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Olanzapine monotherapy and olanzapine combination therapy in the treatment of mania: 12-week results from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) observational study
Journal of Affective Disorders 106 (2008) 63 – 72 www.elsevier.com/locate/jad
Research report
Olanzapine monotherapy and olanzapine combination therapy in the treatment of mania: 12-week results from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) observational study☆ Eduard Vieta a,b,⁎, Francesco Panicali a , Iris Goetz c , Catherine Reed c , Merce Comes a,b , Mauricio Tohen d,e for the EMBLEM Advisory Board b
a Bipolar Disorders Program, Hospital Clinic, University of Barcelona IDIBAPS, Barcelona, Spain Red de Enfermedades Mentales (REM-TAP Network), Instituto de Salud Carlos III, Ministerio de Sanidad, Spain c Eli Lilly, Windlesham, United Kingdom d Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN, USA e McLean Hospital, Harvard Medical School, Belmont, MA, USA
Received 26 March 2007; received in revised form 11 May 2007; accepted 13 May 2007 Available online 20 June 2007
Abstract Background: To evaluate the 12-week outcomes (effectiveness, tolerability, and patterns of medication use) of olanzapine (either in antimanic monotherapy or in combination with other antipsychotics, anticonvulsants, and/or lithium) in patients with bipolar mania or mixed mania. Method: EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) is a 24-month prospective observational study of in- and outpatients with acute mania/mixed mania conducted in 14 European countries. Primary outcome measures included Clinical Global Impressions–Bipolar Disorder scale (overall, mania, and depression); 5-item Hamilton Depression Rating Scale; and Young Mania Rating Scale. Tolerability measures included a questionnaire to assess patients’ symptomatic complaints. Results: Overall, 2004 patients received olanzapine (olanzapine monotherapy, n = 673; olanzapine combination, n = 1331). Concomitant therapy with antidepressants and/or anxiolytics was possible in both groups. The countries significantly differed in the use of olanzapine monotherapy versus olanzapine combination ( p b .0001). Baseline-to-endpoint changes on the CGI-BP subscales, YMRS, and HAMD-5 were significant within both treatment groups ( p b .0001). Olanzapine monotherapy was generally better tolerated than olanzapine combination, particularly with regard to sedation (12% vs 17%; p b .001), tremor (2% vs 5%; p b .001), and akathisia (3% vs 6%; p b .001).
☆ Role of funding source: The EMBLEM study is funded by Eli Lilly and Company Limited, Windlesham, Surrey, UK. Contributors: All the authors have been sufficiently involved in the study submitted. Conflict of interest: Eduard Vieta, has acted as a consultant, received grants, or been hired as a speaker by the following companies: Almirall, AstraZeneca, Bial, Bristol-Myers-Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Merck Sharp & Dohme, Novartis, Organon, Otsuka, Pfizer, Sanofi Aventis, Servier, UCB. He has acted as consultant and has received grants from the Spanish Ministry of Health, Instituto de Salud Carlos III, RETICS RD06/0011 (REM-TAP) and from the Stanley Medical Research Institute. Iris Goetz, Catherine Reed, and Mauricio Tohen are Eli Lilly and Company employees. Francesco Panicali and Merce Comes have no conflict of interest. ⁎ Corresponding author. Director Bipolar Disorders Program, Clinical Institute of Neuroscience, University Clinic Hospital of Barcelona, Villarroel 170, 08036-Barcelona, Spain. Tel.: +34932275401; fax: +34932279876. E-mail address: [email protected] (E. Vieta).
0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.05.009
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Discussion: The acute-phase EMBLEM results suggest that in naturalistic settings, olanzapine (both as monotherapy and combination) may be effective in treating patients with bipolar mania. The use of olanzapine monotherapy or combination varies significantly across countries, but combination is generally the rule, rather than the exception. © 2007 Elsevier B.V. All rights reserved. Keywords: Olanzapine; Mania/mixed; Bipolar disorder; Prospective observational study
1. Introduction
2. Methods
Over the last 5 years, our knowledge on the treatment of mania has outstandingly increased due to the data from randomized clinical trials: Atypical antipsychotics such as olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole have been compared with placebo and with active compounds (haloperidol, lithium, and divalproex), and the evidence base for the use of all these compounds has been considerably enriched (Vieta and Goikolea, 2005). The knowledge of the actual use of antimanic agents in routine clinical conditions is quite limited, however, and large observational studies are rare (Vieta et al., 2001). Observational studies are more likely to be challenged for their internal validity than randomized clinical trials, but provide relevant data about the actual use of therapies either as monotherapy or combination therapy in “real world” patients (that is, without excluding comorbidities or suicide risk, including flexible and broader dose ranges, and across all ranges of illness severity). Olanzapine has been tested in randomized designs in mania and compared with placebo (Tohen et al., 1999, 2000), haloperidol (Tohen et al., 2003), divalproex (Zajecka et al., 2002; Tohen et al., 2002a), and risperidone (Perlis et al., 2006). Olanzapine cotherapy with lithium or divalproex was also compared with lithium and divalproex alone in one trial (Tohen et al., 2002b, 2004). Olanzapine proved to be effective for the acute treatment of mania and beyond (Vieta, 2004). Hence, a good number of studies provide an excellent evidence base for the use of olanzapine (both in mono- and combination therapy) as an antimanic agent, but less is known about the factors that drive the choice of olanzapine as monotherapy or combination, its dosages in routine clinical practice, and the patterns of use across different countries. To close this gap, we conducted the EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication), one of the largest observational studies ever conducted in patients suffering form bipolar mania. The objectives of the EMBLEM were to learn about the clinical and functional outcomes and patterns of use of antimanic therapy including olanzapine (both in monotherapy and in combination therapy) across several European countries.
2.1. Study objective EMBLEM is a large, prospective, multicentre, observational study on the outcomes of patients after an episode of mania. From December 2002 to June 2004, 530 investigators enrolled patients from 14 European countries (Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, The Netherlands, Norway, Portugal, Spain, Switzerland, and the UK). Observations were completed with 5 further data collections as part of the acute phase, which lasted for 12 weeks, until October 2004. Further observations are currently ongoing in the ≤24-month maintenance phase. All countries applied the same core set of measures at each data collection point to capture a broad range of clinical outcomes. The primary objective of the study was to assess the course of bipolar disorder in patients who experienced a manic/mixed episode and started new oral treatment antipsychotics, anticonvulsants and lithium as monotherapy or treatment combinations. Depending on the health-care system in each country, the EMBLEM included investigators from both inpatient and outpatient settings. Both rural and urban locations, as well as public and private facilities, were involved to allow for an accurate representation of current treatment settings for patients with mania across Europe. Participating investigators were psychiatrists practicing in the setting in which the patient was being treated. Data were collected by either the investigators or by their designee. 2.2. Patients Patients were considered for enrolment if they presented within the standard course of care and if, according to the decision of the treating psychiatrist, oral medication with antipsychotics, lithium and/or anticonvulsants was initiated or changed (excluding dose changes) for the treatment of a manic or mixed bipolar episode. Psychiatric diagnosis to determine the presence of a manic/mixed episode was made by each site's leading investigator using the site’s usual standard diagnostic criteria (generally DSM-IV or ICD-10). Patients with comorbidity, substance abuse, and suicidiality, or those
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taking other medications (including antidepressants and sedatives) were not excluded. All patient data were collected and evaluated anonymously using a unique patient identification number. Patient informed consent and ethical board approval were obtained as required by local laws and regulations. This report describes the acute-phase outcomes of the subgroup of patients who were treated with olanzapine either as antimanic monotherapy or in combination with other antipsychotics, anticonvulsants, and/or lithium. 2.3. Medications The decision to initiate or change medication and the type of medication selected were independent from the study design and entirely at the discretion of the treating psychiatrist; once the decision to start a new oral treatment for mania was made, investigators could include the patient in the study. Investigators were asked, but not required, to enroll approximately the same number of patients initiating olanzapine as the number of patients initiating any other antipsychotic, anticonvulsant, or lithium combined. That was to ensure that the sample size of patients treated with olanzapine, who are the focus of this report, was large enough to allow for specific subanalyses. The index medications could be given as antimanic monotherapy or in combination with any other antipsychotic, anticonvulsant, and/or lithium. Cotherapy with antidepressants and sedatives, as well as any other medications required in standard care, was allowed in both groups. Patients were not required to remain on the medication initiated; changes of medication prescribed and doses could be made according to clinical need as determined by the treating psychiatrist. In this report, only patients who were treated with olanzapine, either as antimanic monotherapy (defined as patients taking olanzapine and not taking any other antipsychotic, lithium, or anticonvulsant) or in combination with other antimanic medications, are considered. However, consistent with other studies and controlled trials (Tohen et al., 1999, 2000), patients taking olanzapine and benzodiazepines, antidepressants, or anticholinergics were still considered as being on antimanic monotherapy. In settings where the health-care structure and practices were conducive to linked observation between inpatient and outpatient care, the observations were performed as continuously as possible for patients changing from inpatient to outpatient service or vice versa. Patients who were treated as inpatients during the index episode and were then discharged at any time during the study period were fully evaluated immediately before their discharge from the hospital.
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2.4. Assessments Following the inclusion into EMBLEM, assessments occurred at 1, 2, 3, 6 and 12 weeks after baseline if this coincided with the usual clinical care of the patient. Patients were not excluded if individual assessments were missed. All data collection forms were completed by investigators or their designees. Socio-demographic variables recorded at baseline included gender, age, country of origin, body mass index (BMI), educational status, and history of substance abuse (alcohol or cannabis and other illegal substances). Primary measures of effectiveness used during the index episode and throughout the 12-week acute phase included 1) Clinical Global Impressions– Bipolar Disorder (CGI-BP) overall, mania, depression and hallucinations/delusions (all rated for severity, with the score range 1–7) (Spearing et al., 1997); 2) the Young Mania Rating Scale (YMRS) (Young et al., 1978); 3) the 5item version of the Hamilton Depression Rating Scale (HAMD-5) defined by principal component analysis (Gonzalez-Pinto et al., 2003) to find the core symptoms of depression during mania (depressive mood, suicidal ideation, guilt, obsessions, and psychic anxiety). Two modified items from the SLICE of LIFE were applied to measure patient functional outcomes in terms of work functioning and life satisfaction. Information on olanzapine and concomitant medication for bipolar disorder (other antipsychotics, anticonvulsants, lithium, antidepressants, benzodiazepines, hypnotics, and anticholinergics), as well as their respective doses and mode of intake, was also recorded at baseline and throughout the 12 weeks' follow-up. At each visit during the 12-week follow-up, interviewers recorded (via a custom made tolerability checklist) patients' complaints by describing patients' “assessment for each of the following effects that are judged to be associated with bipolar medication, as of today” with either “not present,” “present but not significantly interfering with patient’s functioning,” or “present and significantly interfering with patient’s functioning.” 2.5. Statistical analyses The distribution of the baseline characteristics of the sample, including sociodemographic and clinical measures, was analysed with descriptive statistics. In continuous data with normal distribution, a twosample t-test was used to test the difference between the olanzapine antimanic monotherapy and olanzapine combination groups. A paired t-test was used to compare changes in outcomes (from baseline to the 12-week endpoint) for patients within each olanzapine treatment group.
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Table 1 Baseline characteristics of patients with mania treated with olanzapine as monotherapy or olanzapine combination therapy Characteristics
Female, n (%) Age, mean ± SD, years Country, n (%) b Belgium Switzerland Germany Denmark Spain Finland France United Kingdom/Ireland Greece Italy Netherlands Norway Portugal Alcohol abuse ever, n (%) Cannabis abuse ever, n (%) BMI, mean ± SD, kg/m2 Work impairment, n (%) Hospitalization status, n (%) Mixed episode, n (%) Psychotropic medication (before baseline), n (%)⁎ No psychotropic meds 1 meds ≥2 meds Antidepressant (before baseline), n (%) CGI-BP overall, mean ± SD CGI-BP mania, mean ± SD CGI-BP depression, mean ± SD HAMD-5 Total, mean ± SD YMRS total, mean ± SD CGI Hallucination delusion, mean ± SD
Patients on olanzapine combination
Statistic‡⁎§
Betweengroup
(M)
(C)
(M vs C)
p value
(N = 673) b
(N = 1331) c .05⁎ − .39‡ 58.47⁎
.83 .70 b.0001
.40⁎ .13⁎ − 5.86‡ .87⁎ 7.01⁎ 5.54⁎ 450.74⁎
.53 .70 b.0001 .35 b.01 .02 b.0001
152 (11) 493 (37) 684 (51) 413 (32)
.049⁎
.82
4.7 ± 1.0 4.8 ± 1.0 1.8 ± 1.2 2.8 ± 2.7 26.9 ± 10.0 3.1 ± 1.8
− 2.63‡ − 1.50‡ 658793§ 625299§ − .77‡ 670454§
b.01 .14 .22 .004 .45 .82
Total sample of patients on olanzapine
Patients on olanzapine monotherapy
(N = 2004) a 1047 (52) 44.2 ± 13.2
347 (52) 44.1 ± 14.2
700 (53) 44.3 ± 12.7
43 (100) 52 (100) 313 (100) 14 (100) 176 (100) 21 (100) 412 (100) 115 (100) 386 (100) 295 (100) 115 (100) 14 (100) 48 (100) 502 (26) 278 (14) 25.9 ± 4.7 1362 (72) 773 (39) 454 (23)
17 (40) 9 (17) 134 (43) 7 (50) 62 (35) 5 (24) 152 (37) 51 (44) 111 (29) 73 (25) 43 (37) 5 (36) 4 (9) 161 (25) 96 (15) 25.1 ± 4.2 448 (70) 233 (35) 175 (26)
26 (60) 43 (83) 179 (57) 7 (50) 114 (65) 16 (76) 260 (63) 64 (56) 275 (71) 222 (75) 72 (63) 9 (64) 44 (91) 341 (26) 182 (14) 26.4 ± 4.9 914 (72) 540 (41) 279 (22)
497 (25) 723 (36) 777 (39) 624 (32)
345 (52) 230 (34) 93 (14) 211 (32)
4.7 ± 1.1 4.8 ± 1.1 1.9 ± 1.2 2.9 ± 2.8 26.8 ± 9.8 3.1 ± 1.8
4.6 ± 1.1 4.8 ± 1.0 1.9 ± 1.3 3.2 ± 3.0 26.6 ± 9.5 3.1 ± 1.7
⁎ Chi-squared test. ‡ 2 sample t-test. § Wilcoxon test. Abbreviations: CGI-BP = Clinical Global Impressions–Bipolar Disorder; HAMD-5 = the 5-item Hamilton Depression Rating Scale; YMRS = Young Mania Rating Scale. a Total n varies for each variable due to missing data. Percentage (%) for each variable refers to total n available for respective variables. b Percentage (%) refers to total n per country.
Where assumptions of normality were not adequately met, differences between groups were tested using the Wilcoxon test. Differences in categorical parameters between groups, as well as within-group changes from baseline to endpoint, were tested using a chi-squared test. For all comparisons a level of significance of .05 was applied. Longitudinal eval-
uation of change in outcome was performed using last observation carried forward (LOCF) after a sensitivity analysis with LOCF, observed case (OC) analysis and mixed-effects model repeated measures (MMRM) revealed no significant differences. All data were analyzed using SAS version 9.1 (SAS Institute, Inc.; Cary, North Carolina).
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3. Results 3.1. Baseline patient characteristics Of 3681 manic patients enrolled in the study, 2004 (54.4%) received olanzapine for the treatment of their manic or mixed symptoms. Of the 2004 patients, 673 (33.6%) were treated with olanzapine as antimanic monotherapy, and 1331 (66.4%) received olanzapine in combination with other antipsychotics, anticonvulsants, and/or lithium. The demographic characteristics of the sample are shown in Table 1. Of the sample studied, 35% of patients were inpatients, and alcohol and cannabis abuse were present in 26% and 14% of patients, respectively. The incidence of these conditions did not differ significantly between the two treatment groups. The proportion of patients treated with olanzapine monotherapy, compared with those treated with olanzapine combination therapy, differed significantly ( p b .0001) across the 14 countries. The mean (±SD) body mass index (BMI) of the total sample at baseline was 25.9± 4.7 kg/m2, with patients treated with olanzapine combination having a significantly higher mean BMI (26.4 ± 4.9 kg/m2) than those treated with olanzapine monotherapy (25.01± 4.2 kg/m2; pb .0001). According to the interviewers' assessment, 72% of patients suffered from work impairment at baseline, with no significant difference between the two treatment groups. The patients in the study were suffering from either a manic (77%) or a mixed episode (23%); the group treated with olanzapine monotherapy had a significantly ( p b .02) higher number of patients with mixed episodes. For the overall sample of patients treated with olanzapine, the mean (±SD) CGI-BP overall score at baseline indicated that patients were moderately to markedly ill (4.7 ± 1.1) at baseline. The mean YMRS score at baseline was 26.8 ± 2.8. Compared with patients in the olanzapine combination group, patients on olanzapine monotherapy had a significantly lower mean score on CGIBP overall (4.6 ± 1.1 vs 4.7 ± 1.0; p b .01) and a significantly higher mean HAMD-5 score (3.2 ± 3.0 vs 2.8 ± 2.7; p = .004) at baseline. Overall, the mean baseline scores on the other psychometric scales did not significantly differ between the groups. 3.2. Effectiveness At 12 weeks, 376 of 2004 (18.8%) of patients taking olanzapine at baseline were lost to follow-up, over half of those due to discharge from the hospital. Retention was similar in both groups: olanzapine monotherapy group,
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Table 2 Within-group changes from baseline to endpoint (12 Weeks) in outcome measures of patients with mania taking olanzapine monotherapy or olanzapine combination therapy Outcomes measure
CGI-BP overall∼ CGI-BP mania∼ CGI-BP depression∼ HAMD-5∼ YMRS total∼ BMI∼ Work impairment⁎
Patients on olanzapine monotherapy (M), N = 673
Patients on olanzapapine combination (C), N = 1331
95% CI
p value 95% CI
p value
− 1.94 (− 2.06, −1.83) − 2.44 (− 2.55, −2.33) − .21 (− .32, − .11) − 1.10 (− 1.39, −.81) − 19.7 (− 20.6, −18.7) .83 (.70, .96) .26 (.18, .33)
b.0001 − 1.99 (− 2.07, − 1.92) b.0001 − 2.49 (− 2.57, − 2.41) b.0001 − .17 (− .24,−.10) b.0001 − .98 (− 1.17,−.79) b.0001 − 20.1 (− 20.8, − 19.4) b.0001 .74 (.66, .83) b.0001 .16 (.10, .22)
b.0001 b.0001 b.0001 b.0001 b.0001 b.0001 b.0001
∼ 95% CI and p-value from paired t-test. ⁎95% CI and p-value from Chi square test. Abbreviations: CGIBP=Clinical Global Impressions–Bipolar Disorder; HAMD-5=the 5-item Hamilton Depression Rating Scale; YMRS=Young Mania Rating Scale.
540 of 673 (80.2%); olanzapine combination group, 1101 of 1331(82.7%). Results showed a significant improvement within both the monotherapy and the combination therapy group in all effectiveness measures at week 12 (Tables 2, 3, p value for total sample not shown in table). Among all the patients treated with olanzapine, mean (±SD) scores on all the CGI-BP subscales significantly decreased from baseline to endpoint: CGI-BP overall, from 4.7 ± 1.1 to 2.7 ± 1.3 ( pb .0001); CGI-BP mania, from 4.8 ± 1.0 to 2.3± 1.2 ( pb .0001); and CGI-BP depression, from 1.9 ± 1.2 to 1.7± 1.1 ( p b .0001). As early as week 1, both treatment groups showed significant improvement in CGI-BP overall (Fig. 1), CGI-BP mania (Fig. 2), and CGIBP depression (Fig. 3) scores. This improvement was maintained for all CGI-BP subscales at subsequent assessments. At endpoint, the groups did not differ significantly in their CGI-BP overall, mania, and depression scores (Table 3). Among all the patients, mean (± SD) HAMD-5 score decreased from 2.9 ± 2.8 at baseline to 2.0 ± 2.4 at endpoint ( p b .0001). At endpoint this score was significantly higher in the olanzapine monotherapy group compared with the olanzapine combination group (2.2± 2.6 vs 1.9 ± 2.3; p = .04; Table 3). Mean (± SD) YMRS score among all the patients significantly decreased from 26.8 ± 9.8 at baseline to
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Table 3 Between-group outcomes results at the 12-week endpoint among patients with mania taking in monotherapy or olanzapine combination therapy Outcomes measures
Dosage of olanzapine, mean ± SD, mg/day CGI-BP overall, mean ± SD CGI-BP mania, mean ± SD CGI-BP depression, mean ± SD HAMD-5 total, mean ± SD YMRS total, mean ± SD BMI, mean ± SD, kg/m2 Work impairment, n (%) Hospitalization status, n (%)
Total sample of patients on olanzapine
Patients on olanzapine monotherapy (M)
Patients on olanzapine combination (C)
N = 2004a
N = 673a
N = 1331a
15.2 ± 7.9 2.7 ± 1.3 2.3 ± 1.3 1.7 ± 1.1 2.0 ± 2.4 6.1 ± 7.2 26.8 ± 4.7 855 (58%) 132 (8%)
14.6 ± 8.4 2.7 ± 1.3 2.3 ± 1.3 1.7 ± 1.1 2.2 ± 2.6 5.8 ± 6.7 25.9 ± 4.1 274 (55%) 43 (8%)
15.5 ± 7.7 2.7 ± 1.3 2.3 ± 1.3 1.7 ± 1.1 1.9 ± 2.3 6.2 ± 7.4 27.2 ± 4.9 581 (59%) 89 (8%)
Statistic (M vs C)‡⁎§
p value
−7.40‡ 660272§ 672918§ 682513§ 393135§ 394966§ −5.02‡ 2.32⁎ .02⁎
b.0001 .28 .90 .30 .04 .83 b.0001 .12 .88
a
Total n varies for each variable due to missing data. Percentage (%) for each variable refers to total n available for respective variables. ⁎ Chi-squared test. ‡ 2 sample t-test. § Wilcoxon test. Abbreviations: CGI-BP = Clinical Global Impressions–Bipolar Disorder; HAMD-5 = the 5-item Hamilton Depression Rating Scale; YMRS = Young Mania Rating Scale.
6.1 ± 7.2 at endpoint ( p b .0001). At endpoint, the treatment groups did not differ significantly on the changes in this score (Table 3). Among all the patients, work impairment declined from 72.0% at baseline to 58.0% at endpoint ( p b .0001). At endpoint, the treatment groups did not significantly differ on this effectiveness measure (Table 3). The hospitalization rate of the total sample decreased from 39.0% at baseline to 8.0% at endpoint ( p b .0001),
with no significant differences at endpoint between the two groups (Table 3). 3.3. Tolerability Symptomatic complaints regarded as “present and significantly interfering with patient’s functioning” and considered to be possibly indicative of being treatment related are shown in Table 4. Overall, pharmacological
Fig. 1. Baseline-to-endpoint changes in mean CGI-BP overall scores (LOCF) for olanzapine patients: monotherapy (N = 673) vs combination (N = 1331). Abbreviations: CGI-BP = Clinical Global Impressions–Bipolar Disorder; LOCF = last observation carried forward.
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Fig. 2. Baseline-to-endpoint changes in mean CGI-BP mania scores (LOCF) for olanzapine patients: monotherapy (N = 673) vs combination (N = 1331). Abbreviations: CGI-BP = Clinical Global Impressions–Bipolar Disorder; LOCF = last observation carried forward.
therapy was well tolerated: The most common symptomatic complaints that were significantly interfering with patient’s functioning were sedation and insomnia, both appearing in 16% of the total sample. Significant cognitive problems (namely, memory loss and concentration difficulties) occurred in 11% of the total sample. The incidence of severe akathisia, sedation, and tremor among patients who received olanzapine monotherapy was
significantly lower ( p b .001) than that among patients on combination therapy. The average weight gain in the overall sample on olanzapine was 2.3 kg. Of the 63.0% of patients who showed weight gain during the 12 weeks of follow-up, the mean weight gain was 4.0± 3.5 kg (olanzapine monotherapy, 4.1± 3.8 kg; olanzapine combination, 3.9 ± 3.3 kg;). Of the total sample, 17.0% of the patients lost weight, with
Fig. 3. Baseline-to-endpoint changes in mean CGI-BP depression scores (LOCF) for olanzapine patients: monotherapy (N = 673) vs combination (N = 1331). Abbreviations: CGI-BP = Clinical Global Impressions–Bipolar Disorder; LOCF = last observation carried forward.
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Table 4 Symptomatic complaints that significantly interfered with the functioning of patients with mania treated with olanzapine monotherapy or olanzapine combination therapy (from baseline to the 12-week endpoint) Symptomatic complaints
Dystonia, n (%) Akathisia, n (%) Parkinsonism, n (%) Tardive dyskinesia, n (%) Sedation, n (%) Memory loss/concentration difficulties, n (%) Dizziness, n (%) Gastrointestinal problems, n (%) Tremor, n (%) Sexual dysfunction, n (%) Polyuria/nocturia, n (%) Insomnia, n (%) Menstrual disturbance, n (%)a
Total sample of patients on olanzapine
Patients on olanzapine monotherapy (M)
Patients on olanzapine combination (C)
N = 2004
N = 673
N = 1331
33 (2) 97 (5) 57 (3) 18 (b1) 314 (16) 227 (11) 71 (4) 61 (3) 74 (4) 130 (6) 33 (2) 317 (16) 30 (3)
10 (1) 18 (3) 16 (2) 5 (b1) 81 (12.) 72 (11) 20 (3) 19 (3) 12 (2) 39 (6) 7 (1) 96 (14) 12 (3)
23 (2) 79 (6) 41 (3) 13 (b1) 233 (17) 155 (12) 51 (4) 42 (3) 62 (5) 91 (7) 26 (2) 221 (17) 18 (3)
Statistic⁎
p value
.16 10.32 .80 .27 10.12 .40 .97 .17 10.40 .80 2.30 1.84 .66
.69 .001 .37 .60 .001 .53 .33 .68 .001 .37 .13 .17 .42
⁎ Chi-squared test. a In Females only: N =699 females were treated with olanzapine, of which n =347 with olanzapine monotherapy and n=699 with olanzapine combination.
a mean weight loss from baseline to endpoint of 2.7 ± 2.7 kg (olanzapine monotherapy, 2.8± 3.2 kg; olanzapine combination, 2.7± 2.5 kg;). Mean BMI scores of the total sample increased from 25.92 ± 4.7 kg/m2 at baseline to 26.78 ± 4.79 kg/m2 at endpoint (p b .001). Both at baseline and at endpoint, the mean BMI was significantly higher in the olanzapine combination group compared with the olanzapine monotherapy group (26.4 ± 4.9 vs, 25.1 ± 4.2 respectively; p b .0001 at baseline; 27.15 ± 4.89 vs 25.9 ± 4.1, respectively; p b .001 at endpoint). During the 12-week follow-up, 24 (4%) in the olanzapine monotherapy group attempted suicide; 1 of the suicide attempts was successful. In the combination group, 33 (2%) attempted suicide, with 2 attempts being successful. As EMBLEM was not designed as a safety Table 5 Patterns of olanzapine combination therapya Patterns of combination therapy
n (%)
Olanzapine + atypical antipsychotic Olanzapine + typical antipsychotic Olanzapine + lithium Olanzapine + Anticonvulsant Olanzapine + Valproate Olanzapine + Carbamazepine Olanzapine + other anticonvulsants Olanzapine + lithium + Anticonvulsant Olanzapine + lithium + typical antipsychotic Olanzapine + anticonvulsant + typical antipsychotic Olanzapine + lithium + anticonvulsant + typical antipsychotic
19 (1) 116 (9) 280 (21) 601 (45) 328 (25) 116 (8.7) 158 (12) 91 (7) 48 (4) 140 (11) 27 (2)
a
After change in oral medication at baseline.
study this numbers are estimates only as there is no information available on patients lost to follow-up. 3.4. Patterns of antimanic medication use At presentation at baseline, 25% of all the patients were not taking any psychotropic medication; 36% were on 1 medication; and 39%, on 2 or more medications (Table 1). Significantly more patients in the olanzapine monotherapy group (p b .0001) were taking no medicine at baseline, whereas patients in the olanzapine combination group were more likely (p b .0001) to take 2 or more medications at baseline (Table 1). At baseline, 32% of the total sample were taking antidepressants, and this characteristic was present in both treatment groups without any significant difference. Table 5 presents the most frequent antimanic medications that patients received in combination with olanzapine. Olanzapine was most frequently combined with anticonvulsants (45%; mainly valproate [25%] and carbamazepine [9%]), followed by lithium (21%). Overall, the mean dose of olanzapine was 15.2 ± 7.9 mg. This dose was significantly lower in the olanzapine monotherapy group compared with the olanzapine combination group (14.6 ± 8.4 vs. 15.5± 7.7, respectively; p b .0001). 4. Discussion The acute-phase results of this large, multicentre, observational study that investigated the use of olanzapine (as either monotherapy or combination therapy) in
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European patients with mania showed significant withingroup improvements from baseline to endpoint in all of the following scales: CGI-BP overall, mania, and depression; YMRS; and HAMD-5. Moreover, the rates of work impairment significantly decreased in both treatment groups at endpoint. Although results of observational studies should be interpreted with caution as far as efficacy is concerned, due to the open design and the absence of comparator, these results are consistent with findings from randomized, controlled trials (Vieta, 2004). In the EMBLEM study, treatment decisions were entirely at the discretion of the treating psychiatrist; however, the treating psychiatrists were asked, but not required, to enrol approximately half of the patients who were initiating olanzapine. It is also remarkable that two thirds of the sample were treated as outpatients, who are generally less severe than inpatients (Montoya et al., 2007); this may reflect the limited availability of beds but also current treatment practice across Europe, due to improved mental health access and treatment availability. This study suggests that the positive findings from controlled trials may be generalized to larger, more representative samples of patients with mania, including those with comorbidities like alcohol and drug abuse that generally preclude them from being enrolled in clinical trials. This study also provides relevant information on the reasons that drive the choice of antimanic monotherapy versus combination therapy with olanzapine: The main factor seemed to be whether the patient was already on any medication or not; the number of drugs before the index episode may be a measure of lifetime severity. On the other hand, patients with a history of good, or at least partial, response to 1 mood stabiliser may also be more likely to receive combination therapy once manic. The overall severity of the index episode also may have been a factor in choosing an antimanic combination therapy. However, the presence of depressive and mixed features during the manic episode was more likely to induce the prescription of olanzapine monotherapy, with or without antidepressants. The use of olanzapine alone in mixed manic episodes is supported by controlled data (Baldessarini et al., 2003), but combination therapy with olanzapine may be efficacious as well (Baker et al., 2004). Therefore, it seems that severity of the manic episode was driving the choice of a combination therapy, whereas the severity of depressive symptoms precluded the use of adjunctive therapies. Although significant, some of the differences in effectiveness findings between the monotherapy and combination therapy groups are small and have to be evaluated in terms of their clinical relevance.
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Finally, cultural factors may play a role as well in the choice of olanzapine monotherapy versus combination therapy: Countries with a tradition of using antipsychotic monotherapy or manic episodes (such as Denmark, Germany, or the UK) seemed more inclined to extrapolate their experience with traditional antipsychotic to olanzapine, whereas other countries may be more prone to combinations (Bowers et al., 2004). Observational studies may provide very useful information about patient-reported tolerability. This study showed good tolerability of treatment with olanzapine. Importantly, the overall rate of severe tardive dyskinesia was very low (b1.0%). The most common complaints were insomnia (which may have been illness related), sedation (which may have been related to the drug treatment), and memory problems (which may have been related to either). Interestingly enough, patients on olanzapine combination therapy were more likely to have tolerability problems, particularly tremor, akathisia, and sedation. The former two are likely associated with the use of conventional antipsychotics in combination with olanzapine, and sedation may be associated with the use of other drugs like valproate as part of the combination therapy. As expected, patients treated with olanzapine (both as monotherapy and combination therapy) gained weight, and their BMIs significantly increased. The mean dosage of olanzapine was slightly, but significantly, higher in the combination group than in the monotherapy group (15.5 mg/day versus 14.6 mg/day). In both treatment groups, the mean dosage is consistent with previous controlled studies of olanzapine (Tohen et al., 1999, 2000, 2002b, 2003, 2004). Because patients who received combination therapy were more severely ill, the higher mean dose in that treatment group may be related to greater illness severity. However, because the betweengroup difference in dosages was small and probably not relevant clinically, it also suggests that in most cases, the alternative to using notably higher olanzapine doses was to add a second antipsychotic or an antimanic drug (such as valproate or lithium). In summary, this report confirms the results of randomized clinical trials concerning the efficacy and tolerability of olanzapine in acute mania in the largest sample of manic patients ever studied within an observational, prospective, multicenter design across Europe. The findings also suggest that the choice of an antimanic combination versus monotherapy may be influenced by severity of illness and cultural factors, but the use itself of a combination of olanzapine with antipsychotics, anticonvulsants, and/or lithium is the rule rather than the exception in “real world” practice, even though olanzapine monotherapy is generally better tolerated.
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Acknowledgements The authors of this report would like to thank the EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) Advisory Board for their participation in the design and conduct of the study: Prof Bernard Sabbe (Belgium); Dr Jens Knud Larsen (Denmark); Prof Hannu Koponen (Finland); Dr Isabelle Gasquet and Prof Jean Michel Azorin (France); Dr Heinz Grunze (Germany); Prof Giovanni Battista Cassano (Italy); Prof Willem Nolen and Prof Jim van Os (Netherlands); Dr Trond Aarre (Norway); Prof Filipe Arriaga (Portugal); Dr Ana Gonzalez Pinto, Dr Josep Maria Haro, and Prof Eduard Vieta (Spain); Prof Jules Angst (Switzerland); Dr John Cookson and Prof Martin Knapp (UK); Dr. Mauricio Tohen (USA). The support of the Spanish Ministry of Health, Instituto de Salud Carlos III, RETICS RD06/0011(REM-TAP Network) is also acknowledged. References Baker, R.W., Brown, E., Akiskal, H.S., Calabrese, J.R., Ketter, T.A., Schuh, L.M., Trzepacz, P.T., Watkin, J.G., Tohen, M., 2004. Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania. Br. J. Psychiatry 185, 472–478. Baldessarini, R.J., Hennen, J., Wilson, M., Calabrese, J., Chengappa, R., Keck Jr., P.E., McElroy, S.L., Sachs, G., Vieta, E., Welge, J.A., Yatham, L.N., Zarate Jr., C.A., Baker, R.W., Tohen, M., 2003. Olanzapine versus placebo in acute mania: treatment responses in subgroups. J. Clin. Psychopharmacol. 23, 370–376. Bowers, L., Callaghan, P., Clark, N., Evers, C., 2004. Comparisons of psychotropic drug prescribing patterns in acute psychiatric wards across Europe. Eur. J. Clin. Pharmacol. 60, 29–35. Gonzalez-Pinto, A., Ballesteros, J., Aldama, A., Perez de Heredia, J.L., Gutierrez, M., Mosquera, F., Gonzalez-Pinto, A., 2003. Principal components of mania. J. Affect. Disord. 76, 95–102. Montoya, A., Gilaberte, I., Costi, M., Perez Sanchez Toledo, J., Gonzalez Pinto, A., Haro, J., Comes, M., Vieta, E., 2007. Bipolar disorder in Spain: functional status and resource use on the basis of the Spanish sample of the observational, Pan European EMBLEM study. Vertex 8, 13–19. Perlis, R.H., Baker, R.W., Zarate Jr., C.A., Brown, E.B., Schuck, L.M., Jamal, H.H., Tohen, M., 2006. Olanzapine versus risperidone in the treatment of manic or mixed states in bipolar I disorder: a randomized, double-blind trial. J. Clin. Psychiatry 67, 1747–1753.
Spearing, M.K., Post, R.M., Leverich, G.S., Brandt, D., Nolen, W., 1997. Modification of the Clinical Global Impressions (CGI) scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res. 73, 159–171. Tohen, M., Sanger, T.M., McElroy, S.L., Tollefson, G.D., Chengappa, K.N., Daniel, D.G., Petty, F., Centorrino, F., Wang, R., Grundy, S.L., Greaney, M.G., Jacobs, T.G., David, S.R., Toma, V., 1999. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am. J. Psychiatry. 156, 702–709. Tohen, M., Jacobs, T.G., Grundy, S.L., McElroy, S.L., Banov, M.C., Janicak, P.G., Sanger, T., Risser, R., Zhang, F., Toma, V., Francis, J., Tollefson, G.D., Breier, A., 2000. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The olanzipine HGGW study group. Arch. Gen. Psychiatry 57, 841–849. Tohen, M., Baker, R.W., Altshuler, L.L., Zarate, C.A., Suppes, T., Ketter, T.A., Milton, D.R., Risser, R., Gilmore, J.A., Breier, A., Tollefson, G.A., 2002a. Olanzapine versus divalproex in the treatment of acute mania. Am. J. Psychiatry 159, 1011–1017. Tohen, M., Chengappa, K.N., Suppes, T., Zarate Jr., C.A., Calabrese, J.R., Bowden, C.L., Sachs, G.S., Kupfer, D.J., Baker, R.W., Risser, R.C., Keeter, E.L., Feldman, P.D., Tollefson, G.D., Breier, A., 2002b. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch. Gen. Psychiatry 59, 62–69. Tohen, M., Goldberg, J.F., Gonzalez-Pinto Arrillaga, A.M., Azorin, J.M., Vieta, E., Hardy-Bayle, M.C., Lawson, W.B., Emsley, R.A., Zhang, F., Baker, R.W., Risser, R.C., Namjoshi, M.A., Evans, A.R., Breier, A., 2003. A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania. Arch. Gen. Psychiatry 60, 1218–1226. Tohen, M., Chengappa, K.N., Suppes, T., Baker, R.W., Zarate, C.A., Bowden, C.L., Sachs, G.S., Kupfer, D.J., Ghaemi, S.N., Feldman, P.D., Risser, R.C., Evans, A.R., Calabrese, J.R., 2004. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br. J. Psychiatry 184, 337–345. Vieta, E., 2004. Olanzapine in bipolar disorder. Expert Opin. Pharmacother. 5, 1613–1619. Vieta, E., Goikolea, J.M., 2005. Atypical antipsychotics: newer options for mania and maintenance therapy. Bipolar Disord. 7 (Suppl 4), 21–33. Vieta, E., Goikolea, J.M., Corbella, B., Benabarre, A., Reinares, M., Martinez, G., Fernandez, A., Colom, F., Martinez-Aran, A., Torrent, C., 2001. Risperidone safety and efficacy in the treatment of bipolar and schizoaffective disorders: results from a 6-month, multicenter, open study. J. Clin. Psychiatry 62, 818–825. Young, R.C., Biggs, J.T., Ziegler, V.E., Meyer, D.A., 1978. A rating scale for mania: reliability, validity and sensitivity. Br. J. Psychiatry 133, 429–435. Zajecka, J.M., Weisler, R., Sachs, G., Swann, A.C., Wozniak, P., Sommerville, K.W., 2002. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J. Clin. Psychiatry 63, 1148–1155.
Research report
Olanzapine monotherapy and olanzapine combination therapy in the treatment of mania: 12-week results from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) observational study☆ Eduard Vieta a,b,⁎, Francesco Panicali a , Iris Goetz c , Catherine Reed c , Merce Comes a,b , Mauricio Tohen d,e for the EMBLEM Advisory Board b
a Bipolar Disorders Program, Hospital Clinic, University of Barcelona IDIBAPS, Barcelona, Spain Red de Enfermedades Mentales (REM-TAP Network), Instituto de Salud Carlos III, Ministerio de Sanidad, Spain c Eli Lilly, Windlesham, United Kingdom d Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN, USA e McLean Hospital, Harvard Medical School, Belmont, MA, USA
Received 26 March 2007; received in revised form 11 May 2007; accepted 13 May 2007 Available online 20 June 2007
Abstract Background: To evaluate the 12-week outcomes (effectiveness, tolerability, and patterns of medication use) of olanzapine (either in antimanic monotherapy or in combination with other antipsychotics, anticonvulsants, and/or lithium) in patients with bipolar mania or mixed mania. Method: EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) is a 24-month prospective observational study of in- and outpatients with acute mania/mixed mania conducted in 14 European countries. Primary outcome measures included Clinical Global Impressions–Bipolar Disorder scale (overall, mania, and depression); 5-item Hamilton Depression Rating Scale; and Young Mania Rating Scale. Tolerability measures included a questionnaire to assess patients’ symptomatic complaints. Results: Overall, 2004 patients received olanzapine (olanzapine monotherapy, n = 673; olanzapine combination, n = 1331). Concomitant therapy with antidepressants and/or anxiolytics was possible in both groups. The countries significantly differed in the use of olanzapine monotherapy versus olanzapine combination ( p b .0001). Baseline-to-endpoint changes on the CGI-BP subscales, YMRS, and HAMD-5 were significant within both treatment groups ( p b .0001). Olanzapine monotherapy was generally better tolerated than olanzapine combination, particularly with regard to sedation (12% vs 17%; p b .001), tremor (2% vs 5%; p b .001), and akathisia (3% vs 6%; p b .001).
☆ Role of funding source: The EMBLEM study is funded by Eli Lilly and Company Limited, Windlesham, Surrey, UK. Contributors: All the authors have been sufficiently involved in the study submitted. Conflict of interest: Eduard Vieta, has acted as a consultant, received grants, or been hired as a speaker by the following companies: Almirall, AstraZeneca, Bial, Bristol-Myers-Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Merck Sharp & Dohme, Novartis, Organon, Otsuka, Pfizer, Sanofi Aventis, Servier, UCB. He has acted as consultant and has received grants from the Spanish Ministry of Health, Instituto de Salud Carlos III, RETICS RD06/0011 (REM-TAP) and from the Stanley Medical Research Institute. Iris Goetz, Catherine Reed, and Mauricio Tohen are Eli Lilly and Company employees. Francesco Panicali and Merce Comes have no conflict of interest. ⁎ Corresponding author. Director Bipolar Disorders Program, Clinical Institute of Neuroscience, University Clinic Hospital of Barcelona, Villarroel 170, 08036-Barcelona, Spain. Tel.: +34932275401; fax: +34932279876. E-mail address: [email protected] (E. Vieta).
0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.05.009
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Discussion: The acute-phase EMBLEM results suggest that in naturalistic settings, olanzapine (both as monotherapy and combination) may be effective in treating patients with bipolar mania. The use of olanzapine monotherapy or combination varies significantly across countries, but combination is generally the rule, rather than the exception. © 2007 Elsevier B.V. All rights reserved. Keywords: Olanzapine; Mania/mixed; Bipolar disorder; Prospective observational study
1. Introduction
2. Methods
Over the last 5 years, our knowledge on the treatment of mania has outstandingly increased due to the data from randomized clinical trials: Atypical antipsychotics such as olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole have been compared with placebo and with active compounds (haloperidol, lithium, and divalproex), and the evidence base for the use of all these compounds has been considerably enriched (Vieta and Goikolea, 2005). The knowledge of the actual use of antimanic agents in routine clinical conditions is quite limited, however, and large observational studies are rare (Vieta et al., 2001). Observational studies are more likely to be challenged for their internal validity than randomized clinical trials, but provide relevant data about the actual use of therapies either as monotherapy or combination therapy in “real world” patients (that is, without excluding comorbidities or suicide risk, including flexible and broader dose ranges, and across all ranges of illness severity). Olanzapine has been tested in randomized designs in mania and compared with placebo (Tohen et al., 1999, 2000), haloperidol (Tohen et al., 2003), divalproex (Zajecka et al., 2002; Tohen et al., 2002a), and risperidone (Perlis et al., 2006). Olanzapine cotherapy with lithium or divalproex was also compared with lithium and divalproex alone in one trial (Tohen et al., 2002b, 2004). Olanzapine proved to be effective for the acute treatment of mania and beyond (Vieta, 2004). Hence, a good number of studies provide an excellent evidence base for the use of olanzapine (both in mono- and combination therapy) as an antimanic agent, but less is known about the factors that drive the choice of olanzapine as monotherapy or combination, its dosages in routine clinical practice, and the patterns of use across different countries. To close this gap, we conducted the EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication), one of the largest observational studies ever conducted in patients suffering form bipolar mania. The objectives of the EMBLEM were to learn about the clinical and functional outcomes and patterns of use of antimanic therapy including olanzapine (both in monotherapy and in combination therapy) across several European countries.
2.1. Study objective EMBLEM is a large, prospective, multicentre, observational study on the outcomes of patients after an episode of mania. From December 2002 to June 2004, 530 investigators enrolled patients from 14 European countries (Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, The Netherlands, Norway, Portugal, Spain, Switzerland, and the UK). Observations were completed with 5 further data collections as part of the acute phase, which lasted for 12 weeks, until October 2004. Further observations are currently ongoing in the ≤24-month maintenance phase. All countries applied the same core set of measures at each data collection point to capture a broad range of clinical outcomes. The primary objective of the study was to assess the course of bipolar disorder in patients who experienced a manic/mixed episode and started new oral treatment antipsychotics, anticonvulsants and lithium as monotherapy or treatment combinations. Depending on the health-care system in each country, the EMBLEM included investigators from both inpatient and outpatient settings. Both rural and urban locations, as well as public and private facilities, were involved to allow for an accurate representation of current treatment settings for patients with mania across Europe. Participating investigators were psychiatrists practicing in the setting in which the patient was being treated. Data were collected by either the investigators or by their designee. 2.2. Patients Patients were considered for enrolment if they presented within the standard course of care and if, according to the decision of the treating psychiatrist, oral medication with antipsychotics, lithium and/or anticonvulsants was initiated or changed (excluding dose changes) for the treatment of a manic or mixed bipolar episode. Psychiatric diagnosis to determine the presence of a manic/mixed episode was made by each site's leading investigator using the site’s usual standard diagnostic criteria (generally DSM-IV or ICD-10). Patients with comorbidity, substance abuse, and suicidiality, or those
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taking other medications (including antidepressants and sedatives) were not excluded. All patient data were collected and evaluated anonymously using a unique patient identification number. Patient informed consent and ethical board approval were obtained as required by local laws and regulations. This report describes the acute-phase outcomes of the subgroup of patients who were treated with olanzapine either as antimanic monotherapy or in combination with other antipsychotics, anticonvulsants, and/or lithium. 2.3. Medications The decision to initiate or change medication and the type of medication selected were independent from the study design and entirely at the discretion of the treating psychiatrist; once the decision to start a new oral treatment for mania was made, investigators could include the patient in the study. Investigators were asked, but not required, to enroll approximately the same number of patients initiating olanzapine as the number of patients initiating any other antipsychotic, anticonvulsant, or lithium combined. That was to ensure that the sample size of patients treated with olanzapine, who are the focus of this report, was large enough to allow for specific subanalyses. The index medications could be given as antimanic monotherapy or in combination with any other antipsychotic, anticonvulsant, and/or lithium. Cotherapy with antidepressants and sedatives, as well as any other medications required in standard care, was allowed in both groups. Patients were not required to remain on the medication initiated; changes of medication prescribed and doses could be made according to clinical need as determined by the treating psychiatrist. In this report, only patients who were treated with olanzapine, either as antimanic monotherapy (defined as patients taking olanzapine and not taking any other antipsychotic, lithium, or anticonvulsant) or in combination with other antimanic medications, are considered. However, consistent with other studies and controlled trials (Tohen et al., 1999, 2000), patients taking olanzapine and benzodiazepines, antidepressants, or anticholinergics were still considered as being on antimanic monotherapy. In settings where the health-care structure and practices were conducive to linked observation between inpatient and outpatient care, the observations were performed as continuously as possible for patients changing from inpatient to outpatient service or vice versa. Patients who were treated as inpatients during the index episode and were then discharged at any time during the study period were fully evaluated immediately before their discharge from the hospital.
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2.4. Assessments Following the inclusion into EMBLEM, assessments occurred at 1, 2, 3, 6 and 12 weeks after baseline if this coincided with the usual clinical care of the patient. Patients were not excluded if individual assessments were missed. All data collection forms were completed by investigators or their designees. Socio-demographic variables recorded at baseline included gender, age, country of origin, body mass index (BMI), educational status, and history of substance abuse (alcohol or cannabis and other illegal substances). Primary measures of effectiveness used during the index episode and throughout the 12-week acute phase included 1) Clinical Global Impressions– Bipolar Disorder (CGI-BP) overall, mania, depression and hallucinations/delusions (all rated for severity, with the score range 1–7) (Spearing et al., 1997); 2) the Young Mania Rating Scale (YMRS) (Young et al., 1978); 3) the 5item version of the Hamilton Depression Rating Scale (HAMD-5) defined by principal component analysis (Gonzalez-Pinto et al., 2003) to find the core symptoms of depression during mania (depressive mood, suicidal ideation, guilt, obsessions, and psychic anxiety). Two modified items from the SLICE of LIFE were applied to measure patient functional outcomes in terms of work functioning and life satisfaction. Information on olanzapine and concomitant medication for bipolar disorder (other antipsychotics, anticonvulsants, lithium, antidepressants, benzodiazepines, hypnotics, and anticholinergics), as well as their respective doses and mode of intake, was also recorded at baseline and throughout the 12 weeks' follow-up. At each visit during the 12-week follow-up, interviewers recorded (via a custom made tolerability checklist) patients' complaints by describing patients' “assessment for each of the following effects that are judged to be associated with bipolar medication, as of today” with either “not present,” “present but not significantly interfering with patient’s functioning,” or “present and significantly interfering with patient’s functioning.” 2.5. Statistical analyses The distribution of the baseline characteristics of the sample, including sociodemographic and clinical measures, was analysed with descriptive statistics. In continuous data with normal distribution, a twosample t-test was used to test the difference between the olanzapine antimanic monotherapy and olanzapine combination groups. A paired t-test was used to compare changes in outcomes (from baseline to the 12-week endpoint) for patients within each olanzapine treatment group.
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Table 1 Baseline characteristics of patients with mania treated with olanzapine as monotherapy or olanzapine combination therapy Characteristics
Female, n (%) Age, mean ± SD, years Country, n (%) b Belgium Switzerland Germany Denmark Spain Finland France United Kingdom/Ireland Greece Italy Netherlands Norway Portugal Alcohol abuse ever, n (%) Cannabis abuse ever, n (%) BMI, mean ± SD, kg/m2 Work impairment, n (%) Hospitalization status, n (%) Mixed episode, n (%) Psychotropic medication (before baseline), n (%)⁎ No psychotropic meds 1 meds ≥2 meds Antidepressant (before baseline), n (%) CGI-BP overall, mean ± SD CGI-BP mania, mean ± SD CGI-BP depression, mean ± SD HAMD-5 Total, mean ± SD YMRS total, mean ± SD CGI Hallucination delusion, mean ± SD
Patients on olanzapine combination
Statistic‡⁎§
Betweengroup
(M)
(C)
(M vs C)
p value
(N = 673) b
(N = 1331) c .05⁎ − .39‡ 58.47⁎
.83 .70 b.0001
.40⁎ .13⁎ − 5.86‡ .87⁎ 7.01⁎ 5.54⁎ 450.74⁎
.53 .70 b.0001 .35 b.01 .02 b.0001
152 (11) 493 (37) 684 (51) 413 (32)
.049⁎
.82
4.7 ± 1.0 4.8 ± 1.0 1.8 ± 1.2 2.8 ± 2.7 26.9 ± 10.0 3.1 ± 1.8
− 2.63‡ − 1.50‡ 658793§ 625299§ − .77‡ 670454§
b.01 .14 .22 .004 .45 .82
Total sample of patients on olanzapine
Patients on olanzapine monotherapy
(N = 2004) a 1047 (52) 44.2 ± 13.2
347 (52) 44.1 ± 14.2
700 (53) 44.3 ± 12.7
43 (100) 52 (100) 313 (100) 14 (100) 176 (100) 21 (100) 412 (100) 115 (100) 386 (100) 295 (100) 115 (100) 14 (100) 48 (100) 502 (26) 278 (14) 25.9 ± 4.7 1362 (72) 773 (39) 454 (23)
17 (40) 9 (17) 134 (43) 7 (50) 62 (35) 5 (24) 152 (37) 51 (44) 111 (29) 73 (25) 43 (37) 5 (36) 4 (9) 161 (25) 96 (15) 25.1 ± 4.2 448 (70) 233 (35) 175 (26)
26 (60) 43 (83) 179 (57) 7 (50) 114 (65) 16 (76) 260 (63) 64 (56) 275 (71) 222 (75) 72 (63) 9 (64) 44 (91) 341 (26) 182 (14) 26.4 ± 4.9 914 (72) 540 (41) 279 (22)
497 (25) 723 (36) 777 (39) 624 (32)
345 (52) 230 (34) 93 (14) 211 (32)
4.7 ± 1.1 4.8 ± 1.1 1.9 ± 1.2 2.9 ± 2.8 26.8 ± 9.8 3.1 ± 1.8
4.6 ± 1.1 4.8 ± 1.0 1.9 ± 1.3 3.2 ± 3.0 26.6 ± 9.5 3.1 ± 1.7
⁎ Chi-squared test. ‡ 2 sample t-test. § Wilcoxon test. Abbreviations: CGI-BP = Clinical Global Impressions–Bipolar Disorder; HAMD-5 = the 5-item Hamilton Depression Rating Scale; YMRS = Young Mania Rating Scale. a Total n varies for each variable due to missing data. Percentage (%) for each variable refers to total n available for respective variables. b Percentage (%) refers to total n per country.
Where assumptions of normality were not adequately met, differences between groups were tested using the Wilcoxon test. Differences in categorical parameters between groups, as well as within-group changes from baseline to endpoint, were tested using a chi-squared test. For all comparisons a level of significance of .05 was applied. Longitudinal eval-
uation of change in outcome was performed using last observation carried forward (LOCF) after a sensitivity analysis with LOCF, observed case (OC) analysis and mixed-effects model repeated measures (MMRM) revealed no significant differences. All data were analyzed using SAS version 9.1 (SAS Institute, Inc.; Cary, North Carolina).
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3. Results 3.1. Baseline patient characteristics Of 3681 manic patients enrolled in the study, 2004 (54.4%) received olanzapine for the treatment of their manic or mixed symptoms. Of the 2004 patients, 673 (33.6%) were treated with olanzapine as antimanic monotherapy, and 1331 (66.4%) received olanzapine in combination with other antipsychotics, anticonvulsants, and/or lithium. The demographic characteristics of the sample are shown in Table 1. Of the sample studied, 35% of patients were inpatients, and alcohol and cannabis abuse were present in 26% and 14% of patients, respectively. The incidence of these conditions did not differ significantly between the two treatment groups. The proportion of patients treated with olanzapine monotherapy, compared with those treated with olanzapine combination therapy, differed significantly ( p b .0001) across the 14 countries. The mean (±SD) body mass index (BMI) of the total sample at baseline was 25.9± 4.7 kg/m2, with patients treated with olanzapine combination having a significantly higher mean BMI (26.4 ± 4.9 kg/m2) than those treated with olanzapine monotherapy (25.01± 4.2 kg/m2; pb .0001). According to the interviewers' assessment, 72% of patients suffered from work impairment at baseline, with no significant difference between the two treatment groups. The patients in the study were suffering from either a manic (77%) or a mixed episode (23%); the group treated with olanzapine monotherapy had a significantly ( p b .02) higher number of patients with mixed episodes. For the overall sample of patients treated with olanzapine, the mean (±SD) CGI-BP overall score at baseline indicated that patients were moderately to markedly ill (4.7 ± 1.1) at baseline. The mean YMRS score at baseline was 26.8 ± 2.8. Compared with patients in the olanzapine combination group, patients on olanzapine monotherapy had a significantly lower mean score on CGIBP overall (4.6 ± 1.1 vs 4.7 ± 1.0; p b .01) and a significantly higher mean HAMD-5 score (3.2 ± 3.0 vs 2.8 ± 2.7; p = .004) at baseline. Overall, the mean baseline scores on the other psychometric scales did not significantly differ between the groups. 3.2. Effectiveness At 12 weeks, 376 of 2004 (18.8%) of patients taking olanzapine at baseline were lost to follow-up, over half of those due to discharge from the hospital. Retention was similar in both groups: olanzapine monotherapy group,
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Table 2 Within-group changes from baseline to endpoint (12 Weeks) in outcome measures of patients with mania taking olanzapine monotherapy or olanzapine combination therapy Outcomes measure
CGI-BP overall∼ CGI-BP mania∼ CGI-BP depression∼ HAMD-5∼ YMRS total∼ BMI∼ Work impairment⁎
Patients on olanzapine monotherapy (M), N = 673
Patients on olanzapapine combination (C), N = 1331
95% CI
p value 95% CI
p value
− 1.94 (− 2.06, −1.83) − 2.44 (− 2.55, −2.33) − .21 (− .32, − .11) − 1.10 (− 1.39, −.81) − 19.7 (− 20.6, −18.7) .83 (.70, .96) .26 (.18, .33)
b.0001 − 1.99 (− 2.07, − 1.92) b.0001 − 2.49 (− 2.57, − 2.41) b.0001 − .17 (− .24,−.10) b.0001 − .98 (− 1.17,−.79) b.0001 − 20.1 (− 20.8, − 19.4) b.0001 .74 (.66, .83) b.0001 .16 (.10, .22)
b.0001 b.0001 b.0001 b.0001 b.0001 b.0001 b.0001
∼ 95% CI and p-value from paired t-test. ⁎95% CI and p-value from Chi square test. Abbreviations: CGIBP=Clinical Global Impressions–Bipolar Disorder; HAMD-5=the 5-item Hamilton Depression Rating Scale; YMRS=Young Mania Rating Scale.
540 of 673 (80.2%); olanzapine combination group, 1101 of 1331(82.7%). Results showed a significant improvement within both the monotherapy and the combination therapy group in all effectiveness measures at week 12 (Tables 2, 3, p value for total sample not shown in table). Among all the patients treated with olanzapine, mean (±SD) scores on all the CGI-BP subscales significantly decreased from baseline to endpoint: CGI-BP overall, from 4.7 ± 1.1 to 2.7 ± 1.3 ( pb .0001); CGI-BP mania, from 4.8 ± 1.0 to 2.3± 1.2 ( pb .0001); and CGI-BP depression, from 1.9 ± 1.2 to 1.7± 1.1 ( p b .0001). As early as week 1, both treatment groups showed significant improvement in CGI-BP overall (Fig. 1), CGI-BP mania (Fig. 2), and CGIBP depression (Fig. 3) scores. This improvement was maintained for all CGI-BP subscales at subsequent assessments. At endpoint, the groups did not differ significantly in their CGI-BP overall, mania, and depression scores (Table 3). Among all the patients, mean (± SD) HAMD-5 score decreased from 2.9 ± 2.8 at baseline to 2.0 ± 2.4 at endpoint ( p b .0001). At endpoint this score was significantly higher in the olanzapine monotherapy group compared with the olanzapine combination group (2.2± 2.6 vs 1.9 ± 2.3; p = .04; Table 3). Mean (± SD) YMRS score among all the patients significantly decreased from 26.8 ± 9.8 at baseline to
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Table 3 Between-group outcomes results at the 12-week endpoint among patients with mania taking in monotherapy or olanzapine combination therapy Outcomes measures
Dosage of olanzapine, mean ± SD, mg/day CGI-BP overall, mean ± SD CGI-BP mania, mean ± SD CGI-BP depression, mean ± SD HAMD-5 total, mean ± SD YMRS total, mean ± SD BMI, mean ± SD, kg/m2 Work impairment, n (%) Hospitalization status, n (%)
Total sample of patients on olanzapine
Patients on olanzapine monotherapy (M)
Patients on olanzapine combination (C)
N = 2004a
N = 673a
N = 1331a
15.2 ± 7.9 2.7 ± 1.3 2.3 ± 1.3 1.7 ± 1.1 2.0 ± 2.4 6.1 ± 7.2 26.8 ± 4.7 855 (58%) 132 (8%)
14.6 ± 8.4 2.7 ± 1.3 2.3 ± 1.3 1.7 ± 1.1 2.2 ± 2.6 5.8 ± 6.7 25.9 ± 4.1 274 (55%) 43 (8%)
15.5 ± 7.7 2.7 ± 1.3 2.3 ± 1.3 1.7 ± 1.1 1.9 ± 2.3 6.2 ± 7.4 27.2 ± 4.9 581 (59%) 89 (8%)
Statistic (M vs C)‡⁎§
p value
−7.40‡ 660272§ 672918§ 682513§ 393135§ 394966§ −5.02‡ 2.32⁎ .02⁎
b.0001 .28 .90 .30 .04 .83 b.0001 .12 .88
a
Total n varies for each variable due to missing data. Percentage (%) for each variable refers to total n available for respective variables. ⁎ Chi-squared test. ‡ 2 sample t-test. § Wilcoxon test. Abbreviations: CGI-BP = Clinical Global Impressions–Bipolar Disorder; HAMD-5 = the 5-item Hamilton Depression Rating Scale; YMRS = Young Mania Rating Scale.
6.1 ± 7.2 at endpoint ( p b .0001). At endpoint, the treatment groups did not differ significantly on the changes in this score (Table 3). Among all the patients, work impairment declined from 72.0% at baseline to 58.0% at endpoint ( p b .0001). At endpoint, the treatment groups did not significantly differ on this effectiveness measure (Table 3). The hospitalization rate of the total sample decreased from 39.0% at baseline to 8.0% at endpoint ( p b .0001),
with no significant differences at endpoint between the two groups (Table 3). 3.3. Tolerability Symptomatic complaints regarded as “present and significantly interfering with patient’s functioning” and considered to be possibly indicative of being treatment related are shown in Table 4. Overall, pharmacological
Fig. 1. Baseline-to-endpoint changes in mean CGI-BP overall scores (LOCF) for olanzapine patients: monotherapy (N = 673) vs combination (N = 1331). Abbreviations: CGI-BP = Clinical Global Impressions–Bipolar Disorder; LOCF = last observation carried forward.
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Fig. 2. Baseline-to-endpoint changes in mean CGI-BP mania scores (LOCF) for olanzapine patients: monotherapy (N = 673) vs combination (N = 1331). Abbreviations: CGI-BP = Clinical Global Impressions–Bipolar Disorder; LOCF = last observation carried forward.
therapy was well tolerated: The most common symptomatic complaints that were significantly interfering with patient’s functioning were sedation and insomnia, both appearing in 16% of the total sample. Significant cognitive problems (namely, memory loss and concentration difficulties) occurred in 11% of the total sample. The incidence of severe akathisia, sedation, and tremor among patients who received olanzapine monotherapy was
significantly lower ( p b .001) than that among patients on combination therapy. The average weight gain in the overall sample on olanzapine was 2.3 kg. Of the 63.0% of patients who showed weight gain during the 12 weeks of follow-up, the mean weight gain was 4.0± 3.5 kg (olanzapine monotherapy, 4.1± 3.8 kg; olanzapine combination, 3.9 ± 3.3 kg;). Of the total sample, 17.0% of the patients lost weight, with
Fig. 3. Baseline-to-endpoint changes in mean CGI-BP depression scores (LOCF) for olanzapine patients: monotherapy (N = 673) vs combination (N = 1331). Abbreviations: CGI-BP = Clinical Global Impressions–Bipolar Disorder; LOCF = last observation carried forward.
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Table 4 Symptomatic complaints that significantly interfered with the functioning of patients with mania treated with olanzapine monotherapy or olanzapine combination therapy (from baseline to the 12-week endpoint) Symptomatic complaints
Dystonia, n (%) Akathisia, n (%) Parkinsonism, n (%) Tardive dyskinesia, n (%) Sedation, n (%) Memory loss/concentration difficulties, n (%) Dizziness, n (%) Gastrointestinal problems, n (%) Tremor, n (%) Sexual dysfunction, n (%) Polyuria/nocturia, n (%) Insomnia, n (%) Menstrual disturbance, n (%)a
Total sample of patients on olanzapine
Patients on olanzapine monotherapy (M)
Patients on olanzapine combination (C)
N = 2004
N = 673
N = 1331
33 (2) 97 (5) 57 (3) 18 (b1) 314 (16) 227 (11) 71 (4) 61 (3) 74 (4) 130 (6) 33 (2) 317 (16) 30 (3)
10 (1) 18 (3) 16 (2) 5 (b1) 81 (12.) 72 (11) 20 (3) 19 (3) 12 (2) 39 (6) 7 (1) 96 (14) 12 (3)
23 (2) 79 (6) 41 (3) 13 (b1) 233 (17) 155 (12) 51 (4) 42 (3) 62 (5) 91 (7) 26 (2) 221 (17) 18 (3)
Statistic⁎
p value
.16 10.32 .80 .27 10.12 .40 .97 .17 10.40 .80 2.30 1.84 .66
.69 .001 .37 .60 .001 .53 .33 .68 .001 .37 .13 .17 .42
⁎ Chi-squared test. a In Females only: N =699 females were treated with olanzapine, of which n =347 with olanzapine monotherapy and n=699 with olanzapine combination.
a mean weight loss from baseline to endpoint of 2.7 ± 2.7 kg (olanzapine monotherapy, 2.8± 3.2 kg; olanzapine combination, 2.7± 2.5 kg;). Mean BMI scores of the total sample increased from 25.92 ± 4.7 kg/m2 at baseline to 26.78 ± 4.79 kg/m2 at endpoint (p b .001). Both at baseline and at endpoint, the mean BMI was significantly higher in the olanzapine combination group compared with the olanzapine monotherapy group (26.4 ± 4.9 vs, 25.1 ± 4.2 respectively; p b .0001 at baseline; 27.15 ± 4.89 vs 25.9 ± 4.1, respectively; p b .001 at endpoint). During the 12-week follow-up, 24 (4%) in the olanzapine monotherapy group attempted suicide; 1 of the suicide attempts was successful. In the combination group, 33 (2%) attempted suicide, with 2 attempts being successful. As EMBLEM was not designed as a safety Table 5 Patterns of olanzapine combination therapya Patterns of combination therapy
n (%)
Olanzapine + atypical antipsychotic Olanzapine + typical antipsychotic Olanzapine + lithium Olanzapine + Anticonvulsant Olanzapine + Valproate Olanzapine + Carbamazepine Olanzapine + other anticonvulsants Olanzapine + lithium + Anticonvulsant Olanzapine + lithium + typical antipsychotic Olanzapine + anticonvulsant + typical antipsychotic Olanzapine + lithium + anticonvulsant + typical antipsychotic
19 (1) 116 (9) 280 (21) 601 (45) 328 (25) 116 (8.7) 158 (12) 91 (7) 48 (4) 140 (11) 27 (2)
a
After change in oral medication at baseline.
study this numbers are estimates only as there is no information available on patients lost to follow-up. 3.4. Patterns of antimanic medication use At presentation at baseline, 25% of all the patients were not taking any psychotropic medication; 36% were on 1 medication; and 39%, on 2 or more medications (Table 1). Significantly more patients in the olanzapine monotherapy group (p b .0001) were taking no medicine at baseline, whereas patients in the olanzapine combination group were more likely (p b .0001) to take 2 or more medications at baseline (Table 1). At baseline, 32% of the total sample were taking antidepressants, and this characteristic was present in both treatment groups without any significant difference. Table 5 presents the most frequent antimanic medications that patients received in combination with olanzapine. Olanzapine was most frequently combined with anticonvulsants (45%; mainly valproate [25%] and carbamazepine [9%]), followed by lithium (21%). Overall, the mean dose of olanzapine was 15.2 ± 7.9 mg. This dose was significantly lower in the olanzapine monotherapy group compared with the olanzapine combination group (14.6 ± 8.4 vs. 15.5± 7.7, respectively; p b .0001). 4. Discussion The acute-phase results of this large, multicentre, observational study that investigated the use of olanzapine (as either monotherapy or combination therapy) in
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European patients with mania showed significant withingroup improvements from baseline to endpoint in all of the following scales: CGI-BP overall, mania, and depression; YMRS; and HAMD-5. Moreover, the rates of work impairment significantly decreased in both treatment groups at endpoint. Although results of observational studies should be interpreted with caution as far as efficacy is concerned, due to the open design and the absence of comparator, these results are consistent with findings from randomized, controlled trials (Vieta, 2004). In the EMBLEM study, treatment decisions were entirely at the discretion of the treating psychiatrist; however, the treating psychiatrists were asked, but not required, to enrol approximately half of the patients who were initiating olanzapine. It is also remarkable that two thirds of the sample were treated as outpatients, who are generally less severe than inpatients (Montoya et al., 2007); this may reflect the limited availability of beds but also current treatment practice across Europe, due to improved mental health access and treatment availability. This study suggests that the positive findings from controlled trials may be generalized to larger, more representative samples of patients with mania, including those with comorbidities like alcohol and drug abuse that generally preclude them from being enrolled in clinical trials. This study also provides relevant information on the reasons that drive the choice of antimanic monotherapy versus combination therapy with olanzapine: The main factor seemed to be whether the patient was already on any medication or not; the number of drugs before the index episode may be a measure of lifetime severity. On the other hand, patients with a history of good, or at least partial, response to 1 mood stabiliser may also be more likely to receive combination therapy once manic. The overall severity of the index episode also may have been a factor in choosing an antimanic combination therapy. However, the presence of depressive and mixed features during the manic episode was more likely to induce the prescription of olanzapine monotherapy, with or without antidepressants. The use of olanzapine alone in mixed manic episodes is supported by controlled data (Baldessarini et al., 2003), but combination therapy with olanzapine may be efficacious as well (Baker et al., 2004). Therefore, it seems that severity of the manic episode was driving the choice of a combination therapy, whereas the severity of depressive symptoms precluded the use of adjunctive therapies. Although significant, some of the differences in effectiveness findings between the monotherapy and combination therapy groups are small and have to be evaluated in terms of their clinical relevance.
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Finally, cultural factors may play a role as well in the choice of olanzapine monotherapy versus combination therapy: Countries with a tradition of using antipsychotic monotherapy or manic episodes (such as Denmark, Germany, or the UK) seemed more inclined to extrapolate their experience with traditional antipsychotic to olanzapine, whereas other countries may be more prone to combinations (Bowers et al., 2004). Observational studies may provide very useful information about patient-reported tolerability. This study showed good tolerability of treatment with olanzapine. Importantly, the overall rate of severe tardive dyskinesia was very low (b1.0%). The most common complaints were insomnia (which may have been illness related), sedation (which may have been related to the drug treatment), and memory problems (which may have been related to either). Interestingly enough, patients on olanzapine combination therapy were more likely to have tolerability problems, particularly tremor, akathisia, and sedation. The former two are likely associated with the use of conventional antipsychotics in combination with olanzapine, and sedation may be associated with the use of other drugs like valproate as part of the combination therapy. As expected, patients treated with olanzapine (both as monotherapy and combination therapy) gained weight, and their BMIs significantly increased. The mean dosage of olanzapine was slightly, but significantly, higher in the combination group than in the monotherapy group (15.5 mg/day versus 14.6 mg/day). In both treatment groups, the mean dosage is consistent with previous controlled studies of olanzapine (Tohen et al., 1999, 2000, 2002b, 2003, 2004). Because patients who received combination therapy were more severely ill, the higher mean dose in that treatment group may be related to greater illness severity. However, because the betweengroup difference in dosages was small and probably not relevant clinically, it also suggests that in most cases, the alternative to using notably higher olanzapine doses was to add a second antipsychotic or an antimanic drug (such as valproate or lithium). In summary, this report confirms the results of randomized clinical trials concerning the efficacy and tolerability of olanzapine in acute mania in the largest sample of manic patients ever studied within an observational, prospective, multicenter design across Europe. The findings also suggest that the choice of an antimanic combination versus monotherapy may be influenced by severity of illness and cultural factors, but the use itself of a combination of olanzapine with antipsychotics, anticonvulsants, and/or lithium is the rule rather than the exception in “real world” practice, even though olanzapine monotherapy is generally better tolerated.
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Acknowledgements The authors of this report would like to thank the EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) Advisory Board for their participation in the design and conduct of the study: Prof Bernard Sabbe (Belgium); Dr Jens Knud Larsen (Denmark); Prof Hannu Koponen (Finland); Dr Isabelle Gasquet and Prof Jean Michel Azorin (France); Dr Heinz Grunze (Germany); Prof Giovanni Battista Cassano (Italy); Prof Willem Nolen and Prof Jim van Os (Netherlands); Dr Trond Aarre (Norway); Prof Filipe Arriaga (Portugal); Dr Ana Gonzalez Pinto, Dr Josep Maria Haro, and Prof Eduard Vieta (Spain); Prof Jules Angst (Switzerland); Dr John Cookson and Prof Martin Knapp (UK); Dr. Mauricio Tohen (USA). The support of the Spanish Ministry of Health, Instituto de Salud Carlos III, RETICS RD06/0011(REM-TAP Network) is also acknowledged. References Baker, R.W., Brown, E., Akiskal, H.S., Calabrese, J.R., Ketter, T.A., Schuh, L.M., Trzepacz, P.T., Watkin, J.G., Tohen, M., 2004. Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania. Br. J. Psychiatry 185, 472–478. Baldessarini, R.J., Hennen, J., Wilson, M., Calabrese, J., Chengappa, R., Keck Jr., P.E., McElroy, S.L., Sachs, G., Vieta, E., Welge, J.A., Yatham, L.N., Zarate Jr., C.A., Baker, R.W., Tohen, M., 2003. Olanzapine versus placebo in acute mania: treatment responses in subgroups. J. Clin. Psychopharmacol. 23, 370–376. Bowers, L., Callaghan, P., Clark, N., Evers, C., 2004. Comparisons of psychotropic drug prescribing patterns in acute psychiatric wards across Europe. Eur. J. Clin. Pharmacol. 60, 29–35. Gonzalez-Pinto, A., Ballesteros, J., Aldama, A., Perez de Heredia, J.L., Gutierrez, M., Mosquera, F., Gonzalez-Pinto, A., 2003. Principal components of mania. J. Affect. Disord. 76, 95–102. Montoya, A., Gilaberte, I., Costi, M., Perez Sanchez Toledo, J., Gonzalez Pinto, A., Haro, J., Comes, M., Vieta, E., 2007. Bipolar disorder in Spain: functional status and resource use on the basis of the Spanish sample of the observational, Pan European EMBLEM study. Vertex 8, 13–19. Perlis, R.H., Baker, R.W., Zarate Jr., C.A., Brown, E.B., Schuck, L.M., Jamal, H.H., Tohen, M., 2006. Olanzapine versus risperidone in the treatment of manic or mixed states in bipolar I disorder: a randomized, double-blind trial. J. Clin. Psychiatry 67, 1747–1753.
Spearing, M.K., Post, R.M., Leverich, G.S., Brandt, D., Nolen, W., 1997. Modification of the Clinical Global Impressions (CGI) scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res. 73, 159–171. Tohen, M., Sanger, T.M., McElroy, S.L., Tollefson, G.D., Chengappa, K.N., Daniel, D.G., Petty, F., Centorrino, F., Wang, R., Grundy, S.L., Greaney, M.G., Jacobs, T.G., David, S.R., Toma, V., 1999. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am. J. Psychiatry. 156, 702–709. Tohen, M., Jacobs, T.G., Grundy, S.L., McElroy, S.L., Banov, M.C., Janicak, P.G., Sanger, T., Risser, R., Zhang, F., Toma, V., Francis, J., Tollefson, G.D., Breier, A., 2000. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The olanzipine HGGW study group. Arch. Gen. Psychiatry 57, 841–849. Tohen, M., Baker, R.W., Altshuler, L.L., Zarate, C.A., Suppes, T., Ketter, T.A., Milton, D.R., Risser, R., Gilmore, J.A., Breier, A., Tollefson, G.A., 2002a. Olanzapine versus divalproex in the treatment of acute mania. Am. J. Psychiatry 159, 1011–1017. Tohen, M., Chengappa, K.N., Suppes, T., Zarate Jr., C.A., Calabrese, J.R., Bowden, C.L., Sachs, G.S., Kupfer, D.J., Baker, R.W., Risser, R.C., Keeter, E.L., Feldman, P.D., Tollefson, G.D., Breier, A., 2002b. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch. Gen. Psychiatry 59, 62–69. Tohen, M., Goldberg, J.F., Gonzalez-Pinto Arrillaga, A.M., Azorin, J.M., Vieta, E., Hardy-Bayle, M.C., Lawson, W.B., Emsley, R.A., Zhang, F., Baker, R.W., Risser, R.C., Namjoshi, M.A., Evans, A.R., Breier, A., 2003. A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania. Arch. Gen. Psychiatry 60, 1218–1226. Tohen, M., Chengappa, K.N., Suppes, T., Baker, R.W., Zarate, C.A., Bowden, C.L., Sachs, G.S., Kupfer, D.J., Ghaemi, S.N., Feldman, P.D., Risser, R.C., Evans, A.R., Calabrese, J.R., 2004. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br. J. Psychiatry 184, 337–345. Vieta, E., 2004. Olanzapine in bipolar disorder. Expert Opin. Pharmacother. 5, 1613–1619. Vieta, E., Goikolea, J.M., 2005. Atypical antipsychotics: newer options for mania and maintenance therapy. Bipolar Disord. 7 (Suppl 4), 21–33. Vieta, E., Goikolea, J.M., Corbella, B., Benabarre, A., Reinares, M., Martinez, G., Fernandez, A., Colom, F., Martinez-Aran, A., Torrent, C., 2001. Risperidone safety and efficacy in the treatment of bipolar and schizoaffective disorders: results from a 6-month, multicenter, open study. J. Clin. Psychiatry 62, 818–825. Young, R.C., Biggs, J.T., Ziegler, V.E., Meyer, D.A., 1978. A rating scale for mania: reliability, validity and sensitivity. Br. J. Psychiatry 133, 429–435. Zajecka, J.M., Weisler, R., Sachs, G., Swann, A.C., Wozniak, P., Sommerville, K.W., 2002. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J. Clin. Psychiatry 63, 1148–1155.