Symbyax Shown to Reduce Symptoms Associated With
Suicidal Thinking in Patients With Bipolar Depression
Those with Early-Onset of Bipolar Disorder Also Shown More Likely to
Respond to Symbyax Treatment
May 05, 2004 -- New data show that
Symbyax™ (olanzapine and
fluoxetine HCl) reduced the symptoms associated with suicidal ideation (having
thoughts of suicide), a predictor of suicidal behavior, in
bipolar depressed patients within the first week of treatment. Another study
demonstrated that having an early onset of bipolar disorder tripled the
likelihood that a patient might respond to Symbyax. These findings were
presented today at the annual meeting of the American Psychiatric Association.
Symbyax is the first and only FDA-approved treatment for the depressive phase
of bipolar disorder.
"These data provide hope to patients whose lives are disrupted by bipolar
depression, a devastating and difficult condition to treat that often results in
suicide or suicide attempts," said Terence A. Ketter, M.D., associate professor
of psychiatry and behavioral sciences, and chief, Bipolar Disorders Clinic,
Stanford University School of Medicine. "The rapid reduction of symptoms
associated with suicidal ideation suggests the potential benefit of Symbyax
among bipolar depressed patients, who are at high risk of taking their own
lives."
Key Findings
Suicidal Ideation Study
An eight-week analysis of 688 people that compared Symbyax (n=73), olanzapine
(n=299) and placebo (n=316) in the treatment of bipolar I depression showed:
- Suicidal ideation, as measured by the Montgomery-Asberg Depression
Rating Scale item 10 (MADRS-10), was significantly reduced in bipolar
depressed patients by the first week of Symbyax treatment compared to
patients receiving placebo or olanzapine.
- Symbyax significantly improved the symptoms of apparent sadness,
reported sadness, pessimistic thoughts, and inner tension - four MADRS items
correlated to suicidal ideation - within one week compared to placebo.
Olanzapine is not indicated for bipolar depression.
Predictors of Response Study
In addition, a statistical analysis performed on acute phase data from a
double-blind, randomized clinical trial comparing Symbyax (n=86), olanzapine
(n=370) and placebo (n=377) in patients with bipolar depression found:
- Having an early onset of bipolar disorder (prior to age 20) tripled the
odds of response to Symbyax among patients with bipolar depression. Response
was defined as a greater than 50 percent decrease in Montgomery-Asberg
Depression Rating Scale (MADRS) total score.
- Early onset was the only independent variable evaluated that was
significant for predicting response to Symbyax among patients with bipolar
depression.
"Since bipolar disorder often emerges in late adolescence or early adulthood,
the high rates of response among bipolar depressed patients who had early onset
suggests that Symbyax may work well in this large, well-defined population,"
said Robert W. Baker, M.D., associate medical director, USMD Neurosciences, Eli
Lilly and Company.
About Bipolar Disorder
Bipolar disorder typically emerges in adolescence or young adulthood, and
episodes continue intermittently throughout life, often disrupting work, school,
family, and social life.
Patients with the disease have a higher risk of committing suicide than those
with other psychiatric or medical disorders, and without effective treatment,
bipolar disorder can lead to suicide in nearly 20 percent of cases. The relative
risk of suicide among patients with bipolar depression has been shown to be
nearly 35 times greater than among patients in the manic phase of bipolar
disorder.
Bipolar disorder, also known as
manic-depressive illness, affects an individual's mood, behavior, and
thinking. Unlike many illnesses, symptoms may be quite different at various
phases of the illness. Treatment is challenging because some therapies that are
effective for one phase of the illness may be counterproductive for another. For
example, antidepressant treatments can precipitate manic episodes.
Bipolar disorder is a complex mental illness characterized by debilitating
mood swings ranging from episodes of deep depression (feelings of extreme guilt,
sadness, anxiety and, at times, suicidal thoughts) to episodes of mania
(abnormal euphoria, elation and irritability), interspersed with periods of
normal mood. Patients with bipolar disorder spend more than three times longer
in the depressive phase than in the manic phase of the disorder and take longer
to recover from it.
More than 2.5 million Americans live with a diagnosis of bipolar disorder but
recent research indicates the real number may be as high as 10 million. The
results of untreated bipolar disorder can be catastrophic. According to the
National Institute of Mental Health, nearly one in every five people with
the illness commits suicide. The World Health Organization estimates that
bipolar disorder is the sixth leading cause of disability in the world.
Important Information About Symbyax
The most common treatment-emergent adverse event associated with Symbyax (vs.
placebo) in clinical trials was somnolence (22 vs. 11%). Other common events
were: weight gain (21 vs. 3%), increased appetite (16 vs. 4%), asthenia (15 vs.
3%), peripheral edema (8 vs. 1%), tremor (8 vs. 3%), pharyngitis (6 vs. 3%),
abnormal thinking (6 vs. 3%) and edema (5 vs. 0%).
Contraindications - Symbyax should not be used with an MAOI or within
at least 14 days of discontinuing an MAOI. At least five weeks should be allowed
after stopping Symbyax before starting an MAOI. Thioridazine should not be given
with Symbyax or within at least five weeks after stopping Symbyax. Symbyax is
contraindicated in patients with known hypersensitivity to the product or any
component of the product.
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.
Cerebrovascular adverse events (CVAE), including stroke, in elderly
patients with dementia - Cerebrovascular adverse events (e.g., 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.
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 (4.6%, 26/571 vs. 5.2%, 25/477). 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.
Concomitant use - Caution should be used when prescribing medications
that contain olanzapine
or fluoxetine HCl with
Symbyax.
Abnormal bleeding - Patients should be cautioned regarding the risk of
bleeding associated with the concomitant use of Symbyax with NSAIDs, aspirin, or
other drugs that affect coagulation.
Mania/hypomania - Because of the cyclical nature of bipolar disorder,
patients should be monitored closely for the development of symptoms of
mania/hypomania during treatment with Symbyax.
Prolactin and serum sodium - As with other drugs that antagonize
dopamine receptors, Symbyax elevates prolactin levels, and a modest elevation
persists during administration; however, possibly associated clinical
manifestations were infrequently observed. Hyponatremia has been observed in
premarketing studies of Symbyax, but the incidence of serum sodium levels
occurring below the reference range was statistically insignificant compared
with placebo (2%, 10/500 vs. 0.5%, 2/380); none of these patients had a
treatment-emergent level less than 130 mmol/L.
Transient, asymptomatic elevations of hepatic transaminase - In
premarketing trials, statistically significant ALT (SGPT) elevations (>3 times
the upper limit of the normal range) were observed in 6.3% (31/495) of patients
exposed to Symbyax compared with 0.5% (2/384) of the placebo patients and 4.5%
(25/560) of olanzapine-treated patients. None of these patients developed
jaundice. Periodic assessment of transaminases is recommended in patients with
significant hepatic disease.
Weight gain - In clinical studies, the mean weight gain for
Symbyax-treated patients was statistically significantly greater than
placebo-treated (3.6 kg vs. -0.3 kg) and fluoxetine-treated (3.6 kg vs. -0.7 kg)
patients but was not statistically significantly different from olanzapine-treated
patients (3.6 kg vs. 3.0 kg). Fourteen percent of Symbyax-treated patients met
criterion for having gained >10% of their baseline weight.
Special populations and elderly - Dysphagia was observed infrequently
in premarketing studies, but as with other psychotropic drugs, Symbyax should be
used cautiously in patients at risk for aspiration pneumonia. Esophageal
dysmotility and aspiration have been associated with antipsychotic drug use. In
2 clinical studies in patients with Alzheimer’s disease, two olanzapine-treated
patients died from aspiration pneumonia, with one of these patients experiencing
dysphagia. As with other CNS-active drugs, Symbyax should be used with caution
in elderly patients with dementia. The lowest starting dose should be considered
in patients with hepatic impairment.
As with all medications that contain an antipsychotic, the following
considerations should be taken into account when prescribing Symbyax:
Neuroleptic malignant syndrome (NMS) - as with all antipsychotic medications,
a rare condition known as NMS has been reported with olanzapine. If signs and
symptoms appear, immediate discontinuation is recommended.
Tardive dyskinesia (TD) - as with all antipsychotic medications, prescribing
should be consistent with the need to minimize the risk of TD. If its signs and
symptoms appear, discontinuation should be considered.
Seizures - occurred infrequently in premarketing clinical trials (4/2066,
0.2%). Confounding factors may have contributed to many of these occurrences.
Symbyax should be used cautiously in patients with a history of seizures or with
conditions that lower the seizure threshold. Such conditions may be more
prevalent in patients age 65 years or older.
Source: Eli Lilly Press Release
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