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INTRODUCTION: Sustained deep neuromuscular blockade (NMB) during laparoscopic surgery may facilitate optimal surgical conditions. This exploratory study assessed whether deep NMB improves surgical conditions and, in doing so, allows use of lower insufflation pressures during laparoscopic cholecystectomy. We further assessed whether use of low insufflation pressure improves patient pain scores after surgery.METHODS: This randomized, controlled, blinded study (NCT01728584) compared use of deep (1-2 post-tetanic-counts) or moderate (train-of-four ratio 10%) NMB, and lower (8 mmHg) or higher (12 mmHg; 'standard') insufflation pressure in a 2 × 2 factorial design. Primary endpoint was surgeon's overall satisfaction with surgical conditions, rated at end of surgery using an 11-point numerical scale. Post-operative pain scores were also evaluated. Data were analyzed using analysis of covariance.RESULTS: Of 127 randomized patients, 120 had evaluable data for the primary endpoint. Surgeon's score of overall satisfaction with surgical conditions was significantly higher with deep versus moderate NMB indicated by a least-square mean difference of 1.1 points (95% confidence interval 0.1-2.0; P = 0.026). Furthermore, strong evidence of an effect was observed for standard versus low pressure: least-square mean difference of 3.0 points (95% confidence interval 2.1-4.0; P < 0.001). No significant difference was observed in average pain scores within 24 h post-surgery for low versus standard pressure [0.17 (95% confidence interval -0.67 to +0.33); P = 0.494].CONCLUSIONS: Although associated with significantly improved surgical conditions, deep NMB alone was insufficient to promote use of low insufflation pressure during laparoscopic cholecystectomy. Furthermore, low insufflation pressure did not result in reduced pain, compared with standard pressure.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01728584.FUNDING: Merck Sharp

INTRODUCTION: Sustained deep neuromuscular blockade (NMB) during laparoscopic surgery may facilitate optimal surgical conditions. This exploratory study assessed whether deep NMB improves surgical conditions and, in doing so, allows use of lower insufflation pressures during laparoscopic cholecystectomy. We further assessed whether use of low insufflation pressure improves patient pain scores after surgery.METHODS: This randomized, controlled, blinded study (NCT01728584) compared use of deep (1-2 post-tetanic-counts) or moderate (train-of-four ratio 10%) NMB, and lower (8 mmHg) or higher (12 mmHg; 'standard') insufflation pressure in a 2 × 2 factorial design. Primary endpoint was surgeon's overall satisfaction with surgical conditions, rated at end of surgery using an 11-point numerical scale. Post-operative pain scores were also evaluated. Data were analyzed using analysis of covariance.RESULTS: Of 127 randomized patients, 120 had evaluable data for the primary endpoint. Surgeon's score of overall satisfaction with surgical conditions was significantly higher with deep versus moderate NMB indicated by a least-square mean difference of 1.1 points (95% confidence interval 0.1-2.0; P = 0.026). Furthermore, strong evidence of an effect was observed for standard versus low pressure: least-square mean difference of 3.0 points (95% confidence interval 2.1-4.0; P < 0.001). No significant difference was observed in average pain scores within 24 h post-surgery for low versus standard pressure [0.17 (95% confidence interval -0.67 to +0.33); P = 0.494].CONCLUSIONS: Although associated with significantly improved surgical conditions, deep NMB alone was insufficient to promote use of low insufflation pressure during laparoscopic cholecystectomy. Furthermore, low insufflation pressure did not result in reduced pain, compared with standard pressure.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01728584.FUNDING: Merck Sharp

Keming Gao,1 Mary Mackle,2 Pilar Cazorla,2 Jun Zhao,2 Armin Szegedi2 1Department of Psychiatry, Mood and Anxiety Clinic in the Mood Disorders Program, Case Western Reserve University, School of Medicine, Cleveland, OH, USA; 2Merck, Rahway, NJ, USA Background: Patients with schizophrenia or bipolar disorder (BPD) may be differentially sensitive to antipsychotics. This study assessed the median time to onset, duration, and rate of somnolence associated with asenapine and other antipsychotics in both indications. Methods: Ten clinical trials (n = 4786) were analyzed as five cohorts pooled according to indication and study design. Results: In the short-term schizophrenia cohort, the incidence of somnolence was 13.1%, 19.1%, 8.5% 5.2%, and 6.9% with asenapine, olanzapine, risperidone, haloperidol, and placebo, respectively. Median time to onset of somnolence was 2 days for asenapine and olanzapine, and 6, 3, and 7 days for risperidone, haloperidol, and placebo, respectively. Median duration was 15 days for asenapine and olanzapine, and 3, 22.5, and 4.5 days for risperidone, haloperidol, and placebo, respectively. In the long-term schizophrenia cohort, the incidence, time to onset, and duration of somnolence with asenapine and olanzapine were 18.4% versus 19.6%, 9.0 days versus 12 days, and 22 days versus 21 days, respectively. In schizophrenia with persistent negative symptoms, the incidence, median time to onset, and duration of somnolence with asenapine and olanzapine were 18.5% versus 21.1%, 9.0 days versus 7.5 days, and 25.0 days versus 41.5 days, respectively. In the monotherapy for BPD cohort, the incidence of somnolence with asenapine, olanzapine, and placebo was 23.8%, 26.4%, and 6.4%, respectively. Median time to onset and duration of somnolence with asenapine, olanzapine, and placebo were 1, 2, and 2 days, respectively, and 7, 8.5, and 5 days. In the adjunctive therapy for BPD cohort, the incidence, median time to onset, and duration of somnolence with asenapin

Pilar Cazorla, Jun Zhao, Mary Mackle, Armin Szegedi Merck, Rahway, NJ, USA Background: An exploratory post hoc analysis was conducted to evaluate the potential differential effects over time of asenapine and olanzapine compared with placebo on the eleven individual items comprising the Young Mania Rating Scale (YMRS) in patients with manic or mixed episodes in bipolar I disorder. Methods: Data were pooled from two 3-week randomized, controlled trials in which the eleven individual items comprising the YMRS were measured over 21 days. An analysis of covariance model adjusted by baseline value was used to test for differences in changes from baseline in YMRS scores between groups. Results: Each of the eleven individual YMRS item scores was significantly reduced compared with placebo at day 21. After 2 days of treatment, asenapine and olanzapine were superior to placebo for six of the YMRS items: disruptive/aggressive behavior, content, irritability, elevated mood, sleep, and speech. Conclusion: Reduction in manic symptoms over 21 days was associated with a broad-based improvement across all symptom domains with no subset of symptoms predominating. Keywords: asenapine, Young Mania Rating Scale, bipolar disorder, YMRS, antipsychotic, olanzapine

Pilar Cazorla,1 Mary Mackle,2 Jun Zhao,2 Xianwei Ha,2 Armin Szegedi21Formerly, Merck Rahway, 2Merck, Rahway, NJ, USABackground: In clinical practice, clinicians often need to switch antipsychotic medications in patients with schizophrenia to optimize treatment outcomes. Here, we describe the safety and tolerability of switching existing antipsychotic treatments to asenapine or olanzapine monotherapy using various switching regimens.Methods: Data were pooled from 949 patients in two 26-week randomized double-blind studies. Patients with persistent negative symptoms of schizophrenia, stable for at least 5 months prior to screening and 1 additional month before randomization, were randomized to and treated with either asenapine (n = 485) or olanzapine (n = 464), and were tapered off existing antipsychotic(s) at variable rates within 28 days.Results: Prior to randomization, most patients were treated with second-generation antipsychotics (SGAs) (asenapine: 79.6%; olanzapine: 78.2%) and first-generation antipsychotics (FGAs) (31.1%; 29.7%), while depot formulations were used by 12.4% and 11.4%, respectively. Median time to taper off previous antipsychotics was 7 days, with approximately 40% of patients abruptly discontinuing their previous medication. Similar percentages of patients in each group reported at least one adverse event (AE) (asenapine: 76.9%; olanzapine: 75.2%). The majority of AEs occurred within the first 28 days. The most frequently reported AEs were somnolence, insomnia, and headache. The incidence of AEs in patients switching from SGAs, FGAs, or depot medications was similar between asenapine and olanzapine (77.5% vs 74.6%, 75.5% vs 79.7%, 85.0% vs 86.8%, respectively). AEs were more frequent in subjects previously treated with two antipsychotics (asenapine: 79.4%; olanzapine: 83.9%) versus one antipsychotic (asenapine: 76.3%; olanzapine: 72.2%) in the switch period.Conclusion: The presented data from post hoc pooled analyses may provide practical guida

André Tadic1, Dan Rujescu2, Matthias J Müller3, Ralf Kohnen4, Hans H. Stassen5, Armin Szegedi6, Norbert Dahmen11Department of Psychiatry, University of Mainz, Germany; 2Department of Psychiatry, University of Munich, Germany; 3Clinic for Psychiatry and Psychotherapy, Marburg-Sued, Germany, and Clinic for Psychiatry and Psychotherapy, Giessen, Germany; 4IMEREM, Nuernberg, Germany; 5Department of Psychiatry, University of Zurich, Switzerland; 6Organon, Roseland, NJ, USAAbstract: This study investigated the possible association of the interleukin-1 beta (IL-1β) C-511T promoter polymorphism and the interleukin-1 receptor antagonist (IL-1Ra) (86bp)n variable number of tandem repeats (VNTR) polymorphism with antidepressant response to paroxetine and mirtazapine treatment. The study group consisted of 101 patients suffering from DSM-IV major depression participating in a randomized double-blind controlled clinical trial. Patients homozygous for the IL-1β-511T allele had a significantly faster and more pronounced response to paroxetine treatment than IL-1β-511C allele carriers. No association was found for the IL-1β C-511T polymorphism with mirtazapine treatment response. The IL-1Ra VNTR showed neither an association with paroxetine nor with mirtazapine treatment response. Our results provide further suggestive evidence that time course of response and antidepressant efficacy of paroxetine, but not of mirtazapine, is influenced in a clinically relevant manner by the IL-1β C-511T gene variant. Our data do not support the hypothesis that the IL-1Ra (86bp)n VNTR affects antidepressant treatment response to paroxetine or mirtazapine. An independent replication of our finding is needed. If replicated, the IL-1β C-511T promoter polymorphism could be considered useful for prospective confirmatory pharmacogenetic trials in patients with major depression.Keywords: major depression, antidepressive agents, treat