ORIGINAL ARTICLE
`
`Efficacy of Olanzapine in Acute Bipolar Mania
`
`A Double-blind, Placebo-Controlled Study
`
`Mauricio Tohen, MD, DrPH; Thomas G. Jacobs, MAS; Starr L. Grundy, BScPharm; Susan L. McElroy, MD;
`Michael C. Banov, MD; Philip G. Janicak, MD; Todd Sanger, PhD; Richard Risser, MS; Fan Zhang, PhD;
`Verna Toma, BS; Judith Francis, MA; Gary D. Tollefson, MD, PhD; Alan Breier, MD;
`for the Olanzapine HGGW Study Group
`
`Background: We compared the efficacy and safety of
`olanzapine vs placebo for the treatment of acute bipolar
`mania.
`
`Methods: Four-week, randomized, double-blind,
`parallel study. A total of 115 patients with a DSM-IV di-
`agnosis of bipolar disorder, manic or mixed, were ran-
`domized to olanzapine, 5 to 20 mg/d (n=55), or placebo
`(n=60). The primary efficacy measure was the Young–
`Mania Rating Scale (Y-MRS) total score. Response and eu-
`thymia were defined, a priori, as at least a 50% improve-
`ment from baseline to end point and as a score of no less
`than 12 at end point in the Y-MRS total score, respec-
`tively. Safety was assessed using adverse events, Extrapy-
`ramidal Symptom (EPS) rating scales, laboratory values,
`electrocardiograms, vital signs, and weight change.
`
`Results: Olanzapine-treated patients demonstrated a sta-
`tistically significant greater mean (± SD) improvement
`in Y-MRS total score than placebo-treated patients
`
`(−14.8±12.5 and −8.1±12.7, respectively; P⬍.001), which
`was evident at the first postbaseline observation 1 week
`after randomization and was maintained throughout the
`study (last observation carried forward). Olanzapine-
`treated patients demonstrated a higher rate of response
`(65% vs 43%, respectively; P=.02) and euthymia (61%
`vs 36%, respectively; P=.01) than placebo-treated pa-
`tients. There were no statistically significant differences
`in EPSs between groups. However, olanzapine-treated pa-
`tients had a statistically significant greater mean (± SD)
`weight gain than placebo-treated patients (2.1±2.8 vs
`0.45±2.3 kg, respectively) and also experienced more
`treatment-emergent somnolence (21 patients [38.2%] vs
`5 [8.3% ], respectively).
`
`Conclusion: Olanzapine demonstrated greater efficacy
`than placebo in the treatment of acute bipolar mania and
`was generally well tolerated.
`
`Arch Gen Psychiatry. 2000;57:841-849
`
`A LTHOUGH ADVANCES have
`
`been made in the treat-
`ment of bipolar disorder,
`existing therapies are not
`always effective or are ac-
`companied by adverse effects that lead to
`noncompliance. The efficacy of lithium
`and valproate has been established by well-
`designed clinical trials1-3; however, side ef-
`fects and treatment failures are present
`with both drugs.1,4 Typical antipsychot-
`ics are also used for the treatment of acute
`mania, although their side effect profiles
`are far from ideal.5
`Olanzapine has also been used for the
`treatment of bipolar disorder. A 21-day,
`double-blind, placebo-controlled study
`found olanzapine to be an effective and safe
`treatment in acute mania.6,7 Limitations of
`that trial included separation of olanzap-
`ine from placebo at week 3 of treatment,
`rather than earlier, as occurred in other
`similarly designed modern trials of val-
`proate and lithium in acute mania.2,3
`
`Possible reasons for the lack of a more
`robust separation between drug and pla-
`cebo were hypothesized to include the
`following: (1) too slow an increase in
`olanzapine dosing (ie, acute mania may
`require more aggressive olanzapine
`dosing for optimal response); (2) too lib-
`eral use of adjunctive lorazepam; (3) in-
`clusion of first-episode patients (who
`showed a disproportionately high rate of
`response to placebo); and (4) too short
`a treatment period. We therefore con-
`ducted a second double-blind, placebo-
`controlled study to further evaluate the
`efficacy and safety of olanzapine in the
`treatment of acute bipolar mania, with
`special attention to the potential method-
`ological limitations of the first trial. Spe-
`cifically, we conducted a 28-day study of
`115 multiple-episode patients from Decem-
`ber 1, 1997, through February 28, 1999,
`that used a more aggressive olanzapine-
`dosing schedule but permitted less con-
`comitant lorazepam use.
`
`From the Lilly Research
`Laboratories, Indianapolis, Ind
`(Drs Tohen, Sanger, Zhang,
`Tollefson, and Breier; Mssrs
`Jacobs and Risser; and Mss
`Grundy, Toma, and Francis);
`the Department of Psychiatry,
`Harvard Medical School,
`McLean Hospital, Belmont,
`Mass (Dr Tohen); the
`Department of Psychiatry,
`University of Cincinnati
`College of Medicine, Cincinnati,
`Ohio (Dr McElroy); Northwest
`Behavioral Medicine, Marietta,
`Ga (Dr Banov); and The
`Psychiatric Institute,
`Department of Psychiatry,
`University of Illinois, Chicago
`(Dr Janicak). Members of the
`Olanzapine HGGW Study
`Group are listed in the
`acknowledgment section
`on page 848.
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, SEP 2000
`841
`
`WWW.ARCHGENPSYCHIATRY.COM
`
`©2000 American Medical Association. All rights reserved.
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`PATIENTS AND METHODS
`
`PATIENTS
`
`Patients, aged 18 through 70 years, with a DSM-IV8 diag-
`nosis of bipolar disorder, manic or mixed, with or without
`psychotic features,were eligible to be enrolled in this study.
`Investigators recruited patients from private practices (13
`sites), inpatient and outpatient services of university-
`affiliated centers (10 sites), and a Veterans Affairs facility.
`In addition, some sites recruited patients through col-
`league referral, and 6 sites advertised the study in local news-
`papers. Diagnosis was based on clinical assessment and con-
`firmed by results of the Structured Clinical Interview for
`the DSM-IV, Patient Version (SCID-P), administered by
`trained clinicians (including principal and subinvestiga-
`tors [all physicians] and study personnel with appropriate
`clinical degrees [PhD in psychology or MSW] and
`experience). After having the protocol explained to them,
`patients provided written informed consent to participate
`in the study. A minimum total score of at least 20 on the
`Young–Mania Rating Scale (Y-MRS)9 was required at the
`screening visit and on the day of randomization (baseline).
`At baseline, patients displayed a clinically severe symp-
`tom profile, with a mean Y-MRS score of 29.10 (range, 14-
`49; 1 patient was enrolled with a baseline Y-MRS total score
`of 14). Patients were excluded with any of the following
`criteria: serious, unstable medical illness; DSM-IV sub-
`stance dependence (except nicotine or caffeine) within the
`past 3 months; and serious suicidal risk.
`
`STUDY DESIGN
`
`Computer-generated codes were used to create random-
`ized blocks of clinical trial material kits before study start-
`up. Each block contained 2 olanzapine and 2 placebo kits.
`Each kit contained all clinical trial material used by a pa-
`tient throughout the 4-week study. Personnel at the site
`assigned a patient the next available kit. Patients were re-
`quired to be hospitalized for a minimum of 1 week after
`randomization and were allowed to leave the hospital af-
`ter that time only if their Clinical Global Impressions–
`Bipolar Version of Severity of Illness (CGI-BP)10 mania score
`was no greater than 3 (mild) and they had at least a 50%
`reduction in their Y-MRS score. Psychotherapy was per-
`mitted, but not controlled for, during the study.
`The starting dose of olanzapine was 15 mg/d. After the
`first day of therapy, the daily dose could be adjusted up-
`ward or downward, as clinically indicated, by 5-mg incre-
`ments or decrements within the allowed dose range of 5
`to 20 mg/d. Modal dose was defined as the dose that the
`patient was prescribed for the most number of days. The
`mean (± SD) modal and median modal doses of olanzap-
`ine were 16.4±4.2 mg/d and 20 mg/d, respectively.
`Concomitant use of lorazepam was allowed during
`double-blind therapy up to 2 mg/d for the first 4 days of
`treatment and thereafter by up to 1 mg/d for the next 6
`days. Lorazepam was not permitted beyond the initial 10
`days after randomization. Benztropine mesylate was per-
`mitted to treat extrapyramidal symptoms (EPSs) up to a
`maximum of 2 mg/d throughout the course of the study.
`However, the use of benztropine as prophylaxis was not
`allowed.
`
`ASSESSMENT
`
`We conducted a 4-week, randomized, double-blind, par-
`allel study. All psychotropic medication therapy (except ben-
`zodiazepines) was tapered during the screening period and
`discontinued at least 1 day before randomization. Patients
`were randomized to olanzapine or placebo, in a 1:1 ratio.
`
`Severity of illness and psychopathologic features were mea-
`sured by the following rating scales: Y-MRS, Hamilton Psy-
`chiatric Rating Scale for Depression–21 Item (HAMD-21),11
`CGI-BP, and the Positive and Negative Syndrome Scale
`(PANSS).12 Safety was monitored by assessing adverse events,
`including EPSs (parkinsonism as measured by the Simpson-
`
`RESULTS
`
`PATIENTS
`
`A total of 115 patients were enrolled in the study. Mean
`age was 39 years; 80.0% were white, and 50.0% were
`men. Based on DSM-IV criteria using the SCID-P, 42.6%
`of the patients were in a mixed episode and 55.7% were
`experiencing psychotic features. Of those 64 patients
`with psychotic features, 47 (73.4%) were experiencing
`mood-congruent psychotic features. There were no sta-
`tistically significant differences in any demographic or
`illness characteristics between treatment groups. His-
`torical illness characteristics and previous medication
`use and response are presented in Table 1. A statisti-
`cally significant greater number of patients randomized
`to the placebo-treated group had a history of previous
`response to valproate than in the olanzapine-treated
`group (P=.02, Fisher exact test). Frequency of recorded
`medication use at the beginning of the screening period
`included benzodiazepines and/or hypnotics (68.7%),
`
`anticonvulsants (23.5%), typical antipsychotics
`(16.5%), anticholinergics (14.8%), lithium (9.6%),
`atypical antipsychotics (7.8%), and antidepressants
`(4.3%). Study completion and discontinuation sum-
`mary details are presented in Table 2. Frequency of
`study completion was significantly greater (P = .04;
`Fisher exact test) in the olanzapine group (61.8%) com-
`pared with the placebo group (41.7%). There were no
`significant differences between groups regarding rea-
`sons for discontinuation.
`
`EFFICACY
`
`The primary efficacy measure was the change in Y-MRS
`score from baseline to end point (LOCF), after up to 4
`weeks of acute double-blind treatment. The olanzapine
`group experienced a 6.65-point greater mean improve-
`ment in Y-MRS total score compared with the placebo
`group (F1,86= 12.47; P⬍.001). The impact of initial
`severity on LOCF change in Y-MRS score was not
`significantly different between the treatment groups
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, SEP 2000
`842
`
`WWW.ARCHGENPSYCHIATRY.COM
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`©2000 American Medical Association. All rights reserved.
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`Angus scale13 and akathisia as measured by the Barnes Aka-
`thisia scale14), laboratory values, electrocardiograms (ECGs),
`vital signs, and weight change. All adverse events re-
`ported by patients during the study were recorded and coded
`using the Clinical Symbol and Thesaurus for Adverse Event
`Terminology (COSTART) dictionary.
`The primary efficacy variable, as defined by the pro-
`tocol, was the reduction from baseline of the Y-MRS total
`score after 4 weeks of therapy. Response and euthymia were
`defined, a priori, as at least a 50% improvement from base-
`line to end point and as a score of no greater than 12 at
`end point in the Y-MRS total score, respectively. Inter-
`rater reliability assessments with the Y-MRS were con-
`ducted before study initiation by measuring the correla-
`tion of each rater with the groupwise median score of each
`item. Raters who did not achieve a correlation of at least
`0.80 were not allowed to rate patients in this study.
`To further investigate the effect of olanzapine on de-
`pressive symptoms, additional analyses were performed. The
`mean change from baseline to end point on the HAMD-21
`score was calculated for all randomized patients and in a
`subset of patients who presented with moderate to severe
`depressive symptoms (HAMD-21 score, ⱖ20 at baseline).
`In addition, the proportion of patients experiencing a clini-
`cally detectable worsening in depressive symptoms at any
`time during acute therapy was assessed. A worsening of
`at least 3 points on the HAMD-21 score was used as a defi-
`nition of clinically detectable worsening of depressive
`symptoms.
`
`STATISTICAL METHODS
`
`Patient data were analyzed on an intent-to-treat basis. For
`analysis of last observation carried forward (LOCF) mean
`change from baseline to end point, patients with a base-
`line and at least 1 postbaseline measurement were in-
`cluded in the analysis. Four placebo-treated patients and
`1 olanzapine-treated patient did not have a postbaseline mea-
`sure and were excluded from all efficacy analyses. Total
`
`scores from rating scales were derived from the individual
`items; if any single item was missing, the total score was
`treated as missing.
`Continuous efficacy and safety parameters were evalu-
`ated using analysis of variance. The models generally in-
`cluded terms for the fixed effects of treatment, investiga-
`tor, and treatment ⫻investigator interaction. Investigators
`with fewer than 2 patients per treatment group were pooled
`as specified in the protocol. Analyses of subgroups in-
`cluded a term for treatment only, owing to sparse data. The
`LOCF change in the Y-MRS total score was also compared
`between treatment groups using the baseline Y-MRS score
`as a covariate to examine change in relation to initial se-
`verity; investigator was not included in this model. An ex-
`amination of the effect of treatment over time was con-
`ducted on the Y-MRS total score using a likelihood-based
`repeated-measures analysis. The Y-MRS total score at each
`postbaseline visit was used as the response variable, and
`the baseline Y-MRS total score was used as a covariate. This
`analysis evaluated treatment and investigator effects along
`with the treatment ⫻investigator and treatment ⫻visit in-
`teractions using an unstructured covariance matrix for the
`within-patient error as specified in the protocol. In addi-
`tion, an examination of the therapy difference stratified by
`treatment time for the Y-MRS total score was performed
`using a pattern-mixture analysis.15 A mixed-effects model
`was used, including the main effects for therapy, visit, treat-
`ment time, investigator, and the interaction effects for
`therapy ⫻ investigator, therapy ⫻ treatment time,
`therapy⫻visit, investigator⫻visit, and therapy⫻treatment
`time ⫻visit. Visit and dropout time were random effects;
`therapy and investigator were fixed effects in the model.
`The Kruskal-Wallis test was used to compare treatments
`for each of the individual items of the Y-MRS. The Fisher
`exact test was used to analyze treatment effects for cat-
`egorical efficacy and safety parameters. All cited P values
`are 2-tailed, with a significance level of .05 as specified in
`the protocol. Unless otherwise indicated, data are given as
`mean±SD.
`
`(F1,106=2.19; P=.14; Figure 1). In addition, olanzapine-
`treated patients demonstrated a statistically significant
`greater mean improvement on the CGI-BP severity of
`mania, CGI-BP severity of overall bipolar illness, and
`PANSS total and positive scores compared with
`placebo-treated patients (Table 3). Efficacy subgroup
`analyses were also performed based on the presence
`or absence of psychotic features and between patients
`in a manic or a mixed episode. Olanzapine-treated
`patients exhibited no statistically significant difference
`in the mean change in Y-MRS scores for any of these
`subtypes. For olanzapine-treated patients, the antimanic
`effect in patients with and without psychotic features
`was similar.
`
`WEEKLY ANALYSIS
`
`The olanzapine group consistently showed greater LOCF
`mean improvement on Y-MRS total score; HAMD-21
`total score; CGI-BP mania, depression, and overall bi-
`polar illness scores; and PANSS total, positive, and nega-
`
`tive scores compared with the placebo group at each week.
`Olanzapine-treated patients demonstrated a statistically
`significant greater improvement in the mean change from
`baseline in the Y-MRS total score at the first postbase-
`line observation at week 1 (F1,86=4.78; P=.03) (Figure 2).
`This statistically significant separation from the placebo
`group was maintained during the 4-week study. In ad-
`dition, treatment differences were statistically signifi-
`cant at each week for CGI-BP severity of mania and over-
`all bipolar illness scores and PANSS total and positive
`scores.
`An examination of treatment effect over time using
`a repeated-measures analysis was conducted on the
`Y-MRS total score as specified in the protocol. Olanza-
`pine demonstrated a statistically significant greater treat-
`ment effect compared with placebo (F1,207=10.47; P=.002).
`The superior treatment effect of olanzapine was evident
`at week 1, and the superiority was maintained over time
`(Table 4).
`A post hoc examination of the effect of dropout time
`on treatment result was performed. Patients who dropped
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, SEP 2000
`843
`
`WWW.ARCHGENPSYCHIATRY.COM
`
`©2000 American Medical Association. All rights reserved.
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`3 of 9
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`Table 1. Patient and Illness Characteristics
`
`Placebo Group
`
`Olanzapine Group
`
`Characteristic
`Age, y
`Current episode, d
`Age at onset of illness, y
`No. of hospital admissions for bipolar I disorder
`No. of previous episodes of mania, lifetime
`No. of previous episodes of mania, previous 12 mo
`No. of previous episodes of depression, lifetime
`No. of previous episodes of depression, previous 12 mo
`No. of previous mixed episodes, lifetime
`No. of previous mixed episodes, previous 12 mo
`
`Sample Size
`60
`60
`59
`59
`49
`60
`49
`59
`49
`59
`
`Mean (SD)
`39.0 (10.1)
`38.2 (21.1)
`21.1 (9.3)
`1.3 (1.8)
`19.9 (45.3)
`3.2 (5.6)
`13.0 (24.8)
`1.5 (2.4)
`9.8 (30.1)
`1.8 (3.7)
`
`Sample Size
`55
`55
`55
`55
`44
`55
`43
`55
`43
`54
`
`Mean (SD)
`38.3 (10.7)
`31.0 (28.0)
`23.2 (9.5)
`0.76 (1.0)
`16.1 (33.0)
`2.3 (3.5)
`9.9 (13.6)
`2.0 (3.0)
`7.5 (17.9)
`2.7 (7.7)
`
`Placebo Group
`
`Olanzapine Group
`
`Male
`White
`Psychotic
`Current episode mixed state
`Rapid cyclers‡
`Lifetime diagnosis of substance abuse
`Previous medication use
`Lithium
`Valproate
`Antipsychotic
`Patients exposed to any of the above 3 medications
`Patients exposed to all
`Previous medication response§
`Lithium
`Valproate
`Antipsychotic
`Patients exposed to any of the above 3 medications
`
`Sample Size
`
`60
`60
`60
`60
`60
`60
`
`60
`60
`60
`60
`60
`
`41
`31
`35
`47
`
`No. (%)
`
`30 (50.0)
`52 (86.7)
`30 (50.0)
`25 (41.7)
`20 (33.3)
`37 (61.7)
`
`41 (68.3)
`31 (51.7)
`35 (58.3)
`47 (78.3)
`21 (35.0)
`
`22 (53.7)
`21 (67.7)
`25 (71.4)
`36 (76.6)
`
`Sample Size
`
`55
`55
`55
`55
`55
`55
`
`55
`55
`55
`55
`55
`
`42
`32
`39
`49
`
`No. (%)
`
`27 (49.1)
`40 (72.7)
`34 (61.8)
`24 (43.6)
`25 (45.5)
`30 (54.5)
`
`42 (76.4)
`32 (58.2)
`39 (70.9)
`49 (89.1)
`22 (40.0)
`
`18 (42.9)
`11 (34.4)
`27 (69.2)
`35 (71.4)
`
`*MeanswereanalyzedusingatypeIIIsumofsquaresanalysisofvariance.
`†FrequencieswereanalyzedusingFisherexacttest.
`‡Definedasanypatientwith4ormoremanic,depressed,ormixedepisodesinthepreviousyear.
`§Definedbasedonphysicianassessment.
`
`P
`.52*
`.74*
`.25*
`.07*
`.35*
`.24*
`.08*
`.43*
`.51*
`.69*
`
`P
`
`⬎.99†
`.10†
`.26†
`.85†
`.25†
`.46†
`
`.41*
`.57*
`.18*
`.14*
`.70*
`
`.38
`.01
`⬎.99
`.65
`
`Table 2. Patient Disposition
`
`Variable
`Completed
`Discontinued
`Adverse event
`Lack of efficacy
`Unavailable for follow-up
`Patient decision
`Physician decision
`
`Treatment Group, No. (%)
`
`Placebo
`(n = 60)
`25 (41.7)
`35 (58.3)
`1 (1.7)
`23 (38.3)
`3 (5.0)
`5 (8.3)
`3 (5.0)
`
`Olanzapine
`(n = 55)
`34 (61.8)
`21 (38.2)
`2 (3.6)
`15 (27.3)
`1 (1.8)
`3 (5.5)
`0
`
`P*
`.04
`
`.61
`.24
`.62
`.72
`.25
`
`*FrequenciesanalyzedusingFisherexacttest.
`
`out at week 1 had a similar response regardless of therapy.
`Placebo-treated patients who dropped out at weeks 2 or
`3 had minimal response. On the other hand, olanzapine-
`treated patients who dropped out at week 2 or 3 did have
`some improvement (Table 5). To estimate the therapy
`difference stratified by treatment time, a pattern-
`mixture analysis15 was performed. The results of this analy-
`sis were similar to the results of the LOCF and repeated-
`
`measures visitwise analyses. The main difference was that
`in this analysis, there was no statistical separation at week
`1 (Table 6).
`In the analysis of the individual items of the Y-MRS,
`olanzapine-treated patients exhibited a statistically signifi-
`cant greater mean improvement than placebo-treated pa-
`tients on the following items: elevated mood (␹2
`1=9.11;
`P=.003), sleep (␹2
`1=12.33; P⬍.001), language-thought dis-
`order (␹2
`
`1=4.66; P=.03), content (␹21=8.48; P=.004), and
`disruptive-aggressive behavior (␹2
`1=6.64; P=.01).
`
`RESPONSE AND EUTHYMIA
`
`Responders were classified as patients with an improve-
`ment of 50% or more in Y-MRS total score from baseline
`to end point (LOCF). The olanzapine group demon-
`strated a significantly greater response rate compared with
`the placebo group (64.8% vs 42.9%, respectively; Fisher
`exact test, P=.02). Patients achieving a Y-MRS total score
`of at least 12 at the final visit of the acute phase were con-
`sidered to be euthymic. A statistically significant greater
`number of olanzapine- than placebo-treated patients met
`the euthymia criterion for mania (61.1% vs 35.7%, re-
`spectively; Fisher exact test, P=.01).
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, SEP 2000
`844
`
`WWW.ARCHGENPSYCHIATRY.COM
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`tively; F1,86=0.30; P=.59), or in the subset of patients who
`presented with moderate to severe depressive symp-
`toms at baseline (−5.52 ± 4.72 vs −3.19 ± 4.34, respec-
`tively; F1,40=2.78; P=.10).
`The effect of olanzapine on induction of depressive
`symptoms was also investigated. A worsening in the
`HAMD-21 score of at least 3 points was used as a defi-
`nition of a clinically detectable worsening. The percent-
`age of olanzapine-treated patients who experienced a clini-
`cally detectable worsening in depressive symptoms at any
`time during double-blind therapy was similar to that seen
`in placebo-treated patients (11.1% vs 17.9%, respec-
`tively; P=.42, Fisher exact test).
`
`BENZODIAZEPINE USE
`
`The categorical rates of patients who received at least 1
`dose of benzodiazepine were 36 (65.5%) of 55 patients
`and 44 (73.3%) of 60 patients in the olanzapine and pla-
`cebo groups, respectively. The between-treatment group
`difference in categorical use was not statistically signifi-
`cant P=.42, Fisher exact test). Of those patients treated
`with a benzodiazepine, placebo-treated patients had a
`higher mean daily dose (0.74 mg/d) compared with olan-
`zapine-treated patients (0.55 mg/d) (F1,55=1.06; P=.31).
`
`SAFETY
`
`Adverse Events
`
`Adverse events that originally occurred or worsened in
`severity during double-blind therapy were considered
`treatment emergent. One patient in the placebo group
`(agitation) and 2 patients in the olanzapine group (un-
`intended pregnancy and rash) discontinued treatment be-
`cause of an adverse event. The only treatment-emergent
`event with a statistically significant more frequent oc-
`currence in the olanzapine group compared with the pla-
`cebo group was somnolence (P⬍.001, Fisher exact test)
`(Table 7). The only treatment-emergent event with a
`statistically significant more frequent occurrence in the
`placebo group was agitation (P=.03, Fisher exact test).
`
`IMPROVEMENT IN
`DEPRESSIVE SYMPTOMS AND
`LACK OF DEPRESSOGENIC EFFECTS
`
`The analysis of change in HAMD-21 score from base-
`line to end point for all randomized patients showed a
`similar improvement in olanzapine- and placebo-
`treated patients (−7.83 ± 7.79 vs −4.45 ± 6.95, respec-
`tively; F1,86=2.91; P=.09). In patients who presented with
`moderate to severe depressive symptoms (HAMD-21
`score, ⱖ20 at baseline), a statistically significant greater
`improvement in olanzapine- compared with placebo-
`treated patients was observed on the change in HAMD-21
`score from baseline to end point (−12.29 ± 8.79 vs
`−6.81±8.43, respectively; F1,40=4.24; P=.05) (Figure 3).
`Using a 6-item subscale score of the HAMD-21 to reflect
`a core mood factor16,17 (items 1, 2, and 7-10,), there was
`no significant difference in change from baseline to end
`point when comparing all olanzapine- and placebo-
`treated patients (−3.06 ± 4.24 vs −2.04 ± 3.69, respec-
`
`Olanzapine Group
`Placebo Group
`
`10
`
`20
`
`40
`30
`Baseline Y-MRS Total Score
`
`50
`
`60
`
`30
`
`20
`
`10
`
`0
`
`–10
`
`–20
`
`–30
`
`–40
`
`–50
`
`From Baseline to End Point
`Change in Y-MRS Total Score
`
`Figure 1. ScatterplotofYoung–ManiaRatingScale(Y-MRS)lastobservation
`carriedforward(LOCF)changefrombaselinevsbaselineseverity.Analysis
`ofcovarianceusingbaselineY-MRSscoreasacovariateindicatedno
`significantdifferencebetweenolanzapine(n=54)andplacebo(n=56)groups
`intheimpactofinitialseverityonbaselinetoendpointLOCFchangeinthe
`Y-MRS(F1,106=2.19;P=.14;baseline⫻therapyinteraction).Solidanddotted
`linesindicateregressiontrendlines.
`
`Table 3. Change in the Severity-of-Illness Scores From Baseline to End Point*
`
`Placebo Group (n = 56)
`
`Olanzapine Group (n = 54)
`
`Measure
`Y-MRS total
`HAMD-21 total
`PANSS total
`PANSS positive
`PANSS negative
`CGI-BP severity of mania
`CGI-BP severity of depression
`CGI severity of overall bipolar illness
`
`Baseline
`29.43 (6.77)
`16.16 (9.49)
`72.61 (21.68)
`20.54 (6.38)
`13.29 (6.15)
`4.80 (0.82)
`2.61 (1.57)
`4.77 (0.89)
`
`Change
`From Baseline
`−8.13 (12.72)
`−4.45 (6.95)
`−7.43 (19.73)
`−2.96 (6.61)
`−0.63 (4.41)
`−0.88 (1.54)
`−0.45 (1.26)
`−0.73 (1.43)
`
`Baseline
`28.76 (6.72)
`17.33 (9.24)
`76.74 (25.72)
`21.72 (6.91)
`14.46 (7.32)
`4.78 (0.77)
`2.89 (1.53)
`4.78 (0.77)
`
`Change
`From Baseline
`−14.78 (12.49)
`−7.83 (7.79)
`−21.19 (23.73)
`−7.76 (7.89)
`−2.78 (6.50)
`−1.83 (1.45)
`−0.74 (1.32)
`−1.72 (1.46)
`
`F1,86
`12.47
`2.91
`13.25
`15.94
`3.21
`15.02
`0.82
`16.20
`
`P†
`⬍.001
`.09
`⬍.001
`⬍.001
`.08
`⬍.001
`.37
`⬍.001
`
`*Atotalof4placebo-treatedpatientsand1olanzapine-treatedpatienthadnopostbaselinescoresforanyoftheefficacymeasuresandwereexcludedfromall
`efficacyanalyses.Nostatisticallysignificantdifferenceswereobservedbetweenbaselinevaluesforanymeasure.Y-MRSindicatesYoung–ManiaRatingScale;
`HAMD-21,HamiltonPsychiatricRatingScaleforDepression–21Item;PANSS,PositiveandNegativeSymptomsScale;andCGI-BP,ClinicalGlobal
`Impressions–BipolarVersionofSeverityofIllness.Dataaregivenasmean(SD).
`†ChangefrombaselinetoendpointmeanswereanalyzedusinganFtestfromanalysisofvariancemodel,whichincludedtermsfortreatment,investigator,
`andinteraction.
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, SEP 2000
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`
`whereas placebo-treated patients experienced a worsen-
`ing in parkinsonism and an improvement in akathisia.
`The difference in mean change at end point between olan-
`zapine- and placebo-treated patients was not statistically
`significant for parkinsonism (−0.27±1.16 vs 0.13±1.61,
`respectively; F1,86=1.81; P=.18) or akathisia (−0.40±0.83
`vs −0.16±0.76, respectively; F1,87=2.07; P=.16).
`
`Vital Signs and Weight
`
`Significant differences between groups were observed for
`mean change in supine systolic blood pressure from base-
`line to end point (5.04±15.98 vs −3.86±17.92 mm Hg
`for olanzapine- vs placebo-treated patients, respec-
`tively; F1,86=9.84; P=.04). Patients in the olanzapine group
`had a statistically significant larger mean weight gain com-
`pared with the placebo group (2.11±2.83 vs 0.45±2.31
`kg, respectively; F1,88=4.22; P=.002).
`
`Laboratory Values
`
`The only statistically significant difference in laboratory
`values between treatment groups occurred in alanine ami-
`notransferase (ALT) and aspartate aminotransferase
`(AST). Patients in the olanzapine group had a statisti-
`cally significant higher incidence of increased ALT and
`AST levels than patients in the placebo group (ALT, 21.6%
`vs 3.9%; P=.02, Fisher exact test; AST, 17.3% vs 0%;
`P=.003, Fisher exact test). High and low limits that are
`of potential clinical concern were determined a priori for
`each laboratory test. Patients who met these criteria at
`end point or for 2 consecutive observations were defined
`to have a potentially clinically significant abnormality. One
`olanzapine-treated patient met this definition for ALT
`(ⱖ165 U/L) and AST levels (ⱖ150 U/L). No patients dis-
`played clinical symptoms of hepatic dysfunction at any time
`during the study, and none were discontinued because of
`abnormal results of liver function tests.
`
`Electrocardiogram
`
`There were no statistically significant differences in
`ECGs between treatment groups, although fewer
`olanzapine- than placebo-treated patients experienced a
`treatment-emergent ECG abnormality (13.3% vs 33.3%,
`respectively; P=.11, Fisher exact test). No statistically-
`
`EPS Rating Scales
`
`Emergence of EPSs was low, and anticholinergic use was
`negligible for both groups (mean, 0.33±0.26 vs 0.22±0.17
`mg/d for olanzapine- vs placebo-treated patients, respec-
`tively; F1,3=2.28; P=.23). Olanzapine-treated patients ex-
`perienced an improvement in parkinsonism (Simpson-
`Angus) and akathisia (Barnes) from baseline to end point,
`
`Placebo Group
`Olanzapine Group
`
`1
`
`2
`Week
`
`3
`
`4
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`Y-MRS Total Score
`
`Figure 2. Young–ManiaRatingScale(Y-MRS)weeklyanalysis.Forthelast
`observationcarriedforwardchangefrombaseline(mean±SD),olanzapine
`(n=54)andplacebo-treated(n=56)groups:week1,F1,86=4.78(P=.03);
`week2,F1,86=8.87(P=.004);week3,F1,86=16.13(P⬍.001);andweek4,
`F1,86=12.47(P⬍.001).
`
`Table 4. Repeated Measures Analysis
`for Y-MRS Total Score*
`
`Placebo Group,
`LS Mean (SE)
`(n = 56)
`24.8 (1.3)
`21.8 (1.6)
`21.6 (1.8)
`17.2 (1.6)
`
`Olanzapine Group,
`LS Mean (SE)
`(n = 54)
`19.8 (1.4)
`16.0 (1.6)
`13.5 (1.7)
`11.5 (1.5)
`
`Week
`1
`2
`3
`4
`
`F1,207
`6.85
`6.61
`10.69
`6.46
`
`P
`.01
`.01
`.001
`.01
`
`*Y-MRSindicatesYoung–ManiaRatingScale;LS,leastsquares;SE,SEof
`theleastsquaresmean.Y-MRStotalscoremeanswereanalyzedwitha
`repeated-measures,mixed-effectsmodelincludingtermsfortreatment,
`investigator,visit,treatment⫻ investigatorinteraction,treatment⫻ visit
`interaction,andbaselineY-MRStotalscore.Visitwasmodeledasarandom
`effect,whereastreatmentandinvestigatorweremodeledasfixedeffects.
`Thewithin-patienterrorwasestimatedusinganunstructuredcovariance
`structure.
`
`Table 5. Mean Y-MRS Total Score by Treatment Time*
`
`1
`
`2
`
`3
`
`4
`
`Therapy Week, Y-MRS Mean Total Score
`
`Placebo
`Group
`(n = 16)
`32.7
`32.8
`. . .
`. . .
`. . .
`
`Olanzapine
`Group
`(n = 10)
`28.8
`28.9
`. . .
`. . .
`. . .
`
`Placebo
`Group
`(n = 11)
`26.5
`23.9
`25.8
`. . .
`. . .
`
`Olanzapine
`Group
`(n = 4)
`28.8
`15.8
`17.8
`. . .
`. . .
`
`Placebo
`Group
`(n = 4)
`29.5
`22.3
`26.5
`29.5
`. . .
`
`Olanzapine
`Group
`(n = 5)
`27.8
`19.0
`24.4
`23.6
`. . .
`
`Placebo
`Group
`(n = 25)
`28.6
`19.2
`13.8
`14.2
`10.6
`
`Olanzapine
`Group
`(n = 35)
`28.9
`16.8
`11.7
`9.3
`7.9
`
`Week
`Baseline
`1
`2
`3
`4
`
`*Y-MRSindicatesYoung–ManiaRatingScale.
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, SEP 2000
`846
`
`WWW.ARCHGENPSYCHIATRY.COM
`
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`Table 6. Pattern Mixture Analysis for Y-MRS Total Score*
`
`Table 7. Treatment-Emergent Adverse Events*
`
`Event
`Somnolence
`Agitation
`Anxiety
`Personality disorder
`Dry mouth
`Hostility
`Nervousness
`Dyspepsia
`Asthenia
`Dizziness
`Constipation
`Headache
`
`Placebo Group
`(n = 60)
`5 (8.3)
`15 (25.0)
`9 (15.0)
`7 (11.7)
`3 (5.0)
`6 (10.0)
`12 (20.0)
`3 (5.0)
`3 (5.0)
`4 (6.7)
`5 (8.3)
`13 (21.7)
`
`Olanzapine Group
`(n = 55)
`21 (38.2)
`5 (9.1)
`2 (3.6)
`1 (1.8)
`9 (16.4)
`1 (1.8)
`5 (9.1)
`7 (12.7)
`6 (10.9)
`7 (12.7)
`6 (10.9)
`10 (18.2)
`
`P†
`⬍.001
`.03
`.06
`.06
`.07
`.12
`.12
`.19
`.31
`.35
`.76
`.82
`
`*Treatment-emergentadverseeventsareeventsthatfirstoccurredor
`worsenedinseverityduringdouble-blindtherapyinatleast10%ofany
`treatmentgrouporstatisticallysignificantbetween-groupdifference.
`†FrequenciesareanalyzedusingtheFisherexacttest.
`
`and maintained throughout the 4-week trial. In olanza-
`pine-treated patients, 65% responded (Y-MRS improve-
`ment, ⱖ50%) and 61% (Y-MRS, ⱕ12) achieved eu-
`thymia at their final visit. Most important, olanzapine
`achieved statistical significance on the elevated mood item
`on the Y-MRS, suggesting efficacy in core manic symp-
`toms. In addition, olanzapine exhibited antimanic effi-
`cacy in the main subtypes of acute bipolar mania. The Y-
`MRS mean score change observed in the olanzapine group
`was similar for patients with and without psychotic fea-
`tures,