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Efficacy of Olanzapine in Combination With Valproate or Lithium in the Treatment of Mania in Patients Partially Nonresponsive to Valproate or Lithium Monotherapy
Mauricio Tohen, MD, DrPH;
K. N. Roy Chengappa, MD;
Trisha Suppes, MD, PhD;
Carlos A. Zarate, Jr, MD;
Joseph R. Calabrese, MD;
Charles L. Bowden, MD;
Gary S. Sachs, MD;
David J. Kupfer, MD;
Robert W. Baker, MD;
Richard C. Risser, MSc;
Elisabeth L. Keeter, RN, MSN;
Peter D. Feldman, PhD;
Gary D. Tollefson, MD, PhD;
Alan Breier, MD
Arch Gen Psychiatry. 2002;59:62-69.
ABSTRACT
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Background 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 ( 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 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 episodes.
INTRODUCTION
THE EXPERT Consensus Guidelines Series, published in the year 2000,
recommends lithium and valproate as first-line treatments for bipolar mania.1 However, up to 40% of patients respond poorly to monotherapy
with either treatment.2 When monotherapy fails,
the guidelines recommend combination therapies. A number of authors have recently
reviewed the use of such cotherapies for bipolar mania. Freeman and Stoll3 concluded that the combination of lithium and valproate
is better tolerated and more efficacious in maintenance therapy than other
combination treatments.
Typical neuroleptics have been suggested to be superior in efficacy
to lithium monotherapy.4 Conversely, the addition
of a mood stabilizer to conventional antipsychotic therapy seems superior
to antipsychotic agents alone.5 In support
of this, Müller-Oerlinghausen et al6 compared
the efficacy of combined therapy with conventional antipsychotics and valproate
vs valproate monotherapy in patients with bipolar or schizoaffective disorder
and found combination therapy to be superior to monotherapy.
Olanzapine, an atypical antipsychotic, has been shown in 2 placebo-controlled
studies to have acute antimanic effects.7-8
Moreover, a previous report has suggested that olanzapine is effective when
used in combination with other psychotropic agents.9
The present study was conducted to investigate the efficacy and safety of
combined therapy with olanzapine and either valproate or lithium compared
with valproate or lithium monotherapy.
SUBJECTS AND METHODS
SUBJECTS
All patients were diagnosed as having bipolar disorder, manic or mixed
episode, with or without psychotic features, using the Structured Clinical
Interview for the DSM-IV10
(SCID).11 Patients had to have at least 2 previous
depressed, manic, or mixed episodes as well as a Young Mania Rating Scale12 (YMRS) total score of 16 or greater at visit 1 and
visit 2 (2-7 days later). Patients were required to have had a documented
trial of treatment, with a therapeutic blood level of lithium (0.6-1.2 mmol/L)
or valproate (50-125 µg/mL), for at least 2 weeks immediately prior
to visit 1. Patients were included only if they showed inadequate response
to monotherapy (YMRS total score 16). Prior to participation, all patients
signed an informed consent document approved by their study site's institutional
review board.
STUDY DESIGN
Participants in the study initially entered a 2- to 7-day screening
and washout period (study period 1) during which all concomitant medications
other than lithium or valproate were discontinued. Patients already receiving
valproate or lithium continued to do so throughout the study. Patients receiving
other forms of treatment started receiving either lithium or valproate at
investigator discretion for the 2 weeks immediately prior to visit 1. Plasma
levels of the medications were documented to be within the therapeutic ranges.
Only patients scoring greater than or equal to 16 on the YMRS were randomized
to receive concurrent treatment combined with either olanzapine or placebo
(study period 2).
Study period 2 consisted of a 6-week acute, double-blind phase, during
which levels of lithium or valproate were maintained within the therapeutic
range. Patients were assessed weekly. Patients were randomized 2:1 to receive
either olanzapine (flexible dose range of 5, 10, 15, or 20 mg/d) added to
valproate or lithium or placebo added to valproate or lithium. Olanzapine
therapy was initiated at 10 mg/d. To maintain blinding, treatment took the
form of two 5-mg capsules (either olanzapine or placebo), titrated up in increments
of 1 capsule or down by any number of decrements at investigator discretion
as indicated by each patient's tolerance. Patients unable to tolerate the
minimum dose were discontinued. Patients were permitted adjunctive use of
benzodiazepine ( 2 mg/d of lorazepam equivalents) for no more than 14 days
cumulatively. Anticholinergic therapy (benztropine mesylate, 2 mg/d) was
permitted throughout the study for treatment of extrapyramidal symptoms but
not for prophylaxis. Aside from study drugs, benzodiazepines, and anticholinergics,
no other drugs were permitted during the study.
ASSESSMENTS
Patient assessments were conducted by mental health care professionals,
including psychiatrists, psychologists, nurses, and other mental health caregivers
with a clinical degree or certification. Raters were trained in the use of
the SCID and symptom-rating scales before study initiation. To ensure high
interrater reliability, investigators were required to achieve a reliability
coefficient of 0.75 or greater. The primary measure of efficacy to assess
severity of manic symptoms was the mean change from baseline to end point
in the YMRS total score. Secondary measures included the 21-item Hamilton
Depression Rating Scale13 (HAMD-21); the Positive
and Negative Syndrome Scale14; and the Clinical
Global Impressions Severity of Bipolar Disorder scale14
(CGI-BP) total scores, and mania and depression subscale scores. Clinical
responses on the YMRS and HAMD-21 were defined a priori as an improvement
of 50% or greater. Clinical remission (euthymia) was defined a priori as achievement
of a YMRS total score of less than or equal to 12. A subsample of patients
with moderate to severe depressive symptoms was defined by a current mixed
episode and a HAMD-21 total score of 20 or greater at baseline. Secondary
assessments, also defined a priori, included analyses of treatment differences
following stratification by the current course of illness, the presence or
absence of psychotic features, and the use of lithium or valproate.
Scales for the assessment of neurologic adverse events included the
Simpson-Angus Scale,15 the Barnes Akathisia
Scale,16 and the Abnormal Involuntary Movement
Scale.14 Assessment of vital signs, weight,
and clinical laboratory analytes (including prolactin, nonfasting glucose,
and electrolyte levels and hematologic analysis) was performed at each visit.
Serum concentrations of mood stabilizers were collected at every visit.
STATISTICAL ANALYSES
Data were analyzed on an intent-to-treat basis,17
included all patients who met the entry criteria (including inadequate responsiveness
to the minimum 2-week prior treatment with lithium or valproate), and provided
both a baseline and at least 1 postbaseline data measurement. Total scores
from rating scales were derived from the individual items; if any item was
missing, the total score was treated as missing. All tests were 2-sided, with
an  level of .05. Analysis of variance (ANOVA) models were used to
evaluate continuous data, including terms for treatment, investigator, and
treatment-investigator interaction. The linear model for this analysis included
terms for baseline, treatment, investigator, treatment-investigator interaction,
visit, and treatment-visit interaction. The Fisher exact test was used for
categorical analyses, including laboratory values, vital signs, and treatment-emergent
adverse events. Data are given as mean (SD) unless otherwise indicated.
RESULTS
PATIENT CHARACTERISTICS AND DISPOSITION
A total of 501 patients entered the screening phase and 344 patients
were randomized and enrolled (33 US centers, 5 Canadian), with a mean enrollment
of 9 patients per site. Patients were recruited from both academic and nonacademic
sites from existing clinical patient populations seeking treatment at those
sites. Of the 344 randomized patients, 322 came from outpatient centers. The
other 20 (cotherapy, n = 16; monotherapy, n = 4) came from inpatient settings.
Patients were initially screened on the basis of face-to-face interviews,
medical record reviews, and information obtained from family members and referring
clinicians. Reasons for lack of enrollment included entry criteria not met
(86 patients, including 24 failing to meet the YMRS total score criterion
of 16); patient decision or loss to follow-up during the screening phase
(58); investigator decision (8); protocol violation (4); and a single death
that occurred before completion of screening or exposure to the study drug.
Ultimately, 229 patients were randomized to receive olanzapine cotherapy and
115 to receive monotherapy (Table 1).
One patient in the monotherapy group received both valproate and lithium and
accordingly was excluded from the subgroup analyses. The median duration of
mood-stabilizer therapy prior to randomization was 67 days; 203 patients had
a duration of therapy longer than 6 weeks. One patient in the monotherapy
group and 9 in the cotherapy group had no postbaseline measures and were excluded
from all efficacy analyses.
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Table 1. Patient Characteristics
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The percentage of patients completing the study was roughly equal in
the 2 treatment groups (cotherapy, 69.9%; monotherapy, 71.3%). Significantly
more patients in the monotherapy group discontinued treatment due to lack
of efficacy (12.2% vs 3.1%; P = .002), whereas significantly
more patients in the cotherapy group withdrew due to adverse events (10.9%
vs 1.7%; P = .002) (Table 2).
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Table 2. Patient Disposition*
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Patient demographics and illness characteristics were not significantly
different between the cotherapy and monotherapy treatment groups overall (Table 1). In the overall study group (n
= 344), the mean age was 40.6 (11.1) years. One hundred sixty-five patients
(48.0%) had mixed episodes at enrollment; the remainder had pure manic episodes.
Overall baseline mean YMRS total scores for the olanzapine cotherapy (n =
220) and monotherapy (n = 114) groups were 22.31 (5.39) and 22.67 (5.15),
respectively, and mean HAMD-21 scores were 14.52 (8.46) and 13.54 (7.63),
respectively (Table 3).
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Table 3. Summary of Efficacy Results, Baseline to End Point Changes*
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Mean modal dose of olanzapine in the cotherapy group (n = 224) was 10.4
(4.9) mg/d). Mean plasma levels of lithium among the cotherapy (n = 74) and
monotherapy (n = 41) patients were 0.76 (0.16) and 0.82 (0.19) (F1,86 = 4.26; P = .04) mEq/L, respectively, while
mean plasma levels of valproate for cotherapy (n = 145) and monotherapy (n
= 73) were 63.6 (18.4) µg/mL and 74.7 (18.6) µg/mL, respectively
(F1,188 = 18.38; P<.001). Benzodiazepine
use was not statistically different between patients in the cotherapy (66/229
[28.8%]) and monotherapy (39/115 [33.9%]) groups (P
= .38).
PRIMARY OUTCOMES
Both groups of patients improved during the course of treatment as indicated
by the primary measure of efficacy, the YMRS total score (Table 3). However, the olanzapine cotherapy group (n = 220) showed
a mean decrease in YMRS total score of 13.1 (8.53) points, corresponding to
a 58.8% improvement from baseline compared with a decrease of 9.10 (9.36)
points F1,276 = 9.08; P = .003) for the
monotherapy group (n = 114), which corresponded to an improvement of 40.1%.
Itemwise analysis of the YMRS revealed that, compared with monotherapy,
olanzapine cotherapy brought about significantly greater improvement at end
point on the items of Irritability (cotherapy, -1.82 [2.09], n = 220;
monotherapy, -1.02 [2.37], n = 114; F1,276 = 5.69; P = .02); Speech (cotherapy, -2.45 [2.03], n = 220;
monotherapy, -1.63 [2.53], n = 114; F1,276 = 5.24; P = .02); Language/Thought Disorder (cotherapy, -0.94
[0.91], n = 220, monotherapy, -0.72 [1.00], n = 114; F1,276
= 5.34; P = .02); and Disruptive/Aggressive Behavior
(cotherapy, -1.18 [1.64], n = 220; monotherapy, -0.46 [1.77],
n = 114; F1,276 = 10.16; P = .002).
Clinical response was defined a priori in the protocol as improvement
of 50% or greater from baseline to end point in the YMRS total score. On this
basis, 149 (67.7%) of the 220 patients in the olanzapine cotherapy group responded
to treatment compared with 51 (44.7%) of the 114 patients in the monotherapy
group (P<.001). In addition, time to response
was significantly shorter for cotherapy (P = .002,
log rank test), with a median response time of 18 days for cotherapy vs 28
days for monotherapy.
SECONDARY OUTCOMES
Clinical remission was defined a priori in the protocol as achievement
of a YMRS total score of less than or equal to 12. On this basis, 173 (78.6%)
of the 220 patients in the olanzapine cotherapy group demonstrated evidence
of remission. In the monotherapy group, 75 (65.8%) of the 114 evaluated patients
demonstrated evidence of remission. This difference in remission rates was
also significant (P = .01). Time to remission was
significantly shorter in the cotherapy group (log rank test, P = .002), with a median remission time of 14 days for cotherapy vs
22 days for monotherapy.
Compared with the patients in the monotherapy group, patients in the
olanzapine cotherapy group showed significantly greater improvement on the
HAMD-21 at each time point throughout the study. By week 6, the cotherapy
group (n = 220) experienced a mean last observation carried forward decrease
in HAMD-21 scores of 4.98 (7.61) points, significantly greater (F1,276 = 18.05; P<.001) than the decrease of 0.89
(6.90) points in the monotherapy group (n = 114). An exploratory itemwise
analysis showed significantly greater improvement in the dimensions of depressed
mood, feelings of guilt, suicidality, early insomnia, anxiety-psychic, and
paranoid symptoms.
Analysis of end point HAMD-21 scores conducted in the subset of patients
experiencing a mixed episode with moderate to severe depressive symptoms at
baseline (HAMD-21 total score 20 at baseline) showed a decrease of 10.31
(8.19) points for olanzapine cotherapy (n = 51) compared with 1.57 (7.73)
points (F1,70 = 17.50; P<.001) for
monotherapy (n = 21). Within this subset, 43.1% of patients in the cotherapy
group showed 50% improvement of depressive symptoms compared with 9.5%
in the monotherapy group (P = .006).
Other secondary measures of efficacy included the Positive and Negative
Syndrome Scale (total; Positive, Negative, and Cognitive clusters; and Hostility
subscores) and the CGI-BP (overall, Severity of Mania, and Severity of Depression).
Olanzapine cotherapy brought about significantly greater improvement than
monotherapy on patients' last observation carried forward, Positive and Negative
Syndrome Scale total, and Hostility item scores, as well as on the CGI-BP
overall and Severity of Depression scores (Table 3).
SUBGROUP ANALYSES
Subgroup analyses, defined a priori, were conducted on baseline to end
point YMRS total scores. No significant interactions were seen between previous
exposure to psychotropics (antidepressants, antipsychotics) and therapy (cotherapy,
monotherapy). However, among all patients without psychotic features, olanzapine
cotherapy was significantly more efficacious than monotherapy (cotherapy: -13.25
[7.76], n = 150; monotherapy: -8.32 [8.68], n = 76; F1,196
= 16.97; P<.001). Among patients without psychotic
features, olanzapine cotherapy was more effective than monotherapy regardless
of whether patients received lithium or valproate. However, among patients
with psychotic features, responses to treatment were not different between
the cotherapy and monotherapy groups regardless of whether patients received
lithium or valproate—this despite the lack of association between the
presence of psychotic features and the differential effect of therapy (ANOVA
test of interaction: F1,274 = 0.60; P
= .44).
Among patients with a current mixed episode, olanzapine cotherapy was
superior to monotherapy (cotherapy: -12.92 [8.37], n = 121; monotherapy: -7.46
[10.15], n = 54; F1,146 = 17.31; P<.001).
However, among patients presenting with pure mania, the treatment difference
did not achieve statistical significance (cotherapy: -13.34 [8.77],
n = 99; monotherapy: -10.57 [8.40], n = 60; F1,129 = 2.95; P = .09). The superiority of olanzapine cotherapy over
monotherapy seen in patients with mixed episodes was found only in patients
receiving valproate (cotherapy: -13.18, [8.49], n = 84; monotherapy: -7.48
[10.74], n = 42; F1,124 = 10.53; P = .002),
whereas the treatment difference seen with lithium did not achieve statistical
significance (cotherapy: -12.32 [8.15], n = 37; monotherapy: -7.42
[8.14], n = 12; F1,47 = 3.28; P = .08),
again despite the lack of association between course of illness and the differential
effect of therapy (ANOVA test of interaction, F1,274 = 0.14; P = .71).
Finally, among patients receiving valproate, olanzapine cotherapy brought
about significantly greater improvement in YMRS total scores compared with
patients receiving valproate monotherapy (cotherapy: -12.85 [8.64],
n = 146; monotherapy: -8.39 [9.76], n = 72; F1,188 = 13.44; P<.001). Among patients receiving lithium, the greater
improvement seen with olanzapine cotherapy relative to monotherapy did not
achieve statistical significance (cotherapy: -13.62 [8.36], n = 74;
monotherapy: -10.39 [8.69], n = 41; F1,86 = 3.74; P = .06). The type of mood stabilizer was not associated significantly
with a differential effect of cotherapy compared with monotherapy (ANOVA test
of interaction, F1,273 = 0.74; P = .39).
RISKS
No statistically significant changes from baseline were seen in extrapyramidal
symptoms on the Simpson–Angus Scale, Abnormal Involuntary Movement Scale,
and Barnes Akathisia Scale. Rates of adverse events (Table 4) more frequently reported in the cotherapy group included
somnolence, dry mouth, weight gain, increased appetite, tremor, and speech
disorder (cotherapy: slurred speech n = 14, speaking difficulties n = 1; monotherapy:
stuttering n = 1). In the cotherapy group, 25 patients discontinued treatment
due to adverse events (Table 1).
Six (2.6%) discontinued due to somnolence, 3 (1.3%) due to weight gain, and
3 (1.3%) due to peripheral edema. The remaining 13 discontinuing patients
in the olanzapine cotherapy group withdrew due to 13 different adverse events
(1 patient per event class). The 2 patients (1.7%) in the monotherapy group
who discontinued both withdrew due to depression (Table 1). Post hoc subgroup analysis showed that, among patients
receiving valproate, a significantly higher incidence of the adverse event
"dizziness" was seen in patients receiving cotherapy (16.3% vs 4.1%; P = .009).
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Table 4. Treatment-Emergent Adverse Events*
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No statistically or clinically significant differences emerged between
the monotherapy and olanzapine cotherapy groups for changes in vital signs.
However, the cotherapy group experienced a 3.6% increase in body weight, significantly
higher than that seen in the monotherapy group (cotherapy: 3.08 [3.04] kg,
n = 219; monotherapy: 0.23 [2.48] kg, n = 113; F1,302 = 73.88; P<.001). With the exception of a greater incidence of
treatment-emergent elevated prolactin levels (upper limit: 0.81 nmol/L for
men, 1.05 nmol/L for women) at end point in the cotherapy group (19.1% vs
4.3%; P = .001), there were no other statistically
and clinically significant differences in treatment-emergent laboratory test
result abnormalities at end point, including nonfasting glucose levels, between
the olanzapine cotherapy group and the monotherapy group.
COMMENT
This double-blind, placebo-controlled study suggests that, in patients
with inadequate responses to at least 2 weeks of lithium or valproate monotherapy,
the addition of olanzapine may confer additional significant efficacy. No
significant changes were seen in extrapyramidal symptoms but a number of adverse
events were reported more frequently by patients receiving cotherapy.
The findings in this patient population, characterized as partially
nonresponsive to monotherapy, are comparable with those of Müller-Oerlinghausen
et al,6 who compared the efficacy of combined
therapy with conventional antipsychotics and valproate vs valproate monotherapy
in patients with bipolar or schizoaffective disorder. Sachs18
recently reported preliminary results comparing the addition of risperidone,
haloperidol, or placebo to lithium or valproate, and found that the addition
of risperidone showed a significantly improved response compared with monotherapy.
Considering the exclusion of patients who showed a response after 2
weeks of monotherapy, our patient population should be classified as lithium-
or valproate-nonresponders or partial responders. A significantly larger percentage
of patients who received cotherapy with olanzapine achieved euthymia than
did patients receiving valproate or lithium monotherapy. A potential limitation
of this finding is the reliance on a single definition of euthymia, which
in this study was based on a YMRS total score less than or equal to 12 as
suggested in the original publication of the scale.12
It is possible that another definition may have led to substantially different
remission rates.
One of the most interesting findings was the improvement in depressive
symptoms in this population of patients with bipolar manic and mixed episodes.
This was particularly striking among patients with moderate-to-severe symptoms
of depression, who are particularly resistant to antimanic treatment.19 Among these patients, a nearly 7-fold greater improvement
on the HAMD-21 scale was seen in the cotherapy group. Furthermore, nearly
5 times as many patients in the cotherapy group showed at least a 50% improvement
of depressive symptoms. These findings suggest that cotherapy may provide
substantial efficacy against depressive symptoms in this patient population.
Subgroup analysis also produced noteworthy findings. In patients without
psychotic features, cotherapy was significantly superior to monotherapy. However,
in those with psychotic features, the difference did not reach statistical
significance, doubtlessly due to the greater statistical power in the group
of patients without psychotic features.
Patients with mixed episodes who received cotherapy had a significantly
larger response rate than did those who received monotherapy. By contrast,
patients who had purely manic episodes showed no significant difference between
treatments. The response to cotherapy was similar in magnitude in both patient
types. However, patients with mixed episodes showed weaker responses to monotherapy
than did patients who were purely manic. These results again suggest that
patients who had bipolar disorder whose illness characteristics include the
presence of depressive symptoms may particularly benefit from the addition
of olanzapine.
Overall YMRS responses to cotherapy with valproate were similar in magnitude
to responses to cotherapy with lithium. On a numeric basis, response to lithium
monotherapy was larger than the response to valproate monotherapy. This, plus
the larger number of patients receiving valproate, might explain the significant
difference between responses to valproate cotherapy vs valproate monotherapy
and the nonsignificant difference between responses to lithium cotherapy vs
lithium monotherapy.
Adverse events occurring at a significantly higher rate in the cotherapy
group and severe enough to result in discontinuation included somnolence and
weight gain. Importantly, however, the olanzapine cotherapy group did not
experience a significant increase in nonfasting plasma glucose levels or any
treatment-emergent hyperglycemia. Weight gain during treatment with olanzapine
has been described previously.20-21
However, lithium and valproate are both known to be associated with weight
gain.22-23 Weight gain in the
cotherapy group was similar to that reported for olanzapine monotherapy, suggesting
that there is no clear synergism between olanzapine and either lithium or
valproate in causing weight gain.
Our study has several limitations. First, assignment to valproate or
lithium was not randomized but reflected the treatment preferences of clinicians
and investigators. The larger recruitment of patients receiving valproate
monotherapy reflects the current practice in the United States of a more extensive
use of valproate than lithium by patients who have bipolar disorder with manic
or mixed episodes. Because the study was not powered to show significant differences
in the primary outcome variables stratified by mood stabilizer, significant
differences were found only when comparisons were made between monotherapy
and cotherapy; few differences were found when patients were stratified by
mood stabilizer. Second, our sample was restricted to partial responders to
lithium or valproate. Patients received monotherapy for only 2 weeks, with
mean blood levels of 0.76 mmol/L and 63.6 µg/mL for lithium and valproate,
respectively. In clinical practice, practitioners may be inclined to maximize
the dose of monotherapy treatment before initiating cotherapy treatment. Finally,
the lack of an olanzapine-monotherapy arm prevented us from considering a
possible synergistic effect between olanzapine and the mood stabilizer. Moreover,
the lack of a comparator arm, such as a mood stabilizer plus another agent,
also limits our conclusions about olanzapine's unique effects when added to
mood stabilizers. It would be of considerable benefit to investigate the efficacy
of olanzapine cotherapy vs a combination therapy consisting of lithium plus
valproate, thereby more accurately reflecting current clinical practice.
In summary, our findings suggest that, in patients with bipolar manic
or mixed episodes who demonstrate inadequate responsiveness to at least 2
weeks of mood-stabilizer monotherapy, the combination of lithium or valproate
plus olanzapine may provide additional efficacy compared with either agent
alone. Patients treated with combination therapy experienced more adverse
events but none seemed to be life-threatening. The response in patients without
psychotic features and the improvement of depressive symptoms suggests that
the combination of olanzapine and lithium or valproate may have mood-stabilizing
properties in the acute treatment of bipolar manic or mixed episodes.
AUTHOR INFORMATION
Accepted for publication June 26, 2001.
This study was sponsored by Eli Lilly & Co, Indianapolis, Ind.
This study was presented at the annual meeting of the American Psychiatric
Association, Chicago, Ill, May 15, 2000.
| Study Sites Principal Investigators
North Bay Psychiatric Hospital, North Bay, Ontario: S. Adams, MD; The International Mood Center, La
Jolla, Calif: H. S. Akiskal, MD; University of Pennsylvania,
Philadelphia, Pa: J. D. Amsterdam, MD; Princeton
Biomedical Research, Princeton, NJ: J. T. Apter, MD; University of Texas Health Science Center, San Antonio: C. L. Bowden,
Jr, MD; Case Western Reserve University School of Medicine,
Cleveland, Ohio: J. R. Calabrese, MD; McLean Hospital/Harvard
Medical School, Belmont, Mass: F. Centorrino, MD; Western Psychiatric Institute and Clinic/University of Pittsburgh Medical
Center, Pittsburgh, Pa: K. N. R. Chengappa, MD; Reno, Nev: M. De Priest, MD; Falls Church, Va:
D. G. Daniel, MD; Clinical Investigation Specialists Inc,
Little Rock, Ark: B. Diner, MD; Pharmacology Research
Corporation, Salt Lake City, Utah: J. M. Ferguson, MD; Polyclinique Saint Laurent, Quebec City, PQ: M. J. Filteau; Riverview Consultants, Calgary, Alberta: C. Gorman, MD; Baltimore Veterans Affairs Medical Center, Baltimore, Md: P. Hauser,
MD; St Luke's Roosevelt Outpatient Clinic, New York, NY: S. E. Hyler, MD; Montefiore Medical Center/Albert
Einstein College of Medicine, New York: N. Iqbal, MD; Center for Addiction and Mental Health, Toronto, Ontario: S. Kennedy,
MD; Stanford University School of Medicine, Stanford, Calif: T. A. Ketter, MD; Clinic Bois de Boulogne, Montreal,
Quebec: J. Leblanc, MD; Birmingham Psychiatric Pharmaceutical
Studies, Birmingham, Ala: H. E. Logue, MD; University
of Cincinnati Medical Center, Cincinnati, Ohio: S. L. McElroy, MD; University of New Mexico Health Sciences Center, Albuquerque: H. G. Nurnberg; Veterans Affairs Medical Center,
Dallas, Tex: F. Petty, MD, PhD; Mesa Vista Hospital,
San Diego, Calif: M. Plopper, MD; Bio Behavioral
Research Center, Decatur, Ga: R. A. Riesenberg, MD; Massachusetts General Hospital, Boston, Mass: G. S. Sachs, MD; University of Texas Southwestern Medical Center, Dallas:
T. Suppes, MD, PhD; Crozer Chester Medical Center, Philadelphia: S. D. Targum, MD; University of Colorado Health
Sciences Center, Denver, Colo: M. Thomas, MD; Medstream
Inc, Milwaukee, Wis: R. I. H. Wang, MD, PhD; Raleigh,
NC: R. H. Weisler, MD; Psychiatric Institute of Florida,
Orlando: S. A. West, MD.
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Corresponding author and reprints: Mauricio Tohen, MD, DrPH, Lilly
Research Laboratories, Eli Lilly & Co, Indianapolis, IN 46285.
From the Department of Psychiatry, Harvard Medical School, McLean Hospital,
Belmont, Mass (Dr Tohen); Lilly Research Laboratories, Indianapolis, Ind (Drs
Tohen, Baker, Feldman, Tollefson, and Breier, and Mr Risser and Ms Keeter);
Western Psychiatric Institute & Clinic, University of Pittsburgh Medical
Center, Pittsburgh, Pa (Drs Chengappa and Kupfer); Department of Psychiatry,
University of Texas Southwestern Medical Center, Dallas (Dr Suppes); Mood
and Anxiety Disorders Program, National Institute of Mental Health,
Bethesda, Md (Dr Zarate); Department of Psychiatry, Case Western Reserve,
Cleveland, Ohio (Dr Calabrese); Department of Psychiatry, Massachusetts General
Hospital, Harvard Medical School, Boston (Dr Sachs); Department of Psychiatry,
University of Texas Health Science Center, San Antonio (Dr Bowden). Drs Tohen, Feldman, Tollefson, and Breier and Mr Risser and Ms Keeter
are stockholders in Eli Lilly & Co.
REFERENCES
| |
1. Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP. The expert consensus guideline series: medication treatment of bipolar
disorder 2000. Postgrad Med. 2000;Spec No:1-104.
2. Swann A. Practical management of depressive and manic episodes. In: Garza-Trevino ES, ed. Medical Psychiatry: Theory
and Practice. Vol 1. Teaneck, NJ: World Scientific; 1989.
3. Freeman MP, Stoll AL. Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry. 1998;155:12-21.
FREE FULL TEXT
4. Kane JM. The role of neuroleptics in manic-depressive illness. J Clin Psychiatry. 1988;49(suppl):12-14.
5. Klein E, Bental E, Lerer B, Belmaker RH. Carbamazepine and haloperidol vs placebo and haloperidol in excited
psychoses: a controlled study [abstract]. Am J Psychiatry. 1984;137:782-790.
FREE FULL TEXT
6. Müller-Oerlinghausen B, Retzow A, Henn FA, Giedke H, Walden J. Valproate as an adjunct to neuroleptic medication for the treatment
of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled,
multicenter study. J Clin Psychopharmacol. 2000;20:195-203.
FULL TEXT
|
ISI
| PUBMED
7. Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KNR, Daniel DG, Petty F, Centorrino F, Wang R, Grundy SL, Greaney MG, Jacobs TG, David SR, Toma V. Olanzapine vs placebo in the treatment of acute mania. Am J Psychiatry. 1999;156:702-709.
FREE FULL TEXT
8. Tohen M, Jacobs TG, Grundy SL, Banov MC, McElroy SL, Janicak PG, Zhang F, Toma V, Francis BJ, Sanger TM, Tollefson GD, Breier A. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled
study. Arch Gen Psychiatry. 2000;57:841-849.
FREE FULL TEXT
9. Zarate C Jr, Narendran R, Tohen M, Greaney JJ, Berman A, Pike S, Madrid A. Clinical predictors of acute response with olanzapine in psychotic
mood disorders. J Clin Psychiatry. 1998;59:24-28.
10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994.
11. First MB, Spitzer RL, Gibbon M, Williams JB. Structured Clinical Interview for the Diagnostic
and Statistical Manual, Fourth Edition, Patient Version. Washington, DC: American Psychiatric Press; 1997.
12. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity, and sensitivity. Br J Psychiatry. 1978;133:429-435.
FREE FULL TEXT
13. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62.
14. Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised. Bethesda, Md: US Dept of Health, Education, and Welfare; 1976.
15. Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11-19.
PUBMED
16. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676.
FREE FULL TEXT
17. Gillings D, Koch G. The application of the principle of intention-to-treat to the analysis
of clinical trials. Drug Inf J. 1991;25:411-425.
18. Sachs GS. Safety and efficacy of risperidone vs placebo as add-on therapy to
mood stabilizers in the treatment of the manic phase of bipolar disorder. Presented at the 2000 annual meeting of the American Psychiatric
Association; May 17, 2000; Chicago, Ill.
19. Dilsaver SC, Swann AC, Shoaib AM, Bowers TC, Halle MT. Depressive mania associated with nonresponse to antimanic agents. Am J Psychiatry. 1993;150:1548-1551.
FREE FULL TEXT
20. Kelly DL, Conley RR, Love RC, Horn DS, Ushchak CM. Weight gain in adolescents treated with risperidone and conventional
antipsychotics over six months. J Child Adolesc Psychopharmacol. 1998;8:151-159.
ISI
| PUBMED
21. Tollefson GD, Beasley CM Jr, Tran PV, Street JS, Krueger JA, Tamura RN, Graffeo KA, Thieme ME. Olanzapine vs haloperidol in the treatment of schizophrenia and schizoaffective
and schizophreniform disorders: results of an international collaborative
trial. Am J Psychiatry. 1997;154:457-465.
ABSTRACT
22. Chen Y, Silverstone T. Lithium and weight gain. Int Clin Psychopharmacol. 1990;5:217-225.
PUBMED
23. Sachs GS, Guille C. Weight gain associated with use of psychotropic medications. J Clin Psychiatry. 1999;60(suppl 21):16-19.
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