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 News Release - May 22, 2006

First Head-to-Head Study Suggests Significantly Greater Symptom Improvement for Symbyax(R) Compared to Lamotrigine in Bipolar Depression

INDIANAPOLIS, May 22 (HSMN NewsFeed) -- Long-term data from the first head-to-head study comparing Symbyax® (olanzapine and fluoxetine HCl capsules) to lamotrigine in the treatment of bipolar depression suggests that patients taking Symbyax experienced significant improvement in overall severity of illness and depressive and manic symptoms, based upon three commonly used scales that measure improvement in depressive and manic symptoms.* The results were presented today at a major medical meeting.

Symbyax is the first and currently the only acute treatment approved by the U.S. Food and Drug Administration (FDA) for the depressive phase of bipolar disorder. Bipolar disorder -- which may affect as many as 10 million Americans and is sometimes referred to as manic depression -- is a complex mental illness characterized by extreme and debilitating mood swings. The World Health Organization estimates that bipolar disorder is the sixth leading cause of disability in the world. The associated mood swings, or "highs and lows," can range from episodes of deep depression (feelings of extreme guilt, sadness, anxiety, and, at times, thoughts of suicide) to episodes of mania (abnormal euphoria, elation and irritability) interspersed with periods of normal mood. Treatment is challenging because some therapies that are effective for one phase of bipolar disorder may be counterproductive for another. For example, studies have shown that antidepressant treatments can precipitate manic episodes in patients with bipolar disorder.

* Clinical Global Impression Severity (CGI-S); Montgomery-Asberg Depression Rating Scale (MADRS); Young-Mania Rating Scale (YMRS).

"The six-month results showed the benefit of using Symbyax to treat bipolar depression in appropriate patients," said David L. Dunner, M.D., Director, Center for Anxiety and Depression, and Professor, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle. "Bipolar patients need treatments that can stabilize their condition as much as possible."

Study Design:

-- In the multicenter, randomized, double-blind, parallel six-month (25- week) study, patients suffering from an acute episode of bipolar I depression were randomized to treatment with Symbyax (6/25, 6/50, 12/25, or 12/50 mg/day, n=205) or lamotrigine (200 mg/day; n=205).

-- Symbyax was started at the 6/25 mg dose and was titrated up to 12/25 mg after one week. After one day, the dosing was flexible within the allowed dosing range (6/25, 6/50, 12/25, or 12/50 mg/day).

-- Lamotrigine was titrated from 25 mg/day to 200 mg/day by the beginning of week six; afterward, the lamotrigine dose was maintained in a dose range of 150 to 200 mg/day (allowed dosing was 200 mg/day).

-- Efficacy measures of improvement in both depressive and manic symptoms associated with bipolar depression included Clinical Global Impression Severity (CGI-S) (primary) as the primary outcome measure, as well as the Montgomery-Asberg Depression Rating Scale (MADRS) and Young-Mania Rating Scale (YMRS).

Key Findings:

-- Patients treated with Symbyax vs. lamotrigine had -1.70 and -1.46 (p=0.008) on the CGI, -16.63 and -14.70 (p=0.005) on MADRS, and -1.92 and -1.05 (p < 0.001) on YMRS, respectively.

-- Time to 50% reduction in MADRS scores were 21 median days for Symbyax vs. 33 median days for lamotrigine (p=0.013).

-- Rates of treatment-emergent mania were 5.0% (10/202) for Symbyax and 7.3% (14.191) for lamotrigine.

-- Response was well maintained in both treatment groups, with no difference in the incidence of relapse (Symbyax, 13/95 patients (13.7%); lamotrigine, 14/77 (18.2%); p=0.528).

-- Symbyax-treated patients experienced a significantly greater incidence of weight gain (22.4% vs. 2.9%, p < 0.001), somnolence (21% vs. 9.3%, p=0.001), increased appetite (19.5% vs. 9.3%, p=0.005), dry mouth (17.1% vs. 5.9%, p < 0.001), sedation (14.1% vs. 2.9%, p < 0.001), tremor (10.7% vs. 1.5%, p < 0.001), lethargy (5.9% vs. 1.5%, p=0.032), disturbance in attention (5.4% vs. 1.0%, p=0.020), and peripheral edema (5.4% vs. 0%, p < 0.001).

-- Significantly more patients treated with lamotrigine reported insomnia (14.7% vs. 5.9%, p=0.003), irritability (7.4% vs. 2.9%, p=0.46), and arthralgia, or joint pain (5.9% vs. 1.5%, p=0.019).

-- There were significant differences for the incidence of treatment- emergent abnormally high laboratory values for cholesterol (Symbyax, 15.9% vs. lamotrigine, 3.7%; p < .001), LDL cholesterol (Symbyax, 8.9% vs. lamotrigine, 1.5%; p=.006), and prolactin (Symbyax, 18.5% vs. lamotrigine, 7.6%; p=.006).

Important Information on Symbyax

Suicidality in Children and Adolescents -- Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of SYMBYAX or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. SYMBYAX is not approved for use in pediatric patients.

Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis -- Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-controlled patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure or sudden death) or infectious (eg, pneumonia) in nature. SYMBYAX is not approved for the treatment of elderly patients with dementia-related psychosis.

SYMBYAX should not be used with an MAOI or within at least 14 days of discontinuing an MAOI. At least 5 weeks should be allowed after stopping SYMBYAX before starting an MAOI. Thioridazine should not be given with SYMBYAX or within at least 5 weeks after stopping SYMBYAX. Concomitant use of SYMBYAX in patients taking pimozide is contraindicated.

Clinical worsening and suicide risk: All adult and pediatric patients being treated with an antidepressant for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially when initiating drug therapy and when increasing or decreasing the dose. A health professional should be immediately notified if the depression is persistently worse or there are symptoms that are severe, sudden, or were not part of the patient's presentation. If discontinuing treatment, taper the medication.

Safety experience in elderly patients with dementia-related psychosis -- In placebo-controlled clinical trials of elderly patients with dementia- related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs. 1.5%, respectively). Olanzapine is not approved for the treatment of patients with dementia-related psychosis.

Cerebrovascular adverse events (CVAE), including stroke, in elderly patients with dementia -- Cerebrovascular adverse events (eg, stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of CVAE in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis.

Hyperglycemia and diabetes mellitus -- Hyperglycemia, in some cases associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics including olanzapine alone, as well as olanzapine taken concomitantly with fluoxetine. All patients taking atypicals should be monitored for symptoms of hyperglycemia. Persons with diabetes who are started on atypicals should be monitored regularly for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing.

Orthostatic hypotension -- SYMBYAX may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia, and in some patients, syncope, especially during the initial dose-titration period. Particular caution should be used in patients with known cardiovascular disease, cerebrovascular disease, or those predisposed to hypotension.

Allergic events and rash -- In premarketing trials, the overall incidence of rash or allergic events with SYMBYAX was similar to that with placebo. In fluoxetine clinical studies, 7% of 10,782 fluoxetine-treated patients developed various types of rashes and/or urticaria. If rash or other possibly allergic phenomena appear for which an alternative etiology cannot be determined, immediate discontinuation is recommended.

Prescribing should be consistent with the need to minimize the risk of neuroleptic malignant syndrome, tardive dyskinesia, seizures, and orthostatic hypotension.

The most common treatment-emergent adverse event associated with SYMBYAX in placebo-controlled clinical trials was somnolence. Other common events were weight gain, increased appetite, asthenia, peripheral edema, tremor, pharyngitis, abnormal thinking, and edema.

For complete safety information, please see the full Prescribing Information at

About Eli Lilly and Company

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of first-in-class and 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. Additional information about Lilly is available at

This press release contains forward-looking statements about the potential of Symbyax for the treatment of the depressive phase of bipolar disorder and reflects Lilly's current beliefs. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. There is no guarantee that the product will prove to be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's filings with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.

Source: Eli Lilly

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