Am J Psychiatry 159:1011-1017, June 2002
© 2002 American Psychiatric
Association
Olanzapine Versus Divalproex in the Treatment of Acute Mania
Mauricio Tohen, M.D., Dr.P.H., Robert W.
Baker, M.D., Lori L. Altshuler, M.D., Carlos A.
Zarate, M.D., Trisha Suppes, M.D., Ph.D., Terrence A.
Ketter, M.D., Denai R. Milton, M.S., Richard Risser,
M.S., Julie A. Gilmore, Ph.D., Alan Breier,
M.D., and Gary A. Tollefson, M.D., Ph.D.
 |
Abstract |
OBJECTIVE:
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 (
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 
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.
|
Introduction |
Bipolar
disorder affects approximately 1% of the U.S. population (1,
2).
It represents a major public health concern, and the search for more
effective and safe treatments is ongoing. In 1972, lithium was
approved by the U.S. Food and Drug Administration (FDA) for the
treatment of acute mania. More than 20 years elapsed before the next
drug, divalproex, was approved. More recently, olanzapine, a
thiobenzodiazepine previously approved for treatment of psychotic
disorders, was the third drug approved by the FDA for treatment of
acute mania.
Both divalproex (3,
4)
and olanzapine (5,
6)
have demonstrated acute antimanic efficacy in two placebo-controlled,
parallel-group trials. Although placebo-controlled trials are
instrumental in demonstrating efficacy of a drug, active comparison
studies address more directly the relative benefits of efficacious
treatments. The primary objective of the study reported here was to
compare the efficacy of olanzapine versus divalproex in the
treatment of acute mania over a 3-week period. Herein, we report the
results of a multicenter, double-blind, randomized, parallel-group
study comparing olanzapine to divalproex.
|
Method
|
Patients
Patients
aged 18 to 75 with a diagnosis of bipolar I disorder, manic or mixed
episode, with or without psychotic features, were enrolled in this
study. Clinical diagnoses were confirmed with the Structured Clinical
Interview for DSM-IV, Patient Version. After the protocol was
explained to them, patients provided written informed consent to
participate in the study. A minimum total score of 20 on the Young
Mania Rating Scale (7)
was required at both the screening visit and on the day of random
assignment to study groups (baseline). Patients with any of the
following criteria were excluded: serious and unstable medical
illness, DSM-IV substance dependence within the past 30 days
(except nicotine or caffeine), documented history of intolerance
to olanzapine or divalproex, and treatment with lithium, an
anticonvulsant, or an antipsychotic medication within 24 hours of
random assignment to study groups.
Study Design
This was a 3-week, double-blind,
parallel-group study with a double-blind continuation phase of 44
weeks. This manuscript reports findings only for the 3-week acute
phase. Patients were hospitalized at baseline and for at least the
first week of double-blind treatment. All psychotropic medications
(except benzodiazepines) were tapered and discontinued during the
screening period.
Patients were randomly assigned to receive either olanzapine (5–20
mg/day) or divalproex (500–2500 mg/day). The initial daily doses were
15 mg/day of olanzapine and 750 mg/day of divalproex, consistent with
the recommendations of the manufacturers. Investigators made dose
adjustments primarily on the basis of clinical response but also on
plasma levels and adverse events. Patients who did not tolerate the
minimum dose level for treatment (5 mg/day olanzapine or 500 mg/day
divalproex) were discontinued from participation in the study.
Plasma levels were obtained to evaluate whether divalproex trough
levels were maintained within the targeted therapeutic range of
50–125 µg/ml. Assessment of olanzapine plasma levels has not been
shown to be helpful in its clinical use. To maintain the blind, all
patients randomly assigned to receive olanzapine had blood drawn, and
sham "divalproex" plasma level results were reported. Despite the use
of this procedure, all investigators at the clinical sites and at
Lilly Research Laboratories remained blind to subjects’ treatment
assignments. Blood was drawn from all patients on days 5, 7, and 21
and shipped to an independent reference laboratory; a coordinator at
the reference laboratory was unblinded to treatment assignment.
Divalproex levels below 35 µg/ml were reported as "well below
target level," levels from 35 to 49 µg/ml as "below target level,"
levels from 126 to 150 µg/ml as "above target level," and levels
above 150 µg/ml as "well above target level." For each report sent by
the laboratory of an out-of-target-range plasma level for a
divalproex-treated patient, a similar sham out-of-target-range report
for divalproex was sent for a randomly selected olanzapine-treated
patient at a different research center. Thus, if the investigator
decided to change the medication dose on the basis of the "sham"
divalproex plasma level for a patient taking olanzapine, increments
or decrements affected only the number of placebo tablets given
to that patient. This method ensured maintenance of the blind
procedure.
Concomitant lorazepam use was restricted to a maximum dose of 2
mg/day, and administration was not allowed within 8 hours of the
administration of a symptom rating scale. Benztropine was permitted
to treat extrapyramidal symptoms up to a maximum of 2 mg/day
throughout the course of the study. Benztropine was not allowed as
prophylaxis for extrapyramidal symptoms.
Assessment
Severity of illness was assessed with the
11-item Young Mania Rating Scale (7)
and the 21-item Hamilton Depression Rating Scale (8).
These assessments were performed daily during the first week and
weekly thereafter. A priori categorical definitions included
symptomatic remission, defined as endpoint Young Mania Rating Scale
total score 12, and clinical
response, defined as 50% baseline-to-endpoint reduction in Young Mania Rating
Scale total score. Safety was assessed by monitoring adverse
events, as well as by monitoring laboratory test values, ECG
results, vital signs, changes in weight, and scores on extrapyramidal
symptoms rating scales (Simpson-Angus Scale [9],
Barnes akathisia rating scale [10],
and Abnormal Involuntary Movement Scale [11]).
Adverse events that originally occurred or worsened in severity
during double-blind therapy were considered treatment emergent;
these events were recorded and coded by using the FDA’s Coding
Symbols for Thesaurus of Adverse Reaction Terms dictionary (12).
Statistical Methods
Patient data were analyzed on an
intent-to-treat basis. Patients with a baseline and at least one
postbaseline measurement were included in the analysis of mean
improvement with the last observation carried forward.
Efficacy and extrapyramidal symptoms rating scale scores were
evaluated by using analysis of variance. Rank-transformed data
were analyzed, as appropriate, when significant nonnormality
was found in the analysis of raw data. The models included terms
for the fixed effects of treatment, investigator, and the
treatment-by-investigator interaction. Models for analyses of
subgroup data included terms for investigator, treatment, the
subgroup, and the treatment-by-subgroup interaction. The
Kruskal-Wallis test was used to compare effects of the treatments on
each Young Mania Rating Scale item. Fisher’s exact test was used to
analyze treatment effects for completion rate, reason for
discontinuation, categorical efficacy, treatment-emergent adverse
events, and abnormalities in vital signs, ECG, and laboratory test
results. Time to discontinuation, time to response, and time to
symptomatic remission were assessed by using Kaplan-Meier estimated
survival curves, and the curves for each treatment group were
compared with the log-rank test.
The primary objective of the study was to assess the noninferiority
of olanzapine compared to divalproex in the reduction (from
baseline to endpoint) of manic symptoms as measured by the Young
Mania Rating Scale total score (with the last observation carried
forward) after 3 weeks of acute therapy. The assessment of
noninferiority was planned as a one-tailed comparison (one-tailed 95%
confidence interval [CI]) evaluating whether olanzapine was no worse
than divalproex in reducing manic symptoms by a predefined
amount. In this trial, olanzapine was considered noninferior only
if the reduction in the Young Mania Rating Scale score was no
more than 1.9 points less than the reduction associated with
divalproex. This a priori margin of noninferiority was equivalent to
20% of the reduction in manic symptoms (9.5 points on the Young
Mania Rating Scale) reported previously for divalproex therapy
(3).
The protocol was designed for approximately 325 patients per group to
be enrolled. This number of subjects was needed to provide 80% power
that the lower limit of the 95% one-sided CI for the difference in
mean change in Young Mania Rating Scale total scores between the two
treatment groups was greater than or equal to –1.9. The calculation
assumed that 5% of patients would not have a postbaseline visit, that
the expected mean change from baseline was –10.3 in the olanzapine
group and –9.5 in the divalproex group, and that the common
standard deviation was 13. A standard assessment of a statistical
difference in symptom reduction by means of a two-tailed test
of significance was planned with p<0.05 (superiority) and
performed only after a significant assessment of noninferiority.
This secondary assessment of statistical superiority after a
significant assessment of noninferiority was made without penalty
for multiple testing (13).
An interim analysis of the last-observation-carried-forward change in
the Young Mania Rating Scale total score was performed under the
auspices of a data monitoring board. Analysis for the first 117
patients randomly assigned to treatment groups (59 olanzapine
patients and 58 divalproex patients) resulted in a recommendation
from the data monitoring board for early termination of enrollment
after at least 200 total patients had been enrolled. The
recommendation was based on the interim analysis finding of
conditional power, derived by using the method of Lan and Wittes (14),
in excess of 95% for the assessment of noninferiority. The final
enrollment of 251 patients was a result of ethical considerations of
allowance made to investigators to enroll patients already scheduled
for screening after the data monitoring board had made its
recommendation. The interim analysis employed a significance level
(alpha) of 0.015. Adjusted alpha for the final analysis of the
primary efficacy measure was calculated by using the method of
Armitage et al. (15).
Therefore, the final analysis with N=251 utilized a 95.76% one-tailed
CI for noninferiority (or alpha=0.0412 for a two-tailed test of
significance). Otherwise, cited p values are based on two-tailed
tests with a significance level of 0.05.
|
Results |
Patients
The
baseline characteristics of the patients in each treatment group are
summarized in Table
1. A total of 330 patients were screened and entered into the
study across 48 sites in the United States. Seventy-nine patients
were recruited into the study but were not randomly assigned to
treatment groups. Of these 79 excluded patients, 28 met protocol
exclusionary criteria, 35 refused to participate, 15 were excluded by
investigators, and one additional patient was unable to be contacted
after study entry. A total of 126 and 125 patients were randomly
assigned to receive divalproex and olanzapine, respectively. There
were no statistically significant differences in the demographic
or illness characteristics between the two treatment groups.
Response during the most recent episode to antipsychotic medications,
lithium, or valproate occurred in 84.0% of the 206 patients for
whom data were available (84 divalproex patients and 89 olanzapine
patients); 79.9% of the 194 patients for whom data were available (77
divalproex patients versus 78 olanzapine patients) responded to
either lithium or valproate during their most recent exposure. There
were no significant treatment group differences in rates of
completion of the 3-week acute phase of therapy between
olanzapine-treated (N=86, 68.8%) and divalproex-treated (N=81, 64.3%)
patients (p=0.50, Fisher’s exact test). Further, reasons for
discontinuation did not differ significantly between groups
with 9.6% (N=12) and 8.8% (N=11) of olanzapine-treated patients
discontinuing because of adverse events or lack of efficacy,
espectively, compared to 7.1% (N=9) (p=0.50, Fisher’s exact test) and
9.5% (N=12) (p=1.00, Fisher’s exact test) of patients treated with
divalproex. Kaplan-Meier estimated time-to-discontinuation curves did
not differ significantly between groups (
2=0.57, df=1, p=0.45). By day 7,
a total of 15 divalproex-treated patients and 14 olanzapine-treated
patients had discontinued; by day 14, discontinuations totaled 28
patients for divalproex therapy and 29 patients for olanzapine
therapy. Three patients treated with divalproex had no postbaseline
assessment and were excluded from analyses of the Young Mania Rating
Scale primary efficacy variable.
Treatment
Mean modal doses for olanzapine and divalproex
were 17.4 mg/day and 1401.2 mg/day, respectively. Mean blood level of
divalproex at scheduled sampling visits was 77.4 µg/liter
(SD=27.8, N=108) at day 5; 82.1 µg/liter (SD=33.1, N=105) at day
7; and 83.9 µg/liter (SD=32.1, N=77) at day 21. A blood level
of divalproex 50 µg/liter was
achieved by 94 (87.0%) of 108, 91 (86.7%) of 105, and 68 (88.3%) of
77 patients at days 5, 7, and 21, respectively.
The groups did not differ significantly in use of allowed
anticholinergic (12.8% versus 9.5%; p=0.43, Fisher’s exact test) or
benzodiazepine (65.6% versus 65.9%; p=1.00, Fisher’s exact test)
adjunctive medication for olanzapine and divalproex patients,
respectively.
Efficacy
The mean improvement in the Young Mania Rating
Scale total score was 13.4 points (SD=8.8) in the olanzapine
treatment group and 10.4 points (SD=10.4) in the divalproex treatment
group. The lower limit of the 95.76% one-tailed confidence interval
for the assessment of noninferiority was 0.96, well in excess of
the predefined –1.9 margin of therapeutic equivalence. Further,
this 3.0 difference in mean Young Mania Rating Scale improvement
favoring the olanzapine treatment group was statistically significant
(F=4.92, df=1, 190, p<0.03) (Table
2). Baseline-to-endpoint (last observation carried forward) Young
Mania Rating Scale total score improvement was significantly greater
in the olanzapine group at day 2 (F=4.70, df=1, 190, p<0.04), day
14 (F=5.64, df=1, 190, p<0.02), and day 21 (F=4.92, df=1, 190,
p<0.03) but not at day 1 and days 3–7. Mean improvement from
baseline to endpoint (last observation carried forward) was
significantly greater for olanzapine-treated patients on three of the
individual Young Mania Rating Scale items: increased motor activity
(2=4.30,
df=1, p<0.04), sleep (2=8.21, df=1, p=0.004), and language–thought
disorder (2=6.24, df=1, p<0.02). There was no significant
between-group difference in mean improvement in any of the other
eight individual Young Mania Rating Scale items.
Response and Remission
Clinical response, based on 50% improvement in the Young
Mania Rating Scale score at endpoint, was achieved by 54.4% of
olanzapine-treated patients (N=68) and 42.3% of divalproex-treated
patients (N=52) (p=0.058, Fisher’s exact test). However, among
responders, the estimated time-to-response curves for the two
treatment groups were significantly different (2=4.28, df=1, p<0.05),
occurring more rapidly in the olanzapine group. The rates of
symptomatic remission (endpoint Young Mania Rating Scale total
score 12 ) were 47.2% for
the olanzapine-treated patients (N=59) and 34.1% for the
divalproex-treated patients (N=42) (p<0.04, Fisher’s exact test).
The estimated time-to-remission curves for the two therapy groups
were significantly different (2=4.45, df=1, p<0.04); the
estimated 25th percentile for time to remission was 3 days for
olanzapine patients and 6 days for divalproex patients (Figure
1).
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|
Figure 1. Kaplan-Meier Estimates of Time
to Remission for Subjects in a 3-Week Randomized, Double-Blind Trial
of Divalproex and Olanzapine in the Treatment of Acute
Maniaa
aRemission was defined as endpoint score 12 on the Young Mania Rating
Scale. Significantly shorter time to remission in the olanzapine
group (2=4.45, df=1, p<0.04, log-rank test).
| |
Mean baseline-to-endpoint change in the Hamilton depression scale
score was similar in the olanzapine-treated and the divalproex-treated
patients (mean=–4.92, SD=7.22, and mean=–3.46, SD=6.40,
respectively) (F=1.05, df=1, 188, p=0.31). Among the subset of
patients with a Hamilton depression scale total score of 20 or more
at baseline, the mean change at endpoint was –10.3 (SD=8.2) among 29
olanzapine-treated patients and –8.1 (SD=7.4) among 24
divalproex-treated patients (F=1.06, df=1, 51, p=0.31).
Efficacy in Psychotic and Nonpsychotic
Subgroups
Differential results were found on the basis of the
presence or absence of psychotic features (F=3.55, df=1, 247,
p=0.06). Among patients without psychotic features, the improvement
with olanzapine therapy (mean change from baseline=–14.1,
SD=8.6) was 5.4 points greater than with divalproex therapy (mean
change from baseline=–8.7, SD=8.5) (F=13.46, df=1, 107,
p<0.001). In the subgroup with psychotic features, there was no
statistically significant difference in improvement between the
olazapine patients (mean change from baseline=–12.6, SD=9.0) and
the divalproex patients (mean change from baseline=–12.8,
SD=12.4) (F=0.98, df=1, 112, p=0.93).
Safety
Adverse
events
Nine patients in the divalproex treatment group and 12
patients in the olanzapine treatment group discontinued treatment
because of an adverse event. Table
3 lists treatment-emergent adverse events reported significantly
more frequently in one treatment group compared to the other and/or
reported by at least 10% of the patients in either treatment
group.
Extrapyramidal symptom ratings
There
were no significant differences between treatment groups in
baseline-to-endpoint mean change in scores on the extrapyramidal
symptoms rating scales (Table
4).
Vital signs
There were no
statistically significant differences between treatment groups in the
incidence rates of potentially clinically relevant changes in vital
signs. Patients in the olanzapine treatment group had a significantly
larger mean weight gain, compared to the patients in the divalproex
treatment group (mean=2.5 kg, SD=2.5, and mean=0.9 kg, SD=2.5,
respectively) (F=20.40, df=1, 188, p<0.001) (Table
4).
Laboratory measures
The only
statistically significant differences between treatment groups in
treatment-emergent abnormalities in laboratory measures occurred in
the alanine aminotransferase/serum glutamic-pyruvic transferase
(ALT/SGPT) value and the platelet count. Patients in the olanzapine
treatment group had a significantly higher incidence of increased
ALT/SGPT (based on reference range limits that were specific to age,
ethnic origin, and sex categories and that ranged from >80 U/liter
for Caucasian women between age 18 and 49 to >125 U/liter for
Caucasian men between age 18 and 49) than patients in the divalproex
treatment group (5.1% versus 0%, respectively) (p<0.03, Fisher’s
exact test). The incidence of decreased platelet count (based on
reference range limits that were specific to age, ethnic origin, and
sex categories and that ranged from <151 x 109/liter for Caucasian
women between age 18 and 49 down to <114 x 109/liter for non-Caucasian
women between age 50 and 99) was significantly higher for
divalproex-treated patients than for the olanzapine-treated patients
(8.0% versus 0%, respectively) (p=0.001, Fisher’s exact test). There
were no significant between-group differences in rates of
treatment-emergent abnormalities in other chemistry, hematology, and
ECG tests at endpoint.
|
Discussion |
To our
knowledge, this study is the largest double-blind comparison of
divalproex and olanzapine in the treatment of acute mania.
Olanzapine-treated patients improved significantly more on the
primary efficacy variable (Young Mania Rating Scale total score).
In a recent 4-week, placebo-controlled trial that used 15 mg/day
of olanzapine as the starting dose (6),
the mean reduction in the Young Mania Rating Scale score at week 3
(last observation carried forward) was 13.9 points, comparable to the
13.4-point reduction for olanzapine-treated patients in the current
trial. Few available data address whether the 10.4-point mean
improvement in the divalproex group is in line with expectations. A
placebo-controlled valproate trial reported by Pope et al. (4)
used the Young Mania Rating Scale as the primary outcome variable,
but the results may not be directly comparable to those of the
current trial because the Pope et al. study was a smaller,
single-center trial that enrolled lithium-refractory and/or
intolerant patients. In that 3-week study, 17 valproate-treated
patients had a mean improvement on the Young Mania Rating Scale of
11.4 points, slightly higher than that observed in the current
study.
It is noteworthy that the reported average divalproex plasma
levels in a study by Bowden et al. (3)
were 77 µg/ml at day 8 and 93 µg/ml at day 21, compared to 82
µg/ml at day 7 and 84 µg/ml at day 21 in the current trial.
The slightly higher mean levels at endpoint in the Bowden et
al. trial may reflect differences in methods; in that study,
six upward titrations of divalproex were mandated, unless the
subject’s blood level was more than 150 µg/ml or contravening
side effects developed. In the study by Pope et al. (4),
blood levels of valproate were not reported. However, the authors
indicated that most of the clinical improvement was observed within
1–4 days of achieving serum levels of at least 50 mg/liter.
A report recently presented by Zajecka et al. (16)
described another study comparing divalproex sodium (N=63) to
olanzapine (N=57) in the treatment of acute mania. Zajecka and
collaborators used a starting loading dose of 20 mg/kg per day for
divalproex sodium (mean maximum dose=2115 mg/day) and 10 mg/day for
olanzapine (mean maximum dose=14.7 mg/day). As in the present study,
more improvement in the Young Mania Rating Scale was observed
during olanzapine treatment than during divalproex treatment.
However, unlike our findings, the difference observed by Zajecka et
al. was not statistically significant. This difference may be
explained by the smaller study group size of 120 patients, compared
to 251 in the present study. The results indicated a reduction
of 17.2 points for olanzapine and 14.8 for divalproex (p=0.21)
on the Young Mania Rating Scale from baseline to 21 days of
treatment. Dropout rates due to adverse events were similar
between treatments, and more individual adverse event terms—including
somnolence, weight gain, rhinitis, edema, and speech disorder—were
observed significantly more often during treatment with olanzapine.
In the current study, olanzapine produced greater improvement,
compared to divalproex, as measured by the change in score on
the Young Mania Rating Scale at days 2, 14, and 21. It is possible
that the brief early separation reflects slower achievement of
therapeutic dosing for divalproex than for olanzapine. Divalproex
dosing was titrated in accordance with the manufacturer’s
recommendation, starting at 750 mg on day 1 and was thereafter
adjusted on the basis of clinical response and serum levels.
Improvement in the early stages of divalproex therapy appears
more likely if the serum level has reached at least 45 µg/ml (17).
Therefore, standard dose initiation at 750 mg/day potentially
achieves efficacy less promptly than divalproex "loading" strategies,
with first day doses of 20–30 mg/kg. Several open studies have
supported the feasibility and utility of loading (18–21),
and one double-blind trial focusing on safety and tolerability
found more efficacy for loaded than for standard titration after
3 days of treatment (22).
Based on the findings of Hirschfeld et al. (22),
olanzapine’s transient separation during week 1 may have been less
likely if divalproex had been loaded.
It is interesting to note that olanzapine’s antimanic advantage in
this 3-week study cannot be solely ascribed to treatment of psychotic
symptoms. Without correcting for multiple comparisons, the treatments
separated on only three of the 11 items of the Young Mania Rating
Scale, with olanzapine superior on sleep, increased motor activity,
and language–thought disorder items. Furthermore, Young Mania Rating
Scale improvement among these psychotic patients was similar between
the two treatments, and olanzapine treatment produced significantly
greater improvement for the manic patients without psychotic
features. A treatment-by-subgroup interaction in Young Mania Rating
Scale improvement was observed when patients were categorized on the
basis of presence or absence of psychotic features. Among
olanzapine-treated patients, mean Young Mania Rating Scale
improvement was similar in the psychotic and nonpsychotic subgroups
(mean change of –12.6 and –14.1 points, respectively). Among
divalproex-treated patients, Young Mania Rating Scale score reduction
was greater in the psychotic subgroup (–12.8 points) than in the
nonpsychotic subgroup (–8.7 points). To our knowledge, previous
controlled trials of divalproex have not reported whether antimanic
efficacy varied according to the presence or absence of psychotic
features.
|
Conclusions |
During a
3-week, randomized, double-blind trial of treatment for acute mania
that compared flexibly dosed olanzapine versus divalproex, olanzapine
produced greater improvement in symptoms of mania as rated by the
Young Mania Rating Scale. In analyses using a priori clinically
meaningful definitions of remission and response, olanzapine was
statistically superior for remission and had superiority approaching
significance for clinical response, compared with divalproex. Both
drugs appeared to be well tolerated, and the two treatment groups had
similar rates of discontinuation because of adverse events. However,
more adverse events, including weight gain, occurred significantly
more frequently during treatment with olanzapine than with
divalproex. Although in this trial the primary outcome favored
olanzapine, the selection of pharmacological treatment should
consider both safety and efficacy parameters as well as
patient-specific considerations.
|
Acknowledgments |
The authors
acknowledge the following institutions and individuals who
participated in this clinical trial: Jay Amsterdam, M.D., University
of Pennsylvania, Philadelphia; George Bartzokis, M.D., Little Rock
Veterans Affairs Medical Center, North Little Rock, Ark.; Louise
Dabiri-Beckett, M.D., IPS Research Company, Oklahoma City; Gary
Booker, M.D., IPS Research Company, Shreveport, La.; Ron Brenner,
M.D., St. John’s Episcopal Hospital, Far Rockaway, N.Y.; David Brown,
M.D., Community Clinical Research, Inc., Austin, Tex.; Timothy Byrd,
M.D., Charter Springs Behavioral Clinic, Ocala, Fla.; Franca
Centorrino, M.D., McLean Hospital, Belmont, Mass.; James Chou, M.D.,
Bellevue Hospital, New York; Anthony Claxton, M.D., and Hermant
Patel, M.D., University of Oklahoma Health Sciences Center, Oklahoma
City; Lori Davis, M.D., Veterans Affairs Medical Center, Tuscallosa,
Ala.; Jose E. De La Gandara, M.D., North Broward Neurological
Institute Memory Disorder Center, Pompano Beach, Fla.; G. Michael
Dempsey, M.D., Memorial Hospital, Albuquerque, N.M.; Rif
El-Mallakh, M.D., University of Louisville School of Medicine,
Louisville, Ky.; Louis Fabre, M.D., Fabre Research Clinics, Houston;
David Feifel, M.D., University of California at San Diego
Medical Center, San Diego; Brent Forester, M.D., Mental Health
Center of Greater Manchester, Manchester, N.H.; Arthur Freeman
III, M.D., Louisiana State University Medical Center,
Shreveport, La.; Mark Frye, M.D., UCLA Neuropsychiatric Institute and
Hospital, Los Angeles; Alan Green, M.D., Massachusetts Mental Health
Center, Boston; Sanjay Gupta, M.D., Psychiatric Network, P.C.,
Olean, N.Y.; Robert Horne, M.D., Lake Meade Hospital, Las Vegas;
Fuad Issa, M.D., Clinical Research Center of Northern Virginia,
Falls Church, Va.; Robert Jamieson, M.D., Psychiatric
Consultants, P.C., Nashville, Tenn.; Christopher Kelsey, M.D., San
Diego Center for Research, San Diego; Louis Ari Kopolow, M.D.,
Associated Psychotherapy Centers, Gaithersburg, Md.; Jeff Mitchell,
M.D., Laureate Psychiatric Clinic and Hospital, Tulsa, Okla.;
Cesar Munoz, M.D., University of Alabama at Birmingham,
Birmingham, Ala.; Fred Petty, M.D., Ph.D., Veterans Affairs Medical
Center, Dallas; Michael, Plopper, M.D., Mesa Vista Hospital, San
Diego; Joanchim Raese, M.D., Knollwood Psychiatric and Chemical
Dependency Center of Charter Hospital, Murietta, Calif.; Jeffery
Rausch, M.D., Medical College of Georgia, Augusta, Ga.; Robert
Riesenberg, M.D., Atlanta Center for Medical Research, Decatur, Ga.;
Leon Rubenfaer, M.D., Harbor Oaks Hospital, Farmington Hills,
Mich,; John Schmitz, M.D., Midwest Psychiatric Consultants, P.C.,
Kansas City, Mo.; Taylor Segraves, M.D., Ph.D., MetroHealth
Medical Center, Cleveland; Philip Seibel, M.D., Contemporary
Behavioral Research, L.L.C., Washington, D.C.; G. Michael Shehi,
M.D., Mountain View Hospital, Gladsden, Ala.; Marshall Thomas,
M.D., University of Colorado Health Sciences Center, Denver;
Kathleen Toups, M.D., Bay Area Research Institute, Lafayette,
Calif.; Dan Wilson, M.D., Pauline Warfield Lewis Center,
Cincinnati; Tai P. Yoo, M.D., Mercy Hospital, Detroit; and John
Zajecka, M.D., Rush Presbyterian St. Lukes, Chicago.
|
Footnotes |
Received Jan. 16, 2001; revision received Nov. 2, 2001;
accepted Dec. 17. 2001. From Lilly Research Laboratories; the
Department of Psychiatry, Harvard Medical School and McLean Hospital,
Belmont, Mass.; UCLA Neuropsychiatric Institute and Hospital, Los
Angeles; National Institute of Mental Health, Bethesda, Md.;
University of Texas Southwestern Medical Center, Dallas; and Stanford
University, Stanford, Calif. Address reprint requests to Dr. Tohen,
Lilly Research Laboratories, Indianapolis, IN 46285; m.tohen@lilly.com (e-mail).
Sponsored by Lilly Research Laboratories.
|
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