Rendell JM, Gijsman HJ, Keck P, Goodwin GM, Geddes JR.
alone or in combination for acute mania.
Syst Rev. 2003;(3):CD004040.
"BACKGROUND: Olanzapine, an atypical antipsychotic,
is used in the treatment of mania both as monotherapy and combined with other
medicines. OBJECTIVES: To review the efficacy and tolerability of olanzapine in
the treatment of mania SEARCH STRATEGY: The Cochrane Collaboration Depression,
Anxiety and Neurosis Controlled Trials Register (CCDANCTR), The Cochrane Central
Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, CINAHL and PsycINFO
were searched. SELECTION CRITERIA: Randomised trials comparing olanzapine with
placebo or other drug in acute manic or mixed episodes. DATA COLLECTION AND ANALYSIS:
Two reviewers independently extracted data from trial reports MAIN RESULTS: Six
trials (1422 participants) were included in the review. There was a high rate
of failure to complete treatment on all treatments which may have biased the estimates
of relative efficacy. Olanzapine was superior to placebo at reducing manic symptoms
as monotherapy (Young Mania Rating Scale (YMRS) - weighted mean difference (WMD):
-5.94, 95% CI -9.09 to -2.80) and in combination with lithium/valproate (YMRS)
(WMD -4.01, 95% confidence interval -6.06 to -1.96). Olanzapine monotherapy was
superior at reducing psychotic symptoms (PANSS positive symptoms subscale WMD:
-3.54, 95% CI -5.28 to -1.80). Olanzapine was superior to divalproex at reducing
manic symptoms (standardised mean difference (SMD): -0.29, 95% CI -0.50 to -0.08).
Olanzapine did not lead to a statistically higher rate of clinical response than
haloperidol (RR: 1.03, 95% CI 0.77 to 1.38). Fewer patients discontinued treatment
on olanzapine than placebo (RR: 0.62, 95% CI 0.48 to 0.80). Olanzapine caused
greater weight gain than placebo (WMD 1.91Kg, 95% CI 1.29 to 2.53) and somnolence
(RR: 2.13 95% CI 1.62 to 2.79) but not more depressive symptoms (RR: 0.95, 95%
CI 0.65 to 1.40) or movement disorder (WMD: -0.33, 95% CI -0.74 to 0.09). Olanzapine
caused more prolactin elevation than placebo (RR: 4.35 95%CI 1.77 to 10.70). Olanzapine
caused greater weight gain (WMD: 1.54, 95% CI 1.02 to 2.05); somnolence (RR: 1.80
95% CI 1.32 to 2.46) and movement disorders (SAS - WMD: 0.72 95% CI 0.11 to 1.33)
than divalproex but less nausea ( RR: 0.36 95% CI 0.20 to 0.65). Olanzapine caused
more weight gain than haloperidol (RR: 3.59, 95% CI 1.49 to 8.64) but less movement
disorder (EPS RR: 0.10, 95% CI 0.04 to 0.24). REVIEWER'S CONCLUSIONS: Olanzapine
is an effective treatment for mania and may be more efficacious than divalproex,
though leads to more weight gain. Clinicians should consider both the relative
efficacy and the different incidence of specific adverse effects of available
Zajecka JM, Weisler R, Sachs G, Swann AC, Wozniak
P, Sommerville KW.
Rush-Presbyterian St. Luke's Medical Center, Chicago, Ill
60612-3824, USA. John_Zajecka@rush.edu
A comparison of the efficacy,
safety, and tolerability of divalproex sodium and olanzapine in the treatment
of bipolar disorder.
J Clin Psychiatry. 2002 Dec;63(12):1148-55.
This study compared the efficacy, safety, and tolerability of divalproex and olanzapine
in the treatment of acute mania associated with bipolar disorder. METHOD: This
randomized, 12-week, double-blind, parallel-group, multicenter study included
DSM-IV-defined bipolar disorder type I patients hospitalized for acute mania and
randomly assigned to treatment with divalproex or olanzapine. After an inpatient
period of up to 21 days, subjects were followed as outpatients. Dose adjustment
was permitted during the inpatient period. Efficacy was assessed using change
from baseline in Mania Rating Scale (MRS) score to day 21; other efficacy measures
included the Brief Psychiatric Rating Scale, the Hamilton Rating Scale for Depression,
and the Clinical Global Impressions-Part I, Severity of Illness scale. The primary
safety endpoint was change from baseline in weight. Other safety and tolerability
endpoints included spontaneous adverse event reporting and changes from baseline
in laboratory measures and vital signs. RESULTS: 120 subjects (N = 63 divalproex,
N = 57 olanzapine) were randomly assigned to treatment. No significant differences
between groups were found for any efficacy variable for change from baseline to
day 21. Mean MRS score changes from baseline to day 21 were -14.8 for divalproex
and -17.2 for olanzapine (p =.210). A significantly (p <.05) greater proportion
of olanzapine-treated subjects experienced somnolence, weight gain, edema, rhinitis,
and speech disorder (slurred speech); no adverse events were significantly greater
in the divalproex group. A number of laboratory measures also demonstrated significant
treatment differences, but the clinical significance of many of these is uncertain.
Mean body weight changes were significantly greater in the olanzapine group (+
8.8 lb [+ 4.0 kg]) than the divalproex group (+ 5.5 lb [+ 2.5 kg], p <.050).
One death occurred during the study (olanzapine group, diabetic ketoacidosis).
CONCLUSION: No significant difference in efficacy was found between treatment
groups. Divalproex was associated with a more favorable adverse event profile
and significantly less weight gain than olanzapine." [Abstract]
M, Ketter TA, Zarate CA, Suppes T, Frye M, Altshuler L, Zajecka J, Schuh LM, Risser
RC, Brown E, Baker RW.
Lilly Research Laboratories, IN 46285, USA. email@example.com
versus divalproex sodium for the treatment of acute mania and maintenance of remission:
a 47-week study.
Am J Psychiatry. 2003 Jul;160(7):1263-71.
Few double-blind trials have compared longer-term efficacy and safety of medications
for bipolar disorder. The authors report a 47-week comparison of olanzapine and
divalproex. METHOD: This 47-week, randomized, double-blind study compared flexibly
dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed
episodes of bipolar disorder (N=251). The only other psychoactive medication allowed
was lorazepam for agitation. The primary efficacy instrument was the Young Mania
Rating Scale; a priori protocol-defined threshold scores were > or =20 for
inclusion, < or =12 for remission, and > or = 15 for relapse. Analytical
techniques included mixed model repeated-measures analysis of variance for change
from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and
Kaplan-Meier estimates of time to events of interest. RESULTS: Over 47 weeks,
mean improvement in Young Mania Rating Scale score was significantly greater for
the olanzapine group. Median time to symptomatic mania remission was significantly
shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant
differences between treatments in the rates of symptomatic mania remission over
the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania
or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly
more frequently during olanzapine treatment were somnolence, dry mouth, increased
appetite, weight gain, akathisia, and high alanine aminotransferase levels; those
for divalproex were nausea and nervousness. CONCLUSIONS: In this 47-week study
of acute bipolar mania, symptomatic remission occurred sooner and overall mania
improvement was greater for olanzapine than for divalproex, but rates of bipolar
relapse did not differ." [Abstract]
DA, Paramore LC, Sommerville KW, Swann AC, Zajecka JM; Depakote Comparator Study
Center for Outcomes Research, MEDTAP International, Bethesda, MD 20814,
Divalproex sodium versus olanzapine in the
treatment of acute mania in bipolar disorder: health-related quality of life and
medical cost outcomes.
J Clin Psychiatry. 2003 Mar;64(3):288-94.
Divalproex sodium is a mood stabilizer used in the United States for the treatment
of acute mania associated with bipolar disorder. Recently, olanzapine, an atypical
antipsychotic, was approved for the treatment of acute mania. This study compares
the clinical, health-related quality of life (HRQL), and economic outcomes of
divalproex and olanzapine in the treatment of acute mania associated with bipolar
disorder. METHOD: This 12-week, double-blind, double-dummy, randomized clinical
trial included 120 subjects with DSM-IV bipolar disorder type I hospitalized for
an acute manic episode recruited from 21 U.S. clinical centers. Subjects were
randomly assigned to treatment with either divalproex or olanzapine and were followed
in hospital for up to 21 days. If after 21 days clinical improvements (based on
the Mania Rating Scale [MRS]) were not observed, subjects were discontinued. Subjects
showing clinical improvement were treated for up to 12 weeks. HRQL was assessed
using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) after
hospital discharge (baseline) and at 6 and 12 weeks. Medical resource use and
costs were collected over the 12-week study. RESULTS: A total of 120 subjects
(N = 63 divalproex, N = 57 olanzapine) were randomized, and 78 (65%) were followed
beyond 21 days. No statistically significant differences between the treatment
groups for baseline-to-endpoint MRS or Q-LES-Q scores were observed. Total 12-week
outpatient medical costs were significantly lower for the divalproex-treated group
(541 US dollars) compared with the olanzapine-treated group (1080 US dollars)
(p =.004). There was no significant difference in total medical costs between
the 2 groups (divalproex = 13,703 US dollars; olanzapine = 15,180 US dollars;
p =.88). CONCLUSION: Divalproex is associated with lower 12-week outpatient costs
compared with olanzapine. Divalproex and olanzapine have similar short-term effects
on clinical or HRQL outcomes in bipolar disorder subjects." [Abstract]
M, Baker RW, Altshuler LL, Zarate CA, Suppes T, Ketter TA, Milton DR, Risser R,
Gilmore JA, Breier A, Tollefson GA.
Lilly Research Laboratories, Indianapolis,
IN 46285, USA. firstname.lastname@example.org
Olanzapine versus divalproex in
the treatment of acute mania.
Am J Psychiatry. 2002 Jun;159(6):1011-7.
The effects of olanzapine and divalproex for the treatment of mania were compared
in a large randomized clinical trial. METHOD: A 3-week, randomized, double-blind
trial compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500
mg/day in divided doses) for the treatment of patients hospitalized for acute
bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton
Depression Rating Scale were used to quantify manic and depressive symptoms, respectively.
Safety was assessed with several measures. RESULTS: The protocol defined baseline-to-endpoint
improvement in the mean total score on the Young Mania Rating Scale as the primary
outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for
patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex
(N=123). A priori categorizations defined response and remission rates: 54.4%
of olanzapine-treated patients responded (> or = 50% reduction in Young Mania
Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of
olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania
Rating Scale < or = 12), compared to 34.1% of divalproex-treated patients.
The decrease in Hamilton depression scale score was similar in the two treatment
groups. Completion rates for the 3-week study were similar in both groups. The
most common treatment-emergent adverse events (incidence >10%) occurring more
frequently during treatment with olanzapine were dry mouth, increased appetite,
and somnolence. For divalproex, nausea was more frequently observed. The average
weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex
treatment. CONCLUSIONS: The olanzapine treatment group had significantly greater
mean improvement of mania ratings and a significantly greater proportion of patients
achieving protocol-defined remission, compared with the divalproex treatment group.
Significantly more weight gain and cases of dry mouth, increased appetite, and
somnolence were reported with olanzapine, while more cases of nausea were reported
with divalproex." [Abstract]
RM, Baker JD, Wozniak P, Tracy K, Sommerville KW.
University of Texas Medical
Branch at Galveston, Galveston, USA. email@example.com
and early efficacy of oral-loaded divalproex versus standard-titration divalproex,
lithium, olanzapine, and placebo in the treatment of acute mania associated with
J Clin Psychiatry. 2003 Jul;64(7):841-6.
Previous studies have examined the safety and tolerability of oral-loaded divalproex
sodium in the treatment of acute mania, but not the early efficacy of this dosing
strategy. The purpose of this study was to evaluate the early efficacy of oral-loaded
divalproex. METHOD: In this pooled analysis, 348 subjects from 3 randomized, double-blind,
parallel-group, active- or placebo-controlled studies were used to compare the
efficacy, safety, and tolerability of oral-loaded divalproex with standard-titration
divalproex, lithium, olanzapine, or placebo. Subjects were inpatients diagnosed
with acute mania associated with bipolar I disorder (DSM-III-R or -IV and SADS-Change
Version). Patients were administered oral-loaded divalproex (20 or 30 mg/kg/day
on days 1 and 2 followed by 20 mg/kg/day, and increased at physician's discretion),
standard-titration divalproex initiated at 250 mg t.i.d. and titrated to 40-150
microg/mL, lithium (300 mg t.i.d. initial dose) titrated to 0.4 to 1.5 mEq/L,
olanzapine (10 mg q.d. initial dose) up to 20 mg/day, or placebo. RESULTS: The
results demonstrate an early efficacy advantage for oral-loaded divalproex compared
to standard-titration divalproex at days 5, 7/8, and 10. Efficacy was improved
over lithium on day 7/8. There were no efficacy differences between divalproex
loading and olanzapine. Divalproex loading showed greater efficacy than placebo
at all time points. Divalproex loading was as well tolerated or better tolerated
than the other active treatments as measured by adverse events and changes in
laboratory parameters. CONCLUSION: These results suggest the oral loading of divalproex
leads to a more rapid antimanic effect when compared with standard-titration divalproex,
lithium, or placebo and is better tolerated than olanzapine and as well tolerated
as lithium or standard-titration divalproex." [Abstract]
M, Ichim L, Brook S.
Department of Psychiatry, University of the Witwatersrand
Medical School, Parktown, South Africa. firstname.lastname@example.org
compared to lithium in mania: a double-blind randomized controlled trial.
Clin Psychopharmacol. 1999 Nov;14(6):339-43.
"Neuroleptics are of established
efficacy in mania. Controlled data on the use of olanzapine in mania is however,
absent. In this study, 30 patients meeting DSM-IV criteria for mania were randomly
allocated to receive either olanzapine or lithium in a 4 week double-blind randomized
controlled design. There were no significant outcome differences between the two
groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale
(lithium 28.2; olanzapine 28.0; P = 0.44); Clinical Global Impression (CGI) improvement
scale (lithium 2.75, olanzapine 2.36; P = 0.163) or the Mania Scale (lithium 13.2,
olanzapine 10.2; P = 0.315). Olanzapine was however, significantly superior to
lithium on the CGI-severity scale at week 4 (lithium 2.83, olanzapine 2.29; P
= 0.025). Olanzapine did not differ from lithium in terms of treatment emergent
extrapyramidal side-effects as measured by the Simpson-Angus Scale. Olanzapine
appears to be at least as effective as lithium in the treatment of mania."
M, Goldberg JF, Gonzalez-Pinto Arrillaga AM, Azorin JM, Vieta E, Hardy-Bayle MC,
Lawson WB, Emsley RA, Zhang F, Baker RW, Risser RC, Namjoshi MA, Evans AR, Breier
Lilly Research Laboratories, Indianapolis,
Ind 46225, USA. email@example.com
12-week, double-blind comparison of olanzapine vs haloperidol in the treatment
of acute mania.
Arch Gen Psychiatry. 2003 Dec;60(12):1218-26.
This randomized controlled trial compares the efficacy and safety of olanzapine
vs haloperidol, as well as the quality of life of patients taking these drugs,
in patients with bipolar mania. METHODS: The design consisted of 2 successive,
6-week, double-blind periods and compared flexible dosing of olanzapine (5-20
mg/d, n = 234) with haloperidol (3-15 mg/d, n = 219). RESULTS: Rates of remission
(Young-Mania Rating Scale score of < or =12 and 21-item Hamilton Rating Scale
for Depression score of < or =8 at week 6) were similar for olanzapine- and
haloperidol-treated patients (52.1% vs 46.1%, respectively; P =.15). For the subgroup
of patients whose index episode did not include psychotic features, rates of remission
were significantly greater for the olanzapine group compared with the haloperidol
group (56.7% vs 41.6%, P =.04). Relapse into an affective episode (mania and/or
depression) occurred in 13.1% and 14.8% of olanzapine- and haloperidol-treated
patients, respectively (P =.56). Switch to depression occurred significantly more
rapidly with haloperidol than with olanzapine when using survival analysis techniques
(P =.04), and significantly more haloperidol-treated patients experienced worsening
of extrapyramidal symptoms, as indicated by several measures. Weight gain was
significantly greater in the olanzapine group compared with the haloperidol group
(2.82 vs 0.02 kg, P<.001). The olanzapine group had significant improvement
in quality of life on several dimensions compared with the haloperidol group.
CONCLUSIONS: These data suggest that olanzapine does not differ from haloperidol
in achieving overall remission of bipolar mania. However, haloperidol carries
a higher rate of extrapyramidal symptoms, whereas olanzapine is associated with
weight gain." [Abstract]
L, Namjoshi MA, Zhang F, Gandhi G, Edgell ET, Tohen M, Breier A, Haro JM.
Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. firstname.lastname@example.org
versus haloperidol in the treatment of acute mania: clinical outcomes, health-related
quality of life and work status.
Int Clin Psychopharmacol.
"We aimed to compare clinical outcomes, health-related
quality of life (HRQOL) and work status associated with olanzapine and haloperidol
treatment in patients with bipolar disorder. This double-blind, randomized controlled
trial, comparing flexible dosing of olanzapine (5-20 mg/day, n = 234) to haloperidol
(3-15 mg/day, n = 219), consisted of a 6-week acute phase, followed by a 6-week
continuation phase. Symptomatic remission rates were similar for olanzapine- and
haloperidol-treated patients at weeks 6 and 12. At week 6, significant changes
in five dimensions of the Medical Outcomes Study 36-Item Short Form Health Survey
(SF-36) [general health (P = 0.010), physical functioning (P < 0.001), role
limitations due to physical problems (P < 0.001), social functioning (P <
0.05) and vitality (P < 0.01)] and the SF-36 physical components summary score
were found in favour of olanzapine compared to haloperidol. At week 12, olanzapine
treatment maintained the significantly favourable HRQOL changes. At the end of
week 12, patients on olanzapine showed significantly greater improvement than
haloperidol in work activities impairment and household activities impairment
scores on the Streamlined Longitudinal Interview Clinical Evaluation from the
Longitudinal Interval Follow-up Evaluation (SLICE/LIFE) activities impairment
scores. Subgroup analyses revealed that olanzapine treatment significantly increased
a proportion of employed patients and their weekly paid working hours. In conclusion,
compared to haloperidol, olanzapine treatment was comparably effective in the
remission of bipolar mania and significantly improved HRQOL and work status in
patients with bipolar I disorder." [Abstract]
RJ, Hennen J, Wilson M, Calabrese J, Chengappa R, Keck PE Jr, McElroy SL, Sachs
G, Vieta E, Welge JA, Yatham LN, Zarate CA Jr, Baker RW, Tohen M.
Consortium for Bipolar Disorder Research, Department of Psychiatry and Neuroscience
Program, Harvard Medical School, Boston, MA, USA. email@example.com
versus placebo in acute mania: treatment responses in subgroups.
Clin Psychopharmacol. 2003 Aug;23(4):370-6.
"Two double-blind, placebo-controlled
trials of olanzapine in acute mania showed significant overall antimanic efficacy,
based on reductions in mania ratings. Their subject-level data were pooled to
increase statistical power to test for differences in treatment responses among
10 subgroup pairs of interest using generalized estimating equations methods.
Similar drug/placebo superiority and responsiveness to olanzapine was found in
men versus women, psychotic versus nonpsychotic subjects, and those presenting
in mania versus mixed states, and responses were independent of onset age, current
age, or prior illness based on episodes, hospitalizations, recent rapid cycling,
lifetime substance use, or previous antipsychotic treatment. Olanzapine and placebo
responses paralleled closely (r(s) = 0.73). Patients were relatively more responsive
to olanzapine who were younger at illness onset, lacked prior substance abuse,
and had not previously received antipsychotic treatment (efficacy ratios 1.5-1.7,
all P < 0.01). These well-powered comparisons of subgroups of interest indicate
broad efficacy of olanzapine in the treatment of acute mania." [Abstract]
KN, Baker RW, Shao L, Yatham LN, Tohen M, Gershon S, Kupfer DJ.
Institute & Clinic, Mayview State Hospital, University of Pittsburgh Medical
Center, PA 15213-2593, USA. firstname.lastname@example.org
Rates of response,
euthymia and remission in two placebo-controlled olanzapine trials for bipolar
Bipolar Disord. 2003 Feb;5(1):1-5.
Clinically meaningful recovery from acute mania may not be captured by conventionally
reported response categorizations. We defined new and stringent criteria for remission
in bipolar mania. Using a cohort of patients with acute mania randomized to treatment
with either olanzapine or placebo, we contrasted remission rates to findings using
previously reported but more lenient categorical outcome measures of response
and euthymia. METHODS: We pooled and reanalyzed results through 3 weeks from two
published randomized double-blind trials of olanzapine versus placebo for treating
acute bipolar mania (1, 2). Response was previously defined as > or = 50% decrease
from baseline to endpoint total Young Mania Rating Scale (3) (Y-MRS) scores, and
euthymia as an endpoint total Y-MRS score of < or = 12. In this report, remission
required an endpoint total Y-MRS score of < or = 7, and an endpoint total Hamilton
Depression Rating Scale, (HAM-D21) (4) score of < or = 7 and an endpoint Clinical
Global Impression Scale - Bipolar version, CGI-BP (5), overall severity score
of < or = 2. RESULTS: Olanzapine treated subjects achieved statistically significantly
greater rates of clinical response, euthymia and remission than those assigned
to placebo, 55% versus 29.5%, 50% versus 27%, and 18% versus 7%, respectively.
CONCLUSIONS: Olanzapine monotherapy resulted in discernable clinical improvements
in mania in over 50% of subjects and just under 20% of subjects achieved a near
complete resolution of manic and accompanying depressive symptoms after 3 weeks
of treatment. Full remission is an important but potentially elusive goal during
short-term management of acute mania." [Abstract]
MA, Rajamannar G, Jacobs T, Sanger TM, Risser R, Tohen MF, Breier A, Keck PE Jr.
Research Laboratories, Eli Lilly & Co., Indianapolis, IN, USA. email@example.com
clinical, and quality-of-life outcomes associated with olanzapine treatment in
mania. Results from a randomized controlled trial.
Disord. 2002 May;69(1-3):109-18.
"INTRODUCTION: The objectives of this
study were to determine the economic, clinical, and quality-of-life outcomes associated
with olanzapine treatment in patients diagnosed with mania. METHODS: Patients
with a diagnosis of bipolar I disorder with manic or mixed episodes were enrolled
in a randomized controlled trial. The study design comprised a 3-week acute phase
followed by a 49-week open label extension. In the open label extension, the use
of lithium and fluoxetine was permitted for patients who experienced breakthrough
symptoms. Clinical, economic, and quality-of-life outcomes of treatment were assessed.
RESULTS: During the acute phase, olanzapine patients experienced a statistically
significant greater mean improvement from baseline on the Y-MRS total score compared
to the placebo patients. In the open label extension, patients experienced a statistically
significant mean change of 11.8 units on the Y-MRS from the end of the acute phase.
When compared to costs incurred in the previous 12 months of therapy, patients
experienced savings of almost $900 per month during the 49 weeks of olanzapine
therapy. These cost savings were largely driven by reductions in in-patient costs
during the open label extension. Health-related quality of life improvements measured
by the SF-36 were seen on several dimensions both in the 3-week acute phase as
well as in the 49-week open label extension. CONCLUSION: From a clinical, economic,
and quality-of-life outcomes standpoint, olanzapine had a significant impact in
the treatment of mania, and could be considered a cost-effective treatment option
for use in this population if these findings are extrapolated to non-clinical
trial populations." [Abstract]
Tohen M, Chengappa KN, Suppes T, Zarate CA Jr, Calabrese
JR, Bowden CL, Sachs GS, Kupfer DJ, Baker RW, Risser RC, Keeter EL, Feldman PD,
Tollefson GD, Breier A.
Lilly Research Laboratories, Eli Lilly & Co, Indianapolis,
IN 46285, USA.
Efficacy of olanzapine in combination with valproate
or lithium in the treatment of mania in patients partially nonresponsive to valproate
or lithium monotherapy.
Arch Gen Psychiatry. 2002 Jan;59(1):62-9.
A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine
the efficacy of combined therapy with olanzapine and either valproate or lithium
compared with valproate or lithium alone in treating acute manic or mixed bipolar
episodes. METHODS: The primary objective was to evaluate the efficacy of olanzapine
(5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured
by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar
disorder (n = 344), manic or mixed episode, who were inadequately responsive to
more than 2 weeks of lithium or valproate therapy, were randomized to receive
cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer).
RESULTS: Olanzapine cotherapy improved patients' YMRS total scores significantly
more than monotherapy (-13.11 vs -9.10; P = .003). Clinical response rates (>
or = 50% improvement on YMRS) were significantly higher with cotherapy (67.7%
vs 44.7%; P< .001). Olanzapine cotherapy improved 21-item Hamilton Depression
Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98
vs 0.89 points; P< .001). In patients with mixed-episodes with moderate to
severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of > or = 20
at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared
with 1.57 for monotherapy (P< .001). Extrapyramidal symptoms (Simpson-Angus
Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly
changed from baseline to end point in either treatment group. Treatment-emergent
symptoms that were significantly higher for the olanzapine cotherapy group included
somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech.
CONCLUSION: Compared with the use of valproate or lithium alone, the addition
of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar
Baker RW, Brown E, Akiskal HS, Calabrese JR, Ketter TA, Schuh LM, Trzepacz PT, Watkin JG, Tohen M
Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania.
Br J Psychiatry. 2004 Dec;185472-8.
BACKGROUND: Few controlled studies examine the treatment of depressive features in mania. AIMS: To evaluate the efficacy of olanzapine, in combination with lithium or valproate, for treating depressive symptoms associated with mania. METHOD: Secondary analysis of a 6-week, double-blind, randomised study of olanzapine (5-20 mg/day) or placebo combined with ongoing valproate or lithium open treatment for 344 patients in mixed or manic episodes. This analysis focused on a dysphoric subgroup with baseline Hamilton Rating Scale for Depression (HRSD) total scores of 20 or over contrasted with non-dysphoric patients. RESULTS: In the dysphoric subgroup (n=85) mean HRSD total score improvement was significantly greater in olanzapine co-therapy patients than in those receiving placebo plus lithium or valproate (P<0.001). Substantial contributors to this superiority included the HRSD Maier sub-scale (P=0.013) and the suicide item (P=0.001). Total Young Mania Rating Scale improvement was also superior with olanzapine co-therapy. CONCLUSIONS: In patients with acute dysphoric mania, addition of olanzapine to ongoing lithium or valproate monotherapy significantly improved depressive symptom, mania and suicidality ratings. [Abstract]
M, Chengappa KN, Suppes T, Baker RW, Zarate CA, Bowden CL, Sachs GS, Kupfer DJ,
Ghaemi SN, Feldman PD, Risser RC, Evans AR, Calabrese JR.
prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood
stabiliser v. mood stabiliser alone.
Br J Psychiatry. 2004
BACKGROUND: Few controlled studies have examined the use of
atypical antipsychotic drugs for prevention of relapse in patients with bipolar
I disorder. Aims To evaluate whether olanzapine plus either lithium or valproate
reduces the rate of relapse, compared with lithium or valproate alone. METHOD:
Patients achieving syndromic remission after 6 weeks'treatment with olanzapine
plus either lithium (0.6-1.2 mmol/l) or valproate (50-125 microg/ml) received
lithium or valproate plus either olanzapine 5-20 mg/day (combination therapy)
or placebo (monotherapy), and were followed in a double-masked trial for 18 months.
RESULTS: The treatment difference in time to relapse into either mania or depression
was not significant for syndromic relapse (median time to relapse: combination
therapy 94 days, monotherapy 40.5 days; P=0.742), but was significant for symptomatic
relapse (combination therapy 163 days, monotherapy 42 days; P=0.023). CONCLUSIONS:
Patients taking olanzapine added to lithium or valproate experienced sustained
symptomatic remission, but not syndromic remission, for longer than those receiving
lithium or valproate monotherapy. [Abstract]
RW, Goldberg JF, Tohen M, Milton DR, Stauffer VL, Schuh LM.
Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN
46285, USA. firstname.lastname@example.org
The impact of response to previous
mood stabilizer therapy on response to olanzapine versus placebo for acute mania.
Disord. 2002 Feb;4(1):43-9.
"OBJECTIVES: A clinically important question
for any new treatment for bipolar disorder is whether its efficacy extends to
patients who have both responded and failed to respond to other mood stabilizers.
In this secondary analysis of a placebo-controlled trial demonstrating olanzapine's
efficacy for acute mania, we explore whether its usefulness extends to those patients
with a history of poor response to other mood stabilizers. METHODS: This 4-week,
double-blind, placebo-controlled trial studied olanzapine monotherapy 5-20 mg/day
for hospitalized patients in acute manic or mixed bipolar episodes. The primary
outcome variable was beginning to endpoint change in the Young-Mania Rating Scale
(Y-MRS) total score. We investigated whether prospectively identified history
of recent failure to respond to other mood stabilizers predicted response to olanzapine.
RESULTS: As previously reported, olanzapine-treated patients experienced significantly
greater improvement in Y-MRS total score and higher remission rates relative to
placebo-treated patients. The current analysis compared these outcome parameters
in patients with known poor prior response to lithium and/or valproate with all
other patients and found no significant group by treatment interactions, i.e.,
treatment effects were not significantly diminished in non-responders to older
mood stabilizing agents. CONCLUSIONS: Olanzapine has been shown to be superior
to placebo for the treatment of mania. This secondary analysis suggests that olanzapine
monotherapy is similarly effective for patients whether or not they previously
have failed to respond to another mood stabilizer for mania. A study limitation
is that response to lithium or valproate was determined retrospectively."
TM, Tohen M, Vieta E, Dunner DL, Bowden CL, Calabrese JR, Feldman PD, Jacobs TG,
Lilly Research Laboratories, Indianapolis, IN 46285, USA.
in the acute treatment of bipolar I disorder with a history of rapid cycling.
Affect Disord. 2003 Jan;73(1-2):155-61.
"BACKGROUND: A substantial proportion
of patients with bipolar disorder are characterized by a rapidly cycling course
and are particularly resistant to conventional treatment. METHODS: This secondary
analysis, defined a priori, was conducted on a larger data set from patients with
bipolar I disorder to determine the efficacy of a 3-week treatment with the atypical
antipsychotic olanzapine (5-20 mg/day, n=19) versus placebo (n=26) in patients
with >or=4 episodes in the preceding year. RESULTS: Significantly fewer placebo
patients completed treatment (34.6 vs. 73.7%, P=0.016), and more than half discontinued
due to lack of efficacy (53.8 vs. 21.1%, P=0.035). Olanzapine reduced Young Mania
Rating Scale (YMRS) total scores significantly more than placebo (-13.9 vs. -4.1,
P=0.011). Clinical responses, defined as >or=50% improvement in YMRS, were
achieved in 58% of olanzapine patients, compared with 28% of placebo patients
(P=0.066). Extrapyramidal symptoms were not significantly changed in either group.
Somnolence was the most common adverse event in both groups (olanzapine: 52.6%,
placebo: 23.1%; P=0.060). No event occurred significantly more frequently with
olanzapine than with placebo. No patients discontinued due to an adverse event.
LIMITATIONS: The duration of this study was limited to 3 weeks, precluding conclusions
about long-term efficacy of olanzapine. Moreover, a sizeable placebo effect was
obtained, possibly masking optimal therapeutic effect. Despite these limitations,
treatment differences in efficacy were highly significant. CONCLUSIONS: These
results indicate that olanzapine was effective in reducing symptoms of mania and
well tolerated in patients with bipolar I disorder with a rapid-cycling course."
Vieta E, Calabrese JR, Hennen J, Colom F, Martínez-Arán A, Sánchez-Moreno J, Yatham LN, Tohen M, Baldessarini RJ
Comparison of rapid-cycling and non-rapid-cycling bipolar I manic patients during treatment with olanzapine: analysis of pooled data.
J Clin Psychiatry. 2004 Oct;65(10):1420-8.
INTRODUCTION: Rapid-cycling (RC) bipolar disorder patients experience high levels of morbidity, typically respond unsatisfactorily to available treatments, and, so, require additional studies of novel treatments. We report on the first controlled study comparing acute and continuous clinical outcomes in RC and non-RC manic patients treated with olanzapine. METHOD: We analyzed data pooled from 2 placebo-controlled, double-blind, 3- to 4-week trials of olanzapine in mania (N = 254), 1 with an open-label extension up to 1 year (N = 113) and controlled supplementation with lithium or fluoxetine as needed, to compare demographic, clinical, and outcome measures between RC and non-RC subgroups of 254 DSM-IV bipolar I manic subjects. RESULTS: RC (N = 90, 35%) versus non-RC subjects (N = 164, 65%) were younger at intake (p = .02), less often psychotic (p < .0001), and more likely to have familial bipolar disorder (p < .0001), abused substances (p = .01), more previous hospitalizations (p = .004), and many more illness episodes (p < .001). In initial blinded trial outcomes, relative responses (> or = 50% improvement of mania) to olanzapine/placebo were similar in RC and non-RC subjects, though early responses to olanzapine favored RC over non-RC subjects (p = .003), and long-term outcomes favored non-RC subjects (p = .05). Fewer RC subjects achieved strictly defined initial symptomatic remission (p = .014) within a year; RC subjects were more likely to experience recurrences (p = .002), especially of depressive illness (< .001), and had more rehospitalizations (p = .01) and suicide attempts (p = .03). CONCLUSIONS: RC bipolar I patients showed major initial differences and more rapid initial clinical changes, especially toward depression, with less favorable long-term outcomes than non-RC cases during treatment with olanzapine. Inclusion of RC bipolar disorder patients can complicate therapeutic trials, but these patients require further study for differential responsiveness to innovative treatments with methods of assessing clinical response that take their mood instability into account. [Abstract]
M, Jacobs TG, Grundy SL, McElroy SL, Banov MC, Janicak PG, Sanger T, Risser R,
Zhang F, Toma V, Francis J, Tollefson GD, Breier A.
Lilly Research Laboratories,
Lilly Corporate Center, Indianapolis, IN 46285. USA. email@example.com
of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study.
The Olanzipine HGGW Study Group.
Arch Gen Psychiatry. 2000
"BACKGROUND: We compared the efficacy and safety of olanzapine
vs placebo for the treatment of acute bipolar mania. METHODS: Four-week, randomized,
double-blind, parallel study. A total of 115 patients with a DSM-IV diagnosis
of bipolar disorder, manic or mixed, were randomized to olanzapine, 5 to 20 mg/d
(n = 55), or placebo (n = 60). The primary efficacy measure was the Young-Mania
Rating Scale (Y-MRS) total score. Response and euthymia were defined, a priori,
as at least a 50% improvement from baseline to end point and as a score of no
less than 12 at end point in the Y-MRS total score, respectively. Safety was assessed
using adverse events, Extrapyramidal Symptom (EPS) rating scales, laboratory values,
electrocardiograms, vital signs, and weight change. RESULTS: Olanzapine-treated
patients demonstrated a statistically significant greater mean (+/- SD) improvement
in Y-MRS total score than placebo-treated patients (-14.8 +/- 12.5 and -8.1 +/-
12.7, respectively; P<.001), which was evident at the first postbaseline observation
1 week after randomization and was maintained throughout the study (last observation
carried forward). Olanzapine-treated patients demonstrated a higher rate of response
(65% vs 43%, respectively; P =.02) and euthymia (61% vs 36%, respectively; P =.
01) than placebo-treated patients. There were no statistically significant differences
in EPSs between groups. However, olanzapine-treated patients had a statistically
significant greater mean (+/- SD) weight gain than placebo-treated patients (2.1
+/- 2.8 vs 0.45 +/- 2.3 kg, respectively) and also experienced more treatment-emergent
somnolence (21 patients [38.2%] vs 5 [8.3% ], respectively). CONCLUSION: Olanzapine
demonstrated greater efficacy than placebo in the treatment of acute bipolar mania
and was generally well tolerated." [Abstract]
Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa
KN, Daniel DG, Petty F, Centorrino F, Wang R, Grundy SL, Greaney MG, Jacobs TG,
David SR, Toma V.
Lilly Research Laboratories, Eli Lilly and Co., Indianapolis,
IN 46285, USA.
Olanzapine versus placebo in the treatment of acute
mania. Olanzapine HGEH Study Group.
Am J Psychiatry. 1999
"OBJECTIVE: The primary intent of this study was to
compare the efficacy and safety of olanzapine and placebo in the treatment of
acute mania. METHOD: The design involved a random-assignment, double-blind, placebo-controlled
parallel group study of 3 weeks' duration. After a 2- to 4-day screening period,
qualified patients were assigned to either olanzapine (N = 70) or placebo (N =
69). Patients began double-blind therapy with either olanzapine, 10 mg, or placebo
given once per day. After the first day of treatment, the daily dose could be
adjusted upward or downward, as clinically indicated, by one capsule (olanzapine,
5 mg/day) within the allowed range of one to four capsules. The primary efficacy
measure in the protocol was defined as a change from baseline to endpoint in total
score on the Young Mania Rating Scale. Clinical response was defined a priori
as a decrease of 50% or more from baseline in Young Mania Rating Scale total score.
RESULTS: The olanzapine group experienced significantly greater mean improvement
in Young Mania Rating Scale total score than the placebo group. On the basis of
the clinical response criteria, significantly more olanzapine-treated patients
(48.6%) responded than those assigned to placebo (24.2%). Somnolence, dizziness,
dry mouth, and weight gain occurred significantly more often with olanzapine.
There were no statistically significant differences between the olanzapine-treated
and placebo-treated patients with respect to measures of parkinsonism, akathisia,
and dyskinesias. No discontinuations of treatment due to adverse events occurred
in the olanzapine treatment group. CONCLUSIONS: The results from this study suggest
that compared with placebo, olanzapine has superior efficacy for the symptoms
of acute mania." [Abstract]
L, Namjoshi MA, Swindle R, Yu X, Risser R, Baker RW, Tohen M.
Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
of olanzapine alone and olanzapine/fluoxetine combination on health-related quality
of life in patients with bipolar depression: secondary analyses of a double-blind,
placebo-controlled, randomized clinical trial.
BACKGROUND: Improving patients' health-related quality
of life (HRQOL) could be a treatment goal for bipolar depression. OBJECTIVES:
The objectives of these secondary analyses of a previous report were to determine
the benefits of olanzapine alone and olanzapine-fluoxetine combination (OFC) for
improving HRQOL in patients with bipolar depression using both a generic and a
depression-specific HRQOL instrument, and to examine the association between the
2 HRQOL instruments and the construct validity of the depression-specific HRQOL
instrument. METHODS: This was a double-blind, placebo-controlled, 83-site, international,
randomized trial. Adults with bipolar I disorder, most recent episode depressed
(according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition), were randomly assigned to receive olanzapine (6-20 mg/d), OFC (6/25,
12/25, or 12/50 mg/d), or placebo for 8 weeks. HRQOL improvement was calculated
as last-observation-carried-forward changes in dimension and component summary
scores on Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and
total score on the Quality of Life in Depression Scale (QLDS). Results: Patients
were assigned to receive olanzapine (n = 377), OFC (n = 86), or placebo (n = 370)
for 8 weeks. Of 833 enrolled patients, 454 discontinued (olanzapine, 232/377 [61.5%];
OFC, 31/86 [36.0%]; and placebo, 191/370 [51.6%]). Compared with placebo, olanzapine-treated
patients exhibited greater improvements on SF-36 mental component summary (MCS)
score ( P=0.002) and 3 of 8 SF-36 dimension scores (mental health [P=0.015], role-emotional
[P=0.046], and social functioning [P=0.006). OFC-treated patients exhibited greater
improvements on MCS score ( P<0.001) vs both placebo and olanzapine), 5 SF-36
dimension scores (general health perception (P<0.001) vs placebo; (P<0.001)
vs olanzapinel, mental health [ P=0.001] vs both placebo and olanzapine], role-emotional
[ P<0.001] vs placebo; [P=0.007] vs olanzapine], social functioning [ P=0.001]
vs placebo; [P=0.032] vs olanzapine], and vitality [P=0.002] vs placebo; [P=0.011]
vs olanzapine]), and QLDS total score ( P<0.001] vs both placebo and olanzapine).
Changes in SF-36 scores of mental health, social functioning, role-emotional,
and vitality were highly correlated to changes in the QLDS total score (all p
< -0.5). CONCLUSIONS: Based on these analyses, patients with bipolar depression
receiving olanzapine or OFC for 8 weeks had greater improvement in HRQOL than
those receiving placebo. OFC treatment was associated with greater improvement
in HRQOL than olanzapine alone. The correlation results support the construct
validity of the QLDS. [Abstract]
Baker RW, Milton DR, Stauffer VL, Gelenberg A, Tohen
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center,
Drop Code 4133, Indianapolis, IN 46285, USA. firstname.lastname@example.org
trials do not find association of olanzapine with exacerbation of bipolar mania.
Affect Disord. 2003 Jan;73(1-2):147-53.
"BACKGROUND: Published case reports
describe apparent induction or exacerbation of manic-like symptoms during treatment
with the atypical antipsychotics olanzapine and risperidone. To date, such reports
are from uncontrolled clinical experience and therefore cannot clarify whether
the atypical antipsychotics caused such manic-like states or simply failed to
prevent them. Presumably, bipolar patients would be at increased risk for this
putative adverse event. Therefore, we evaluated the potential of olanzapine to
exacerbate symptoms of mania compared to placebo during treatment of bipolar mania.
METHODS: Two inpatient, double-blind, randomized trials investigating the efficacy
of olanzapine 5-20 mg daily versus placebo for the treatment of acute mania were
combined. Two hundred and fifty-four subjects participated (placebo n=129; olanzapine
n=125) in the two studies. Severity of mania was quantified with the 11-item Young-Mania
Rating Scale (Y-MRS). In a post-hoc analysis, after double-blind therapy up to
3 weeks, categorical comparison of olanzapine and placebo groups was made for
any worsening and worsening by 10 or 20% from baseline Y-MRS scores (LOCF). RESULTS:
The percentage of subjects with exacerbation at endpoint were: any worsening,
placebo 37.7%, olanzapine 21.8% (P=0.005); >or=10% worsening, placebo 24.6%,
olanzapine 14.5% (P=0.039); >or=20% worsening, placebo 15.6%, olanzapine 8.1%
(P=0.064). CONCLUSION: Mania rating scores worsened for some patients during olanzapine
therapy. However, this was significantly less common with olanzapine than with
placebo. These controlled data suggest that clinical case reports of occurrence
of 'mania' during treatment with olanzapine, and possibly those with other atypical
antipsychotics, reflect exacerbation in the natural history of bipolar illness,
rather than an adverse pharmacological effect. LIMITATIONS: Post-hoc analysis
of pooled data from two different studies." [Abstract]
Meehan K, Zhang F, David S, Tohen M, Janicak P, Small
J, Koch M, Rizk R, Walker D, Tran P, Breier A.
Lilly Research Laboratories,
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
double-blind, randomized comparison of the efficacy and safety of intramuscular
injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients
diagnosed with bipolar mania.
J Clin Psychopharmacol. 2001
"There are no rapid-acting intramuscular formulations
of atypical antipsychotics available for quickly calming an agitated patient with
bipolar disorder. In this study, 201 agitated patients with bipolar mania were
randomly assigned to receive one to three injections of the atypical antipsychotic
olanzapine (10 mg, first two injections; 5 mg, third injection), the benzodiazepine
lorazepam (2 mg, first two injections; 1 mg, third injection), or placebo (placebo,
first two injections; olanzapine, 10 mg, third injection) within a 24-hour period.
Agitation was measured at baseline, every 30 minutes for the first 2 hours, and
at 24 hours after the first injection using the Positive and Negative Syndrome
Scale-Excited Component subscale and two additional agitation scales. At 2 hours
after the first injection, patients treated with olanzapine showed a significantly
greater reduction in scores on all agitation scales compared with patients treated
with either placebo or lorazepam. At 24 hours after the first injection, olanzapine
remained statistically superior to placebo in reducing agitation in patients with
acute mania, whereas patients treated with lorazepam were not significantly different
from those treated with placebo or olanzapine. Furthermore, no significant differences
among the three treatment groups were observed in safety measures, including treatment-emergent
extrapyramidal symptoms, the incidence of acute dystonia, or QTc interval changes.
These findings suggest that intramuscular olanzapine is a safe and effective treatment
for reducing acute agitation in patients with bipolar mania." [Abstract]