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Faculty Focus

Alan I. Green, M.D.: "Glee" club

brain injuries; and sleep disorders. Managing such a diverse and influential department is an all-consuming job, so Green now does his own research "around the edges," as he puts it. "It's been possible for me to have a large administrative job and continue to do research . . . because I have a number of terrific people working with me."

Green's primary research interest has been a drug called clozapine, a highly effective but also highly toxic treatment for schizophrenia. Clozapine was studied in the late 1960s and early 1970s, Green explains, but was taken off the market because of its side effects. Then in the late 1980s, studies showed that clozapine was more effective than any other antipsychotic in treating schizophrenia, and the Food and Drug Administration approved it for use in patients who did not respond to any other drugs.

"I became preoccupied with the idea," says Green. "Why does this drug work? Why is it better than the other ones?" He and his collaborators discovered that clozapine caused the levels of norepinephrine, a neurotransmitter, to skyrocket. "That has sort of puzzled me for the last 15 years," says Green. "I have been trying to understand what does that and how is that related to the effects of clozapine."

A major piece of the clozapine puzzle fell into place as a result of a lab meeting when Green was still at MMHC. He and his colleagues were discussing the fact that half of the patients who wanted to enroll in a trial had to be excluded because of substance abuse. One of the lab technicians raised her hand. "She said to me," Green recalls, "'Alan, have you ever thought about maybe trying to understand why it is that people with schizophrenia have so much substance abuse?" He hadn't. "Maybe we should study those patients," she suggested.

So Green started reading about substance abuse and schizo- phrenia. He then asked some of the nurses at MMHC if clozapine seemed to affect patients' alcoholism or other addictions. "Well, you know," Green

Grew up: South Norwalk, Conn.
Education: Columbia College '65 (A.B. in history), Johns Hopkins University School of Medicine '69 (M.D.)
Training: Beth Israel Hospital, Boston, Mass.; Massachusetts Mental Health Center
Earliest jobs: Counting cars for a traffic survey, lifeguarding, and selling encyclopedias
Little-known fact: Helped set up a Head Start program in Mississippi in 1965
Family: Wife Franny Cohen, a trial lawyer in Boston, and 14-year-old twins, Isobel and Henry, both students at Milton (Mass.) Academy
Musical interests: Plays the piano and guitar
What he did while he was bedridden: Listened to baseball games; wrote a novel about a scientist who gets sick; and read a lot, including novels by Charles Dickens and William Makepeace Thackeray and books "about people . . . confined against their will," such as Thomas Mann's Magic Mountain

"That man loves his work," says a colleague, who recalls Green "giggling with glee" about some study data.

recalls their telling him, "it might be helpful."

One day, he shared some of these budding ideas in a lecture, and not long after that he got a call from a colleague. "We have two patients over here who had been put on clozapine who had longtime, long-standing problems with alcohol [and] who stopped using alcohol," Green recalls the colleague telling him. Soon other providers began sharing similar anecdotes.

That impelled Green to contact Dr. Robert Drake, a psychiatrist at Dartmouth who is acclaimed for his work studying and developing treatments for people who suffer from both severe mental illness and addiction. Drake shared with Green some data that he had on patients with schizophrenia who had taken clozapine.

"We looked back and found that, in fact, those who had been put on clozapine had

a dramatic decrease in alcohol abuse compared to those who hadn't," observes Green. Those initial findings led him to pursue a whole series of studies about clozapine, which, in turn, helped him to piece together his central theory about schizophrenia and substance abuse.

"Schizophrenia itself," he explains, "is a disorder that is associated with certain brain abnormalities . . . in the area of the brain that, among other things, regulates brain reward circuitry—the [system] that perhaps allows us to appreciate things in the world.

"Drugs of abuse all work through this circuit," Green continues. "Maybe the circuit is faulty in people with schizophrenia . . . and the drugs of abuse may make them transiently better even though, over time, it makes the disease much worse."

For the past several years, Green has been exploring this theory by doing brain-imaging studies. At the same time, he and his lab have been "trying to take clozapine apart," he explains, "take the pharmacologic actions of the drug apart and then add them back together to see if we can create a clozapine-like drug [that] would be safer."

When Green reflects on his career, he chuckles at how his interests have come full circle. It was seeing patients who had experienced bad reactions to illicit drugs that first sparked his interest in the inner workings of the brain. Then, he muses, "I had nothing to do with substance abuse for years. And before you know it, I'm back in the field of substance abuse."

Although his research interests may have followed a circuitous path, his compassion for people with chronic mental illness has been constant—in part because of his own struggle to get well. "I had a chronic illness . . . and I didn't know whether I was going to get better," he recalls.

But fortunately for him—and for those who suffer from schizophrenia and addictions—he did.

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Jennifer Durgin has been a member of the staff of Dartmouth Medicine magazine since 2004 and was recently promoted to associate editor.

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