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|--| | | | | | | |--| |---| | | | | | | | - | | 4 | | - | | | |---| 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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