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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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: When considering antiplatelet therapy for acute coronary syndrome (ACS), it is essential to balance benefits (less thrombotic/ischaemic events) versus bleeding risks related to intense platelet inhibition via antagonism of P2Y12 receptors. This analysis aimed to identify predictors of bleeding events among A Comparison of Prasugrel at the Time of PCI or as Pretreatment at the Time of Diagnosis in Patients with NSTEACS (ACCOAST) study population., Methods and Results: The ACCOAST study randomised 4033 patients with non-ST-segment elevation myocardial infarction (NSTEMI) to (A) a 30 mg prasugrel loading dose (LD) followed by coronary angiography with an additional 30 mg prasugrel at the time of percutaneous coronary intervention (PCI) or (B) a placebo LD followed by a 60 mg prasugrel at the time of PCI. Patients received standard of care, including use of aspirin. Independent predictors of Thrombolysis in Myocardial Infarction (TIMI) major bleeding not related to coronary artery bypass grafting (CABG) within 7 days were assessed using stepwise Cox proportional model for time to first occurrence of the event. Non-CABG-related TIMI major or minor bleeding was similarly analysed. Non-CABG-related TIMI major bleeding occurred in 36 (0.9%) patients, and TIMI major or minor bleeding occurred in 81 (2.0%) patients. Independent predictors for TIMI major bleeding alone were pretreatment with prasugrel LD (HR 3.02; 95% CI 1.42 to 6.43), femoral access (HR 2.45; 95% CI 1.11 to 5.38), female sex (HR 2.57; 95% CI 1.32 to 5.00), placement of >1 stent (HR 2.50; 95% CI 1.26 to 4.95) and age (HR 1.05; 95% CI 1.02 to 1.09). Pretreatment with prasugrel LD (HR 3.05; 95% CI 1.84 to 5.07), femoral access (HR 3.06; 95% CI 1.74 to 5.38), female sex (HR 2.62; 95% CI 1.67 to 4.12), performed PCI (HR 2.21; 95% CI 1.23 to 3.99), therapy with glycoprotein IIb/IIIa inhibitors (HR 1.88; 95% CI 1.06 to 3.33) and age (increased bleed per year of age HR 1.04; 95% CI 1.02 to 1.06) were independent predictors of TIMI major or minor bleeding through 7 days., Conclusions: Pretreatment, age, gender and procedural variables predicted bleeding risk in patients with NSTEMI., Clinical Registration No: NCT01015287., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Aims: Several methods provide new insights into understanding clinical trial composite endpoints, using both conventional and novel methods. The TRILOGY ACS trial is used as a contemporary example to prospectively compare these methods side by side., Methods and Results: The traditional time-to-first-event, Andersen-Gill recurrent events method, win ratio, and a weighted composite endpoint (WCE) are compared using the randomized, active-control TRILOGY ACS trial. This trial had a neutral result and randomized 9326 patients managed without coronary revascularization within 10 days of their acute coronary syndrome to receive either prasugrel or clopidogrel and followed them for up to 30 months. The traditional composite, win ratio, and WCE demonstrated no significant survival advantage for prasugrel, whereas the Andersen-Gill method demonstrated a statistical advantage for prasugrel [hazard ratio (HR), 0.86 (95% CI, 0.72-0.97)]. The traditional composite used 73% of total patient events; 40% of these were derived from the death events. The win ratio used 66% of total events; deaths comprised 57% of these. Both Andersen-Gill and WCE methods used all events in all participants; however, with the Andersen-Gill method, death comprised 41% of the proportion of events, whereas with the WCE method, death comprised 64% of events., Conclusion: This study addresses the relative efficiency of various methods for assessing clinical trial events comprising the composite endpoint. The methods accounting for all events, in particular those incorporating their clinical relevance, appear most advantageous, and may be useful in interpreting future trials. This clinical and statistical advantage is especially evident with long-term follow-up where multiple non-fatal events are more common., Clinical Trial Registration: NCT00699998., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: After percutaneous coronary intervention (PCI) for non-ST-segment elevation myocardial infarction (NSTEMI), treatment with a P2Y12 antagonist with aspirin is recommended for 1 year., Objectives: The oral P2Y12 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)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Context: The relationship of platelet function testing measurements with outcomes in patients with acute coronary syndromes (ACS) initially managed medically without revascularization is unknown., Objective: To characterize the differences and evaluate clinical outcomes associated with platelet reactivity among patients with ACS treated with clopidogrel or prasugrel., Design, Setting, and Patients: Patients with medically managed unstable angina or non-ST-segment elevation myocardial infarction were enrolled in the TRILOGY ACS trial (2008 to 2011) comparing clopidogrel vs prasugrel. Of 9326 participants, 27.5% were included in a platelet function substudy: 1286 treated with prasugrel and 1278 treated with clopidogrel., Interventions: Aspirin with either prasugrel (10 or 5 mg/d) or clopidogrel (75 mg/d); those 75 years or older and younger than 75 years but who weighed less than 60 kg received a 5-mg prasugrel maintenance dose., Main Outcome Measures: Platelet reactivity, measured in P2Y12 reaction units (PRUs), was performed at baseline, at 2 hours, and at 1, 3, 6, 12, 18, 24, and 30 months after randomization. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke through 30 months., Results: Among participants younger than 75 years and weighing 60 kg or more, the median PRU values at 30 days were 64 (interquartile range [IQR], 33-128) in the prasugrel group vs 200 (IQR, 141-260) in the clopidogrel group (P < .001), a difference that persisted through all subsequent time points. For participants younger than 75 years and weighing less than 60 kg, the median 30-day PRU values were 139 (IQR, 86-203) for the prasugrel group vs 209 (IQR, 148-283) for the clopidogrel group (P < .001), and for participants 75 years or older, the median PRU values were 164 (IQR, 105-216) for the prasugrel group vs 222 (IQR, 148-268) for the clopidogrel group (P < .001). At 30 months the rate of the primary efficacy end point was 17.2% (160 events) in the prasugrel group vs 18.9% (180 events) in the clopidogrel group (P = .29). There were no significant differences in the continuous distributions of 30-day PRU values for participants with a primary efficacy end point event after 30 days (n = 214) compared with participants without an event (n = 1794; P = .07) and no significant relationship between the occurence of the primary efficacy end point and continuous PRU values (adjusted hazard ratio [HR] for increase of 60 PRUs, 1.03; 95% CI, 0.96-1.11; P = .44). Similar findings were observed with 30-day PRU cut points used to define high on-treatment platelet reactivity-PRU more than 208 (adjusted HR, 1.16; 95% CI, 0.89-1.52, P = .28) and PRU more than 230 (adjusted HR, 1.20; 95% CI, 0.90-1.61; P = .21)., Conclusions: Among patients with ACS without ST-segment elevation and initially managed without revascularization, prasugrel was associated with lower platelet reactivity than clopidogrel, irrespective of age, weight, and dose. Among those in the platelet substudy, no significant differences existed between prasugrel vs clopidogrel in the occurence of the primary efficacy end point through 30 months and no significant association existed between platelet reactivity and occurrence of ischemic outcomes., Trial Registration: clinicaltrials.gov Identifier: NCT00699998.

Background: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated., Methods: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel., Results: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group., Conclusions: Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

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 >or=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 >or=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 (c) 2010 Mosby, Inc. All rights reserved.)

Objective: The aim of this study was to compare fluoxetine dosage titration to 40-60 mg/day with fixed fluoxetine 20-mg/day treatment for an additional 10 weeks in pediatric outpatients with major depressive disorder (MDD) who had not met protocol-defined response criteria after 9-week acute fluoxetine treatment., Methods: Patients unresponsive (less than or equal to 30% decrease in Children's Depression Rating Scale-Revised [CDRS-R] score) after 9-week fluoxetine treatment were randomly reassigned to continue at 20 mg/day or to increase to 40 mg/day. After 4 weeks, patients unresponsive to 40 mg/day could receive 60 mg/day., Results: Twenty-nine (29) patients, 9-17 years of age, received fluoxetine 40-60 mg/day (n = 14) or 20 mg/day (n = 15). At the conclusion of this study phase, 10 patients (71%) on 40-60 mg/day met the response criteria, versus 5 patients (36%) on 20 mg/day (p = 0.128). Mean CDRS-R scores improved in both treatment groups (fluoxetine 40-60 mg/day, -9.4; fluoxetine 20 mg/day, -1.5; p = 0.099). Adverse events were similar in both groups. However, this study phase was statistically underpowered for detecting differences between treatment groups., Conclusion: More than two thirds of patients whose dosage was increased responded within 10 weeks, suggesting dose escalation may benefit some patients. Approximately one third of patients unresponsive to initial treatment with fluoxetine 20 mg responded to this fixed dosage within another 10 weeks. Fluoxetine 20-60 mg/day was well tolerated.

Objective: Failure to recognize bipolar disorder in patients who experience a major depressive episode may lead to inappropriate treatment and poorer outcomes. Clinical features that could distinguish bipolar from unipolar depression would facilitate more appropriate treatment selection., Method: The authors used data from nonpsychotic outpatients participating in three large multicenter clinical trials conducted in the United States for the treatment of major depressive episodes to compare 477 subjects with a diagnosis of bipolar disorder and 1,074 with major depressive disorder., Results: Bipolar depression was associated with family history of bipolar disorder, an earlier age at onset, a greater previous number of depressive episodes, and eight individual symptom items on the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale. Fears were more common in patients with bipolar disorder, whereas sadness; insomnia; intellectual (cognitive), somatic (muscular), respiratory, genitourinary complaints; and depressed behavior were more common in patients with unipolar depression. A logistic regression model correctly classified 86.9% of the subjects., Conclusions: Bipolar depression and major depressive disorder exhibit subtle differences in presentation, which may help guide the initial diagnosis.

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.

Background: Few controlled studies examine the treatment of depressive features in mania., Aims: To evaluate the efficacy of olanzapine, in combination with lithium or valproate, for treating depressive symptoms associated with mania., Method: Secondary analysis of a 6-week, double-blind, randomised study of olanzapine (5-20 mg/day) or placebo combined with ongoing valproate or lithium open treatment for 344 patients in mixed or manic episodes. This analysis focused on a dysphoric subgroup with baseline Hamilton Rating Scale for Depression (HRSD) total scores of 20 or over contrasted with non-dysphoric patients., Results: In the dysphoric subgroup (n=85) mean HRSD total score improvement was significantly greater in olanzapine co-therapy patients than in those receiving placebo plus lithium or valproate (P<0.001). Substantial contributors to this superiority included the HRSD Maier sub-scale (P=0.013) and the suicide item (P=0.001). Total Young Mania Rating Scale improvement was also superior with olanzapine co-therapy., Conclusions: In patients with acute dysphoric mania, addition of olanzapine to ongoing lithium or valproate monotherapy significantly improved depressive symptom, mania and suicidality ratings.

Background: We sought to develop and validate an excitement subscale from the Positive and Negative Syndrome Scale (PANSS) to allow the investigation of mania-like excitement symptoms in clinical trials of patients with schizophrenia using the PANSS and to provide clinicians with a short assessment tool for these states., Methods: Baseline PANSS data from six double-blind, randomized registration trials of olanzapine, three in schizophrenia and three in acute bipolar mania, were used in these post-hoc analyses. Schizophrenia study data were pooled and randomly split in half. Exploratory principal component factor analysis was performed on half of the data. Factors were extracted based on minimum eigenvalue criteria (eigenvalue> or =1); loadings were determined using an equamax rotation. Confirmatory principal component factor analysis was performed on the other half of the data, retaining the original number of factors. Principal component factor analysis was also done for the pooled bipolar studies. Change in the new mania-like factor scores was then correlated with Young Mania Rating Scale (Y-MRS) scores in each bipolar study., Results: Exploratory principal components analysis on the pooled schizophrenia data extracted five factors: negative, positive, excitement, cognitive, and depressive factors. The mania-like excitement factor was represented by four items (uncooperativeness, poor impulse control, excitement, and hostility), with only moderate loadings by tension and suspiciousness/persecution. Results were similar in the confirmatory analysis and the pooled bipolar studies. Change from baseline to endpoint for the mania-like factor correlated reasonably well (0.64-0.78) with change in Y-MRS scores in the bipolar studies. At baseline, bipolar patients scored higher than patients with schizophrenia on three of four PANSS mania-like factor items: poor impulse control, excitement, and hostility; the converse was true for most other PANSS items., Conclusion: Factor analyses of the PANSS consistently uncovered an excitement factor including uncooperativeness, poor impulse control, excitement, and hostility items. This factor may be useful in examining manic symptoms in studies where the addition of a scale specific to mania would be burdensome and where symptoms of excitement are part of the clinical presentation.

Objective: Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder. The authors report a 47-week comparison of olanzapine and divalproex., Method: This 47-week, randomized, double-blind study compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed episodes of bipolar disorder (N=251). The only other psychoactive medication allowed was lorazepam for agitation. The primary efficacy instrument was the Young Mania Rating Scale; a priori protocol-defined threshold scores were > or =20 for inclusion, < or =12 for remission, and > or = 15 for relapse. Analytical techniques included mixed model repeated-measures analysis of variance for change from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and Kaplan-Meier estimates of time to events of interest., Results: Over 47 weeks, mean improvement in Young Mania Rating Scale score was significantly greater for the olanzapine group. Median time to symptomatic mania remission was significantly shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels; those for divalproex were nausea and nervousness., Conclusions: In this 47-week study of acute bipolar mania, symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ.

Objective: The aim of this study was to use the data from two clinical trials to evaluate premenstrual dysphoric disorder symptom severity after the discontinuation of fluoxetine treatment., Study Design: A retrospective analysis of two clinical trials was performed. Patients were treated with fluoxetine or placebo for three cycles, with the use of several different dosing regimens, followed by single blind placebo treatment for one cycle. Assessments of relapse included the daily record of severity of problems, the Sheehan disability scale, the premenstrual tension scale-clinician rated, and the clinical global impressions-severity., Results: Premenstrual dysphoric disorder symptoms significantly increased after fluoxetine discontinuation. The scores did not return to baseline; however, the fluoxetine group was no longer significantly superior to placebo., Conclusion: The two trials demonstrate that, after three cycles of treatment, premenstrual dysphoric disorder symptoms recur within the first cycle after treatment discontinuation. The rapid recurrence of symptoms further supports the view of premenstrual dysphoric disorder as a clinical entity distinct from depression.

Background: Little is known about the effect of pharmacotherapy in the prevention of post-traumatic stress disorder (PTSD) relapse., Aims: To assess the efficacy and tolerability of fluoxetine in preventing PTSD relapse., Method: This was a double-blind, randomised, placebo-controlled study. Following 12 weeks of acute treatment, patients who responded were rerandomised and continued in a 24-week relapse prevention phase with fluoxetine (n=69) or placebo (n=62). The primary efficacy assessment was the prevention of PTSD relapse, based on the time to relapse., Results: Patients in the fluoxetine/fluoxetine group were less likely to relapse than patients in the fluoxetine/placebo group (P=0.027). There were no clinically significant differences in treatment-emergent adverse events between treatment groups., Conclusions: Fluoxetine is effective and well tolerated in the prevention of PTSD relapse for up to 6 months.

Objective: Because many women who receive pharmacologic therapy with antidepressants are also prescribed oral contraceptives, it is important to assess the risk of clinically significant drug interactions. We reviewed the United States fluoxetine clinical trial database, specifically analyzing women ages 18 to 45 years, for differences in safety, antidepressant efficacy, and unplanned pregnancies that were associated with oral contraceptive use., Study Design: Data from 17 double-blind, placebo-controlled clinical trials in 1698 women were analyzed retrospectively. A subgroup of women with oral contraceptive use was compared with a subgroup of women with no oral contraceptive use. Differences in treatment-emergent adverse events, unplanned pregnancies, and 17-item Hamilton Depression Scale (HAMD-17) scores were analyzed., Results: The only treatment-emergent adverse events that showed a statistically significantly different odds ratio for oral contraceptive use versus no oral contraceptive use were headache, asthenia, and pain. There was not a statistically significant interaction in the incidence of unintended pregnancies (P =.111) or in the changes from baseline in HAMDD-17 scores., Conclusion: There is no clinical evidence that concomitant use of oral contraceptives and fluoxetine affects the safety or efficacy of either agent.

Objective: To evaluate premenstrual daily dosing with fluoxetine for treatment of premenstrual dysphoric disorder., Methods: After a two-cycle screening and one-cycle single-blind placebo period, 260 women were randomized to fluoxetine 10 mg, fluoxetine 20 mg, or placebo (dosed daily from 14 days before next expected menses through the first full day of bleeding) for three cycles. Women recorded premenstrual dysphoric disorder symptoms daily using a computerized version of the Daily Record of Severity of Problems., Results: Premenstrual daily fluoxetine 20 mg demonstrated significant improvement in mean Daily Record of Severity of Problems luteal scores compared with placebo (P =.005); premenstrual daily fluoxetine 10 mg did not (P =.100). Daily Record of Severity of Problems total scores were statistically significantly improved by the first treatment cycle for both active treatment groups. However, only fluoxetine 20 mg remained statistically significantly superior to placebo throughout the active treatment phase of the trial. Both fluoxetine groups showed significant treatment advantage over placebo for mood-related symptoms (P <.05). Only premenstrual daily fluoxetine 20 mg showed significant treatment advantage over placebo for physical symptoms of breast tenderness (P <.001), bloating (P =.001), and joint/muscle pain (P =.037). Treatment was well tolerated; discontinuations due to adverse events did not differ among the three groups (P =.316)., Conclusion: Premenstrual daily dosing with fluoxetine effectively treats mood, physical, and social functioning symptoms associated with premenstrual dysphoric disorder. Fluoxetine 20 mg appears to have comparable tolerability with, and better efficacy than, fluoxetine 10 mg.

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 I of 3 treatment groups: enteric-coated fluoxetine 90 mg on both days (LPWDx2); placebo 14 days before menses and enteric-coated fluoxetine 90 mg 7 days before menses (LPWDx1); 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 LPWDx2 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 LPWDx1 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 LPWDx2 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.