Here's a long but interesting read, from the NYTimes, on the development of new anti-psychotics. Schizophrenia is such a terrible disease. One can only wish that these research efforts do meet with success.
jwm
February 24, 2008
Daring to Think Differently About Schizophrenia
By ALEX BERENSON
NORTH 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 neurotransmitter, dopamine.
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 — and relief.
“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 on glutamate.
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 schizophrenia.
Article continues in the next post
jwm
February 24, 2008
Daring to Think Differently About Schizophrenia
By ALEX BERENSON
NORTH 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 neurotransmitter, dopamine.
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 — and relief.
“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 on glutamate.
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 schizophrenia.
Article continues in the next post
