YMRS Total Score Research Articles

Bioenergetic changes and mitochondrial dysfunction in mania versus euthymia in bipolar disorder type I

IntroductionCurrent evidence has hypothesized the involvement of mitochondrial dysfunction during the acute episodes of BD compared to symptomatic remission. So far, no studies have compared mitochondrial and bioenergetic functions both in-vivo (respiratory parameters) and ex-vivo (cellular respiration) in different phases of the disease in the same individuals.ObjectivesThis multidisciplinary pilot study aims at assessing bioenergetic and mitochondrial intra-individual differences between manic and euthymic states.MethodsFour patients with a manic episode admitted to our acute psychiatric ward were recruited. Bioenergetic parameters were measured at admission (T0) and after symptomatic remission (T1).At admission (T0) and before discharge (T1), HAMD and YMRS total scores were obtained. For the assessment of cellular respiration, polymorphonuclear cells were obtained by a Ficoll density gradient centrifugation procedure. To determine oxygen consumption (at T0 and T1), a million of living peripheral blood mononuclear cells (PBMC) were used. High-resolution respirometry was performed at 37°C by polarographic oxygen sensors in a two-chamber Oxygraph-2k system.Specific oxygen uptakes (Routine: basal oxygen consumption; Proton Leak: oxygen consumption not coupled to ATP synthesis; and ETC: maximal capacity of the electron transport chain) rates were obtained using mitochondrial chain inhibitors and uncouplers. Oxygen consumption was normalized for protein concentration. Results are expressed as picomoles of oxygen per millilitre (pmol O2/s*μg prot).Also, a constant work rate exercise test was performed on a cycle ergometer and basal and effort respiratory variables were measured.Statistical analysis was performed with the SPSS v. 25.0 and GraphPad. Results were expressed as means and SD. Nonparametric tests (Mann–Whitney, Pearson) were used to determine differences (significant at p value <0.05).ResultsOne patient was a man and three patients were women, with a mean age of 28 years old. HAMD initial and final mean scores were 11.0 and 7.0, and mean YMRS scores were 21.5 and 7.0 respectively.Results from mitochondrial oxygen consumption revealed that mean basal oxygen consumption tended to be higher in T1 (0.98±0.45) than in T0, and maximal respiratory capacity was significantly increased in T1 (2.26±0.33; p=0.028) compared to T0.Mean lactate levels and pH levels were similar in T0 and T1. Scales scores were not correlated to different pH or lactate changes after the effort task. Higher initial oxygen consumption was significantly correlated to higher maximal capacity (p<0.05) in T0 and T1.Image:ConclusionsOur preliminary results suggest that mania could imply lower oxygen consumption capacity, which should be confirmed in future studies. A bigger study is planned to determine changes in bioenergetic patterns and capacity for aerobic response in manic and depressive episodes.Disclosure of InterestNone Declared

Validity of the Aktibipo Self-rating Questionnaire for the Digital Self-assessment of Mood and Relapse Detection in Patients With Bipolar Disorder: Instrument Validation Study.

BackgroundSelf-reported mood is a valuable clinical data source regarding disease state and course in patients with mood disorders. However, validated, quick, and scalable digital self-report measures that can also detect relapse are still not available for clinical care.ObjectiveIn this study, we aim to validate the newly developed ASERT (Aktibipo Self-rating) questionnaire—a 10-item, mobile app–based, self-report mood questionnaire consisting of 4 depression, 4 mania, and 2 nonspecific symptom items, each with 5 possible answers. The validation data set is a subset of the ongoing observational longitudinal AKTIBIPO400 study for the long-term monitoring of mood and activity (via actigraphy) in patients with bipolar disorder (BD). Patients with confirmed BD are included and monitored with weekly ASERT questionnaires and monthly clinical scales (Montgomery-Åsberg Depression Rating Scale [MADRS] and Young Mania Rating Scale [YMRS]).MethodsThe content validity of the ASERT questionnaire was assessed using principal component analysis, and the Cronbach α was used to assess the internal consistency of each factor. The convergent validity of the depressive or manic items of the ASERT questionnaire with the MADRS and YMRS, respectively, was assessed using a linear mixed-effects model and linear correlation analyses. In addition, we investigated the capability of the ASERT questionnaire to distinguish relapse (YMRS≥15 and MADRS≥15) from a nonrelapse (interepisode) state (YMRS<15 and MADRS<15) using a logistic mixed-effects model.ResultsA total of 99 patients with BD were included in this study (follow-up: mean 754 days, SD 266) and completed an average of 78.1% (SD 18.3%) of the requested ASERT assessments (completion time for the 10 ASERT questions: median 24.0 seconds) across all patients in this study. The ASERT depression items were highly associated with MADRS total scores (P<.001; bootstrap). Similarly, ASERT mania items were highly associated with YMRS total scores (P<.001; bootstrap). Furthermore, the logistic mixed-effects regression model for scale-based relapse detection showed high detection accuracy in a repeated holdout validation for both depression (accuracy=85%; sensitivity=69.9%; specificity=88.4%; area under the receiver operating characteristic curve=0.880) and mania (accuracy=87.5%; sensitivity=64.9%; specificity=89.9%; area under the receiver operating characteristic curve=0.844).ConclusionsThe ASERT questionnaire is a quick and acceptable mood monitoring tool that is administered via a smartphone app. The questionnaire has a good capability to detect the worsening of clinical symptoms in a long-term monitoring scenario.

Is there a relationship between depression with anxious distress DSM-5 specifier and bipolarity? A multicenter cohort study on patients with unipolar, bipolar I and II disorders

BackgroundTo estimate the prevalence of DSM-5 anxious distress specifier (ADS) in depressed patients with major depressive disorder (MDD) or bipolar I or II disorder (BD), and to compare socio-demographic and clinical characteristics, and response to naturalistic short-term treatment between ADS and non-ADS group. Methods241 outpatients with a major depressive episode (MDE) were consecutively recruited. Outcome were remission (HDRS21 total score < 7), response (≥50% reduction of baseline HDRS21) and improvement (CGI-i score ≤ 2) after 12 weeks of treatment sustained for 4 weeks. ResultsADS was more frequent in BD than in MDD (respectively, 66.9% and 51.2%, χ2 = 6.1, p = 0.013). Compared with those non-ADS, patients with ADS had more severe depressive (respectively, HDRS21 total score 20.0 ± 4.4 and 18.6 ± 3.9, t-test = 2.67, p = 0.008) and mania symptoms (respectively, Y-MRS total score 2.2 ± 2.9 and 1.3 ± 2.3, M–W-test = 2.86; p = 0.004) at intake, a higher rate of BD family history (respectively, 35.2% and 22.2%, Χ2-test 10.4, p = 0.004) and more previous hypomanic episodes (respectively, (median (range) 0 (0–20) and 0 (0–15), MW-test = 2.39 p = 0.017). In the MDD group, patients with ADS had higher scores on hyperthymic temperament and mania symptoms (Y-MRS total score (median (range) 2.2 (0–26) and 0 (0–11), respectively, M–W test 2.071, p = 0.038). ADS and no-ADS patients did not significantly differ on outcome measures. LimitationsThe observational nature of the study and the absence of blinding in outcome assessment. ConclusionsADS is the most common DSM-5 specifier for MDE, is more frequent in BD and need a personalized treatment with moderate use of antidepressants, mostly tricyclic.

Baseline Characteristics and Early Response at Week 1 Predict Treatment Outcome in Adolescents With Bipolar Manic or Mixed Episode Treated With Olanzapine: Results From a 3-Week, Randomized, Placebo-Controlled Trial.

Early predictors of response and remission in pediatric mania are lacking, requiring further study. This was a post hoc analysis of a 3-week, randomized, placebo-controlled trial of olanzapine conducted between November 2002 and May 2005 in 161 adolescents aged 13-17 years who were diagnosed with a DSM-IV acute manic or mixed episode of bipolar I disorder. Data from the olanzapine arm were analyzed to investigate the predictive power of early response or early nonresponse (≥25% or < 25% reduction in Young Mania Rating Scale [YMRS] score, respectively) at week 1 for ultimate response or nonresponse (≥ 50% or < 50% reduction in YMRS score, respectively) and for remission (YMRS total score ≤ 12 [standard definition] or ≤ 8 [stringent definition]) at week 3. Correlates of early response and ultimate response were examined in multivariable regression models. By week 1, 69.2% of olanzapine-treated adolescents (n = 104, 2.5-20.0 mg/d) achieved early response, and 49.0% reached ultimate response at week 3. Patients with early response and early nonresponse were similar regarding baseline variables except higher scores for sleep and thought content were found with early response (P < .05) and higher olanzapine doses with early nonresponse (P < .01). At week 3, early response was associated with significantly greater improvements in YMRS, Clinical Global Impressions-Severity of Illness scale (both P < .001), and Overt Aggression Scale scores (P = .024). Adverse events were similar in patients with early response and early nonresponse, except for higher AIMS scores for patients with early nonresponse (P = .036). Early response significantly predicted ultimate response (OR = 5.61, P < .001; sensitivity = 86.3, specificity = 47.2, positive predictive value = 61.1, negative predictive value = 78.1). Significantly more early response than early nonresponse patients achieved ultimate response (61.1% vs 21.9%, P < .001) and remission defined by YMRS score ≤ 12 (45.8% vs 12.5%, P < .001) and YMRS score ≤ 8 (33.3% vs 3.1%, P < .001). In multivariable analyses, among other variables, early response remained an independent correlate of ultimate response and remission. In acute pediatric manic or mixed episodes, early response to olanzapine at week 1 was strongly associated with ultimate response and remission at week 3, while absence of early response predicted the unlikely success of further treatment. ClinicalTrials.gov identifier: NCT00050206.

Neurotrophic and inflammatory markers in bipolar disorder: A prospective study

Altered neurotrophic signaling is thought to impair neuroplasticity in bipolar disorder (BD). Brain-derived neurotrophic factor (BDNF) is proposed as a neurotrophic marker in BD. However, the current evidence for its use in monitoring disease activity and illness progression is conflicting and an exploration of additional neurotrophic markers is needed. This prospective case-control study investigated mood-specific changes in potential neurotrophic markers and their association to inflammatory activity. Patients with BD were included during an acute mood episode, either depressive (n=35) or (hypo)manic (n=32). Fifty-nine patients (88%) and 29 healthy controls (97%) completed the study. Peripheral blood levels of BDNF, vascular endothelial growth factor A (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and tumor necrosis factor alpha (TNF-α) were measured at baseline and after 2 months. Biomarker levels in patients were compared to controls and correlated to HDRS-17 and YMRS total scores and the PANSS positive subscale scores. Linear mixed model analysis revealed no significant differences in neurotrophic markers between patients and controls. We found significantly increased TNF-α levels in patients and a subsequent normalization during euthymia. None of the biomarkers strongly correlated to mood symptom severity. Despite standardized methodological practices, BDNF and VEGF levels had a wide distribution range. We need a better understanding of methodological aspects influencing the analysis of neurotrophic factors to improve future research on markers for mood state monitoring and illness progression in BD.

Efficacy of olanzapine in the treatment of bipolar mania with mixed features defined by DSM-5

BackgroundThese analyses compared efficacy of olanzapine in patients with bipolar mania with or without mixed features, as defined in the DSM-5. MethodsPooled data from 3 placebo-controlled olanzapine studies in patients having bipolar I disorder with manic/mixed episode were analyzed (N=228 olanzapine; N=219 placebo). Patients were categorized for mixed features by number of concurrent depressive symptoms at baseline (0, 1, and 2 [category A; without mixed features], and ≥3 [category B; with mixed features]), as determined by HAM-D17 item score ≥1. Depressive symptoms corresponded to 6 HAM-D17 items in the DSM-5 definition of manic episode with mixed features. Primary efficacy was evaluated by changes in the baseline-to-3-week YMRS total score. ResultsPatients were categorized into A (N=322; 72.0%) or B (N=125; 28.0%). Mean baseline YMRS total scores were 28.1 in category A and 27.8 in category B. Least-squares mean change of YMRS total scores in categories A and B (olanzapine versus placebo) were −11.78 versus −6.86 and −13.21 versus −4.72, respectively. Patients in the olanzapine- compared with placebo-group experienced a greater decrease in YMRS total score for both categories (p<0.001). An interaction between mixed features and treatment was seen in YMRS change at a 0.3 significance level (p=0.175). LimitationsThe results are from post-hoc analyses. ConclusionsOlanzapine was efficacious in the treatment of bipolar I mania, in patients both with and without mixed features, defined by DSM-5; however, greater efficacy was observed in patients with mixed features having more severe depressive symptoms.

EPA-1128 – Long-acting second-generation antipsychotics: Improving subjective experience of pharmacological treatment and quality of life

Long-acting injectable (LAI) antipsychotics have been used as an alternative to oral antipsychotic formulations. to evaluate the impact of switching to a LAI second-generation antipsychotic (SGA) in terms of changes in patient's psychopathology, subjective experience of drug and quality of life. 18 adult outpatients diagnosed with Schizoaffective disorder (by means of the SCID-I/P) and attending the Psychiatric Unit of the University of Florence were recruited. All patients were under a stabilized therapy with a single oral SGA (either olanzapine or paliperidone) and were switched to its corresponding LAI formulation (olanzapine pamoate or paliperidone palmitate). Patients were assessed by means of the following questionnaires: MADRS, YMRS, PANSS, DAI-10, SWN and SF-36 at enrolment (T0) and after 6 months (T1). A significant reduction was found between T0 and T1 (p<.05) in PANSS total, negative and general psychopathology mean scores, as well as in mean MADRS and YMRS total scores. No difference was found for positive PANSS mean scores. We observed a significant increase of mean DAI-10 and SWN total scores between T0 and T1 (p<.05). A reduction of side effects like sedation and blunted affect between T0 and T1 (p<.05) was confirmed by significant increases in mean SF-36 subscales scores, such as: general health (p<.01) change in health (p<.01) and social integration (p<.05). Treatment with LAI SGAs seems to be a valid alternative in patients with Schizoaffective disorder. Our preliminary data suggest an improvement in patient's subjective experience of pharmacological therapy and health-related quality of life, together with a similar efficacy on psychopathology.

Abstracts

Background: Manic episodes with depressive symptoms represent a severe presentation of bipolar disorder. The effi-cacy of drugs shown useful for pure mania is largely unproven in the subset of patients with depressive symptoms. We reviewed different post-hoc analyses evaluating asenapine's effects in patients experiencing depressive symptoms during manic episodes. Methods: Different post-hoc analyses have been conducted using pooled data of two 3-week, randomized, placebo-and olanzapine-controlled trials. 1,2 Different definitions have been used to ascertain the presence of clinically relevant depressive symptoms at baseline: MADRS total score ≥ 20, CGI-BP-D scale severity score ≥ 4, DSM-IV mixed episode; 3,4 DSM-IV mixed episode with MADRS total score ≥ 20; 5 DSM-5 mixed features using different severity cut offs. 6 For each population, asenapine and olanzapine were compared with placebo on different depression endpoint (remission rates: MADRS ≤ 12, mean change in MADRS total score). Effect on manic symptoms was also assessed in some populations (remission rates: YMRS ≤ 12, mean change in YMRS total score) end points. Results: In all populations, asenapine was significantly superior to placebo at days 7 and 21 in reducing depressive symptoms and significantly superior to olanzapine at day 7. In a few populations, olanzapine also tended to improve depressive symptoms at day 21. Asenapine significantly improved manic symptoms as compared to placebo as early as day 2 in patients with DSM-IV mixed episodes or DSM-5 mixed features, and was significantly superior to olanzapine at day 2 in patients with the most severe depressive symptoms. Olanzapine did not separate from placebo in reducing manic symptoms severity. Conclusion: In all post-hoc analyses asenapine signifi-cantly improved both manic and depressive symptoms in bipolar patients experiencing manic episodes with depressive symptoms. Anti-manic agents appear to have differential efficacy in people who experience depressive symptoms during a manic episode. (Less)

Efficacy of aripiprazole versus placebo as adjuncts to lithium or valproate in relapse prevention of manic or mixed episodes in bipolar I patients stratified by index manic or mixed episode

BackgroundDifferences in response to treatment have been observed for bipolar disorder (BPD) patients with manic or mixed episodes. This post-hoc analysis examined the maintenance effect of aripiprazole in combination with lithium or valproate in subpopulations of patients entering a relapse prevention study with either manic or mixed bipolar episodes. MethodsA long-term relapse prevention study of BPD patients with manic or mixed episodes included a single-blind stabilization phase, in which patients were stabilized with single-blind aripiprazole plus lithium or valproate (maintaining stability for 12 weeks), and a double-blind relapse assessment phase, where patients were randomized to aripiprazole or placebo plus lithium or valproate for up to 52 weeks. Lithium and valproate groups were pooled. ResultsThe time to relapse of any mood episode was longer in the adjunctive aripiprazole group versus the lithium/valproate monotherapy group for the manic (p<0.01) but not mixed population (p=0.59). The LOCF analysis indicated a significantly greater reduction in YMRS total score from baseline with continued aripiprazole versus placebo at 52 weeks in both manic (treatment difference=−3.32, p<0.01) and mixed episode populations (treatment difference=−2.56, p=0.02). Overall, adverse event profiles were similar between the populations. LimitationThe lithium and valproate subgroups were combined. ConclusionsThe continuation of aripiprazole in stabilized BPD patients treated with lithium or valproate increased the time to relapse of any mood episode for manic but not mixed patients; both groups achieved greater stability in YMRS total score with adjunctive aripiprazole. Thus, adjunctive aripiprazole may be more appropriate for stabilized patients with manic episodes.

Ziprasidone in Pediatric Bipolar Disorder: A 6-Week, Open-Label Comparison of Rapid vs. Slow Dose Titration

Objective: This open- label clinical trial evaluated the dosing, safety, and effectiveness of rapid vs. slow titration of ziprasidone in pediatric bipolar disorder over a period of 6 weeks. Methods: Study participants (aged 10-17 years) were diagnosed with bipolar disorder using standardized diagnostic instruments. Additionally, standardized rating scales were used to assess changes in mood, adverse effects, and overall functioning. Twenty-eight participants were randomly assigned to either the rapid- or slow-dose titration of ziprasidone. Linear mixed model analyses of repeated measures—adjusting for the age and respective baseline clinical score— were used to evaluate the main effects and the 2-way interaction effect (incorporating titration group and time). Cox Proportional Hazards Regression, adjusting for age, compared the time-to-treatment response for the rapid- vs. the slow-dose titration of ziprasidone. Treatment response was defined as ≥ 50% reduction from baseline on the Young Mania Rating Scale total scores for at least two sustained periods. Results: Irrespective of titration group assignment, mean YMRS total scores decreased significantly across the 6 weeks of treatment for the combined groups (p=.008). The median time to response was 2 weeks for the rapid titration group and 3 weeks for the slow group, but the two survival curves of treatment response did not differ significantly between the two titration groups (p=0.92). Overall, ziprasidone was tolerated well by the study participants in both groups (slow and rapid titration). Conclusions: No significant difference emerged between the rapid- and slow-titration groups over the 6 weeks of ziprasidone treatment on severity of manic symptoms or time-to-response. There was a reduction in manic symptoms in both the rapid and slow titration groups over the 6 week period. A much larger sample is required to test for meaningful differences between the two titration groups, in regards to improving clinical symptoms and minimizing adverse effects from ziprasidone.

P-213 - Early improvement as a predictor of outcome in manic/mixed episodes associated with bipolar I disorder: Post-hoc analyses of asenapine studies

To determine whether early manic symptom improvement predicts outcome in bipolar I disorder patients experiencing manic or mixed episodes. Pooled data from two 3-week trials; asenapine (5 or 10 mg BID; n = 372), olanzapine (5-20 mg QD; n = 391), or placebo (n = 197). Early improvement (YMRS total score changes from baseline ≥15%, ≥20%, and ≥25%) was assessed at days 2, 4, and 7. Associations between early improvement and week 3 outcomes (YMRS response [≥50% total score reduction] and remission [total score ≤12]) were calculated using Fisher's exact tests; odds ratios classified their relative strength. Sensitivity (SN), specificity (SP), and positive (PPV) and negative (NPV) predictive values were calculated as previously described ( J_Clin_Psychiatry_ 2009;70:344–353). Early improvement was strongly associated with positive outcomes. The earliest positive associations across all cutoffs occurred with asenapine at day 2 (response, all P < 0.04; remission, all P < 0.007), olanzapine at day 4 for response (all P < 0.02) and day 2 for remission (all P < 0.002), and placebo on day 7 (response, all P < 0.003; remission, all P ≤ 0.0005). Odds ratios were higher for asenapine (1.8–9.1) than olanzapine (1.4–3.5) and placebo (1.3–8.0). Respective day 4 remission values for SN, SP, PPV, and NPV at the ≥ 15% cut-off were 80%, 58%, 48%, and 85% for asenapine; 76%, 43%, 49%, and 71% for olanzapine; and 50%, 67%, 31%, and 82% for placebo. Early improvement was strongly associated with week 3 response and remission; high NPVs indicated little chance of stable remission in the absence of early improvement.

Asenapine

Asenapine is an atypical antipsychotic agent available in sublingual formulations (5 or 10 mg) and indicated in the US (Saphris) for the acute treatment, as monotherapy or adjunctive therapy, of manic and mixed episodes and in the EU (Sycrest) for the treatment of moderate to severe manic episodes, in adult patients with bipolar I disorder. In two large (both n = 480), well designed, 3-week trials in adult patients with bipolar I disorder, asenapine monotherapy was significantly more effective than placebo at improving mania symptoms, as assessed using the Young Mania Rating Scale total score (YMRS; primary endpoint), with significant differences between the asenapine and placebo groups occurring after 2 days of treatment. In both trials, Clinical Global Impression for Bipolar Disorder (CGI-BP) scale mania severity scores exceeded those of placebo. In one trial, response and remission rates exceeded those of placebo. In a 9-week extension study that recruited completers from the monotherapy trials, there were no significant differences between asenapine and olanzapine groups in terms in Montgomery-Åsberg Depression Rating Scale (MADRS) scores, CGI-BP mania severity scores, YMRS response rates or YMRS remission rates during the extension phase. In the extension study, the efficacy of asenapine monotherapy appeared to be maintained over 40 weeks (total treatment duration of 52 weeks). In a 12-week trial of asenapine as adjunctive therapy to lithium or valproate, asenapine was more effective than placebo in improving manic symptoms, based on the difference between groups in the YMRS total score at week 3 (primary endpoint). Most adverse events associated with asenapine were of mild to moderate severity, with <7% of asenapine recipients experiencing serious adverse events (vs 7% with placebo). In a pooled analysis of the monotherapy trials, the most common adverse events (occurring in ≥ 5% of patients and at twice the incidence of placebo) reported during acute phase asenapine monotherapy for bipolar mania were somnolence, dizziness, extrapyramidal symptoms (EPS, other than akathisia) and increased bodyweight, which were similar in nature to those occurring during longer-term monotherapy with asenapine. EPS did not worsen in severity during longer-term asenapine monotherapy. Asenapine had minimal effects on plasma glucose, lipid and prolactin levels over both short- and longer-term treatment periods, and had little pro-arrhythmogenic potential. Further active comparator trials and longer-term tolerability and safety data are required. In the meantime, asenapine is a further option for the management of manic and/or mixed symptoms in patients with bipolar I disorder and may be of particular value for patients who are at high risk for metabolic abnormalities.

A comparison of two fixed doses of aripiprazole with placebo in acutely relapsed, hospitalized patients with bipolar disorder I (manic or mixed) in subpopulations (CN138-007)

This study evaluated the efficacy and safety of two fixed doses of aripiprazole (15 mg/day, n = 131 and 30 mg/day, n = 136) compared with placebo (n = 134) in acutely manic or mixed bipolar I hospitalized patients. The mean change from baseline to Week 3 in the YMRS Total Scores was − 10.01 (95% CI: − 11.92, − 8.09) for aripiprazole 15 mg/day, − 10.80 (95% CI: − 12.71, − 8.90) for aripiprazole 30 mg/day, and − 10.12 (95% CI: − 12.01, − 8.24) for placebo. The most frequent adverse events (≥ 10% and greater than placebo) for either of the aripiprazole treatment groups were headache, nausea, dyspepsia, insomnia, agitation, constipation, akathisia, anxiety, lightheadedness, vomiting, diarrhea, asthenia and extremity pain. Aripiprazole 15 or 30 mg/day was not significantly more effective than placebo in the treatment of bipolar I disorder acute mania at endpoint (Week 3). A high placebo response rate may have accounted for the lack of separation between treatment groups.

Evaluation of the efficacy and safety of paliperidone extended-release in the treatment of acute mania: A randomized, double-blind, dose-response study

Atypical antipsychotics are effective in the treatment of bipolar I disorder. In this 3-week double-blind study, the efficacy and safety of paliperidone extended-release (ER) tablets were assessed in patients with acute mania. Patients experiencing a manic or mixed episode (Young Mania Rating Scale [YMRS] total score ≥20), were randomly assigned to 1 of 3 fixed doses of once-daily paliperidone ER (3, 6, or 12-mg), or placebo (1:1:1:1 ratio). In total, 469 patients were randomly assigned to treatment with paliperidone ER 3mg (n=112), 6 mg (n=120), or 12 mg (n=115); or placebo (n=122). Mean (SD) change in YMRS total score from baseline to the 3-week endpoint (primary variable) was statistically significantly different for the paliperidone ER 12 mg group (-13.5 [9.17], p=0.025), but not the 6 mg (-11.4 [9.98], p=0.57) or 3mg (-9.1 [11.18], p=0.79) groups compared with placebo (-10.1 [10.21]). Headache was the most common treatment-emergent adverse event (17% total paliperidone ER versus 12% placebo). A statistically significant (p=0.0032) treatment-by-country interaction occurred, which confounded interpretation of study results. Paliperidone ER and placebo did not differ statistically for the primary efficacy variable among patients from the United States sites (74% of the intent-to-treat analysis set). Paliperidone ER 12 mg/day was superior to placebo in the treatment of acute mania. Change from baseline in YMRS total score increased with the dose of paliperidone ER. Paliperidone ER was generally tolerated by patients with bipolar I disorder and no new safety signal was detected.

Assessment of safety, tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar mania: a 46-week, open-label extension following a 6-week double-blind study

Objective:This study evaluated the long-term tolerability and effectiveness of aripiprazole adjunctive to lithium or valproate in partial responders with bipolar mania.Methods:Completers of a 6-week double-blind comparison of adjunctive aripiprazole versus placebo in bipolar mania partially responsive to lithium or valproate monotherapy could enter a 46-week extension treatment with open-label adjunctive aripiprazole plus lithium (ARI + LI) or valproate (ARI + VAL). Safety, efficacy and functioning were assessed.Clinical trial registration:CN138-134LT: Study of Aripiprazole in Patients With Bipolar I Disorder; ID number: NCT00257972; registry: www.clinicaltrials.govResults:In total, 283 (ARI + LI n = 108; ARI + VAL n = 175) patients entered and 146 (ARI + LI n = 55; ARI + VAL n = 91) completed the 46-week, open-label extension. Frequently reported adverse events (AEs) that occurred with ARI + LI vs. ARI + VAL were: tremor (17.0% vs. 12.1%), akathisia (6.6% vs. 8.6%), headache (6.6% vs. 4.0%), insomnia (9.4% vs. 10.3%), depression (7.5% vs. 9.2%) and weight increase (11.3% vs. 8.6%). Extrapyramidal symptom-related AEs occurred in 24 (22.6%) ARI + LI- and 38 (21.8%) ARI + VAL-treated patients, with eight discontinuations. The majority of new-onset events of akathisia and insomnia occurred early. Mean (SE) weight change from double-blind endpoint to Week 46 (LOCF) was 2.3 (0.6) kg with ARI + LI and 2.0 (0.4) kg with ARI + VAL. Significant improvements from baseline over the 52 weeks (LOCF) occurred with ARI + LI and ARI + VAL on mean (95%CI) YMRS total score (−16.5 [−18.1; −14.8] and −17.6 [−18.9; −16.3], both p < 0.001 vs. baseline) and MADRS total score (−1.7 [−3.3; −0.1], p < 0.05 vs. baseline vs. −2.7 [−4.0; −1.4], p < 0.001 vs. baseline). Over the 46-week extension, continued aripiprazole provided continued YMRS improvement with ARI + LI (−2.9) and ARI + VAL (−3.3), while mean MADRS total changes were +1.1 and +1.0, respectively, and LIFE-RIFT changes were 0.2 and −0.5, respectively.Conclusions:Long-term aripiprazole adjunctive to lithium/valproate in bipolar mania was safe and well tolerated. Improvements in manic symptoms and functioning were maintained. Aripiprazole, adjunctive to either lithium or valproate, appeared to be equally safe and effective combinations for the treatment of bipolar disorder.Limitations:As an open-label extension study with a low completion rate, a conservative interpretation of the findings is warranted. Additionally, the study population was not randomly selected but chosen at the discretion of the investigator, and patients did not maintain therapeutic levels of their mood stabiliser consistently.

Asenapine in the treatment of acute mania in bipolar I disorder: A randomized, double-blind, placebo-controlled trial

Background Asenapine is indicated in adults for acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features. This randomized, double-blind, placebo-controlled trial assessed the efficacy, safety, and tolerability of asenapine in bipolar I disorder. Methods Adults experiencing manic or mixed episodes were randomized to 3 weeks of flexible-dose treatment with sublingual asenapine (day 1: 10 mg BID, 5 or 10 mg BID thereafter; n = 185), placebo ( n = 98), or oral olanzapine (day 1: 15 mg QD, 5–20 mg QD thereafter; n = 205). Primary efficacy, YMRS total score change from baseline to day 21, was assessed using ANCOVA with last observation carried forward. Results Mean daily doses were 18.4 mg asenapine and 15.9 mg olanzapine. Least squares mean changes in YMRS total score on day 21 were significantly greater with asenapine than placebo (− 11.5 vs − 7.8; P < 0.007), with advantage seen as early as day 2 (− 3.2 vs − 1.7; P = 0.022). Changes with olanzapine on days 2 and 21 also exceeded placebo (both P < 0.0001). YMRS response and remission rates with olanzapine, but not asenapine, exceeded those of placebo. Incidence of EPS-related adverse events was 10.3%, 3.1%, and 6.8% with asenapine, placebo, and olanzapine, respectively; incidence of clinically significant weight gain (7.2%; 1.2%; 19.0%). Mean weight change (baseline to endpoint) was 0.9, 0.1, and 2.6 kg with asenapine, placebo, and olanzapine, respectively. Limitations As this short-term study was designed for comparisons with placebo, any comparisons between asenapine and olanzapine should be interpreted cautiously. Conclusions Asenapine was superior to placebo in reducing YMRS total score and was well tolerated.

PW01-36 - The long-term safety, tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar I patients partially non-responsive to mood stabilisers

ObjectiveTo evaluate the long-term tolerability and effectiveness of aripiprazole adjunctive to lithium or valproate in bipolar mania.MethodsCompleters of a 6-week double-blind comparison of adjunctive aripiprazole versus placebo in bipolar mania partially responsive to monotherapy were followed up over 46-weeks on open-label aripiprazole plus lithium (ARI+LI) or valproate (ARI+VAL).Results283 (ARI+LI n=108; ARI+VAL n=175) patients entered and 146 (ARI+LI n=55; ARI+VAL n=91) completed the 46-week extension. Safety results for both combinations were consistent with the known tolerability profile of aripiprazole, lithium and valproate. No clinically significant changes in lipids or glucose were observed with either ARI+LI or ARI+VAL. Mean (SE) weight change from double-blind endpoint to Week 46 (LOCF) was 2.3 (0.6) kg with ARI+LI and 2.0 (0.4) kg with ARI+VAL. Temporal analysis of the time of first onset of adverse events showed that akathisia and insomnia tended to occur early in treatment, with few new cases in patients previously treated with aripiprazole during the 6-week study.Significant improvements from baseline in YMRS total score and MADRS total score were sustained over the 52 weeks with both ARI+LI and ARI+VAL treatment.Mean reduction from baseline at Week 52 LOCF[95%CI], p value vs baselineARI+LIARI+VALYMRS total score-16.5 [-18.1; -14.8], p&lt;0.001-17.6 [-18.9; -16.3] p&lt;0.001MADRS total score-1.7 [-3.3; -0.1] p&lt;0.05-2.7 [-4.0; -1.4] p&lt;0.001ConclusionsLong-term aripiprazole adjunctive to lithium/valproate in bipolar mania was safe and well-tolerated. Improvements in manic and depressive symptoms observed during the first 6 weeks of treatment were maintained.

Translation of Randomised Controlled Trial Findings into Clinical Practice: Comparison of Olanzapine and Valproate in the EMBLEM Study

The aim of this study was to compare the outcomes of olanzapine- and valproate-treated patients in an observational study of acute mania with the results of a randomised controlled trial (RCT) assessing the same treatments. EMBLEM (European Mania in Bipolar Evaluation of Medication) was a 2-year, prospective, observational study of health outcomes associated with the treatment of mania. Severity of mania and depression were assessed at baseline and 6 weeks using the YMRS and the 5-item version of the HAMD, respectively. 621 patients were analysed (n=107 valproate, n=514 olanzapine). Both groups improved from baseline to 6 weeks in mean YMRS and HAMD-5 total scores, with greater mean improvements in the olanzapine compared with the valproate group. Olanzapine was associated with more weight gain and less gastrointestinal difficulties than valproate. The EMBLEM results support those of the RCT, which suggest that olanzapine monotherapy seems to be more effective than valproate monotherapy in the treatment of acute mania.

FC05-02 Translation of randomised controlled trial findings into clinical practice: Comparison of olanzapine and valproate in the emblem study

Aims:To contrast the outcomes of olanzapine- and valproate-treated patients in an observational study of acute mania with the results of a RCT assessing the same treatments (Tohen et al., 2002).Methods:EMBLEM (European Mania in Bipolar Evaluation of Medication) was a 2-year, prospective, observational study of health outcomes associated with treatment of mania. Severity of mania and depression was assessed at baseline and 6 weeks using the YMRS and 5-item version of the HAMD, respectively. The RCT was a 3-week, randomised, double-blind comparison of olanzapine (n=125) and divalproate-treated (n=123) patients hospitalised for acute manic or mixed episodes. The YMRS and HAMD were used to quantify manic and depressive symptoms, respectively.Results:621 EMBLEM patients were analysed (n=107 valproate, n=514 olanzapine). Both observed groups improved from baseline to 6 weeks in mean YMRS and HAMD-5 total scores, with significantly greater mean improvements in the olanzapine compared with the valproate group using linear regression to adjust for baseline differences. The RCT reported significantly greater mean YMRS improvement (but not HAMD) in the olanzapine-treated group. EMBLEM patients treated with olanzapine experienced significantly greater weight gain than patients treated with valproate, similar to RCT results. There was a significantly greater incidence of treatment-emergent gastrointestinal adverse events in EMBLEM patients treated with valproate.Conclusions:The EMBLEM results support those of the RCT, which suggest that olanzapine monotherapy may be more effective than valproate monotherapy in the treatment of acute mania. Contrasting observational and RCT results present methodological challenges but can provide important complementary information.

Aripiprazole monotherapy in the treatment of acute bipolar I mania: A randomized, double-blind, placebo- and lithium-controlled study

ObjectivesTo evaluate the efficacy and safety of aripiprazole as acute and maintenance of effect monotherapy for acute bipolar mania. MethodsPatients with acute bipolar I mania (DSM-IV-TR: YMRS ≥20), manic or mixed (with or without psychotic features) were randomized to double-blind aripiprazole (15–30 mg/day; n=155), placebo (n=165) or lithium (900–1500 mg/day; n=160) (1:1:1) for 3 weeks. Aripiprazole- and lithium-treated patients remained on blinded treatment for 9 additional weeks. The primary outcome was the mean change from baseline in YMRS Total score (LOCF) to Week 3. Secondary outcomes included the mean change from baseline in YMRS Total score (LOCF) at all other timepoints up to Week 12. ResultsAripiprazole demonstrated significantly greater improvement than placebo in mean YMRS Total score from baseline to Day 2 (−4.3 vs.−2.8; p=0.003), and up to Week 3 (−12.6 vs. −9.0; p<0.001). Significant improvement in YMRS Total score was also seen with lithium versus placebo at Week 3 (−12.0 vs. −9.0; p=0.005). Improvements in YMRS Total score were maintained to Week 12 for aripiprazole (−14.5) and lithium (−12.7). Response rates at Week 3 were significantly higher with aripiprazole (46.8%) and lithium (45.8%) than placebo (34.4%; both p<0.05, LOCF); increasing to Week 12 with aripiprazole (56.5%) and lithium (49.0%). Most common adverse events with aripiprazole were headache, nausea, akathisia, sedation, and constipation; with lithium were nausea, headache, constipation, and tremor. ConclusionsAripiprazole provided statistically significant improvement of acute mania within 2 days, continuing over 3 weeks and sustained over 12 weeks. The magnitude of improvement to Week 12 was similar with aripiprazole and lithium.