——2—m@
`
`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]. 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
`
`Background: A 6-week double-blind, randomized, pla-
`cebo-controlled trial was conducted to determine the ef-
`
`ficacy 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 ef-
`ficacy of olanzapine (5-20 mg/d) vs placebo when added
`to ongoing mood-stabilizer therapy as measured by re-
`ductions 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 random-
`ized 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 (25096 improve-
`ment on YMRS) were significantly higher with cotherapy
`(67.7% vs 44.7%; P<.OO1). Olanzapine cotherapy im-
`
`proved 21-item Hamilton Depression Rating Scale (l-IAMD-
`21) total scores significantly more than monotherapy (4.98
`vs 0.89 points; P<.OO1). In patients with mixed-episodes
`with moderate to severe depressive symptoms (DSM-IV
`mixed episode; I-IAMD-21 score of 220 at baseline), olan-
`zapine cotherapy improved HAMD-21 scores by 10.3 1
`points compared with 1.57 for monotherapy (P< .001 ). Ex-
`trapyramidal symptoms (Simpson-Angus Scale, Barnes Aka-
`thisia Scale, Abnonnal Involuntary Movement Scale) were
`not significantly changed from baseline to end point in ei-
`ther 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 su-
`perior efficacy in the treatment of manic and mixed bi-
`polar episodes.
`
`Arch Gen Psychiatry. 2002;59:62-69
`
`
`HE EXPERT Consensus
`
`Guidelines Series, pub-
`lished in the year 2000,
`recommends lithium and
`
`valproate as first-line treat-
`ments for bipolar mania.‘ However, up to
`40% of patients respond poorly to mono-
`therapy with either treatment} When mono-
`therapy fails, the guidelines recommend
`combination therapies. A number of au-
`thors have recently reviewed the use of such
`cotherapies for bipolar mania. Freeman and
`Sto1l3 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 sug-
`gested to be superior in efficacy to lithium
`monotherapy." Conversely, the addition of
`a mood stabilizer to conventional antipsy-
`
`A list of the Principal
`Investigators appears in
`the box on page 69. Author
`affiliations appear in the
`acknowledgment section.
`Drs Tohen, Feldman, Tollefson,
`and Breier and Mr Risser and
`Ms Keeter are stockholders
`in Eli Lilly 6' Co.
`
`chotic therapy seems superior to antipsy-
`chotic agents alone.5 In support of this,
`Muller-Oerlinghausen et al‘‘ compared the
`efficacy of combined therapy with con-
`ventional antipsychotics and valproate vs
`valproate monotherapy in patients with bi-
`polar or schizoaffective disorder and found
`combination therapy to be superior to
`monotherapy.
`Olanzapine, an atypical antipsy-
`chotic, has been shown in 2 placebo-
`controlled studies to have acute antimanic
`
`effects.” Moreover, a previous report has
`suggested that olanzapine is effective when
`used in combination with other psycho-
`tropic agents.” The present study was con-
`ducted to investigate the efficacy and safety
`of combined therapy with olanzapine and
`either valproate or lithium compared with
`valproate or lithium monotherapy.
`
`
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`SUBJECTS AND METHODS
`
`SUBJECTS
`
`All patients were diagnosed as having bipolar disorder, manic
`or mixed episode, with or without psychotic features, us-
`ing the Structured Clinical Interview for the DSM—IV'°
`(SCID)." Patients had to have at least 2 previous de-
`pressed, manic, or mixed episodes as well as a Young Ma-
`nia Rating Scale“ (YMRS) total score of 16 or greater at visit
`I 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 mmoVL) or valproate (50-
`125 ug/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 216). Prior
`to participation, all patients signed an informed consent
`document approved by their study sites institutional re-
`view board.
`
`STUDY DESIGN
`
`Participants in the study initially entered a 2- to 7-day screen-
`ing 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 fomis of treatment started receiving either
`lithium or valproate at investigator discretion for the 2 weeks
`immediately prior to visit 1. Plasma levels of the medica-
`tions 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 pe-
`riod 2).
`Study period 2 consisted of a 6-week acute, double-
`blind phse, during which levels of lithium or valproate were
`maintained within the therapeutic range. Patients were as-
`sessed weekly. Patients were randomized 2:1 to receive ei-
`ther olanzapine (flexible dose range of 5, 10, 15, or 20 mg/d)
`added to valproate or lithium or placebo added to valpro-
`ate 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 in-
`crements of 1 capsule or down by any number of decre-
`ments at investigator discretion as indicated by each pa-
`tient’s tolerance. Patients unable to tolerate the minimum
`dose were discontinued. Patients were permitted adjunc-
`tive use of benzodiazepine (52 mg/d of lorazepam equiva-
`lents) for no more than 14 days cumulatively. Anticholin-
`ergic therapy (benztropine mesylate, S 2 mg/d) was
`permitted throughout the study for treatment of extrapy-
`ramidal 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 en-
`sure high interrater reliability, investigators were re-
`quired 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 Scale" (HAMD-21);
`the Positive and Negative Syndrome Scale"; and the Clini-
`cal Global Impressions Severity of Bipolar Disorder scale”
`(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. Clini-
`cal remission (euthymia) was defined a priori as achieve-
`ment 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. Second-
`ary assessments, also defined a priori, included analyses of
`treatment differences following stratification by the cur-
`rent course of illness, the presence or absence of psy-
`chotic features, and the use of lithium or valproate.
`Scales for the assessment of neurologic adverse events
`included the Simpson-Angus Scale," the Barnes Akathisia
`Scale,“ and the Abnormal Involuntary Movement Scale."
`Assessment of vital signs, weight, and clinical laboratory
`analytes (including prolactin, nonfasting glucose, and elec-
`trolyte levels and hematologic analysis) was perfonned at
`each visit. Serum concentrations of mood stabilizers were
`
`collected at every visit.
`
`STATISTICAL ANALYSES
`
`Data were analyzed on an intent-to-treat basis,” included
`all patients who met the entry criteria (including inad-
`equate responsiveness to the minimum 2-week prior treat-
`ment with lithium or valproate), and provided both a base-
`line 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 or level of .05.
`Analysis of variance (ANOVA) models were used to evalu-
`ate continuous data, including temis for treatment, inves-
`tigator, and treatment-investigator interaction. The linear
`model for this analysis included terms for baseline, treat-
`ment, 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.
`
`ma
`
`PATIENT CHARACTERISTICS AND DISPOSITION
`
`A total of 501 patients entered the screening phase and
`344 patients were randomized and enrolled (33 US cen-
`ters, 5 Canadian), with a mean enrollment of 9 patients
`
`per site. Patients were recruited from both academic and
`nonacademic sites from existing clinical patient popu-
`lations seeking treatment at those sites. Of the 344 ran-
`domized 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 re-
`
`
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`Table 1. Patient charictaristtes
`
`characteristic
`
`Age. mean 1 SD. y
`
`Male. No. (%)
`
`White, No. (%)
`
`Current course, No. ('75)
`Manic
`Mixed
`
`Manic
`Mixed
`
`Manic
`Mixed
`Wlthout psychotic features. N0. (%)T
`
`Cotherapeutic agent. No. (%)
`Lithium
`valproate
`
`Mood stabilizer
`
`Lithium
`Valproate
`
`Lithium
`valproate
`
`Lithium
`valproate
`
`Lithlum
`
`Valproate
`
`Lithium
`Valproate
`
`olanzapine cotherapy
`(n = 229)
`40.7 1 11.2
`40.3 1 12.4
`40.7 1 10.7
`101 (44.1)
`41 (54.0)
`50 (39.2)
`195 (35.5)
`35 (35.5)
`131 (35.5)
`
`104 (45.4)
`125 (54.6)
`
`33 (50.0)
`33 (50.0)
`
`37 (53.9)
`53 (43.1)
`154 (57.3)
`54 (71.1)
`100 (35.4)
`
`75 (33.2)
`153 (53.3)
`
`Monotherapy
`(n = 115)
`40.4 1 10.3
`43.4 1 11.0
`33.3 1 10.5
`54 (55.5)
`25 (33.4)
`33 (52.1)
`97 (34.4)
`34 (32.9)
`53 (35.3)
`
`61 (53.0)
`54 (47.0)
`
`12 (29.3)
`29 (70.7)
`
`42 (57.5)
`31 (42.5)
`75 (55.1)
`23 (53.3)
`43 (35.3)
`
`41 (35.0)
`73 (54.0)
`
`*Treatment difference. olanzapine cotherapy vs monotherapy; derived from analysis of variance for age and from the Fisher exact test otherwise.
`1'Based on n = 114 for monotherapy.
`
`views, 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 2 16);
`patient decision or loss to follow-up during the screen-
`ing phase (58); investigator decision (8); protocol vio-
`lation (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
`('I'¢IIIIe I). One patient in the monotherapy group re-
`ceived both valproate and lithium and accordingly was
`excluded from the subgroup analyses. The median du-
`ration of mood-stabilizer therapy prior to randomiza-
`tion 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.
`The percentage of patients completing the study was
`roughly equal in the 2 treatment groups (cotherapy,
`69.9%; monotherapy, 71.3%). Significantly more pa-
`tients in the monotherapy group discontinued treat-
`ment 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).
`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 mono-
`therapy (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).
`Mean modal dose of olanzapine in the cotherapy
`group (n=224) was 10.4 (4.9) mg/d). Mean plasma lev-
`els of lithium among the cotherapy (n=74) and mono-
`therapy (n=41) patients were 0.76 (0.16) and 0.82 (0.19)
`(Fm-,=4.26; P=.O4) mEq/L, respectively, while mean
`plasma levels of valproate for cotherapy (n=145) and
`monotherapy (n=73) were 63.6 (18.4) pg/mL and 74.7
`(18.6) pg/mL, respectively (F1_138= 18.38; P<.001). Ben-
`zodiazepine use was not statistically different between
`patients in the cotherapy (66/229 (28.8%)) and mono-
`therapy (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 effi-
`cacy, the YMRS total score (Table 3). However, the olan-
`zapine cotherapy group (n=220) showed a mean de-
`crease 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 F1l75= 9.08;
`P= .003) for the monotherapy group (n= 114), which cor-
`responded to an improvement of 40.1%.
`ltemwise analysis of the YMRS revealed that, com-
`pared with monotherapy, olanzapine cotherapy brought
`about significantly greater improvement at end point on
`the items of irritability (cotherapy, -1.82 [2.09], n= 220;
`
`
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`
`table 2. Patient Disp0sitl0n*
`
`Characteristic
`
`Completed study, No.
`
`Reasons for discontinuation
`Adverse event
`
`Lack of etficacy
`
`Lost to follow-up
`
`Patient decision
`
`Criteria not metlcompllance
`
`Sponsor decision
`
`Physician decision
`
`Satisfactory response
`
`Mood stabilizer
`
`Olanzapine cotherapy
`(n = 229)
`
`Monotherapy
`(II = 115)
`
`Full sample
`Lithium
`Valproate
`
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Valproate
`Full sample
`Llthlum
`Valproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Valproate
`
`160 (69.9)
`53 (76.3)
`102 (66.7)
`
`25 (10.9)
`5 (6.6)
`20 (13.1)
`7 (3.1)
`2 (2.6)
`5 (3.3)
`5 (2.2)
`2 (2.6)
`3 (2.0)
`13 (5.7)
`3 (4.0)
`10 (6.5)
`12 (5.2)
`3 (4.0)
`9 (5.9)
`1 (0.4)
`0
`1 (0.7)
`5 (2.2)
`2 (2.6)
`3 (2.0)
`1 (0.4)
`1 (1.3)
`0
`
`82 (71.3)
`32 (78.1)
`50 (88.5)
`
`2 (1.7)
`0
`2 (2.74)
`14 (12.2)
`4 (9.8)
`9 (12.3)
`3 (2.6)
`2 (4.9)
`1 (1.4)
`2 (1.7)
`1 (2.4)
`1 (1.4)
`5 (4.3)
`1 (2.4)
`4 (5.5)
`1 (0.9)
`1 (2.4)
`0
`6 (5.2)
`0
`6 (3.2)
`
`*Data are given as number (percentage) unless otherwise indicated.
`flreatment difference, olanzapine cotherapy vs monotherapy; derived from the Fisher exact test.
`
`monotherapy, -1.02 [2.37], n= 114; Fu75=5.69; P=.02);
`Speech (cotherapy, -2.45 [2.03], n=220; monotherapy,
`-1.63 [2.53], n=114; F1.m=5.24; P=.02); Languagel
`Thought Disorder (cotherapy, -0.94 [0.91], n=220,
`monotherapy, -0.72 [1.00], n= 114; Fu75=5.34; P= .02);
`and Disruptive/Aggressive Behavior (cotherapy, -1.18
`[1.64], n=220; monotherapy, -0.46 [1.77], n= 114;
`F1375: 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 re-
`sponded to treatment compared with 51 (44.7%) of the 114
`patients in the monotherapy group (P<.O01). In addi-
`tion, time to response was significantly shorter for co-
`therapy (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 1 14 evaluated patients demonstrated evidence of re-
`mission. This difference in remission rates was also sig-
`nificant (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 sig-
`nificantly greater improvement on the HAMD-21 at each
`time point throughout the study. By week 6, the co-
`therapy group (n= 220) experienced a mean last observa-
`tion carried forward decrease in HAMD-21 scores of 4.98
`
`(7.61) points, significantly greater (F1375: 18.05; P<.001)
`than the decrease of 0.89 (6.90) points in the mono-
`therapy group (n=114). An exploratory itemwise analy-
`sis showed significantly greater improvement in the di-
`mensions 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 220 at baseline) showed a de-
`crease 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 250%
`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 sub-
`scores) and the CGI-BP (overall, Severity of Mania, and
`Severity of Depression). Olanzapine cotherapy brought
`
`
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`
`Table 3. Summary of Eiticacy Results, Baseline to End Point changes*
`
`Measurement
`Scale
`
`YMRS Total
`
`HAMD-21 Total
`
`CGl—BP Overall
`
`CGI-BP Mania
`
`CGI-BF Depression
`
`PANSS Total
`
`PANSS Cognition
`
`PANSS Hostility
`
`olanzapine cotl1erapv(n = 220)
`
`Monotherapy
`(n = 114)
`
`comparison
`
`Mood
`Stabilizer
`
`Full sample
`Lithium
`valproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithlum
`Valproate
`Full sample
`Lithium
`Valproate
`Fuii sample
`Lithium
`valproate
`Full sample
`Lithium
`valproate
`Full sample
`Lithium
`Vaiproate
`
`Baseline:
`mean (80)
`22.31 (5.39)
`22.34 (5.26)
`22.29 (5.40)
`14.52 (0.45)
`14.26 (0.33)
`14.55 (0.55)
`4.10 (0.74)
`4.12 (0.70)
`4.10 (0.73)
`4.06 (0.79)
`4.12 (0.72)
`4.03 (0.02)
`2.76 (1.40)
`2.59 (1.32)
`2.04 (1.43)
`52.10 (17.20)
`61.43 (15.05)
`52.45 (10.00)
`14.36 (4.32)
`14.12 (4.04)
`14.49 (4.46)
`9.54 (3.36)
`9.57 (2.95)
`9.53 (3.55)
`
`change:
`mean (SD)
`
`-13.11 (0.53)
`-13.52 (0.35)
`-12.05 (0.54)
`-4.90 (7.61)
`-4.15 (0.10)
`-5.40 (7.30)
`-1.20 (1.15)
`-1.23 (1.24)
`-1.19 (1.12)
`-1.40 (1.25)
`-1 .51 (1 .23)
`-1.42 (1.25)
`-0.50 (1.33)
`-0.35 (1.45)
`-0.50 (1.25)
`-12.90 (15.72)
`-14.03 (15.15)
`-12.34 (16.02)
`-3.00 (4.12)
`-3.39 (4.10)
`-2.92 (4.13)
`-2.99 (3.52)
`-3.49 (3.40)
`-2.73 (3.71)
`
`Baseline:
`mean (SD)
`22.57 (5.15)
`22.22 (4.65)
`22.75 (5.31)
`13.54 (7.53)
`10.90 (5.54)
`15.04 (7.09)
`4.10 (0.72)
`4.00 (0.71)
`4.20 (0.72)
`4.13 (0.70)
`4.02 (0.59)
`4.10 (0.70)
`2.52 (1.37)
`2.07 (1.05)
`2.93 (1.44)
`51.75 (15.51)
`50.63 (13.27)
`53.31 (15.50)
`14.50 (3.90)
`14.41 (3.75)
`14.50 (4.00)
`9.50 (3.11)
`9.49 (2.93)
`9.57 (3.20)
`
`change:
`mean (SD)
`-9.10 (9.36)
`-10.39 (0.59)
`-0.39 (9.75)
`-0.09 (5.90)
`-1.32 (5.19)
`-0.67 (7.77)
`-0.09 (1.31)
`-0.90 (1.44)
`-0.02 (1.24)
`-1.15 (1.39)
`-1.10 (1.55)
`-1.10 (1.31)
`0.12 (1.45)
`0.10 (1.15)
`0.17 (1.50)
`-5.95 (15.39)
`-9.02 (12.59)
`-5.05 (10.20)
`-2.29 (4.23)
`-3.37 (4.07)
`-1.72 (4.24)
`-1.59 (3.55)
`-2.05 (3.07)
`-1.49 (3.90)
`
`F
`Statistlct
`9.00
`3.10
`4.51
`10.05
`3.50
`14.77
`4.40
`0.24
`2.00
`2.94
`1.70
`0.10
`13.04
`0.45
`15.79
`0.70
`0.93
`7.00
`2.59
`0.01
`4.90
`4.95
`3.56
`1.00
`
`Etlect
`Size
`0.47
`0.42
`0.50
`0.50
`0.40
`0.55
`0.27
`0.20
`0.33
`0.26
`0.40
`0.20
`0.40
`0.36
`0.57
`0.42
`0.40
`0.42
`0.21
`0.01
`0.31
`0.39
`0.45
`0.39
`
`P
`Value:
`.003
`.00
`.04
`.001
`.05
`.001
`.04
`.52
`.15
`.09
`.2
`.75
`.001
`.5
`—..- .001
`.003
`.34
`.006
`.12
`.92
`.03
`.03
`.05
`.10
`
`*YMFlS indicates Young Mania Rating Scale; HAMD-21, Hamilton Depression Ratin, 21-item; CGI-BP, Clinical Global lmpressions—Severity of Bipolar Disorder;
`and PANSS, Positive and Negative Syndrome Scale.
`1'All tests based on 1 df.
`flreatment difierence, olanzapine cotherapy vs monotherapy; derived from analysis of variance.
`
`about significantly greater improvement than mono-
`therapy on patients’ last observation carried forward, Posi-
`tive 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 psy-
`chotropics (antidepressants, antipsychotics) and therapy
`(cotherapy, monotherapy). However, among all pa-
`tients without psychotic features, olanzapine cotherapy
`was significantly more efficacious than monotherapy (co-
`therapy: -13.25 [7.76], n=150; monotherapy: -8.32
`[8.68], n=76; F1_1g6= 16.97; P<.O01). 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 mono-
`therapy groups regardless of whether patients received
`lithium or valproate—this despite the lack of associa-
`tion between the presence of psychotic features and the
`differential effect of therapy (ANOVA test of interac-
`(ion: F1‘l74=O.60; P:-.44’).
`Among patients with a current mixed episode, olan-
`zapine cotherapy was superior to monotherapy (co-
`
`therapy: -12.92 [8.37], n= 121; monotherapy: -7.46
`[10.15], n=54; F1,H5= 17.31; P<.O01). However, among
`patients presenting with pure mania, the treatment dif-
`ference did not achieve statistical significance (co-
`therapy: -13.34 [8.77], n=99; monotherapy: -10.57
`[8.40], n=60; F1_u9= 2.95; P= .09). The superiority of olan-
`zapine cotherapy over monotherapy seen in patients with
`mixed episodes was found only in patients receiving val-
`proate (cotherapy: -13. 18, [8.49], n= 84; monotherapy:
`-7.48 [10.74], n=42; F1314: 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; FH7=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_27.,=0.14; P=.71).
`Finally, among patients receiving valproate, olanza-
`pine cotherapy brought about significantly greater im-
`provement in YMRS total scores compared with patients
`receiving valproate monotherapy (cotherapy: -12.85 [8.64] ,
`n= 146; monotherapy: -8.39 [9.76] , n= 72; Fuss: 13.44;
`P<.O01). Among patients receiving lithium, the greater
`improvement seen with olanzapine cotherapy relative to
`monotherapy did not achieve statistical significance (co-
`therapy: -13.62 [8.36] , n= 74; monotherapy: -10.39 [8.69],
`n=41; F1,35=3.74; P= .06). The type of mood stabilizer was
`not associated significantly with a differential effect of co-
`therapy compared with monotherapy (ANOVA test of in-
`teraction, Fun: 0.74; P= .39).
`
`
`WWW ARC}-lGENPSYCHlATRY.COM
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`5 o? 8
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`
`Table 4. Treatment-Emergent Adverse Events*
`
`Event (COSTART Term)
`Somnoience
`
`Dry mouth
`
`Weight gain
`
`increased appetite
`
`Tremor
`
`Asthenia
`
`Depression
`
`Headache
`
`Dizziness
`
`Diarrhea
`
`Nervousness
`
`Thirst
`
`Speech disorder
`
`Mood Stabilizer
`
`Full sample
`Lithium
`Vaiproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Vaiproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Vaiproate
`Full sample
`Lithium
`Vaiproate
`Full sample
`Lithium
`Vaiproate
`Full sample
`Lithium
`Valproate
`Full sample
`Lithium
`Vaiproate
`
`olanzapine cotherapy
`(I1 =
`(%l
`51 .5
`51 .3
`51 .6
`31 .9
`25.0
`35.3
`26.2
`21 .1
`28.8
`23.6
`15.8
`27.5
`23.1
`25.0
`22.2
`18.3
`23.7
`15.7
`17.9
`18.4
`17.6
`15.7
`13.2
`17.0
`13.5
`7.9
`16.3
`11.8
`11.8
`11.8
`10.5
`10.5
`10.5
`10.0
`5.3
`12.4
`6.6
`7.9
`5.9
`
`Monntherapy
`(I1 =
`(%)
`27.0
`12.9
`26.0
`7.8
`7.3
`8.2
`7.0
`4.9
`8.2
`7.8
`4.9
`9.6
`13.0
`9.8
`15.1
`13.0
`17.1
`11.0
`17.4
`14.6
`19.2
`18.3
`22.0
`16.4
`7.0
`9.8
`4.1
`14.8
`19.5
`12.3
`14.8
`19.5
`12.3
`6.1
`7.3
`5.5
`0.9
`0.0
`1 .4
`
`*|ncidence in the olanzapine group greater than or equal to 10% or statistically significantly greater than placebo.
`flreatment difference. olanzaplne cotherapy vs monotherapy: derived from the Fisher exact test.
`
`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 in-
`cluded 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 dis-
`continued 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 olanza-
`pine cotherapy group withdrew due to 13 different ad-
`verse 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 sub-
`
`group analysis showed that, among patients receiving val-
`proate, a significantly higher incidence of the adverse event
`“dizziness” was seen in patients receiving cotherapy
`(16.3% vs 4.1%; P=.009).
`No statistically or clinically significant differences
`emerged between the monotherapy and olanzapine co-
`therapy groups for changes in vital signs. However, the co-
`therapy 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= 1 13; F130;: 73.88; P<.001). With the excep-
`tion of a greater incidence of treatment—emergent elevated
`prolactin levels (upper limit: 0.81 nmol/L for men, 1.05
`nmoVL for women) at end point in the cotherapy group
`(19.1% vs 4.3%; P=.001), there were no other statisti-
`cally and clinically significant differences in treatment-
`emergent laboratory test result abnormalities at end point,
`including nonfasting glucose levels, between the olanza-
`pine cotherapy group and the monotherapy group.
`
`
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`(REPRINTED) ARCH GEN PSYCHIATRYI VOL 59, JAN 2002
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`
`7%
`
`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 olan-
`zapine may confer additional significant efficacy. No sig-
`nificant changes were seen in extrapyramidal symp-
`toms but a number of adverse events were reported more
`frequently by patients receiving cotherapy.
`The findings in this patient population, character-
`ized as partially nonresponsive to monotherapy, are com-
`parable with those of Muller-Oerlinghausen et a1,“ who
`compared the efficacy of combined therapy with con-
`ventional antipsychotics and valproate vs valproate mono-
`therapy in patients with bipolar or schizoaffective dis-
`order. Sachs” recently reported preliminary results
`comparing the addition of risperidone, haloperidol, or
`placebo to lithium or valproate, and found that the ad-
`dition of risperidone showed a significantly improved re-
`sponse compared with monotherapy.
`Considering the exclusion of patients who showed a
`response after 2 weeks of monotherapy, our patient popu-
`lation should be classified as lithium- or valproate-
`nonresponders or partial responders. A significantly larger
`percentage of patients who received cotherapy with olan-
`zapine achieved euthymia than did patients receiving val-
`proate or lithium monotherapy. A potential limitation of
`this finding is the reliance on a single definition of eu-
`thymia, which in this study was based on a YMRS total score
`less than or equal to 12 as suggested in the original pub-
`lication of the scale.” It is possible that another definition
`may have led to substantially different remission rates.
`One of the most interesting findings was the improve-
`ment in depressive symptoms in this population of pa-
`tients with bipolar manic and mixed episodes. This was par-
`ticularly striking among patients with moderate-to-severe
`symptoms of depression, who are particularly resistant to
`antirnanic treatment.” Among these patients, a nearly 7-fold
`greater improvement on the I-IAMD-21 scale was seen in
`the cotherapy group. Furthermore, nearly 5 times as many
`patients in the cotherapy group showed at least a 50% im-
`provement of depressive symptoms. These findings sug-
`gest that cotherapy may provide substantial efficacy against
`depressive symptoms in this patient population.
`Subgroup analysis also produced noteworthy find-
`ings. 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 sta-
`tistical power in the group of patients without psy-
`chotic features.
`
`Patients with mixed episodes who received co-
`therapy 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 co-
`therapy 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 par-
`ticularly 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 mono-
`therapy was larger than the response to valproate mono-
`therapy. This, plus the larger number of patients receiv-
`ing valproate, might explain the significant difference
`between responses to valproate cotherapy vs valproate
`monotherapy and the nonsignificant difference between re-
`sponses to lithium cotherapy vs lithium monotherapy.
`Adverse events o