify people early so that we might be able to prevent the consequences of this condition. I’m joined by my colleague, Dr. Francis McMahon, who’s also an investigator in the intramural program. Francis?

FRANCIS J. MCMAHON: Hello, everyone. Thank you for joining us today. I’m the chief of the human genetics branch here at the National Institute of Mental Health. And it’s a real pleasure to join my colleague, Dr. Merikangas, today to talk with you about bipolar disorder. The research in my lab is aimed at discovering and characterizing genes that are involved in mood and anxiety disorders so that better methods of diagnosis and treatment can be developed. During the next half hour together today, we’ll be focusing on bipolar disorder in adults. Dr. Merikangas and I will lead a discussion on the signs and symptoms, the risk factors, treatments, and the latest NIMH-supported research in this really important area of mental health. We’ll also take the last 10 minutes or so to answer some of your questions. So please enter them as comments under the live stream post below, and we’ll do our very best to answer as many as we can before the end of our discussion. Kathleen?

KATHLEEN R. MERIKANGAS: Okay. It’s also important to note that we are not here to provide medical advice. There are some resources that are on the NIMH website, and they are shown here. So if you need help, you can go to any of these sites. There is a 24-7 lifeline that is free and confidential for people who need urgent attention for distress prevention. And other resources, if you or your loved one needs help.

FRANCIS J. MCMAHON: So what is bipolar disorder? Let’s start first by describing this illness. Everyone experiences normal ups and downs, but with bipolar disorder, the range of mood changes can be extreme. Bipolar disorder’s a mental illness that occurs occasionally at irregular intervals. What doctors call episodic. But it can also be pretty persistent and recurring, what we call chronic. People with bipolar disorder have manic episodes. These are distinct periods of elevated moods during which you might feel very happy, very irritable, very high, or some combination of all these moods. Manic episodes are not always pleasant experiences for the patient. During a manic episode, people are usually very active, have lots of energy, need less sleep, talk a lot, and have racing thoughts running through their heads very quickly. Mania affects judgment – that’s part of the definition of a manic episode – so that people in a manic state can make bad decisions, like spending too much money, driving too fast, getting into arguments, or acting out sexually. In severe manias, people may even experience hallucinations, hearing voices or seeing things that other people can’t; or delusions, where they have a belief that’s not true; or other psychotic symptoms that can be mistaken for schizophrenia. Some people have what are called hypomanic episodes, which are like manic episodes in terms of the change in mood and activity but are not so severe that people are unable to carry out the usual work or social life and are not accompanied by those severe errors of judgment that tend to occur in manic episodes.

FRANCIS J. MCMAHON: Now, most people with bipolar disorder also have episodes of depression. In fact, more time is often spent feeling depressed than feeling manic for people with this illness. During depression, people feel sad, indifferent, hopeless, or anxious. Along with these mood changes, depressed people may sleep too much, feel a lack of energy, and have trouble thinking clearly or making decisions. Suicidal thoughts or behavior can also occur during depression, which makes depression a dangerous and potentially life-threatening condition. Now, most of the time, bipolar disorder symptoms start during late adolescence, late teens, or early adulthood. Although bipolar disorder can occur even later in life. Occasionally, children may experience bipolar disorder symptoms, although this is uncommon. Now, psychiatrists recognize at least four types of bipolar disorder, although we recognize that bipolar disorder probably exists on a spectrum of severity, ranging from mild to more severe. You can learn more about the various types of bipolar disorder by visiting nimh.nih.gov/bipolardisorder. Now, the four types that you’ll see described in the diagnostic manuals include Bipolar I disorder with manic episodes and usually depression. This is classic manic depression with severe episodes of mania. Bipolar II disorder has the hypomanic, the less severe mood elevations, and also depression. Schizoaffective disorder is a term that’s used to describe bipolar disorder in which psychotic symptoms – hallucinations or delusions – persist beyond episodes of mania or depression. And then there’s cyclothymic disorder, which is also called cyclothymia, where someone’s mood is almost always either up or down, either elevated or depressed, but little time in between with a normal mood. Kathleen, would you like to talk about the symptoms of bipolar disorder?


KATHLEEN R. MERIKANGAS: Okay. Sorry. So as Dr. McMahon said, people during episodes of mania may also have a lot of behaviors that they may not have insight into the changes of how they are speaking more quickly. They seem to be moving more quickly. They seem to be doing things that they wouldn’t normally do. So it’s very important to have family members who may observe these changes. Who may help to prevent them from doing things that may be out of character or get them into trouble. So I think with something like bipolar disorder, families become extremely important in getting them the help that they need. As described by Dr. McMahon also, the changes in motor activity are one of the– one of the most recent developments from studies of people over time. Increasing recognition that motor activity may change without concomitant changes where people have increased elevated mood or distressed mood. So observing people moving more quickly, talking more quickly may be an important observational tool that we have to identify that people are moving into manic states. I wanted to contextualize what we’re presenting today a little bit to talk about how common bipolar disorder is in the general population. I’m an epidemiologist, and as an epidemiologist, we’re interested not only in people who come into treatment settings but about people who have suffered from some of the symptoms of bipolar disorder or the full disorder with impairment in the general population. Because there’s increasing evidence that many people do not come to treatment in specialty care, and they may, therefore, appear in the legal system. They may be evaluated in the medical system because of physical conditions and so forth. So it’s really important to understand the spectrum of bipolar disorder in the population.

KATHLEEN R. MERIKANGAS: So data suggests that about 1% of people across the world will suffer from bipolar disorder that’s diagnosable according to the criteria that Dr. McMahon mentioned, but another four to five percent may suffer from the symptoms and the syndrome that’s a broader spectrum, and that would be fluctuations in mood and activity and speech and so forth. So it’s important to identify the spectrum of conditions as well because that could either be a sign that people would develop the disorder in the future or may have had the disorder and these are lingering symptoms. We know that it probably begins earlier than we were all taught when we were trained about bipolar disorder. 20 to 30 years ago, it was believed it didn’t really begin until the ages of 40 and later, and now the more we move into general population samples, we see that the symptoms begin in adolescence and early adulthood, providing an important time for us to think about prevention of its consequences. The consequences of bipolar disorder are probably one of the most important opportunities that we have to prevent people developing lifelong disorders. So oftentimes people with bipolar develop alcoholism and drug abuse, they develop problems with their physical health because they tend to have poor health habits, and may ultimately end up having obesity, heart disease, and so forth. And with substance abuse, we may encounter somebody later in development of this condition, and we will not know that it really began by these fluctuations in mood and activity earlier in life. And it’s very difficult to go backwards and understand that. So receiving the right diagnosis is really important. And we hear time and time again, family members will say, they went to many physicians, and nobody recognized that this was really bipolar disorder. So people come to treatment either after a serious suicide attempt, severe depression, or something that may lead people into the point that they really need help. And thus, it’s very important that they go to a professional with experience in understanding what bipolar disorder is and properly making this diagnosis, so they can get on the right track. Okay. Now, we’re going to talk about – we’re going to turn to – what are the causes of bipolar disorder. And Dr. McMahon is going to talk about his work on the genetics of bipolar disorder, which he is an international expert and has explored the possible role of genes in our understanding and treating bipolar disorder.

FRANCIS J. MCMAHON: Thanks, Kathleen. Yes, the exact causes of bipolar disorder are unknown. But research suggests that a combination of genes and environmental factors, life experiences, are involved. First, let me talk about genes. Bipolar disorder often runs in families, and research has shown that this is mostly explained by heredity. People with certain genes are more likely to develop bipolar disorder than others. Many genes are involved, and no one gene causes the disorder. Only a fraction of the genetic causes of bipolar disorder have been identified so far. The biological mechanisms underlying the development of the disorder are still unknown. In the last 10 or 15 years, we’ve learned a lot about the genetics of bipolar disorder and other common health problems through what are called genome-wide association studies. In these studies, genetic markers spread across all 23 chromosomes are tested, looking for markers that are more or less common in people with bipolar disorder than in those without. Millions of markers can be tested in tens of thousands of people. The more people we study, the more genetic markers we tend to find. The most recent genome-wide association study of bipolar disorder, which I was involved in along with a large group of international collaborators, had over 40,000 patients and more than 350,000 healthy controls from all over the world. We found 64 different genetic markers, but we expect that more will be found the more patients we’re able to study. For this study, we analyzed genetic data from study participants living in Europe, North America, and Australia. These participants included individuals who were receiving clinical care for bipolar disorder, as well as those who are classified as having bipolar disorder based on data from health registries, electronic health records, or repositories, and who had consented to share their diagnostic information with the study.

FRANCIS J. MCMAHON: We also found overlap between genetic markers of bipolar disorder and markers linked to other psychiatric disorders, such as schizophrenia, major depression, and attention-deficit/hyperactivity disorder. These kinds of overlaps among psychiatric disorders at the genetic level have been seen repeatedly over the years and have told us a lot about how we can think about genes and the role they play in contributing to mental illness. This study also found genetic overlaps or genetic correlations between bipolar disorder and many other traits. For example, the results showed a genetic overlap between bipolar disorder, alcohol use, and smoking, which may help explain some of the physical health-related conditions that are more common in people with bipolar disorder. There were also genetic overlaps with some aspects of sleep. Such as genes controlling daytime sleepiness, insomnia, and how long someone sleeps in a 24-hour period. This is interesting, given that sleep disturbances are often a big part of bipolar disorder. Suggesting that some of the genes that contribute to the risk for bipolar disorder are also genes that control aspects of sleep. 64 genetic markers we found may actually implicate more than a 160 different genes. Some of these genes play a role in how nerve cells communicate with each other in the brain across what are called synapses. Some of these genes are also known to be targets for certain types of drugs that are currently used to treat bipolar disorder, such as antipsychotics, mood stabilizers, and anti-epileptics, although many of these genes are still unknown in their function and the role they play in the brain. Some genes are known to be targets for other drug types, such as calcium channel blockers, which are more typically used to treat conditions like high blood pressure, and certain anesthetics. By studying these genes, we may learn how to develop new treatments that would be effective also for bipolar disorder.

FRANCIS J. MCMAHON: Now, it’s important to remember that in studies like this, each marker has a very small effect on a person’s risk for bipolar disorder. Something like 1%. So everybody carries some of these markers, although people with bipolar disorder often carry more. And taken together, these markers can explain about one-third of an individual person’s risk for bipolar disorder. So a lot of the risk is still unexplained even by these large studies. Now, since each marker plays such a small role, we don’t really have any genetic tests that can help with the diagnosis of bipolar disorder. We also don’t have any good way to predict who will benefit most from a particular treatment. These kinds of tests may be on the horizon for the distant future, but for now, the diagnosis and treatment of bipolar disorder is still based on a person’s life story and symptoms. There are no blood tests, brain scans, or other tests that will establish the diagnosis. This hard fact remains a big challenge for all psychiatric disorders.

FRANCIS J. MCMAHON: Now, let me tell you about another recent study that we conducted at NIMH that suggested that differences in the way genes are turned on and off, what we call gene expression, may help us understand how mental illnesses with shared genetic roots, like bipolar disorder and schizophrenia, may actually result in different patterns of onset of symptoms and the course of illness and the treatment response. As I made mentioned before, the most common mental illnesses, such as bipolar disorder, schizophrenia, and major depressive disorder also share common genetic roots, but we know that each disorder can present differently across individuals. We wanted to investigate why disorders present differently despite this seeming genetic similarity. To study this, we turn to a brain bank where people who had had psychiatric disorders as well as those who did not agreed to donate their brains after death for medical research. We measured how much each gene in the brain was actually turned on or turned off in people with bipolar disorder. We also compared these brains to those from people without bipolar disorder, would had also donated their brains to the brain bank. We found that many genes were expressed differently, hundreds, and some were produced at higher or lower levels in people with bipolar disorder. Some of these genes were actually increased in bipolar disorder and decreased in schizophrenia or depression, or vice versa. So an opposite change in gene expression. For example, one of the genes called SMARCA2 showed different readouts in bipolar disorder than it did in schizophrenia. This genes already been shown to play a role in other psychiatric conditions, such as autism spectrum disorder, and it’s known that it regulates the expression of many other genes important in the developing brain, suggesting that the genetic effects of bipolar disorder may be felt in the brain long before symptoms occur. Now, a lot more research is needed before we can understand what drives these gene expression differences. And not all of them may be driven by heredity, but the differences may ultimately help us understand how the brain functions differently in bipolar disorder when compared to other mental illnesses.

FRANCIS J. MCMAHON: Let me tell you briefly about some ongoing research here at the NIMH my colleagues and I are conducting, where we’re continuing to look for genes that may affect a person’s chances of developing bipolar disorder. Now, having found so many common genes that have small effects, we’re focusing now on trying to find rarer genes that may have larger effects in certain individuals or families because those genes may give us particular insight into the underlying neurobiology of this illness. You can participate in this study if you’re over 18, have a bipolar disorder diagnosis, or have a family member with bipolar disorder. Families and individuals who have the disorder are asked to contribute personal information and a blood sample to an anonymous national database, and this information will aid scientists around the world who are working together to develop better treatments for this serious mood disorder. You can learn more about this study and other studies being conducted at NIMH by visiting nimh.nih.gov/joinastudy. Kathleen will tell you more about what we know about the causes of bipolar disorder.

KATHLEEN R. MERIKANGAS: Ongoing right now, by our ability to follow people in real-time using mobile technologies. And we use mobile phones and devices that can track people’s activity, such as those that are now in widespread use in watches and devices that people can use. And we have now developed scientific ways to analyze, to use these tools to understand the day-to-day fluctuations of bipolar disorder. And I think one of the most important developments during the last decade has been a growing insight into the role of circadian rhythms as one of the underlying causes of bipolar disorder. And that has to do with someone’s interaction between their biology and their environments. So much of what we’re doing is on the other side of the genetic equation to look at people in real-time to see how susceptible they are to various changes in the environment, including seasons, light, stress, and so forth. And there’s growing information that people with bipolar disorder may be more sensitive to these kinds of perturbations in daily lives. So we wanted to leave a few moments for questions, so I’d like to just make a couple of summary comments. Dr. McMahon talked about the treatments for bipolar. What are the treatments for mania? What are the treatments for depression? And then more importantly, how do we stabilize them in between? So this combination of medications and tracking people in real-time by helping them to adjust the regularity of their rhythms and their daily lives might be an important tool for the future for us to help people with bipolar disorder manage these fluctuations in daily life. I will mention a new study that we’re doing – again, you can go to the same website – where we’re going to be studying how sleep, motor activity, and mood fluctuations run in families, by using these kinds of tools in real-time and bringing people to the clinical center at the NIH so that we can identify some of the signs that may occur earlier in the development of bipolar disorder so that we might be able to prevent its consequences. So I’d like to now turn it over to Francis. You were going to start to take questions, I believe. I think we just have? —

FRANCIS J. MCMAHON: Yes. [crosstalk].

FRANCIS J. MCMAHON: –[crosstalk] minutes left.

FRANCIS J. MCMAHON: I see some questions in the box here. Why don’t I start with the first?


FRANCIS J. MCMAHON: Is it possible for bipolar disorder to manifest off and on slowly in the early stages? Absolutely is. In fact, one of the things we know about bipolar disorder is it often takes years for individuals to get a correct diagnosis. So one of the important things your question refers to suggests that we really need to take early symptoms very seriously, particularly in families where other people have bipolar disorder. Second question. Can hypomania turn into bipolar I or bipolar II? Absolutely it can. And while the diagnosis of bipolar I or bipolar II is stable later in life, early on people can easily end up being classified as one or the other until the nature of their illness becomes clear. Kathleen, do you want to take question three about kids being diagnosed with bipolar disorder [crosstalk]–?

KATHLEEN R. MERIKANGAS: Yeah. Right. It’s becoming increasingly more recognized in kids. And now in child psychiatry, I see a major broadening of their ability and experience to diagnose bipolar disorder. And yes, it can be diagnosed. Generally, we don’t see the full syndrome until about 10, 11, 12, you may see it. But prior to that, it’s confounded with other disorders, such as attention-deficit disorder, anxiety disorders, depression, and so forth. But yes, that’s a very important question.

FRANCIS J. MCMAHON: So, unfortunately, we’re just about out of time. We want to thank you all for joining us today for this important discussion. And we hope that the information was helpful. Please reach out for help if you need it. As a reminder, if you or someone you know is in crisis, please call or text the 988 suicide and crisis lifeline at 988. You can also visit 988lifeline.org for more information and help. A great place to start for finding help is to go to the NIMH website at nimh.nih.gov/findhelp. You can also get more information about bipolar disorder from the same website.

KATHLEEN R. MERIKANGAS: Okay. And thank you for listening.


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