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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.
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.
? 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
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
"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
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.,
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