The outer limits of schizophrenia treatment

Researchers are treating teenagers for schizophrenia before they are diagnosed. Some bioethicists think that's insane.

Published December 1, 1999 5:00PM (EST)

The photo was a standard elementary school head shot of a beautiful little boy with big, bright eyes and a smile on his face. Eric would keep it in his pocket, and although it was a picture of him years earlier, at age 12, it was a constant reminder of the way things were before. Routinely, he would take it out of his pocket and pass it around for his family to see. He knew something had changed but didn't understand it.

And neither did they. When Eric (not his real name) was diagnosed at the age of 18 with schizophrenia, he and his family watched as his whole world came crashing down. His friends shunned him. His mind played tricks on him, making him believe that angels were speaking to him. And as a result of the antipsychotic drugs, his tall, thin frame became heavy with an extra 50 pounds, sending him over 200 pounds. His hair and beard grew long, giving him a disheveled, wild look. He had become physically intimidating; kids, who once adored him, became afraid.

Even though his family sensed his anguish and pain, nothing could have prepared them for the news. On a February afternoon, a passerby found his body outside a parking structure in Hollywood. He had fallen four stories to his death. He was only 24 years old.

When Eric was growing up, there was no reason to suspect that he would later become mentally ill. Schizophrenia, which affects 2.3 million Americans, or 1 percent of the population, is the most debilitating of the mental illnesses. It can be chronic and all-encompassing; personalities become tainted by hallucinations, delusions, strange behavior, social withdrawal and confusion; one in 10 ends up committing suicide. Its chokehold varies from person to person -- from the shy, quietly paranoid types to someone like Andrew Goldstein, who is accused of inexplicably pushing a young woman named Kendra Webdale into the path of an oncoming subway train in New York last January.

Patients' rights advocates, psychiatrists, psychologists and family members are trying to find a way to intervene before tragedy can strike. New medications for treating schizophrenics are a vast improvement over the drugs in the past, but they still don't come close to curing it, or dramatically altering its course. Although many schizophrenics are living happy and productive lives, many others spend their years homeless, in jail or in and out of psychiatric wards. And even if a patient ends up getting treatment -- which has always been after the person becomes sick -- the prognosis usually isn't good. Only one in five recovers.

But researchers testing the implications of a new theory are hoping to change that, by preempting the illness and treating people for schizophrenia before they have had their first psychotic episode, let alone diagnosis. They posit that the short period of time before a person begins to exhibit psychotic symptoms may be the key to preventing mental illness. Although it's not conclusive, there is some evidence that the earlier a person is treated, the better the outcome can be. These psychiatrists believe that if they can find a way to intervene before the first psychotic break, then possibly schizophrenia can be prevented, or at least tempered.

"It's important to treat them in the pre-psychotic stage because that's when a lot of the ill occurs," says Dr. Patrick McGorry. He's a professor of psychiatry at the University of Melbourne. "By the time they present their first psychotic symptom -- delusions and hallucinations -- it's already quite late in [terms of] the effects on their lives."

McGorry, along with several other pioneers, including Dr. Thomas McGlashan at Yale, are trying to see if medication might be the answer. They are studying the effects of administering medication to individuals before the diagnosis stage. They are eyeing the "prodromal" stage, the early phase of schizophrenia, to find out if drugs can reduce the symptoms that seem to precede psychosis.

While the practice holds promise for the millions of people who will become schizophrenic, it has become the center of a controversy among researchers studying it. Some ask this simple question: If you're treating people before they become ill, how do you know you're actually treating the right people? Two weeks ago a conference was held in Washington to discuss the ethical ramifications of forging ahead into an area where no one yet knows the consequences.

"The conundrum people in this field deal with is the closer you get to the actual appearance of psychotic symptoms, the more reliably you can make the diagnosis," says Dr. Paul Appelbaum, professor and chairman of the department of psychiatry at the University of Massachusetts Medical School and vice president of the American Psychiatric Association. "But the value also becomes greater the earlier you can identify the people who will later develop the disorder, so you can slow the deterioration and slide that people experience as they enter the schizophrenic illness."

Since there are no concrete predictors at this point, some bioethicists worry that individuals who would never have developed schizophrenia may be roped into the category of "at risk," treated and left to face the consequences.

"I think there is an earnest desire to use the medications and prevent this dreaded disease," says Laura Lee Hall, research director for the National Alliance for the Mentally Ill (NAMI). "Perhaps that perception is pushing more caution to the wayside, which is why it's important for other voices to come forward and push for more patient protections."

As an advocate for the mentally ill who helped raise concern for this issue, she thinks that the risks are just too great right now. For one, there are no accurate predictors of schizophrenia. Many of the subjects of these studies therefore pay the price of a mental illness -- suffering the stigma attached to it and the sometimes severe side effects of the drugs -- when they might have had mere cognitive dysfunction, or nothing at all.

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"Yes, that risk is there," says McGlashan, head of the Yale Psychiatric Institute, "and we try to minimize it. We only enroll people in the study who are clearly having trouble, so in a way they would probably be in treatment of some kind. It's not like we're bringing in people who are feeling quite fine and saying, 'You have something to worry about; and we're going to put you in a study.'"

McGlashan believes that he has taken appropriate precautions in his study, which has been going on for the last two years. In order to be admitted, patients must exhibit some type of "worrisome" behavior, such as social isolation, difficulty focusing and functioning (like suddenly flunking out of school), anxiety or hallucinations.

For this ongoing study, he gives the antipsychotic Zyprexa to half the people and a placebo to the others. Both groups get therapy. In the second year, they are monitored to see if they become mentally ill. Although it's too early to tell what the results will be, he believes that he is at least enrolling the right people in his study. So far, out of 21 patients deemed to be "at risk," 40 percent of them have come down with psychosis. At this point, McGlashan doesn't know if those people were the ones taking the medication -- or the placebo -- since it's double-blind. And he won't know until the study is completed. But he believes that this high rate of psychosis is proof that he is being prudent in selecting his subjects.

"Even though our prediction is by no means perfect, it's nevertheless good enough in our estimation that it justifies the risk," he says. "If we took the same group of people and we didn't do anything, we would be putting 40 percent of them at risk for potentially getting worse because we were doing nothing. So there are risks both ways: risks for doing the treatment and risks for not doing the treatment."

Still, it's too early to tell what the results will be. McGlashan's 21 patients so far represent only about one quarter of the number of people he needs to complete his study. And finding potential subjects has been difficult. Although several million people in the U.S. have schizophrenia, the rate of new cases is about one in 10,000 people per year. There are only about 13 new cases a year in New Haven, Conn., so McGlashan has clinics in other cities to increase the pool of potential subjects.

"I'm a little concerned that we sell it as preventing this disease. We don't know if that's true," says Dr. Fuller Torrey, psychiatrist and executive director of the Stanley Foundation, which funds mental-illness research. "I think it's always a slippery slope any time you use medication in a preventative way. It's something that you need to look at carefully."

These days, all sorts of drugs are used in a preventative way -- people take an aspirin a day to decrease the risk of heart attack, and pop cholesterol-decreasing medication to ward off arteriosclerosis. Health benefits aside, those companies that manufacture and sell pharmaceuticals like the idea of medicines taken in great quantities to prevent disease. Both McGlashan and McGorry have come under criticism for being funded, at least partially, by pharmaceutical companies. Psychiatrists such as Torrey worry that pre-psychotic people might just end up becoming another market for drug companies to target. The pharmaceutical companies "are making extremely high profits on the medications and have a strong interest in having these widely used," he says. "I think everyone who is doing research in this field needs to be aware of that conflict of interest."

McGlashan and McGorry say that's nonsense. They both contend that their studies are not influenced at all by these companies. Eli Lilly & Company, the maker of Zyprexa, is funding McGlashan's, and Jannsen Pharmaceutica, which distributes Risperdal, has given a small grant to McGorry for his study.

The Australian psychiatrist, McGorry, who is credited with leading this wave of research, is about to complete a key study looking at the effects of medication on those deemed to be at risk. His preliminary findings suggest that medication has made a difference; he will be starting another study shortly to confirm this. The study showed that people given both medication and therapy were less likely to develop psychosis. Thirty-one people were treated with cognitive therapy and a low-dose regimen of a medication called Risperdal over a six-month period. Only four became psychotic. In another group, subjects were treated with cognitive therapy only. Ten out of 31 became mentally ill. Unlike the subjects in McGlashan's double-blind study, who don't know if they are taking medication or not, those in McGorry's study do.

When asked about risks to patients in his studies, McGorry sends out a warm Aussie invitation to critics to come to his clinic and see for themselves. "My response would be to invite many of the ethicists to talk to people in the clinic and their relatives and see if they think there's any harm coming to them," says McGorry. "I actually see it as a valuable clinical service that's available." He also says that by monitoring these people at risk, he provides the added benefit of close psychological supervision. If they develop any other psychiatric problems along the way, they are treated as soon as possible.

This early intervention era probably wouldn't be here -- at least so soon -- if it weren't for the development of new antipsychotic drugs. The old medications, called typicals -- Mellaril, Navane, Prolixin, Thorazine, Haldol, Stelazine and Trilafon -- controlled "positive" symptoms like hallucinations. But they also commonly induced seizures and the involuntary movements known as tardive dyskinesia, which include facial tics, lip smacking, panting and grimacing. For some people, taking the old meds could be worse than the mental condition itself, so to prescribe the drugs pre-diagnosis was too risky.

But times have changed. New drugs in the 1990s, called atypicals, can treat both the positive and negative symptoms of schizophrenia -- such as patients' ability to concentrate, their awareness of another person's feelings and their quality of life.

Of course, these drugs -- Zyprexa, Risperdal, Serlect and Clozaril -- have side effects as well: Patients seem sedated, and have experienced 50-pound weight gains. Clozaril has the added risk of destroying white blood cells.

While the immediate side effects are known, some ethicists worry about what the long-term effects of these medications will be. What complicates matters further is that even administering medication to people diagnosed as schizophrenic is inherently risky, since it's based on interviews -- not medical tests.

"In a way it's paradoxical that every diagnosis of schizophrenia depends on a careful interview with the [ill] person and a relative," says Irv Gottesman, a psychiatric geneticist at the University of Virginia. "Unlike other solid parts or widely accepted parts of medicine where you, say, look at your blood, there is no single or even multiple indicator at the biological level that would distinguish someone with schizophrenia from someone who has an atypical form of bipolar disorder, or someone who has been using a new street drug."

And with an illness like schizophrenia, where the average onset is between 17 and 19 years of age, you're going to deal with a volatile time in patients' life, when it's difficult to differentiate a teenager's mood swings from mental illness. The mean age in McGorry's study is 20; the youngest subject is 15. McGlashan is now accepting anyone who is showing pre-psychotic signs between the ages of 12 and 45. (Dr. Ming Tsuang at Harvard is also looking at the effects of medication before diagnosis, but only accepts adults.)

Just ask Dr. Nikki Erlenmeyer-Kimling, professor of psychiatry at Columbia University, how hard it is to predict who will develop the illness. After following the children of schizophrenic parents for the last 28 years, she still can't fully define what makes someone susceptible to psychosis. Some tests, which looked at verbal short-term memory, have identified as many as 83 percent of those tested as future sufferers of mental illness. But there were many false positives (people who fit all the designated schizophrenia predictors but didn't come down with it) and false negatives.

Erlenmeyer-Kimling believes that the field isn't mature enough to go to the next level -- treatment of those who are determined by these as-yet unreliable models to be at risk of developing the disease. She believes there should be another round of high-risk studies before moving to the medication phase.

"If there were a reasonable basis for treating adolescents with an innocuous treatment, like cognitive or social-skills therapy, by all means do that," Erlenmeyer-Kimling says. "But treating them with drugs is, in my mind, a little premature."

Some researchers feel that they are getting closer to identifying more precisely who may be at risk. At Long Island's Hillside Hospital, psychologists Barbara Cornblatt and Michael Obuchowski have been looking at scores of teenagers for the past six years to try to develop a schizophrenia profile. Some are in the prodromal stages of psychosis; others have nothing wrong with them, but have a sibling who is ill. These psychologists believe that if they can come up with the right combination of tests, it may act as a kind of clinical crystal ball, allowing a glimpse into a person's mental-health future.

They are creating their psychiatric oracle in the basement of the old hospital in a room off a long hallway. This is where the "eye movement test" is conducted. You put on glasses with a tangle of wires strung from them and place your head on a chin rest. The lights go off; you are left immobile with no choice but to stare at the wall straight ahead. And then instructions are given: Wait there until a red laser dot appears. Then follow it as it moves back and forth, back and forth, like a person pacing, for three minutes. Every blink or wander of the eye is measured and recorded. Researchers then analyze how well you can follow a moving target.

For some reason, schizophrenics routinely do poorly on this test. Obuchowski says that 60 to 80 percent have problems following something like the red dot. Also, about 40 percent of their first-degree relatives have problems as well. So it is believed that there must be a genetic component to this type of dysfunction.

Another test they believe has great promise measures attention. Called the Continuous Performance Test -- Identical Pairs (CPT-IP), it tests how well a person can respond to a series of four-digit numbers flashed on a computer screen at 50-millisecond intervals. The directive here: Click your mouse every time you see the same number repeated. Another test uses shapes instead of numbers. Both researchers acknowledge that none of the markers are ready for clinical application but they have great hope for the ramifications of their studies.

"If we can treat attention impairment, and if attention impairment precedes other symptoms, then possibly you can prevent expression of clinical symptoms," says Obuchowski. "We don't know, but it's such a juicy logical step. We might be totally wrong."

Obuchowski and Cornblatt believe that the eye-tracking and attention tests, along with others, are predictors, and will be part of their profile one day. "A large number of people with schizophrenia have difficulty living their lives," says Cornblatt, the lead researcher in this study. "What we're hoping is to keep the kids out of the hospital and in school, and eventually to make sure that they are functioning adults. Whether we can eradicate the disease from the face of the earth, that I doubt; but at least we can dent the disability associated with the disease."

But at the same time, Cornblatt tempers her excitement for the second part of the equation -- the actual early intervention phase -- because she believes that there should be more definitive markers before moving on to the treatment stage.

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In retrospect, Libby Pedrazzani knows she saw signs that something was wrong with her son Kevin. But at the time it was difficult to figure out if his behavior was a normal part of adolescence or symptomatic of an illness. He came home at Christmas time, wanting to take time off from college to decide on a major. But he withdrew from his friends and family and began staying up at night and sleeping during the day, retreating more and more into his room and away from the world. Between that December and the next summer, something happened.

"He was sitting on the sofa and hadn't been working. I was talking to him while he was watching TV and saying, 'You have to do something, go back to school or get a job.' He didn't appear to be listening. So I gently put my hand on his shoulder, and he sprang out of the chair -- and I don't think he meant for it to happen, didn't realize how strong he was -- but he sent me flying across the room. When I looked into his eyes, I knew that it wasn't my Kevin. I knew that he had lost control." He was 22 years old, and having his first psychotic episode.

Pedrazzani's husband came running into the room, and while the two of them tried to subdue Kevin, their daughter called the police. The police then gave him two choices: treatment at a hospital or jail. He chose the hospital, and was diagnosed as schizophrenic. "That's something that cuts through to the soul of a person but that was the only way to get him to a hospital," she says. "When I look back at it, I think that some higher entity was helping us out because he didn't see a problem or a need for help."

Four years later, Kevin now lives in an efficiency apartment in Baltimore and spends his days at a center where there are others with mental illnesses. He hasn't worked since or kept in touch with his friends from college. Every two weeks he gets an injection of the antipsychotic Prolixin, and hasn't acted out since.

Unlike other brain diseases such as Alzheimer's, Kevin's schizophrenia allows him to stay aware of what's going on around him. He sees his friends marry, get new jobs and move on with their lives while his life remains more or less static. His mother says if she could turn back the clock and change things, she would, including cautiously enrolling him in a study like McGlashan's that might change the way things are now.

"If I had reasonable assurance that it would not harm him, yeah, I would have. I would want reasonable assurance that it would be the lowest dosage possible and that he would be closely monitored to make sure that there are no ill affects. If all of those things were in place [and it worked], Kevin's life would be so different and I've got to admit, my two other children's lives would be changed too." But she says she could make this decision right now because she has the advantage of hindsight. Other mothers don't.

By Dawn MacKeen

Dawn MacKeen is a former senior writer for Salon, and author of a forthcoming book about her grandfather’s survival of the Armenian Genocide, "The Hundred-Year Walk: An Armenian Odyssey" (Houghton Mifflin Harcourt, January 2016).

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