Hidden Valley Road: Inside the Mind of an American Family (29 page)

2000

State University of New York at Stony Brook

It had been a decade since Lynn DeLisi first met the Galvin family, and she was still steadfastly collecting families, still acquiring DNA, in hopes of finding a genetic abnormality that helped explain schizophrenia. She wasn’t having much luck, and neither was anyone else.
In 1994,
The New England Journal of Medicine
published a survey of schizophrenia research that concluded that very little had been learned about schizophrenia and no headway had been made in its treatment. All the doctors could do, it seemed, was what they’d been doing for years: prescribe medication and hope for the best. This, for a disease that the editor of
Nature
had a few years earlier called “
arguably the worst disease affecting mankind, even AIDS not excepted.’’

In 1995, however, DeLisi’s work attracted the attention of a well-funded investor: Sequana Therapeutics, a privately held pharmaceutical company that would eventually partner with Parke-Davis to develop schizophrenia drugs. Sequana’s director of genetics, Jay Lichter, was clear about what DeLisi had to offer: “
Dr. DeLisi and her collaborators have assembled one of the largest collections of families whose members include one or more sibling pairs with schizophrenia,” he said. Sequana thought DeLisi had an inside track on finding a genetic link to the illness—the advance everyone was waiting for. In return, the company offered DeLisi access to the most sophisticated genetic-analysis equipment available—technology “
beyond the practical capabilities of a small laboratory,” she said. “As a result, we expect to move much more quickly.”

With DeLisi in charge, the company funded
the largest single-investigator multiplex family study to date, studying the linkages of about 350 different markers spread throughout the genome. The Galvin family’s DNA was part of that study. DeLisi seemed poised for a breakthrough. But within a few years, she, like Robert Freedman, learned the hard way about the vagaries of the marketplace. In 2000, Parke-Davis was bought by Pfizer. Almost right away, DeLisi learned that Pfizer was canceling DeLisi’s project. All work would stop immediately. And all the genetic material she had accumulated at Parke-Davis, including the Galvin family’s DNA, would remain the property of Pfizer—unavailable for DeLisi to use, unless she found another company willing to fund the project.

Why was Pfizer not interested in DeLisi’s family research? She had been making slow progress, that was true. But in research, you only have to go fast if someone else is outrunning you.

THE HUMAN GENOME
Project was a highly publicized effort to map out and understand the structure, organization, and function of every single human gene—the entire DNA blueprint for building a human. The project started in the 1980s at the U.S. Department of Energy, which engaged in a sort of friendly competition with NIH to raise money for the effort. In 1990, the project launched in earnest with an estimated $3 billion in funding. This was like a moon shot for biology. If the project could successfully diagram the human genome, nothing about the study of virtually any genetic disease would be the same—even complex diseases like schizophrenia.

Before the Human Genome Project, Lynn DeLisi and others had been working with the understanding that if you wanted to go looking for the genetic mutations for schizophrenia, the easiest place to find them was in families like the Galvins. That their linkage studies had proved to be unfruitful so far, they thought, was evidence of how complicated the illness was. The alternative—searching for schizophrenia mutations by studying the genetic code of the general population—had seemed ludicrous. All that changed, however, with the Human Genome Project.

Human beings have more than twenty thousand genes that, by encoding the proteins that build our bodies and keep them functioning, play a crucial role in making us who we are—quite a massive haystack to go searching for needles in. But in theory, once the Human Genome Project collected and mapped out the genetic information of enough people, that haystack would suddenly become much easier to search. Now, all one would have to do is compare the genomes of a sampling of sick people—for any genetic disease, take your pick—with a control group, and whatever abnormality existed in the genome of the sick people would be impossible not to notice. Just like that, drug companies would have a gene to target—a specific genetic process to manipulate with medication.

With the Human Genome Project, new treatments and cures for any number of diseases seemed to be a few short years away.
In 1995, the cancer researcher Harold Varmus, the director of the National Institutes of Health, organized a two-day workshop on schizophrenia at the National Academy of Sciences. Varmus, who with J. Michael Bishop had won a Nobel Prize for identifying the cellular origin of certain cancerous genes, had invited many of the usual suspects—E. Fuller Torrey, Irving Gottesman, Daniel Weinberger, Yale’s Patricia Goldman-Rakic—to present their latest research. Varmus was not impressed. At some point,
Weinberger recalled Zach Hall, Varmus’s newly installed chief of NIH’s neurological disorders division, standing up and saying, “You people have been studying this disease for thirty years, and from where I sit, you have accomplished virtually nothing.”

Many of the researchers at the workshop were appalled. Some pushed back a little. Then Varmus himself weighed in, saying what he might have been planning to say all along. “You people don’t get it.” Everyone in the room could forget all about their enzyme research, their MRI studies, their CT scans, their PET scans. If you’re not studying genes, Varmus said, “you are going to be dinosaurs.”

COLLABORATING AROUND THE
world, the scientists with the Human Genome Project thought the job would take fifteen years. They finished ahead of schedule, in 2003. Not only was the recipe book for human life now readable, beginning to end, for the very first time, but along the way scientists had identified new genetic markers spaced throughout the genome that could be used for research. Whereas DeLisi had previously been limited to about a few hundred different markers spread throughout the genome, the Human Genome Project opened the door to the discovery of literally millions more. With this wealth of new markers, researchers could now develop a tool for rapidly analyzing the genome, to home in on regions of DNA that seem to be associated with disease: the genome-wide association study, or GWAS.

The first step in a successful GWAS is to collect as many DNA samples as possible from people diagnosed with an illness of interest (for example, schizophrenia) and likewise to collect samples from a large number of apparently healthy people without that illness—the more samples, the better. With computer assistance, the GWAS method compares the information of these two groups, looking for any markers that are far more common among the people who are ill. Upon making this comparison, the theory goes, the genetic marker for any disease should be unmasked, almost instantly, for all to see.

In the first decade of the new millennium, there was a GWAS, and often more than one, under way for practically every disease suspected of having a genetic source: heart disease, diabetes, rheumatoid arthritis, Crohn’s disease, bipolar disorder, hypertension. In 2005, DeLisi was chairing a meeting of the International Society of Psychiatric Genetics in Boston when Edward Scolnick, a researcher from the Broad Institute of MIT and Harvard, announced that his institution planned to become the world’s clearinghouse for genetic data on schizophrenia, with an aim toward identifying schizophrenia genes with a GWAS. By 2008, virtually every researcher in the field, including DeLisi, participated in a new group called the Psychiatric GWAS Consortium (now the Psychiatric Genomics Consortium), which collected some 50,000 DNA samples from people with a range of psychiatric conditions, including DeLisi’s samples from the Galvin family. And in 2009, using information from that consortium, a study of 75,000 irregularities from more than 3,000 people with schizophrenia and bipolar disorder revealed “
thousands of common alleles [possibly mutated genes] of very small effect.”

This psychiatric GWAS was finding potentially relevant genetic locations all over the place, suggesting a new and deeper understanding of how mental illness operated in the brain. In the years to come, this new knowledge would help geneticists see how schizophrenia and other mental illnesses significantly correlated with copying errors—or
copy number variations (CNVs)—in which whole chunks of DNA are either overproduced or go missing altogether. But for those hoping that the GWAS approach would find just a few genes to pin the blame on, this was hardly encouraging. And this was just the beginning. The schizophrenia GWASes that followed identified the first several genetic locations that seemed especially relevant to the illness.
One GWAS, published in
Nature Genetics
in 2013, included about 21,000 genetic samples and found 22 such locations.
Another GWAS, published in
Nature
in 2014, involved 36,989 patients and found 108 locations. Robert Freedman’s CHRNA7 gene was in one of these suspect locations, which offered him some nice outside validation. But the more they found, the less meaningful the results seemed.

Each of these genetic irregularities, taken by itself, only accounted for a minuscule increased chance of an individual having schizophrenia. The researchers tried to make lemonade out of lemons by considering all of these insignificant factors together, combining them to come up with what they touted as a “
polygenic risk score.” But to many researchers, the polygenic risk score was merely a lumping together of trivialities into something only slightly less trivial. The genetic markers identified in the 2014
Nature
GWAS, taken together, would only increase one’s chances of having the disease
by about 4 percent. “
It’s sort of a mindless score,” said Elliot Gershon, DeLisi’s old boss at NIMH, who had moved on to the University of Chicago a few years after DeLisi left. “You can’t really tell anything from the polygenic risk factor.”

The GWAS approach was not delivering the tidy ending that geneticists like Varmus had expected. In the face of blistering disappointment, the leaders of the Broad Institute, which had been leading the GWAS efforts for schizophrenia, decided to double down—resolving to build a bigger and better GWAS. “
The guess among my colleagues is that we’ll need 250,000 schizophrenia patients,” said Steven Hyman, the head of the Broad Institute’s Stanley Center for Psychiatric Research, “which is daunting, but feasible for this disease.” By the time they were done, Hyman predicted, “there will be thousands of variants in many hundreds of genes” all pointing toward schizophrenia.

Some suspected that the entire process might be leading the field astray—sending researchers once again to go look for their lost keys where the light was, not where the keys really might be. After all that work, the underlying nature of schizophrenia remained a matter of intense debate. “
Is it a classical organically based biomedical disorder,” the psychiatric geneticist Kenneth Kendler wondered in 2015—like, say, Alzheimer’s disease was thought to be—“or is it the severe end of a spectrum of syndromes that aggregate together in families?”

Lynn DeLisi knew where she stood on the matter. She’d known for years. “My thought was, ‘I don’t believe that these hundred genes or markers are going to lead to anything,’ ” she said. “I want to see what’s causing schizophrenia in these large families like the Galvin family.”

WHEN PFIZER PULLED
the plug on DeLisi’s research into families with schizophrenia in 2000, she was forced to stop all of her work. Like the parties in a divorce, she and Pfizer divided her physical samples from her families straight down the middle. The term in research is “aliquoted”: She and Pfizer each walked away with one half of each of her blood samples, enough material, in theory, for both parties to continue work. But in a cruel irony, no work would continue: DeLisi had the will to keep going but not the money, while Pfizer had the money but lacked the will.

Why would any large pharmaceutical company not want to try to develop a better drug for schizophrenia—one that might hit a genetic target and resolve issues that Thorazine and its offshoots never could touch? The reasoning at the time, according to professionals dealing with those companies, was pretty clear. Even with a genetic target, like Freedman’s
α
7 receptor, the pipeline to develop and test such a drug was extremely expensive, requiring human subjects willing to endure unpredictable side effects. Which would be all right if there was a likely financial benefit at the end of that pipeline. As it stood, Thorazine and its offshoots had been around for so long that virtually every company had its own version; these drugs were so stable and so effective at soothing psychotic episodes that it was hard to financially justify spending money to develop something new.

DeLisi called what happened with Pfizer “
a disaster.” With no other options, she kept her half of more than a thousand blood samples from three hundred families—including her half of each of the samples from members of the Galvin family—in a freezer at her new position at New York University. After a blackout hit New York City in 2003, DeLisi gave her samples to a colleague at another institution for safekeeping—first Cold Spring Harbor, then the University of California in San Diego.

DeLisi’s family samples weren’t so much gone as they were in exile. She had no idea how long it would take to bring them home again.

After his time in Boulder with Lindsay, Peter returned to the same revolving door between Pueblo and Hidden Valley Road. His sister gave up her legal guardianship so that Peter would be treated as a ward of the state, allowing him to stay for long periods at state hospitals if needed. His current diagnosis was bipolar disorder, rounded out by the occasional delusional episode. For a decade, each hospitalization lasted just long enough to get him out on his own again. Each trip into the real world lasted only as long as he took his meds.

By 2004, he was forty-three years old, more ragged around the edges, thinner, more addled. On February 26, after a two-month stay at Pueblo, he was released on Risperdal, an antipsychotic, and Depakote, an epilepsy medication that also works as a mood stabilizer for bipolar patients. He had not been taking either when he was readmitted three days later, on February 29, convinced that George W. Bush was bombing the Broadmoor Hotel in downtown Colorado Springs. This would be his twenty-fifth admission to Pueblo.

This time, the doctors gave him three different neuroleptic drugs, Thorazine every two hours and two atypical neuroleptics, clozapine and Zyprexa, twice daily. Once a day he was also given Neurontin, an anti-seizure drug sometimes prescribed for alcoholism. Nothing seemed to work. In April, two female patients on the ward said he grabbed and kissed them. In June, he was spotted purposely throwing up his medications in the bathroom. Over the summer, he lunged at a hospital staff member, pounded on the walls, and called other patients “pussy,” “bastard,” and “asshole.” To one staffer, he said, “Don’t you come near me with your medication, you bitch”; to another, he said, “I am going to kill you.” Peter grabbed the phone receiver while fellow patients were on a call and hung up, turned off the TV while others were watching, flooded the bathroom. And he began preaching to everyone around him. “I am Moses. You will burn in hell. Take your clothes off. You are all lepers. You’re dead. I will take a bat to your head. Shut up, or I will fuck you up.” More than once, he received the ultimate disciplinary measure at the time: seclusion and restraints. By August, Peter’s regimen had expanded to include eight different drugs: Geodon, Risperidone, Neurontin, Risperdal Consta (an injectable drug), Zyprexa, Prolixin, Trileptal, and Thorazine. That, too, didn’t work.

And so, on September 14, for the very first time, after the doctors acquired the proper court order, Peter started a course of ECT—better known as shock therapy.

NO PROCEDURE FROM
the dark ages of mental illness treatments has experienced as unlikely a cultural rehabilitation as electroconvulsive therapy, or ECT. The use of electricity to induce a seizure and calm the brain had been a cultural shorthand for medical torture for decades—since, perhaps, Ken Kesey made it the climactic stroke of barbarism inflicted on McMurphy in
One Flew Over the Cuckoo’s Nest
. By the time Peter first had the treatment, however, a fine-tuned version of the same technique was
being described as effective, safe, and even relatively painless. ECT’s ability to nip mania in the bud with bipolar patients is so well documented that it was a matter of time, perhaps, before Peter became a prime candidate.

Everything about this new, improved ECT seemed designed to counter all that had been said about it decades earlier. Patients are sedated when receiving the shocks. They’re given a muscle relaxant to reduce anxiety, and everything happens while they’re asleep. The procedure still is known to have adverse effects on patients’ memories, particularly after many treatments. And yet in some cases ECT seems to be able to adjust serotonin and dopamine levels more effectively than any medication. There are many stories now of accomplished, talented people—Vladimir Horowitz, Senator Thomas Eagleton, Thelonious Monk, Carrie Fisher, and Dick Cavett among them—using ECT to right themselves, usually with just a few treatments or even just one.

What happens if you need more than just a few treatments is another matter. Would Peter lose his memory, his sense of self, his personality? Risk aside, the decision was no longer Peter’s to make. He was a ward of the state now, and his doctors had the ability to petition the court on his behalf. Mimi, assuming she was consulted at all, was not inclined to contest any decision the doctors made. This may be the only thing that actually helps Peter, she’d say. How much worse off might he be without it?

ON THE SECOND
floor at Pueblo, Peter would change into scrubs, lie on a table, and receive general anesthesia. His mouth was covered, a machine helping with his breathing. He was given a caffeine tablet to lower his resistance to seizures—allowing the doctors to use less voltage—and a drug called Robinul that would prevent drooling. There was no arching of the body, no movement at all, except, perhaps, the jaw. When he awoke, Peter would be groggy. He’d get more caffeine, a pill or some coffee, to clear his head.

Peter never liked it. “I’m not having that shit,” he said on November 8, 2004. “It messes with my bones. I’m calling the Air Force Academy and having them bomb this place.”

He was placed in seclusion with restraints many times in December, once for forty continuous hours. He was still receiving ECT once a week, and he continued to throw up his defenses at every turn. He told one staffer, “You’re a bitch. You will be fired if you mess with me and my attorney. I am suing you for fifty billion trillion million dollars….You are whores of Babylon….My arm broke last night, but I healed it.”

When one hospital staffer told him not to drink any fluids the night before his ECT session, he said, “Fuck you, bitch. I can do what I want. You are going to die.” That same month, he kicked a hospital worker in the side, breaking her rib.

It took more court orders for the mental hospital to get the authority to administer more treatments, but once they increased the frequency, the doctors noticed a difference. Peter averaged three ECTs a week for three weeks and then twice a week through January 2005. Finally in May, he was declared symptom-free. “He exhibited no evidence of dangerousness. He had earned privileges. He had gone on pass with family members and had done well,” his discharge document reads. “The problem is that Mr. Galvin continues to lack insight into his illness….Mr. Galvin has not bought into the idea that ECT is all that necessary for his future stability, or something that he envisions continuing on an indefinite basis.” It was for this reason that the doctors designated his long-term prognosis as “guarded.”

A year later, in June 2006, Peter was back at Pueblo, declaring, “I had a restoration of the spirit.” He refused to eat because he believed his food was poisoned. He had been talking to Jesus. He was Saint Peter, and the devil was after him.

The staff at Pueblo scheduled more court hearings to maintain the frequency of his ECT sessions—once a week or even more, as needed. Peter didn’t want this. But it wasn’t up to him; it never had been. As he said in one intake meeting—asked, one more time, to recite his medical history—“Mental Health got ahold of me and ruined my life.”