Subject: Lilly Press Release
From: [email-masked]
To: [email-masked], [email-masked], [email-masked], [email-masked], [email-masked], [email-masked], [email-masked]
Cc: [email-masked]
Date: Wed, 13 Sep 2000 03:06:00 -0700 (PDT)

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 Study Shows Efficacy of Zyprexa Superior to Valproate in the Treatment of
               Acute Mania Associated with Bipolar Disorder
          Study is the largest comparison of two mood stabilizers

Zyprexac (olanzapine, Lilly) provides better control of manic symptoms

during treatment of acute manic or mixed manic episodes compared with

valproate (Depakotec, Abbott), according to new data presented today at the

13th European College of Neuropsychopharmacology Congress (ECNP) in Munich.

The study is the first head-to-head comparison of Zyprexa and valproate

since the FDA's approval of the use of Zyprexa for bipolar mania in March.

Key Findings

Dosing was based on both drugs' package inserts (see Study Design for more

information). The study's primary efficacy measure was the Young-Mania

Rating Scale (Y-MRS), an 11-item scale used to assess the severity of a

patient's mania. Key study endpoint findings included:

?    The Zyprexa group experienced a significantly greater improvement on
the Y-MRS total score than did patients treated with valproate (49% vs.
38%).
?    A greater proportion of Zyprexa patients achieved remission from manic
symptoms (defined as Y-MRS Total Score < 12) compared with valproate
patients (47% vs. 34%).
?    54% of patients on Zyprexa experienced a 50% or more improvement in
Y?MRS scores compared with 42% of the valproate patients.
?    Zyprexa patients demonstrated a statistically significant improvement
in certain Y-MRS Individual Item Scores compared with valproate patients:
activity/energy (53% vs. 41%), sleep (69% vs. 45%) and language-thought
disorder (49% vs. 35%).  Changes in other core symptoms of mania as defined
by the Y-MRS Individual Item Scores were similar for the two treatment
groups.

Study Design

The three-week, randomized, parallel, double-blind, acute-phase study

examined 251 hospitalized patients at 44 sites who met the DSM-IV criteria

for a diagnosis of bipolar I disorder and were experiencing acute manic or

mixed episodes. Subjects received olanzapine in a flexible dose range of 5

to 20 mg/day (once daily) or valproate in a flexible does range of 500 to

2,500  mg/day (multiple doses per day). The mean ending dose for Zyprexa

was 17 mg/day and the mean ending dose for valproate was 1500 mg/day. In

addition, plasma levels were monitored to ensure valproate trough levels

were maintained within the targeted therapeutic range of 50-125 ?g/mL; the

mean value of all levels obtained was 79.4 ?g/mL. Clinicians determined

dosing based on each patient's clinical response as well as the blood

levels in patients taking valproate. Lorazepam use was restricted to a

maximum dose of 2 mg/day, and administration was prohibited within eight

hours of a psychiatric exam.

Additional Study Results

Neither Zyprexa nor valproate induced depressive symptoms in bipolar manic

or mixed patients.  In fact, both Zyprexa and valproate patients showed an

improvement in depressive symptoms as measured by the Hamilton Depression

Rating Scale (HAMD-21).  However, Zyprexa patients showed greater

improvement at the study endpoint in HAMD-21 scores (35% vs. 24%).  The

effects of Zyprexa have not yet been studied in bipolar depression.

Zyprexa was generally well tolerated. The most common and significantly

different adverse events for Zyprexa were somnolence (39.2% vs. 20.6% for

valproate), dry mouth (33.6% vs. 6.3%), and increased appetite (12.0% vs.

2.4%).  The most common adverse event for valproate was nausea (28.6% vs.

10.4% for Zyprexa). Additional safety information for Zyprexa and valproate

can be obtained from their package inserts.

"These data support the value of Zyprexa as a much needed treatment

option," said Mauricio Tohen, M.D., Dr. P.H., medical adviser, Lilly

Research Laboratories, Eli Lilly and Company, and lead investigator for the

study.  "The findings provide further evidence that Zyprexa effectively

stabilizes mood in patients with bipolar disorder."

Manic symptoms occur during the manic phase of bipolar disorder, a lifelong

illness characterized by disruptive swings in mood.  Symptoms include

abnormal elation and/or irritability, often accompanied by an unrealistic

belief in one's own abilities, increased sex drive, delusions and alcohol

or drug abuse.  People with bipolar disorder also may experience mixed

episodes, marked by symptoms of mania and clinical depression occurring

simultaneously. Diagnostic and Statistical Manual of Mental Disorders,

Fourth Edition (DSM-IV).  American Psychiatric Association, 1994.

Zyprexa (olanzapine, Lilly)
valproate (Depakote, Abbott)

The study findings are particularly pertinent in light of valproate's

recent revised black box warning from the Food and Drug Administration

following reports of life-threatening pancreatitis in both children and

adults.

"Physicians have good reason to take these new data into account," said

Carlos A. Zarate, M.D., associate professor of psychiatry and director,

bipolar and psychotic disorders program, University of Massachusetts

Medical Center.  "The efficacy of Zyprexa coupled with its favorable safety

profile suggest that it may provide a timely treatment alternative for

patients with bipolar disorder."

Zyprexa is indicated in the United States for the management of the

manifestations of psychotic disorders as demonstrated in short-term

clinical trials with schizophrenia patients.  It is also approved for the

short-term treatment of acute manic episodes associated with bipolar

disorder.

In the original schizophrenia registration trials, olanzapine was generally

well tolerated.  However, as with all medications, olanzapine was

associated with some side effects.  In the original six-week, acute-phase

schizophrenia trials, the most common treatment-emergent adverse event

associated with olanzapine was somnolence.  Other common events were

dizziness, weight gain, constipation, akathisia (restlessness), and

postural hypotension.  Modest elevations of prolactin were also seen,

although mean changes from baseline to endpoint were not statistically

significantly different between olanzapine and placebo.  A small number of

patients experienced asymptomatic elevations of hepatic transaminase; none

of these patients developed jaundice or drug-induced hepatitis.

In short-term (three- and four-week) acute bipolar mania trials, the most

common treatment-emergent adverse event associated with olanzapine was

somnolence.  Other common events were dry mouth, dizziness, asthenia,

constipation, dyspepsia, increased appetite, and tremor.

Lilly, a leading innovation-driven corporation, is developing a growing

portfolio of best-in-class pharmaceutical products by applying the latest

research from its own worldwide laboratories and from collaborations with

eminent scientific organizations.  Headquartered in Indianapolis, Ind.,

Lilly provides answers ? through medicines and information ? for some of

the world's most urgent medical needs.

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