Drugs 2004; 64 (23): 2709-2726

ADIS DRUG EVALUATION 0012-6667/04/0023-2709/$34.00/0

© 2004 Adis Data Information BV. All rights reserved.

Olanzapine
A Review of its Use in the Management of Bipolar
I Disorder
Paul L. McCormack and Lynda R. Wiseman
Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:

C.L. Bowden, Department of Psychiatry, University of Texas Health Sciences Center at San Antonio, San
Antonio, Texas, USA; P.F. Brambilla, Department of Pathology and Experimental and Clinical Medicine,
Section of Psychiatry, University of Udine, Udine, Italy; H. Grunze, Department of Psychiatry,
Ludwig-Maximilians-University, Munich, Germany; S. Kasper, Department of General Psychiatry,
University of Vienna, Vienna, Austria; K. Melkersson, Psychiatric Polyclinic, Sollentuna Hospital, Stockholm,
Sweden; E. Richelson, Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, Florida, USA;
R.C. Shelton, Department of Psychiatry, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Data Selection
Sources: Medical literature published in any language since 1980 on olanzapine, identified using Medline and EMBASE, supplemented by
AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles.
Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘olanzapine’ and (‘bipolar disorder’ or ‘mania’ or ‘manic’). EMBASE search terms were
‘olanzapine’ and (‘bipolar’ or ‘manic’ or ‘mania’). AdisBase search terms were ‘olanzapine’ or (‘bipolar-disorder’ or ‘mania’ or ‘manic’).
Searches were last updated 6 October 2004.
Selection: Studies in patients with mania associated with bipolar I disorder who received olanzapine. Inclusion of studies was based mainly
on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred.
Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Olanzapine, bipolar disorder, manic episodes, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2710
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2711
2. Overview of Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2712
3. Overview of Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2713
3.1 Potential Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2714
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2714
4.1 Acute Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2715
4.1.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2715
4.1.2 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2717
4.2 Maintenance Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2717
5. Health-Related Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2719
6. Pharmacoeconomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2720
7. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2721
2710 McCormack & Wiseman

8. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2722

9. Place of Olanzapine in the Management of Bipolar I Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2722

Summary
Abstract Olanzapine is an atypical antipsychotic that is approved in the US and Europe for
the oral treatment of acute manic episodes in patients with bipolar I disorder, and
for maintenance therapy to prevent recurrence in responders.
Oral olanzapine is effective in the treatment of bipolar mania, both as single
agent therapy and as adjunctive therapy in combination with lithium or valproate
semisodium. In the treatment of acute episodes, olanzapine is superior to placebo
and at least as effective as lithium, valproate semisodium, haloperidol and
risperidone in reducing the symptoms of mania and inducing remission. Addition-
al comparative studies are required to determine the efficacy of olanzapine
relative to newer atypical antipsychotics, such as quetiapine, ziprasidone and
aripiprazole. Olanzapine is also effective at delaying or preventing relapse during
long-term maintenance therapy in treatment responders, and is currently the only
atypical antipsychotic approved for this indication. Current evidence suggests that
olanzapine may be more effective than lithium in preventing relapse into mania,
but not relapse into depression or relapse overall. Olanzapine is generally well
tolerated, and although it is associated with a higher incidence of weight gain than
most atypical agents, it has a low incidence of extrapyramidal symptoms (EPS).
Therefore, oral olanzapine is a useful first-line or adjunctive agent for both the
acute treatment of manic episodes and the long-term prevention of relapse into
manic, depressive or mixed episodes associated with bipolar I disorder.

Pharmacological Olanzapine is believed to exert its antimanic and antipsychotic effects predomin-
Properties antly by binding to and blocking dopamine D2 and serotonin (5-hydroxy-
tryptamine) 5-HT2A receptors. Long-term administration of olanzapine
selectively blocks dopaminergic neurons in the mesolimbic (A10) pathway, but
not in the nigrostriatal (A9) pathway, which may account for the lower incidence
of EPS than is seen with conventional antipsychotic agents. Olanzapine binds with
high or moderate affinity to 5-HT2A–C,3,6,7, D1–5, muscarinic M1–5, histamine H1,
and α1- and α2-adrenergic receptors, giving rise to many of the recognised clinical
and adverse effects of the drug.
Olanzapine displays linear pharmacokinetics across the dose range 0.5–30mg,
with steady-state peak plasma levels of 20 μg/L attained after orally administering
10mg once daily for 8 days. The drug is widely distributed in the body. Olanza-
pine is rapidly and extensively metabolised by cytochrome P450 (CYP) 1A2,
CYP2D6 and the flavin mono-oxygenase-3 system, and is excreted mainly in the
urine, with an elimination half-life of approximately 33 hours. The clearance of
olanzapine is moderately reduced by inhibitors of CYP1A2 (fluvoxamine) and
CYP2D6 (fluoxetine), and increased by potent inducers of CYP1A2 (carbamaze-
pine, smoking).

© 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (23)
Olanzapine: A Review 2711

Therapeutic Efficacy In randomised, double-blind trials, olanzapine was superior to placebo and was at
least as effective as lithium, valproate semisodium, haloperidol or risperidone in
the treatment of acute mania associated with bipolar I disorder. Olanzapine was
also superior to placebo in treating acute bipolar mania when added to existing
therapy with lithium or valproate semisodium.
During maintenance therapy over 12 months in responders, olanzapine was
superior to placebo in delaying relapse and reducing the rate of relapse into an
affective episode. Olanzapine was also superior to lithium in preventing relapse
into mania, but not in preventing relapse into a depressive episode or for relapse
overall. Olanzapine was not different from valproate semisodium with respect to
time to relapse or rate of relapse.
Health-Related Quality Olanzapine improved the health-related quality of life (HR-QOL) of patients with
of Life and bipolar disorder relative to either baseline or placebo during both acute and
Pharmacoeconomic maintenance therapy. Improvements in patients’ HR-QOL produced by olanza-
Considerations pine were significantly greater than those with haloperidol and equal to or greater
than those with valproate semisodium.
Limited pharmacoeconomic data suggest that the cost effectiveness of olanza-
pine is largely similar to that of risperidone, lithium or valproate semisodium.
Tolerability Olanzapine was generally well tolerated during both acute and long-term mainten-
ance therapy. The adverse events with a significantly higher incidence with
olanzapine than with placebo were somnolence, dry mouth, dizziness and
bodyweight gain during acute therapy, and bodyweight gain, fatigue and akathisia
during maintenance therapy. The incidence of EPS with olanzapine was low and
similar to that with placebo, lithium or valproate semisodium, but was significant-
ly less than that with haloperidol. The overall incidence of adverse events, and
bodyweight gain in particular, was higher with olanzapine than all comparators in
clinical trials.

1. Introduction Approximately 15% of patients with bipolar disor-

Bipolar I disorder (bipolar affective disorder;
manic depression) can have a highly variable
course.[1-3] Patients may experience erratic cycles of
severe mania and depression or mixed episodes of
simultaneous mania and depression. Psychotic fea-
tures may or may not be present during affective
episodes. Some patients may experience a rapid-
cycling course with four or more affective episodes
per year, while others may experience extended
periods of stabilisation or remission. Bipolar I disor-
der has an estimated worldwide lifetime prevalence
of 0.4–1.6%, with a higher incidence in first degree
relatives of affected patients.[1,2] Bipolar I disorder is
associated with significant socioeconomic costs.[3]
der commit suicide.[2] Manic episodes decrease the
quality of life of patients, reduce their occupational
productivity and often result in patient hospitalisa-
tion.[2,3]
Manic episodes associated with bipolar I disorder
are commonly treated with lithium carbonate, val-
proate semisodium (divalproex sodium), carbama-
zepine or antipsychotics, with the addition of other
agents, such as gabapentin or topiramate, for residu-
al symptoms.[4,5] The term ‘mood stabiliser’ is com-
monly used to refer to lithium or valproate semi-
sodium (and sometimes other agents such as olanza-
pine, carbamazepine and lamotrigine), although
purists consider that only lithium fulfils the more

© 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (23)
2712
rigorous definition of proven antimanic, antidepres-
sant and prophylactic activity.[6]
The utility of conventional (typical) antipsychot-
ics, such as haloperidol, in bipolar mania is limited
by adverse effects, especially extrapyramidal symp-
toms (EPS) consisting of acute dystonia, akathisia
and parkinsonism, plus late-appearing tardive dys-
kinesia. Newer, ‘atypical’ antipsychotics are now
more often preferred, since they have a reduced
incidence of acute EPS and tardive dyskinesia and
most also produce less elevation of serum prolactin
levels.[7,8]
Olanzapine (Zyprexa®)1, a thienobenzodiazepine
derivative, is an atypical antipsychotic with proven
efficacy in the oral treatment of schizophrenia and
bipolar I disorder.[2] An intramuscular formulation is
available for the treatment of acute agitation asso-
ciated with either disorder.[9,10] This review focuses
on the use of oral olanzapine to treat mania asso-
ciated with bipolar I disorder, including both the
acute treatment of manic or mixed episodes and
long-term maintenance therapy to prevent recur-
rence in responders, a new indication for which
olanzapine was approved recently in both the US
and Europe.[11,12]
2. Overview of
Pharmacodynamic Properties
The pathophysiology of bipolar I disorder is not
well understood; hence, the mechanism of action of
olanzapine in this indication (and in schizophrenia
as well) is not fully known. Nevertheless, it is gener-
ally thought that antagonism of central neurotrans-
mitters by binding to their receptors, predominantly
dopamine D2 and serotonin (5-hydroxytryptamine)
5-HT2A receptors, is responsible for the therapeutic
actions of olanzapine and other atypical antipsy-
chotics.[2,13,14]
The neurotransmitter receptor binding properties
of olanzapine are well established and this section,
therefore, provides only a brief summary based on
1 The use of trade names is for product identification purposes only and does not imply endorsement.
© 2004 Adis Data Information BV. All rights reserved.
McCormack & Wiseman
information reviewed in detail elsewhere.[2,13,14]
Olanzapine binds to a broad range of neurotransmit-
ter receptors, with a receptor affinity profile similar
to that of clozapine, the prototype atypical anti-
psychotic agent. Olanzapine binds with high affinity
to 5-HT2A–C, 5-HT6, D2–4, histamine H1 and α1-ad-
renergic receptors, and with moderate affinity to
muscarinic M1–5, 5-HT3,7, D1,5 and α2-adrenergic
receptors. Olanzapine has approximately 2-fold
higher affinity for 5-HT2A receptors than for D2
receptors. It has been proposed that the atypical
properties of newer antipsychotics, rather than being
related to interaction with multiple receptor types,
derive principally from low D2 receptor occupancy
(<80%) as a result of low affinity for and fast
dissociation from D2 receptors.[15,16] D2 receptor
occupancy appears to increase with dose, suggesting
that at higher doses (>20 mg/day) olanzapine may
lose some of its atypical benefits and show a higher
incidence of EPS and greater prolactin elevation.[16]
During long-term administration, olanzapine de-
creases the number of spontaneously active dopa-
minergic neurons in the mesolimbic (A10) pathway,
but not in the nigrostriatal (A9) pathway.[17] This
selective effect on A10 neurons may be predictive of
atypical antipsychotic activity and a low propensity
to cause EPS, since the blockade of dopaminergic
receptors in the A9 region has been hypothesised to
be the cause of EPS with antipsychotic agents.[18]
Antagonism at muscarinic receptors by atypical
antipsychotics is thought to be responsible for ad-
verse effects such as dry mouth, constipation,
blurred vision and urinary retention, while ant-
agonism at H1 receptors is possibly related to the
somnolence and bodyweight gain observed with
certain of these agents, such as olanzapine (section
7).[2,13,14] In addition, blockade of α1-adrenergic re-
ceptors is likely to be responsible for the adverse
effects of dizziness and orthostatic hypotension.
Olanzapine has shown activity in numerous
animal models predictive of antipsychotic activity
Drugs 2004; 64 (23)
Olanzapine: A Review
and displays effects on CNS function in human
volunteers, as reviewed elsewhere.[2]
Compared with conventional antipsychotics, the
increases in serum prolactin levels produced by
olanzapine are more modest and occur with a lower
incidence.[19]
There have been a number of case reports of
corrected QT (QTc) interval prolongation on ECG,
hyperglycaemia, treatment-emergent diabetes mel-
litus, blood lipid abnormalities, pancreatitis and
mania in patients with schizophrenia or bipolar dis-
order treated with olanzapine (or other atypical anti-
psychotics for most of these effects).[20-25] Although
the pharmacological basis for each of these effects is
uncertain or unknown and the relationship to drug
use not yet clearly established, the potential risks of
some of these reported effects, especially the ad-
verse metabolic effects,[22] need to be taken into
account with the use of olanzapine.
3. Overview of
Pharmacokinetic Properties
Although there are no published pharmacokinetic
data in patients with bipolar I disorder, the pharma-
cokinetic properties of olanzapine in healthy volun-
teers and patients with schizophrenia are well estab-
lished[9] and have been reviewed in detail else-
where.[2,26] Therefore, only a brief overview of the
pharmacokinetic properties of olanzapine are pre-
sented in this section (table I).
Olanzapine displays linear pharmacokinetics
across the dose range of 0.5–30mg, with the peak
plasma concentration (Cmax) and the area under the
plasma concentration-time curve (AUC) being lin-
early related to the dose administered. Steady-state
Cmax, which is approximately 2-fold higher than
after a single dose, is attained after about 1 week of
once-daily administration (table I). The absorption
of olanzapine is not affected by food. The oral
bioavailability of olanzapine is reduced because the
drug undergoes extensive (up to 40%) first-pass
metabolism. The drug is highly bound to plasma
© 2004 Adis Data Information BV. All rights reserved.
2713
Table I. Overview of the pharmacokinetic properties of oral olanza-
pine in healthy adult volunteers or patients with schizophrenia[2,9,26]
Parameter Mean value
tmax 5h
Cmax 11 μg/L (10mg single dose)
Cmax steady state 20 μg/L (10 mg/day for 8 days)
Oral bioavailability 60–80%
Plasma protein binding 93%
AUC (10mg single dose) ≈530 μg • h/L
Vd 1148L
t1/2β ≈33h
Mean residence time 48h
CL 26 L/h
Urinary excretion 7% (unchanged); 57% (metabolites)
AUC = area under the plasma concentration-time curve; CL =
apparent plasma clearance; Cmax = peak plasma concentration;
t1/2β = terminal elimination half-life; tmax = time to Cmax; Vd =
apparent volume of distribution.
proteins and is widely distributed in the body (table
I).[2,9,26]
Olanzapine is extensively metabolised in the liv-
er by glucuronidation or oxidation (primarily by
cytochrome P450 [CYP] 1A2 and the flavin-con-
taining mono-oxygenase-3 system, with minor oxi-
dation by CYP2D6). The major metabolites are
olanzapine 10-N-glucuronide and 4′-N-desmethyl
olanzapine, while the minor metabolites are 2-
hydroxymethyl olanzapine and olanzapine 4′-N-oxi-
de.[9]
The terminal elimination half-life of olanzapine
is about 33 hours.[26] The drug is predominantly
excreted in the urine, mainly as metabolites (table
I).[2,9,26]
The clearance of olanzapine is about 25% lower
in female than in male patients with schizophrenia
and is increased in smokers compared with non-
smokers (approximately 40% lower clearance in
nonsmokers in the high-clearance subgroup of pa-
tients).[26] Clearance is also reduced by 30% in the
elderly and by 30–50% in children. However, owing
to the wide intra- and inter-individual variability
observed for most pharmacokinetic parameters, dos-
age adjustment to allow for individual factors is not
considered necessary, although adjustment may be
necessary for combinations of factors. The pharma-
Drugs 2004; 64 (23)
2714
cokinetics of olanzapine are not significantly affect-
ed by race, or renal or hepatic impairment.[26] Pla-
cental transfer of olanzapine occurs and the drug is
excreted in breast milk in humans.[2]
3.1 Potential Drug Interactions
A lack of pharmacokinetic interaction with olan-
zapine has been demonstrated for a variety of drugs
including valproate semisodium, warfarin, di-
azepam, imipramine, biperiden, cimetidine,
antacids, aminophylline and alcohol.[2,9,26] Although
olanzapine does not appear to alter the pharmaco-
kinetics of lithium,[9,26] coadministration with lithi-
um or trimipramine was observed to significantly
lower the mean plasma concentration of olanzapine
(≈24% and 23% reductions, respectively) in patients
with schizophrenia.[27] Coadministration of olanza-
pine with lamotrigine is practical, since only the
exposure to lamotrigine was reduced slightly (20%
reduction in Cmax and 24% reduction in AUC from 0
to 24 hours) during coadministration for 2 weeks.[28]
The CYP1A2 inhibitor fluvoxamine and the
CYP2D6 inhibitor fluoxetine decreased the clear-
ance of olanzapine by 50% and 15%, respectively,
and increased the Cmax by 84% and 18%, respec-
tively.[2,26]
Potent CYP1A2 inducers, such as carbamazepine
and smoking, increase the clearance and decrease
the Cmax of olanzapine.[2,26]
4. Therapeutic Efficacy
The efficacy of oral olanzapine, alone or in com-
bination with lithium or valproate semisodium, in
the treatment of acute mania in patients with bipolar
I disorder or as maintenance therapy to prevent
recurrence of affective episodes has been assessed in
a number of randomised, double-blind, comparative
trials,[29-39] and it is these studies that form the basis
for this review of the therapeutic efficacy of olanza-
pine. Data from nonblind extensions[40,41] of a place-
bo-controlled trial[30] and a comparison with val-
proate semisodium[34] are also available.
© 2004 Adis Data Information BV. All rights reserved.
McCormack & Wiseman
The relative change in the mania symptom score
was the primary[29,30,33-36] or a coprimary[31,32] effi-
cacy parameter in all studies assessing the treatment
of acute mania. Mania symptoms were most often
quantified using the Young Mania Rating Scale
(YMRS),[29,30,32,34-39] but two studies used either the
Mania Scale (MAS)[31] or the Schedule for Affective
Disorders and Schizophrenia-Change Version
(SADS-C) Mania Rating Scale (MRS).[33] Response
rates, usually defined as a ≥50% reduction in mania
symptom scores, were commonly reported. Some
studies also used other psychiatric rating scales as
coprimary assessments,[31,32] but most often they
were secondary endpoints; these commonly includ-
ed the Brief Psychiatric Rating Scale (BPRS), the
Hamilton Depression (HAM-D) Rating Scale (either
the 17- or 21-item [HAM-D21] version), the Clinical
Global Impression of severity (CGI-S) or improve-
ment (CGI-I) and the Global Assessment Function-
ing (GAF) scale. The primary endpoint of trials
assessing maintenance therapy of bipolar I disorder
was either the rate of relapse into an affective epi-
sode[39] or the time to relapse.[37,38]
Patients enrolled in the acute treatment studies
were aged 18–86 years and had manic symptoms,
usually of ≥2 weeks’ duration, that scored above a
defined threshold on the particular mania symptom
rating scale used in the study (e.g. ≥20 on the YMRS
or ≥25 on the SADS-C MRS). The affective epi-
sodes experienced by the patients could be either
manic or mixed manic/depressive episodes. Patient
populations included those with a rapid-cycling
course and those with or without psychotic symp-
toms. Where stated, all efficacy analyses in control-
led trials were performed on the intent-to-treat popu-
lation, usually using the last observation carried
forward for those prematurely discontinuing ther-
apy.[29-34,36-38]
Many reports refer to valproic acid derivatives
with the nonspecific term valproate. In the context
of treating bipolar mania this is assumed to refer to
valproate semisodium (divalproex sodium) rather
than sodium valproate or valproic acid, since the
Drugs 2004; 64 (23)
Olanzapine: A Review 2715

Table II. Efficacy of oral olanzapine (OLA) vs placebo (PL) as monotherapy for the treatment of acute bipolar mania. Results (intent-to-treat
analyses) of multicentre, randomised, double-blind, placebo-controlled studies in patients (pts) aged 18–70 years with bipolar I disorder,a
with or without psychotic featuresb
Study Episode type: Duration of Dosage (mean modal)c No. of pts Mean change in Response rate
manic/mixed treatment (w) [mg/day] YMRS score from (% of pts)e
(% of pts) baseline (LOCF)d
Tohen et al.[30] 83/17 3 OLA 2–15 (14.9) 70 –10.3* 49**
PL 69 –4.9 24
Tohen et al.[29] 57/43 4 OLA 2–15 (16.4) 54 –14.8*** 65*
PL 56 –8.1 43
a Pts had manic or mixed episodes of ≥2w duration and a YMRS total score ≥20 at baseline.
b 53%[30] and 56%[29] of pts in the two studies exhibited psychotic symptoms, while 32%[30] and 39%[29] were rapid cyclers.
c The modal dose was the daily dose most often taken.
d Primary efficacy endpoint.
e A reduction in YMRS total score of ≥50% between baseline and study end (LOCF).
LOCF = last observation carried forward; YMRS = Young Mania Rating Scale; * p < 0.05, ** p < 0.01, *** p < 0.001 vs PL.

semisodium form is the one licensed for use in
bipolar mania in the US and the UK.
4.1 Acute Therapy
4.1.1 Monotherapy
The efficacy of olanzapine in the treatment of
acute mania associated with bipolar I disorder has
been compared with placebo in two controlled
trials[29,30] and with other mood stabiliser or anti-
psychotic therapies in five head-to-head, controlled
trials.[31-35] In all studies where details were pro-
vided, existing medications were discontinued 1–4
days prior to randomisation, with the exception of
benzodiazepines (usually lorazepam) to treat agita-
tion or aggression, and anticholinergics (usually
benzatropine [benztropine mesylate] or biperiden)
used to treat EPS.[29-34] One study also permitted
concomitant use of the hypnotics chloral hydrate
and zolpidem.[33]
Versus Placebo
Two well controlled trials have demonstrated
olanzapine to be more effective than placebo in the
treatment of acute manic or mixed episodes in pa-
tients with bipolar I disorder for the primary efficacy
parameter consisting of the change in YMRS score
from baseline to end of treatment (table II).[29,30]
Secondary analysis of the pooled results from
these two trials indicated that olanzapine also pro-
duced superior rates for euthymia (50% vs 27%; p =
0.001) and remission (18% vs 7%; p < 0.05) com-
pared with placebo.[42] In this analysis, euthymia
was defined as a YMRS total score ≤12, while
remission was defined as a YMRS total score ≤7
with all items rated no more than mild in severity, a
HAM-D21 score ≤7, and a CGI-S (bipolar version)
score ≤2.[42]
Versus Lithium
Following 4 weeks of treatment, there were no
significant differences in response between adult
patients receiving oral olanzapine 10 mg/day (n =
15) and those receiving lithium carbonate 400mg
twice daily (n = 15) with respect to scores for the
MAS, BPRS, CGI-I and the GAF scale (coprimary
outcome measures).[31] At 4 weeks, but not at 1, 2 or
3 weeks, the CGI-S score in the olanzapine group
was significantly lower than in the lithium group
(2.29 vs 2.83; p < 0.05) indicating significantly
greater percent change from baseline (48.6% vs
38.3%; p < 0.05).[31]
Versus Valproate Semisodium
Olanzapine was at least as effective as valproate
semisodium in two well controlled trials.[33,34] In the
larger trial,[34] improvements in mania symptoms
(primary endpoint) with olanzapine were signifi-
cantly greater than those with valproate semisodium
(table III). The rate of symptomatic remission

© 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (23)
2716 McCormack & Wiseman

Table III. Comparative efficacy of oral olanzapine (OLA) vs valproate semisodium (VSS) in the treatment of acute bipolar mania. Results
(intent-to-treat analyses) from multicentre, randomised, double-blind trials in patients (pts) aged 18–75 years with bipolar I disorder and an
acute manic or mixed episodea
Study Episode type: Duration Dosage (mean modal)b [mean maximum] No. of Mean change in Response
manic/mixed (w) ptsc mania rating score rate (% of
(% of pts) from baseline pts)e
(LOCF)d
Tohen et al.[34] 57/43 3 OLA 5–20 (17.4) mg/day 125 –13.4* 54
VSS 500–2500 (1401.2) mg/day 123 –10.4 42
Zajecka et al.[33] 52/48 3f OLA 10–20 [14.7] mg/day 57 –17.2 NA
VSS 20 mg/kg/day + ≤1000 mg/dayg [2115 mg/day] 63 –14.8 NA
a SADS-C MRS score ≥25 with ≥4 items rated ≥3,[33] or a YMRS score ≥20.[34]
b The modal dose was the daily dose most often taken.
c In the two studies, 57.4%[34] and 29.2%[33] of pts were rapid cyclers, while 45.4%[34] and 33.3%[33] exhibited psychotic symptoms.
d Primary efficacy endpoint. The scales used to score mania symptoms were the SADS-C MRS[33] and the YMRS.[34]
e Response was defined as ≥50% improvement in the YMRS score.
f Total study duration was 12w (tolerability assessment), but efficacy was only assessed over the initial 21d.
g Optionally increased by 500 mg/day to a maximum dosage of 20 mg/kg/day + 1000 mg/day.
LOCF = last observation carried forward; MRS = Mania Rating Scale; NA = not assessed; SADS-C = Schedule for Affective Disorders and
Schizophrenia-Change Version; YMRS = Young Mania Rating Scale; * p < 0.05 vs VSS.

(YMRS score ≤12) was also significantly greater
with olanzapine than with valproate semisodium
(47% vs 34%; p < 0.05) and the estimated time to
remission in responders was significantly shorter for
olanzapine than for valproate semisodium (3 vs 6
days for the estimated 25th percentile; p < 0.05).[34]
Reductions from baseline in HAM-D21 scores did
not differ significantly between the olanzapine and
valproate semisodium groups (–4.9 vs –3.5).[34] In
the subgroup of patients without psychotic symp-
toms (n = 137), olanzapine reduced YMRS scores
from baseline to a significantly greater extent than
valproate semisodium (–14.1 vs –8.7; p < 0.001),
but in the subgroup with psychotic symptoms (n =
114), reductions in YMRS score did not differ be-
tween olanzapine and valproate semisodium recipi-
ents (–12.6 vs –12.8).
In the smaller study,[33] there were no differences
between treatments with respect to changes in
SADS-C MRS scores (table III) or scores for secon-
dary efficacy parameters (BPRS, HAM-D and CGI-
S). There were also no significant differences be-
tween treatments with respect to BPRS scores in the
subgroup of patients (n = 40) with psychotic symp-
toms.[33]
In neither study, was there any significant differ-
ence between treatment groups in the use of benzo-
diazepine or anticholinergic adjunctive medica-
tion.[33,34]
Versus Haloperidol
The rates of symptomatic remission (primary
endpoint) after the treatment of acute bipolar mania
for 6 weeks with olanzapine 5–20 mg/day (n = 234)
or haloperidol 3–15 mg/day (n = 219) did not differ
significantly between the treatment groups (52% vs
46%, respectively).[32] Remission, defined as a
YMRS score ≤12 and a HAM-D21 score ≤8, was
achieved at a median time of 34 days with olanza-
pine and 29 days with haloperidol.[32] The rates of
symptomatic relapse into any affective episode (ma-
nic, depressive or mixed) during the following
6-week, double-blind treatment continuation phase
were similar between the olanzapine and haloperi-
dol groups (13% vs 15%).[32] YMRS scores did not
differ significantly between the treatment groups at
12 weeks. Mean dosages at weeks 6 and 12 were
15.0 and 11.4 mg/day, respectively, for olanzapine
and 7.1 and 5.2 mg/day for haloperidol.
In the subgoup of patients without psychotic
symptoms (n = 193), the rate of symptomatic remis-

© 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (23)
Olanzapine: A Review
sion was significantly higher in olanzapine recipi-
ents than in haloperidol recipients (57% vs 42%; p <
0.05), while the time to remission did not differ
between the treatment groups.[32] However, in the
subgroup of patients with psychotic symptoms (n =
260), the rate of remission did not differ between the
treatment groups (49% in both).
Versus Risperidone
Olanzapine 5–20 mg/day (n = 165) and risper-
idone 1–6 mg/day (n = 164) for 3 weeks were
equally effective in reducing YMRS scores from
baseline (primary endpoint; values not reported;
published as an abstract) in patients with bipolar
disorder experiencing an acute manic or mixed epi-
sode.[35] However, olanzapine recipients showed
significantly (p < 0.05) greater improvements in
HAM-D and CGI-S scores (values not reported)
than risperidone recipients.[35]
4.1.2 Combination Therapy
The efficacy of olanzapine in combination with
other mood-stabiliser therapy for the treatment of
acute bipolar mania has been demonstrated in a
placebo-controlled trial in patients not adequately
responsive to ≥2 weeks of therapy with lithium or
valproate semisodium (YMRS score ≥16).[36] Pa-
tients received olanzapine 5–20 mg/day (n = 229) or
placebo (n = 115) in addition to their existing ther-
apy with lithium (34% of patients) or valproate
semisodium (66%) for 6 weeks, following a 2- to
7-day washout of other existing medications. How-
ever, concomitant benzodiazepine use was permit-
ted. Olanzapine combination therapy produced a
significantly greater reduction from baseline in
YMRS total score (primary endpoint) than mono-
therapy with a mood stabiliser (figure 1). Subgroup
analysis showed that the combination of olanzapine
with valproate semisodium was significantly more
effective than valproate semisodium alone, but the
combination of olanzapine with lithium was not
significantly more effective than lithium alone (fig-
ure 1).[36] Combination therapy was also superior to
monotherapy with respect to reductions from base-
© 2004 Adis Data Information BV. All rights reserved.
2717
16 OLA
Reduction in YMRS total score
14 PL
** *
12
10
8
6
4
2
0
LIT or VSS LIT VSS
Fig. 1. Efficacy of olanzapine (OLA) combination therapy in acute
bipolar mania. Results of a randomised, double-blind trial compar-
ing OLA 5–20 mg/day (n = 229) with placebo (PL) [n = 115] for 6
weeks in combination with lithium (LIT) [34% of patients] or val-
proate semisodium (VSS) [66% of patients] with respect to reduc-
tions from baseline in the Young Mania Rating Scale (YMRS) total
score (primary endpoint).[36] Results are displayed for the full study
population and the subgroups of patients taking each mood
stabiliser. * p < 0.05, ** p < 0.005 vs PL.
line in HAM-D21 (–4.98 vs –0.89; p < 0.001), CGI-S
(–1.20 vs –0.89; p < 0.05) and Positive and Negative
Syndrome Scale (–12.90 vs –6.96; p < 0.01) scores,
as well as the clinical response rate (68% vs 45%;
p < 0.001), remission rate (79% vs 66%; p = 0.01)
and time to remission (14 vs 22 days; p < 0.01).
Clinical response was defined as ≥50% improve-
ment in YMRS and HAM-D21 scores, and remission
was defined as a YMRS score ≤12.[36]
Results from a number of small (n ≤ 30), uncon-
trolled studies[43-46] also suggest that olanzapine pro-
duces improved clinical responses when added to
existing mood-stabiliser therapy in patients with
bipolar mania not responding optimally to existing
therapy, including those with a rapid cycling
course.[46]
4.2 Maintenance Therapy
Three controlled trials, two of which are pub-
lished as abstracts,[38,39] have assessed the efficacy
of olanzapine in the long-term maintenance treat-
ment of patients with bipolar I disorder to prevent
the recurrence of affective (manic, depressive or
mixed) episodes (table IV).[37-39] All patients en-
rolled in these studies were in symptomatic (YMRS
score ≤12 and HAM-D21 score ≤8) or syndromic
Drugs 2004; 64 (23)
2718 McCormack & Wiseman

Table IV. Efficacy of long-term olanzapine (OLA) maintenance therapy in the prevention of relapse into an affective episode (manic,
depressive or mixed). Results from randomised, double-blind comparisons with placebo (PL) or other mood stabilising agents (lithium [LIT]
or valproate semisodium [VSS]) in adult patients (pts) with bipolar I disorder in symptomatic (YMRS score ≤12 and HAM-D21 score ≤8) or
syndromic (DSM-IV criteria) remission
Study Duration Regimen (mg/day) No. of Symptomatic relapse rate (% of pts) Median time to relapse (days)
(mo) pts
any manic depressive symptomatic syndromic
Placebo comparison
Tohen et al.[38]a 12 OLA 12.5 225 47** 16** 35* OLA>PL**bc
PL 136 80 41 48

Comparison with LIT

Tohen et al.[39]a 12 OLA 5–20 217 30c 14† 16
LITd 214 39c 28 15

Combination vs mood stabiliser monotherapy

Tohen et al.[37] 18 OLA 5–20 + LIT or VSSe 30 (51)f 37 20 23 163‡ 94c
LIT or VSSe 38 (48)f 55 29 40 42 41c
a Published as an abstract.
b Data only reported in the form of Kaplan-Meier survival curves.
c Primary efficacy endpoint.
d Serum LIT level of 6–1.2 mEq/L.
e Serum levels for LIT of 0.6–1.2 mmol/L and for VSS of 50–125 μg/mL.
f Of the 99 pts in syndromic remission (assessed for syndromic relapse), 68 pts were also in symptomatic remission (assessed for
symptomatic relapse).
DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; HAM-D21 = Hamilton Depression Rating Scale (21-item
version); YMRS = Young Mania Rating Scale; * p < 0.05, ** p < 0.001 vs PL; † p < 0.001 vs LIT; ‡ p < 0.05 vs LIT or VSS monotherapy.

(meeting DSM-IV [Diagnostic and Statistical Man-
ual of Mental Disorders, Fourth Edition] criteria)
remission following short-term therapy with olanza-
pine alone[38] or olanzapine in combination with
lithium or valproate semisodium.[37,39] Symptomatic
relapse was commonly defined as a YMRS total
score ≥15 for mania, a HAM-D21 score ≥15 for
depression or hospitalisation for an affective epi-
sode after having previously met the criteria for
remission. The studies consist of a 12-month place-
bo comparison,[38] a 12-month comparison with lith-
ium,[39] and an 18-month comparison between com-
bination therapy with olanzapine plus lithium or
valproate semisodium versus lithium or valproate
semisodium alone.[37]
Compared with placebo, olanzapine significantly
increased the time to symptomatic relapse (primary
endpoint) and reduced the rate of relapse into either
a manic or depressive episode (table IV).[38] Addi-
tionally, twice as many placebo recipients compared
with olanzapine recipients discontinued therapy as a
result of lack of efficacy (57% vs 28%; p =
0.001).[38]
Olanzapine was more effective than lithium in
preventing relapse into mania, but not in preventing
relapse into a depressive episode or for relapse over-
all (primary endpoint; table IV).[39] Significantly
more olanzapine recipients than lithium recipients
completed the full 52 weeks of double-blind therapy
(47% vs 33%; p < 0.005).[39]
Olanzapine in combination with lithium or val-
proate semisodium was more effective than lithium
or valproate semisodium monotherapy with respect
to delaying symptomatic, but not syndromic (prima-
ry endpoint), overall relapse (table IV).[37] However,
combination therapy and monotherapy did not differ
for time to relapse (symptomatic or syndromic) into
mania or depression alone.[37] The combination was
also not significantly different from monotherapy
with respect to the rates of both symptomatic (table
IV) and syndromic relapse.

© 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (23)
Olanzapine: A Review
Nonblind treatment with olanzapine for 49 weeks
(n = 113) in an extension of the 3-week randomised,
double-blind comparison with placebo (section
4.1.1),[30] also demonstrated continued improvement
in YMRS scores (–18.01 change from baseline [last
non-olanzapine observation]), a high mania remis-
sion rate (88% of patients) and a low mania relapse
rate (26%) throughout long-term treatment.[40]
In a 44-week, double-blind continuation (n =
251) of the 3-week, randomised, double-blind com-
parison between olanzapine (mean modal dose of
16.2 mg/day) and valproate semisodium (mean mo-
dal dose of 1584.7 mg/day) [section 4.1.1],[34]
YMRS total scores after 47 weeks improved from
baseline significantly more overall in the olanzapine
group than in the valproate semisodium group
(–15.4 vs –12.5; p = 0.03).[41] The times to sympto-
matic (14 vs 62 days; p = 0.05) and syndromic (28 vs
109 days; p = 0.01) remission of mania were shorter
with olanzapine, but the rates of remission of mania
were not significantly different between olanzapine
and valproate semisodium recipients (51–57% vs
38–46%, respectively).[41] With respect to sympto-
matic or syndromic remission of both mania and
depression, there were no differences between
groups for time to remission or rates of remission.
Similarly, there were no significant between-group
differences in time to symptomatic or syndromic
recurrence of any affective episode (mania, depres-
sion or mixed) or their frequency of occurrence.[41]
5. Health-Related Quality of Life
Health-related quality-of-life (HR-QOL) assess-
ments[3,47-50] were performed in several of the ran-
domised controlled trials or their extensions dis-
cussed in sections 4.1 and 4.2,[32,33,36,40,41,49,50] al-
though details are limited for some owing to
publication only as abstracts.[49,50]
Treatment with olanzapine for 49 weeks signifi-
cantly (p < 0.05) improved mean HR-QOL scores
relative to baseline in four of the eight domains of
the 36-item Short Form Health Survey (SF-36)
questionnaire (bodily pain [+10.1], general health
© 2004 Adis Data Information BV. All rights reserved.
2719
[+5.9], social functioning [+11.6] and role limitation
due to emotional problem [+14.6]), but the score for
the vitality domain decreased significantly (–9.3;
p < 0.01).[3] Similarly, when used in combination
with lithium or valproate semisodium for 6 weeks,
olanzapine produced significantly (p < 0.05–0.001
vs placebo) greater improvement from baseline than
did placebo for six of the scales from the Lehman’s
Brief Quality of Life Interview (values not report-
ed).[50]
One study comparing olanzapine with valproate
semisodium for acute and maintenance therapy
demonstrated that olanzapine recipients (n = 69) had
significantly (p < 0.05–0.01) greater improvement
than valproate semisodium recipients (n = 63) in
five of the eight SF-36 domains (general health,
mental health, physical functioning, social function-
ing and role limitation-emotional) after approxi-
mately 10 months of therapy (values not report-
ed),[49] while another study found no difference be-
tween the olanzapine (n = 25) and valproate
semisodium (n = 27) treatment groups in HR-QOL
scores after 6 or 12 weeks using the Quality of Life
Enjoyment and Satisfaction Questionnaire.[48] This
study did note that patients reporting bodyweight
gain as an adverse effect had less improvement in
HR-QOL in the first 6 weeks of therapy than pa-
tients not reporting bodyweight gain, with the differ-
ence reaching statistical significance for three of
seven domains. The difference was no longer appar-
ent at 12 weeks.[48]
In the trial comparing olanzapine with haloperi-
dol,[32] changes in scores in four of the eight SF-36
domains significantly favoured olanzapine over
haloperidol at 12 weeks (figure 2), compared with
five domains (plus social functioning) at 6 weeks.[47]
Haloperidol caused a worsening of status relative to
baseline in five domains (general health, mental
health, physical functioning, role limitation due to
physical problem and vitality) compared with only
one for olanzapine (vitality). The extent of the de-
crease in vitality with olanzapine was significantly
less than that with haloperidol (figure 2). The sum-
Drugs 2004; 64 (23)
2720 McCormack & Wiseman

25 OLA
HAL
20

15
Mean change in score from baseline

10
*
5
**
** **
0

−5

−10 *

−15

−20
Bodily pain General Mental Physical Role- Role- Social Vitality Summary Summary
health health functioning emotional physical functioning physical mental
Fig. 2. Health-related quality of life during randomised, double-blind therapy with olanzapine (OLA) or haloperidol (HAL) for bipolar mania.[47]
Mean change from baseline to 12 weeks in the 36-item Short Form Health Survey domain and summary scores in patients with acute
bipolar mania treated with OLA 5–20 mg/day (n = 161) or HAL 3–15 mg/day (n = 137). * p < 0.01, ** p ≤ 0.001 vs HAL.

mary scores for the physical components of the SF-
36 were significantly higher with olanzapine than
with haloperidol at both 6 (p = 0.01) and 12 (p <
0.001; figure 2) weeks. Symptomatic remission was
positively associated with higher SF-36 scores for
the mental components, but not the physical com-
ponents.[47]
6. Pharmacoeconomic Considerations
There have been no fully published cost-effec-
tiveness studies on the use of olanzapine either as
monotherapy or in combination with mood
stabilisers to treat bipolar mania. Preliminary data
from one such study published as an abstract suggest
that risperidone or olanzapine in combination with
lithium or valproate semisodium, as well as lithium
or valproate semisodium alone, provide similar life-
time quality-adjusted life expectancy for discounted
lifetime costs (≈$US31 900–32 900; 2001 values)
that differ by ≤$US2000.[51]
The direct costs (1995 values) incurred in treat-
ing 76 patients with olanzapine 5–20 mg/day in a
49-week, open-label extension[40] of a 3-week, ran-
domised, double-blind comparison with placebo[30]
were compared retrospectively with the estimated
non-drug treatment costs incurred in these patients
during the previous 52 weeks.[3] The comparison
indicated significant (p < 0.01) reductions in both
inpatient ($US248 vs $US1179) and outpatient
($US73 vs $US354) mean monthly costs during
olanzapine therapy.[3]
Two analyses of randomised controlled trials in-
dicated that there was no difference between olanza-
pine and valproate semisodium therapy with respect
to total medical costs ($US18 933 vs $US19 918
[2000 values];[49] $US15 180 vs $US13 703 [year
not stated][48]). Although the drug acquisition costs
for olanzapine were considerably higher than those
for valproate semisodium, they were offset by lower
inpatient and/or outpatient costs for olanzapine.[48,49]
Several retrospective analyses based on claims data,

© 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (23)
Olanzapine: A Review
published as abstracts, suggest that olanzapine ther-
apy is associated with marginally higher costs than
those of risperidone or quetiapine.[52-54] The cost
differences appeared to be largely the result of
higher drug acquisition costs for olanzapine.
7. Tolerability
In clinical trials discussed in section 4, oral olan-
zapine 5–20 mg/day was generally well tolerated in
the treatment of mania associated with bipolar I
disorder.[29-41] The treatment-emergent adverse
events occurring in ≥9% of patients receiving short-
term olanzapine monotherapy in placebo-controlled
trials were somnolence, dry mouth, dizziness, head-
ache, agitation, dyspepsia, asthenia, anxiety/ner-
vousness, depression, constipation and bodyweight
gain.[29,30] Despite suggestions that olanzapine might
paradoxically induce mania,[25] worsening of mania
symptom rating scores in these controlled trials oc-
curred significantly (p < 0.01) more often in placebo
than in olanzapine recipients (37.7% vs 21.8% of
patients).[55]
In short-term monotherapy trials,[29,30] the ad-
verse events having a significantly higher incidence
with olanzapine than with placebo were somnolence
(33–38% vs 8–17%; p < 0.05–0.001),[29,30] dry
mouth (25.7% vs 8.7%; p = 0.01),[30] dizziness
(22.9% vs 5.8%; p < 0.01)[30] and bodyweight gain
(11.4% vs 1.4%; p < 0.05).[30] During combination
therapy, other adverse events also occurring with
significantly higher incidences in olanzapine recipi-
ents than in placebo recipients were increased appe-
tite (23.6% vs 7.8%; p < 0.001), tremor (23.1% vs
13.0%; p = 0.03) and speech disorder (6.6% vs
0.9%; p = 0.02).[36] Treatment discontinuation as a
result of adverse events was similarly low between
olanzapine and placebo recipients in monotherapy
trials (1.6% vs 2.3%),[29,30] but was notably higher
with olanzapine compared with placebo during
combination therapy for 6 weeks (11% vs 2%; p <
0.01).[36] The laboratory abnormalities with a signif-
icantly (p < 0.05–0.001) higher incidence in olanza-
pine recipients than placebo recipients were elevat-
© 2004 Adis Data Information BV. All rights reserved.
2721
ed liver enzymes (AST/ALT)[29,30] and elevated pro-
lactin levels,[36] both common events with
antipsychotics.[19,21] These laboratory abnormalities
were not considered clinically significant.
During long-term maintenance therapy for 12–18
months, with few exceptions, treatment-emergent
adverse events were similar in type and frequency to
those observed during short-term therapy;[37,38,40] the
adverse events with a significantly (p < 0.05) higher
incidence than placebo were bodyweight gain, fa-
tigue and akathisia.[37,38]
EPS were infrequent during both short- and long-
term treatment, such that anticholinergic medication
use was negligible. The incidence of EPS was simi-
lar between olanzapine and placebo recipi-
ents,[29,30,36,37] and was usually reduced relative to
baseline during long-term therapy.[37,40]
In controlled trials,[29,30,36,37] there were no signif-
icant differences between the olanzapine and place-
bo groups in ECGs or vital signs, although one study
showed a significantly (p < 0.05) higher change in
mean supine systolic BP with olanzapine compared
with placebo (+5.0 vs –3.9mm Hg).[29] In longer-
term studies, there were no clinically relevant differ-
ences between olanzapine and placebo recipients
with respect to non-fasting blood glucose or choles-
terol levels.[36-38]
In comparative trials, the mean bodyweight gain
during therapy was consistently significantly higher
with olanzapine than with lithium (p < 0.001),[39]
valproate semisodium (p ≤ 0.05–0.001),[33,34,41]
haloperidol (p < 0.001)[32] or risperidone
[35]
(p < 0.05). Olanzapine recipients generally had a
higher overall incidence of adverse events and sig-
nificantly (p < 0.05–0.001) higher incidences of par-
ticular adverse events (in addition to bodyweight
gain) than recipients of valproate semisodium (som-
nolence, dry mouth, increased appetite, tremor,
speech disorder, elevated liver enzymes),[33,34,41]
haloperidol (somnolence, infection, dizziness, fever,
increased salivation)[32] or risperidone (dry mouth,
elevated liver enzymes),[35] although some of these
comparative agents in turn had higher incidences
Drugs 2004; 64 (23)
2722
than olanzapine of different adverse events (e.g.
nausea, nervousness and manic reaction with val-
proate semisodium;[34,41] anxiety and joint stiffness
with risperidone[35]).
The incidence of EPS was similar between olan-
zapine and lithium[31] or valproate semisodium,[33,34]
but was significantly (p < 0.05–0.001) higher with
haloperidol than with olanzapine.[32] Over 47 weeks
of therapy, olanzapine was associated with a signifi-
cantly greater mean increase in cholesterol level
compared with valproate semisodium (+9.7 vs –2.3
mg/dL; p < 0.01).[41] In a 12-week study, olanzapine
produced significantly greater elevations than val-
proate semisodium in mean total cholesterol (+13.3
vs –1.7 mg/dL) and low-density lipoprotein (LDL)
cholesterol (+8.8 vs –4.4 mg/dL), as well as albu-
min, alkaline phosphatase, total protein and platelet
counts.[33] One patient on olanzapine therapy died of
diabetic ketoacidosis that was considered possibly
or probably related to the study drug.[33]
8. Dosage and Administration
In Europe and the US, oral olanzapine, either
alone or in combination with lithium or valproate
semisodium, is indicated for the short-term treat-
ment of adults with acute moderate-to-severe manic
(or mixed) episodes associated with bipolar I disor-
der, with or without psychotic symptoms.[9,10] Olan-
zapine is also approved as long-term maintenance
monotherapy for the prevention of recurrence in
adult patients whose manic episode has responded to
olanzapine.[9,10]
The effective dosage range of oral olanzapine for
the treatment of acute mania associated with bipolar
I disorder is 5–20mg once daily without regard to
meals.[9] This dosage range applies to both acute and
maintenance therapy, and to both monotherapy and
combination therapy with lithium or valproate semi-
sodium. The usual starting dosage for monotherapy
is 10 or 15mg once daily, while that for combination
therapy is 10mg once daily. Dosage adjustments
(5mg increments or decrements) should be made at
intervals of 24 hours or more.[9]
© 2004 Adis Data Information BV. All rights reserved.
McCormack & Wiseman
Dosage adjustment may be necessary in patients
who exhibit multiple factors known to delay the
metabolism of olanzapine (section 3.1).[9] For more
detailed information, refer to the local manufactur-
er’s prescribing information.
9. Place of Olanzapine in the
Management of Bipolar I Disorder
While varying in specific details, treatment
guidelines generally all recommend lithium, val-
proate semisodium, carbamazepine and antipsychot-
ics as the predominant first-line treatment options
for managing acute manic episodes associated with
bipolar I disorder.[4,5,56,57] Lithium is the cornerstone
of both acute therapy and prophylaxis, but is less
effective in patients with atypical disease, such as
those with mixed episodes, a rapid cycling course,
concurrent psychotic symptoms or comorbid disor-
ders.[58] Valproate semisodium appears to have a
broader spectrum of activity across the bipolar dis-
order subtypes and a faster onset of effect,[59] but is
not licensed for prophylactic use. Carbamazepine
has efficacy similar to lithium in acute treatment[5]
and is approved in Europe, but not the US, for
maintenance therapy. Antipsychotics are fast acting,
have a broad spectrum of activity and are partic-
ularly recommended in bipolar patients with
psychotic symptoms.[4,5,56]
Atypical antipsychotics (e.g. olanzapine, risper-
idone and quetiapine) have largely replaced conven-
tional antipsychotics (e.g. haloperidol and chlor-
promazine) in the treatment of bipolar mania. This is
the result of their improved tolerability, especially
their lower propensity to produce EPS, which is
thought to be a consequence of these agents having
either higher ratios of 5-HT2A to D2 receptor affinity
than typical antipsychotic agents,[8,14] or just a low
D2 receptor occupancy.[15] Of the atypical antipsy-
chotics, olanzapine, risperidone and quetiapine are
currently approved in both the US and Europe, and
ziprasidone is approved only in the US, as mono-
therapy or adjunctive therapy for the acute treatment
of bipolar mania. Olanzapine is the only atypical
Drugs 2004; 64 (23)
Olanzapine: A Review
antipsychotic approved for long-term maintenance
therapy of bipolar I disorder to prevent recurrence in
responders (section 8).[9,10]
In the treatment of acute manic or mixed epi-
sodes, controlled clinical trials have demonstrated
that oral olanzapine is more effective than placebo
and is at least as effective as lithium, valproate
semisodium, haloperidol or risperidone (section
4.1.1). Olanzapine effectively reduces mania symp-
toms and increases the rates for response, euthymia
and remission compared with placebo. One trial
demonstrated superiority of olanzapine over val-
proate semisodium with respect to reductions in
mania symptom scores and symptomatic remission
rates, but this was not confirmed in another smaller
study. Olanzapine is an effective adjunctive treat-
ment, producing greater responses in combination
with mood stabilisers than mood stabilisers alone
(section 4.1.2), and may be safely coadministered
with lithium or valproate semisodium, since it does
not significantly interact pharmacokinetically with
these agents (section 3.1).
In patients responding to olanzapine treatment of
an acute manic episode, olanzapine maintenance
therapy for up to 12 months delays relapse and
reduces relapse rates compared with placebo (sec-
tion 4.2). Olanzapine appears to be more effective
than lithium at preventing relapse into mania, but
not relapse into depression or relapse overall, over
12 months. In contrast, olanzapine and valproate
semisodium did not differ with regard to time to
relapse or relapse rate during maintenance therapy
for up to 44 weeks. However, further controlled
comparative trials are required to fully determine the
relative efficacies of the different antimanic agents
as maintenance therapy.
Olanzapine alone or in combination with lithium
or valproate semisodium improves the HR-QOL of
patients with bipolar I disorder, apparently to a
greater extent than haloperidol, and possibly to a
greater extent than valproate semisodium, although
current evidence is conflicting (see section 5) and
requires clarification.
© 2004 Adis Data Information BV. All rights reserved.
2723
Olanzapine is also being evaluated in the treat-
ment of bipolar depression, and was more effective
than placebo in reducing the symptoms of depres-
sion in a large (n = 833), randomised, double-blind
trial.[60] Olanzapine in combination with fluoxetine
was more effective than olanzapine alone, although
whether the combination was more effective than
fluoxetine alone was not tested.[60]
Olanzapine is generally well tolerated during
both short- and long-term therapy of bipolar mania.
Somnolence, dry mouth, dizziness and bodyweight
gain were the most common adverse effects with an
incidence higher than with placebo during acute
therapy, while bodyweight gain, fatigue and akathi-
sia had a higher incidence than placebo in long-term
therapy. Elevated serum levels of liver transami-
nases and prolactin were the only statistically signif-
icant laboratory abnormalities noted (section 7), but
were of little clinical significance. The incidence of
EPS with olanzapine was similar to that with place-
bo, lithium or valproate semisodium, and was signif-
icantly less than that with the conventional anti-
psychotic haloperidol. Although bodyweight gain is
associated with most antipsychotics and is usually
greater with atypical agents, the weight gain observ-
ed with olanzapine was consistently higher than
with any of the comparators, including both halo-
peridol and risperidone. Although not apparently a
major reason for treatment discontinuation, weight
gain was the cause of withdrawal in at least some
patients,[36,41] and was noted in one study to adverse-
ly influence HR-QOL in the early phase of treatment
(section 5).
There has been concern expressed that olanza-
pine might provoke mania, induce glucose intoler-
ance and type 2 diabetes, alter lipid metabolism, or
prolong the QTc interval on ECG (see section 2).
Most of these effects have not been thoroughly
assessed in controlled clinical trials in patients with
bipolar I disorder, although diabetic ketoacidosis
and altered lipid profiles have been noted in trials
conducted to date (section 7).[33,41] The effects have
mostly been observed in patients with schizophrenia
Drugs 2004; 64 (23)
2724
receiving treatment with olanzapine, but there is no
reason to believe that they would not be equally
likely to occur in patients with bipolar I disorder.
The US FDA has mandated the inclusion of a warn-
ing regarding a potential increased risk of develop-
ing hyperglycaemia and diabetes in the package
inserts for all atypical antipsychotics, including
olanzapine.[61]
The limited pharmacoeconomic data available
suggest that the cost effectiveness of olanzapine
therapy is similar to that of lithium, valproate semi-
sodium or risperidone (section 6). The acquisition
cost of olanzapine was higher than for the compara-
tor agents in a number of cost comparisons, yet these
studies indicate that olanzapine therapy is similar or
only marginally more expensive than the compara-
tors with respect to total medical costs. However,
none of these analyses appear particularly robust.
In general, no single agent for the treatment of
bipolar mania has been consistently shown to be
more effective than any other agent and few have
been rigorously assessed as maintenance therapy.
Treatment choices are often determined by a pa-
tient’s disease characteristics and drug tolerability,
as much as by relative efficacy.[62] In practice, pa-
tients may be treated with a variety of agents, de-
spite there being only a limited number of approved
medications. This off-label use is especially evident
with maintenance therapy, where only lithium and
olanzapine (plus carbamazepine in the UK and
lamotrigine [for depression recurrence] in the US)
are approved, yet valproate semisodium appears to
have dominated the market, at least in the US.[1]
Although having proven efficacy in acute bipolar
mania, the atypical antipsychotics risperidone and
quetiapine have not been fully evaluated for efficacy
as maintenance therapy. Ziprasidone is a new atypi-
cal agent that was recently approved in the US
(August 2004) for the acute treatment of bipolar
mania, including manic and mixed episodes, and
appears to have a lower incidence of bodyweight
gain than most other atypical antipsychotics.[7,63]
Aripiprazole is another new atypical antipsychotic,
© 2004 Adis Data Information BV. All rights reserved.
McCormack & Wiseman
currently approved for treating schizophrenia, that is
being assessed in bipolar mania. Aripiprazole is
effective in both the acute and maintenance treat-
ment of bipolar mania and does not appear to cause
bodyweight gain, QTc prolongation or serum pro-
lactin elevation;[64] it has been submitted to the US
FDA for supplemental approval for acute and main-
tenance therapy of bipolar mania.
In conclusion, oral olanzapine is effective in the
treatment of bipolar mania, both as single agent
therapy and as adjunctive therapy in combination
with lithium or valproate semisodium. In the treat-
ment of acute episodes, olanzapine is superior to
placebo and at least as effective as lithium, valproate
semisodium, haloperidol and risperidone in reduc-
ing the symptoms of mania and inducing remission.
Additional comparative studies are required to de-
termine the efficacy of olanzapine relative to newer
atypical antipsychotics, such as quetiapine, ziprasi-
done and aripiprazole. Olanzapine is also effective
at delaying or preventing relapse during long-term
maintenance therapy in treatment responders, and is
currently the only atypical antipsychotic approved
for this indication. Current evidence suggests that
olanzapine may be more effective than lithium in
preventing relapse into mania, but not relapse into
depression or relapse overall. Olanzapine is general-
ly well tolerated, and although it is associated with a
higher incidence of weight gain than most atypical
agents, it has a low incidence of EPS. Therefore,
oral olanzapine is a useful first-line or adjunctive
agent for both the acute treatment of manic episodes
and the long-term prevention of relapse into manic,
depressive or mixed episodes associated with bi-
polar I disorder.
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Correspondence: Paul L. McCormack, Adis International
Limited, 41 Centorian Drive, Private Bag 65901, Mairangi
Bay, Auckland 1311, New Zealand.
E-mail: demail@adis.co.nz
Drugs 2004; 64 (23)