Lilly Research Laboratories, Indianapolis, Indiana, and Harvard Medical School/McLean Hospital, Belmont, Massachusetts
Western Psychiatric Institute and Clinic, University of Pittsburgh, Pennsylvania
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
Lilly Research Laboratories, Indianapolis, Indiana
Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Maryland
Department of Psychiatry, University of Texas Health Science Center, San Antonio, Texas
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
Department of Psychiatry, Harvard Medical School/Cambridge Hospital, Cambridge, Massachusetts
Lilly Research Laboratories, Indianapolis, Indiana
Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, USA
Correspondence: Dr M.Tohen, Lilly Research Laboratories, Indianapolis IN46285, USA. Tel: (317) 277 9585; fax: (317) 433 5101; e-mail: m.tohen{at}lilly.com
Declaration of interest M.T., R.W.B., P.D.F., A.R.E. and R.C.R. are stockholders in Eli Lilly & Company, the sponsor of this study.
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ABSTRACT |
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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 weekstreatment with olanzapine plus either lithium (0.61.2 mmol/l) or valproate (50125 µg/ml) received lithium or valproate plus either olanzapine 520 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.
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INTRODUCTION |
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METHOD |
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Patients who received combination treatment during the acute phase and had
achieved syndromic remission of both mania and depression as defined above
were randomly reassigned at visit 8 (week 6 of the acute phase) in a 1:1 ratio
to receive an additional 18 months of double-masked therapy, consisting of
either olanzapine (flexible dosage range of 5 mg, 10 mg, 15 mg or 20 mg per
day) in combination with lithium or valproate (combination therapy), or
placebo added to lithium or valproate (monotherapy). Patients continued taking
the same mood stabiliser that they had received during the acute phase, the
choice of which was determined by the site investigator. As in the acute
phase, mood stabiliser therapy was not masked; only the addition of olanzapine
or placebo was conducted under double-masked conditions. Patients in the
combination therapy group began treatment with 10 mg per day of olanzapine,
given on the evening of visit 8. The period between visits was 1 week for the
first two assessments (visits 9 and 10), 2 weeks for the next assessment
(visit 11), 4 weeks for the assessment after that (visit 12), and 8 weeks for
the remainder of the study (visits 13 to 20). To maintain masking, treatment
took the form of two 5 mg capsules (either olanzapine or placebo), titrated up
in increments of one capsule, or down by any number of decrements at the
investigators discretion, as indicated by each patients symptom
improvement and treatment tolerance. Patients unable to tolerate the minimum
dose (one capsule) were withdrawn from the study. During this relapse
prevention phase of the study, the blood levels of lithium and valproate
remained within the therapeutic range (lithium 0.61.2 mmol/l, valproate
50125 µg/ml), as previously defined. If lithium or valproate levels
deviated from this therapeutic range, the investigator adjusted the dosage of
either drug to re-establish blood levels within the range. Patients were
permitted adjunctive use of benzodiazepines (2 mg lorazepam equivalent per
day) for no more than 5 consecutive days, or 60 days cumulatively.
Anticholinergic therapy (benzatropine mesylate
2 mg per day) was permitted
throughout the study for treatment of extrapyramidal side-effects but not for
prophylaxis. Aside from study drugs, benzodiazepines and anticholinergics, no
other psychiatric drug was permitted during the study.
Assessments
Relapse was assessed as:
Patients who not only met the requirements for syndromic remission at the
end of the acute phase but also met the symptomatic remission criteria (YMRS
total score 12 and HRSD21 total score
8) were assessed for
symptomatic relapse during this extension phase. Symptomatic relapse of mania
was defined as a YMRS total score rating of 15 or greater after having
previously met the criteria for symptomatic and syndromic remission.
Symptomatic relapse of depression was defined as an HRSD21 total score
rating of 15 or greater after having previously met the criteria for both
symptomatic and syndromic remission.
To assess relapse prevention, survival analyses were conducted to determine the times to syndromic relapse (the studys primary outcome measure) and symptomatic relapse of any mood episode, whether manic, depressive or mixed. Times to relapse were based on the date of the assessment when relapse criteria were first met or, if censored to relapse, the final assessment date, each relative to the date of randomisation. Patient assessments were conducted by mental health care professionals, including psychiatrists, psychologists, nurses and other mental health caregivers with an advanced clinical degree or certification. Raters were trained in the use of symptom rating scales before the study began. Changes in dosage levels of randomised therapy were made by the prescribing principal investigator at each site. This investigator might have also been responsible for outcomes assessment, but was not necessarily the rater.
Serum concentrations of lithium or valproate were assessed at every visit to determine if the therapeutic blood level was maintained. To estimate the mean blood level, the area under the serum concentration curve (AUC) was determined for each patient. The AUC was calculated with a weighted average of mean serum concentrations at each pair of consecutive visits, weighted by the number of days between those two visits.
Scales for assessment of extrapyramidal side-effects included the SimpsonAngus Scale (Simpson & Angus, 1970), the Barnes Akathisia Rating Scale (BARS; Barnes, 1989) and the Abnormal Involuntary Movement Scale (AIMS; Guy, 1976). Treatment-emergent parkinsonism was defined as a SimpsonAngus Scale score greater than 3 at any time following a score of 3 or less during the acute period. Treatment-emergent akathisia was defined as a BARS score of 2 or more at any time following a score of less than 2 during the acute period. A score of 3 or more on any of the first seven AIMS items, or a score of 2 or more on any two of the first seven AIMS items, was taken to be indicative of long-term treatment-emergent dyskinetic symptoms, given that neither of these criteria was met during the acute period. This definition of treatment-emergent dyskinetic symptoms is consistent with the cross-sectional symptom severity criteria suggested by Schooler & Kane (1982) as research diagnostic criteria. Assessment of vital signs and weight and a full blood analysis (including prolactin and non-fasting glucose levels) were performed at each visit.
Statistical analyses
The sample size was planned on the assumption that 75% of patients
receiving olanzapine plus lithium or valproate during the preceding acute
phase would be in syndromic remission, yielding approximately 168 eligible
patients for the relapse prevention phase of the study. With equal allocation
into the combination and monotherapy treatment groups, this sample size
provided 96% power to detect a difference in time to relapse using the
log-rank test assuming an 18-month syndromic relapse of bipolar disorder of
30% and 60% for combination therapy and monotherapy respectively, and a 10%
loss to follow-up in each group. Time-to-relapse curves for the therapy groups
were estimated with the KaplanMeier technique and the curves were
compared using the log-rank test. Median length of follow-up to the point of
relapse or censoring is used to describe time to relapse in each group.
Similar analyses were performed to examine time to discontinuation. A Cox
proportional hazards regression approach allowed examination of differential
time to relapse comparing the therapies based on subgroup factors (age,
gender, racial origin, psychotic features, history of cycling course, type of
index episode) by inclusion of a therapysubgroup interaction. For
rating scales, total scores were derived from the individual items; if any
item was missing, the total score was treated as missing. Analysis of variance
was used to evaluate quantitative change, including terms for treatment,
investigator, and treatmentinvestigator interaction; treatment
differences are characterised with 95% confidence intervals about the mean
change difference. Fishers exact test was used to compare rates of
relapse and discontinuation; incidence rates of treatment-emergent adverse
events and scale-based extrapyramidal side-effects are shown with an
asymptomatic 95% confidence interval about the risk difference (combination
therapy minus monotherapy). Tests of treatment differences were two-sided,
with an level of 0.05; significance of interactions was tested at an
level of 0.10. Measurements taken at the last acute-phase visit
(end-point, week 6 of acute phase) served as the baseline for all continuous
measures of efficacy and safety. Categorical treatment-emergent events were
defined as those that worsened or first occurred after the acute phase of
therapy.
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RESULTS |
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Prior to randomisation in the acute treatment period, the median duration of mood stabiliser therapy immediately before study entry was 67 days, and 203 of the 344 patients enrolled in the acute phase had a duration of therapy greater than 6 weeks. Of the 99 patients entering the relapse prevention phase, almost two-thirds (n=63) were receiving valproate. As characterised by their index episode at study initiation, patients with mania (n=50) and mixed states (n=49) were about equally represented. A rapid-cycling course was present in 41 patients, and 26 exhibited psychotic features in their index episode of mania. The duration and nature of the illness appear consistent between treatment groups (Table 1).
The mean drug dosages and serum concentrations in the two groups are shown in Table 2. Concomitant use of benzodiazepines in the combination therapy group (10 of 51, 20%) was similar to that in the monotherapy group (14 of 48, 29%). In addition, concomitant use of anticholinergics was similar in the two groups (combination treatment 5 of 51, 10%; monotherapy 7 of 48, 15%).
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The percentage of patients completing the 18-month follow-up period was
nearly three times higher in the combination treatment group than in the
monotherapy group (combination treatment 31%, monotherapy 10%;
P=0.014). Moreover, time to discontinuation differed significantly
between treatment groups (21=3.86,
P=0.049, log-rank test), with median length of follow-up of 111 days
for combination therapy compared with 82 days for monotherapy. The proportions
of specific reasons for discontinuation were not significantly different
between treatment groups.
Relapse prevention
At the start of the relapse prevention phase, 99 patients were assessed as
being in syndromic remission of bipolar disorder. Time to relapse into a
syndromic affective episode, whether mania or depression, was not
significantly different between the treatment groups
(21=0.11, P=0.742, log-rank test; hazard
ratio 1.13, 95% CI 0.552.31), with median times to relapse occurring at
40.5 days for the monotherapy group and 94 days for the combination therapy
group. Rates of syndromic relapse into either mania or depression were also
not significantly different between treatment groups: combination therapy 15
of 51 (29%), monotherapy 15 of 48 (31%); P>0.99.
Of the 99 patients in syndromic remission at entry to the relapse
prevention phase, 68 were assessed to be free from either manic or depressive
symptoms (specified a priori as YMRS score 12 and HRSD21
score
8) at randomisation. During the maintenance phase, time to
symptomatic relapse into either mania or depression was significantly longer
for the combination therapy group compared with the monotherapy group
(
21=5.19, P=0.023, log-rank test, hazard
ratio 2.29, 95% CI 1.104.78), with median times to relapse of 163 days
for combination treatment and 42 days for monotherapy
(Fig. 2). Rates of symptomatic
relapse into either mania or depression were not significantly different
between the treatment groups: combination therapy 11 of 30 (37%); monotherapy
21 of 38 (55%); P=0.149.
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Time to symptomatic relapse into mania alone during the prevention phase
following both syndromic and symptomatic remission of both mania and
depression was longer for the combination therapy group, but not significantly
so (21=2.27, P=0.132, log-rank test;
hazard ratio 2.12, 95% CI 0.785.77), with median times to relapse of
171.5 days for combination therapy v. 59 days for monotherapy. Rates
of symptomatic relapse into mania only were also lower in the combination
therapy group (6 of 30, or 20%) than in the monotherapy group (11 of 38, or
29%), but not significantly so (P=0.574). Median times to symptomatic
relapse into depression alone during the extension phase (combination therapy
163 days, monotherapy 55 days) were not statistically significantly different
between treatment groups (
21=3.27,
P=0.071, log-rank test; hazard ratio 2.24, 95% CI 0.915.50).
Likewise, rates of relapse into depression alone, although lower in the
combination therapy group (7 of 30, or 23%) than in the monotherapy group (15
of 38, or 40%), were not significantly different (P=0.197).
Subgroup analyses
Stratification of data regarding time to relapse into either symptomatic
mania or depression was conducted using the patient characteristics of age,
gender, racial origin, presence of psychotic features, type of index manic
episode, presence of rapid-cycling course, and mood stabiliser used.
Differences in treatment responsiveness were noted between patients stratified
by gender or racial origin (Table
3). Reflecting the overall group results, women receiving
combination therapy were found to have significantly longer times to a
symptomatic affective (mania or depression) relapse than did women receiving
monotherapy (Fig. 3): median
time to relapse for combination therapy 177 days v. monotherapy 27.5
days; P=0.001, log-rank test. However, men
(Fig. 4) showed no such
treatment difference (median time to relapse for combination therapy 84 days
v. monotherapy 67 days; P=0.811, log-rank test). Similarly,
stratifying the group by racial origin revealed possible differences in
treatment responsiveness, with White patients showing significantly longer
times to symptomatic relapse with combination therapy than with monotherapy,
whereas non-White patients showed no significant difference in treatment
responsiveness. No significant interaction was seen between treatment and any
other subgroup characteristic (presence v. absence of psychotic
features, manic v. mixed index episode, presence v. absence
of history of rapid cycling, use of valproate v. lithium).
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Safety measures
Incidences of common treatment-emergent adverse events
(Table 4) were for the most
part not dissimilar in the two treatment groups, with the exception of
insomnia, which occurred in more than a quarter (n=13) of monotherapy
patients compared with only 2 (4%) combination treatment patients, and weight
gain, which was more common with combination therapy than monotherapy
(combination therapy 20%, monotherapy 6%).
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On measures of extrapyramidal sideeffects, mean within-group changes and treatment differences in changes on the AIMS and the SimpsonAngus and Barnes scales were generally small and not clinically meaningful (Table 5). Incidence rates of scale-based treatment-emergent parkinsonism (combination treatment 6.4%, monotherapy 8.9%; risk difference 2.5%, 95% CI 13.4 to 8.4), akathisia (combination therapy 7.5%, monotherapy 5.9%; risk difference 1.6%, 95% CI 9.7 to 13.0) and dyskinesia (combination treatment 0%, monotherapy 4.2%; risk difference 4.2%, 95% CI 9.8 to 1.5) also did not differ in a clinically meaningful manner.
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There was no common or clinically relevant treatment-related difference in
vital signs or electrocardiographic measure, including orthostasis and
corrected QT interval. Mean change in body weight from baseline to end-point
was 3.8 kg greater for combination therapy than for monotherapy
(Table 5), and the clinically
relevant increase in weight (7% change from baseline) was greater for
patients receiving combination therapy: combination therapy 27%, monotherapy
6%; risk difference 21.2% (95% CI 7.2 to 35.2). In terms of laboratory
measures (Table 5), patients in
the monotherapy group showed an elevation of mean corpuscular haemoglobin and
platelet count values that was greater than that seen among patients in the
combination therapy group. Mean baseline to end-point changes in non-fasting
glucose and non-fasting cholesterol levels were small, and there was no case
of clinically relevant increase in non-fasting glucose concentration (
11.1
mmol/l at any post-baseline assessment if less than 11.1 mmol/l at baseline)
or in non-fasting cholesterol concentration (
6.20 mmol/l at any
post-baseline assessment if less than 5.17 mmol/l at baseline) in either
therapy group.
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DISCUSSION |
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An interesting finding of this study was that women were more likely to relapse sooner with monotherapy than with combination therapy; this differential treatment response was not observed for men; nor did the treatmentgender interaction occur during the acute phase of this trial. There is some published evidence of gender differences in treatment response (Tohen et al, 2003), and with respect to olanzapine, women patients with a first-episode psychosis appear to have a greater response to olanzapine than to haloperidol an outcome not found with male patients (Goldstein et al, 2002).
Tolerability
Both the lithium and valproate monotherapies and the combined treatment
with olanzapine were generally well tolerated. During the 18-month study,
patients receiving combination therapy gained 2.0 kg, compared with a loss of
1.8 kg in the monotherapy group. It should be noted, however, that patients
had already gained an average of 3.1 kg during the 6-week acute phase
(Tohen et al, 2002). The loss of weight in the monotherapy patients was probably secondary to the
discontinuation of olanzapine. Thus, the weight gain of 2.0 kg in the relapse
prevention phase should be considered additional weight gain after a longer
exposure to olanzapine. These mean long-term weight increases of 56 kg
with the use of olanzapine in combination with lithium or valproate are
similar to those reported during long-term monotherapy of bipolar disorder
(Bowden et al, 2003)
and in schizophrenia (Kinon et
al, 2001). Extrapyramidal side-effects were minimal in both
treatment groups. The association with extrapyramidal side-effects,
particularly tardive dyskinesia, has long been regarded as a major drawback of
typical antipsychotics, as patients with bipolar disorder appear to be more
susceptible to such effects than are patients with schizophrenia
(Kane & Smith, 1982).
There was no abnormal increase in non-fasting blood glucose or cholesterol levels at any time in the study group on the 18-month follow-up period. This study might not have had sufficient power to determine treatment differences; furthermore, assessment of the potential impact of treatment on glucose homoeostasis was limited because the glucose measurements were non-fasting. Laboratory changes that were noted included an increase in platelet count with monotherapy, but not with combination therapy; the significance of this difference, however, is not readily apparent.
Methodological limitations
Several limitations of the current study bear mentioning. First, the
statistical power of the study was based on the assumption that 168 patients
receiving olanzapine plus lithium or valproate during the preceding acute
phase would have met remission criteria; however, only 99 patients were
available for the second randomisation. This reduced sample size provided
approximately 79% power (using assumed relapse rates for combination therapy
and monotherapy as in the original estimation) and might have prevented the
primary outcome variable from being statistically significant. Second, the
clinical characteristics of the patient sample might not have been
representative of the general patient population treated in clinical settings,
as it contained a high proportion of patients whose bipolar I disorder had had
a rapid-cycling course in the previous year. Patients with a rapid-cycling
course may be refractory to treatment with lithium
(Bench et al, 1996);
it would therefore be expected that patients in the monotherapy group would
have a particularly poor outcome owing to a weak response to lithium
treatment, and indeed we found that the median time to relapse in this group
was shorter than that observed during prophylactic lithium treatment in other
trials (Cuesta et al,
2001). Related to this point is the fact that the patients in this
study represented a somewhat enriched sample, inasmuch as they
were required to show incomplete responses to a preceding 2-week treatment
with lithium or valproate and then respond satisfactorily to concomitant
treatment with olanzapine. This may limit our ability to generalise the
results of the study to all patients. On the other hand, this study is thereby
one of only a few to address the question of whether a particular treatment
that produces an improvement acutely in this case, olanzapine
is able to maintain that improvement; that is, whether what gets the patient
well can keep the patient well. Another limitation of our study is that
although plasma concentrations of both lithium and valproate were maintained
well within the target range and were in line with those of other maintenance
studies (Cuesta et al,
2001), the valproate levels were nevertheless towards the lower
end of the therapeutic range. In addition, as was discussed in the report of
the preceding study phase (Tohen et
al, 2002), assignment of patients to lithium or valproate was
made on the basis of the treatment preferences of the attending clinicians,
rather than through randomisation. Accordingly, the study was not powered to
show significant differences in outcome variables stratified by lithium or
valproate treatment. It was therefore not possible to determine the relative
efficacies and safety consideration of these two agents during the course of
this 18-month treatment period. Another limitation was the small sample size
in several of the subgroup analyses, which might have prevented detection of
differential treatment responses. Finally, a treatment group for olanzapine
monotherapy was not included. Therefore, an assessment of any synergistic
effect between olanzapine plus lithium or valproate cannot be made, as it
would be necessary to demonstrate that the combination treatment is more
effective than each of the monotherapies alone.
In summary, our results indicate that long-term use of the combination of olanzapine plus lithium or valproate may prolong the time spent in symptomatic remission compared with lithium or valproate monotherapy in patients who have achieved remission with the combination treatment. The most clinically meaningful adverse event was a mean increase in body weight in the combination therapy group amounting to a gain of 2.0 kg over the 18-month relapse prevention phase, compared with a loss of 1.8 kg in the monotherapy group. These findings may be useful to clinicians for evaluating the relative risks and benefits for each individual patient in determining the selection of pharmacological treatment.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication May 2, 2003. Revision received August 28, 2003. Accepted for publication September 25, 2003.
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