Experimental Schizophrenia Drug Has Potential To Reduce Acute Symptoms

According to the National Institute of Mental Health, schizophrenia is a chronic, severe, and disabling brain disorder that affects about 1.1 percent of the U.S. population age 18 and older on an annual basis. The symptoms of the condition include hallucinations, delusions, disordered thinking, movement disorders, flat affect, social withdrawal, and cognitive deficits.

The cause of schizophrenia is not clearly known. That is why currently available methods of treating schizophrenia focus on treating the symptoms of the disease rather than its cause. Antipsychotic medications are one of the main avenues of treating schizophrenia.

According to the NIH, older antipsychotic medications include chlorpromazine (Thorazine®), haloperidol (Haldol®), perphenazine (Etrafon®, Trilafon®), and fluphenzine (Prolixin®).

These drugs often target neurotransmitters like dopamine or serotonin for treating the disease. However they have many unpleasant side-effects like rigidity, persistent muscle spasms, weight gain, tremors, and restlessness.

The new drug currently under trial promises to eliminate these side effects. LY2140023 successfully reduced the acute symptoms of schizophrenia without causing any of the above-mentioned side effects. The randomized, double-blind, placebo-controlled clinical trial was a phase II study involving 196 patients with schizophrenia.

The Ely Lilly researchers used olanzapine as an active control. the latter is a common antipsychotic medication that targets dopamine and serotonin receptors Before the beginning of the trial, patients were tapered off from any anti-psychotic medications they were using. Additionally all participants were hospitalized in order to ensure patient safety in case of unforeseen emergencies.

The patients were either given 40mg of LY2140023 twice daily; 15 mg of olanzapine daily or a placebo. The trial lasted for four weeks and was completed by 118 patients.

The main findings of the study include:
* LY2140023 and olanzapine showed significant improvement in the symptoms of schizophrenia as compared to placebo. Researchers used the PANSS (Positive and Negative Syndrome Scale) to measure the response to treatment.

* LY2140023 did not cause certain adverse effects like increased prolactin elevations, weight gain or muscle stiffness.

* In a dose of 40mg twice daily, LY2140023 was found to be safe and well-tolerated.

The most common side effects for the new drug included insomnia, affect lability, nausea, headache, somnolence and an increase in the level of blood creatine phosphokinase.

Reporting in the journal Nature Medicine, researchers said patients in the olanzapine group suffered from side effects like weight gain, elevation in blood triglyceride levels, somnolence, akathisia, agitation and periodontitis.

LY2140023 is different from currently available anti-psychotic medications because it targets the neurotransmitter glutamate expressed by mGlu2/3 receptors.

"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," said Steven Paul, M.D., Lilly's executive vice president of science and technology.

Eli Lilly's own Zyprexa was approved as an anti-psychotic medication in 1996 The drug is used for the short- and long-term treatment of schizophrenia, acute mixed and manic episodes of bipolar I disorder, and maintenance treatment of bipolar disorder.

Like Zyprexa, other anti-psychotic medications work by targeting receptors that elaborate neurotransmitters dopamine and serotonin. Although the exact cause of schizophrenia is not known, it is thought that these neurotransmitters play a significant role in the related symptoms.

According to the National Institutes of Health, symptoms of schizophrenia usually start in the late teens and early 20s for men. They include hallucinations, or seeing things, and delusions such as hearing voices. For women, they start in the mid-20s to early 30s. Other symptoms include

    * Unusual thoughts or perceptions
    * Disorders of movement
    * Difficulty speaking and expressing emotion
    * Problems with attention, memory and organization

However it is a known premise that medications can reduce the acuity of these symptoms and allow patients to lead comfortable and relatively stable lives.

1. 07-09-2007 05:09

It seems a little premature for Lilly to be announcing an 'exciting new discovery' based on a clinical trial of only 28 days.

"OVERALL, LY2140023 40 mg given twice daily was found to be safe and well-tolerated, with MOST adverse events being mild-to-moderate in severity and not treatment-limiting."

HOW severe were the minority of severe adverse events (those not include under "most") and what WERE those severe adverse events that showed within such a short period? In the interests of transparency in SCIENCE upon which safety depends, should we not be informed of these events as enthusiastically as we are of the perceived possible benefits? Severe adverse drug events in a minority population amount to a considerably large problem when a drug is prescribed to millions as is clearly and repeatedly evidenced when, years after a drug is marketed, additional safety information and black box warnings are required, and withdrawal of many drugs from the market becomes necessary. http://en.wikipedia.org/wiki/List_of_withdrawn_drugs

Lilly state: "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."

While Lilly announce that "Treatment with LY2140023 was not observed to have certain adverse events that often occur with currently approved schizophrenia medications, including... extrapyramidal symptoms (involuntary movements or muscle stiffness)" it should also be noted that TD (Tardive Dyskinesia) is a disfiguring and often permanent "extrapyramidal" symptom and that Lilly document:

"The risk of developing TD and the likelihood that it will become irreversible are believed to INCREASE as the DURATION of treatment and the total cumulative dose of antipsychotic increase." Tardive Dyskinesia is unlikely to emerge in short term clinical studies.

Lilly also state that "The most COMMON treatment-emergent adverse events in the LY2140023 group were insomnia, AFFECT LABILITY (P = 0.03

, nausea, headache, somnolence and BLOOD CREATINE PHOSPHOKINASE INCREASE".

Affect lability, or mood swings, can pose serious psychological risks particularly alongside an inability to sleep, including that of suicidal ideation, and increases in creatine phosphokinase are often seen in, and indicators of, muscle damage such as rhabdomyolitis for which Baycol earned its notoriety. Once again, what are the severe side side effects not included in 'common' or 'mild to moderate in severity'?

Finally there is the question of the integrity of a 28 day study wherein a drugmaker compares its investigational compound to its own established drug.