By Judy Foreman, Globe Staff, 04/25/00

Michael Penney, 53, of Holliston used to have, as he puts it, "a charmed life." Marriage. A son. A master's degree in marine economics and law, and good jobs, including an eight-year stint at the state office of Coastal Zone Management.

But his charmed life came to an end five years ago when he worked for an employer who humiliated him in meetings. One day, Penney erupted in a rage that stunned him as much as his colleagues. He was hustled away when he couldn't stop sobbing.

Though the explosion seemed to come out of the blue, there had been clues. His mother and father were both mentally ill, and Penney had been very depressed in college. Even so, it took years for his psychiatrist to put the pieces together: Penney's problem, it turns out, was manic depression, a hard-to-diagnose brain disorder that afflicts 5 to 10 million Americans.

People with manic depression have profound mood swings from paralyzing despair to agitated "highs" that can include paranoia and delusions. "Rapid cyclers" swing between these two extremes more than four times a year, and some, like Penney, swing even faster: "I can go from real bereavement to laughing like a nut in seconds," he said.

For most of the last 50 years, there has been only one treatment for manic depression - lithium, a mood stabilizer. But lithium causes troublesome side effects, such as tremors and intestinal problems. It also may be only partially effective, and raising the dose can make side effects worse without improving symptoms.

Today, however, the outlook for people with manic depression, also known as bipolar disorder, is brightening considerably and should improve even more as a new study of manic depression - the largest psychiatric clinical research program ever undertaken - gets underway at Massachusetts General Hospital in Boston and elsewhere.

Central to the improving prospects for those with manic depression is psychiatrists' discovery that drugs designed to treat schizophrenia - in which sufferers often endure hallucinations as well as emotional numbness - also work against manic depression.

That may be because of a common biochemical pathway between manic depression and schizophrenia, according to Dr. Andrew Stoll, director of the psychopharmacology research lab at McLean Hospital in Belmont. Because delusions, which are false beliefs that cannot be rationally refuted, and hallucinations, hearing or seeing things that aren't there, often occur in both schizophrenia and mania, drugs that treat these symptoms in one disorder may help in the other as well.

In addition, these antipsychotic drugs help some people with manic depression even if they are not out of touch with reality, suggesting that the drugs directly affect mood as well as psychoses, said Dr. Nassir Ghaemi, an MGH psychiatrist.

The antipsychotic drugs that help most with manic depression include Risperdal, Seroquel and Clozaril, a medication that can also cause a potentially fatal drop in infection-fighting white blood cells. Because of this, patients taking Clozaril must get frequent blood tests.

In March, the US Food and Drug Administration increased the options for people with manic depression by approving a drug for mania called Zyprexa, already on the market for schizophrenia.

Zyprexa causes fewer side effects than the somewhat similar Clozaril and does not necessitate frequent blood tests, said Dr. Franca Centorrino, a Zyprexa researcher and director of bipolar and psychotic disorders at McLean Hospital. Its expanded approval is exciting, she said, because it's "the first antipsychotic approved for acute mania."

And it's not just antipsychotic drugs that help with manic depression, but drugs that prevent convulsions, such as Depakote, Tegretol and Lamictal, as well. Two other anti-convulsants, Neurontin and Topamax, also may help stabilize mood, though the data is less clear. Designed for epilepsy, these anticonvulsant drugs may reduce the intensity of both mania and depression.

But perhaps even more important than the growing array of drug treatments - including two dozen new drugs in the pipeline - is an emerging understanding of how to combine these medications with specific talk therapies.

At MGH, the University of Pittsburgh, the University of Colorado and 17 other sites nationwide, a five-year, $20 million research project is gearing up to find the best drug and talk therapy combinations for manic depression.

Sponsored by the National Institute of Mental Health and led by Dr. Gary Sachs, director of the bipolar treatment center at Massachusetts General Hospital, the Systematic Treatment Enhancement Program for Bipolar Disorder project is now enrolling 5,000 people with bipolar disorder.

All participants in the project, known by its acronym, STEP-BD, will get one or more state-of-the-art medications for bipolar disorder; no one will be put on placebo alone.

Here's how it will work. If a patient cruises along feeling well for months and then lapses into depression, he or she may choose whether to keep on receiving standard treatment such as lithium plus Depakote and an antidepressant such as Paxil or Wellbutrin, or to be randomized to get some combination of these and other medications, but not know which ones.

This design is aimed at getting answers to crucial questions, such as the pros and cons of using antidepressants in people with bipolar disorder. Many patients, including those misdiagnosed as depressive when they actually have manic depression, are given antidepressants. But in some people, antidepressants can trigger mania or cause rapid cycling and a long-term worsening of disease.

In addition to choosing to be randomized for medicine, patients who relapse also will be offered a chance to be randomized to one of the talk therapies.

Talk therapies include cognitive behavioral therapy in which patients learn how to cope with their symptoms. There is also family therapy, and "interpersonal social rhythms" therapy, in which patients learn to keep normal sleep-wake cycles, a problem for people with manic depression.

It will be several years - probably 2005 - before answers from the study are in. But the mere fact that resources are being committed to the disease sends a long overdue signal that manic depression is not a matter of minor mood swings but a brain disorder that can lead to suicide.

Michael Penney knows all too well how serious his condition is. So far, his illness has kept him out of work for nearly five years, although he's recently begun to work works 12 hours a week at Blockbuster Video in Milford. On a good day, he said, he's grateful for the work and is reasonably content.

But on a bad day - and he still has many, despite medications and psychotherapy - he fears he will never rebuild his life. "I enjoyed all the work I used to do," he said. "I'll never get back to all of that."

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