Effectiveness of olanzapine monotherapy and olanzapine combination treatment in the long term following acute mania — Results of a two year observational study in bipolar disorder (EMBLEM)

Journal of Affective Disorders 131 (2011) 320–329

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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d

Research report

Effectiveness of olanzapine monotherapy and olanzapine combination treatment in the long term following acute mania — Results of a two year observational study in bipolar disorder (EMBLEM) Ana Gonzalez-Pinto a,⁎, Eduard Vieta b, Catherine Reed c, Diego Novick c, Alessandra Barraco d, Jaume Aguado e, Josep Maria Haro e a International Mood Disorders Research Centre, Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Hospital Santiago Apóstol, University of the Basque Country, Vitoria, Spain b Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Spain c Lilly Research Centre, Windlesham, UK d Medical Department, Eli Lilly Italia, Sesto Fiorentino, Italy e Sant Joan De Deu-SSM, Fundació Sant Joan de Déu, CIBERSAM, Barcelona, Spain

a r t i c l e

i n f o

Article history: Received 17 July 2009 Received in revised form 30 November 2010 Accepted 30 November 2010 Available online 31 December 2010 Keywords: Bipolar disorder Combination therapy Maintenance therapy Monotherapy Olanzapine Prospective observational study

a b s t r a c t Background: This study compared the 2-year outcomes of patients with a manic/mixed episode of bipolar disorder taking olanzapine monotherapy or olanzapine in combination with other agents. Methods: EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) is a 2-year, prospective, observational study of clinical and functional outcomes of bipolar patients with an index manic/mixed episode. The study consisted of two phases: acute (12 weeks) and maintenance (follow-up over 2 years). The longitudinal outcome measure was the Clinical Global Impression-Bipolar Disorder scale. Cox regression models compared outcomes of both therapy groups using intention-to-treat and switching medication analysis. Treatment-emergent adverse events were also assessed. Results: 1076 patients were included in this analysis. 29% took olanzapine as monotherapy (n=313) and 71% as combination (n=763) at 12-weeks post-baseline (end of study acute phase). After adjusting for patient characteristics using switching medication analysis, only relapse rates differed (p=0.01) in favour of monotherapy-treated patients. There was no significant difference in rates of improvement, remission, and recovery. Patients treated with combination therapy reported more tremor (OR 2.37, 95%CI 1.44–3.89) and polyuria (OR 3.08, 95%CI 1.45–6.54) treatment-emergent events than monotherapy, although weight change was greater in the monotherapy group. Limitations: Unknown confounding and potential selection bias may differentially impact treatment outcomes. Conclusions: EMBLEM patients benefitted from the selected therapy to a similar extent. Differences in patient characteristics between those prescribed monotherapy and combination therapy appear to be clinically relevant in the treatment decision. Physicians must balance the benefits and risks when determining appropriate treatment for individual patients. © 2010 Elsevier B.V. All rights reserved.

1. Introduction

⁎ Corresponding author. Tel.: +34 945007769; fax: +34 945007764. E-mail address: [email protected] (A. Gonzalez-Pinto). 0165-0327/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2010.11.037

Bipolar disorder is a chronic, recurrent mood disorder characterized by episodes of mania/hypomania, depression or mixed states. It is a difficult and complex disorder to treat (Fountoulakis et al., 2007) due to frequent relapses/recurrences,

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residual symptoms, frequent medical and psychiatric co-morbidities, suicidal behaviour, and poor adherence/tolerance to medications. There are a variety of medications available for the management of patients with acute manic and mixed episodes and for maintenance therapy of bipolar disorder following an acute manic episode, including lithium, anticonvulsants (e.g. valproate, carbamazepine), typical antipsychotics, atypical antipsychotics and antidepressants. Current guidelines provide recommendations for monotherapy or combination therapy in the acute and maintenance treatment of bipolar disorder (American Psychiatric Association, 2002; Grunze et al., 2003; National Institute of Health and Clinical Excellence, 2006). However, studies indicate that everyday clinical practice often differs from guideline recommendations (Baldessarini et al., 2008; Lim et al., 2001). Olanzapine is indicated for the treatment of acute manic or mixed episodes associated with bipolar I disorder (as monotherapy or in combination with lithium or valproate) and as monotherapy maintenance for bipolar patients after achieving a responder status for an average duration of 2 weeks (SPC, 2010). Rapid reduction of symptoms is the main aim of acute phase treatment, whereas effective maintenance therapy aims to prevent relapse/recurrence and enable patients to achieve their premorbid levels of functioning. At present, whether olanzapine is primarily used as monotherapy or in combination therapy for the long-term treatment of bipolar disorder in routine clinical practice warrants further study. Moreover, additional data are needed regarding the characteristics of patients receiving these treatments, and the long-term clinical effectiveness and tolerability of olanzapine combination therapy vs. olanzapine monotherapy in the routine care setting. Observational studies can provide relevant data about the actual use of therapies either as monotherapy or combination therapy in “real world” bipolar patients (that is, without excluding co-morbidities or suicide risk, including flexible and broader dose ranges, and across all ranges of illness severity). EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) is a 2-year, prospective, observational study of the clinical and functional outcomes of patients with a mixed/manic episode. Due to its study design and primary objective of comparing treatment effectiveness in olanzapine- vs. non-olanzapine-treated patients, approximately half of patients received olanzapine both as monotherapy and in combination with other anti-manic medications. Thus, EMBLEM may help us learn more about factors that influence the choice of olanzapine as monotherapy or in combination therapy in routine clinical practice and the outcomes of such treatment. A comparison of olanzapine monotherapy vs. combination therapy in the acute treatment of mania has already been reported (Vieta et al., 2008). The 12-week results from the acute phase of the EMBLEM study showed that about one-third of all olanzapine-treated patients received monotherapy while twothirds received olanzapine in combination with other antipsychotics, anticonvulsants and/or lithium; the use of olanzapine as monotherapy or combination therapy varied across countries. The effectiveness of olanzapine monotherapy and combination therapy was similar, with significant improvements in all symptom scales and a decrease in work impairment during the 12-week follow-up period (Vieta et al., 2008). Treatment-emergent adverse events was significantly greater in

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the olanzapine combination therapy group for akathisia, tremor and sedation, although there was no significant difference in weight gain between groups. The primary objective of the present analysis of the EMBLEM study was to compare improvement, remission, recovery and relapse outcomes of a European sample of outpatients treated with olanzapine monotherapy vs. those treated with a combination of olanzapine and other treatments during a 2-year follow-up period after an acute manic or mixed episode utilising clinical trial methods (intention to treat analysis, ITT). The secondary objective was to compare outcomes using observational methods which would take into account switching medication. 2. Methods EMBLEM is a 24-month, prospective, observational study of in- and outpatients with acute mania/mixed mania conducted in 14 European countries. The study design, methods, patient population and baseline characteristics have been described in detail elsewhere (Goetz et al., 2007; Haro et al., 2006; Cruz et al., 2008; Vieta et al., 2008). Briefly, data were collected during the acute phase (up to 12 weeks post-baseline) and during the maintenance phase (6 months, 12 months, 18 months and 24 months post-baseline). All follow-up occurred as part of the normal clinical care of patients. 2.1. Patients Patients were considered for enrolment in the EMBLEM study 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 sites leading investigator using the sites usual standard diagnostic criteria (generally DSM-IV or ICD-10). Patients with co-morbidity, substance abuse, and suicidality, or those 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. A total of 3684 patients were enrolled in the EMBLEM study. However, of those, only 2416 came from countries that were eligible for participation in the maintenance phase (as 10 of the 14 countries took part in the full study). This report describes the maintenance phase outcomes of the subgroup of patients who were treated with olanzapine either as monotherapy or in combination with other antipsychotics, anticonvulsants, and/ or lithium from the end of the acute phase (12 weeks postbaseline). 2.2. Medications All treatment decisions were at the discretion of the treating physician and the decision to initiate or change medication and the type of medication prescribed was made independently of the study design. Investigators were asked to enrol approximately equal numbers of patients starting

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olanzapine as starting any other antipsychotic, anticonvulsant or lithium. The reason for this was to achieve the primary objective of the study, which was to compare treatment effectiveness on manic symptoms for patients receiving olanzapine with patients receiving other treatments. Medications could be given as monotherapy or in combination. Patients were not required to remain on the medication initiated at baseline. Changes in medication, dosing and concomitant medication were possible at any time during the study as determined by the treating psychiatrist. Antidepressants and concomitant medications (anticholinergics, benzodiazepines, other hypnotics) were prescribed as required. 2.3. Assessments Data collected at baseline included socio-demographics, psychiatric history, history of substance abuse (cannabis, alcohol, other substances), history of suicide attempts, frequency of manic and depressive symptoms during previous 12 months, number of inpatient admissions in previous 12 months, compliance with treatment, and functional status (housing status, relationship status, social activities, work impairment, life satisfaction). Information on functional status, suicide attempts and substance abuse was also collected at follow-up visits. Symptom severity was assessed at every visit using the Clinical Global Impression-Bipolar Disorder (CGI-BP) scale for mania, depression and overall symptoms (Spearing et al., 1997). A CGI hallucinations/delusions item was added to assess the presence of these symptoms. All items were rated on a scale of 1–7. Severity of mania and depression symptoms was also assessed using the Young Mania Rating Scale (YMRS, score range 0–64) (Young et al., 1978) and the 5-item version of the Hamilton Depression Rating scale (HAMD-5, score range 0–18) (Gonzalez-Pinto et al., 2003, 2009), respectively, but only up to the 12-week visit. Information on medication for bipolar disorder and concomitant medication was recorded at every visit. Bipolar disorder medication tolerability was assessed at every visit by physician assessment of the presence or absence of the following adverse events: dystonia, akathisia, parkinsonism, tardive dyskinesia, sedation, memory loss/concentration difficulties, dizziness, gastro-intestinal problems, tremor, sexual dysfunction, polyuria/nocturia, insomnia and menstrual disturbance. Body weight of patients was measured by the investigator at each visit (without any standardised procedure) for calculation of mean weight change during the maintenance phase. 2.4. Definition of improvement, relapse, remission and recovery The following outcomes were defined from the 12-week post-baseline visit for the four periods of the maintenance phase (12 weeks–6 months, 6–12 months, 12–18 months, and 18–24 months). Improvement was defined as a decrease of at least 2 points in the CGI-BP overall score. Relapse was defined as any one of the following: an increase in the CGI-BP overall score from the previous visit, with an end rating of 4 or more at the event visit; inpatient admission for an acute episode of bipolar disorder; or psychiatrists' report of a relapse since previous assessment of the patient. Remission was defined as a CGI-BP overall score of 1 (normal) or 2 (borderline) at two consecutive

visits and no relapse or inpatient admission for an acute episode of bipolar disorder between the visits. Recovery was defined as achieving remission (as defined above) plus having adequate functioning, which was defined as having no/mild work impairment, living independently, and having four or more social activities in the past 4 weeks or being in a relationship.

2.5. Statistical analyses These post-hoc analyses were carried out on patients who were taking olanzapine monotherapy or olanzapine combination therapy at the 12 week post-baseline visit. The baseline characteristics of patients taking olanzapine and of those not taking olanzapine at 12 weeks as well as the baseline characteristics and 12-week post-baseline (start of the follow-up phase) characteristics of both treatment groups were summarized using descriptive statistics. Differences between the groups were compared using odds ratios (OR) for categorical data using the monotherapy group as the reference group and effect sizes for numerical variables, using the standard deviation of the monotherapy group as the reference. Kaplan–Meier survival curves were used to estimate the time to discontinuation of olanzapine treatment from 12 weeks post-baseline and the time to first occurrence of mania improvement, relapse, remission and recovery for the monotherapy and combination therapy groups. The Log-rank test was used to compare survival curves between groups. For the primary objective, Cox regression models were adjusted to analyse the effect of olanzapine monotherapy or combination therapy on the time to discontinuation of olanzapine treatment from 12 weeks post-baseline, and on the time to improvement, remission, relapse and recovery. Patients lost to follow-up were censored from the visit they were lost to followup. Covariates included in the final models were selected by a backwards reduction method using pb 0.05. The covariates initially entered into the model are: sex, age, country, education, patient status, type of episode, duration of mania, rapid cycling, presence of hallucinations/delusions during index episode, current abuse or dependence of alcohol/cannabis/other substance, relationship status, housing situation, number of social activities, work impairment, adherence to treatment, change in ratings on CGI-BP mania/depression/overall/CGI hallucinations/ delusions since baseline, number of manic or mixed episodes in the past 12 months, number of depressed episodes in the past 12 months, number of suicide attempts in the past 12 months, reason for new medication at baseline, use of anticholinergics/ benzodiazepines/other hypnotics/other concomitant medications, BMI, age at bipolar onset, age at first manic/depressed episode, number of hospital admissions, alcohol/cannabis/other substance use problem, satisfaction with life, number of dependents, clinical ratings on CGI-BP mania, depression, overall illness, overall illness in past 12 months, CGI hallucinations/ delusions, HAMD-5 and YMRS total score. A further analysis of Kaplan–Meier survival curves and Cox regression models was completed for all outcomes using identical methods as reported, except patients who switched medication during follow-up were censored at the time of switching medication. All data were analyzed using SAS version 9.1 (SAS Institute, Inc.: Cary, North Carolina).

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3. Results Of the 2416 patients eligible to participate in the 2-year follow-up period, 1076 (45%) were taking olanzapine, either as monotherapy or in a combination, at the end of the acute phase of treatment (12 weeks post-baseline). Compared to the patients not taking olanzapine (n = 1340), patients taking olanzapine reported hallucinations or delusions during the index episode more frequently (OR= 1.41 95%CI 1.18, 1.68), were less frequently living with a partner (OR =0.79 95%CI 0.67, 0.94), less dissatisfied with life (OR =0.70 95%CI 0.56, 0.87) and more compliant with medication (OR= 4.03 95%CI 1.50, 10.83). Patients taking olanzapine were less likely to experience a depressive (OR= 0.65 95%CI 0.49, 0.86) or mixed episode at 12 weeks (OR=0.58 95%CI 0.42, 0.80). They were also less frequently prescribed antidepressants (OR=0.78 95%CI 0.65, 0.95), anticholinergics (OR =0.58 95%CI 0.43, 0.78) and hypnotics (other than benzodiazepines) (OR= 0.78 95%CI 0.60, 0.97). Patients not taking olanzapine had lower frequency of 4 or more manic or mixed episodes at baseline (OR =0.42, 95%CI 0.22, 0.79). Patients taking olanzapine had lower depression and overall bipolar illness ratings as well as higher ratings on hallucination/delusion at 12 weeks (end of study acute phase). Of patients taking olanzapine, 29.1% (n = 313) were taking olanzapine as monotherapy and 70.9% (n = 763) were taking olanzapine in combination with other antipsychotics, anticonvulsants, and/or lithium. Of these 1076 patients, the majority (92%) had been prescribed olanzapine at the baseline visit, and all except 5 patients in combination group had taken olanzapine during the acute treatment phase. In addition, 84.6% (n = 253) of patients taking monotherapy had been prescribed monotherapy at baseline and 88.4% (n = 612) of combination-treated patients had been prescribed combination treatment at baseline. The mean (±SD) dose of olanzapine at 12 weeks postbaseline was significantly lower in the monotherapy group compared with the combination therapy group: 12.4 (±6.0) mg vs. 14.4 (±12.8) mg; p = 0.001. In the olanzapine combination group (n=763), the majority of patients (74.4%; n=568) took just two medications, 21.1% (n=161) took three medications, and 4.5% (n=34) took four or more medications. Olanzapine was most frequently combined with valproate (27.8%), lithium (20.3%) or other anticonvulsants (19.7%), and only a few patients took a typical antipsychotic (5.9%) or another atypical antipsychotic (0.7%) in combination with olanzapine. Use of concomitant benzodiazepines was similar in both groups (44.6% with combination treatment and 40.1% with monotherapy) but other hypnotics were used more frequently in the monotherapy group (19.4% vs. 11.0% in the combination treatment group, p=0.039). Anticholinergic use was more frequent in the olanzapine combination treatment group (13.6% vs. 7.7% in the monotherapy group, p=0.007). Of the 313 patients in the monotherapy group and 763 patients in the combination therapy group at 12 weeks postbaseline, 82 (26.2%) and 235 (30.8%), respectively, were lost to follow-up at 2 years. 3.1. Baseline patient characteristics The patient characteristics at the start of the study of the groups receiving olanzapine monotherapy or combination

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therapy at 12 weeks post-baseline are summarized in Tables 1 and 2. Combination treatments were used to a greater degree in patients who had a younger age at onset, experienced a higher number of manic or mixed episodes in the previous year, were inpatients at baseline, had a higher BMI, and a shorter duration of the acute episode at baseline. Monotherapy was used more in patients who experienced a mixed episode at baseline. A greater proportion of patients in the olanzapine monotherapy group had received no medication before the baseline visit. Patients receiving combination therapy had significantly fewer depressive symptoms at baseline as measured by HAMD-5. There were no differences in any of the other patient characteristics collected. 3.2. Characteristics at 12 weeks Table 3 summarizes the patient characteristics at 12 weeks post-baseline (at the end of the acute phase) that were significantly different between the two olanzapine treatment groups (monotherapy or combination therapy). Patients taking combination treatments were more likely to live in a dependent residence and to have some work impairment at 12 weeks. In addition, they more frequently used anticholinergic medications, and less frequently used non-benzodiazepine hypnotics at 12 weeks. In general, there were no differences in symptom severity or co-morbidities between patients in the two groups at 12 weeks. 4. Analysis 4.1. Intention to treat analysis 4.1.1. Kaplan–Meier analysis Kaplan–Meier analysis showed no significant difference in the survival curves of the time to discontinuation of olanzapine between the monotherapy and combination therapy groups (Log-rank test p = 0.133): 29.8% of monotherapy patients and 33.8% of combination therapy patients had discontinued olanzapine at 2 years (Fig. 1). There were some differences in long-term outcomes between patients taking olanzapine as monotherapy and those taking olanzapine in combination treatment. Fig. 2(A) shows that the survival curves of the time to remission were significantly different between the two groups (Log-rank test, p = 0.002): 77.0% of patients taking olanzapine monotherapy vs. 67.2% in the combination group were in remission at 2 years; the median time to remission was 281 days vs. 428 days for the monotherapy and combination therapy groups, respectively. The survival curves of the time to relapse (Fig. 2(B)) were also significantly different (Log-rank test, p = 0.027): 46.8% of patients taking combination therapy vs. 40.8% in the monotherapy group had relapsed at 2 years. An estimated 25% of patients will have relapsed by 276 days in the combination therapy group and by 316 days in the monotherapy group (median time to relapse could not be estimated because 50% relapse was not reached). There were no significant differences between the survival curves for olanzapine monotherapy and combination therapy groups for time to improvement (17.4% vs. 24.2% were improved at 2 years), and time to recovery (37.2% vs. 33.6% were recovered at 2 years).

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Table 1 Baseline characteristics (categorical) of patients prescribed olanzapine monotherapy and combination therapy at 12 weeks post-baseline (N = 1076). Characteristic

Monotherapy (N = 313)

Male, % 41.3 Number of manic/mixed episodes in previous 12 months, % a 1 61.0 2 24.4 3 5.8 4 or more 2.9 Number of depressive episodes in previous 12 months, % b 0 42.6 1 32.9 2 10.6 3 3.2 4 or more 1.3 Duration of mania at time of study enrolment, % b1 week 17.4 1–2 weeks 27.7 3–4 weeks 28.4 5–8 weeks 15.2 N8 weeks 11.3 Reason for new oral medication at baseline,% No previous medication 41.2 Lack of compliance 4.2 Ineffectiveness 40.6 Patient request 6.8 Intolerability 2.9 Other 4.2 Compliance, % Medication not prescribed 37.6 Almost always complies 40.8 Complies half the time 15.8 Almost never complies 5.8 Inpatient status, % 23.3 Mixed episode, % 27.5 Delusions/hallucinations, % 48.3 Rapid cycler, % 14.1 Current alcohol abuse/dependence, % 9.8 Current cannabis abuse/dependence, % 3.4 Current substance abuse/dependence, % 2.6 Relationship: living together, % 40.6 Housing conditions: independent residence, % 61.7 Some social activities, % 77.0 Some work impairment, % 89.1 Dissatisfaction with life, % 48.4 Antidepressant use % 19.5 Anticholinergic, % c 7.7 c Benzodiazepine, % 62.6 c Other hypnotics, % 21.6 Other concomitant medication, % c 4.5

Combination therapy (N = 763)

OR 95%CI

45.1

1.17 (0.89, 1.53) vs. female

54.1 29.7 7.9 4.8

1 1.38 (1.01, 1.88) vs. 1 1.52 (0.87, 2.65) vs. 1 1.85 (0.87, 3.92) vs. 1

46.7 32.5 10.2 3.3 1.3

1 0.90 0.87 0.93 0.93

(0.66, (0.55, (0.44, (0.29,

1.22) 1.37) 1.99) 3.02)

vs. vs. vs. vs.

0 0 0 0

19.6 35.7 24.9 12.9 6.9

1 1.15 0.78 0.76 0.55

(0.77, (0.52, (0.48, (0.32,

1.70) 1.17) 1.21) 0.93)

vs. vs. vs. vs.

b1 week 0 0 0

15.1 8.2 61.3 4.3 5.9 5.1

1 5.32 4.12 1.73 5.54 3.32

(2.78, (2.98, (0.94, (2.59, (1.68,

10.20) vs. no previous medication 5.68) vs. no previous medication 3.17) vs. no previous medication 11.86) vs. no previous medication 6.54) vs. no previous medication

11.8 57.0 23.3 7.9 36.2 21.3 54.8 17.2 9.5 2.8 2.2 40.3 53.3 79.7 89.7 37.5 17.0 13.6 65.3 16.3 7.9

1 4.45 4.72 4.38 1.87 0.72 1.30 1.26 0.97 0.83 0.85 0.99 0.71 1.18 1.07 0.67 0.85 1.88 1.13 0.71 1.81

(3.17, (3.10, (2.42, (1.38, (0.53, (0.99, (0.85, (0.62, (0.38, (0.36, (0.76, (0.54, (0.86, (0.69, (0.49, (0.61, (1.18, (0.85, (0.51, (0.99,

6.25) 7.19) 7.94) 2.52) 0.97) 1.71) 1.87) 1.53) 1.79) 1.99) 1.29) 0.93) 1.61) 1.66) 0.91) 1.19) 2.99) 1.48) 0.98) 3.29)

vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs.

medication not prescribed medication not prescribed medication not prescribed outpatient manic none none none none none not living together dependent residence no social activities no impairment satisfaction none none none none none

Country was also significant (p b 0.001). OR Odds Ratio, 95% CI 95% Confidence Interval. a The number of manic/mixed episodes in previous 12 months was unknown for 5.8% and 3.5% of the monotherapy and combination therapy groups, respectively. b The number of depressive episodes in previous 12 months was unknown for 9.4% and 6.1% of the monotherapy and combination therapy groups, respectively. c Prescribed at baseline visit.

4.1.2. Cox regression analysis Once differences in patient characteristics at baseline and 12-weeks post-baseline were included in the regression models, there were no significant differences in long-term outcomes between the olanzapine monotherapy and combination therapy groups (Table 4).

the survival curves between the monotherapy and combination therapy groups in time to discontinuation (p = 0.133), time to improvement (p = 0.202) and time to recovery (0.271), but the olanzapine combination therapy group had significantly faster time to remission (p = 0.003) and time to relapse (p = 0.013) than the monotherapy group.

4.2. Observational method

4.2.2. Cox regression analysis The only difference from the ITT analysis was that the combination therapy became significantly associated with higher rates of relapse than the monotherapy group at the p b 0.05 level of significance (Table 4).

4.2.1. Kaplan–Meier analysis This analysis showed a similar pattern of results to the intent to treat analysis. There was no significant difference in

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Table 2 Baseline characteristics (numerical) of patients prescribed olanzapine monotherapy and combination therapy at 12 weeks post-baseline (N = 1076). Characteristic

Monotherapy (N = 313)

Combination therapy (N = 763)

Effect size

Mean age, years (SD) Mean BMI, kg/m2 (SD) Mean age at first bipolar symptoms, years (SD) Mean age at first manic/mixed episode, years (SD) Mean number of bipolar disorder related admissions (SD) CGI-BP overall, mean (SD) YMRS total score, mean (SD) HAMD-5 total score, mean (SD)

44.9 25.4 31.6 32.8 0.8 4.63 26.44 3.65

44.5 26.4 28.9 30.2 0.9 4.72 27.24 2.88

0.035 − 0.199 0.262 0.235 − 0.036 − 0.086 − 0.083 0.270

(13.9) (4.3) (11.3) (12.2) (3.8) (1.06) (8.58) (3.38)

(12.5) (5.1) (10.0) (10.5) (1.8) (1.08) (10.08) (2.60)

Table 3 Patient characteristics at 12 weeks that were significantly different between patients prescribed olanzapine monotherapy and combination therapy at 12 weeks post-baseline (N = 1076). Characteristic

Monotherapy (N = 313)

Combination therapy (N = 763)

OR (95% CI)

Housing conditions: independent residence, % Some work impairment, % Anticholinergics, % a Other hypnotics, % a

63.0 70.1 3.3 19.4

52.6 80.4 9.3 11.0

0.65 1.75 3.00 0.51

(0.50, (1.28, (1.52, (0.36,

0.86) 2.40) 5.91) 0.74)

vs. vs. vs. vs.

dependent residence no impairment none none

Also significant were country, mean age at first bipolar symptoms, mean age at first manic/mixed episode, number of manic/mixed episodes in previous 12 months, current duration of mania, and reason for new oral medication [data same as at baseline; see Table 1]. a Prescribed at 12-week visit.

4.3. Study completers There was no significant difference in the number of patients lost to follow-up between monotherapy and combination therapy groups. Of those patients who completed the study, 52.7% remained on olanzapine as monotherapy and 47.7% remained on olanzapine as combination therapy during the follow-up period. 4.4. Treatment-emergent adverse events At the end of the study, significantly more patients taking combination therapy had tremor (14.2% vs. 8.4%) and sexual dysfunction (19.2% vs. 13%). Table 5 shows that during the

maintenance phase (from 12 weeks post-baseline to 2 years), more patients in the combination therapy group had any akathisia episode (16% vs. 10.3%), gastro-intestinal problems (19.3% vs. 13.5%), tremor (28.3% vs. 16%), any sexual dysfunction (32.4% vs. 25.7%), and polyuria/nocturia (16.3% vs. 8.3%). No adverse event occurred significantly more often in the monotherapy group. During the maintenance phase of the study (from 12 weeks post-baseline to 2 years), there was a greater mean change in weight in the olanzapine monotherapy group (mean change 1.4 kg, SD 5.5) compared with the combination therapy group (mean change 0.4 kg, SD 7.4; p = 0.024). In addition, significantly more patients taking olanzapine monotherapy had ≥7% weight gain (54.8% vs. 19.4% in the combination treatment group; p b 0.001).

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5. Discussion

% No discontinuation

90 80 70 60 50 40 30 20 10 0 0

50 100 150 200 250 300 350 400 450 500 550 600 650

Days Since 12 weeks Olanzapine at 12 weeks (T6)

Monotherapy

Combination

Fig. 1. Kaplan–Meier survival analysis (ITT) of time to discontinuation of olanzapine from week 12 post-baseline in patients treated with olanzapine as monotherapy or in combination therapy.

These results from the EMBLEM study show that olanzapine is prescribed in monotherapy or combination therapy in response to clinical need. Although more than twice as many patients receiving olanzapine for the long-term treatment of bipolar disorder following an acute manic or mixed episode took olanzapine in combination with other anti-manic medications, olanzapine monotherapy was as effective as combination therapy after adjusting for differences in patient characteristics between the two groups. These findings over 2 years of follow-up tend to support the results of the 12week acute phase (Vieta et al, 2008) and imply that physician prescribing of olanzapine (monotherapy or combination therapy) for maintenance treatment is predominantly driven by patient characteristics at the index episode and at the end of the acute treatment phase.

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A

Table 4 Hazard ratios of improvement, relapse, remission and recovery over 2 years in patients treated with olanzapine combination therapy vs. olanzapine monotherapy (Cox regression analysis) using (A) ITT analysis and (B) switching medication analysis methods.

100

% No remission

90 80 70 60

A

Hazard ratio

95% CI

P value

50

Improvement Remission Recovery Relapse

1.21 0.92 1.16 1.27

0.76, 1.94 0.77, 1.10 0.87, 1.53 1.00,1.62

0.421 0.350 0.309 0.054

B

Hazard ratio

95% CI

P value

Improvement Remission Recovery Relapse

1.57 0.97 1.25 1.47

0.87, 2.84 0.80, 1.18 0.92, 1.69 1.10,1.97

0.138 0.771 0.154 0.010 a

40 30 20 10 0 0

50 100 150 200 250 300 350 400 450 500 550 600 650 700

Days Since 12 weeks Olanzapine at 12 weeks (T6)

Monotherapy

Combination

B 100

Hazard ratios N1 indicates olanzapine combination therapy has higher rates than monotherapy and b 1 indicates that olanzapine combination therapy has lower rates than monotherapy. a Significant at p b 0.05.

90

% No relapse

80 70 60 50 40 30 20 10 0 0

50 100 150 200 250 300 350 400 450 500 550 600 650 700

Days Since 12 weeks Olanzapine at 12 weeks (T6)

Monotherapy

Combination

Fig. 2. Kaplan–Meier survival analysis (ITT) of time to remission* (A) and time to relapse** (B) from 12 weeks post-baseline in patients treated with olanzapine as monotherapy or in combination therapy. * Remission defined as a CGI-BP overall score 1 (normal) or 2 (borderline) at two consecutive visits and no relapse or inpatient admission for an acute episode of bipolar disorder between the visits. ** Relapse defined as any one of the following: increasing the CGI-BP overall score from the previous visit, with an end rating of 4 or more; inpatient admission for an acute episode of bipolar disorder; or psychiatrists' report of a relapse since previous assessment of the patient.

The hazard ratios for improvement, remission and recovery were not significantly different between the combination therapy and monotherapy groups, and the hazard ratio for relapse approached statistical significance when using ITT analysis but did reach statistical significance using the observational analysis method. This marginal difference identified between the two analysis techniques around the 5% level of significance for relapse rates indicates no clear superiority of either olanzapine treatment approach and should be interpreted conservatively. Regarding tolerability, there was a significantly higher incidence of sexual dysfunction, tremor, gastro-intestinal problems, polyuria/nocturia and akathisia in patients treated with combination therapy but there was significantly greater weight gain in patients treated with monotherapy. The mania severity (YMRS) and overall severity of symptoms (CGI-BP overall) did not differ between the monotherapy and combination therapy groups at baseline or at 12 weeks

post-baseline and, therefore, may not be a major factor in physician choice of monotherapy or combination therapy for long-term treatment. The severity of depressive symptoms may play a role as the monotherapy group had a significantly higher mean HAMD-5 total score at baseline and at 12 weeks postbaseline, compared with the combination therapy group. However, the difference in HAMD-5 scores was small and may not be clinically significant. Taken together, these findings indicate that patients with a longer duration of disease, more severe illness, and poorer functioning after the acute phase of mania are likely to be treated with combination therapy in the maintenance phase. An important finding was that the majority (88%) of patients taking combination therapy during the maintenance phase had been prescribed combination therapy at baseline. The same was true for monotherapy. This suggests that for maintenance treatment of bipolar disorder in routine clinical practice, physicians tend to continue to prescribe the same Table 5 Tolerability: patients (%) with bipolar disorder treatment-emergent adverse events present at any time between 12 weeks post-baseline and 2 years. Monotherapy Combination OR (95% CI) vs. not present (N = 313) therapy (N = 763) Sedation Memory loss/ concentration difficulties Sexual dysfunction Tremor Dizziness Insomnia Gastro-intestinal problems Polyuria/nocturia Akathisia Parkinsonism Menstrual disturbance Dystonia Tardive dyskinesia

49.4 46.5

47.2 48.5

0.93 (0.70, 1.24) 1.15 (0.86, 1.54)

25.7 16.0 23.7 21.8 13.5

32.4 28.3 20.5 23.6 19.3

1.52 2.37 0.55 1.50 1.40

(1.06, (1.44, (0.35, (0.96, (0.82,

2.18) 3.89) 0.84) 2.36) 2.42)

8.3 10.3 10.6 8.5 5.1 3.5

16.3 16.0 13.2 9.9 7.8 4.9

3.08 2.54 1.25 0.83 2.35 1.93

(1.45, (1.36, (0.69, (0.46, (0.90, (0.55,

6.54) 4.76) 2.27) 1.49) 6.15) 6.78)

Total n varies for each variable due to missing data. The percentages given for each variable refer to the total n available for the respective variable.

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medications used in the acute phase, especially if they have been effective (as shown for this study by Vieta et al., 2008). In a US pharmacy and medical claims database, monotherapy was used by 67% of patients and combination therapy by 33% of patients initiating therapy (including antidepressants) for bipolar disorder (Baldessarini et al., 2008). However, unlike the present study (which included only patients with acute manic/mixed mania), almost one-third of the patients studied by Baldessarini and colleagues were in a depressive state at baseline. The most commonly prescribed drugs were antidepressants (71% of patients including 44% of those taking monotherapy, despite their use being not recommended for treatment in a manic or mixed episode which represented over 50% of the patient sample clinical state), followed by anticonvulsants (28%) and antipsychotics (23%); olanzapine was the antipsychotic most frequently prescribed as monotherapy and in combination therapy for these patients (Baldessarini et al., 2008). At 12 months follow-up, only 31% of patients were on monotherapy, 32% on combination therapy and 37% on no psychotropic medication. It is difficult to compare the findings of the present study with those of Baldessarini et al. (2008) because of the differences in study populations and inclusion of antidepressants in the combination therapy category. In a cross-sectional analysis of the large naturalistic STEP-BD study population, Ghaemi et al. (2006) reported that 14% of the first 500 bipolar patients enrolled were prescribed olanzapine at the initial presentation. Notably, 72% of patients were prescribed a combination of lithium and anticonvulsants at baseline, and 41% were given antidepressants. Combination therapy was also used more frequently than monotherapy (57% vs. 38%) in a naturalistic study of the pharmacological treatment of older adult patients (over 65 years) with acute episodes of bipolar disorder (Beyer et al., 2008). These latter two studies suggest that combination therapy is the norm rather than the exception in bipolar disorder (Vieta and Rosa, 2007). Recent reviews have concluded that combination therapy with olanzapine is effective in acute bipolar mania and can provide additional clinical benefits over monotherapy (Lin et al., 2006; Smith et al., 2007). Combination therapy, however, may be less well-tolerated than monotherapy, depending on the combination of drugs used, and safety profiles must be taken into account when selecting medications. Possible combinations of agents for the long-term management of bipolar disorder specifically mentioned in the UK guidelines (NICE, 2006) are lithium in combination with olanzapine or valproate, and olanzapine in combination with valproate. However, the further study of combination therapy for maintenance treatment is needed. Tohen et al. (2002) conducted a 6-week, randomized, placebo-controlled study of olanzapine in combination with valproate or lithium in North America. Patients (n= 99) who achieved remission from the index manic or mixed episode at the end of the 6-week acute phase entered an 18-month relapse prevention phase during which they were randomized to treatment with olanzapine plus valproate/lithium vs. placebo plus valproate/lithium; 64% of patients took valproate (Tohen et al., 2004). Long-term use of olanzapine in combination with lithium/valproate prolonged the time to symptomatic relapse, but not syndromic relapse. Monotherapy with lithium or valproate and combination therapy with olanzapine were well tolerated, but the combination therapy group experienced significantly more weight gain and less insomnia than the

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monotherapy group during the 18-month study (Tohen et al., 2004). However, the patient sample was somewhat different from the EMBLEM study sample in that about half of the patients in the randomised controlled trial had a mixed index episode and a high proportion (about 40%) had a rapid cycling course, which may reflect the inclusion criteria requirement of an incomplete response to 2-week's treatment with lithium or valproate. Moreover, patients with serious and unstable medical illness, substance dependence or serious suicide risk were excluded from the study. Thus, the results should not be generalised to all bipolar patients. Moreover, the evidence supporting the use of olanzapine in combination with other mood-stabilizers, such as carbamazepine or lamotrigine, is limited (Tohen et al., 2008). Olanzapine has demonstrated efficacy both as monotherapy and in combination therapy for the treatment of bipolar disorder (reviewed in Soares-Weiser et al., 2007). Some studies suggest that olanzapine may be effective as maintenance therapy for the prevention of relapse in bipolar disorder, especially manic relapse (Soares-Weiser et al., 2007). During a 48-week maintenance phase in bipolar I patients who responded to acute treatment with olanzapine for an acute manic/mixed episode, Tohen et al. (2006) reported a relapse rate of 46.7% in the olanzapine monotherapy group compared with 80.1% in the placebo group. However, there was no significant difference in the relapse rate (syndromic) between patients taking olanzapine plus valproate or lithium (29%) vs. valproate or lithium monotherapy (31%) in the 18-month relapse prevention study reported by Tohen et al. (2004). In our study, the relapse rates were b50% in both the olanzapine monotherapy and combination therapy groups over 2 years. ITT analysis can be used in observational data to mimic techniques used in clinical trials. However, observational studies allow patients to follow clinical practice, which means that patients can change medication at any time in response to symptoms, tolerability, adherence and choice. Therefore, we have been able to utilise analysis methods to assess these outcomes allowing for switching medication. During long-term treatment of bipolar disorder, the tolerability of medications is an important factor that can impact on medication compliance/adherence (Baldessarini et al., 2008). There may be an increased risk of adverse events and drug interactions during combination therapy. In general, the use of multiple antipsychotic medications for the treatment of severe mental disorders is associated with more adverse events than antipsychotic monotherapy without little, if any, difference in clinical benefits (Centorrino et al., 2004). Greater weight gain in patients treated with monotherapy is more likely because they were antipsychotic naïve, as the baseline results of the current analyses show that monotherapy patients were also those more likely to have no previous medication. Observational studies can provide useful information about patient-reported tolerability. The most common treatmentemergent adverse events were sedation, memory loss/concentration difficulties and sexual dysfunction. Patients treated with combination therapy experienced a significantly higher incidence of akathisia and tremor. The increased incidence of akathisia and tremor may be related to the use of conventional antipsychotics in combination with olanzapine. Patients treated with olanzapine (both as monotherapy and in combination therapy) experienced weight gain during the maintenance

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phase as has been previously reported (Torrent et al, 2008), which was significantly greater in the monotherapy group, and was additional to the weight gain that occurred during the 12week acute treatment phase (Vieta et al., 2008). Although, the mean dose of olanzapine was significantly higher in the combination group compared with the monotherapy group, the actual difference in dosage was small. Moreover, the olanzapine dose was consistent with that used in controlled studies and with the recommended therapeutic dose. This study has several limitations. Firstly, the large number of patients prescribed olanzapine was driven by the study design, which required that about half of the patients should be included after starting on olanzapine, although this provides sufficient numbers to allow for this post-hoc comparison with olanzapine monotherapy and olanzapine combination treatment. Patients were not required to remain on the medication initiated and could be prescribed different medications at any time at the discretion of the treating psychiatrists. Secondly, although all available characteristics have been included in the multivariate analysis, there remains the potential for unknown variables to exist which may confound the outcomes. As investigators made the decision to invite patients to enrol in the study, there is the potential for participation bias, such that these patients may not be representative of the population of bipolar patients treated in routine practice. Selection bias may manifest if patients in either the monotherapy or combination therapy differ in some unknown characteristic resulting in different treatment outcomes. This is a particular issue when assessing comparative effectiveness. Due to the potential biases of the observational study design described, the results should be interpreted conservatively. Thirdly, our classification of patients taking olanzapine monotherapy and combination therapy was based on the medication they were taking at the end of the 12-week acute phase of treatment, and patients could have changed treatment at any time during the 2-year follow-up. Finally, the definitions of remission, recovery and relapse were not the same as in previous studies, which limit any comparisons between studies. Thus, the results presented in this paper should be interpreted conservatively. In conclusion, this study has increased our understanding of the use of olanzapine in European patients with bipolar disorder, and confirms that olanzapine is effective and well-tolerated when administered as monotherapy or in combination with other antipsychotics, anticonvulsants and/or lithium in the longterm management of patients with acute/mixed mania in the naturalistic setting. Certain patient characteristics at the index episode and at the end of the acute treatment phase appear to influence the choice of whether olanzapine is prescribed as monotherapy or combination therapy for maintenance treatment. Olanzapine monotherapy was at least as effective as combination therapy using ITT analysis. Relapse rates were higher in patients treated with combination therapy compared to monotherapy when using techniques to allow for switching medication, demonstrating how results can be dependent on statistical methods utilised. With monotherapy, there was a significantly lower incidence of sexual dysfunction, tremor, gastro-intestinal problems, polyuria/nocturia and akathisia but significantly greater weight gain. These findings may have implications for clinical practice, as they confirm the usefulness

of maintenance treatment with olanzapine during at least two years of follow-up, both in monotherapy and combination therapy and indicate that physicians select the appropriate olanzapine treatment (either as monotherapy or in combination) depending on the patient characteristics. It also adds data about the doses prescribed in clinical practice, which approximate doses used in clinical trials. Role of funding source The EMBLEM study was funded by Eli Lilly and Company Limited, Windlesham, Surrey, UK. Conflict of interest Ana González-Pinto has received grant support, acted as consultant, or given presentations for the following pharmaceutical companies: Almirall (Barcelona, Spain), Astra-Zeneca, Bristol-Myers-Squibb, Otsuka, Eli Lilly, GlaxoSmith-Kline, Janssen-Cilag, Sanofi-Aventis, Lundbeck, Novartis, Organon, Schering-Plough, Spanish Ministry of Science and Innovation, Department of Health of the Basque Government, University of the Basque Country and Pfizer. Eduard Vieta received honoraria as member of the EMBLEM Advisory Board from Eli Lilly and Co, and has also received grants unrelated to this study, acted as consultant, or served on advisory boards for the following entities: Astra-Zeneca, Bristol-Myers-Squibb, Eli Lilly, Forest Research Institute, Glaxo-Smith-Kline, Janssen-Cilag, Jazz, Merck-Sharpe & Dohme, Novartis, Organon, Otsuka, Pfizer, Sanofi, Servier, Seventh European Framework Programme (ENBREC), Shering-Plough, Spanish Ministry of Science and Innovation, United Biosource Corporation, and Wyeth. Catherine Reed, Diego Novick and Alessandra Barraco are employees of Eli Lilly and Company Ltd. Josep Maria Haro has received economic compensation for his participation in the EMBLEM Advisory Board. He has also acted as a consultant or participated in advisory boards for the following entities: GlaxoSmithKline, Astra-Zeneca, and Lundbeck.

Acknowledgements The authors would like to thank all the EMBLEM Advisory Board for their participation in the design and conduct of the study. We also thank Deirdre Elmhirst for writing and editorial assistance with the manuscript. References American Psychiatric Association, 2002. Practice guideline for the treatment of patients with bipolar disorder revision. Am. J. Psychiatry 159 (4 Suppl), 1–50. Baldessarini, R., Henk, H., Sklar, A., Chang, J., Leahy, L., 2008. Psychotropic medications for patients with bipolar disorder in the United States: polytherapy and adherence. Psychiatr. Serv. 59, 1175–1183. Beyer, J.L., Burchitt, B., Gersing, K., Krishnan, K.R., 2008. Patterns of pharmacotherapy and treatment response in elderly adults with bipolar disorder. Psychopharmacol. Bull. 41, 102–114. Centorrino, F., Goren, J.L., Hennen, J., Salvatore, P., Kelleher, J.P., Baldessarini, R.J., 2004. Multiple versus single antipsychotic agents for hospitalized psychiatric patients: case-control study of risks versus benefits. Am. J. Psychiatry 161, 700–706. Cruz, N., Vieta, E., Comes, M., Haro, J.M., Reed, C., Bertsch, J., the EMBLEM Advisory Board, 2008. Rapid-cycling bipolar I disorder: course and treatment outcome of a large sample across Europe. J. Psychiatr. Res. 42, 1068–1075. Fountoulakis, K.N., Vieta, E., Siamouli, M., Valenti, M., Magiria, S., Oral, T., Fresno, D., Giannakopoulos, P., Kaprinis, G.S., 2007. Treatment of bipolar disorder: a complex treatment for a multi-faceted disorder. Ann. Gen. Psychiatry 6, 27. Ghaemi, S.N., Hsu, D.J., Thase, M.E., Wisniewski, S.R., Nierenberg, A.A., Miyahara, S., Sachs, G., 2006. Pharmacological treatment patterns at study entry for the first 500 STEP-BD participants. Psychiatr. Serv. 57, 660–665. Goetz, I., Tohen, M., Reed, C., Lorenzo, M., Vieta, E., EMBLEM Advisory Board, 2007. Functional impairment in patients with mania: baseline results of the EMBLEM study. Bipolar Disord. 9, 45–52.

A. Gonzalez-Pinto et al. / Journal of Affective Disorders 131 (2011) 320–329 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. Gonzalez-Pinto, A., Mosquera, F., Reed, C., Novick, D., Barbeito, S., Vega, P., Bertsch, J., Alberich, S., Haro, J.M., 2009. Validity and reliability of the Hamilton Depression Rating Scale (5 items) for manic and mixed bipolar disorders. J. Nerv. Ment. Dis. 197, 682–686. Grunze, H., Kasper, S., Goodwin, G., Baldwin, D., Licht, R.E., Vieta, E., Moller, H.-J., WFSBP Task Force on Treatment Guidelines for Bipolar Disorders, 2003. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders, Part II: Treatment of mania. World J. Biol. Psychiatry 4, 5–13. Haro, J.M., Van Os, J., Vieta, E., Reed, C., Lorenzo, M., Goetz, I., EMBLEM Advisory Board, 2006. Evidence for three distinct classes of ‘typical’, ‘psychotic’ and ‘dual’ mania: results from the EMBLEM study. Acta Psychiatr. Scand. 113, 112–120. Lim, P.Z., Tunis, S.L., Edell, W.S., Jensik, S.E., Tohen, M., 2001. Medication prescribing patterns for patients with bipolar I disorder in hospital settings: adherence to published practice guidelines. Bipolar Disord. 3, 165–173. Lin, D., Mok, H., Yatham, L.N., 2006. Polytherapy in bipolar disorder. CNS Drugs 20, 29–42. National Institute of Health Clinical Excellence (NICE), 2006. Bipolar disorder. The management of bipolar disorder in adults, children and adolescents, in primary and secondary care. . National Clinical Practice Guideline number 38. Available at: www.nice.org.uk/CG038. Smith, L.A., Cornelius, V., Warnock, A., Tacchi, M.J., Taylor, D., 2007. Acute bipolar mania: a systematic review and meta-analysis of co-therapy vs. monotherapy. Acta Psychiatr. Scand. 115, 12–20. Soares-Weiser, K., Bravo Vergel, Y., Beynon, S., Dunn, G., Barbieri, M., Duffy, S., Geddes, J., Gilbody, S., Palmer, S., Woolacott, N., 2007. A systematic review and economic model of the clinical effectiveness and costeffectiveness of interventions for preventing relapse in people with bipolar disorder. Health Technol. Assess. 11 (39), 1–226. SPC (Summary of Product Characteristics) for Zyprexa (olanzapine) downloaded from Electronics Medicines Compendium http://www.medicines. org.uk/emc/medicine/7284 (last updated 19/01/2010).

329

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., Chengappa, K.N.R., 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., 2002. 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., Chengappa, K.N.R., 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 moor stabilizer v. mood stabiliser alone. Br. J. Psychiatry 184, 337–345. Tohen, M., Calabrese, J.R., Sachs, G.S., Banov, M.D., Detke, H.C., Risser, R., Baker, R.W., Chou, J.C.-Y., Bowden, C.L., 2006. Randomized, placebocontrolled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am. J. Psychiatry 163, 247–256. Tohen, M., Bowden, C.L., Smulevich, A.B., Bergstrom, R., Quinlan, T., Osuntokun, O., Wang, W.V., Oliff, H.S., Martenyi, F., Kryzhanovskaya, L.A., Greil, W., 2008. Olanzapine plus carbamazepine vs. carbamazepine alone in treating manic episodes. Br. J. Psychiatry 192, 135–143. Torrent, C., Amann, B., Sánchez-Moreno, J., Colom, F., Reinares, M., Comes, M., Rosa, A.R., Scott, J., Vieta, E., 2008. Weight gain in bipolar disorder: pharmacological treatment as a contributing factor. Acta Psychiatr. Scand. 118, 4–18. Vieta, E., Rosa, A.R., 2007. Evolving trends in the long-term treatment of bipolar disorder. World J. Biol. Psychiatry 8, 4–11. Vieta, E., Panicali, F., Goetz, I., Reed, C., Comes, M., Tohen, M., EMBLEM Advisory Board, 2008. 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. J. Affect. Disord. 106, 63–72. 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.