Novel Schizophrenia Drug Shows Promise in Trials

By Nacumen · Sep 3, 2007 · Updated Sep 3, 2007 · ·
  1. Nacumen (use link if you find the copy-paste difficult to read, some of the formatting was lost)

    New Schizophrenia Drug Shows Promise in Trials

    Published: September 3, 2007
    In a clinical trial of about 200 patients, an experimental drug from Eli Lilly lessened schizophrenia symptoms without the serious side effects of current treatments, according to a paper published Sunday in the journal Nature.
    The drug must still be tested on many more patients and 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 weight gain and tremors.
    Lilly will begin a new and 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 and usually begins in the late teens or 20s, 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 Lilly 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 the same way, 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 even have a name yet and is referred to only 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 finding led some companies and scientists to look for 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.
    His goal was to find a chemical that would work as a medicine by stimulating the receptors without producing an excessively strong response. Lilly’s new medicine appears to fit that profile.
    “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 research.
    Dr. Schoepp deserves praise for persuading Lilly to invest in a field that appeared to be a longshot, 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 they were confident that his departure would not hurt the development of Lilly’s new medicine
    Dr. Joseph Coyle, a professor of psychiatry and neuroscience at Harvard Medical School, said the Lilly clinical trial validated the theory that modulating glutamate receptors may control the symptoms of schizophrenia. Even if this drug fails in later trials, companies and scientists are likely to pursue glutamate research much 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.
    Researchers are excited in part because existing therapies have so many drawbacks, he said. “We’ve had one class of drugs for treating schizophrenia, and it was discovered originally over 50 years ago,” Dr. Coyle said. “Fifty years later, most people with schizophrenia remain rather profoundly impaired.”
    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 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 on Sunday , 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 in all 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 a couple of thousand 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.

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  1. enquirewithin
  2. robertone
    High hopes for new schizophrenia drugs

    Drug trial hailed as first major breakthrough for 50 years.

    Allison Abbott

    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.

  3. Broshious
    Re: High hopes for new schizophrenia drugs

    I'm confused. Isn't PCP an NMDA antagonist that works against the Glutamate system? Wouldn't high activity be the opposite of PCP?
  4. robertone
    In the post of Nacumen one can read:
    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 finding led some companies and scientists to look for 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.
    Does that answer the question?
  5. Broshious
    Haha thanks. I guess I should learn to read, huh?
  6. Zaprenz
    What it doesn't really touch on is the fact that drugs that affect glutamate have previously not been considered due to the strong link between excess glutamate and neuronal cell death.

    SWIM is very interested in glutamate, Ampakines etc but wonders if side effects like increased risk of alzeimers, parkinsons (if risk increases, who knows some of these drugs may reduce the risk but as yet we don't know) would be noticed within the small time frame of a clinical trial.

    SWIM even wonders whether some drugs like modafinil may show negative neurological side effects way way in the future of the patient. I guess it can be said with a lot of psychoactive drugs though.

    SWIM may have also got it completely wrong (only time will tell) but the article above definately reminds SWIM of how SSRIs were marketed as the complete solution everyone had been waiting for [compared to tricyclics] and how benzos were going to cure everyone of stress.
  7. Broshious
    Benzo's are pretty good for stress at least. SSRIs, to me, are a miserable failure.
  8. FooDawg
    I was just gonna post this article as a professor of mine passed it along to me recently. I think this is a great research drug with high potential. There have been many theories of where schizophrenic hallucinations and psychotic breaks are being derived from (NMDA and glutamate problems, dopamine issues, etc.) With the current antipsychotics, patients can acquire such issues as tardive dyskinisia which is a nasty side effect. I think any type of new research into solving the problems of those facing schizophrenia would be beneficial to the field and hopefully soon enough we can help alleviate these horrible diseases, if not cure them. Great post.
  9. stoneinfocus
    I´d try a different route... why not take exacerbation of a psychosis, if you could call it that under aphetamines, and lower thus the levels of dop, ser. and others, when the drug leaves teh system? intermitted dexiesa and pauses to tune the levels of the neurotransmitters and no sides, and ther are all sides, even with the newer ones, it´s just a hype! Alzheimer and lower life-expectaion opposed to amphetamine is no fun too, in fact these drugs are no fun to anyone, becuase its the drugs nature to eliminate all fun-drugs from the brain or block them, plus 5-HT receptors, once gone, donßt come back, so one would fgace life long sleeplessness or changes in feeding/weight-gain...

    And why not an opiate to calm a psychotic episode down? Has this even been considered or are these drugs from hell too dangerous to treat psychosis?

    But this seems to be a good approach, leaving alone the dopamine, useless or not, this drug will have a much better patience compliance and thus marketing chances, over the other psychotics, whre most of teh püatientes are forced to take them by law, to initialize a sort of compliance.

    If the receptor agonist /antagonist proves effective, like letrozol, exemestane, etc. in i.e. breast-cancer treatment, then it might be a major step forward, althougu it took me years to find out a receptor blocker or estrogenen inhibitor, that had no sides in me, and I doubt any docotr would have had this surge in searhcign the right medicine or teh money or the time minus his pharmaceutical -sponsor ./
  10. FooDawg

    If your interested in someone who has done major research and case studies with schizophrenics, look into R.D. Laing's work. He was an advocate of allowing the schizophrenics to experience their psychotic breaks in atmospheres comfortable in nature and allowing them to gain knowledge of themselves through the experience. Whether he used opiates to attempt to treat schizophrenia is beyond my knowledge, but I can only imagine that there is a high possibility of this. He was also the only person to ever fully understand schizophrenese (Word Salad) to certain extents with certain patients. His work is quite amazing and very inspiring and for anyone with an interest in existential psychology and alternative treatment of schizophrenia (as opposed to just antipsychotic cocktails) would gain a lot from reading his work.
  11. hoodabudda
    what effect does rimobrant (SP) (opposite of thc pill) do to a schitzophrenic attack?
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