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Abstract: Background: Gaps remain between rating scale changes obtained in a clinical trial and what those results mean in clinical practice. Objective: To better understand the relevance of results from a clinical trial we examined the relationship between rating scale measures and the clinicians'' assessment of illness severity. Methods: Data from a randomized double-blind 8-week study of bipolar I depression were examined post hoc in patients who received placebo (PLA, n =355), olanzapine (n =351) (OLZ, 5 to 20 mg/d), or olanzapine–fluoxetine combination (n =82) (OFC, 6 and 25, 6 and 50, or 12 and 50 mg/d). Principal components analysis identified related symptoms (factors) from Montgomery–Åsberg Depression Rating Scale (MADRS) item scores. Regression analysis examined baseline to endpoint changes in factor scores and Clinical Global Impression (CGI) scores. Mixed-effects model repeated measures analysis assessed differences between treatment groups. Results: MADRS factors identified were: sadness, negative thoughts, detachment, and neurovegetative symptoms. Factor and CGI scores were significantly reduced from baseline to endpoint (LOCF) in the combination therapy group as compared with placebo (p <.01). Changes in factor scores were highly correlated (p <.001) with changes in the CGI. Over 80% of this treatment effect was attributable to indirect effects of improvements in the MADRS factors, the remaining difference could not be explained even when changes in the YMRS and HAMA scores were included in the analytical model. Conclusions: The changes in MADRS factors were closely aligned with the clinician''s assessment of overall depression severity, which may suggest a high degree of clinical relevance for differences observed between treatments. [Copyright &y& Elsevier]

Abstract: Background: Rapid cycling in bipolar disorder has been associated with greater morbidity. We examine whether rapid cycling affects treatment response to olanzapine or divalproex in acute mania. Methods: A post hoc analysis of a 47-week, randomized, double-blind study compared olanzapine (5–20 mg/day) to divalproex sodium (500–2500 mg/day) for bipolar manic or mixed episodes (N =251). Young Mania Rating Scale (YMRS) scores ≥20 were required for inclusion. Patients were classified at study entry as “rapid cyclers” if they experienced ≥4 episodes within the last year. A repeated measures analysis of variance was used to analyze YMRS change from baseline. Results: A significant three-way interaction (cycling frequency by medication by visit) was found when modeling change in YMRS total scores. For patients with bipolar I disorder identified as rapid cyclers, mania improvement across the trial did not differ significantly between treatment groups (p =0.181). Among non-rapid cyclers, olanzapine-treated patients had significantly greater YMRS improvement than divalproex-treated patients across the trial (p <0.001) and at most time points. Among olanzapine-treated patients, non-rapid cyclers experienced numerically greater YMRS improvement than rapid cyclers throughout the trial; statistically significant differences occurred at weeks 11, 15 and 39. In contrast, among divalproex-treated patients, YMRS scores were significantly better in rapid cyclers than non-rapid cyclers during the first two study weeks but were comparable thereafter. A similar pattern was seen in Clinical Global Impressions-Mania Severity scores. Hamilton Depression scores in rapid versus non-rapid cycling patients differed at some time points but not over the entire trial and differences by cycling status were not treatment-specific. Limitations: Apart from the post hoc nature of the analyses, there were high dropout rates in both groups, and cycle frequency was not taken into account. Conclusions: Rapid cycling patients did less well over long-term treatment than non-rapid cycling patients. Among rapid cycling patients, olanzapine and divalproex appear similarly effective against manic symptoms; however, among non-rapid cycling patients, olanzapine-treated patients experienced superior mania improvement. Olanzapine-treated, non-rapid cyclers experienced greater mania improvement than rapid cyclers. The converse was true of divalproex-treated patients early in treatment. [Copyright &y& Elsevier]

Background: Because the symptoms of premenstrual dysphoric disorder (PMDD) are limited to the luteal phase of the menstrual cycle, the potential benefit of luteal-phase dosing has been hypothesized.Objective: This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluated the efficacy and tolerability of enteric-coated fluoxetine 90 mg given once or twice during the luteal phase for the treatment of PMDD.Methods: Study drug was given 14 and 7 days before expected menses during the luteal phase of 3 menstrual cycles. After a screening period and single-blind placebo lead-in period, eligible women were randomized to 1 of 3 treatment groups: enteric-coated fluoxetine 90 mg on both days (LPWD×2); placebo 14 days before menses and enteric-coated fluoxetine 90 mg 7 days before menses (LPWD×1); or placebo on both days (PLC). The primary efficacy measure was change from baseline in mean luteal-phase scores on the Daily Record of Severity of Problems (DRSP). Secondary efficacy measures included scores on the Rating Scale for Premenstrual Tension Syndrome, Clinician-Rated (PMTS-C); the Clinical Global Impression (CGI)—Severity scale; and the Patient Global Impression (PGI)—Improvement scale. Quality of life was assessed using the Sheehan Disability Scale.Results: Two hundred fifty-seven women were randomized to treatment. At the end of the study, the LPWD×2 group had statistically significant improvements in DRSP total, DRSP mood subtotal, DRSP social functioning subtotal, PMTS-C, CGI-Severity, PGI-Improvement, and Sheehan Disability Scale work and family life scores compared with LPWD×1 and PLC (each measure, P < 0.05). There was also a statistically significant improvement in the score on the social life section of the Sheehan Disability Scale with LPWD×2 compared with PLC (P = 0.037). Across all treatment groups, 5 patients discontinued due to nonserious adverse events. Rates of discontinuation for any reason did not differ between the 3 treatment groups.Conclusion: The findings of this study support the efficacy and tolerability of enteric-coated fluoxetine 90 mg given twice during the luteal phase of the menstrual cycle for the treatment of PMDD. [Copyright &y& Elsevier]

Objectives: We evaluated impact of timing of coronary artery bypass grafting (CABG) and prasugrel pretreatment in patients with non-ST-segment elevation myocardial infarction undergoing CABG in the ACCOAST study.Methods: Of 4033 enrolled patients, 314 (7.8%) underwent isolated CABG through 30 days. Primary efficacy end point for this analysis was any cardiovascular death, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor bailout through 30 days.Results: More CABG versus percutaneous coronary intervention or medically managed patients were men, diabetic, or had peripheral arterial disease. Per randomization, 157 of 314 patients received a 30-mg prasugrel loading dose before CABG, and 157 of 314 received placebo. Patients were stratified by tertile of time from randomization to CABG: <2.98 days (n = 104), ≥2.98 and <6.95 days (n = 106), and ≥6.95 days (n = 104). Primary end point occurred in 12.5%, 4.7%, and 4.8%, respectively (<2.98 days vs other tertiles, hazard ratio [HR] = 2.80; P = .011). Similarly, the rate of all TIMI major bleeding was highest in the lowest tertile (26.0% vs 10.4% and 4.8%; P < .001), but no difference in all-cause death was observed through 30 days (3.9% vs 1.9% and 1.9%; P = .30). Time from randomization to CABG (HR = 0.84 for each day delay), left main disease (HR = 1.76), region of enrollment (Non-Eastern Europe vs Eastern Europe; HR = 3.83), but not prasugrel pretreatment and baseline troponin ≥3× upper limit of normal, were independent predictors of combined 30-day end point of all-cause death/myocardial infarction/stroke/TIMI major bleeding.Conclusions: In ACCOAST, early (<2.98 days) surgical revascularization carried increased risk of bleeding and ischemic complications without affecting all-cause mortality through 30 days. Baseline troponin and prasugrel pretreatment did not impact ischemic clinical outcomes. [ABSTRACT FROM AUTHOR]

Practice guidelines recommend dual antiplatelet therapy with aspirin and clopidogrel for patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS) regardless of in-hospital management strategy. Prasugrel—a thienopyridine adenosine diphosphate receptor antagonist that provides higher and less variable levels of platelet inhibition than clopidogrel—has demonstrated benefit when used to treat ACS patients undergoing percutaneous coronary intervention. However, the optimal approach to antiplatelet therapy for high-risk, medically managed NSTE ACS patients remains uncertain, as these patients have not been the focus of previous clinical trials of these therapies. TRILOGY ACS is a phase 3, randomized, double-blind trial enrolling approximately 10,300 NSTE ACS patients within 10 days of presentation with either unstable angina or NSTE myocardial infarction who are not intended to undergo revascularization procedures for their index event. Patients will be randomly allocated to prasugrel + aspirin versus clopidogrel + aspirin for a median duration of 18 months. A reduction in the maintenance dose of prasugrel for elderly patients (age ≥75 years) and those with body weight <60 kg is planned. The primary composite efficacy end point will be time to first occurrence of cardiovascular death, myocardial infarction, or stroke in patients aged <75 years. If the superiority of prasugrel is established in patients aged <75 years, the treatment arms will then be compared for all subjects (including those aged ≥75 years). TRILOGY ACS is the largest randomized clinical trial to date focusing exclusively on medically managed NSTE ACS patients and will provide important information regarding the optimal approach to oral antiplatelet therapy for this high-risk, understudied population. [Copyright &y& Elsevier]

Background: While emotional symptoms such as depressed mood and loss of interest have traditionally been considered to constitute the core symptoms of major depressive disorder (MDD), the prevalence and importance of painful physical symptoms such as back pain, abdominal pain, and musculoskeletal pain is becoming increasingly appreciated. Antidepressants possessing dual serotonin/norepinephrine (5-HT/NE) reuptake inhibition may demonstrate greater efficacy in the alleviation of pain. The efficacy of duloxetine, a balanced and potent dual reuptake inhibitor of 5-HT and NE, was evaluated within a cohort of depressed patients with associated painful physical symptoms.Methods: In this multicenter, double-blind, placebo-controlled study, patients meeting DSM-IV criteria for MDD were randomized to receive placebo (N=141) or duloxetine 60 mg QD (N=141). Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD17) total score ⩾15, a Clinical Global Impression of Severity (CGI-S) score ⩾4, and a Brief Pain Inventory (BPI) Average Pain score ⩾2 at baseline. The primary efficacy measure was the BPI Average Pain score, while secondary measures included other BPI items, the HAMD17 total score, CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQSS). Safety was evaluated by recording treatment-emergent adverse events (spontaneously reported), vital signs, and laboratory analytes.Results: Mean changes in BPI Average Pain for duloxetine- and placebo-treated patients differed significantly at most visits, but only approached significance at endpoint (p=0.066). For the main effect of treatment (pooling all visits), significant advantages for duloxetine-treated patients were found in 10 of 11 assessed BPI pain severity and pain interference items, in addition to VAS overall pain and back pain. Mean changes in pain measures for duloxetine-treated patients corresponded to improvements of 25–50%, compared with 19–39% for placebo. Mean changes at endpoint in depression rating scales (HAMD17, CGI-S, PGI-I) did not differ significantly between duloxetine and placebo treatment groups due to unusually high placebo response. The magnitude of placebo treatment effects (as measured by HAMD17 total score and Maier subscale) was significantly smaller in patients with ⩾1 previous depressive episode, compared to those patients with no previous episodes. In patients with ⩾1 previous depressive episode the advantage of duloxetine over placebo was similar to previous studies. Rates of discontinuation due to adverse events were 14.2% vs. 2.1% for duloxetine and placebo, respectively (p<0.001). Treatment-emergent adverse events reported at a significantly higher rate by duloxetine-treated patients included nausea, dry mouth, fatigue, and decreased appetite.Conclusions: In this study, duloxetine (60 mg QD) was shown to be an effective treatment for the painful physical symptoms which are frequently associated with depression. Improvements in pain severity occurred independently of changes in depressive symptom severity. [Copyright &y& Elsevier]

Background After percutaneous coronary intervention (PCI) for non–ST-segment elevation myocardial infarction (NSTEMI), treatment with a P2Y 12 antagonist with aspirin is recommended for 1 year. Objectives The oral P2Y 12 antagonists ticagrelor and prasugrel have higher recommendations than clopidogrel, but it is unknown if administration before the start of PCI is beneficial. Methods In the randomized, double-blind ACCOAST (A Comparison of prasugrel at the time of percutaneous Coronary intervention Or as pre-treatment At the time of diagnosis in patients with non–ST-segment elevation myocardial infarction) trial, 4,033 patients were diagnosed with NSTEMI and 68.7% underwent PCI; 1,394 received pre-treatment with prasugrel (30-mg loading dose), and 1,376 received placebo. At the time of PCI, patients who received pre-treatment with prasugrel received an additional 30-mg dose of prasugrel, and those who received placebo received a 60-mg loading dose of prasugrel. Primary efficacy was a composite of cardiovascular death, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa bailout through 7 days from randomization. Investigators captured the presence of thrombus on initial angiography and during PCI. Results The incidence of the primary endpoint through 7 days from randomization in the pre-treatment group versus the no pre-treatment group was 13.1% versus 13.1% (p = 0.93). Pre-treatment with prasugrel was not associated with decreases in any ischemic event, including total mortality. Patients with thrombus on angiography had a 3-fold higher incidence of the primary endpoint than patients without thrombus. There was no impact of pre-treatment with prasugrel on the presence of thrombus before PCI or on occurrence of stent thrombosis after PCI. There was a 3-fold increase in all non–coronary artery bypass graft Thrombolysis In Myocardial Infarction (TIMI) major bleeding and a 6-fold increase in non–coronary artery bypass graft life-threatening bleeding with pre-treatment with prasugrel; the same trends persisted in patients who had radial or femoral access even with use of a closure device. Conclusions These findings support deferring treatment with prasugrel until a decision is made about revascularization in patients with NSTEMI undergoing angiography within 48 h of admission. (A Comparison of prasugrel at the time of percutaneous Coronary intervention Or as pre-treatment At the time of diagnosis in patients with non—ST-segment elevation myocardial infarction [ACCOAST]; NCT01015287 ) [ABSTRACT FROM AUTHOR]

Presents results from the treatment phase of a clinical trial designed to confirm the efficacy of fluoxetine in patients with depressive disorders. Safety of fluoxetine; Criteria for the inclusion of patients in the clinical trial; Response of patients to the treatment.