When Tony Lamadrid, a Schizophrenic Patient and Research Subject at UCLA, Committed Suicide, It Set Off a National Debate: What Is Acceptable in Human Experimentation and Who Decides?
At 8:43 a.m. March 28, 1991, two UCLA campus police officers responding to an emergency call found a burly young man lying face down outside of Boelter Hall. He had jumped from the roof of the nine-story classroom building; at 9:23 he was pronounced dead at UCLA Medical Center. His name was Tony Lamadrid.
A coroner's report included this notation: "This 23-year-old male with a history of depression and schizophrenia was being treated for same at UCLA Medical Center Psychiatric Department . . . (his) social worker was . . . trying to place him into a new psychiatric program and was trying to convince decedent on 3-22-91 to commit himself to UCLA because she felt he was suicidal. Decedent contacted his brother, Enrique Lamadrid, and advised him he wanted to take poison to end it all . . . ."
In the days that followed, police discovered an answering machine tape that included a message from Debbie Gioia-Hasick, his social worker at UCLA's Aftercare Clinic. "Hi, Tony. It's Debbie," she began, "Even later today, (if) you're just feeling really bad, go over to UCLA and just check yourself into the hospital. Tell them you're suicidal and that you think you're really going to hurt yourself. Check yourself in, and then we'll go from there."
But the institution that was supposed to help Tony Lamadrid had another interest in him as well. From 1985 to 1989, according to government records, he had been both a patient at the UCLA Medical Center and an active participant in a sweeping psychiatric study approved by the university. In the spring of 1991, even though he was no longer directly involved in experiments, Lamadrid continued to be monitored by the research staff, including Gioia-Hasick. The study, "Developmental Processes in Schizophrenic Disorders," was directed by psychologist Keith H. Nuechterlein, with psychiatrist Michael Gitlin, and its aim was to gather data on the how and why of schizophrenic relapse.
Racked with guilt and unanswered questions in the weeks following his youngest brother's funeral, Enrique Lamadrid, a Spanish professor at the University of New Mexico, began to focus on Tony's dual role as patient and research subject. In a letter to the federal Office for Protection from Research Risks, which polices government-funded experiments, he wrote: After considerable soul-searching and intensive consultation with my family, I would like to request an inquiry into the suicide of my brother. . . . I have grave concerns that he may have been a victim of the questionable ethics of the professionals who were conducting research on his illness. I am personally tormented with the responsibility of having allowed him to participate in a program that emphasized research over treatment of mental illness. . . . I have the horrible feeling that my brother has simply become another statistic in their research findings.
Enrique Lamadrid's anguish, and the complaints of the parents of another young patient-subject, Gregory Aller, would trigger a federal investigation. For three years, the scientists and the university would be the subject of a probe involving their ethics, their motives, their practices. An interim report demanded changes in study procedures. The final report, released last May, concluded that UCLA had violated key aspects of "informed consent" rules governing human-subject experimentation but it also found that the care given the patient-subjects and the study design itself were appropriate and ethical.
No one was happy with the outcome. Not UCLA or the scientists, who continue to deny any wrongdoing, and not the Lamadrids or the Allers, who have gone on to file medical malpractice suits against Nuechterlein, Gitlin and the university. From Congress to law journals to university board rooms, "Developmental Processes in Schizophrenic Disorders"--which the National Institute of Mental Health had heralded as the most comprehensive, intensive study of schizophrenic disorder ever--has become a flash point over the use of human beings in experimental research.
The case poses troubling questions. What is good for science and future patients--trying out promising new treatments, investigating the mechanics of an illness, conducting randomized clinical trials to test "what if" variables--almost always carries hazards for human subjects. But when are those risks unacceptable and who decides?
The history of medical experimentation is rife with abuse, from concentration camp atrocities to the infamous Tuskegee study, conducted by the U.S. Public Health Service from 1932 to 1972, in which 399 African-American men with syphilis were purposely not treated and some allowed to die in order to study the progress of that disease.
To prevent such abuses, as well as subtler hazards, the federal government in 1981 set up a two-tiered system for protecting patients in medical experiments. The design, or "protocol," of a study must be approved by an institutional review board that weighs its risks and benefits. And informed consent must be obtained: the nature of the experiment, its suspected risks and even the pros and cons of not participating in the study are supposed to be clearly explained to potential subjects, who then can choose to sign on.
But is the system working? Are the guidelines strict enough, is the oversight strong enough? Are the safeguards adequate to protect against the conflict that so troubled Enrique Lamadrid? Doctors who are also researchers have a dual allegiance, to their patient-subjects and to their research protocols. Despite the best of intentions, they are, according to one ethicist, "double agents with conflicting loyalties."
Had Tony Lamadrid's social worker alluded to just such a conflict in her telephone message to him? Gioia-Hasick, who declined an interview request, offered one last piece of advice on the answering machine. "Using the staff there (UCLA)," she said, "and trying to get into a better and kind of cleaner program at Saint John's (Hospital) would be great. Anyway," she finished, "I wish you a lot of luck. And let me know what happens. Thanks. Bye-bye."
IT WAS SUMMER OF 1978 WHEN PROFESSOR KEITH NUECHTERLEIN, WHO had just earned his Ph.D in clinical psychology from the University of Minnesota, arrived at UCLA's School of Medicine. He had dreamed of becoming a minister or a physicist, but he picked research psychology because he saw it as the perfect way to combine his talents as a people person and a scientist. About the same time, Michael Gitlin, a bright young graduate of the University of Pennsylvania School of Medicine, was finishing up his psychiatric residency at UCLA.
Nuechterlein was particularly interested in an aspect of neuropsychology--the subtle abnormalities in the way some people perceive things. As he followed the literature, he began to wonder if it might not be possible to look at such factors as a way of measuring and predicting a predisposition for schizophrenia, which includes such devastating perception problems as hearing nonexistent voices and feeling persecuted by nonexistent forces.
Gitlin, meanwhile, was becoming a respected authority on the treatment of mood disorders, especially manic depression and schizophrenia. In his growing practice, he was seeing many young adults having their first manic episode. And the question he kept confronting was this: Should a 21-year-old face a lifetime of lithium use, the drug of choice for manic depression? The cost-benefit ratio is a complicated one. Though the relapse rate is high, without lithium, the drug may have toxic side effects. Gitlin was well aware that the drugs that helped control much worse disorders, like schizophrenia, could also have serious side effects.
It seemed only natural that these two bearded boy wonders--dubbed by colleagues as "compulsively conscientious" (Nuechterlein) and "a real mensch " (Gitlin)--would join forces in research: If doctors could predict the onset of mental disease symptoms they could also better control the use of drugs. Gitlin and Nuechterlein decided to go after a piece of the $5 billion the government annually spends on biomedical research involving human subjects.
Their big break came in 1983, when the National Institute of Mental Health awarded Nuechterlein, as the study's director, the first of what would amount to $2 million in grants over 11 years for the "Developmental Processes in Schizophrenic Disorders" project. The study would include hundreds of subjects, most of them recruited as they were admitted to Camarillo State Hospital, Harbor/UCLA Medical Center, Olive View Medical Center and the UCLA Neuropsychiatric Hospital. These were "recent onset" patients who had experienced their first psychotic breaks within the past two years. The project offered them free treatment at UCLA's prestigious medical center in a program for outpatients called the Aftercare Clinic.
The research included two protocols, approved by the university's Human Subjects Protection Committee and by the government. The first involved putting the patient-subjects on a standardized dose of the antipsychotic drug Prolixin while the researchers tracked their symptoms and tested for factors associated with relapses, defined as a "return to a state of active and severe psychotic symptoms." The variables to be studied included environmental stresses thought to trigger symptoms--"high expressed emotion" within families, for example, things like emotional over-involvement, criticism and hostility--and physiological components such as "smooth pursuit eye movements," breathing rate, blood pressure and the like.
Every two weeks, a van would pick up the participants at home and bring them to the Aftercare Clinic, where they received a shot of Prolixin, attended group therapy sessions and saw their social worker and a psychiatrist. From time to time, the subjects and their families filled out questionnaires and were interviewed; they were given MRI scans and hooked to electrodes.
In the controversial second protocol of the experiment, the researchers continued to track symptoms and test for relapse variables, but now the patient-subjects were withdrawn from the stabilizing Prolixin in a "Double Blind Drug Crossover and Removal." The subjects were randomly divided into two groups, with 12 weeks on medication, then 12 weeks on a placebo, or vice versa. After that, "all clinically appropriate" subjects--those who had remained relatively stable on a placebo--received no medication at all for as long as 18 months.
The goal of "Developmental Processes" was to identify predictors of schizophrenic psychosis. Such research, the doctors said, would not only further basic understanding of the disease, it would be of immense practical value in treatment, especially the results of the drug-withdrawal protocol. That information could help establish when and if recent-onset patients could do without medication, and thereby escape such horrific side effects as tardive dyskinesia, a sometimes irreversible neuromuscular disorder marked by facial grimaces, tics, trembling hands and tongue thrusts.
And the risks? "The potential risk in the study," one of Nuechterlein's grant applications said of the second protocol, "is that clinical exacerbation or relapse can be expected to occur in some of our patient subjects, probably in most. . . ." By comparison, the application indicated, if the patient-subjects stayed on antipsychotics, most would also be expected to backslide, but "the exacerbation or relapse would be later in many cases. . . ." If the symptoms were deemed serious according to certain criteria, a "decompensating" participant would be withdrawn from the study and treated "as per the clinical needs" of the situation. In any case, the researchers expected some of their patient-subjects to regress to the point of experiencing "hallucinations, unusual thought content, bizarreness, self-neglect, hostility, depressive mood and suicidality." They just didn't know who, or when.
TONY LAMADRID HAD ALWAYS HAD A TOUGH LIFE, BUT UNTIL HIS MIND BEGAN to unravel, when he was a freshman at UCLA, he managed to keep a sense of humor about it. The youngest of four brothers, he was born "in that town where Bugs Bunny always makes a wrong turn, Albuquerque," he once wrote in an essay. When he was 2, his mother died of cancer. At his 15th birthday party, his father died of a heart attack. He was raised "in a traditional Hispanic fashion" by his father's sister and his grandmother in Santa Monica. An honors student at Santa Monica High School, he appears in his picture in the 1984 Nautilus yearbook as a baby-faced teen-ager with a turned-up nose and elfin grin, wearing a sports coat and a thick-striped tie.
As his brothers Larry and Mark remember it, Tony's deterioration was sudden, "literally overnight." In the fall of 1985, their brother, who lived with them in a small Santa Monica apartment, got on a bus to go to UCLA to visit some friends and never got off. Disoriented, he was beginning to show signs of paranoia and wound up in Downtown Los Angeles, where he was mugged and picked up by police. He spent the night in County Jail and was transferred to UCLA Harbor General. From there, doctors referred him to UCLA.
This past April, I met with Larry and Mark Lamadrid. Larry teaches science at Lennox Middle School and Mark teaches English as a second language at a Westside high school. Remembers Larry: "We thought, UCLA--great. Aftercare Clinic? Sounds great. Sounds very positive. Very progressive. We really didn't realize at that point it was primarily a study."
"UCLA had a lot of prestige," adds Mark. "He was taking classes there, anyway. They were going to give him medication and counseling. They told us it was an experimental project. In return, the family would be taking part in a study. They interviewed us individually and with our brother, Tony."
Once their brother had been stabilized, he was ready to enter the double-blind phase of the experiment. But the brothers claim that if they had understood the possible harm to Tony, they would never have participated or allowed him to, either. What they had to go on, they say, was primarily the consent form their brother was required to sign.
"The purpose of this study is to take people like me off medication in a way that will give the most information about the medication, its effects on me, on others and on the way the brain works," the form read, in part. It detailed trivial risks, like the possible pain of a needle prick from drawing blood, and devoted less space to central issues, like how severe a relapse might be. It in no way indicated what the researchers had written in the protocol, that they expected "most" of the subjects to backslide. "New symptoms may occur," it allowed, and "my condition may improve, worsen or remain unchanged." And it put a positive spin on going off "meds": "I may benefit from this study by being taken off medication in a careful way while under close medical supervision."
By the time Tony Lamadrid joined the second protocol in 1987, however, Nuechterlein and Gitlin's risk hypothesis was being backed up by their preliminary data. Most of their patient-subjects were relapsing. According to a document obtained through the Freedom of Information Act, on Feb. 10, 1986, a government peer review team, conducting a site visit of the project, expressed concern over the ethical implications of these preliminary results. In its summary report, the team noted that "a comment was made about the risk/benefit ratio for the withdrawal protocol, since, to date, 11 of 14 patients have relapsed during the 18 months of neuroleptic (drug) withdrawal."
Nuechterlein responded with a list of benefits, saying, "that most study patients are eager to discontinue neuroleptics, that many clinicians would consider drug discontinuation to be clinically indicated by this time, and that the study will yield clinically important information about predictors of early relapse." Ultimately, the NIMH reviewers were satisfied: "In light of project staff's ability to reinstate neuroleptics very rapidly if clinical decompensation begins, the site visitors judged that subjects are adequately protected."
But were they? The informed consent document was reassuring but once again vague. "If I do show a significant return of symptoms," it read, "I understand that the clinic staff will use active medication again to improve my condition"--never defining "significant return of symptoms."
The 1986 grant application omitted specific references to exactly how relapsing patient-subjects like Tony Lamadrid would be handled. In a 1988 application, the methodology was more specific: Participants would be removed from the study (and presumably remedicated) when their symptoms were rated at specific levels. But rating symptoms is something of a judgment call, the doctors would later admit, and the protocol description also said that the participants' clinical interests would be deferred, at least temporarily, until the researchers could conduct their tests and make their measurements: "Information-processing, psychological, and blood testing will be done, and the patient will then be treated. . . ."
As troubling is a 1988 article Nuechterlein and one of his graduate students published in the Journal of Abnormal Psychology. They analyzed relapses in the UCLA study that reached the "severe or extremely severe level," noting that the research had not been restricted "by the necessity to increase medication to avoid a possible relapse." However rapidly decompensation was treated during the protocols, this sub-analysis found 17 instances of severe psychotic symptoms in 23 patient-subjects. Later, Nuechterlein would say that the choice of words in the article had been bad, and that it didn't accurately reflect the criteria for relapse and remedication in the main study.
Some families I spoke to said their relatives were put back on medication as soon as they noticed minor symptoms, like acting bizarrely or not sleeping or pacing. One parent, whom the researchers asked to speak to me and who requested anonymity, told me how much she respected Gitlin, explaining he would "break the blind" (intervene during the double-blind phase) at any time. The problem was she lacked authority over her adult son, who was relapsing on the placebo but "fooling everyone"--hearing voices yet denying it because he wanted to stay off the medication. She began crying. "I'll tell you the truth," she said of the study during which her son was hospitalized. "I don't resent the fact that my son went through it. But I wish he hadn't. It caused him a lot of pain. And a lot of months of recuperation." At one point during the recuperation, she said, he tried to jump out of his car on the freeway.
Other families say their efforts to reinstate medication were rebuffed, and whatever the study called for, they allege that the doctors' response to relapse was inadequate. Enrique Lamadrid, concerned that his little brother was spiraling out of control, made a special trip to Santa Monica. "Even though I had made an appointment in advance and had traveled 1,000 miles to see (Gitlin), I was brusquely turned away after a three-minute explanation that no information, support or advice could be offered to me for reasons of confidentiality," Enrique Lamadrid wrote federal investigators. His brother was subsequently hospitalized at Camarillo State Hospital. "He was just allowed to crash without a support system in place," Enrique Lamadrid told me.
Gregory Aller, now 30 and attending UCLA part-time, recently told a congressional panel what happened during the months in 1990 that his parents said they were begging the research leaders to reinstate his medication but were told that their insistence on becoming involved was part of their son's problem:
"This time my symptoms were much more severe than the symptoms at the onset of my schizophrenia. What ensued was a nightmare. My ability to concentrate fell apart. I was unable to do schoolwork. I became manic and hyperactive. Some days I would hardly sleep at all. One night I woke up screaming, actually believing that I was sprouting another leg. I started to have paranoid delusions about government agents chasing me. I became violent with my father and threatened to kill him. I believed there were hidden cameras on the wall of my parents' living room. Much later, still in a delusional state, I started hitchhiking to Washington to assassinate President Bush. Though I had slipped back into paranoid symptoms, my doctor asked me if I felt I needed medication. Since I was paranoid by that time, I said I was fine, I didn't need medication. Dr. Gitlin never delved into what was really going on in my life."
Elizabeth de Balogh, 34, another UCLA subject-patient, now lives in an Artesia board and care home. She blames herself for her predicament. At UCLA, she says, she was stabilized for a year--able to drive and go to the beach and hold a job. But then, as she participated in the drug withdrawal protocol, her life began slipping away. She thought musical notes were chasing her and her "eyes rolled up," meaning she would hallucinate.
"But I wanted to get off the medications," she says. "So, it's not really their fault, I guess." Her long blond hair is washed, her purple dress and scarf offset by sneakers, no socks. Her vivid blue eyes grow sad, her little-girlish voice plaintive. "Why didn't they give me medications when I got sick?" Looking agitated, she says, "I'm starting to get bad thoughts. I'm scared the devil is trying to take my soul way from me."
Her brother, Frank de Balogh, wrote government officials that when his sister began to relapse over a weekend in 1985, her family frantically tried to contact the UCLA research team by phone but only got a recorded message about the clinic's business hours. Frustrated, they ended up taking her to Metropolitan State Hospital, where she stayed for a year before she was placed in long-term care.
For the Allers, the De Baloghs and the Lamadrids, such experiences add up to monstrous flaws in the Nuechterlein-Gitlin project. They feel betrayed--their relatives were enrolled at an institution renowned for the quality of its treatment, the study's head clinician had an excellent reputation (as one of Gitlin's colleagues commented, "If he can't do research right, who can?"), yet they watched their loved ones get worse and worse--by design, as they see it. They feel outraged that anyone could think that this study was acceptable.
Documentary filmmaker Bob Aller, Gregory's father, has become "obsessive compulsive" in his quest for justice. In many ways, the controversy over the UCLA study is as much about his persistence--his letter writing, his research, his trips to Washington, his family's lawsuit--as it is about his son's experiences. The Lamadrids call him their "spiritual leader."
"What you're looking at is a psychiatric community that says it's ethical to harm people because they're gathering data," he told me when we met at a restaurant near his apartment in West Los Angeles. "There's no morality there. They just do what they think is right. The patients are being told it's the illness. But the researchers are withholding information from patients and families. The relapsing of patients with schizophrenia should come to a grinding halt."
ASK ANYONE CLOSELY INVOLVED IN THE UCLA SCHIZOPHRENIA RESEARCH project and he will tell you that the study has absolutely nothing to do with purposefully relapsing schizophrenic patients.
"In no way," says Michael Gitlin, "were we trying to create or produce relapse in any way, shape or form." Says Keith Nuechterlein: "The simple idea that someone would accuse us of things like being unethical, and gee, trying to induce relapses and making all our patients do poorly--it just blew my mind."
Despite the findings of the federal report, the researchers show little sign of accepting responsibility for their patient-subjects' difficulties. They sit side by side in Gitlin's small, corner office on the second floor of a medical building at UCLA. Gitlin says he doesn't like the word "regret," because "it's a tricky one." But he does say he feels bad about "what happened globally." He is proud of his work, pleased that he managed to keep the study's hospitalization rate--the rate of extreme relapse--so low, at 10%. For his part, Nuechterlein dismisses the idea that there is a fundamental conflict in being a clinician and a researcher: "We designed and carried out the study, trying to keep the best clinical interests of the patient in mind and at the same time trying to learn as much as we could about the early period of the illness."
The two researchers offer a stark contrast in style and manner. A New Yorker and fast talker, Gitlin, with his frizzy mop of black hair and laconic delivery, exudes an imperious, if gentle, attitude; Nuechterlein's even-pitched voice has the flat-vowelled ring of the Midwest, his contact lenses giving his blue eyes a glassy, almost spacey look.
"You didn't expect to produce relapse?" I ask them.
"We expected relapses," says Gitlin, "because you can't work with schizophrenic patients without having relapses--on medications, off medications or in any other way. So, it is the nature of the beast to have relapses in schizophrenia. In fact, there are sizable relapse rates in the best studies of patients who remain on medications at any point along the way. So, no, we were not trying to create relapses."
They spend much of their time defending themselves now, in writings and talks. Nuechterlein and Gitlin speak calmly and cogently about their predicament. The researchers know that the public picture of them is that of mad scientists. From their standpoint, if there is a problem it is in the regulation system and they are merely fall guys. On their own behavior, they are adamant.
"Do I feel that patients were not adequately informed as to what the study entailed and what the potential risk and benefit was?" Gitlin asks. "No, I feel absolutely clear the patients were and their families were informed, both from the written documents as well as the much more voluminous oral discussions. I feel very genuinely that this is a very ethical, important research project."
Nuechterlein adds that there is no universal agreement as to how much should be written into an informed consent document versus how much is told verbally. "I wish now," he says, "we had tape recordings of the conversations where we provided this information." He says the subjects understood that relapse was part of the process of the disease and were well aware of what it entailed.
Both researchers sigh deeply when they are asked to offer specifics about the Aller and Lamadrid cases, citing patient confidentiality. They are, in essence, protecting the privacy of the same people making allegations against them. Even though UCLA was still keeping track of Tony Lamadrid, they say that his suicide shouldn't be blamed on the research protocols because it happened more than two years after his active participation in the study. In general, they defend their study as naturalistic, reflecting standard treatment. In the first phase, they were stabilizing patients on antipsychotic drugs as they watched for possible relapse; in the second, they withdrew drugs, as doctors or the patients themselves might, as they tried to avoid the terrible side-effects of the meds.
To interview them is to walk a semantic tightrope. They never intentionally caused severe relapses, they repeat. Rather, they allowed their patient-subjects to suffer milder psychotic exacerbations--a slight increase in paranoia, say. Nuechterlein now says he regrets using terms like "severe" in his published papers and he regrets that in the protocol descriptions he sometimes lumped together exacerbations (which he says would rate a 4 on a 1 to 7 scale) and relapses (which would rate a 6 or 7). They emphasize now that Gitlin, as the treating clinical psychiatrist, had the power to override his patients' involvement in the research if he thought they were too sick to continue. He might pull them, they claim, even if their symptoms weren't as bad as the protocol's withdrawal criteria.
"So we caught more of them early on rather than later on," Gitlin tells me. "Now, if we really wanted to let schizophrenic patients go bad, they would have all ended up in the hospital. It took very little change in symptoms for us to say, 'Oops, we've gotta intervene.' That's very different than saying, 'Gee, let's let this person be floridly psychotic and severely ill while we watch them and see what it does.' That bears zero resemblance to what we did."
Sometimes, though, things got messy. "We intervened if we saw symptoms in a mild stage, as long as it was clear that the person was getting psychotic," Gitlin explains. "But there were some people we saw on Mondays who were fine and by Wednesday night they were floridly psychotic, and the first phone call I got, we'd intervene at that point. They were clearly symptomatic. That's because they'd go from 0 to 6 like that," he says, snapping his fingers. "But had I spoken to them when they were a 4, I would have intervened at that point."
They say they did everything "by the book." Every year, they got approval from the UCLA Human Subjects Protection Committee. Every patient who was in the study signed the informed consent form. The project itself was approved at least three different times by the NIMH, and that federal agency reviewed the informed consent forms at least once with no objections. "So," Gitlin says, "it's not as if we secretly had this informed consent and didn't tell anybody what was in it and did something in any way deviously or illegally. There's absolutely none of that."
In our conversation, the researchers seem less than persuasive once--when I ask about research suggesting that relapse causes irreversible injury. "The famous Richard Wyatt thing," Gitlin says derisively, referring to a 1991 article by Wyatt, chief of the NIMH Neuropsychiatry Branch. In his review of 22 studies, Wyatt found evidence that stable schizophrenic patients whose neuroleptics are discontinued and suffer relapses may have a difficult time returning to their previous level of function because of scarring to their brains. "What Wyatt is talking about is psychosis left untreated is probably not good for brains," Gitlin tells me. "That bears no resemblance to anything that went on in our project."
When I phone Wyatt to clarify his lengthy paper, he disputes Gitlin's view. He says he meant what he wrote when he cautioned that "greater consideration should be given to the usual clinical practice of taking patients off neuroleptics after they have recovered from an acute psychosis and appear stable." The problem, Wyatt adds, "is there is a risk, and it's a risk people hadn't previously thought about."
What bearing does this have on the UCLA researchers? One scientific paper, appearing late in their decade of research, doesn't amount to evidence that what they had been doing was a mistake. "But they would have to reconsider a bit," Wyatt says. "It puts them in a bind, I suppose."
But even Wyatt, like other clinical researchers, is less worried about the ethical ramifications than the practical ones that might impede progress of conducting research for schizophrenia. "The work is so hard to do," he says. "Anything like this will set us back, whether Nuechterlein and Gitlin were right or wrong. Having this come up--who needs it?"
IN MAY, THE OFFICE FOR PROTECTION FROM RESEARCH RISKS RELEASED its final report on the Nuechterlein-Gitlin study. Two years earlier, when the researchers were still enrolling participants, the federal investigators had recommended that the project's consent form be modified to more clearly disclose risks, treatment options and the fact that the study design, not individual needs, would determine drug dosage for those enrolled in the Aftercare program.
The final report was mostly a formality: UCLA, the government confirmed, had violated federal regulations by failing to adequately protect its subjects in the informed consent process. It now required changes in the university review system and made more suggestions about the study's already modified consent forms.
It also addressed the question of Tony Lamadrid's suicide. According to the OPRR, even though he was no longer part of a protocol at the time of his death, he was still being treated by research staff and his progress was still being charted for study data. UCLA, which was allowed to respond in the report, dug in its heels at the implication of this finding: "No factual or legal connection between the study and (Lamadrid's) suicide . . . has been established."
On the day before the report was made public (a few copies had been leaked earlier to news organizations), I went to Yale to visit Jay Katz, a psychoanalyst and professor emeritus of law, medicine and psychiatry at Yale Law School. Katz has been an outspoken critic of the UCLA study. When I suggested to him that the researchers believed their experiment reflected what any good doctor would offer a recently diagnosed schizophrenic, he scoffed: "With all due respect, they must be crazy if they say that. Because they put down 1-2-3-4-5-6-7--delusions, suicidality, etc. If they didn't mean to do that, what the hell is it doing in the protocol?" A good doctor's first priority, he pointed out, would be to prevent exacerbation and relapse.
An expert on ethics and medical experiments, Katz was a member of an advisory committee in 1973 that helped to first promulgate federal regulations to protect human subjects in the wake of revelations about the Tuskegee study. Now, he is a member of a presidential commission considering recent disclosures about Cold War-driven radiation experiments conducted without consent. He is always skeptical of physician authority and the ways in which doctor-researchers rationalize their behavior. In his mind, Tuskegee and UCLA are on the same continuum--in both instances, in his estimation, patients were deliberately left unmedicated; in both instances, consent was manipulated. The UCLA study, he will concede, is a subtler example, but the problem remains the same.
"There is persistent confusion between research and (clinical) practice and the obfuscation of the two," he told me as he tugged on a cigarette and sipped sherry at lunch. "This is what happened at Tuskeegee. (The researchers) had the best of intentions of combining the two, but in the process they confused themselves and their patient-subjects, because the objectives of treatment and the objectives of research aren't the same."
I asked Katz whether Nuechterlein and Gitlin had been guilty of nothing more than setting up a design that adhered to most schizophrenics' wishes to stop taking medication. "C'mon, c'mon," he said impatiently. "They want to find out, and that is laudable, when, if ever, and under what circumstances can you take patients off medications. But in getting laudable results, which I heartily endorse, they were running roughshod over human beings' autonomy. And that's the issue. You cannot use people--or you should not use people--as means for other's ends and for ends that might ultimately even be good."
Informed consent is Katz's area of expertise, and it is the bottom-line ethical consideration in human subject experimentation, though he views it as it is currently practiced as little more than an "empty ritual."
"In my mind," he said of the UCLA study, "it was immoral from the perspective of informed consent, because (they) were deceiving subjects." In a 1993 law review article, he tore into the new form that UCLA created in response to the government's requirements, still finding it misleading, vague and inadequate. "The (revised) consent form did not state with sufficient clarity that the primary objective of the study was to conduct research for the sake of future patients . . . that it was not therapy for the subject's individual present needs." And, Katz says, there's a whole other consent question that the UCLA controversy sidestepped: Are schizophrenics competent enough to give informed consent? Katz would like to see the mentally ill included in the same "vulnerable" class as children, prisoners and fetuses, and extended the same heightened protections--experimentation involving them must have a therapeutic benefit and be of minimal risk.
Katz also agrees with the OPRR report that the trouble at UCLA was as much the fault of the institutional review board as it was the research itself. Part of the problem is that the federal regulations cannot be applied rigidly to make determinations of whether a proposed research activity is ethically right or wrong. The process is a flexible one. As such, the IRBs are in a position of unbridled power.
Despite the presence of non-scientists on these boards, one of the central problems in the ethics of research is that review boards are chiefly made up of colleagues of the researchers. When the Nuechterlein-Gitlin study was approved, UCLA's IRB for medical research consisted of 12 faculty members, two nurses, two pharmacists and two public members representing the community at large. "It's a very clubby situation," explains UCLA psychology professor Irving Maltzman, who has been on the faculty for 45 years. "You don't blow the whistle on (your colleagues) because they might be on your committee the next time you're up for promotion."
Not all of Katz's colleagues in the world of medical ethics feel as strongly as he does about the right and wrong of the UCLA study. Dr. Frederick K. Goodwin, former director of the NIMH, wrote a memo on the researchers' behalf: "Are we to hold researchers responsible for events which may well be a part of the . . . course of a severe illness?" he asked. Katz's "respected colleague and friend," Dr. Robert J. Levine, who heads Yale Medical School's review board, wrote Katz a note: "My perception of the investigator's motivation continues to be very different from yours." Levine believed in the distinction Nuechterlein and Gitlin made when they said they were not inducing relapse, merely studying it when it occurred as part of the normal procedure of drug withdrawal. And then there's the OPRR's decision that except for informed consent, the study passed clinical muster.
All the more reason, Katz believes, to use the UCLA case as a foothold to radically transform the current system and create new oversight mechanisms. Katz says the answer is to dismantle the bureaucracy of the independent review boards and to create a national review board with the authority to oversee and audit experiments that pose especially difficult moral questions. "They would not be unregulated, invisible bodies that make decisions," he says. "Even though they have been established under federal regulations, I think (the review boards are) assuming an authority that they are (not) competent to exercise, like making all the decisions they're making by using vulnerable subjects for the purposes of research." The meetings of such a review panel would be publicly conducted--not wrapped in a shroud of secrecy as is currently done.
In his crusade, Katz is joined by patients' rights groups like the Alliance for the Mentally Ill, with chapters nationwide. Schizophrenic relapse studies have become one of these groups' main targets. Adil E. Shamoo, a member of AMI, and a biological researcher and ethicist at the University of Maryland's School of Medicine, has found that 2,471 patients in 41 research projects during the past three decades have had their medications withdrawn to study relapse or new drug treatments. Shamoo says that 950 of the patients relapsed and 250 dropped out of the studies. "That sounds benign," he tells me, "but it's not. Those who dropped out could be homeless, could have committed suicide or be well. That's 250 people just lost in the shuffle. The researchers make no mention whatsoever of what happened and they feel no responsibility."
In addition to medication withdrawal studies, there is also research involving chemically induced relapse. In at least two recent studies currently under federal investigation, schizophrenics at Veterans Administration hospitals were given drugs such as amphetamines to bring on psychosis.
"Nobody until now has even questioned that this was being done," says Vera Hassner Sharav, a board member of the New York branch of AMI. "For many of us, it was a revelation that experiments actually induce relapse, rather than prevent it. This is like creating Humpty Dumpty and not putting pieces back again."
Katz agrees. "The caring dimension of medicine requires taking most seriously the idea that research subjects possess human rights that are inviolate," he wrote in his law journal article. Progress in science, he noted, may have to be slowed down--by stricter guidelines, a permanent federal review board, consent forms that are as frank as possible--and that is a price he thinks is eminently reasonable.
He adds, "People assume the caring dimension of medicine is automatically transferred to the caring dimension of research. And it's not."
"DEVELOPMENTAL PROCESSES IN Schizophrenic Disorders" is in recess at UCLA, at least the part of it that garnered headlines. The last patient-subject was enrolled in the study's drug-withdrawal phase in May, 1992, and many of the original participants continue to receive treatment at the Aftercare Clinic, where new research is ongoing.
Since the government report, UCLA has agreed to substantially change its review policies, adding one more public member, as a patient advocate, to the Human Subjects Review Committee, and to better monitor research where researchers also provide clinical care. Another result of the investigation, this one required by the OPRR, once again shows the semantic delicacy of the issues involved here: The Aftercare Clinic must now be called the Aftercare Research Clinic, the better to remind future patient-subjects that this is not a treatment center so much as a laboratory--the "clinic" only admits individuals willing to participate in research.
But from all appearances, the controversy over the Nuechterlein-Gitlin study hasn't caused any deep soul-searching at UCLA. Even after the final report was issued, UCLA sent a spokesman to Washington, D.C., to testify in defense of Gitlin and Nuechterlein at the same hearing on informed consent where Gregory Aller's story was told. From the school's point of view, it has all but won the first round in this battle--their researchers and the rest of the review apparatus are now complying with federal standards, which is exactly what they did before.
Still, the university, Gitlin and Nuechterlein are facing the families' malpractice suits, with a trial date being set in November. "The sad truth," Bob Aller said in response to the government investigation, "is that subject-patients are currently not protected in any substantive way by any office of the government." What the families are looking for, says their attorney Elizabeth Mann, is to ensure that "the consequences of human experimentation that is not carefully regulated and administered (will) be severe."
Meanwhile, Gitlin and Nuechterlein are synthesizing the final results of their study, working on the papers that will showcase their conclusions. This much they will say: The research included a total of 107 patients. Fifty-three of them entered the double-blind crossover and removal protocol, and about 40 entered the 18-month withdrawal program. About 70% of them became worse, suffering some level of psychotic symptoms.
Nuechterlein has already taken these results to heart in his latest research. All his current patient-subjects, he says, are on meds and staying on them. That suggests that "Developmental Processes" at the least will make this contribution to science: Withdrawing drugs from recent-onset schizophrenics is not medically advisable.
published in the Los Angeles Times