The Biology of Bipolar Disorder

Bipolar disorder has come out of the shadows. Most people have heard of the disease, which used to be shrouded in stigma and mystery. But there's still a great deal unknown about how and why the disorder arises, what's happening in the brains of those afflicted, and how best to treat it. NEWSWEEK's Mary Carmichael asked the psychiatrists and psychologists who are conducting cutting-edge research to explain what they do know. (Read more about how bipolar disease is diagnosed in children here and find out how parents of bipolar children can get help here.)

What's going on in a bipolar child's brain?
Ellen Leibenluft, chief of the Section on Bipolar Spectrum Disorders, Emotion and Development Branch, Mood and Anxiety Disorders Program, National Institute of Mental Health, Washington, DC: "We've begun to learn something about the brain mechanisms. There is evidence that the amygdala is involved in a number of disorders in both children and adults, and bipolar disorder is one. The amygdala, which processes emotions—it looks around the environment and says, 'what's important to me, what do I like, what do I not like, what am I afraid of?'—is smaller in kids with bipolar disorder, and it's also somewhat hyperactive. We don't really know why the amygdala is smaller—we don't know for sure if that's a consequence of the disorder, or a cause of it. One hypothesis would be there are neurotransmitters that are excitotoxic; they fire too much and they can damage the tissue. There's also a regulatory loop between the amygdala and the prefrontal cortex. If the amygdala is overreacting, it could be because the prefrontal cortex isn't doing a good enough job of shutting it down. One of the ways that children both learn and are taught to regulate their emotions is by directing their attention away from upsetting things. We have a paper from 2007 in the American Journal of Psychiatry where we had children play a frustrating game, and what we found was that the bipolar children had difficulty with it when emotion was high. They could not redirect their attention. And attention is very much controlled by the prefrontal cortex, among other places."

Kiki Chang, associate professor of psychiatry and behavioral sciences at the Stanford University School of Medicine: "When these kids are young, they're having to recruit extra brain areas to deal with hyperactivity in the amygdala. They're trying to stamp it down. But over time, if they're not treated, they're not able to do that. As they become adults, believe the prefrontal areas of their brain become less and less functional. We have evidence of neuronal loss. Eventually the brakes wear out. We believe that psychotherapy and medication boost those things. But we don't have it really nailed down yet. ... There are [treatment] centers that are using brain-imaging modalities to aid in diagnosis and treatment. We're trying to spread the word that, 'hey, we're not ready for that yet. A picture of your brain is not going to tell us what we want to know.'"

Children with bipolar disease are often given powerful medications. How might psychoactive drugs affect a developing brain?
Leibenluft: "We know about the side effects that people experience, but we don't really have data as to what these drugs do to the brain. There is data in adults that lithium has growth-promoting effects on the brain, but we don't know what effects there are in children. There are a few studies here and there. You'll be seeing more and more of that in the future. Within the next couple of years, we won't have all the answers, but we will have progress. ... We're always looking to develop better treatments. Everybody worries about putting kids on medication. That's the rock and the hard place: The first thing is, does it work or not? If you're a parent, that's what you want to know. You also want to know about long-term effects on the brain, but you need to help your child today."

Robert Whitaker, author, 'Mad in America: Bad Science, Bad Medicine, and the Enduring Mistreatment of the Mentally Ill:' "The brain is this incredibly complex thing, and it responds to the environment. The frontal lobes are still developing when kids are 19 or 20. Nature has honed that development over millions of years, and you muck with that at some risk. When you put a kid on a psychotropic drug, the brain will try to compensate and you will end up with a changed brain. Let's start with the anti-psychotics—the standard ones block dopamine in the brain. There are three dopaminergic tracts, one that controls motor movement; one in the limbic system, related to emotions and paranoia; and one in the frontal lobes. The drugs perturb normal function in these areas, and the brain tries to compensate for that. Initially what will happen is the neurons release a bit of extra dopamine. That compensatory mechanism burns out after a while, but people on anti-psychotics also end up with a dramatic increase in dopamine receptors, and it may never come back to normal. Once you're in that unusual state, you're actually more vulnerable to psychosis than you were in the first place. So when a kid is coming off his meds, it's not the same as if he'd never been put on them. This is one of the real difficulties for parents. When they start down the path [of medicating], they're going to change their child."

Ross Baldessarini, professor of psychiatry, McLean Hospital, Boston: "Almost any psychotropic drug that's given for more than a few weeks leads to changes in brain function such that when you stop, the brain has to reset its thermostat. If you withdraw abruptly or rapidly there's a very high risk of recurrence of the illness that you're treating. Some years ago we treated a young man who had been a very successful student and was just starting in college and had a major psychotic breakdown. He got put on lithium and did very, very well on it, but against medical advice he took himself off it. Everything was fine for a few weeks, and then all hell broke loose and he developed a horrendous recurrence of psychotic mania. It was really like getting Humpty Dumpty back together."

Adelaide Robb, child psychiatrist, Children's National Medical Center, Washington, DC: "I think we don't know all the effects of medication. What we do know from our adult work is that many of the adults who entered into treatment 10 years ago never got treatment as children. And we know untreated bipolar disorder leads to a lot of bad outcomes—more symptoms, increased resistance to treatment, less achievement, lost social interaction. It's really hard to finish high school and it's very hard to keep a job or have anybody in your family support you. We talk about medicines having side effects, but the risk of not treating also has side effects."

Janet Wozniak, assistant professor of psychiatry, Harvard Medical School, Boston: "Our tools are not advanced enough to fully explain the extraordinary complexity of the brain. We have a general knowledge about, for example, dopamine: some drugs act as dopamine antagonists. But please don't believe the idea that we understand everything that this medicine is doing. I think part of our job as clinicians is to help parents understand how little we know. This is not an experiment or a wild guess. We are doing evidence-based medicine. But there is still very much that is unknown. The question is, what are the long-term effects of treatment vs. the long-term effects of no treatment? Part of making the decision of using a treatment that may have unknown long-term effects is having some respect for how the disorder can wreak havoc. It's easy to talk about the miseries of treatment. And the treatments are terrible. On the other hand, is life compatible with not treating? For most of the kids I'm seeing, the answer is no."

What do we know about the genetics of bipolar disorder?
Baldessarini: "People have tried genetic studies, but they haven't gotten all that far. It's been difficult in adults, and it's at least that fuzzy in children. This illness probably has very subtle genetics, a lot like heart disease and diabetes. It certainly runs in families, probably more than any other psychiatric illness. But there's not a nice, crisp single gene."

Wozniak: "In psychiatry all we have is the symptoms. We don't have the tests yet. One of the things we're trying to do is collect large enough samples to thoughtfully look for genes in the lab. But in general, with psychiatric illness, mapping the genome in and of itself hasn't provided us with easy answers. We also need to figure out which genes might be protective against bipolar disorder, and whether environmental factors determine which genes get expressed."

Leibenluft: "Most children who are at risk for bipolar disorder by virtue of having a parent with the illness will not themselves develop it. People have the mistaken idea that most children of bipolar parents will develop it themselves, and most don't. Somewhere between 15 and 30 percent, maybe around 20 percent, will develop it. But we do certainly know it's a heritable illness. We've identified a number of genes associated with small increases in risk, not big ones. There does appear to be some overlap in adult samples between genetics for bipolar disorder and the genetics for schizophrenia. It's a very, very rapidly evolving field. But there's a lot of work that still needs to be done."

Chang: "Right now, there's really no good way we have to integrate what we've found so far regarding biological markers into our clinical practice. [But] it's starting to happen. John Kelsoe is marketing a test for a gene that may, in 3 to 6 percent of cases, have some relevance. He's a well-respected researcher. But this is such a complex disorder—there are so many genes that could contribute."

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