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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: August 2004
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SYMBYAX
THE FIRST FDA-APPROVED
DRUG FOR THE TREATMENT
OF BIPOLAR DEPRESSION


Bernie Renner, Pharm.D. Candidate


Introduction
Bipolar disorder is a devastating disease
that has a severe impact on patients, their family
members, and society. The prevalence of bipolar
disorder is estimated at 1 to 2 percent of the adult
population.'2 However, the true prevalence is
thought to be much higher when misdiagnosis and
a broader spectrum of the disease is taken into ac-
count.'2'3 Bipolar disorder is the sixth leading
cause of disability in the world.4
The economic burden of bipolar disorder is
significant. It is estimated that the lifetime cost to
care for patients who developed bipolar disorder in
1998 was 24 billion dollars.1 In that study, the av-
erage lifetime cost per case ranged from $11,720
for people with a single manic episode to $624,785
for those with chronic episodes. Lost employment
and use of the criminal justice system contribute to
the economic and societal impact of bipolar dis-
ease.
Bipolar depression is the most difficult
phase of bipolar disorder to treat. It causes greater
morbidity and mortality than the manic phase.5 Ac-
cording to DSM-IV, bipolar depression is defined
as a major depressive episode in a person who has
had at least one manic episode (bipolar I), or a hy-
pomanic episode (bipolar II). In general, patients
spend far more time in the depressed phase than the


manic phase of the disease.3 As many as 15 per-
cent of people with bipolar disorder will commit
suicide.2'3'5 Patients are nearly 35 times more likely
to commit suicide during depressive episodes.5
Pharmacotherapy for bipolar depression is
different than pharmacotherapy for unipolar depres-
sion. Antidepressant medications are not recom-
mended as monotherapy in bipolar depression due
to the risk of precipitating an affective switch into
mania and increased mood-cycling.2'6'7 The cur-
rent American Psychiatric Association (APA)
guidelines, last revised in 2002, recommend using
lithium or lamotrigine (Lamictal) as first-line treat-
ment for bipolar depression.2 According to the
APA guideline, adding paroxetine (Paxil), sus-
tained-release bupropion (WellbutrinSR), or lamo-
trigine to a mood stabilizer may be considered in
patients that have breakthrough symptoms on opti-
mal doses of a mood stabilizing agent alone. In
contrast to unipolar depression, the recommenda-
tion is to discontinue the antidepressant upon symp-
tom relief. Long-term continuation of the antide-
pressant may induce rapid cycling. 2,5,6,7
Symbyax is a combination of the atypical
antipsychotic olanzapine (Zyprexa) and the antide-
pressant fluoxetine (Prozac). Symbyax
(olanzapine/fluoxetine) is the first medication


INSIDE THIS ISSUE:
SYMBYAX: THE FIRST FDA-APPROVED
DRUG FOR THE TREATMENT OF BIPOLAR
DEPRESSION
BRIEF UPDATE: NEW GUIDELINES FOR
MANAGING OF LYME DISEASE

,1-4


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-4- Placebo -- Olanzapine -A- Olanzapine/fluoxetine j


Figure 1. Mean change in Montgomery-Asberg Depression Rating Scale (MADRS) during 8-week study. Improvement in MADRS scores in the olanzapine and
olanzapine-fluoxetine combination groups was significantly greater than placebo at all time points (P<0.001). Improvement in MADRS scores in the olanzapine/
fluoxetine combination group was significantly greater than the olanzapine group at weeks 4 to 8 (P<0.02). 8


approved by the U.S. Food and Drug Administra-
tion for the treatment of bipolar depression. Olan-
zapine/fluoxetine is marketed by Eli Lilly and was
released in January 2004. This this article will dis-
cuss the efficacy, safety, and tolerability of olan-
zapine/fluoxetine.

Pharmacology and Pharmacokinetics
Like many psychotropic medications, the
exact mechanism of olanzapine/fluoxetine is not
known. Animal studies show that the combination
of olanzapine and fluoxetine produces synergistic
increases in norepinephrine and dopamine in the
prefrontal cortex compared to either agent alone.9
The combination also increases serotonin, but to a
lesser extent than fluoxetine alone. 9 It is hypothe-
sized that the action on these three monoaminergic
neuronal systems (norepinephrine, dopamine, and
serotonin) is responsible for the enhanced antide-
pressant effects of olanzapine/fluoxetine.10
Olanzapine is an antagonist at 5-HT2A/2C,
D1-4, muscarinic M15, histamine HI, and alphal re-
ceptors.10 Olanzapine has higher affinity for 5-HT2
receptors than dopamine D2 receptors. Because
olanzapine has lesser affinity for D2receptors than
older typical antipsychotics, such as haloperidol
(Haldol), it is associated with less extrapyramidal
side effects (EPS) and hyperprolactinemia than the
older agents. 10 Antagonism at muscarinic, hista-


mine, and alphal receptors may explain some of the
side effects of olanzapine, including anticholinergic
actions, somnolence, and orthostatic hypotension,
respectively. Olanzapine binds weakly to GABAA,
benzodiazepine and alpha-adrenergic receptors.10
Fluoxetine inhibits the reuptake of serotonin
by antagonizing the serotonin transporters of the
presynaptic neurons. Fluoxetine is also a weak in-
hibitor of norepinephrine and dopamine reuptake.10
Fluoxetine and olanzapine are well ab-
sorbed from the gastrointestinal (GI) tract. Food
does not affect the rate or extent of absorption of
olanzapine. Food may delay the absorption of
fluoxetine by 1 to 2 hours; however, it does not al-
ter the extent of absorption.10 Peak serum concen-
trations of olanzapine and fluoxetine occur at ap-
proximately 4 and 6 hours, respectively.10
Olanzapine has linear pharmacokinetics
over the therapeutic dosing range. The mean half-
life of olanzapine is 30 hours; once daily dosing
leads to steady-state concentrations in approxi-
mately 1 week. The half-life of olanzapine is 1.5
times longer in the elderly population. Olanzapine
is primarily metabolized by glucuronidation and
cytochrome P450 1A2 (CYP1A2). Cigarette smok-
ing induces the CYP1A2 enzyme and may decrease
serum concentrations of olanzapine. Metabolism
via CYP2D6 is a minor pathway of olanzapine.
Fluoxetine is a potent inhibitor of CYP2D6. Con-


PharmaNote Volume 19, Issue 11 August 2004


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Table 1. Change in Montgomery-Asberg Depression Rating Scale Score (MADRS) at 8 Weeks 8
Change in MADRS Score vs Placebo vs Olanzapine
Treatment Mean SE (95%CI) P Value P Value
Placebo -11.9 0.8 (-13.4 to -10.4) NA NA
Olanzapine -15.0 + 0.7 (-16.4 to -13.6) .002 NA
Olanzapine/fluoxetine -18.5 1.3 (-21.1 to -16.0) <.001 .01


sequently, there is a small decrease in olanzapine
clearance that does not appear to be clinically im-
portant. Fluoxetine and its active metabolite nor-
fluoxetine reach steady-state concentrations in 2 to
4 weeks. The half-life of fluoxetine is 2 to 3 days,
while the half-life of norfluoxetine is 7 to 9 days.10
Hepatic impairment can affect the elimination of
fluoxetine. For instance, in patients with cirrhosis
the half-life of fluoxetine and norfluoxetine are pro-
longed to 8 and 12 days, respectively. 10

Clinical Trials
Olanzapine and other atypical antipsychot-
ics have demonstrated efficacy in treating acute
mania."8' There is evidence to suggest that fluoxet-
ine's efficacy is augmented by concomitant treat-
ment with olanzapine.12 The efficacy of olanzap-
ine/fluoxetine in bipolar depression was demon-
strated in an eight-week, double-blind, parallel, ran-
domized controlled trial.8 Notably, there were no
statistically significant differences in treatment-
emergent mania among treatment and placebo
groups.
The clinical trial was designed to compare
the efficacy and safety of olanzapine monotherapy
to placebo in depressed bipolar I patients, but
olanzapine/fluoxetine was also tested in an explora-
tory analysis.8 Patients were randomized in a 4:4:1
allocation to receive olanzapine monotherapy 5 to
20mg/d (n=370); placebo (n=377); or olanzapine/
fluoxetine, 6 and 25, 6 and 50, or 12 and 50mg/d in
a flexible dosing schedule (n=86). All patients
were 18 years or older and met DSM-IV criteria for
diagnosis of bipolar I depression. Of the 833 pa-
tients, 13 percent were inpatients, 82.6 percent were
white, and 63 percent were female. The primary
outcome was the change in Montgomery-Asberg
Depression Rating Scale (MADRS) from baseline
to week 8. The MADRS is a 10-item clinician-


rated scale with total scores ranging from 0 to 60.13
All groups were moderately to severely depressed
at baseline, with mean MADRS scores of 31.3,
32.6, and 30.8 for the placebo, olanzapine, and
olanzapine/fluoxetine groups, respectively. Start-
ing at week 1 and continuing throughout the study,
the olanzapine monotherapy and olanzapine/
fluoxetine groups showed significantly greater
mean improvements in MADRS scores versus pla-
cebo (P<0.001) (Figure 1). Beginning at week 4
and continuing to week 8, olanzapine/fluoxetine
demonstrated significantly greater mean improve-
ment in total MADRS scores compared to olanzap-
ine monotherapy and placebo (P<0.02). Table 1
summarizes the mean improvement in total
MADRS scores at 8 weeks.

Safety/Monitoring
In the clinical trial there were no statisti-
cally significant differences in treatment-emergent
mania among the groups. (Table 2) Table 3 lists
the adverse events associated with olanzapine/
fluoxetine. The adverse event profile for olanzap-
ine/fluoxetine was similar to that for olanzapine
monotherapy; however, olanzapine/fluoxetine was
associated with significantly higher rates of nausea
and diarrhea compared to olanzapine alone (Table
3).
Olanzapine is associated with metabolic
side effects, including weight gain, hyperglycemia,
and dyslipidemia.15'16 In some cases, the hypergly-
cemia has resulted in ketoacidosis and death.10 All
patients taking atypical antipsychotics should be
monitored for hyperglycemia. People who already
have diabetes should be monitored more frequently.
Before beginning olanzapine/fluoxetine, clinicians
should collect baseline weight, lipids, and measures
of glucose control.
Olanzapine/fluoxetine may cause orthostatic


PharmaNote Volume 19, Issue 11 August 2004


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Volume 19, Issue 11 August 2004







hypotension, which can induce tachycardia, dizzi-
ness, and rarely syncope.10 For this reason, caution
should be used in patients with cardiovascular dis-
ease, cerebrovascular disease, and in patients pre-
disposed to hypotension. This is most likely to oc-
cur during initial dose-titration.
Olanzapine/fluoxetine should not be taken
with a monoamine oxidase inhibitor (MAOI) or
within 14 days of discontinuing a MAOI. An
MAOI should not be started for at least 5 weeks af-
ter discontinuing olanzapine/fluoxetine in order to
allow sufficient time for fluoxetine and its metabo-
lites to be eliminated.10

Dosing/Cost
Olanzapine/fluoxetine is taken once daily in
the evening to minimize the consequences of som-
nolence. Olanzapine/fluoxetine comes in capsules
containing 6 or 12 mg of olanzapine and 25 to 50
mg of fluoxetine (table 4). The starting dose of
olanzapine/fluoxetine is 6 mg/25 mg.10 Dose ad-
justments can be made based on efficacy and toler-
ability. The safety for doses above 18 mg/75 mg
has not been evaluated, nor has the efficacy of olan-
zapine/fluoxetine been proven after 8 weeks of
therapy. Therefore, 18 mg/75 mg is the maximum
recommended daily dose. No adjustments for renal
impairment are required. Dose adjustments for he-
patic impairment may be needed depending on the
severity of impairment, but there are no specific
recommendations available.10 Olanzapine/
fluoxetine has not been evaluated in children < 18
years old or in the elderly > 65 years of age.
Unlike unipolar depression, there are no guidelines
for how long depressive episodes should be treated
with antidepressant medications in patients with bi-
polar disorder.
Olanzapine/fluoxetine is not more expen-
sive than taking olanzapine and fluoxetine sepa-
rately (Table 4).14 Taking the two drugs separately
would allow greater flexibility in dose titration.
However, for some patients, taking one pill may be
convenient and foster improved adherence.


Table 2. Treatment-Emergent Mania 8

Placebo Olanzapine Olanzapine/fluoxetine

6.7% (23/345) 5.7% (19/335) 6.4% (5/78)


Table 3. Most Common Treatment-Emergent Adverse
Events For Olanzapine/fluoxetine Combination (OFC)8


Adverse Event
Somnolence
Diahrrhea
Weight gain
Dry mouth
Headache
Increased appetite
Asthenia
Nausea
Nervousness
Insomnia


OLZ (%)
28.1
6.5
17.3
11.1
12.4
13.5
9.7
4.3
10.5
8.4


OFC (%)
20.9
18.6
17.4
16.3
14.0
12.8
12.8
11.6
9.3
9.3


Placebo (%)
12.5
6.6
2.7
6.1
18.6
5.0
3.2
8.8
8.0
15.1


Summary
The depressive phase of bipolar disorder is
difficult to treat and associated with higher morbid-
ity and mortality than the manic phase of the dis-
ease. Olanzapine/fluoxetine is the first FDA-
approved medication indicated for depressive epi-
sodes in people with bipolar disorder.10 One ran-
domized controlled trial demonstrated that olanzap-
ine/fluoxetine significantly reduced depressive
symptoms over 8 weeks as measured by MADRS.
The efficacy of olanzapine/fluoxetine treatment
longer than 8 weeks has not been evaluated. There
are no guidelines for how long depressive episodes
should be treated with antidepressant medications
in patients with bipolar disorder. Olanzapine/
fluoxetine is not more expensive than taking olan-
zapine and fluoxetine separately and may be less
expensive. Common side effects include somno-
lence, diarrhea, orthostatic hypotension, weight
gain, and dry mouth. There is concern that using
the fixed doses of olanzapine/fluoxetine may lead
to overuse of olanzapine. In addition to weight
gain, olanzapine has been associated with dyslipi-
demia and diabetes. Practitioners should be cogni-
zant of these adverse effects and closely monitor
weight, lipids, blood glucose, and HbA1C. It is
likely that different atypical antipsychotic and anti-
depressant combinations will be investigated for the
treatment of bipolar disorder in the future.

References

1. Stimmel GL. Economic grand rounds: the economic bur-
den of bipolar disorder. Psychiatr Serv 2004;55:117-8.
2. American Psychiatric Association. Practice guideline for
the treatment of patients with bipolar disorder (revision).
Am J Psychiatry 2002; 159 Suppl 4:1-50.


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Table 4. Retail Price
Cost*
Drug Strength
Avg Range
6 mg/25 mg $265.82 $242.88 $293.99
Symbyax 6 mg/50 mg $265.82 $242.88 $293.99
(Olanzapine/fluoxetine) 12mg/25mg $396.68 $362.46 $446.69
12 mg/50 mg $396.68 $362.46 $446.69
7.5 mg $254.15 $239.68 $273.79
Zyprexa 20 mg $38.05 $38.68 $42.99
+ Fluoxetine (average generic) Total: $292.20 $278.36 $312.47

15 mg $473.02 $448.88 $515.30
Zyprexa" 40 mg $79.79 $67.58 $93.99
+ Fluoxetine (average generic) Total: $552.81 $516.46 $609.29

*Cost for a 30-day supply at three community pharmacies and one online.


3. Silverstone PH, Silverstone T. A review of acute treat-
ments for bipolar depression. Int Clin Psychopharmacol
2004;19:113-24.
4. Bowden CL. Strategies to reduce misdiagnosis of bipo-
lar depression. Psychiatr Serv 2001;52:51-5.
5. Baldassano CF. What drugs are best for bipolar depres-
sion? Ann Clin Psychiatry 2003;15:225-32.
6. Ghaemi SN, Hsu DJ Soldani F et al. Antidepressants in
bipolar disorder: the case for caution. Bipolar Disord
2003;5:421-433.
7. El-Mallakh RS, Karrippot A. Use of antidepressants to
treat depression in bipolar disorder. Psychiatr Serv
2002;53:580-4.
8. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olan-
zapine and olanzapine-fluoxetine combination in the
treatment of bipolar I depression. Arch Gen Psychiatry
2003;60:1079-88.
9. Koch S, Perry KW, Bymaster FP. Brain region and dose
effects of an olanzapine/fluoxetine combination on ex-
tracellular monoamine concentrations in the rat. Neuro-
pharmacology 2004;46:232-42.
10. Symbyax [Package insert]. Indianapolis, IN; Eli Lilly
and Company; 2004.
11. Masand PS, Wang X, Gupta S, et al. Comparison of
Risperidone and Olanzapine in Bipolar and Schizoaffec-
tive Disorders. Prim Care Companion J Clin Psychiatry
2002;4:70-73.
12. Corya SA, Andersen SW, Detke HC, et al. Long-term
antidepressant efficacy and safety of olanzapine/
fluoxetine combination: a 76-week open-label study. J
Clin Psychiatry 2003;64:1349-56.
13. Muller MJ, Himmerich H, Kienzle B, et al. Differentiat-
ing moderate and severe depression using the Montgom-
ery-Asberg depression rating scale (MADRS). J Affect
Disord 2003;77:255-60.
14. Olanzapine/Fluoxetine (Symbyax) for Bipolar Depres-
sion. Med Lett Drugs Ther 2004;15;46:23-24.
15. Jin H, Meyer JM, Jeste DV. Phenomenology of and risk
factors for new-onset diabetes mellitus and diabetic keto-
acidosis associated with atypical antipsychotics: an


analysis of 45 published cases. Ann Clin Psychiatry
2002;14:59-64.
16. Torrey EF, Swalwell CI. Fatal olanzapine-induced keto
acidosis. Am J Psychiatry 2003;160:2241.





New Drugs and Dosage Forms

Gabapentin tablets (Neurontin) will
now be formulated with a "functional
score" in the 600 and 800 mg strength.
Tablets that have been split must be
administered within "several" days.
Metformin hydrochloride extended
release (Fortamet), now available in
500 and 1000 mg tablets, incorporates
single-composition osmotic technology
(SCOT). It is indicated as monotherapy
or combination therapy with a
sulfonylurea or insulin, in addition to diet
and exercise. The recommended starting
dose is 1000 mg daily as a single dose
with the evening meal. The dose can be
titrated in 500 mg increments to the
maximum of 2500 mg/d.
Rifaximin tablets (XifaxanTM), a
rifampin analogue, is indicated for the
treatment of patients age 12 years or
older with traveler's diarrhea due to
noninvasive strains of Escherichia coli;
rifaximin is essentially unabsorbed.


PharmaNote Volume 19, Issue 11 August 2004


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Volume 19, Issue 11 August 2004










UPDATE:
LYME DISEASE



Benjamin J. Epstein, Pharm.D.
Associate Editor


We reviewed the treatment and prevention
of Lyme disease in January of 2003.1 The review
was based upon guidelines endorsed by the Infec-
tious Disease Society of America (IDSA).2 Subse-
quently, the International Lyme and Associated
Disease Society (ILADS) developed a working
party to evaluate current practices and establish
new standards of care for patients with Lyme dis-
ease. In November of 2003, ILADS released
guidelines for the management of Lyme disease.3
There is some inconsistency between the two sets
of guidelines that merit mention. The purpose of
this report is to alert readers to the existence of the
ILADS guidelines and succinctly contrast them
with those from IDSA.
ILADS classifies "chronic Lyme disease" as
persistent fatigue, cognitive dysfunction, head-
aches, sleep disturbance, neuropsychiatric presenta-
tions, cardiac presentations, or musculoskeletal
problems. ILADS recognizes and defines chronic
Lyme disease whereas IDSA attributes persistent
symptomatology to an immune mediated response.
ILADS places less emphasis on the specific
antibiotic chosen, recognizing amoxicillin, azithro-
mycin, cefuroxime, clarithromycin, doxycycline, or
tetracycline as acceptable oral therapies. Likewise,
ceftriaxone, cefotaxime, penicillin, imipenem,
azithromycin, and doxycyline are all credited with
antispirochetal activity and identified as appropriate
intravenous therapies. In contrast, IDSA is more
specific in its recommendations regarding antibiotic
therapy.2
ILADS endorses a broader application of
antibiotics, including longer courses of therapy,
compared to IDSA. ILADS acknowledges that
some of their recommendations are predicated upon


expert opinion (when controlled trials are not avail-
able).
Both IDSA and ILADS recognize the im-
portance of Lyme disease and a disturbing increase
in the number of cases annually. The lack of a con-
sensus opinion is a testament to the need for further
research. Until such time, optimal management of
Lyme disease will remain a goal for all practitio-
ners.

References
1. Trask A. Lyme disease: treatment and prevention.
PhamaNote 2003;18:1-8.
2. Wormser GP, Nadelman RB, Dattwyler RJ, Dennis DT,
Shapiro ED, Steere AC, Rush TJ, Rahn DW, Coyle PK,
Persing DH, Fish D, Luft BJ. Practice guidelines for the
treatment of Lyme disease. The Infectious Diseases Soci-
ety of America. Clin Infect Dis 2000;31 Suppl 1:1-14.
3. Evidence-based guidelines for the management of Lyme
disease. The International Lyme and Associated Disease
Society. Expert Rev Anti-infect Ther 2004;2 Suppl: S1-
S13.




FDA-approved labeling changes

SWarfarin was added as a Precaution in
the labeling for pantoprazole sodium
(Protonix) to alert providers to the need
for more vigilant monitoring.





The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor
Pharm.D.

9 www wwwy~~wy~y^ -0 1


~
PharmaNote Volume 19, Issue 11 August 2004


PharmaNote


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