“If I were advising my mom 32 years ago, knowing what I know now, I’d tell her not to have me,” Jeremy Fuller says. At first meeting, you’d never expect such hopelessness from this bright and well-spoken young man. But Fuller has bipolar disorder, otherwise known as manic depression.

In his gray fleece jacket and tidy jeans, Fuller has the youthful good looks of an Ivy League graduate. But in the 11 years since his first manic episode, he’s been unable to hold down a job, has earned a “helluva criminal record,” and has tried to kill himself more than once.

Does he want to have children? “Not until I know there’s a likelihood they won’t inherit this.” Bipolar disorder has a strong genetic component. Half of all kids with a bipolar parent develop some form of mental illness—most often attention deficit hyperactivity disorder and bipolar disorder. For kids with two bipolar parents, the outcomes are worse.

Not everyone with bipolar disorder feel as hopeless as Fuller does. Many are educated, have steady work, marry, and have children. Some claim the illness is a source of great creativity.

Still, those familiar with bipolar illness would never wish it on anyone, least of all their kids. The 2.2 million Americans who suffer from manic depressive illness endure not only periods of crippling depression, but also severe and disabling highs (mania). “Being manic is bad like being depressed is bad,” says Fuller, “because you’re not in control. You’re not thinking about consequences.”

For a psychiatrist to diagnose mania, the high must last more than a week. The patient cannot function socially and has an inflated sense of his or her abilities. Typically, manic patients sleep little, talk incessantly, have racing thoughts and seek out pleasurable activities that can be personally destructive. Classic examples include engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments.

Despite this litany of symptoms, bipolar disorder can be hard to diagnose and control. Often, it is misdiagnosed as depression until the first manic episode occurs. Or the mania is only diagnosed when the person’s life is already a shambles. Perhaps the most startling statistic about bipolar disorder is the extraordinarily high suicide rate. Nearly 15% die by their own hands.

Bipolar parents, whose own experiences make them familiar with the disorder’s potentially disastrous consequences, may agonize over a child’s tantrums that last too long or have no apparent cause, fearing these are early signs of the mood disorder. But there’s no sure-fire way to diagnose manic-depressive illness before it appears, so these parents just have to wait and see.

To shorten that wait, some doctors are trying to identify early signs of the disorder. They’re even looking for ways to prevent bipolar in youngsters with early symptoms. Others are trying to find a simple, biological way to identify kids at risk, even if they have no early symptoms. And still others are trying to find the right medications for particular children before endless mood cycles rob them of their lives.

“Mental illness in a kid is something that many think is foreign, so kids often don’t receive the treatment they need,” says child psychiatrist Robert Findling of Case Western Reserve University in Cleveland, Ohio. “Our kids deserve better.”

PREVENTION WORTH A POUND OF CURE

Diana Galbraith had early signs of bipolar disorder that were completely ignored. They started when she was 13. She felt kind of high all the time; everything made her laugh. Her seventh grade friends thought she was fun to be with, but she knew something wasn’t right. When she was 16, things changed. She couldn’t get out of bed, get dressed, take a shower, read a book, or even go to the dance classes she’d always loved.

Only when she was in college and on academic probation did Galbraith finally seek the help of a psychiatrist. The diagnosis: bipolar disorder. “I wish I were half the person I was when I was five years old,” she says. “When the disease hit, I felt myself recede from my own life.”

Galbraith, now 24, might not have been diagnosed even if she had seen a psychiatrist in seventh grade. For people with classic bipolar symptoms, which Galbraith probably didn’t have, the average wait for a correct diagnosis is 10 years. But today, doctors are homing in on the early signs of bipolar disorder and even hoping to prevent its development.

One of these doctors is Kiki Chang at Stanford University’s Pediatric Mood Disorders Clinic, who is studying 125 children of bipolar parents. Attention deficit hyperactivity disorder (ADHD) is common among these kids, and is one possible early sign of bipolar disorder in this population. That’s not to say that all kids with ADHD will become bipolar. But if they have a bipolar parent, the chances are higher than normal. And if they have ADHD plus some other symptoms, the chances are even higher. In particular, Chang looks for kids who get into a mood and can’t get out of it, and kids who are overwhelmed by changes in their environment or schedule.

Dr. Findling, at Case Western Reserve, studies a similar population. He describes them as suffering from spontaneous and unpredictable mood extremes. “Kids won’t want to leave the room for hours, or will buzz around like a bee. These are mood extremes outside the norm, and they are spontaneous, without any apparent cause. The magnitude and duration are outside the realm of a typical kid’s experience.”

Why try to identify these early signs of bipolar? “By the time it develops,” says Chang, “it’s in some ways too late.”

The first time people have a bipolar episode, it’s usually a response to an event such as puberty, a death in the family, or taking drugs. Once that first episode happens, the brain is altered, says Chang. It is sensitized in a way that makes further episodes more likely—even in the absence of stresses.

This theory, called “kindling,” comes from research about seizures. Give a mouse a low-level shock, and it will not react. Give it that same shock 15 times, and it will eventually have a seizure. After that, the likelihood of a seizure goes up. The early shocks kindle the fire.

Researchers have applied the kindling theory to bipolar disorder since 1982, when Robert Post at the National Institute of Mental Health recognized the parallels between bipolar illness and seizures. He saw that, as with seizure disorders, bipolar patients had an early episode with an obvious cause, then a stable period, then a worse second episode with a less obvious cause. Over time, the episodes worsened and the causes weakened. Eventually, the patients had episodes without any stressors at all.

If Post is right about kindling, early intervention is the key to curing bipolar disorder: Fix the brain before it changes irreversibly. Chang is trying to do just that by treating high-risk kids with an anti-kindling agent. The medication, called divalproex or Depakote‰, is an anti-convulsant. Already proven effective for treating and slowing the progression of bipolar disorder in adults, it just might prevent progression of bipolar disorder in ADHD kids who have a bipolar parent.

At a meeting of the American Academy of Child and Adolescent Psychiatry in October 2000, Chang reported that the medication improved the symptoms in at least 8 of the 14 children studied. Its effectiveness suggests these kids have an early form of bipolar disorder rather than simply ADHD, mild depression, or manic tendencies, conditions that don’t typically benefit from anti-convulsants. Until he follows the kids for a few years, Chang can’t say whether Depakote will prevent progression into bipolar disorder, but he’s hopeful.

Findling’s research at Case Western Reserve is slightly different. He’s using depakote only with kids who have both bipolar disorder itself and a bipolar parent. He says Chang’s study gives the impression that earlier treatment can be beneficial, but he’s concerned that Depakote may have a placebo effect. He also says that Chang’s research is controversial: “When does one intervene?” Is it appropriate to treat kids for a disorder they don’t have?

But Chang defends his study. To participate, children need to have manic or depressive symptoms just short of fully diagnosable bipolar disorder. Also Chang knows there’s a high placebo response rate for some mood disorders in kids, but he’s optimistic that it is not merely a placebo because Depakote worked on kids who did not respond to other medications. He sees his study as an essential first step showing that blinded, placebo-controlled studies need to be done.

Chang also thinks Depakote may be safer than stimulants or anti-depressants—the standard treatments for kids with ADHD or childhood depression. Theoretically, such treatments may kindle bipolar disorder in this population. It may be irresponsible to give stimulants or anti-depressants to the children of bipolar parents, he says.

Fuller, the young man who wished he’d never been born, is a prime example of medication-kindled mania, though it happened to him as an adult. He says he was depressed his entire life until age 21. His depression kept him from getting good grades or functioning normally, he says. “Things always seemed ten times harder for me than for people around me.”

After being diagnosed at age 21 with dysthymia, a mild form of depression, he took his first anti-depressants. At first, they gave him mild mania—he felt like he could do anything he set his mind to. He asked a girl on a date for the first time in his life and he made the Dean’s list in college, but he wasn’t sleeping much. Eventually, though, the anti-depressants pushed him into extreme mania, or even psychosis. One day, believing he knew the secret of life and that everything he saw had a meaning intended only for him, he climbed onto a garbage truck and rode around on top. When he jumped inside, each item of trash seemed to hold a secret message. Finally, the police came and took him away, but not before he had stripped naked in front of his health club, where the truck had stopped.

Taking the drugs was a “Faustian bargain,” he says. They showed him what life could be, but they also gave him bipolar disorder, an illness that has turned him into a criminal.

Had Chang treated Jeremy Fuller or Diana Galbraith when they were kids, would he have considered them high risk for bipolar? Would he have let them into his Depakote study? Probably not. Neither was diagnosed with ADHD and neither has a bipolar parent, though each had a grandmother who they believe had undiagnosed mental illness.

So if medical science is to prevent the childhood kindling of bipolar illness in people like Fuller or Galbraith, it needs something more than what Chang’s research can provide. It needs a diagnostic test.

DIAGNOSIS: LOOKING AT A STICKY SWITCH

Most researchers say a reliable test for bipolar is still remote. But Dr. John Pettigrew at the University of Queensland in Australia has an idea for a test in which the patient simply stares at an optical illusion and clicks a computer mouse.

Pettigrew studies the brains of fish, owls, primates, and platypuses. He also has bipolar disorder. His brain research led him to an accidental discovery when he tried a visual test that measures the way our two eyes compete with each other. In a “binocular rivalry” test a person looks at vertical lines through one eye and horizontal lines through the other. What the subject sees is an alternation of the two patterns: first one eye wins the rivalry, then the other. He or she clicks a mouse each time the pattern appears to switch.

Pettigrew’s students rapidly alternated between seeing the horizontal and vertical stripes—it took less than 10 seconds. But when Pettigrew looked through the apparatus, he switched very slowly—10-20 seconds. This “slow hemispheric switching rate” occurs, Pettigrew hypothesizes, because bipolar people are stuck in one hemisphere of the brain at a time.

After his discovery, Pettigrew tested the switch rates of 18 bipolar adults when they were neither depressed nor manic. Compared to 49 normal controls, the bipolar subjects had a significantly slower rate of alternation. And the more severe their disorder, the slower they switched. Individuals with less severe illness sometimes had switch rates that overlapped with the rates of normal people, so there is no cutoff level above which he can be sure someone is safe from the disorder. Still, says Pettigrew, the method works fairly well, even on kids down to five years of age whom he has tested with only slightly modified procedures.

Pettigrew’s current research uses slow switching to identify otherwise healthy young people who might be vulnerable to the development of bipolar disorder. “Having identified ‘slow switchers,’ I then follow them to see if the slow rivalry rate is a predictor of later episodes of mania and/or depression.” This research will help clarify whether switching rates can be an effective diagnostic test.

DIAGNOSIS: LOOKING TO THE BRAIN

Other possible diagnostic tests are much more high-tech. Genetics researchers have found several candidate genes that might make a person vulnerable to bipolar disorder, but they have no definite predictors.

Brain imaging is a popular area of study that offers some promise, but will not provide a diagnostic test anytime soon, says Chang. Using various methods to scan the brain, researchers look at what areas of the bipolar patients’ brain act differently. “It’s like we’re searching around in the dark with a very bright flashlight,” he says. There are lots of places to look, but no key has been found yet.

One scan offers some promise. In images of bipolar kids’ brains, Chang is finding lower levels of a chemical associated with healthy neurons. The chemical, called N-acetyl aspartate, or NAA, is made only in neurons. Using an ordinary magnetic resonance imaging (MRI) machine, Chang can see how NAA levels vary in different parts of the brain. A lower NAA level means there are fewer healthy neurons in the mood centers of bipolar kids’ brains than in those of normal kids. To use NAA levels as a diagnostic test, Chang would have to find a cutoff level: below it, all kids would get bipolar, and above it none of them would. “That would be great because we could just take a child with a bipolar parent and determine who is safe and who isn’t,” says Chang. But so far Chang has not found a cutoff line that’s clear enough for diagnostic purposes.

Chang is also comparing the brains of kids with ADHD to those of kids with ADHD and a parent diagnosed bipolar.He’s wondering whether these are two different kinds of ADHD. While the children are in the MRI scanner, he asks them to do a task like “press the button anytime you see any letter except X.” The kids must both pay attention and control their impulse to press the button at the wrong time—neither of which is easy for a kid with ADHD. Looking at activity in parts of the brain responsible for inhibition, Chang is seeing some differences between the groups, but he needs to study more kids. If the work pans out, he’ll be able to distinguish ADHD kids at risk for bipolar from ADHD kids who are not at risk.

Chang is only one of many people using brain imaging to study bipolar disorder. Dr. Jon-Kar Zubieta at the University of Michigan found significantly more of a particular protein in key parts of the brains of bipolar patients even when they were showing no symptoms of the disorder. His study was published in October 2000 in the American Journal of Psychiatry. Thus far Zubieta has scanned only 48 people—24 with bipolar disorder and 24 without—but he hopes the research will lead to a test for bipolar disorder.

The protein Zubieta studied is unusual because it stays at a constant level during a person’s lifetime, except in degenerative diseases such as Parkinson’s. Because it is unchanging, Zubieta thinks the higher concentration of the protein in bipolar patients’ brains is a genetic trait rather than a symptom of the disease. This may mean kids can be genetically tested for the trait, but Zubieta can’t be sure because no one has studied the protein levels in children.

How can a fixed protein concentration explain the extreme variability in bipolar patients’ moods? The protein has an unusual job. Called a vesicular monoamine transporter, it loads a cargo of mood-changing chemicals (monoamines) onto ships headed to other parts of the brain. The more loaders you have, the more of these chemicals you ship. The result: mood swings become more extreme.

Dr. Robert Edwards, a neurologist at the medical school of the University of California, applauds Zubieta’s efforts. “It’s a potentially very powerful technique,” he says. Before it can be used diagnostically, however, he would need to see more dramatic differences in the density of the protein in bipolar patients. He also thinks it’s important for Zubieta to test a much larger sample.

TREATMENT: DELAY KINDLES THE FIRE

But even if bipolar disorder could be reliably diagnosed, patients would still struggle to find a reliable treatment that fits their needs. These days, doctors tend to prescribe medications in a variety of combinations. It can take weeks, months or years for a bipolar patient to find a recipe that works. Given the kindling effect, it’s time that shouldn’t be wasted.

Five years after being diagnosed bipolar, Diana Galbraith hasn’t found a drug cocktail that works right for her yet. She’s now using both lithium and what she refers to as “Dr. Ketter’s wonder drug,” Lamictal. It’s an anti-convulsant approved only for epilepsy. Terence Ketter, the director of Stanford’s Bipolar Disorders Clinic, is testing it on bipolar patients. Lamictal can have terrible side effects including a skin rash, colitis, blood clotting, and even liver or kidney failure and death, if given to people who can’t metabolize it. Though Lamictal makes Galbraith agitated at night, and her hair is falling out, she says it works better for her than other drugs have.

Ketter and Dr. Po Wang at Stanford are looking for faster ways to find the right drugs for people. Using brain imaging, they have found a few spots in bipolar patients’ brains that predict which drug will work best. Elevated blood flow in one spot predicts responsiveness to drug A and not to drug B; decreased blood flow in another spot predicts the reverse. And increased blood flow in the front part of the brain means Depakote is likely to work.

“Eventually,” Wang says, “we could have a clinical diagnosis of bipolar disorder, and do a scan for drug treatment.” But there is not enough data yet to be sure the test works. The scans also use radiation, take five hours, and are very expensive. These factors make the test particularly inappropriate for kids.

If parents want to give their kids the right medication early—before kindling takes over—researchers need to have a better understanding of the various treatment options. Wang and Dr. Anna Lembke at Stanford’s Clinic are part of a nationwide research effort to understand which treatments are most effective in bipolar patients 15 years of age and older. It’s called the Systematic Treatment and Evaluation Program, or STEP. Seventeen colleges and universities are performing the research, which started in the fall of 2000 and is funded by the National Institute of Mental Health. STEP is looking at what happens to bipolar patients who receive a reasonable standard of care.

“Many bipolar people are functioning well,” Lembke says, “but we really have no idea how many; and we don’t know what treatment was successful.” STEP will fill in that gap by following more than 5,000 bipolar patients. All will be monitored the same way, with notes taken on the same computerized forms. The STEP physicians are all trained by videotapes to use a fixed menu of treatment options and to report their findings consistently.

Not only will STEP physicians look at medication regimes, they will also examine the efficacy of various types of therapy: psychotherapy, cognitive behavioral therapy, and family therapy, for example.

“Patients need to learn how to respond to episodes,” Wang says, “Cognitive behavioral therapy can help with that.” And a good family connection can make a difference. “If someone they trust tells them, ‘hey, you’re going too far,’ then they can take medications and perhaps bring themselves back to a normal state. If they burn their bridges, though, it can be hard to recruit people to provide that kind of support.”

Galbraith says she can’t talk to her parents, but at least she’s still living with them. And she finally found a psychiatrist she “clicks with.” She started seeing him weekly when she became suicidal a year ago. “When my disease takes over, suicide makes all too much sense,” she says.

Physicians won’t know the results of STEP for 5 to 8 years. But if STEP is successful in clarifying which treatments work for which types of patients, it may help prevent kindling in kids who have either early signs of bipolar disorder or bipolar itself. This will allow physicians to give patients the right treatment sooner, which is exactly what is needed to prevent the first sparks of bipolar from becoming a fire.

Fuller’s situation is truly bleak. His support system collapsed long ago. His relationship with his family is “decimated,” he says. And medications are a Catch-22: without them he’s always depressed; but with them he becomes manic. Though people laugh when he says it, there’s one option he’s seriously considering: cryogenics, the practice of being frozen after you die in hopes of being brought back to life in the future. “If there’s hope for a cure, I might get frozen until it’s available,” he says. “I have nothing to lose by trying it.”

But deep-freezing kids at risk for bipolar disorder is hardly a reasonable treatment option. They need a more realistic solution, and one just doesn’t exist yet. At least some physicians are trying to find one. Still, says Findling, “the key to doing right by a youngster is to find a good clinician: someone who can take the time and energy, who will make the effort, and who has experience with this group. That’s hard to find.”

Chang concurs. “If there were more child psychiatrists there’d probably be less need for general psychiatrists,” he says. “It’s the age-old joke of psychiatry—‘so, tell me about your childhood.’ Well, that’s where it all starts.”