New Study Suggests Symbyax(R) Significantly Improves Symptoms of Treatment-Resistant Depression
24 May 2006 - 6:00AM
PR Newswire (US)
INDIANAPOLIS, May 23 /PRNewswire-FirstCall/ -- The results of a
pooled analysis of two new parallel, randomized, double-blind
studies suggest that Symbyax(R) (olanzapine and fluoxetine HCl
capsules) significantly improved symptoms of treatment-resistant
depression (TRD) when compared to either drug alone during a
two-month period, based on the Montgomery-Asberg Depression Rating
Scale (MADRS). Study results were presented today at a major
medical meeting. "Treatment-resistant depression is one of the
greatest clinical challenges that psychiatrists face today, which
is compounded by the fact that there is no FDA-approved medication
for this illness," said Michael E. Thase, M.D., professor of
psychiatry at the University of Pittsburgh Medical Center and the
Western Psychiatric Institute and Clinic. "This is a rigorously
designed study conducted in TRD patients who have not responded to
two previous, adequately dosed antidepressants. TRD is a condition
in which some people with major depressive disorder (MDD) fail to
sustain or achieve remission despite adequate antidepressant
therapy. Adequate antidepressant therapy is defined as receiving an
appropriate medication, at the proper dosage, for a suitable length
of time.(i) Conservative estimates indicate that between 10 percent
and 20 percent of MDD patients continue experiencing symptoms
despite multiple treatments.(ii) The lack of effective medications
for TRD can also lead to significant costs for the patient and
their employers. Studies have shown that TRD led to substantial
indirect costs to employers resulting from high rates of
depression-associated disability.(iii) Study Design (two
identically designed trials) Lead-in Period: * 1,313 patients
between 18 and 65 years of age who met DSM-IV criteria for
recurrent major MDD without psychotic features were enrolled into
an eight-week, open-label Prozac lead-in period. * Patients could
only be enrolled if they did not respond to an antidepressant
(except Prozac) after at least six weeks of therapy at an adequate
dosage during the current MDD episode. * 605 patients did not
respond to Prozac therapy. Studies 1 and 2: * 605 non-responders
were randomized in these two eight-week, double- blind studies
(Studies 1 and 2) and were assigned 1:1 to Symbyax (olanzapine 6,
12, or 18 mg/day plus fluoxetine 50 mg/day), Zyprexa alone (6, 12,
or 18 mg/day), or Prozac alone (50mg/day). There were approximately
300 patients in each of the two studies. * Mean modal doses
(mg/day) for the double-blind studies were 8.6 and 48.8 for Symbyax
(olanzapine and fluoxetine, respectively), 8.7 for Zyprexa alone,
and 49.5 for Prozac alone. * Of the 605 randomized patients, 441
patients (72.9 percent) completed the studies. * A pooled analysis
of both double-blind studies was conducted at the end of the
eight-week trial period. * TRD was defined as current episode
antidepressant failure and prospective Prozac failure. * Upward
dose titrations were required at two-week intervals if no
tolerability or safety issues were identified. * The primary
efficacy measure was improvement from baseline to endpoint on the
MADRS. Key Findings Study 1: * While all three treatment arms
demonstrated improvements from baseline, this double-blind study
showed no statistically significant differences in MADRS
improvement among the three treatment arms (Symbyax: -10.8; Prozac:
-9.4; Zyprexa: -10.1). Study 2: * This parallel double-blind study
showed that patients taking Symbyax had average scores of -14.6 on
the MADRS compared to Prozac (-9.0, p < 0.001) and Zyprexa
(-7.7, p < 0.001) alone. * Forty-four percent of the Symbyax
patients responded to therapy, as opposed to 30 percent of Prozac
patients and 17 percent of Zyprexa patients. Pooled Analysis: *
Pooled results of both double-blind studies (Studies 1 and 2)
showed significantly greater MADRS improvement for Symbyax (-12.6)
versus Prozac (-9.2, p < .001) and Zyprexa (-8.9, p < .001)
alone. * Forty percent of Symbyax patients responded to therapy, as
opposed to 30 percent of Prozac patients and 26 percent of Zyprexa
patients. * Within three to four days, Symbyax patients began to
show significantly greater symptom improvement when compared to
Prozac patients. At seven days, Symbyax also showed significantly
greater symptom improvement when compared to Zyprexa. * Adverse
events in 10 percent or more of Symbyax patients were weight gain,
increased appetite, dry mouth, somnolence, fatigue, headache,
peripheral edema, hypersomnia, and tremor. * Over the course of the
study, the following changes occurred from baseline: -- Mean weight
change (kg) was +4.9 for Symbyax, +0.4 for Prozac, and +5.5 for
Zyprexa (p < 0.001). -- Cholesterol mean change (mg/dL) was
+15.1 for Symbyax, +0.8 for Prozac, and +2.7 for Zyprexa (p <
0.001). -- Triglyceride mean change (mg/dL) was +39.8 for Symbyax,
+15.9 for Prozac, and +51.3 for Zyprexa (p=0.040). 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 http://www.symbyax.com/. 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 http://www.lilly.com/.
P-LLY This press release contains forward-looking statements about
the potential of Symbyax for the treatment of treatment-resistant
depression 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. (i) Rush, AJ, Crismon, ML,
Toprac MG, et al. Consensus Guidelines in the Treatment of Major
Depressive Disorder. J. Clin Psychiatry 1998; 59 (suppl. 20):
73-84. (ii) Souery D., et al. Treatment-resistant depression:
methodological overview and operational criteria. Eur
Neuropsychopharmacol. 1999;9: 83-91. (iii) Corey-Lisle, P. et al.
Identification of a Claims Data "Signature" and Economic
Consequences for Treatment-Resistant Depression. J Clin Psychiatry
2002; 63: 717-726. (Logo:
http://www.newscom.com/cgi-bin/prnh/20031219/LLYLOGO )
http://www.newscom.com/cgi-bin/prnh/20031219/LLYLOGO DATASOURCE:
Eli Lilly and Company CONTACT: Carole Copeland of Eli Lilly and
Company, cell: +1-317-610-6196; or Jaime Geiger, cell:
+1-646-319-6459, for Eli Lilly and Company
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