September 03, 2007

New Schizophrenia Medication Shows Early Positive Test Results

A new study published in the scientific journal Nature Medicine has demonstrated that a new medication in early testing helps reduce the symptoms of schizophrenia, potentially without the side effects that are common in existing schizophrenia medications. The study was sponsored by Eli Lilly and Company. The new drug that is in testing is at least three to four years from completing regulatory (FDA) review, after which, if it passes, it would be made available to for sale and use.

The New York Times reported today that "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."

Unlike many other most other types of schizophrenia drugs, the Lilly compound works not by targeting dopamine, a chemical found in a person's brain, and one of the key neurotransmitters that is involved in schizophrenia. Rather, this new drug influences glutamate levels, which is a brain chemical necessary for learning and memory that is also known to be involved in schizophrenia.

This is just the second of the three phase FDA approval process - so its too soon to know if this drug will eventually make it to market, or be effective in the long term treatment of schizophrenia. However, it is a hopeful sign that progress is being made in the search for better treatments for schizophrenia.

In this study - a randomized, double-blind, placebo-controlled clinical trial - patients were assigned to four weeks of treatment with either Lilly's investigational compound LY2140023; olanzapine, an atypical antipsychotic medication that targets dopamine and serotonin receptors as an active control; or placebo. The study demonstrated that:

-- LY2140023 and olanzapine showed statistically significant improvement versus placebo in PANSS (Positive and Negative Syndrome Scale), the most common scale used for measuring symptoms of patients with schizophrenia. Both groups showed a rapid response, within one week.

-- Treatment with LY2140023 was not observed to have certain adverse events that often occur with currently approved schizophrenia medications, including increased prolactin elevations, extrapyramidal symptoms (involuntary movements or muscle stiffness), or weight gain.

-- Overall, LY2140023 40 mg given twice daily was found to be safe and well-tolerated, although no testing was done on the longer term side effect profile of the medication.

Some early side effects that were seen in this early test included insomnia, affect lability (mood changing), nausea, headache, somnolence (drowsiness, or sleepiness) and blood creatine phosphokinase increase. The adverse event profile of LY2140023 did not include prolactin increase or worsening of extrapyramidal symptoms (EPS). Although mood lability seems to represent the most important potential adverse event, it should be noted that this outcome was observed primarily at one clinical site. In the olanzapine group, treatment-emergent adverse events included elevation in blood triglyceride levels, insomnia, weight gain, somnolence, akathisia, agitation and periodontitis.

"These data provide compelling new evidence that mGlu2/3 receptor agonists have antipsychotic properties and may provide a completely new therapeutic approach for treating schizophrenia and, perhaps, other neuropsychiatric disorders," said Steven Paul, M.D., Lilly's executive vice president of science and technology. "Additional and longer-term studies are needed to confirm and extend these exciting initial findings. However, these data suggest that LY2140023 may provide a new alternative for the treatment of this often devastating condition."

Study Design

The trial was a proof of concept study designed to determine LY2140023 superiority versus placebo. Olanzapine was used as an active control. 196 patients with schizophrenia were randomly assigned to LY2140023 (40 mg twice daily), olanzapine (15 mg daily) or placebo. All participants were hospitalized to ensure patient safety, tapered off from any pre-trial antipsychotic medications (no therapeutically stable patients were included in the trial), and treated in a double-blind manner for four weeks. In all, 118 patients completed four weeks of the planned study treatment.


Treatment with LY2140023 or olanzapine resulted in statistically significant improvement in PANSS (Positive and Negative Syndrome Scale) total score compared to placebo , After four weeks of treatment, the study showed that both the LY2140023 group and the olanzapine group demonstrated significantly greater response rates compared to the placebo group. Response was measured primarily by the PANSS, the most common scale used for measuring symptoms of patients with schizophrenia. A patient showing a 25% or more decrease in PANSS total score was defined as a responder. Additionally, a mean 0.51-kg weight reduction from baseline was observed in the LY2140023 group. A moderate but statistically significant weight gain was observed in the olanzapine group relative to the placebo group.

Results showed that the placebo arm experienced the highest rate of study discontinuation due to lack of efficacy, however, discontinuation due to adverse events was not significantly different across the three treatment groups.

About LY2140023

LY2140023 is an investigational drug from Lilly, which is being developed as a new treatment option for schizophrenia. LY2140023 is an oral "prodrug," meaning it is devoid of intrinsic biological activity and, once administered, is metabolized to provide the active mGlu2/3 receptor agonist called LY404039. Most currently approved antipsychotic medications work by affecting the neurotransmitters dopamine or serotonin. For LY2140023, the active substance, LY404039, is thought to work by reducing the presynaptic release of another neurotransmitter, glutamate, in brain regions where mGlu2/3 receptors are expressed. Further studies are planned or are ongoing to learn more about the safety and effectiveness, including determining an optimal therapeutic dose for LY2140023.

Additional Related Stories:

LY2140023: Progress in Schizophrenia Treatment? (Corpus Callosum Blog)

Schizophrenia trials 'promising' (BBC News)

Lilly's Schizophrenia Drug Targets Different Brain Chemicals (Bloomberg)

Source Research Paper: "Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial" Nature Medicine

Source of Press Release: Eli Lilly


This article throws up more questions than answers, what is the significance of these findings?..Does this mean the dopamine and serotonin theory is incorrect?..Does this mean these types of medications are blunt instruments and are affecting several parts of the brain? Does this mean shutting down one set of receptors shuts down others? Where’s a PhD professor when you need one?

Posted by: Grissom at September 4, 2007 02:19 AM

Some answers to the comment (not by a PhD professor):

- There is no serotonine theory of schizophrenia as such. Serotonine does play an important role in addition to the main dopamine-2 blocking properties of anti-psychotics.
Inhibiting glutamate transmission is seen by the pharmaceutical company Lilly as a third pathway to prevent psychosis. The present research suggests it is less effective than Zyprexa, which combines dopaminergic and serotonergic properties. So it seems the new compound is indeed a third way. However, when the right dosage is established we'll know more.

- The new glutamatergic medication seems to have less of the expected side effects, so is less 'blunt'. But with new types of medication an unexpected side effect might always pop up in an unexpected corner. Let's hope it stays this 'clean'.

- Glutamate is a different neurotransmitter, ubiquitous throughout the brain. The nerve cells using dopamine, serotonine, glutamte, etc, are in close contact. And yes, a signal from one part of the brain can trigger another part. But glutamate is probably more basic than serotonine for the disease schizophrenia. Up to now dopamine-2 receptor seems the main culprit, but this is science in progress, so we'll keep a close watch!

Posted by: freeZotic at September 4, 2007 04:05 AM

Seeing as glutamate is the major neurotransmitter in the brain I think this medicine could could have many unwanted affects in such areas as mood, emotion and cognition as schizophrenia does not affect the whole brain but this medicine does.

Posted by: Matt at September 4, 2007 05:33 AM

If you're interested there are excellent descriptions of this drug and the trial at This drug is based on Glutamate Hypothesis of Schizophrenia (read a review by Bita Moghaddam at the same site). Best regards.

Posted by: CopperKettle at September 4, 2007 09:02 AM

Anybody that comes up with a drug with the cognitive benefits of Zyprexa and the energy levels of INVEGA will get a bouquet delivered to their house!

Posted by: hmmned at September 4, 2007 09:13 AM

New medicine is not always better and more effective, however, patients and families need hope! And even a small step forward is a good thing!

Posted by: Hao at September 4, 2007 10:13 PM

As Prof. Nancy Andreasen very clearly indicates in her nice book "Brave New Brain" (which is highly recommended reading), our mind is the result of the activities of countless neurons distributed over numerous circuits. She also quite rightly reminds us that there is no neuronal circuit using only a single neurotransmitter.
Moreover, the same neurotransmitter (and its receptors) may be used both in "normal" circuits and in circuits affected by the illness. That's the reason why neuroleptics cannot be devoid of so-called "secondary" side effects: they are active in all brain regions, whether these are "sane" or not, which means that their influence on affected neurons is beneficial, but you cannot avoid that they also act on unaffected neurons, which causes adverse consequences.
Within a neuronal circuit, abnormal activity of some neurons or of synaptic connexions between neurons necessarily results in a chain of abnormal activity in other neurons "downstream". That's the reason why it is very difficult to the decide, when an excess (or a lack) of neurotransmitter is found (in dopamine or in glutamate, or GABA, among others), where the chain of abnormal events began, which are the neurons that are the "first culprits" (try to visualize a Calder mobile where a piece is faulty: how do you find out which one is responsible for the unbalance of the whole work of art?)
So, as long as medications only indiscriminately target receptors for a given neuromediator, they won't achieve entirely satisfactory results. The only way to significantly improve the effects of medication is by identifying the neurons responsible for the trouble and to target them specifically. I don't know how long it will take in order to be able to do this. Meanwhile, we have to content ourselves with using existing medications by trials and errors, and hope that unavoidable adverse side effects won't be too numerous or too heavy.
Just the two cents of opinion of the father of a very ill young man (and, incidentally, from a retired MD. and PhD. who once was active in neuroanatomical research, who should know what he is talking about ;^)... )
Thank you for bearing with my poor english!
Jean (John) Desclin (Brussels)

Posted by: Jean Desclin at September 5, 2007 01:50 AM

It may be that the effectiveness of glycine based treatments for schizophrenia are related to its effect on glutamates. That's why I take 750mg of N-N-Dimethyl Glycine a day. I eagerly await the arrival of this new drug.

Posted by: Ray Kinserlow at September 21, 2007 09:09 PM

My daughter is 33 and has schizophrenia,I am very interested in this new drug,and would like to know if she could be a part of the trail.

Posted by: nancy hause at December 3, 2007 01:09 AM

My daughter, 29, has had schizophrenia for about 9 months, on top of having had severe depression--diagnosis:chronic treatment-resistant depression-for years--now she is extremely depressed, hears voices that even keep her from sleeping, and is suicidal--has tried Symbyax, Invega, and now is on Abilify-none have helped--all have intolerable side effects--one is that they block the signal to let her body know she is full and she eats A LOT--she is a very weight conscious person and having no control over the eating makes her more depressed and more suicidal--how can she get on this trial???? Thank you!

Posted by: Carol Stork at April 13, 2008 09:37 AM

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