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First Head-to-Head Study Suggests Significantly Greater Symptom Improvement for Olanzapine and Fluoxetine Combination Capsules Compared to Lamotrigine in Bipolar Depression

INDIANAPOLIS, I.N. -- May 30, 2006 -- Long-term data from the first head-to-head comparative study suggests that patients with bipolar depression taking Symbyax® (olanzapine and fluoxetine HCl capsules) experienced significant improvement compared to lamotrigine 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 at the American Psychiatric Association annual 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
Symbyaxshould 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 Symbyaxbefore starting an MAOI. Thioridazine should not be given with Symbyaxor within at least 5 weeks after stopping SYMBYAX. Concomitant use of Symbyaxin 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 -- Symbyaxmay 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 Symbyaxwas 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 Symbyaxin placebo-controlled clinical trials was somnolence. Other common events were weight gain, increased appetite, asthenia, peripheral edema, tremor, pharyngitis, abnormal thinking, and edema.


SOURCE: Eli Lilly and Company

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