11 International Review of Bipolar Disorders 4-6 April 2011, Rome

th

Ninth International Conference on Bipolar Disorder, 9-11 June, 2011, Pittsburgh, PA, USA

Oral Platform Presentations & Abstracts

An open label, multicenter, single arm, 4-week study to evaluate the efficacy and safety of flexible dose of quetiapine fumarate (Seroquel) switching from other drugs in the treatment of acute manic patients with bipolar disorder Jie Li, YanBin Jia,XiaoDong Chen,MeiEn Gong, HongWei Zhang Objective: To evaluate the efficacy and safety of flexible dose of quetiapine fumarate switching from others used as mono-therapy in the treatment of acute mania in patients with bipolar disorder. To explore the relationship between BDNF and quetiapine fumarate by checking the BDNF level change from baseline to end point. Method: This was a multicenter, open label, 4-week study. Study subjects are defined in Chinese Han nationality patients with acute mania of bipolar disorder (YMRS?22). The target dose was 400-800mg/day, and treatment period lasted 4 weeks. YMRS MADRS PANNSS SAS AIMS and serum BDNF level were evaluated from baseline to the endpoint. Results: 105 subjects aged from 18 to 62 (32.0510.48) were enrolled and assigned into the study, all of them were given other antipsychotics or mood stabilizers before enrolling (olanzepine, risperidone, lithium carbonate, valporate). 60 of them were males (57.1%).15 subjects didnt complete the study (expulsion rate: 14.29%). The average dose of quetiapine was 657.62mg/d. The score of YMRS at the endpoint was significantly lower than baseline (endpoint vs. baseline: 12.9611.23 vs. 32.05 16.64, P Conclusion: Monotherapy of quetiapine fumarate is efficacious and safe in treating patients of bipolar mania who show inefficacy or intolerability to other atypical antipsychotics or mood stabilizers. Quetiapine treatment mechanism probably related with BDNF.

Poster Abstracts

An Open Label, 4-Week, Randomised, Multi-Centre, Phase IV Study to Compare the Efficacy and Safety of Quetiapine Fumarate (SeroquelTM) as Mono-Therapy or adjunct to lithium in the Treatment of Patients with Acute Mania in Bipolar Disorder Zhang Hongyan; Liu Qi, Wang Xiuzhen, Zhao Zhenhuan, Gao Shuhe, Xu Xiufeng, Wang Gang Wang Xueyi, Tang Qingrong, Wang Xiaoping, Chen Qinggang, Yang Fude, Guo Weigang, Li Keqing, Lv Luxian, Yao Peifen; Sun Xueli, Jia Fujun, Zhang Jinbei, Xu Yi, Chen Wen Objective: Bipolar disorder is a psychiatric disorder that is characterized by manic or mixed episodes. The primary objective of this study was to compare the efficacy of quetiapine fumarate used as monotherapy or adjunct therapy to lithium in the treatment of patient with acute mania in bipolar disorder. Method: This is a 4-week, multi-centre, open label, parallel group, active-controlled, randomised study to compare the efficacy and safety of quetiapine fumarate given as mono-therapy or adjunct therapy to lithium in the treatment of patients with acute mania in bipolar disorder. Patients with a documented clinical diagnosis of bipolar mania according to DSM-IV criteria are required to have a YMRS total score of 20 at enrolment and randomisation. The primary efficacy assessment was the change from baseline in the YMRS total score to Day 28. The secondary efficacy assessment were change from baseline in the YMRS total score to each assessment, the change from baseline in the CGI-BP severity of illness score to each assessment, proportion of much improved or very much improved in the CGI-BP Global improvement score at Day 28, the change from baseline in the PANSS total score, the change from baseline in the MADRS total score to each assessment. The safety assessments include: Incidence and severity of Adverse Events (AEs). Vital sign and lab examinations abnormality, the change from baseline in the Simpson Angus Scale (SAS), the Barnes Akathisia Rating Scale (BARS), or the Abnormal Involuntary Movement Scale (AIMS) to Day 28. The treatment and safety were assessed during each visit.

Results: The changes from baseline in YMRS total score at day 28 (LOCF) of two groups (monotherapy and adjunct therapy) are -25.713.7 and -26.113.4 (PPS), and LS means estimates are 23.720.969 and -23.900.978 respectively, The difference between two groups (LS means of Adjunct therapy group minus that of Mono-therapy group) is -0.181.174 and its 95% CI is (-2.489 to 2.131). The low limit of 95% CI is within non- inferiority margin -3.5. The results from the PPS were confirmed in the FAS population. Analyses based on ob- served cases (OC) of the change from baseline in YMRS total score at Day 28 also provided confirmation of these results. The change from baseline in the YMRS total score to each assessment, all the p values of treatment at each assessment are larger than 0.05.For the change from baseline in the CGI-BP severity of illness score to each assessment, all the p values of treatment at each assessment are larger than 0.05. At Day 28, 91(48.148%) patients got the improvement (proportion of much improved or very much improved in the CGI-BP Global improvement score at Day 28) in the adjunct therapy group, and 92(49.198%) patients got the improvement in mono-therapy group. The OR is 0.959, its 95%CI is (0.612 to 1.504), p=0.8567. Thus, there is no difference in improvement rate of quetiapine fumarate used as mono-therapy and adjunct therapy to lithium in the treatment of patients with acute mania in bipolar disorder. The change from baseline in the PANSS total score to each assessment, the difference between two groups (LS means of Adjunct therapy group minus that of Mono- therapy group) is 0.24 0.769 and its 95% CI is (-1.27 to 1.756), and -0.16 0.834 (-1.798 to 1.483) at visit 5 (14 days treatment), and 0.65 0.862 (-1.04 to 2.35) at visit 6 ( 21 days treatment), and 0.65 0.923 (-1.162 to 2.468) at visit 7 ( 28 days treatment). All the p values of treatment at each assessment are larger than 0.05. The change from baseline in the MADRS total score to each assessment, in FAS population, at visit 4 assessment (7 days treatment), the difference between two groups (LS means of Adjunct therapy group minus that of Mono- therapy group) is -0.09 0.23 and its 95% CI is (-0.541 to 0.364), and -0.19 0.229 (-0.637 to 0.264) at visit 5 (14 days treatment), and -0.06 0.21 (-0.473 to 0.353) at visit 6 ( 21 days treatment), and 0.03 0.223 (-0.412 to 0.464) at visit 7 ( 28 days treatment). All the p values of treatment at each assessment are larger than 0.05. For the safety assessments, AEs with gastrointestinal disorders were more common in the adjunct therapy group (29.1%) than in the mono-therapy group (17.6%). Conclusion: Quetiapine fumarate used as mono-therapy is not inferior to adjunct therapy to lithium in the treat- ment of patients with acute mania in bipolar disorder as measured by the change from baseline in the YMRS total score to Day 28. There is no difference for quetiapine fumarate used as mono-therapy and adjunct therapy to lithium in the treatment of patients with acute mania in bipolar disorder as measured by the secondary variables, including YMRS response rate, CGI-BP score, PANSS total score, and MADRS total score. Quetiapine fumarate is generally safe and well tolerated as mono-therapy or as adjunct to lithium in the treatment of patients with acute mania in bipolar disorder.

Quetiapine efficacy and tolerability in bipolar ii disorder with comorbid cluster c personality disorder Daniel VASILE, Octavian VASILIU, Gabriela Diana OJOG Objective: To assess the efficacy and tolerability of quetiapine medium term administration in patients diagnosed with bipolar II disorder and co morbid cluster C personality disorder. Method: All patients diagnosed with bipolar II disorder according to DSM IV TR criteria (n=45), admitted in our department for a mood episode, were screened for personality disorder using Structured Clinical Interview for DSM IV Personality Disorders (SCID-II) and 22 were positive. After the corroboration of psychological evaluation with clinical status a number of 10 patients were diagnosed with cluster C personality disorders (avoidant n=4, dependent n=3, obsessive-compulsive n=3). Quetiapine was administered in an open-label manner (420 mg mean daily dose) in all 45 patients diagnosed with bipolar II disorder. Patients were evaluated weekly during the first month and every 4 weeks for the rest of the trial using Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAMD) 21 items, Clinical Global Impressions- Severity (CGI-S) and Global Assessment of Functioning (GAF). Results: Patients with cluster C personality disorder and bipolar II disorder had a favourable evolution from the baseline values of HAMD (27.4 mean value) and YMRS (14.2 mean value) to week 24 (-19.9 points on HAMD and -7.4 on YMRS). CGI-S and GAF values had a parallel evolution with YMRS and HAMD scores: -2.3 and +26.5 compared to baseline. Patients with cluster C personality disorders needed a larger dose of medication (+20.5 mg daily), but didnt reach a level of significance (p=0.154). The rate of drop-out was larger in the dual diagnosis patients than in the bipolar II disorder

single diagnosed subjects (33.3% vs. 21.7%). The number of medium and severe adverse events was larger in the dual diagnosed patients, but not within the range of statistical significance (p=0.331). Conclusion: Multiaxial diagnosis is important in bipolar II disorder because, at least in the case of cluster C personality disorders, this co morbidity correlates with larger dose of quetiapine and higher rate of drop-out and reported adverse events. However, larger trials are needed in order to evaluate the statistical significance of these correlations.

An open label, randomised, valproate-controlled study to evaluate the efficacy and safety of quetiapine fumarate in the treatment of acute manic patients with bipolar disorder Peifen Yao Objective: The objective of this trial was to assess the efficacy and safety of quetiapine treatment of acute manic patients with bipolar disorder compared with valproate. Method: In this open label, randomised, valproate-controlled study, patients between 18-65 years old meeting the Chinese Classification and Diagnostic Criteria of Mental Disorders -3rd Edition (CCMD-3) bipolar disorder, as well as the Young Mania Rating Scale (YMRS) score over 20 were involved. The dose of quetiapine could be adjusted from 300 mg/day up to 800 mg/day. The dose of valproate could be adjusted from 500 mg/day to 1500 mg/day. Efficacy and safety were assessed by interviews physical examinations and laboratory tests conducted at baseline and on Days 7,14 and 28. The primary variable of this study was the reduction in mean YMRS total score from baseline to Day 28. The secondary efficacy variables were were the change from baseline to Day 28 in YMRS response rate ,the mean Positive and Negative Syndrome Scale( PANSS) total score, and the mean Montgomery-Asberg Depression Rating Scale( MADRS). Safety was assessed using the Treatment Emergent Symptom Scale (TESS) and laboratory tests recording of AEs. Results: Of the 74 patients screened two discontinued due to informed consent withdrawal and another two due to blood sample collection failure before randomization. Of the 70 patients radomized (X to quetiapine; Y to valproate), all completed the trial. The mean dosage in quetiapine group was 632mg/day, and in valproate group was 915mg/day. The mean reduction in YMRS total score from baseline to Day 28was greater for quetiapine ( 19.097.83 vs. 16.237.17, P=0.116), while it had no significant difference between groups. However, significant intergroup differences could be found at Days 7 and 14. The response rate of YMRS score at Day 28 was higher in quetiapine group, while it had no significant difference between groups (quetiapine vs. Valproate 0.610.24 vs. 0.510.21, P=0.06), while significant intergroup differences were seen at Days 7, 14 and 21. There was no significant difference found in the reduction of PANSS at Day 28 between groups, while significant differences could be found at Days 7 and 14. There was no significant intergroup difference in the change of MADRS score at Day 28 or in other interviews between the two groups. For the safety variables, there were few AEs in either group, with three cases of constipation and one of drowsiness in the quetiapine group and six cases of constipation, two of heart palpitation, two of diarrhoea and one of dysphasia in the valproate group. Conclusion: The results suggest that quetiapine and valproate are both effective in the treatment of acute manic patients with bipolar disorder, although quetiapine may have an earlier onset of effect. Both agents were well tolerated and there were no withdrawals.

Effectiveness of quetiapine versus bupropion as adjunctive treatment for bipolar depression KJ Leea, H Kimb aIlsan Paik Hospital, Ilsan, and Inje University, Gimhae, Korea, bIlsan Paik Hospital, Ilsan, Korea Objective: Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. Bupropion has been suggested for the treatment of bipolar depression because of its efficacy and a probably lower risk of inducing switches to mania. This study compared the efficacy of quetiapine and bupropion as add-on therapy to ongoing treatment with a mood stabilizer in patients with bipolar depression. Methods: The patients with DSM-IV-defined bipolar depression types I and II were randomized to receive escalating doses of either quetiapine (300 - 600mg/day) or bupropion SR (150 - 300 mg/day) for eight weeks. Twenty-three patients openly received quetiapine; 25 patients received bupropion SR adjunctive to either lithium or divalproex. The Hamilton Depression Rating Scale (HDRS-21), Clinical Global Impressions for Bipolar Disorder (CGI-BP), and Young Mania Rating Scale were assessed. Results: A significant reduction in depressive symptoms was observed from baseline to endpoint following quetiapine and bupropion SR treatment, according to a 50% reduction in the HDRS-21. Total meanHDRS-21scores significantly decreased from baseline to endpoint in both groups (p<0.01). Differences between the quetiapine-treated group and the bupropion SR-treated group were not significant at eight weeks (p>0.05). Adjunctive quetiapine or bupropion SR resulted in significant improvements in CGI-BP depressionratings.BothquetiapineandbupropionSRweregenerally well tolerated. There were no cases of affective switch in either arm. Conclusions: These data suggest that adjunctive administration of either quetiapine or bupropion SR may reduce depressive symptom severity in bipolar depression. As this was an observational study, the antidepressant effect and tolerability profile of these compounds requires validation via double-blind placebocontrolled investigations.

Long-term efficacy of quetiapine in combination with lithium or divalproex on mixed symptoms in bipolar I disorder E Vietaa, T Suppesb, U Gustafssonc, B Paulssonc aUniversity of Barcelona, Barcelona, Spain, bStanford University School of Medicine, Stanford, CA, USA, cAstraZeneca R&D, Sweden Objective: To determine the efficacy of quetiapine (QTP) in patients with bipolar I disorder with mixed symptoms. Method: Data from two phase III studies (D1447C00126 and D1447C00127) were pooled. Unlike previous analyses of these studies, mixed events were analyzed separately. Patients received QTP (400-800 mg/day) +lithium (Li)/divalproex (DVP) to achieve 12 weeks of clinical stability followed by double-blind treatment with QTP (400-800 mg/d) +Li/DVP or placebo (PBO) +Li/DVP for up to 104 weeks. Primary endpoint was time to first mood event post-randomization. Results: One thousand three hundred twenty-six patients were included in the intent-to-treat (ITT) population. Relative to PBO,

QTP significantly increased time to recurrence of mixed events (P < 0.0001). Four hundred forty-five ITT patients had a most recent mixed episode at study entry. In these patients, mood events were reported by fewer patients on QTP+Li/DVP (21.0%) than on PBO+Li/DVP (53.9%). These events included mixed (6.4% versus 22.1%), pure manic (5.0% versus 13.3%), and pure depressed events (9.6% versus 18.6%). Time to recurrence of mood events was significantly longer for patients on QTP+Li/DVP than for those on PBO+Li/DVP for mixed (HR, 0.23, 95% CI, 0.13 - 0.42, P < 0.0001), pure manic (HR, 0.30, 95% CI, 0.15 - 0.60, P = 0.0007), and pure depressed events (HR, 0.38, 95% CI, 0.22 - 0.64, P = 0.0003). No new safety concerns were noted. Conclusions: In stable patients with bipolar I disorder, QTP+Li/ DVP significantly increased: a) time to recurrence of mood events compared with PBO in patients with mixed symptoms at study entry; and b) time to occurrence of mixed mood events in patients with any mood episode at study entry. Supported by funding from AstraZeneca Pharmaceuticals LP. The efficacy of quetiapine monotherapy in bipolar II depression: combined data from the BOLDER and EMBOLDEN studies AH Younga, JR Calabreseb, U Gustafssonc, B Paulssonc, GS Malhid, DJ Bonda, N Ferriere aUniversity of British Columbia, Vancouver, Canada, bUniversity Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA, cAstraZeneca R&D, Sweden, dCADE Clinic, and University of Sydney, Sydney, Australia, eInstitute of Neuroscience, Newcastle University, Newcastle-upon-Tyne, UK Objectives: Combined data are presented from four placebo (PBO)-controlled studies (BOLDER I and II; EMBOLDEN I and II) that evaluated the efficacy of quetiapine (QTP) monotherapy in patients with bipolar II disorder. Methods: All studies included an eight-week, double-blind treatment phase in which patients were assigned to QTP 300 mg/d, 600 mg/d, or PBO. The EMBOLDEN studies also included a 2652-week continuation phase, in which patients achieving remission continued on the same dose of QTP or switched to PBO. Outcome measures included change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at week eight and time-to-recurrence of any predefined mood event (EMBOLDEN only). MADRS response and remission rates and Hamilton Rating Scales for Depression and Anxiety were also assessed. Results: Improvements in MADRS total scores from baseline to week eight were significantly greater with QTP 300 mg/d and 600 mg/d (-15.58 and -14.88; P < 0.001) compared with PBO (-11.61). MADRS effect sizes were 0.44 and 0.47 for QTP 300 mg/d and 600 mg/d (P < 0.0001 versus PBO). In the EMBOLDEN studies, continued treatment with both doses of QTP significantly reduced the risk of recurrence of a mood event versus PBO (hazard ratios, 0.47 [95% CI, 0.25 - 0.92] and 0.18 [95% CI, 0.07 - 0.51]; P 0.05 versus PBO). Common adverse events associated with QTP included dry mouth, somnolence, sedation, dizziness, and headache. Rates of mania/hypomania were similar for QTP and PBO. Conclusions: QTP monotherapy demonstrated significant efficacy, compared with PBO, in the treatment of bipolar II depression. QTP was generally well tolerated in all four studies. Supported by funding from AstraZeneca Pharmaceuticals LP.