| | Olanzapine versus lithium in the acute treatment of bipolar mania: A double-blind, randomized, controlled trial☆Received 7 December 2006; received in revised form 15 April 2007; accepted 24 April 2007. Abstract BackgroundThis multicenter, double-blind, randomized, controlled study conducted in China examined the efficacy and safety of olanzapine versus lithium in the treatment of patients with bipolar manic/mixed episodes. LimitationsNo placebo arm was included; however both treatments have previously been reported to be more effective than placebo. ConclusionsThese results suggest that olanzapine has superior efficacy to lithium in the acute treatment of patients with bipolar mania over a 4-week period. However, adverse events were experienced by a greater number of olanzapine patients than lithium patients. 1. Introduction  Treatment guidelines, while often varied, commonly emphasize the use of lithium, valproate (divalproex), and atypical antipsychotics in the treatment of bipolar mania (Fountoulakis et al., 2005). Olanzapine is an atypical antipsychotic with proven efficacy in the treatment of bipolar mania in the acute and maintenance settings (Tohen et al., 1999, Tohen et al., 2000, Tohen et al., 2006). To our knowledge, only one study has directly compared olanzapine and lithium in the acute treatment of bipolar mania (Berk et al., 1999). Unfortunately, the small sample size (n =30) limited the interpretation of the study results. Olanzapine and lithium have also been compared as maintenance therapy in bipolar disorder patients that were acutely stabilized with concomitant olanzapine and lithium therapy (Tohen et al., 2005). In the present study, conducted in China, the efficacy and safety of olanzapine were compared to lithium in the treatment of patients with bipolar disorder, manic or mixed episodes, with or without psychotic features, as measured by mean change on the CGI Bipolar Version — Overall Severity of Illness scale (CGI-BP; Spearing et al., 1997) over a 4-week period. Secondary objectives included a further comparison of the efficacy of olanzapine and lithium, utilizing the Young Mania Rating Scale (YMRS; Young et al., 1978), Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1988), and the Montgomery–Åsberg Depression Rating Scale (MADRS; Montgomery and Åsberg, 1979). 2. Methods 2.1. Patients Inpatients and outpatients aged ≥18 years were recruited at seven sites in China. Patients met the DSM-IV criteria (APA, 1994) for an index manic or mixed episode of bipolar disorder (with or without psychotic features), based on a clinical assessment. Patients were required to have a YMRS total score≥20 at screening (Visit 1), and prior to the start of active treatment (Visit 2). This study was reviewed and approved by the institutional review board at each site, and was conducted in accordance with the International Conference on Harmonisation (ICH) good clinical practice guidelines. Written informed consent was obtained from all participants. 2.2. Study design Patients who met all enrollment criteria after a 2–7 day screening period were randomized in a 1:1 ratio to double-blind treatment with either oral olanzapine (5–20 mg/day, starting dose 15 mg/day; n=69) or lithium carbonate (600–1800 mg/day in a divided dose, starting dose 300–600 mg/day; n=71) over a 4-week period. After 1 day on therapy, the olanzapine starting dose could be adjusted within the allowed dose range of 5–20 mg/day, based on clinical response (i.e., adverse effects and efficacy). By Day 3, all lithium patients were required to be at a minimum dose of 600 mg/day after which the daily dose could be adjusted, as clinically indicated, within the allowed dose range of 600–1800 mg/day. Lithium dosing was based on clinical response as well as lithium blood level. Those patients who could not tolerate olanzapine 5 mg/day or lithium carbonate 600 mg/day after Day 3 of the double-blind treatment phase were discontinued from the study. In order to maintain double-blinding of non-identical medications, patients also received placebo tablets similar in appearance to the treatment they had not been randomized to receive (double-dummy treatment). To further maintain the double-blind nature of the study, all patients had serum specimens collected to test for lithium blood levels throughout the study, regardless of which treatment they were randomized to. An independent laboratory performed lithium blood level monitoring only for those patients randomized to receive lithium, although all patients received a laboratory report. Lithium blood levels were reported as “well below target” (below 0.60 mEq/L), “below target” (0.61–0.80 mEq/L), “within target” (0.81–1.20 mEq/L), “above target” (1.21–1.40 mEq/L), or “well above target” (1.41–2.0 mEq/L), and corresponding recommendations were made to increase, decrease, or leave unchanged the daily “lithium” dose (regardless of whether the patient was actually receiving active lithium treatment). Olanzapine patients were randomly assigned to the various report categories. Concomitant medications with primarily central nervous system activity were excluded; however, the use of lorazepam (or lorazepam equivalent) up to 2 mg/day was permitted to alleviate manic agitation, but not within 8 h of a psychiatric evaluation. Benzhexol hydrochloride (or equivalent) was permitted up to 6 mg/day to alleviate extrapyramidal symptoms. 2.3. Efficacy and safety assessments The primary efficacy assessment was the mean change from baseline to endpoint in the CGI-BP (Overall Severity) total score. Secondary efficacy assessments included the mean change from baseline to endpoint in the CGI-BP (Severity of Mania), CGI-BP (Severity of Depression), YMRS, BPRS, and MADRS total scores. For all efficacy scales, validated Chinese translations were used (Zhang et al., 1993). Rates of clinical response (defined as a ≥50% decrease from baseline in YMRS total score) and remission (defined as YMRS total score of ≤12 at endpoint) were also assessed. Safety was assessed by treatment-emergent adverse events (TEAEs; coded using MedDRA, version 8.0), change in vital signs, laboratory analytes, and electrocardiograms (ECGs). The Simpson Angus Scale (SAS; Simpson and Angus, 1970) was used to assess the change in severity of extrapyramidal symptoms from baseline to endpoint. The screening assessment included a medical history, psychiatric and physical examinations, a hepatitis screen, and an ECG. Weight measurements and laboratory testing were conducted at screening and again at endpoint. Vital signs, adverse events, and concomitant medications were collected at all visits. Patients were assessed on the CGI-BP and YMRS at randomization, and at Days 3, 7, 14, 21 and 28. Patients were assessed on the BPRS and MADRS at randomization, and at all subsequent visits except Day 3. SAS total scores were obtained at randomization and endpoint. 2.4. Statistical methods The study was powered at 80% to detect a mean difference of 0.54 (Berk et al., 1999) in the primary efficacy measure, change on the CGI-BP (Overall Severity) scale after 4 weeks of treatment, using a common standard deviation of 1.0, α=0.05, and a two-sided t-test. From this, it was suggested that 110 patients would be needed. A total of 140 patients were planned to be randomized to achieve this sample size. Patient data was analyzed on an intent-to-treat (ITT) basis, including all randomized patients with at least one dose of study drug, with endpoint defined as the last post-baseline observation carried forward (LOCF). Comparisons of treatment groups at endpoint were performed using analysis of covariance (ANCOVA) with term for baseline score, logistic regression (reported as odds ratio, OR), Cox proportional hazard model, Fisher's exact or Cochran Mantel Haenszel tests, as appropriate, and included a term for investigator (except for the Fisher’s exact test). Analyses of change over time were conducted using mixed effects models with investigator, visit, treatment group, visit-by-treatment interaction, and baseline score as fixed effects and within-patient errors modelled using an unstructured covariance structure. Statistical analyses were conducted using SAS software version 8.2 (SAS Institute, Cary, N.C., USA; site license 0002027016), and used a two-sided significant level of 0.05. 3. Results 3.1. Patient characteristics Of the 155 patients who entered screening, 140 patients were enrolled and participated in this study between December 2003 and June 2005. Table 1 summarizes the demographic and clinical characteristics, and baseline disease severity of these patients. All patients were diagnosed as experiencing a manic episode at baseline. On average, patients were moderately to markedly ill at baseline, as measured by the mean (±SD) CGI-BP (Overall Severity), YMRS, BPRS, and CGI-BP (Severity of Mania) scores across the two treatment groups (Table 1). Mean scores on the MADRS and CGI-BP (Severity of Depression) indicated that most patients were not experiencing symptoms of depression at baseline. 3.4. Efficacy measures Patients in both treatment groups had a statistically significant mean improvement in disease symptoms over the 4-week study period, as shown by mean change from baseline to endpoint in total scores for all scales except the CGI-BP (Severity of Depression) (Table 4). The mean change was significantly greater for the olanzapine treatment group than the lithium group in CGI-BP (Overall Severity) score (mean difference: −0.61, P=0.009), YMRS total score (−4.48, P=0.013), BPRS total score (−2.12, P=0.032), and CGI-BP (Severity of Mania) score (−0.58, P=0.012). No significant differences were observed between the two treatment groups in mean change of MADRS or CGI-BP (Severity of Depression) scores. | | |  | Rating scale | Mean change (endpoint–baseline)a | Mean difference (olz–lith) | |
|---|
| Olz (N=69) | Lith (N=71) | |
|---|
| CGI-BP (Overall) | | | Estimate (SE) | −2.83 (0.17) | −2.22 (0.17) | −0.61 (0.23) | | | (95% CI) | (−3.18 to −2.48) | (−2.57 to −1.88) | (−1.06 to −0.15) | | | P-value | <0.001 | <0.001 | 0.009 | | | YMRS | | | | | | Estimate (SE) | −24.63 (1.36) | −20.15 (1.35) | −4.48 (1.78) | | | (95% CI) | (−27.32 to −21.95) | (−22.82 to −17.48) | (−8.01 to −0.96) | | | P-value | <0.001 | <0.001 | 0.013 | | | BPRS | | | | | | Estimate (SE) | −11.16 (0.75) | −9.04 (0.75) | −2.12 (0.98) | | | (95% CI) | (−12.65 to −9.67) | (−10.51 to −7.56) | (−4.06 to −0.18) | | | P-value | <0.001 | <0.001 | 0.032 | | | CGI-BP (Mania) | | | | | | Estimate (SE) | −2.91 (0.17) | −2.33 (0.17) | −0.58 (0.23) | | | (95% CI) | (−3.25 to −2.56) | (−2.67 to −1.99) | (−1.03 to −0.13) | | | P-value | <0.001 | <0.001 | 0.012 | | | CGI-BP (Depression) | | | Estimate (SE) | 0.09 (0.07) | 0.12 (0.07) | −0.03 (0.09) | | | (95% CI) | (−0.04 to 0.22) | (−0.01 to 0.25) | (−0.20 to 0.15) | | | P-value | 0.171 | 0.077 | 0.767 | | | MADRS | | | | | | Estimate (SE) | −3.26 (0.45) | −2.51 (0.45) | −0.75 (0.59) | | | (95% CI) | (−4.16 to −2.37) | (−3.40 to −1.63) | (−1.92 to 0.42) | | | P-value | <0.001 | <0.001 | 0.205 | | | | |
The mixed effects model of mean change over time demonstrated no statistically significant treatment by time (visit) interaction [CGI-BP (Overall Severity): P=0.94; YMRS: P=0.98; BPRS: P=0.57; MADRS: P=0.24], which suggests that the magnitude of the treatment difference did not vary over time. Estimates of the mean change from baseline to each time point are illustrated in Fig. 1a–d, and indicate differences as early as 3 days on some scales [CGI-BP (Overall Severity); YMRS]. No significant differences were seen in the mean change over time between treatment groups on the MADRS (Fig. 1d). A significantly greater percentage of olanzapine patients experienced a clinical response (≥50% decrease in YMRS score) to treatment compared to lithium patients [olz, 87.0%; lith, 73.2%; OR=2.71 (95% CI: 1.07–6.87); P=0.035], corresponding to a number needed to treat of 7. No statistically significant difference between treatment groups was observed in remission rate [olz, 82.6%; lith, 70.4%; OR=2.20 (95% CI: 0.93–5.22); P=0.073], with remission defined as a YMRS total score of ≤12 at LOCF endpoint. A post-hoc sensitivity analysis conducted on change in CGI-BP (Overall Severity) and YMRS scores, excluding the 15 lithium-treated patients with a final lithium blood level “well below target”, produced comparable results to those from the a priori ITT analyses (data not shown, but available on request). 3.5. Treatment-emergent adverse events The percentages of patients experiencing at least one TEAE during the study were 55.1% and 42.3% in the olanzapine and lithium treatment groups, respectively (P=0.176). The most common (≥5%) TEAEs experienced by patients receiving olanzapine were constipation (13%), nausea (7.2%), somnolence (7.2%), nasopharyngitis (5.8%), vomiting (5.8%), diarrhea (5.8%), dizziness (5.8%), and restlessness (5.8%). The most common TEAEs experienced by patients receiving lithium were nausea (12.7%) and nasopharyngitis (5.6%). The percentage of patients experiencing an adverse event possibly related to study drug was statistically significantly greater in the olanzapine treatment group (olz, 36.2%; lith, 19.7%; P=0.038). A greater number of olanzapine-treated patients reported TEAEs relating to the following MedDRA system organ classes: metabolism and nutrition disorders (olz, 5.8%; lith, 1.4%), nervous system disorders (somnolence, dizziness, tremor, extrapyramidal disorder, hypersomnia) (olz, 13.0%; lith, 5.6%), and psychiatric disorders (restlessness) (olz, 5.8%; lith, 0.0%) compared to lithium patients. None of these differences were statistically significant. There were no serious adverse events or deaths during this study. One patient in the lithium treatment group discontinued from the study due to an adverse event (abnormal hepatic function). 3.6. Vital signs, electrocardiograms, laboratory analytes Patients in both treatment groups had an increase in weight and body mass index over the 4-week duration of the study; however the mean increases were statistically significantly higher in the olanzapine treatment group (weight: olz, 1.85 kg; lith, 0.73 kg; P=0.014; BMI: olz, 0.69 kg/m2; lith, 0.27 kg/m2; P=0.012). In addition, significantly more olanzapine patients had a clinically significant weight increase (≥7% of baseline weight) compared to lithium patients (olz, 16.2%; lith, 2.9%; P=0.009). Overall, no significant mean change was observed in either treatment group in other vital signs, ECG results or laboratory analytes. One patient in the olanzapine group had a high blood glucose level at endpoint (baseline: 100.8 mg/dL; endpoint: 194.4 mg/dL) that was considered potentially clinically significant. Three patients in the olanzapine group (n=3/60; 5.0%) and one patient in the lithium group (n=1/62; 1.6%) had high total cholesterol levels at endpoint. 3.7. Extrapyramidal symptoms A total of three patients (2.2%) were experiencing abnormal extrapyramidal symptoms at final visit, based on their SAS total scores. Of these patients, one was receiving olanzapine, while the remaining two patients were receiving lithium. 4. Discussion To our knowledge, this is the first double-blind, randomized, controlled trial comparing an atypical antipsychotic versus lithium in the treatment of acute bipolar mania in a study with a large enough sample size to detect a significant difference between the two treatments. The results from this study suggest that olanzapine is more effective than lithium in improving symptoms of bipolar mania, as indicated by significantly greater mean changes from baseline to 4 weeks in CGI-BP (Overall Severity), YMRS, BPRS, and CGI-BP (Severity of Mania) scores. The rate of response was also significantly greater in the olanzapine treatment group compared to the lithium group, although there was no difference between the two treatment groups in terms of remission rate. Although more than 20% of patients in the lithium treatment group had a final blood lithium level “well below target” (<0.60 mEq/L), a post-hoc analysis indicated that the exclusion of these patients in our analyses did not affect results relating to the comparative efficacy of olanzapine to lithium. The response rates for both treatments seen in this study (olanzapine, 87%; lithium, 73%) were higher than those previously reported for acute treatment of bipolar mania. In two placebo-controlled studies of 3-week and 4-week duration, the response rates (≥50% decrease from baseline to endpoint in YMRS score) in the olanzapine treatment group were 49% and 65%, respectively (Tohen et al., 1999, Tohen et al., 2000). In a 3-week study comparing olanzapine and divalproex, the response rate of the olanzapine treatment group was 54% (versus divalproex, 42%) (Tohen et al., 2002). In a study comparing olanzapine and haloperidol, Tohen et al. (2003) reported the response rate of the olanzapine treatment group as 72% after 6 weeks of treatment (versus haloperidol, 74%). Compared to these studies, the higher response rates in our study may be explained by the lack of patients in our study with characteristics that may be more difficult to treat, such as mixed episodes, rapid cycling, and the presence of psychotic features. Another explanation may be the patient population, as it is possible that patients who enroll in clinical trials in China may be less likely to be non-responsive to treatment than those enrolled in Western countries. While there were no significant differences observed between the treatment groups in mean change in MADRS or CGI-BP (Severity of Depression) scores, both groups had a significant mean change in MADRS score from baseline to endpoint. It should be noted however that the mean MADRS and CGI-BP (Severity of Depression) scores at baseline were low, indicating that on average patients were not displaying symptoms of depression at baseline. Although significantly more lithium patients discontinued from the study early, the reasons for discontinuing were similar to those in the olanzapine treatment group (“lack of efficacy” and “subject decision”). Only one lithium patient discontinued due to an adverse event. In general, both treatments were relatively well tolerated by patients in this study. The TEAEs experienced by patients in this study were not unexpected, and were similar to those reported previously. The mean weight increase in olanzapine patients in this study was comparable to that reported in other studies of similar duration. Mean weight increase in olanzapine-treated bipolar mania patients over 3 or 4 weeks has been previously reported in the range of 1.65 to 2.5 kg (Tohen et al., 1999, Tohen et al., 2000, Tohen et al., 2002). This study has several limitations. Firstly, these results may not be generalized to all bipolar manic patients as there were no patients included that were experiencing a mixed episode, and only one patient was identified as a rapid cycler. Second, diagnoses were not confirmed with a structured interview which may, in part, explain the near absence of mixed episode or rapid cycling patients. Third, while it should also be noted that these results were derived from patients of Chinese ethnicity, to date there have been no data to demonstrate any race-specific effect of olanzapine, and moreover, the pharmacokinetic profile of olanzapine has been reported to be similar between Chinese and Caucasian patients (Sathirakul et al., 2003). Fourth, there was no placebo arm in this study. However, both olanzapine and lithium have been shown to be more effective than placebo in the treatment of bipolar mania. Fifth, although this study design aimed to maintain double-blind lithium dose monitoring and reporting, the investigators may have been able to predict which treatment patients were receiving based on the known differences in side effect profiles of these treatments. In conclusion, results from this study suggest that olanzapine has superior efficacy to lithium in the treatment of patients with acute mania, as measured by mean change in CGI-BP (Overall Severity), YMRS, BPRS, and CGI-BP (Severity of Mania) scores. However, a significantly greater number of patients who received olanzapine experienced study drug-related adverse events, including weight gain, compared to those patients who received lithium. Acknowledgements This study (F1D-GH-LOBV) was sponsored by Eli Lilly and Company. Results from this study are presented in part on the clinical trial registry located at www.lillytrials.com, and have been presented in part at the Chinese Psychiatric Association 2006 Academic Congress. References [APA] American Psychiatric Association, 1994. 1.[APA] American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. 4th ed.. Washington, DC: American Psychiatric Association; 1994;. Berk et al., 1999. 2.Berk M, Ichim L, Brook S. 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Zhang et al., 1993. 16.Zhang M, Wu W, Zhu C. Handbook of Rating Scales in Psychiatry. Hunan: Hunan Science and Technology Press; 1993;. a Shanghai Mental Health Center, Shanghai, People's Republic of China b Lilly Research Laboratories, Indianapolis, Indiana, USA c McLean Hospital, Harvard Medical School, Belmont MA, USA d Eli Lilly Asia, Shanghai, People's Republic of China e Beijing Hui Long Guan Hospital, Beijing, People's Republic of China f Eli Lilly Australia, New South Wales, Australia g Suzhou Psychiatric Hospital, Suzhou, People's Republic of China h Renmin Hospital of Wuhan University, Wuhan, People's Republic of China i Nanjing Brain Hospital, Nanjing, People's Republic of China j 2nd Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, People's Republic of China k Institute of Mental Health, Peking University, Beijing, People's Republic of China  Corresponding author. Lilly Research Laboratories, Indianapolis, IN 46285, USA. Tel.: +1 317 277 9585; fax: +1 317 276 7845.
☆ Conflict of interest. This study was sponsored by Eli Lilly and Company. M. Tohen, A. Qiuqing, H. McElroy, and E. Pope are employees of Eli Lilly and Company. G. Niufan, Y. Fude, L. Ming, W. Gaohua, Z. Xinbao, L. Huichun, and S. Liang are clinical investigators for the F1D-GH-LOBV study (upon which the manuscript is based), for which their institutions were funded by Eli Lilly and Company for the time spent and assessment cost. The authors have no other potential conflicts of interest to disclose. Contributors. M. Tohen and A. Qiuqing were involved in the conception and design of the study. H. McElroy undertook the statistical analyses. E. Pope conducted the literature searches, and drafted the manuscript. G. Niufan, Y. Fude, L. Ming, W. Gaohua, Z. Xinbao, L. Huichun, and S. Liang were involved in the acquisition of data. All authors contributed to the interpretation of the data, critical revision of the manuscript for important intellectual content, and have approved the final manuscript. Role of funding source. Eli Lilly and Company (Lilly) provided funding for this study and was involved in the study conception and design. Lilly had no role in the collection of data for this particular manuscript, beyond the provision of clinical report forms and undertaking clinical monitoring of study sites. Lilly was involved in the analysis and interpretation of data for this manuscript, and in the drafting of the manuscript. Outside of the Lilly employees listed as authors (M. Tohen, A. Qiuqing, H. McElroy, and E. Pope), Lilly had no role in the decision to submit the paper for publication. PII: S0165-0327(07)00144-9 doi:10.1016/j.jad.2007.04.020 © 2007 Elsevier B.V. All rights reserved. | |
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