Young Mania Rating Scale Total Score Research Articles

Long-term Safety of Asenapine in Pediatric Patients Diagnosed With Bipolar I Disorder: A 50-Week Open-Label, Flexible-Dose Trial.

BackgroundSublingually administered asenapine was approved in March 2015 by the United States Food and Drug Administration for patients aged 10–17 years with an acute manic or mixed episode associated with bipolar I disorder (BP-1). This is the first long-term safety and tolerability study of asenapine in this population.MethodsFollowing the 3-week randomized, double-blind, placebo-controlled trial of patients aged 10–17 years with an acute manic or mixed episode associated with BP-1, patients could enroll in this flexible-dose (2.5–10 mg twice daily) open-label extension (OLE) study for an additional 50 weeks, conducted from August 2011 to September 2014 in the United States and Russia. Treatment-emergent adverse events (TEAEs) were assessed and predefined TEAEs of interest reported in addition to metabolic and anthropometric parameters. The Young Mania Rating Scale (YMRS) and Clinical Global Impressions scale in bipolar illness (CGI-BP) were used to assess effectiveness.ResultsA total of 321 patients (lead-in study treatment: placebo, n = 80; asenapine, n = 241) were included; 267 (83.2 %) reported one or more TEAE and 181 (56.4 %) discontinued early, 48 (15.0 %) due to TEAEs. Of the predefined TEAEs of interest, combined somnolence/sedation/hypersomnia occurred most frequently (42.4 %) followed by oral hypoesthesia/dysgeusia (7.5 %). In total, 109 (34.8 %) patients experienced clinically significant weight gain (≥7 % increase). No clinically meaningful changes were noted for laboratory parameters measured. Eighteen patients met the criteria for new-onset metabolic syndrome (MBS) post-baseline during the extension study, whereas 10 patients who met MBS criteria at baseline did not meet MBS criteria at endpoint. A total of 12 patients met MBS at baseline and endpoint. Mean change in YMRS total score from OLE baseline was −9.2 points at week 50, and change in CGI-BP severity overall score was similar among all treatment groups (those who initially received asenapine and those who initially received placebo). After 26 weeks of treatment in the OLE, 79.2 % of patients were classified as YMRS 50 % responders relative to acute trial baseline.ConclusionsAsenapine was generally well tolerated in pediatric patients with BP-1 during ≤50 weeks of open-label treatment; among predefined TEAEs of interest, the combination of somnolence/sedation/hypersomnia was the most common.Trial registration ClinicalTrials.gov: NCT01349907.Electronic supplementary materialThe online version of this article (doi:10.1007/s40272-016-0184-2) contains supplementary material, which is available to authorized users.

First-episode bipolar disorder is associated with erythrocyte membrane docosahexaenoic acid deficits: Dissociation from clinical response to lithium or quetiapine

Deficits in long-chain omega-3 (LCn−3) fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may be associated with the pathophysiology of bipolar disorder. However, LCn−3 fatty acid status at the initial onset of mania and its association with treatment response are not known. Erythrocyte membrane fatty acid composition was determined in first-episode bipolar manic or mixed (n=40) and healthy (n=40) subjects. Mood symptom ratings were obtained with the Young Mania Rating Scale (YMRS) and the Hamilton Depression Rating Scale (HDRS). Erythrocyte fatty acid composition and clinical ratings were also determined within a sub-group of bipolar subjects following 8-week (n=19) or 52-week (n=11) open-label treatment with lithium or quetiapine. At baseline bipolar subjects exhibited significantly lower erythrocyte docosahexaenoic acid (DHA, 22:6n−3) composition compared with healthy subjects (−23%, p<0.0001). EPA (20:5n−3) and docosapentanoic acid (22:5n−3), and LCn−6 fatty acids including arachidonic acid were not different. Following 8- or 52-week treatment with lithium or quetiapine, YMRS and HDRS total scores decreased significantly whereas erythrocyte fatty acids including DHA did not change. These data indicate that selective erythrocyte DHA deficits coincide with the initial onset of manic symptoms, and reductions in mood symptoms following treatment are not mediated by changes in fatty acid status.

Asenapine: Efficacy and safety of 5 and 10 mg bid in a 3-week, randomized, double-blind, placebo-controlled trial in adults with a manic or mixed episode associated with bipolar I disorder

BackgroundAsenapine is an atypical antipsychotic for acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. The recommended asenapine starting dose is 10mg bid with the option to reduce the dose to 5mg bid if needed due to adverse effects/tolerability. MethodsPhase IIIb, international, double-blind, fixed-dose, parallel-group, 3-week placebo-controlled trial of asenapine 5 and 10mg bid in adults with an acute bipolar I disorder manic or mixed episode. Primary outcome was difference in asenapine versus placebo in mean change from baseline to day 21 in the Young-Mania Rating Scale (YMRS) total score. Others included difference in asenapine versus placebo in the Clinical Global Impression Scale for Bipolar Severity (CGI-BP-S) and rate of YMRS responders. ResultsBoth asenapine doses were statistically superior to placebo in mean change from baseline to day 21 in YMRS total score (−10.9, −14.4, and −14.9 for placebo, asenapine 5mg bid, 10mg bid, respectively). Both asenapine doses had statistically superior improvement in mean change in CGI-BP-S score at day 21. Neither asenapine dose had significantly more YMRS responders at day 21 than placebo. LimitationsResults may not be generalizable to the entire population with bipolar I disorder owing to strict inclusion criteria. ConclusionsThis study evaluated, by a fixed-dose design, the efficacy and safety of asenapine versus placebo in patients with bipolar I disorder. Both asenapine 5 and 10mg bid were efficacious in treating mania associated with bipolar I disorder and were generally well tolerated.

Electroconvulsive therapy in 197 patients with a severe, drug-resistant bipolar mixed state: treatment outcome and predictors of response.

We prospectively evaluated the short-term outcome and the predictors of response to electroconvulsive therapy (ECT) in a large sample of patients with a bipolar mixed state. From January 2006 to May 2011, we performed an analysis using data obtained from 197 of 203 consecutive patients with a bipolar mixed state, according to DSM-IV-TR diagnostic criteria, who were treated with ECT at the Department of Psychiatry of the University of Pisa. All patients were evaluated prior to and after the ECT course using the Hamilton Depression Rating Scale-17 (HDRS-17), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impressions (CGI) scale. The CGI subscale "global improvement" and final HDRS-17 and YMRS total scores were used to identify nonresponder, responder, and remitter groups. At the end of the ECT course, 55 patients (27.9%) were considered nonresponders, 82 responders (41.6%), and 60 remitters (30.5%). As expected, at the end of the ECT trial, the CGI-Severity scale (CGI-S; P < .0001), HDRS-17 (P < .0001), and BPRS (P < .0001) scores were significantly lower in remitters than in responders and nonresponders. Using backward stepwise logistic regression, the length of current episode, lifetime comorbidity of obsessive-compulsive disorder, and baseline YMRS total mean score were statistically significant predictors of nonresponse versus remission (P < .0001). Less than 30% of the patients included in the study were nonresponders to ECT. Long-lasting mixed episode with excitatory symptoms and lifetime comorbidity of obsessive-compulsive disorder significantly predicted a lack of complete remission.

Predictors of Remission in 208 Drug-Resistant Depressive Patients Treated With Electroconvulsive Therapy

This study aimed to explore predictors of remission to electroconvulsive therapy (ECT) in a sample of depressive patients resistant to pharmacological treatments. Two hundred eight patients, 31 of whom had major depressive disorder, 101 had bipolar disorder II (BP II), and 76 had bipolar disorder I (BP I), diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria were treated with bilateral ECT on a twice-a-week schedule. All patients included were undergoing a depressive episode, excluding patients with mixed and manic episodes. Patients were assessed before (baseline) and a week after the ECT course (final score) using the Hamilton Rating Scale for Depression-17 items (HAM-D-17), the Young Mania Rating Scale (YMRS), the Brief Psychiatric Rating Scale, and the Clinical Global Impression-Improvement (CGI-I). At the end of the ECT course, 56 patients (26.9%) were considered nonresponders, and 80 patients (38.4%) were considered responders (HAM-D score of at least 50% and CGI-I subscale rating of 2, "much improved") and 72 remitters (34.6%) (HAM-D scores ≤8 and a CGI-I subscale rating of 1). On backward stepwise logistic regression length of current episode, Bipolar Disorder and baseline YMRS total mean scores were statistically significant predictors of nonresponders versus remitters. Among the YMRS items at basal evaluation 8 (thought content), 10 (appearance), and 11 (insight), the mean scores were significantly lower in the remitters than in the responders and nonresponders. Major depressive disorder, short duration of the current episode, absence of psychotic symptoms, preserved insight, and adequate personal care are associated with complete remission in our sample of drug-resistant depressive patients treated with ECT.

Cariprazine in the treatment of acute mania in bipolar I disorder: A double-blind, placebo-controlled, Phase III trial

BackgroundThis Phase III, randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of flexibly-dosed cariprazine in patients with acute manic or mixed episodes associated with bipolar I disorder. MethodsPatients were randomized to 3 weeks of double-blind treatment with cariprazine 3–12mg/day (n=158) or placebo (n=154). The primary efficacy parameter was change from baseline to Week 3 in Young Mania Rating Scale (YMRS) total score. The secondary efficacy parameter was change from baseline to Week 3 in Clinical Global Impressions-Severity (CGI-S) score. ResultsMean change from baseline to Week 3 in YMRS total score was significantly greater for patients receiving cariprazine 3–12mg/day versus placebo (P=0.0004). Significant differences between groups in YMRS total score mean change were observed by Day 4 (first postbaseline assessment) and maintained throughout double-blind treatment (all assessments, P<0.01). Cariprazine also demonstrated statistically significant superiority over placebo on YMRS response (≥50% improvement: cariprazine, 58.9%; placebo, 44.1%; P=0.0097) and remission (YMRS total score≤12: cariprazine, 51.9%; placebo, 34.9%; P=0.0025) and mean change in CGI-S (P=0.0027) score and Positive and Negative Syndrome Scale (PANSS) (P=0.0035) total score. The most common cariprazine-related (≥10% and twice placebo) treatment emergent adverse events (TEAEs) were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Mean change from baseline in metabolic parameters were generally small and similar between groups. LimitationsLack of active comparator arm; short duration of study. ConclusionIn this study, cariprazine 3–12mg/day was effective and generally well tolerated in the treatment of manic and mixed episodes associated with bipolar I disorder.

Lithium as add-on to quetiapine XR in adult patients with acute mania: a 6-week, multicenter, double-blind, randomized, placebo-controlled study.

Quetiapine extended release (XR) and lithium are treatments with proven efficacy in acute mania. This randomized study evaluated the efficacy and safety of lithium or placebo as add-on to quetiapine XR in adult patients with manic or mixed symptoms of bipolar I disorder. In this 6-week, double-blind study (Trial D144AC00003), adult patients with DSM-IV-TR-diagnosed bipolar I disorder (current episode manic or mixed), a Young Mania Rating Scale (YMRS) total score ≥20, and score ≥4 on two of four core YMRS items were administered quetiapine XR (400 to 800 mg/day) and randomly assigned to receive add-on lithium (600 to 1,800 mg/day) or placebo. The primary efficacy end point was change in the YMRS total score from baseline to day 43, analyzed using a mixed-model for repeated measures (MMRM) approach. Secondary efficacy and safety end points were also measured. Rating scales were administered by trained staff. Three hundred fifty-six patients treated with quetiapine XR were randomized to add-on lithium (n = 173) or placebo (n = 183). Two hundred ninety-one patients (81.7%) completed the study. At day 43, least squares mean change in YMRS total score was −22.8 for add-on lithium and −20.1 for add-on placebo, a statistically significant treatment group difference of −2.69 (p < 0.001). On secondary measures, add-on lithium was associated with significant improvements in response, remission, illness severity, and overall illness versus add-on placebo (p < 0.05). The number needed to treat was 9.1 for response and 7.9 for remission for add-on lithium compared with add-on placebo. Lithium in combination with quetiapine XR was generally well tolerated, with a similar profile to quetiapine XR in combination with placebo. The addition of lithium to quetiapine XR therapy was associated with significantly greater efficacy than placebo as add-on and was generally well tolerated in patients with acute bipolar I mania. This study was registered under Clinicaltrials.gov Identifier NCT00931723.Electronic supplementary materialThe online version of this article (doi:10.1186/s40345-014-0014-9) contains supplementary material, which is available to authorized users.

Heart rate variability in unmedicated patients with bipolar disorder in the manic phase

Decreased heart rate variability (HRV) has been proposed in bipolar disorder. To date, there has been no adequate study that has investigated resting HRV in unmedicated patients with bipolar disorder in the manic state. To examine whether bipolar mania is associated with decreased HRV, 61 unmedicated patients with bipolar mania and 183 healthy volunteers aged 20-65 years were recruited for this case-control analysis. The Young Mania Rating Scale (YMRS), Clinical Global Impression-Severity, Hamilton Depression Rating Scale (HAM-D), and Hamilton Anxiety Rating Scale (HAM-A) were used for the clinical ratings. Cardiac autonomic function was evaluated by measuring HRV parameters and the frequency-domain indices of HRV were obtained. Patients with bipolar mania exhibited significantly lower mean RR interval, variance, low-frequency (LF)-HRV, and high-frequency (HF)-HRV but higher LF/HF compared to controls. Decreased HRV (variance) was associated with the YMRS total scores. Both the YMRS total scores and the Clinical Global Impression-Severity scores were positively correlated with the LH/HF ratio and inversely correlated with the HF-HRV. There was no significant correlation between the HAM-D/HAM-A scores and any HRV parameter. Bipolar mania is associated with cardiac autonomic dysregulation, highlighting the importance of assessing HRV in manic patients. Further studies examining the influence of anti-manic psychotropic drugs on cardiac autonomic regulation in bipolar mania are needed.

The Efficacy and Safety of Switching to Ziprasidone from Olanzapine in Patients with Bipolar I Disorder: An 8-Week, Multicenter, Open-Label Study

Switching antipsychotic medication in patients undergoing combination therapy for bipolar I disorder is a common clinical practice because of suboptimal drug efficacy or tolerability. Despite the frequency of switching, little is known about the most appropriate switching options. Ziprasidone may be a good alternative for patients with bipolar disorder experiencing a suboptimal response or intolerance to olanzapine in combination with a mood stabilizer because of its mood-stabilizing effect and minimal propensity for clinically significant body weight gain and metabolic disturbances. However, no study has evaluated the efficacy, safety, and tolerability of switching to ziprasidone from olanzapine in combination with a mood stabilizer for treatment of bipolar disorder. The objective of this study was to evaluate the efficacy and safety of switching to ziprasidone in patients with bipolar I disorder experiencing a suboptimal response or intolerance to olanzapine in combination with lithium or valproate. An 8-week, prospective, open-label study was conducted among inpatients and outpatients with bipolar I disorder who were taking olanzapine combined with lithium or valproate to treat recent manic or mixed episodes. In subjects experiencing a suboptimal response [≥16 points on the Young Mania Rating Scale (YMRS) at screening and baseline] or intolerance, olanzapine was switched to ziprasidone while maintaining the same dose of their current combined mood stabilizer during the 8-week trial. The primary efficacy measure was the mean change in the YMRS total score. Metabolic parameters were measured to evaluate the improvement in metabolic syndrome. A total of 56 patients were enrolled, and 46 (82.1 %) completed this study. Switching to ziprasidone was effective and well-tolerated. YMRS total scores were significantly reduced over 8 weeks (mean change, -10.4 ± 10.2). There were significant improvements in metabolic parameters, with mean changes of -0.4 ± 0.8 kg/m(2) in body mass index (BMI), -1.2 ± 2.5 kg in body weight, -21.3 ± 62.7 mg/dL in the fasting triglyceride level, and -13.2 ± 26.6 mg/dL in the total cholesterol level. Greater improvements in BMI, body weight, and dyslipidemia were positively correlated with a higher baseline BMI and abnormal lipid profile. Ziprasidone appears to be a good switching option for patients with bipolar I disorder experiencing suboptimal response or intolerance with olanzapine in combination with lithium or valproate. In addition, switching to ziprasidone improves metabolic parameters, especially in patients experiencing weight gain or dyslipidemia with olanzapine treatment.

Early improvement as a predictor of acute treatment outcome in manic or mixed episodes in bipolar-1 disorder: A pooled, post hoc analysis from the asenapine development program

ObjectiveTo assess whether early symptom improvement predicts later treatment outcome in acute manic/mixed episodes of bipolar I disorder using Young Mania Rating Scale (YMRS) or Clinical Global Impression scale, bipolar disorders (CGI–BP) assessments. MethodsData were pooled from two 3-week randomized controlled studies with asenapine (ASE; n=372), olanzapine (OLA; n=391), or placebo (PL; n=197). Early improvement was defined as reduction of YMRS total scores (≥15%, ≥20%, ≥25%) or CGI–BP severity scores (≥1 point change) at days 2, 4, and 7. Treatment outcome at week 3 was defined as response (YMRS: ≥50% score reduction; CGI–BP severity: “minimally ill” or better) or remission (YMRS total score ≤12; CGI–BP severity: “not at all ill”). Odds ratios (ORs) and predictive performance statistics were calculated. ResultsEarly improvement occurred in a substantial percentage of patients and was associated with significantly increased ORs for response or remission. For ASE, results were significant as early as day 2 on all measures of YMRS and CGI-severity of mania assessment. For all treatments sensitivity and negative predictive values increased from days 2 to 7 for all YMRS and CGI–BP measures, while specificity values decreased. ConclusionIn acute manic/mixed episodes, early improvement within 1 week of treatment was associated with significantly increased ORs of endpoint response or remission. While only a subset of early improvers reach the endpoint treatment goals, absence of improvement within week 1 of treatment initiation strongly predicts the unlikely success of subsequent treatment. Further, CGI-based predictors had predictive properties similar to those based on the YMRS scale.

Aripiprazole for the treatment of pediatric bipolar I disorder: a 30‐week, randomized, placebo‐controlled study

To evaluate the long-term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar I disorder. A randomized, double-blind, 30-week, placebo-controlled study of aripiprazole (10 or 30 mg/day) in youths (10-17 years) with bipolar I disorder (manic or mixed) ± psychotic features (n = 296) was performed. After four weeks, acute treatment completers continued receiving ≤26 weeks of double-blind treatment (n = 210). The primary outcome was Young Mania Rating Scale (YMRS) total score change. Of the 210 subjects who entered the 26-week extension phase, 32.4% completed the study (45.3% for aripiprazole 10 mg/day, 31.0% for aripiprazole 30 mg/day, and 18.8% for placebo). Both aripiprazole doses demonstrated significantly (p < 0.001) greater improvements in YMRS total score at endpoint compared with placebo in protocol-specified last observation carried forward analyses, but not in observed case or mixed-model repeated measures at week 30. Overall time to all-cause discontinuation was longer for aripiprazole 10 mg/day (15.6 weeks) and aripiprazole 30 mg/day (9.5 weeks) compared with placebo (5.3 weeks; both p < 0.05 versus placebo). Both aripiprazole doses were significantly superior to placebo regarding response rates, Children's Global Assessment of Functioning and Clinical Global Impressions-Bipolar severity of overall and mania scores at endpoint in all analyses. Commonly reported adverse events included headache, somnolence, and extrapyramidal disorder. Aripiprazole 10 mg/day and 30 mg/day were superior to placebo and generally well tolerated in pediatric subjects with bipolar I disorder up to 30 weeks. Despite the benefits of treatment, completion rates were low in all treatment arms.

Efficacy and Safety of Quetiapine in Children and Adolescents With Mania Associated With Bipolar I Disorder

To evaluate the efficacy and safety of quetiapine monotherapy in children and adolescents with mania associated with bipolar I disorder. Patients aged 10 to 17 years, with a DSM-IV-TR diagnosis of a manic episode associated with bipolar I disorder and Young Mania Rating Scale (YMRS) total score ≥ 20 were randomized to 3 weeks of quetiapine (400 or 600 mg/d) or placebo. The primary efficacy measure was change in YMRS total score. The study was conducted at 34 centers in the United States between August 2004 and July 2006. The intent-to-treat population included 277 patients. Least squares mean change in YMRS score from baseline to end point by mixed-model, repeated-measures analysis was -14.25, -15.60, and -9.04 for quetiapine 400 mg/d, quetiapine 600 mg/d, and placebo, respectively (P < .001, each quetiapine dose vs placebo). Significant improvement in YMRS score versus placebo was first observed at day 4 (P = .015) with quetiapine 400 mg/d and day 7 (P < .001) with quetiapine 600 mg/d. Mean changes in body weight at day 21 (observed cases) were 1.7 kg for both quetiapine doses and 0.4 kg for placebo. Numerically larger mean increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed with quetiapine than placebo. Adverse events associated with quetiapine were mostly mild to moderate in intensity. In this 3-week study, quetiapine was significantly more effective than placebo in improving manic symptoms in youth with mania associated with bipolar disorder. Treatment was generally well tolerated and adverse events were broadly consistent with the known profile of quetiapine in adults with bipolar disorder. ClinicalTrials.gov identifier: NCT00090311.

2288 – A 12-week, randomized, placebo-controlled study evaluating the efficacy and safety of aripiprazole in combination with lithium/valproate inpartially-responsive bipolar mania

Evaluate the efficacy of aripiprazole combination with lithium/valproate vs. placebo combination in bipolar mania using a titration regimen with a low starting dose (5 mg/day). Eligible adult patients with bipolar mania receiving lithium/valproate and a Young Mania Rating Scale (YMRS) Total score ≥16 who might benefit from combination treatment with aripiprazole, were randomized to aripiprazole (n=181) or placebo (n=189) with lithium/valproate. Primary endpoint was mean change from baseline to Week 12 in YMRS. Secondary endpoints were Clinical Global Impressions-Bipolar Version (CGI-BP) severity of illness score, response rate (≥50% improvement in YMRS Total score), and remission rate (YMRS ≤12). Safety and tolerability were also assessed. Enrolment yielded a 77% power to detect a 2.6-point change in YMRS Total score at endpoint. At endpoint, the mean change in YMRS Total Score (last-observation-carried-forward [LOCF]) for aripiprazole vs. placebo was not significant (treatment difference [-2.04] in favour of aripiprazole (95% CI: -4.14, 0.07; p=0.058). Mean change from baseline to endpoint in CGI-BP showed a treatment difference (-0.30) in favour of aripiprazole vs. placebo (95% CI: - 0.59, -0.01; p=0.044). Response rates were 68.8% vs. 61.3% (p=0.128) and remission rates were 69.9% vs. 64.0% (p=0.211) for aripiprazole and placebo, respectively. No unexpected adverse events (AEs) occurred. Treatment-emergent AEs (≥5% and twice the rate of placebo) were akathisia, depression, and nausea. The target sample size of 388 patients was not achieved in this study and the primary outcome did not reach statistical significance. Now new or unexpected AEs occurred.

P.2.e.016 Cariprazine in the treatment of acute mania in bipolar disorder: a double-blind, placebo-controlled, phase III trial

Background: This Phase III, randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of flexibly-dosed cariprazine in patients with acute manic or mixed episodes associated with bipolar I disorder. Methods: Patients were randomized to 3 weeks of double-blind treatment with cariprazine 3–12 mg/day (n¼158) or placebo (n¼154). The primary efficacy parameter was change from baseline to Week 3 in Young Mania Rating Scale (YMRS) total score. The secondary efficacy parameter was change from baseline to Week 3 in Clinical Global Impressions-Severity (CGI-S) score. Results: Mean change from baseline to Week 3 in YMRS total score was significantly greater for patients receiving cariprazine 3–12 mg/day versus placebo (P¼0.0004). Significant differences between groups in YMRS total score mean change were observed by Day 4 (first postbaseline assessment) and maintained throughout double-blind treatment (all assessments, Po0.01). Cariprazine also demonstrated statistically significant superiority over placebo on YMRS response (Z50% improvement: cariprazine, 58.9%; placebo, 44.1%; P¼0.0097) and remission (YMRS total scorer12: cariprazine, 51.9%; placebo, 34.9%; P¼0.0025) and mean change in CGI-S (P¼0.0027) score and Positive and Negative Syndrome Scale (PANSS) (P¼0.0035) total score. The most common cariprazine-related (Z10% and twice placebo) treatment emergent adverse events (TEAEs) were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Mean change from baseline in metabolic parameters were generally small and similar between groups. Limitations: Lack of active comparator arm; short duration of study. Conclusion: In this study, cariprazine 3–12 mg/day was effective and generally well tolerated in the treatment of manic and mixed episodes associated with bipolar I disorder. & 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

C.06.02 Can our patients do better? The relationship between motivational deficits and functional outcomes

Asenapine is approved in the United States for acute treatment of manic or mixed episodes of bipolar I disorder with or without psychotic features. We report the results of long-term treatment with asenapine in patients with bipolar I disorder.Patients completing either of two 3-week efficacy trials and a subsequent 9-week double-blind extension were eligible for this 40-week double-blind extension. Patients in the 3-week trials were randomized to flexible-dose asenapine (5 or 10 mg BID), placebo, or olanzapine (5–20 mg QD; included for assay sensitivity only). Patients entering the extension phase maintained their preestablished treatment; those originally randomized to placebo received flexible-dose asenapine (placebo/asenapine). Safety and tolerability endpoints included adverse events (AEs), extrapyramidal symptoms, laboratory values, and anthropometric measures. Efficacy, a secondary assessment, was measured as change in Young Mania Rating Scale (YMRS) total score from 3-week trial baseline to week 52 with asenapine or olanzapine; the placebo/asenapine group was assessed for safety only.Incidence of treatment-emergent AEs was 71.9%, 86.1%, and 79.4% with placebo/asenapine, asenapine, and olanzapine, respectively. The most frequent treatment-emergent AEs were headache and somnolence with placebo/asenapine; insomnia, sedation, and depression with asenapine; and weight gain, somnolence, and sedation with olanzapine. Among observed cases, mean ± SD changes in YMRS total score at week 52 were − 28.6 ± 8.1 and − 28.2 ± 6.8 for asenapine and olanzapine, respectively.The study did not have a long-term placebo group.In this 52-week extension in patients with bipolar mania, asenapine was well tolerated and long-term maintenance of efficacy was supported.

Asenapine for elderly bipolar manic patients

BackgroundBipolar disorder (BPD) in the elderly is probably heterogeneous and its etiopathogenesis is complex. The data for the treatment of late-life BPD are limited. Asenapine is approved in the United States for acute treatment of manic or mixed episodes of bipolar I disorder with or without psychotic features. AimWe report the results of acute treatment with asenapine in elderly patients with BPD. MethodElderly patients (N=11), mean age: 67.7±6.1 years, consecutively admitted to the psychogeriatric ward due to acute bipolar mania were treated by asenapine 10mg/BID monotherapy for 4 weeks. Safety and tolerability assessments included adverse events (AEs), laboratory values, and anthropometric measures. Response, a secondary assessment, was measured as change in Young Mania Rating Scale (YMRS) total score from baseline to week 4. ResultsOne patient developed a rash on day 6 of treatment and one patient developed peripheral edema on day 14 of treatment. Both AEs resolved rapidly following discontinuation of asenapine. Only mild sedation was reported by three patients. In all cases, mean (±SD) change (improvement) in YMRS total score at week 4 was −21.4±12.9 and 7/11 (63.6%) of patients remitted (YMRS≤12). ConclusionIn this small open-label study of elderly patients with bipolar mania, acute treatment with asenapine was well tolerated and effective.

Effect of asenapine on manic and depressive symptoms in bipolar I patients with mixed episodes: Results from post hoc analyses

BackgroundThe efficacy of agents useful for mania is largely unproven in patients with mixed episodes. MethodsThe efficacy of asenapine in the treatment of mixed episodes was assessed using post hoc analyses on pooled data from two identically designed 3-week, randomized, double-blind, flexible dose, placebo- and olanzapine-controlled trials and their 9-week, double-blind olanzapine-controlled extension study. Efficacy was measured by changes on Young Mania Rating Scale (YMRS) and Montgomery-Åsberg Depression Rating Scale (MADRS) total scores, and was analysed through analysis of covariance on observed cases of the intent-to-treat dataset. ResultsIn the intent-to-treat population, 295 patients had a DSM-IV-TR mixed episode (placebo: 66; olanzapine: 122; asenapine: 107) in the 3-week trials. Of these, 102 patients (olanzapine: 56; asenapine: 46) entered the 9-week extension study.At week 3, decreases in YMRS and MADRS total scores, were significantly (p<0.01) greater with asenapine (YMRS: −15.0; MADRS: −8.2) versus placebo (YMRS: −11.5; MADRS: −4.5); olanzapine did not separate from placebo (YMRS: −13.3; MADRS: −6.5). At week 12, further decreases in YMRS and MADRS total scores were observed with asenapine (YMRS: −22.4; MADRS: −11.9); non-statistically different from olanzapine (YMRS: −20.2; MADRS: −7.9). LimitationsResults are from post hoc analyses of trials that were not designed to specifically evaluate mixed episodes. ConclusionsThese exploratory analyses provide supportive evidence for the efficacy of asenapine in treating the associated symptoms of mania and depression in bipolar I patients with mixed episodes.

Age-grouped differences in bipolar mania

ObjectiveThis review of published studies compares scores on individual items of mania rating scales that systematically recorded symptom severity in persons diagnosed with bipolar disorder to identify age-grouped differences. MethodsAn extensive literature search identified item scores from mania rating scales, with a particular emphasis on baseline Young Mania Rating Scale (YMRS) item scores in published double-blind, placebo-controlled studies of bipolar I manic disorder. These baseline YMRS item scores were assessed as a proportion of the total YMRS score and compared by age group. Additional YMRS item/total scores in subjects with bipolar spectrum disorders were added to expand the analysis. ResultsPreadolescents with bipolar disorder had significantly higher YMRS item scores than adolescents on aggression, irritability, and motor activity. Young Mania Rating Scale baseline item scores relative to the YMRS total score revealed that adolescents diagnosed with bipolar I mania scored comparatively higher than did adults on YMRS aggression and irritability items, whereas adults with bipolar I manic disorder scored comparatively higher on the grandiosity and sexual interest items. Age-grouped findings from subjects diagnosed with bipolar I, II, and Not Otherwise Specified (NOS) disorders yielded similar age-grouped results. ConclusionIn age-grouped YMRS item assessments of bipolar mania, anger dyscontrol was most prominent for youth, whereas disordered thought content was paramount for adults.

A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole for the treatment of acute manic or mixed episodes in Asian patients with bipolar I disorder (the AMAZE study)

Objectives. To investigate the efficacy and safety of aripiprazole in Asian patients with manic or mixed episodes associated with bipolar I disorder. Methods. Subjects were randomised to aripiprazole (24 mg/day; reduced to 12 mg/day if needed for tolerability; n = 128) or placebo (n = 130) for 3 weeks in this multicentre, double-blind study. The primary efficacy measure was mean change from baseline in Young Mania Rating Scale (YMRS) Total score. Results. A total of 136 patients (aripiprazole 56.3%; placebo 49.2%) completed the study. The majority of patients (92.6%) received aripiprazole 24 mg/day. Aripiprazole produced statistically significant mean improvements in YMRS Total scores compared with placebo from Day 4 through to Week 3 (–11.3 vs. –5.3; P < 0.001). The most common adverse events (> 15% of patients; aripiprazole vs. placebo) were akathisia (22.0 vs. 5.6%) and insomnia (16.3 vs. 9.6%). Aripiprazole treatment resulted in no significant difference from placebo in change in mean body weight from baseline (–0.4 vs. –0.7 kg; P = 0.231). Aripiprazole was not associated with an elevated serum prolactin level. Conclusions. Aripiprazole had significantly greater efficacy than placebo for the treatment of acute manic or mixed episodes associated with bipolar I disorder in Asian patients. Treatment was generally safe and well tolerated.

Safety and efficacy of olanzapine monotherapy and olanzapine with a mood stabilizer in 18-week treatment of manic/mixed episodes for Japanese patients with bipolar I disorder

Objective:To assess the safety and efficacy of 18-week olanzapine monotherapy in Japanese patients with bipolar mania, following a 6-week, placebo- and haloperidol-controlled double-blind study (acute study). For those who discontinued the acute study due to lack of efficacy, safety and efficacy was assessed with a combination therapy of olanzapine and a mood stabilizer.Research design and methods:In this open-label, multicenter extension study, patients who completed the acute study received olanzapine (5–20 mg/day) as monotherapy, and patients who discontinued the acute study due to lack of efficacy with greater Young Mania Rating Scale (YMRS) total score than the acute study baseline, received olanzapine in combination with one of three mood stabilizers: lithium, carbamazepine, or valproate. Safety was assessed by treatment-emergent adverse events (TEAEs), vital signs, weight, and extrapyramidal symptoms (EPSs). Efficacy measures included YMRS total score, and response and remission rates of manic symptoms.Main outcome and measures:There were no deaths or serious adverse events considered potentially related to olanzapine in the monotherapy group (N = 100) or the combination-therapy group (N = 39). TEAEs occurred in 59.0% and 79.5% of patients in the monotherapy and combination-therapy groups, respectively, and their severities were mostly mild or moderate. Regarding the efficacy measures, in the monotherapy group, mean YMRS change from extension study baseline to endpoint was −3.0, and the response and remission rates at endpoint were 97.0% and 93.0%, respectively. In the combination-therapy group, mean YMRS change from extension-study baseline was −19.8; response and remission rates increased from the extension-study baseline (both 0.0%) to 64.1% and 61.5% respectively by endpoint.Conclusion:Olanzapine was generally well tolerated during the 18-week extension period in Japanese patients with bipolar mania. Results of both groups were also generally consistent with US and European studies. Monitoring of metabolic parameters is recommended.