Ohio — She was gone for good, and no amount of meditation could resolve the
grief, even out here in the deep quiet of the woods.
Milt Greek pushed to his feet. It was Mother’s Day 2006, not long after his
mother’s funeral, and he headed back home knowing that he needed help. A change
in the medication for his schizophrenia, for sure. A change in focus, too; time
with his family, to forget himself.
And, oh yes, he had to act on an urge expressed in his psychotic delusions: to
save the world.
So after cleaning the yard around his house — a big job, a gift to his wife — in
the coming days he sat down and wrote a letter to the editor of the local
newspaper, supporting a noise-pollution ordinance.
Small things, maybe, but Mr. Greek has learned to live with his diagnosis in
part by understanding and acting on its underlying messages, and along the way
has built something exceptional: a full life, complete with a family and a
He is one of a small number of successful people with a severe psychiatric
diagnosis who have chosen to tell their story publicly. In doing so, they are
contributing to a deeper understanding of mental illness — and setting an
example that can help others recover.
“I started feeling better, stronger, the next day,” said Mr. Greek, 49, a
computer programmer who for years, before receiving medical treatment, had
delusions of meeting God and Jesus.
“I have such anxiety if I’m not organizing or doing some good work. I don’t feel
right,” he said. “That’s what the psychosis has given me, and I consider it to
be a gift.”
Doctors generally consider the delusional beliefs of schizophrenia to be just
that — delusional — and any attempt to indulge them to be an exercise in
reckless collusion that could make matters worse. There is no point, they say,
in trying to explain the psychological significance of someone’s belief that the
C.I.A. is spying through the TV; it has no basis, other than psychosis.
Yet people who have had such experiences often disagree, arguing that delusions
have their origin not solely in the illness, but also in fears, longings and
psychological wounds that, once understood, can help people sustain recovery
after they receive treatment.
Now, these psychiatric veterans are coming together in increasing numbers, at
meetings and conferences, and they are writing up their own case histories,
developing their own theories of psychosis, with the benefit of far more data
than they have ever had before: one another’s stories.
“It’s a thrilling time, because people with lived experience are beginning to
collaborate in large numbers,” said Gail A. Hornstein, a psychologist at Mount
Holyoke College and author of “Agnes’s Jacket: A Psychologist’s Search for the
Meanings of Madness.” “They are developing their own theories, their own
language about what their experiences means from the inside.”
Mr. Greek is one of the most exceptional, having built a successful life and
career despite having schizophrenia — and, he says, because of it. He manages
the disorder with medication, personal routines, and by minding the messages in
his own strange delusions.
“Schizophrenia is the best thing that ever happened to me,” he said. “I know a
lot of people with the diagnosis don’t feel that way, but the experience changed
me, for the better. I was so arrogant, so narcissistic, so self-involved, and it
humbled me. It gave me a purpose, and that purpose has been very much a part of
Like many idealistic undergraduates, Mr. Greek arrived at Ohio University in
Athens on a mission. Only, like many undergrads, he wasn’t completely sure what
“To discover a psychological code that people should live by, to create world
peace,” he said. “Something like that.”
The town was ready to listen, regardless. It was the fall of 1981, and Athens
still had one sandal planted in the 1960s; communes thrived in the Appalachian
foothills to the north, and big ideas were in the air, at least in the streets
and bars near campus, where professors and students gathered.
One stood out. “You can’t imagine how intense he was back then,” said June
Holley, a friend and business consultant in Athens. “He had this long, very
thick, curly chestnut hair and wild eyes; he looked like a lion. He could be
loud, and I think a lot of people just didn’t want to deal with it.”
Local residents gave him the sidewalk, avoided eye contact, and generally
accepted him as one variety of village lunatic — in a town with a rich history
He knew the role, at some level. The son of a college math professor and a
lawyer, progressives both, Milton Thomas Greek grew up in Roanoke, Ill., and
neighboring Benson, about two hours southwest of Chicago. He declared himself an
atheist early and often, which in a devout Christian community was one way to
stir the air — and the boys who ruled the schoolyard.
“They told me I was damned — damned! — and came after me,” Mr. Greek said. “Now
I see that it was just an excuse, like picking on the fat kid for being fat, or
the nerd for being a nerd. But at the time I thought it was all about religion.”
He did not discover the secret to world peace and, by senior year, was in a
troubled marriage, and began seeing and hearing things others did not. One day
he saw a homeless man in the Athens bus station with eyes “like landscapes that
went back into the man’s head infinitely far, stretching on for eternity.” God’s
eyes; who else?
Later, he was hitchhiking, and a man with long hair and sandals pulled over to
offer a ride, his eyes rippling with the same eternal light as the street
person’s. Jesus? It had to be (“I’d already met God, so it made sense.”) The man
said something about a small town in the woods, and Mr. Greek thought that that
town had to be heaven.
His marriage collapsed. His friends stopped calling. He was back at home in
Illinois when a doctor finally gave him a diagnosis — schizophrenia — and
It seemed like a charade, from start to finish. The doctor never asked what he
thought his hallucinations meant, or whether the strange thoughts were linked to
experiences in his life. He stopped taking the pills.
“I became very suicidal,” he said. “I had no idea what’s happening to me during
this entire time. I had been this big atheist, but here I am thinking that the
rapture is about to start and that I’m the Antichrist — all this religious
The answer was obvious and ultimately liberating, but he had to spend a long
time wandering in the woods — literally — to find it.
It was 1984, he had begged his way back into Ohio University for graduate
studies in sociology, still lost in his own mind, his thoughts turning darker by
the day. He was alienating classmates, professors, friends.
About the only exception was Ms. Holley, a graduate student some 15 years his
senior who enjoyed his company, and one day he decided to visit the commune
where she lived, with her family and several other families. It took him two
days to find it, the first spent wandering the misty woods until dark in a
waking, delusional dream, and the second stumbling into a clearing just off
Hooper Ridge Road, where Ms. Holley and her friends took him in.
Over the next several months they sat with him, accepted him as a member of the
tribe, and encouraged his mission to improve the world at face value. And save
his life they probably did, in part by suggesting that he seek help.
It was Ms. Holley who delivered the message. “I trusted her completely, so when
she said I was hallucinating — when she used the word ‘hallucination’ — I knew
it was true,” Mr. Greek said. “I would have to give the medication another try.”
He was lucky. It worked, blunting the psychosis enough that he was able to
complete a programming course and find work, first in Illinois and later back in
Athens at Ohio University’s Information Technology department. In time he found
something more: During a snowstorm in 1996, Mr. Greek knocked on the door of a
neighbor he had seen around Athens, a single mother with two teenage children,
carrying a full-time job plus graduate classes, who was at that very moment (he
would learn later) praying for something to get her through the winter.
The man at the door did not exactly look like a savior, in his beat-up jeans and
unruly hair, his soft eyes and half-smile. But he offered to cook dinner — stir
fry — on a day when the fridge was nearly empty.
The two neighbors became friendly, then close, and finally fell for each other.
Neither can say exactly when it happened, but she remembers looking out her
window one day to see Mr. Greek pull up to his apartment across the street, his
old Honda coughing white smoke. He popped the hood and backed away from the car
in slow motion, staring at the engine, then turned abruptly toward his apartment
— and vanished, falling face-first into some bushes. “I thought, ‘Well, O.K.,
he’s got something,” she said. “I’m not sure what. Absentmindedness, maybe?”
They married in 2003 (Mr. Greek’s wife, an artist, asked that her name not
appear in this article, for her own privacy), and she helped him fit his
religious delusions, now controlled by medication, into a coherent personal
story that has guided his day-do-day life.
The frightening voices and ominous signs saying that he was damned were no more
than embodiments of his very real childhood terror of being cast out, as the
schoolyard boys threatened. His search for heaven on earth was in part an
attempt to escape that fate, to find a secure place. But it also dramatized a
longing to put the world right, a mission that may have started as vain fantasy,
but in time became an emotional imperative, a need to commit small acts of
kindness, like cooking dinner for a snowed-in neighbor.
“He has this long list of causes that he’s extremely passionate about, and he
has strong opinions about almost everything, but he’s also very sensitive to his
relations with people and open to other philosophies,” said Melissa Van Meter,
who has worked with Mr. Greek at the university and holds very different
political views. “It has just impressed me that he could handle so much
personally and do so well professionally.”
“When I began to see the delusions in the context of things that were happening
in my real life, they finally made some sense,” Mr. Greek said. “And
understanding the story of my psychosis helped me see what I needed to stay
Mr. Greek’s regimen combines meditation, work and drug treatment with occasional
visits to a therapist and a steady diet of charitable acts. Some of these are
meant to improve the community; others are for co-workers and friends,
especially those dealing with a psychiatric diagnosis.
To help others experiencing psychotic delusions, he relies on his own theory of
what delusions may mean. In an analysis of 20 delusional experiences, all
described by sufferers in the first person, Mr. Greek identifies four story
Among them are the rescuer (on a mission to save a particular group); the
self-loathing person (lost in a sense of extreme worthlessness); the visionary
(on a journey to spiritual realms to bring back truth); and the messianic (out
to transform the world through miracles, or contact with deities) — the last of
which is his own psychosis story.
Each, in Mr. Greek’s reading, grows out of a specific fear or trauma, whether
isolation, abuse or family dysfunction, in the same way his own delusional story
symbolized a fear of being a social reject. He is preparing the study for
publication in a psychiatric journal and has put much of his thinking into a
manual for families dealing with psychosis, called “Schizophrenia: A Blueprint
Mr. Greek’s analysis of the story lines in psychosis is certainly not the first
of its kind, nor the most comprehensive. Psychiatrists, psychologists,
therapists and brain scientists have spun out hundreds of ideas about what goes
on during a delusion.
But until recently patients themselves — that is, nonprofessionals who have
lived with hallucinations and delusions — had little more than their own strange
story to study, in any detail. Now they have dozens, and Mr. Greek is one of a
small number of such “native” theorists who argue that the content of a delusion
should not be ignored but engaged, carefully, once a person has his or her
hallucinations under control.
“By exploring a person’s anomalous beliefs and experiences, we are better able
to understand the underlying feeling and needs that give fuel to these
experiences,” said Paris Williams, a psychologist who has struggled with
psychosis and recently published a doctoral dissertation analyzing the content
of six people’s delusions, which has informed Mr. Greek’s work.
For instance, said Dr. Williams, who is working on a book called “Rethinking
Madness,” “we can find ways to make them feel safe when they believe they are
being persecuted by malevolent forces, or find ways to help them feel empowered
when they experience demanding voices.”
One place Mr. Greek feels safe is in a clearing in the woods behind his house,
where on a recent afternoon he disappeared wearing a tie-dyed shirt and old
jeans with the knees worn completely through. He practices mindfulness
meditation here, tuning in to the rhythms of life that usually pass unnoticed.
Back at home, he runs thoughts and perceptions by his wife. “He says things
like, ‘Is that a marching band I’m hearing, or am I just hallucinating?’ ” she
said. “I’ll say, ‘Uh no, I don’t hear a band, Milt,’ and he’s fine.”
And he visits a therapist when stress levels are running very high. The
therapist has given him diagnoses of schizophrenia and “mood disorder, not
otherwise specified,” according to his medical records, and she treats him in
sessions and with an antipsychotic drug, adjusting the dosage up or down
depending on his mood.
Since his mother’s death, Mr. Greek and his wife have taken several more
emotional blows, with other close relatives dying. He has been especially
stretched, between his work, various community projects, and traveling to speak,
often to police groups about how to understand psychotic thinking when dealing
with people on the street.
It was too much, and in August he visited his therapist again, and soon after
made a deal with his wife. “She and I signed a contract identifying and limiting
volunteer work I will do next year,” he said in an e-mail. “I am being coached
on how to say no.”
The world is not yet saved from itself, nor for that matter is Athens. But even
a messianic rescuer needs a day off, if only to come back stronger the next.
WALES, Pa. — SCIENTISTS who develop drugs are familiar with disappointment —
brilliant theories that don’t pan out or promising compounds derailed by
unexpected side effects. They are accustomed to small steps and wrong turns, to
failure after failure — until, in a moment, with hard work, brainpower and a lot
of luck, all those little failures turn into one big success.
For Darryle D. Schoepp, that moment came one evening in October 2006, while he
was seated at his desk in Indianapolis.
At the time, he was overseeing early-stage neuroscience research at Eli Lilly &
Company and colleagues had just given him the results from a human trial of a
new schizophrenia drug that worked differently than all other treatments. From
the start, their work had been a long shot. Schizophrenia is notoriously
difficult to treat, and Lilly’s drug — known only as LY2140023 — relied on a
promising but unproved theory about how to combat the disorder.
When Dr. Schoepp saw the results, he leapt up in excitement. The drug had
reduced schizophrenic symptoms, validating the efforts of hundreds of
scientists, inside and outside of Lilly, who had labored together for almost two
decades trying to unravel the disorder’s biological underpinnings.
The trial results were a major breakthrough in neuroscience, says Dr. Thomas R.
Insel, director of the National Institute of Mental Health. For 50 years, all
medicines for the disease had worked the same way — until Dr. Schoepp and other
scientists took a different path.
“This drug really looks like it’s quite a different animal,” Dr. Insel says.
“This is actually pretty innovative.”
Dr. Schoepp and other scientists had focused their attention on the way that
glutamate, a powerful neurotransmitter, tied together the brain’s most complex
circuits. Every other schizophrenia drug now on the market aims at a different
The Lilly results have fueled a wave of pharmaceutical industry research into
glutamate. Companies are searching for new treatments, not just for
schizophrenia, but also for depression and Alzheimer’s disease and other unseen
demons of the brain that torment tens of millions of people worldwide.
Driving the industry’s interest is the huge market for drugs for brain and
psychiatric diseases. Worldwide sales total almost $50 billion annually, even
though existing medicines have moderate efficacy and have side effects that
range from reduced libido to diabetes.
The glutamate researchers warn that their quest for new treatments for
schizophrenia is far from complete. The results of the Lilly trial covered only
196 patients and must be validated by much larger trials, the last of which may
not be finished until at least 2011. Other glutamate drugs are even further away
from approval. And even if the drugs win that approval, they may be viewed
skeptically by doctors who have been disappointed by side effects in other drugs
that were once been hailed as breakthroughs.
Still, for Dr. Schoepp, the drug’s progress so far is cause for celebration —
“I don’t think people appreciate how much money, time and good technical
research goes into what we do,” he says. “Sometimes, people think the idea is
the thing. I think the idea can be the easy part.”
LILLY continues to develop LY2140023 and has begun a trial of 870 patients that
is scheduled to be completed in January 2009. But Dr. Schoepp is no longer
involved in its development. He left Lilly in April to become senior vice
president and head of neuroscience research at Merck, where he oversees a
division of 300 researchers and support staff members.
Dr. Schoepp’s new base is a modest office on the top floor of a four-story Merck
building here in North Wales, north of Philadelphia. He has a view of the
building’s big front lawn and a busy two-lane road called the Sumneytown Pike.
The huge Merck research complex called West Point, where 4,000 scientists and
support staff members work, is less than a mile to the north.
For Dr. Schoepp, 52, the Merck job is the latest stop in a research career that
began at Osco Drug’s store No. 807 in downtown Bismarck, N.D. He grew up in
Bismarck in a working-class family; at 16, he started working at the Osco, which
has since closed. He quickly decided to become a scientist.
“I just found it fascinating,” he says. “I was hungry for science.” While
reading a magazine for pharmacists, he noticed an ad for a free pamphlet
published by Merck called “Pharmacists in Industry.” He wrote away for the
pamphlet, which convinced him that he could have a career developing medicines.
He applied to North Dakota State University, where he focused on
psychopharmacology, a discipline that studies the way chemicals affect the
brain. “I was really interested in psychiatric disorders,” he says. “I fell in
love with dopamine.”
His love affair was so consuming that his wife joked that “dopamine” would be
his daughter’s first word.
Although scientists sometimes decide to study a disease because of problems it
has caused among family members, Dr. Schoepp says his fascination with mental
illness has been purely academic. “My family has more heart disease than
anything else,” he says.
After graduating from North Dakota State, he received a scholarship to a
doctoral program in pharmacology and toxicology at West Virginia University. He
graduated in 1982. Nearly five years later, he joined Lilly, which was about to
introduce Prozac, the first modern antidepressant — a drug that changed both
psychiatry and the public perception of depression and mental illness.
Prozac became a blockbuster almost instantly after Lilly introduced it in 1987,
making the company one of the most visible players in Big Pharma and giving it
room to invest in long-shot scientific research. Ray Fuller, a Lilly scientist
who was a co-discoverer of Prozac, encouraged Dr. Schoepp to focus his attention
Glutamate is a pivotal transmitter in the brain, the crucial link in circuits
involved in memory, learning and perception. Too much glutamate leads to
seizures and the death of brain cells. Excessive glutamate release is also one
of the main reasons that people have brain damage after strokes. Too little
glutamate can cause psychosis, coma and death.
“The main thoroughfare of communication in the brain is glutamate,” says Dr.
John Krystal, a psychiatry professor at Yale and a research scientist with the
VA Connecticut Health Care System.
Along with Bita Moghaddam, a neuroscientist who was at Yale and is now at the
University of Pittsburgh, Dr. Krystal has been responsible for some of the
fundamental research into how glutamate works in the brain and how it may be
implicated in schizophrenia.
Schizophrenia affects about 2.5 million Americans, about 1 percent of the adult
population, and it usually develops in the late teens or early to mid-20s. It is
believed to result from a mix of causes, including genetic and environmental
triggers that cause the brain to develop abnormally.
The first schizophrenia medicines were developed accidentally about a
half-century ago, when Henri Laborit, a French military surgeon, noticed that an
antinausea drug called chlorpromazine helped to control hallucinations in
psychotic patients. Chlorpromazine, sold under the brand name Thorazine, blocks
the brain’s dopamine receptors. That led the way in the 1960s for drug companies
to introduce other medicines that worked the same way.
The medicines, called antipsychotics, gave many patients relief from the worst
of their hallucinations and delusions. But they also can cause shaking,
stiffness and facial tics, and did not help the cognitive problems or the
so-called negative symptoms like social withdrawal associated with
In the 1980s, drug companies looked for new ways to treat the disease with fewer
side effects. By the mid-1990s, they had introduced several new schizophrenia
medicines, including Zyprexa, from Lilly, and Risperdal, from Johnson & Johnson.
At the time, the new medicines were hailed as a major advance — and the
companies marketed them that way to doctors and patients.
In fact, the new medicines, called second-generation antipsychotics, had much in
common with the older drugs. Both worked mainly by blocking dopamine and had
little effect on negative or cognitive symptoms. The newer medicines caused
fewer movement disorders, but had side effects of their own, including huge
weight gain for many patients. Many doctors now complain that the companies
oversold the second-generation compounds and that new treatments are badly
“People say that there are drugs to treat schizophrenia,” says Dr. Carol A.
Tamminga, professor of psychiatry at the University of Texas Southwestern, in
Dallas. “In fact, the treatment for schizophrenia is at best partial and
inadequate. You have a cadre of cognitively impaired people who can’t fit in.”
WHILE most of the industry focused on second-generation medicines during the
1980s and 1990s, a handful of academic and industry researchers found intriguing
hints that glutamate might provide an alternative treatment pathway.
Psychiatrists and neuroscientists have wondered about a possible connection
between glutamate and schizophrenia since the early ’80s, when they first
learned that phencyclidine, the street drug commonly called PCP, blocks the
release of glutamate.
People who use PCP often have the hallucinations, delusions, cognitive problems
and emotional flatness that are characteristic of schizophrenia. Psychiatrists
noted PCP’s side effects as early as the late 1950s. But they lacked the tools
to determine how PCP affected the brain until 1979, when they found that it
blocked a glutamate receptor, called the NMDA receptor, that is at the center of
the transmission of nerve impulses in the brain.
The PCP finding led a few scientists to begin researching glutamate’s role in
psychosis and other brain disorders. By the early 1990s, they discovered that
besides triggering the primary glutamate receptors — NMDA and AMPA — glutamate
also triggered several other receptors.
They called these newly found receptors “metabotropic,” because the receptors
modified the amount of glutamate that cells released rather than simply turning
circuits on or off. Because glutamate is so central to the brain’s activity,
directly blocking or triggering the NMDA and AMPA receptors can be very
dangerous. The metabotropic receptors appeared to be better targets for drug
“Rather than acting as an all-or-nothing signal, they fine-tune that signal and
modulate that signal,” said P. Jeffrey Conn, director of a Vanderbilt University
drug research program. “It’s really an attempt to be very subtle in the way that
you regulate the system.”
During the 1990s, molecular biologists discovered genes for eight metabotropic
glutamate receptors, which were located at different places inside nerve cells
and had different structures. The finding allowed for the possibility that drug
companies could create chemicals to turn them on and off selectively, rather
than hitting all of them at once.
For Dr. Schoepp and others, finding the receptors was only the first part of the
struggle. They also had to find chemicals that would either block or trigger the
receptors selectively. At the same time, the chemicals had to be relatively easy
to formulate and capable of crossing the blood-brain barrier, which protects the
brain from being easily penetrated by outside agents.
The work was arduous, but the Lilly scientists made slow progress. In 1999, Dr.
Schoepp and two other scientists published a 46-page research paper that
detailed scores of different chemicals that produced reactions at the glutamate
At about the same time, scientists at Yale, led by Dr. Moghaddam, were
demonstrating that activating metabotropic glutamate receptors in rats could
reverse the effects of PCP — a seminal finding, providing the first proof that
altering the path of glutamate transmission in the brain might help relieve the
symptoms of psychosis.
Although the finding in rats was promising, developing animal models for
schizophrenia and other brain diseases is extremely difficult, said Paul
Greengard, professor of molecular and cellular neuroscience at Rockefeller
Even when compared with diseases like cancer, brain disorders are notoriously
complex. Scientists have only a limited understanding of the chemistry of
consciousness, or of how problems in the brain’s electrical circuitry affect the
ability to form memories, learn or think.
“We do not know with any of these neuropsychiatric disorders what the ultimate
basis is,” Dr. Greengard says. “Let’s say you could find that too much of
protein X was involved in schizophrenia. Would you then know what schizophrenia
is? You would not.”
Nonetheless, the findings in rats were promising. Those studies, as well as Dr.
Krystal’s tests in 2001 of volunteers given ketamine, a drug that has effects
similar to PCP, hinted that the glutamate drugs might help to treat the
cognitive and negative symptoms of schizophrenia. Drugs currently on the market
do little to treat those symptoms.
Even before the findings at Yale, Lilly had put its first metabotropic glutamate
receptor compound into human testing. Researchers initially tested the drug on
patients with panic disorder, and it showed some positive results. But Lilly
stopped human testing of the drug in 2001 when long-term testing in animals
showed that it caused seizures.
Even so, Lilly decided that it had enough evidence to justify tests of another
chemical compound, LY404039, that affected the same receptors.
“They had to take a risk on letting these drugs be tested on models or for
disorders that were justified purely on pretty basic science,” Dr. Krystal says.
“There is nothing with these drugs that is straightforward or makes developing
them a basic path.”
When it tried to test LY404039 in humans, the company ran into yet another
hurdle. The human body didn’t easily absorb it. So Lilly created a drug that the
body could absorb, LY2140023, which is metabolized into LY404039 in the body.
Bingo. LY2140023 was the drug that got Dr. Schoepp jumping out of his office
chair in 2006, nearly three years after the first trials in humans began. In the
Lilly test, the drug was slightly less effective over all than Zyprexa, which is
considered the most effective among the widely used schizophrenia treatments.
But LY2140023 also appeared to have fewer side effects than Zyprexa, which can
cause severe weight gain and diabetes. The new drug also appeared to improve
cognition, something that existing treatments don’t do, said Dr. Insel of the
National Institute of Mental Health.
IF Lilly’s new round of tests confirms the drug’s efficacy by early next year,
the company is likely to move ahead to an even larger clinical trial, involving
thousands of patients, that could lead to federal approval for the compound.
Still, approval is at least three to four years away, and other big drug makers
are already scrambling to compete with Lilly.
In January, Pfizer agreed to pay Taisho Pharmaceutical, a Japanese company, $22
million for the rights to develop Taisho’s glutamate drug for schizophrenia.
Taisho will receive more payments if the drug moves forward in development.
Since it hired Dr. Schoepp, Merck has also been moving aggressively. It has
struck two deals since December to work with Addex Pharmaceuticals, a Swiss
company, to develop glutamate drugs for schizophrenia, Parkinson’s and other
diseases. Merck has paid Addex $25 million so far, with more payments to come if
the drugs move forward.
Another glutamate drug, meanwhile, has been shown in preclinical studies to
reverse mental retardation in adult rats, a finding that previously appeared
impossible, Dr. Insel said.
Dr. Steven M. Paul, the president of Lilly Research Laboratories, says Lilly
expects competition in glutamate research to intensify. “We’d like to believe we
have a head start here, and hopefully a good head start,” he says. “But this
area will heat up here; this will be an area where there will be a lot of
For Dr. Schoepp, the sudden interest in glutamate is exciting, and he
acknowledges that he eagerly awaits the results of the large Lilly trial early
next year. And what if the drug fails in that trial, after all the work that he
and scientists around the world have put in?
“I would probably go out and have a beer,” he says. “You have to define failure.
If you collect information and it tells you what you need to know, you’re not a
clinical trial of about 200 patients, an experimental drug from Eli Lilly
reduced schizophrenia symptoms without the serious side effects of current
treatments, according to a paper published yesterday in the journal Nature.
The drug must still be evaluated on many more patients to test for the
possibility of side effects that have not yet emerged, and it is at least three
to four years from completing regulatory review.
But schizophrenia researchers said the trial’s results were surprising and
impressive, especially since the drug works in a different way from existing
antipsychotic medicines, all of which have serious side effects, including
substantial weight gain and tremors.
Lilly will begin a larger clinical trial for the drug this month. If that trial
confirms the results seen so far, the new drug could mark a breakthrough in the
treatment of schizophrenia — and open the way to a broad new class of treatments
for the disease. Schizophrenia, a devastating mental illness that affects 1
percent of adults, or about 2.5 million in the United States, usually begins in
the late teens or 20s and is marked by psychotic delusions as well as social
withdrawal and cognitive impairment.
“This is potentially one giant step forward for patients,” said Dr. Jeffrey
Lieberman, chairman of the psychiatry department at Columbia and the lead
investigator on a federally sponsored clinical trial of schizophrenia medicines.
“This drug may turn out to be not just a comparably good antipsychotic agent,
but a better antipsychotic agent.”
Dr. Lieberman has not been involved with the development of the medicine and
does not receive any payments or consulting fees from Lilly.
The new drug also has the potential to be a blockbuster for Lilly. Medicines for
schizophrenia and bipolar disorder are the fourth-best selling class of
medicines in the United States, with sales of $12 billion in the United States
and $18 billion worldwide last year.
The troubled history of Zyprexa, another antipsychotic medicine from Lilly, will
lead regulators and psychiatrists to scrutinize the new medicine closely for
hidden dangers, Dr. Lieberman said. When it introduced Zyprexa in 1996, Lilly
hailed it as a breakthrough with fewer side effects than older drugs. But
Zyprexa causes severe weight gain, and the American Diabetes Association has
linked it to diabetes. Internal Lilly documents show that the company played
down Zyprexa’s side effects, worrying they would hurt sales.
Despite that history, psychiatrists will be eager to see whether the new Lilly
medicine works, since the existing drugs are of limited help for many patients.
Existing schizophrenia medicines, whether older drugs such as Thorazine or newer
medicines like Zyprexa, all work by blocking the brain’s dopamine receptors.
But the new Lilly drug does not directly affect dopamine. Instead, it modulates
brain activity through a different set of receptors. As a result, it has the
potential to be the first truly novel treatment for schizophrenia since
Thorazine was introduced 1954, Dr. Lieberman and other researchers said.
Lilly’s new drug — which does not have a name yet and is referred to as
LY2140023 — emerged from almost two decades of research by Dr. Darryle D.
Schoepp, a toxicologist and pharmacologist who joined Lilly in 1988.
For decades, psychiatrists have known that users of PCP, a street drug sometimes
called angel dust, have symptoms nearly identical to those of people with
schizophrenia. By the 1980s, scientists had discovered that PCP blocked brain
receptors that are triggered by an amino acid called glutamate. This led some
companies and scientists to study ways to stimulate glutamate receptors as a
treatment for schizophrenia.
But the brain has many different kinds of glutamate receptors, and figuring out
how to stimulate or block them in medically beneficial ways has proved
complicated. Instead of focusing on the receptors blocked by PCP, Dr. Schoepp
concentrated on modulating the action of glutamate receptors in the brain’s
prefrontal cortex, an area responsible for personality and learning.
“This is a system that is so fundamental to the function of your brain that it
is quite powerful,” said Dr. Schoepp.
But because drugs that blocked dopamine had been the only successful
schizophrenia treatments, many researchers viewed the glutamate pathway as
unlikely to produce useful medicines, said Dr. P. Jeffrey Conn, director of the
Vanderbilt University drug discovery program and an expert on glutamate
Dr. Schoepp deserved praise for persuading Lilly to invest in a field that
appeared to be a long shot, Dr. Conn said, adding, “He locked in very early.”
As a result, Lilly appears to have a multiyear lead over its competitors in
glutamate drugs, Dr. Conn said. Dr. Schoepp left Lilly in March to become the
head of neuroscience research for Merck. Dr. Schoepp and Dr. Steven Paul, the
president of Lilly Research Laboratories, both said that his departure would not
hurt the development of Lilly’s new medicine
Dr. Joseph T. Coyle, a professor of psychiatry and neuroscience at Harvard
Medical School, said the Lilly trial validated the theory that modulating
glutamate receptors might control the symptoms of schizophrenia. Even if this
drug fails in later trials, companies and scientists are likely to pursue
glutamate research more aggressively, he said.
“When you see a company that comes up with something that’s completely
different, completely out of the box, that attracts attention,” Dr. Coyle said.
Existing drugs are reasonably good at treating the hallucinations and delusions
of schizophrenia. But they are far less effective at treating the so-called
negative symptoms of the disease — the lack of motivation and emotion that leave
many patients unable to work or have normal social relationships. The side
effects of existing medicines, which affect nearly all patients, are also
severe. Older drugs like Thorazine often cause tics and movement disorders,
while newer medicines typically have fewer effects on movement but can cause
weight gain and other metabolic changes.
In the clinical trial whose results were reported yesterday, LY2140023 had none
of those side effects and appeared to work about as well as Zyprexa at reducing
symptoms. In the trial, which was conducted in Russia from August 2005 to June
2006, patients were given the experimental drug, Zyprexa or a placebo. About 100
patients received the experimental medicine.
For the drug to be approved, Lilly will need to replicate the results in larger
trials. This month, Lilly will begin a trial with 870 patients to determine the
most effective dose of the drug. That trial is expected to be complete in
January 2009, and if it is successful Lilly will probably start a large Phase
III trial that could cover at least 2,000 patients.
“We have to confirm safety and efficacy with multiple studies,” Dr. Paul of
Lilly said. He said he did not want to offer a prediction of when Lilly might
ask the Food and Drug Administration for approval. But he said Lilly intended to
develop the drug aggressively.
“We are very actively working on this target and related targets because we
believe that this mechanism is now validated,” he said.