Scientists test new bipolar remedies

By MALCOLM RITTER
Scientists are casting a wide net to find better treatments for the crushing depression and uncontrolled manias of bipolar disorder, and some approaches they're testing seem pretty surprising.
Like skin patches that prevent seasickness. Or a drug that fights Lou Gehrig's disease. And then there's a newly invented device that resembles a hair dryer in a beauty salon.
Some of the strategies were identified by logic, and others by pure chance. Scientists already have evidence that they may someday prove useful against bipolar disorder, also called manic-depression.
Doctors yearn for better therapies to treat the condition, which can rip careers and marriages apart and drive people to suicide. It is so complex and mysterious that researchers haven't developed a medication specifically for it since lithium, more than half a century ago.
Bipolar disorder appears in various forms and degrees of severity in about one in every 25 American adults at some point in their lives, according to a major study published in May.
The disorder is characterized in part by episodes of mania, which are periods of boosted energy and restlessness that can run for a week or more.
"You have so much energy, you have so many great ideas" said Tamara, 26, a Pittsburgh resident who was diagnosed several years ago. She asked that her last name not be used.
"You feel like you're thinking so clear, you've got the answer for everybody. You need to tell them, you need to phone all your friends... It's so hard to sleep. You keep thinking of all sorts of things."
But mania can also bring extreme irritability. Tamara's energy and charisma made her the life of the party, but "if somebody spilled a drink on me, I would just explode," she recalled. "It's like all your emotions are just completely intensified."
She got into fights and experienced road rage. She made bad decisions, plagiarizing a college paper and behaving promiscuously.
"A lot of things sound like a good idea when you're manic," she said, "and they're really not."
During manic episodes many people even get hallucinations or delusions, and Tamara experienced those too. "I was convinced I could hear other people's thoughts, or at least know what they were," she recalled. "I thought everybody was saying bad things about me."
The disorder also brings episodes of depression that last a week or more.
"Nothing is interesting," Tamara said. "You're bored with everything... Nothing sounds fun anymore. All you want to do is sleep. I slept days and days away."
In her senior year of college, thoughts of suicide frightened her into seeking help.
Doctors currently treat bipolar with a variety of drugs including lithium, anticonvulsant medications that can stabilize mood, and antipsychotics. Psychological therapy and patient education greatly boost the effectiveness of the drugs.
Tamara takes lithium and another drug, and says, "I'm doing fine right now."
She's lucky. Bipolar disorder is hard to treat chiefly because the depressive episodes are more severe and more resistant to therapy than ordinary "unipolar" depression, notes Dr. Andrea Fagiolini, an associate professor of psychiatry at the University of Pittsburgh.
Overall, current medications for bipolar "certainly reduce symptoms but don't do a good enough job," said Dr. Husseini Manji of the National Institute of Mental Health. "Many patients are helped, but they're not well."
What's more, many patients can't tolerate current bipolar medications because of side effects like weight gain, sleepiness, tremor, and the sense of feeling "drugged," Fagiolini said. (Some patients also stop taking their medicine because they miss the "highs" of the disease, he noted).
A study of treated patients published last year found that about 60 percent got well for at least eight weeks, but only half of that group remained well when followed for up to two years. That was with very good therapy, noted Dr. Andrew Nierenberg, professor of psychiatry at Harvard Medical School.
"That means there's a lot of room for improvement," Nierenberg said. "That's why we need new treatments."
Just as heart attacks come from chronic heart disease, the manic and depressive episodes come from an underlying chronic brain disease. And "we just don't really understand what's behind the illness," said Dr. Gary Sachs, who directs bipolar research at Harvard's Massachusetts General Hospital.
The mystery and complexity of the disorder have discouraged scientists from trying to develop drugs for it, Manji said. Not since lithium have they developed a drug specifically for bipolar, Manji said.
Like lithium, some of the latest crop of early candidate drugs revealed their potential simply by chance.
Take the experience of NIMH researchers Maura Furey and Dr. Wayne Drevets with the drug scopolamine, which is normally used to keep people from getting seasick or carsick. Several years ago, they were studying whether scopolamine could improve memory and attention in depressed people. So they gave the drug intravenously to depressed patients, trying to find the right dose for a brain-imaging study.
They noticed that patients started feeling less depressed the night after the injections. Most antidepressants take weeks to kick in.
"Some patients would say it was the best night of sleep they'd had in many years, and the next morning they woke up feeling a substantial lifting of their depression," Drevets said. "In many cases that improvement persisted for weeks or even months."
Drevets and Furey quickly changed their research focus to test the drug's effect on depression itself. And in October 2006 they published an encouraging, though preliminary, result with a small group of depressed patients, some of whom were bipolar.
Now Furey is leading a study using scopolamine skin patches — like travelers wear to prevent motion sickness — to treat depression in bipolar disorder as well as ordinary depression. For now, people shouldn't try patch treatment for depression on their own, she said.
A similar bit of serendipity showed up at McLean Hospital in Belmont, Mass., in 2001. Depressed bipolar patients who were getting their brains scanned for a study of brain chemistry suddenly felt a lot better. Alerted by a research assistant, scientists started taking a closer look. And in 2004, they published their conclusion that the electric fields produced by the brain scans might lift depression. It's still not clear how.
Follow-up studies have had inconsistent results. But researchers have now built a device that resembles a hair-salon dryer to produce electric fields. They plan to start testing it this fall.
Researchers have also used the few insights they have into the disease to develop potential treatments.
That's the story with riluzole, now used to treat the paralyzing disorder Lou Gehrig's disease, also known as ALS or amyotrophic lateral sclerosis. Scientists found that a drug that's effective against depression in bipolar disorder boosts the abundance of a certain protein in rat brain cells, and that riluzole does too. So the researchers tried riluzole in a small number of depressed bipolar patients, and in some patients the symptoms virtually disappeared, Manji said.
So riluzole, which is distributed by Sanofi-Aventis, might become a treatment for bipolar disorder, he said.
Similar research used an off-the-shelf drug to get a lead for developing a new medication. Studies in rats showed that lithium and another anti-mania drug hamper the effect of a particular enzyme in the brain. That suggested other drugs that hamper the enzyme might work against mania too, Manji said.
The best available candidate: tamoxifen, used to fight breast cancer. Manji's recent study in a small group of bipolar patients found that tamoxifen quickly quelled mania. Other studies have found similar results, he said.
That shows the value of blocking the enzyme, and now Manji is trying to develop other drugs that will do that, perhaps for use in emergency rooms. He wants to avoid tamoxifen itself because of concern about long-term side effects, since his work requires a higher dose than women use to stave off breast cancer for years.
Scientists say the real key to unlocking the mysteries of bipolar disorder — and thereby exposing targets for drugs — lies in a new generation of research into DNA.
In recent months, scientific journals have begun to publish the early results of a revolution in DNA analysis: the ability to scan entire genomes in detail to find genetic variants that predispose people to particular diseases. Some of the new work is implicating dozens of variants in bipolar disorder.
Such work can expose the hidden biological underpinnings of disease, and tip off researchers to unsuspected targets for intervening.
"We've been stumbling in the dark for most of our history" of bipolar research, said gene expert Dr. Francis McMahon of NIMH. But "these kinds of studies ... will really give us the chance to reason from biological insights back to the patient."
Sachs, of Harvard, agreed: "I think these whole-genome scans will in fact be the important bridge to better treatments."
And not just in some far-distant future. The new gene studies, Sachs said, help give "a great potential to advance the field in our lifetimes and treat people who are living now."
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On the Net:
Bipolar information: http://www.nimh.nih.gov/healthinformation/bipolarmenu.cfm
National Alliance on Mental Illness: http://www.nami.org
Depression and Bipolar Support Alliance: http://www.ndmda.org
Disease treatment studies: http://www.clinicaltrials.gov