Brain Physiology, Cognition and Consciousness: notice board entry
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Glutamatergic Drug for Schizophrenia!
- Posted by:
- Alfredo Pereira Jr (group admin)
- Date:
- 05 September 2007
- Comments:
- 4 comments
From Nature News
Published online: 2 September 2007; | doi:10.1038/news070827-9
High hopes for new schizophrenia drugs
Drug trial hailed as first major breakthrough for 50 years.
Alison Abbott
The next generation of schizophrenia drugs could target different messenger molecules in the brain.
Psychiatrists have welcomed the unveiling by a US drug company of the first new class of schizophrenia drugs since the 1950s.
According to early clinical-trial data, the prototype drug — codenamed LY2140023 and produced by Eli Lilly researchers in Indianapolis, Indiana — seems to be as effective as olanzapine, the best currently available drug. The drug’s developers hope that it will offer psychiatrists a new alternative for treating their patients, and one that may offer greater benefits in relation to the side effects.
According to the World Health Organization, schizophrenia affects around 1% of the population worldwide. Its broad range of debilitating symptoms can include delusions, hallucination, disordered thinking, social withdrawal and emotional ‘flatness’.
Current anti-schizophrenia drugs all work the same way, by reducing levels of the neurotransmitter dopamine in the brain. But they do not control the disease well in all patients and often have unpleasant side effects. The new drug, LY2140023, is converted in the body into a second compound, called LY404023, which acts by damping down the activity of a different neurotransmitter, glutamate.
Lilly researchers say that the trial is an important proof of principle that their new approach to the disease works, but they don’t yet know if this particular compound will make it into the clinic. “Our study is the first conclusive evidence for a role of glutamate in the pathophysiology of schizophrenia,” says James Monn, one of the research team.
In the trial, 196 schizophrenic patients were treated with either LY2140023, olanzapine, or a placebo for four weeks. The drugs were roughly equally effective, the researchers report in Nature Medicine1.
New approach
“In terms of drug development this is a giant step forward — pretty much the first major step forward since 1952, when chlorpromazine was introduced,” comments Solomon Snyder, a neuropharmacologist at Johns Hopkins University in Baltimore, Maryland.
Chlorpromazine, despite its serious side effects — which include lactation and uncontrolled movements — transformed the treatment of schizophrenia. Before this, most schizophrenics were doomed to lifelong incarceration. Newer drugs of the same class, such as olanzapine, have been chemically fine-tuned to minimize side effects, but many patients still do not like to take them and often abandon therapy. The side effects of LY2140023, including insomnia and emotional instability, are slightly different to those of olanzapine although they are of roughly the same overall severity — but unlike any existing antipsychotic, the new drug did not cause weight gain.
The idea that the glutamate system might be involved in schizophrenia first emerged when doctors noticed that the 1980s party drug phencyclidine (PCP) induced a temporary psychosis similar to the disease. But the new drug is the first to demonstrate that this system can be deliberately manipulated to help schizophrenics.
Monn admits that the scientists don’t know exactly how the new drug produces its antipsychotic actions. But biochemically, the action is relatively subtle because it works on a particular glutamate receptor called mGlu2/3, which is involved in a feedback loop controlling glutamate release, and therefore only works when the glutamate system is very active — bouts of high activity in this system are suspected to be one of the hallmarks of the disease.
References
Patil, S. T. et al. Nature Med. advance online publication, doi: 10.1038/nm1632. (2007).
[a comment by Jonathan Scheff appearing in the New Scientist journal this month]
The Atypical Atypical?
By Jonathan Scheff
A new class of antipsychotics aims at NMDA receptors
Until the 1980s, researchers didn’t consider the excitatory amino acid N-methyl-D-aspartate (NMDA) to be a receptor in mammalian brains. That began to change in 1982, when Joerg Lehmann and Bernard Scatton studied the interaction between excitatory amino acids and striatal cholinergic neurons in vitro (Brain Res, 252:77-89, 1982). They suggested that excitatory amino acids such as glutamate act at NMDA receptors on the dendrites of striatal cholinergic interneurons.
Over the years, this line of research eventually demonstrated that in healthy human subjects, NMDA antagonists could cause the negative symptoms and cognitive impairments observed in schizophrenia (Cell Molec Neurobiol, 26:365-84, 2006). That led to the idea that NMDA agonists such as glutamate could combat those symptoms – leaving drug developers with an option other than the dopamine D2 receptors, which essentially all antipsychotics target.
One obstacle will be the difficulty in modulating the glutamate system…Indeed, researchers say that in the pathophysiology of schizophrenia, NMDA may be a more primary target than dopamine. “When you give animals ketamine or phencyclidine, it causes a disinhibition of pyramidal flow of glutamatergic output; this causes an increase in dopamine release,” says Joseph Coyle, a professor of psychiatry and neuroscience at Harvard Medial School. “The dopamine hypothesis is that [an increase in dopamine levels] causes psychosis.” But from the effect of ketamine on the NMDA receptor, it seems that “the increase in dopamine release is a downstream effect.”
The first compound targeting metabotropic glutamate receptors (mGluR2/3), one kind of NMDA receptor, is currently in Phase II trials and has shown positive results so far. The compound, Eli Lilly’s LY2140023, proved as effective as olanzapine, the study’s positive control, with fewer extrapyramidal symptoms and less weight gain, according to Lilly’s Sandeep Patil, who worked on clinical development and design for the study (Nature Med, 13:1102-7, 2007). Patil notes, however, that the scales for efficacy testing are not linear and lack definitive biomarkers.
Patil, Coyle and others say that researchers must test the long-term effects of this class of compounds to determine its role in the pathophysiology of schizophrenia. One obstacle will be the difficulty in modulating the glutamate system: Overstimulation leads to excitotoxicity, whereas blocking the system can lead to cell death via apoptosis. “It’s a highly regulated system,” says Coyle. “If it goes out of whack, it can do a ton of damage.”
Source: New Scientist
[More on glutamatergic transmission blockers in the news below – Alfredo]
Psychedelic Healing?
Hallucinogenic drugs, which blew minds in the 1960s, soon may be used to treat mental ailments
By David Jay Brown
Source: Scientific American
Mind-altering psychedelics are back-but this time they are being explored in labs for their therapeutic applications rather than being used illegally. Studies are looking at these hallucinogens to treat a number of otherwise intractable psychiatric disorders, including chronic depression, post-traumatic stress disorder, and drug or alcohol dependency.
The past 15 years have seen a quiet resurgence of psychedelic drug research as scientists have come to recognize the long-underappreciated potential of these drugs. In the past few years, a growing number of studies using human volunteers have begun to explore the possible therapeutic benefits of drugs such as LSD, psilocybin, DMT, MDMA, ibogaine and ketamine.
Much remains unclear about the precise neural mechanisms governing how these drugs produce their mind-bending results, but they often produce somewhat similar psychoactive effects that make them potential therapeutic tools. Though still in their preliminary stages, studies in humans suggest that the day when people can schedule a psychedelic session with their therapist to overcome a serious psychiatric problem may not be that far off.
The Trip Begins
Psychedelic drug research began in 1897, when German chemist Arthur Heffter first isolated mescaline, the primary psychoactive compound in the peyote cactus. In 1943 Swiss chemist Albert Hofmann discovered the hallucinogenic effects of LSD (lysergic acid diethylamide) at Sandoz Pharmaceuticals in Basel while studying ergot, a fungus that grows on rye. Fifteen years later, in 1958, he was the first to isolate psilocybin and psilocin-the psychoactive components of the Mexican “magic mushroom,” Psilocybe mexicana.
Before 1972, close to 700 studies with psychedelic drugs took place. The research suggested that psychedelics offered significant benefits: they helped recovering alcoholics abstain, soothed the anxieties of terminal cancer patients, and eased the symptoms of many difficult-to-treat psychiatric illnesses, such as obsessive-compulsive disorder.
For example, between 1967 and 1972 studies in terminal cancer patients by psychiatrist Stanislav Grof and his colleagues at Spring Grove State Hospital in Baltimore showed that LSD combined with psychotherapy could alleviate symptoms of depression, tension, anxiety, sleep disturbances, psychological withdrawal and even severe physical pain. Other investigators during this era found that LSD may have some interesting potential as a means to facilitate creative problem solving.
Between 1972 and 1990 there were no human studies with psychedelic drugs. Their disappearance was the result of a political backlash that followed the promotion of these drugs by the 1960s counterculture. This reaction not only made these substances illegal for personal use but also made it extremely difficult for researchers to get government approval to study them.
Things began to change in 1990, when “open-minded regulators at the FDA decided to put science before politics when it came to psychedelic and medical marijuana research,” says Rick Doblin, a public policy expert and head of the Multidisciplinary Association for Psychedelic Studies (MAPS). “FDA openness to research is really the key factor. Also, senior researchers who were influenced by psychedelics in the sixties now are speaking up before they retire and have earned credibility.” Chemist and neuropharmacologist David E. Nichols of Purdue University adds, “Baby boomers who experienced the psychedelic sixties are now mature scientists and clinicians who have retained their curiosity but only recently had the opportunity to reexplore these substances.”
Research Begins Anew
The efforts of two privately funded organizations have catalyzed much of the recent wave of research: MAPS, founded in 1986 by Doblin, and the Heffter Research Institute, started in 1993. Outside the U.S. there are groups such as the Beckley Foundation in England and the Russian Psychedelic Society. These seek out interested researchers, assist in developing the experimental design for the studies, and help to obtain funding and government approval to conduct clinical trials. They have initiated numerous FDA-approved clinical trials in the U.S., Switzerland, Israel and Spain. So far the agency has approved seven studies, with two under review and more on the way.
Current studies are focusing on psychedelic treatments for cluster headaches, depression, obsessive-compulsive disorder (OCD), severe anxiety in terminal cancer patients, post-traumatic stress disorder (PTSD), alcoholism and opiate addiction. New drugs must pass three clinical milestones before they can be marketed to the public, called phase I (for safety, usually in 20 to 80 volunteers), phase II (for efficacy, in several hundred subjects) and phase III (more extensive data on safety and efficacy come from testing the drug in up to several thousand people). All the studies discussed in this article have received government approval, and their investigators are either in the process of recruiting human subjects or have begun or completed research on human subjects in the first or second stage of this trial process.
Psychedelic drugs affect all mental functions: perception, emotion, cognition, body awareness and one’s sense of self. Unlike every other class of drugs, psychedelic drug effects depend heavily on the environment and on the expectations of the subject, which is why combining them with psychotherapy is so vital.
“Psychedelics may be therapeutic to the extent that they elicit processes that are known to be useful in a therapeutic context: transference reactions and working through them; enhanced symbolism and imagery; increased suggestibility; increased contact between emotions and ideations; controlled regression; et cetera,” says psychiatrist Rick Strassman of the University of New Mexico School of Medicine, who from 1990 to 1995 performed the first human study using psychedelic drugs in about 20 years, investigating the effects of DMT on 60 human subjects. “This all depends, though, on set and setting,” he cautions. “These same properties could also be turned to very negative experiences, if the support and expectation for a beneficial experience aren’t there.”
Mechanisms and Targets
Scientists divide classical psychedelic drugs into two basic chemical groups: tryptamines (such as LSD, DMT and psilocybin) and phenethylamines (such as mescaline and MDMA). In addition, some people consider so-called dissociative anesthetics (such as ketamine and PCP) to be psychedelic drugs, although the way they affect the brain is quite different.
The exact mechanisms differ, but all the tryptamine hallucinogens-which make up the majority of psychedelic drugs-selectively bind to specific serotonin receptors on neurons, mimicking the effects of the nerve-signaling chemical, or neurotransmitter, serotonin on these receptors. Phenethylamines mimic the chemical structure of another neurotransmitter, dopamine. They actually bind to many of the same serotonin receptors activated by the tryptamines, however. Serotonin is responsible for many important functions, including mood, memory, appetite, sex and sleep. It is such an essential neurochemical that any substance-such as a hallucinogen-that interferes with its action might be expected to produce dramatic changes in brain function.
How do the drugs create their perceptual effects? Neuroscientists believe that activation of a particular set of serotonin receptors, the 2A subtype, which are highly expressed (or present) in the cortex, the outermost layer of the brain, interferes with the processing of sensory information. Consciousness is thought to involve a complex interaction among the cortex, the thalamus and the striatum. Disruption of this network by activation of serotonin 2A receptors is now the most popular theory for the mechanism of action for tryptamine and phenethylamine psychedelics.
“There are at least two possible mechanisms for beneficial actions,” Nichols says. “The first simply involves a change in the numbers of brain serotonin 2A receptors. Activation of serotonin 2A receptors by psychedelics causes the number of receptors expressed on the surface of neurons to decrease, a process called downregulation. For some disorders, such as OCD, it may be this receptor downregulation that could be therapeutic,” he explains. “The other possible mechanism is a psychological effect that is harder to define but in some way produces changes in the way the subject perceives pain and distress. Psychedelics seem able to produce a profound cognitive change that provides the patient with a new insight-the ability to see the world from a new perspective-somehow reducing anxiety and raising the pain threshold.”
MDMA (3,4-methylenedioxy-N-methylamphetamine) is also chemically classified as a phenethylamine, but its action in the brain is substantially different from that of other drugs discussed in this article. “In contrast to most psychedelics, MDMA does not directly stimulate serotonin 2A receptors but instead causes dopamine, serotonin and norepinephrine [another neurotransmitter] to be released from their stores in neuron endings,” Nichols says. There is some controversy about whether MDMA has neurotoxic effects. Most researchers believe, however, that the occasional moderate use of MDMA at therapeutic doses would not be damaging. There have been no recent studies using mescaline, although MAPS plans to initiate some in the future.
In contrast to the traditional psychedelics, the dissociative anesthetics selectively bind to N-methyl-D-aspartic acid (NMDA) receptors, blocking the neurotransmitter glutamate from activating these receptors. “Because glutamate is an essential neurotransmitter that activates neurons, this blocking effect seems to prevent the processing of sensory information by the brain,” Nichols states.
Ketamine appears to hold particular promise as a psychedelic therapy because it is already among the selections in Western medicine’s pharmacopoeia. In addition to being part of a different chemical class of drugs than the other psychedelics, ketamine is in a separate legal class as an FDA-approved schedule III drug. This designation means that any physician can administer it for an off-label use if he or she believes it will help the patient.
Although some research indicates that psychedelic drugs may enhance suggestibility and certain aspects of psychotherapy, the benefits of dissociative anesthetics such as ketamine and ibogaine may simply be the result of enduring biochemical changes in the brain. For example, in 2006 Carlos Zarate of the National Institute of Mental Health published a study demonstrating ketamine’s unusual antidepressant properties [see “Good News about Depression,” by Walter Brown; Scientific American Mind, June/July 2007]. A single infusion of ketamine relieved symptoms of depression in some patients within a few hours, and that relief persisted for several days.
This was the third study that showed ketamine’s powerful and enduring antidepressant effects. In an intriguing finding from one of the previous studies, subjects received the ketamine as an anesthetic for orthopedic surgery-so they were not even conscious during the mind-altering segment of the drug’s action in the brain-and the antidepressant effects occurred postoperatively.
In other work seeking to help cure addicts, a preliminary ketamine study, in which psychiatrist Evgeny Krupitsky of St. Petersburg, Russia, treated 59 patients with heroin dependency, produced encouraging results. And the Iboga Therapy House in Vancouver, Canada, has recently begun a study that has so far successfully treated three out of 20 opiate-addicted subjects with ibogaine. The experimental procedure substantially reduced the withdrawal symptoms associated with opiate addiction, helping the addicts to recover and break their dependency on the drug.
OCD, Cluster Headaches and Cancer
In addition to the promising work with ibogaine and the dissociative anesthetics, progress is also being made in the study of conventional psychedelics. In 2006 investigators at the Johns Hopkins School of Medicine published the results of a six-year project on the effects of psilocybin, in which more than 60 percent of the participants reported positive changes in their attitude and behavior after taking the drug, a benefit that lasted for at least several months.
In another 2006 study, researchers at the University of Arizona, led by psychiatrist Francisco Moreno, found that psilocybin relieved the symptoms of nine patients with OCD. The patients suffered from a wide range of obsessions and compulsions. Some of them showered for hours; others put on their clothes over and over again until they felt right. All nine experienced improvements with at least some of the doses tested.
“What we saw was a drastic decrease in symptoms for a period of time,” Moreno says. “People would report that it had been years since they had felt so good.” Moreno cautions that the goal
was simply to test the safety of administering psilocybin to OCD patients and that the true effectiveness of the drug is still in question until a larger controlled study can be conducted. Such a study is being planned, although there are currently no funds available for it. According to Moreno, however, no treatment in the medical literature eases OCD symptoms as fast as psilocybin does. Whereas other drugs take several weeks to show an effect, psilocybin worked almost immediately.
Preliminary results of a current study led by psychiatrist Charles Grob of the Harbor-UCLA Medical Center suggest that psilocybin may reduce the psychological distress associated with terminal cancer. This research seeks to measure the effectiveness of psilocybin on the reduction of anxiety, depression and physical pain in advanced-stage cancer patients. Grob’s study is almost complete; 11 out of 12 subjects have already been treated. Although the formal data analysis has not been completed, “my impression,” Grob says, “from just staying in touch with these people and following them is that some do seem to be functioning better psychologically. There seems to be less anxiety, improved mood and an overall improved quality of life. There also seems to be less fear of death.”
The first studies of psychedelic drugs at Harvard University since 1965 are also now under way. In one study, psychiatrist John Halpern and his colleagues are looking into using LSD and psilocybin to treat the debilitating symptoms of cluster headaches. The researchers, who are in the process of recruiting subjects, will probably begin trials in early 2008.
Acute Anxiety and PTSD
Another study at Harvard, also led by Halpern, will look into MDMA-assisted psychotherapy in subjects with anxiety associated with advanced-stage cancer-similar to Grob’s psilocybin study-using measures to evaluate anxiety, pain and overall quality of life. This study is also in the process of recruiting human subjects.
Psychiatrist Michael Mithoefer in Charleston, S.C., is running an MDMA study for treatment-resistant PTSD victims of crime, war or childhood sexual abuse. So far 17 out of 20 such subjects have already undergone the experimental therapy. “At this point the results are very promising,” Mithoefer says. “I think we’re seeing pretty strong, robust effects in some people. I hasten to add these are preliminary findings-we’re not ready to draw conclusions yet. But assuming it keeps going this way for the rest of the study, it certainly seems that there’s very good reason to go on to larger phase III trials.”
Although we are still in the early days of psychedelic therapy research, the initial data show considerable promise. A growing number of scientists believe that psychedelic drugs may offer safe and effective help for people with certain treatment-resistant psychiatric disorders and could possibly help some people who receive partial relief from current methods to obtain a more complete healing.
[Posted by Robert Karl Stonjek to the MindBrain group]
Now, the exciting news from NY Times (below). I have appreciated the work of Tamminga, Krystal and Moghaddam for a long time – and the connection with consciousness is clear.
Alfredo
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.
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 needed.
“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 treatment.
“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 sites.
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 University.
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 investment.”
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 failure.”
Copyright 2008 The New York Times Company
Also for depression…(below)
Alfredo
Researchers explore the antidepressant effects of ketamine
Medical Research News
Published: Sunday, 24-Feb-2008
Drug treatments for depression can take many weeks for the beneficial effects to emerge.
The excruciating and disabling nature of depression highlights the urgency of developing treatments that act more rapidly. Ketamine, a drug used in general medicine as an anesthetic, has recently been shown to produce improvements in depressed patients within hours of administration. A new study being published in the February 15th issue of Biological Psychiatry provides some new insight into the mechanisms by which ketamine exerts its effects.
Ketamine is classified as an N-methyl d-aspartate (NMDA) glutamate receptor antagonist. Maeng and colleagues now provide new evidence that these antidepressant effects of NMDA receptor antagonists are mediated by their ability to increase the stimulation of á-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptors. In other words, their findings indicate that the antidepressant-like effects of drugs like ketamine are dependent on AMPA receptor stimulation. This suggests that drugs that enhance AMPA receptor function might have rapid antidepressant properties.
Dr. Husseini Manji, corresponding author on this paper and a Deputy Editor of Biological Psychiatry, explains that “by aiming new medications at more direct molecular targets, such as NMDA or AMPA, we may be able to bypass some of the steps through which current antidepressants indirectly exert their effects – a roundabout route that accounts for the long time it takes for patients to begin feeling better with the conventional medications.” He adds, “Today’s antidepressant medications eventually end up doing the same thing, but they go about it the long way around, with a lot of biochemical steps that take time. Now we’ve shown what the key targets are and that we can get at them rapidly.”
This study is especially important because even though this important antidepressant effect has been found in ketamine, its use also has significant drawbacks. According to John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System, “the only NMDA receptor antagonist found to be effective so far, ketamine, produces transient changes in perception and impairments in cognition.” It is also in the same class of drugs as PCP (phencyclidine) and can cause hallucinations, among other side effects. Dr. Krystal notes that “it is possible that drugs that directly enhance the activity of AMPA glutamate receptors, the AMPAkines, would have antidepressant effects similar to ketamine, without the unwanted side effects.” Exploring the antidepressant effects of the AMPAkines will now be an important target for researchers.