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Objectives To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of migraine attacks for up to 1 year. Methods In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit. Results As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received ≥ 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time. Conclusions The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period. Trial registration number: NCT02565186; https://clinicaltrials.gov/ct2/show/NCT02565186

We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine. SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Study drug was to be taken within 4 h (h) of onset of a migraine attack (moderate or severe pain). A second dose of study drug was provided for rescue (patient not pain-free at 2 h and took a second dose 2-24 h post-first dose) or recurrence (patient pain-free at 2 h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24 h after first dose). Randomization to second dose occurred at baseline; patients originally assigned lasmiditan were randomized to the same lasmiditan dose or placebo (2:1 ratio), and those originally assigned placebo received placebo. Data from SAMURAI and SPARTAN were pooled for efficacy and safety assessment of a second dose of lasmiditan. The proportion of patients taking a second dose was lower with lasmiditan versus placebo, and decreased with increasing lasmiditan dose; the majority who took a second dose did so for rescue. In patients taking lasmiditan as first dose, outcomes (pain free, most bothersome symptom [MBS] free) at 2 h after a second dose for rescue were similar whether the second dose was lasmiditan or placebo (p > 0.05 in all cases). In patients taking lasmiditan for first dose, outcomes at 2 h after a second dose for recurrence were as follows: lasmiditan pooled versus placebo - pain free, 50% vs 32% (p > 0.05); MBS free, 71% vs 41% (p = 0.02); pain relief, 77% vs 52% (p = 0.03). In patients whose first dose was lasmiditan, the incidence of treatment emergent adverse events (TEAEs) reported after the second dose was similar whether second dose was lasmiditan or placebo. A second dose of lasmiditan showed some evidence of efficacy when taken for headache recurrence. There was no clear benefit of a second dose of lasmiditan for rescue treatment. The incidences of TEAEs were similar whether the second dose was lasmiditan or placebo. SAMURAI ( NCT02439320 ) [April 2015]. SPARTAN ( NCT02605174 ) [May 2016].

Background Sustained pain freedom is an important attribute of acute migraine therapies for patients and physicians. Here we report efficacy of the centrally penetrant, highly selective, 5-HT1F agonist lasmiditan on sustained pain freedom and other outcomes at 24 and 48 hours post-dose. Study design and methods Data from the similarly designed, Phase 3, double-blind studies SAMURAI (NCT02439320) and SPARTAN (NCT02605174) were pooled to more precisely estimate efficacy effects in these post-hoc analyses. In both studies, inclusion criteria were 3–8 migraine attacks per month and Migraine Disability Assessment Score of ≥ 11 (at least moderate disability). Patients were randomized equally to lasmiditan 200 mg, 100 mg, 50 mg (50 mg only in SPARTAN), or to placebo. The study drug was to be taken within 4 hours of onset of pain for non-improving headache of at least moderate severity. Sustained pain freedom was defined as being pain free at 2 hours and at the given time point (24 or 48 hours) post-dose without use of additional study drug or migraine medications. Sustained responses were assessed similarly for most bothersome symptom-free, total migraine-free, and disability-free outcomes. For comparisons with previously published data on other acute medications, an additional endpoint of modified sustained pain freedom at 24 hours was defined as being pain free at 2 hours and no moderate-to-severe headache at 24 hours post-dose without use of additional study drug or migraine medications. Results Significantly higher proportions of patients treated with lasmiditan versus placebo achieved headache pain freedom at 2 hours post-dose: 200 mg: 35.6%; 100 mg: 29.9%; 50 mg: 28.6%; placebo: 18.3% (all p Conclusion Sustained responses at 24 and 48 hours were noted in significantly more patients treated with lasmiditan versus placebo for several efficacy outcomes including pain freedom, most bothersome symptom-free, total migraine-free and disability-free responses. Clinicaltrials.gov identifier numbers SAMURAI: NCT02439320; SPARTAN: NCT02605174.

Trial design SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies conducted in the United States, as well as the United Kingdom and Germany (SPARTAN only). Individuals with migraine were randomized to receive oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo within 4 hours of onset of a migraine attack. The aim of this analysis was to characterize dizziness reported with lasmiditan treatment. Methods Data from SAMURAI and SPARTAN were pooled for the current post hoc analyses. Onset time and duration of dizziness were analyzed using descriptive statistics. Subgroup analyses based on presence/absence of dizziness were performed for the endpoints of interference with daily activity, patient global impression of change (PGIC), pain at 2 hours, and most bothersome symptom (MBS) at 2 hours based on adverse events occurring within 2 hours of taking study drug. Results Dizziness incidence was as follows: Placebo (N = 1262), 2.9% (0.1% severe); lasmiditan 50 mg (N = 654), 8.6% (0.3% severe); lasmiditan 100 mg (N = 1265), 14.9% (0.7% severe); and lasmiditan 200 mg (N = 1258), 16.8% (1.4% severe). Among participants who received lasmiditan as their first dose, risk factors for dizziness were higher lasmiditan dosage, being non-Hispanic/Latino, mild or moderate severity of migraine attack, and lower body mass index. The median time to onset of dizziness was generally 30-40 minutes, and the median duration was 1.5-2 hours. The presence of dizziness did not appear to have a negative influence on lasmiditan's effect on daily activity, PGIC, freedom from pain, or MBS. Overall, 21 participants experienced vertigo: Lasmiditan 50 mg, n = 2 (0.3%); 100 mg, n = 11 (0.9%); 200 mg, n = 7 (0.6%); and placebo, n = 1 ( Conclusion The incidence of dizziness with lasmiditan increased with dose. Dizziness was generally mild or moderate in severity and of quick onset and short duration. The presence of dizziness did not influence drug efficacy.

Comparison of disease progression between placebo-group patients from randomised controlled trials (RCTs) and real-world patients can aid in assessing the generalisability of RCT outcomes. This analysis compared outcomes between community-dwelling patients with mild Alzheimer’s disease (AD) dementia from two RCTs (pooled European (EU) data from EXPEDITION and EXPEDITION 2) and similar patients from the EU GERAS observational study. Data from placebo-group patients with mild AD dementia from the RCTs (EU countries only) were compared with data from GERAS patients with mild AD dementia. Between-group differences for changes over 18 months were analysed for cognition, functioning, neuropsychiatric symptoms, health-related quality of life (HRQoL) and caregiver time using propensity score-adjusted models. A sensitivity analysis compared EU/North American (EU/NA) EXPEDITION patients with GERAS patients. EU EXPEDITION patients (n = 168) were younger than GERAS patients (n = 566) (mean (standard deviation, SD) age 71.9 (7.4) versus 77.3 (6.9) years; p < 0.001) and were more likely to use AD treatment (95% versus 84%; p < 0.001). Cognitive performance was similar at baseline in both populations, although GERAS patients showed greater functional impairment (p = 0.005) and lower HRQoL (p < 0.05). At 18 months, no statistically significant differences between EXPEDITION (n = 133) and GERAS (n = 417) patients were observed for changes in cognitive, functional, neuropsychiatric and HRQoL outcomes. Least squares mean (95% confidence interval) change in caregiver time (hours/month) spent on instrumental activities of daily living (iADL; 29.22 (19.16, 39.27) versus 3.20 (−11.89, 18.28), p = 0.001) and supervision (66.59 (47.49, 85.69) versus 3.04 (−25.39, 31.48), p < 0.001) showed greater increases in GERAS than EXPEDITION. In the sensitivity analysis, changes in neuropsychiatric and HRQoL scores and caregiver time spent on basic ADL were also significantly greater in GERAS than in EU/NA EXPEDITION patients. Patients with mild AD dementia participating in the EU EXPEDITION RCTs and the GERAS observational study showed a similar decline in cognitive, functional and neuropsychiatric symptoms over 18 months, whereas changes in caregiver time measures were significantly greater in GERAS. Results indicate the importance of using similar regions when comparing real-world and RCT data. ClinicalTrials.gov NCT00905372 EXPEDITION. Registered 18 May 2009. ClinicalTrials.gov NCT00904683 EXPEDITION 2. Registered 18 May 2009.

Background: Randomized placebo-controlled trials in the development of disease-modifying treatments for Alzheimer’s disease are typically of short duration (12–18 months), and health economic modeling requires extrapolation of treatment effects beyond the trial period. OBJECTIVES: To investigate whether observational data can be used to extrapolate data from open-label trials, we compared outcomes (cognition, function, behavior) over 36 months for patients with mild Alzheimer’s disease dementia in the GERAS observational study (proxy for placebo control) with those of the mild Alzheimer’s disease population on active treatment (solanezumab) in two 18-month randomized placebo-controlled trials (EXPEDITION and EXPEDITION2) and the additional 18-month open-label extension study (EXPEDITION-EXT). DESIGN & SETTING: Analysis of longitudinal data from patients with mild Alzheimer’s disease dementia in the GERAS observational study (conducted in France, Germany and the United Kingdom) and the EXPEDITION program (conducted in Europe, North America, South America, Asia and Australia). PARTICIPANTS: European and North American community-living patients, aged ≥55 years, with probable Alzheimer’s disease dementia and their caregivers. Mild Alzheimer’s disease dementia was defined as a Mini-Mental State Examination score of 20–26 in EXPEDITION and 21–26 in GERAS. INTERVENTION: Active treatment in both randomized placebo-controlled trials and the open-label extension study was intravenous solanezumab 400 mg every 4 weeks. Patients in GERAS were receiving treatment as part of standard care. MEASUREMENTS: Between-group differences for changes from baseline over 36 months in cognitive function, ability to perform activities of daily living, and behavioral and psychological symptoms of dementia were assessed using models stratified by propensity score. RESULTS: At baseline, patients and caregivers participating in GERAS were significantly older than those in the EXPEDITION studies, and the GERAS patient cohort had fewer years of education and a shorter time since diagnosis of Alzheimer’s disease. The baseline mean Mini-Mental State Examination score of the GERAS cohort was significantly higher (indicating better cognition) than that of patients receiving placebo or active treatment in the pooled EXPEDITION studies Baseline functional ability scores were significantly lower for the GERAS cohort, indicating poorer functioning. Propensity score stratification achieved a good balance in the baseline variables between GERAS and the two EXPEDITION arms. Over 18 months, least squares mean changes from baseline in outcome measures were similar in the GERAS cohort and the pooled placebo groups from the randomized controlled trials. Also, the 18-month results for the comparison between the GERAS cohort and the pooled active treatment groups from the randomized controlled trials were generally similar to those reported for the comparison with the control group in the randomized trial. Comparison of active treatment (EXPEDITION-EXT) and observational study (GERAS, as proxy control) results over 36 months of the open-label trial showed a significantly smaller decline in activities of daily living (instrumental and basic) in the active treatment group, reflecting better functioning, but no between-group differences at 36 months for cognitive function or behavioral and psychological symptoms of dementia. CONCLUSIONS: Comparing results from clinical trials and observational studies (real-world data) may be a useful methodological approach for informing long-term outcomes in Alzheimer’s disease drug development and could be used to inform health economic modeling. Further research using this methodological approach is needed.

Background: The temporal relationship of cognitive deficit and functional impairment in Alzheimer’s disease (AD) is not well characterized. Recent analyses suggest cognitive decline predicts subsequent functional decline throughout AD progression. Objective: To better understand the relationship between cognitive and functional decline in mild AD using autoregressive cross-lagged (ARCL) panel analyses in several clinical trials. Methods: Data included placebo patients with mild AD pooled from two multicenter, double-blind, Phase 3 solanezumab (EXPEDITION/2) or semagacestat (IDENTITY/2) studies, and from AD patients participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cognitive and functional outcomes were assessed using AD Assessment Scale-Cognitive subscale (ADAS-Cog), AD Cooperative Study-Activities of Daily Living instrumental subscale (ADCS-iADL), or Functional Activities Questionnaire (FAQ), respectively. ARCL panel analyses evaluated relationships between cognitive and functional impairment over time. Results: In EXPEDITION, ARCL panel analyses demonstrated cognitive scores significantly predicted future functional impairment at 5 of 6 time points, while functional scores predicted subsequent cognitive scores in only 1 of 6 time points. Data from IDENTITY and ADNI programs yielded consistent results whereby cognition predicted subsequent function, but not vice-versa. Conclusions: Analyses from three databases indicated cognitive decline precedes and predicts subsequent functional decline in mild AD dementia, consistent with previously proposed hypotheses, and corroborate recent publications using similar methodologies. Cognitive impairment may be used as a predictor of future functional impairment in mild AD dementia and can be considered a critical target for prevention strategies to limit future functional decline in the dementia process.

Introduction Although depression is often associated with poor glycemic control in patients with type 2 diabetes mellitus (T2DM), this observation has been inconsistent. This exploratory, post hoc analysis investigated associations between depression parameters and glycemic control using data from a 24-month, prospective, observational, non-interventional study evaluating glycemic response following insulin initiation for T2DM. Methods We analyzed data from a 24-month, prospective, observational study that evaluated glycemic response in patients with T2DM who initiated insulin therapy (N = 985) in 5 European countries. Secondary measures included patient-reported diagnosis of depression at baseline, severity of depressed/anxious mood (EuroQol (EQ)-5D item) and diabetes-related distress (Psychological Distress domain of the Diabetes Health Profile, DHP-18). The latter two measures were assessed at baseline and 5 time points throughout the study. Glycemic control was measured by glycated hemoglobin (HbA1c) at these same time points. Analyses employed t tests to assess the unadjusted baseline difference in HbA1c between patients with and without the respective depression parameter. The potential effect of demographic and clinical confounding variables was controlled through a linear model structure. Patient HbA1c levels were analyzed by presence/absence of a history of diagnosed depression, depressed mood, and diabetes-related distress. Results Patients with higher depression parameters or distress at baseline had significantly higher rates of microvascular complications at baseline. Patients with a history of diagnosed depression or high diabetes-related distress had higher HbA1c than patients without. HbA1c of patients with or without depressed mood was not significantly different at baseline. The proportion of patients with depressed mood declined after insulin initiation, whereas the proportion of patients with high diabetes-related distress did not significantly change. HbA1c improved following insulin initiation, regardless of presence/absence of studied depression/distress parameters at baseline. Conclusion History of diagnosed depression, diabetes-related distress, and depressed mood were associated with a higher rate of microvascular complications. Diagnosed depression and diabetes-related distress also showed higher HbA1c at baseline when insulin was initiated. Insulin therapy improved glycemic control, while preexisting depressed mood declined and diabetes-related distress remained unchanged. Electronic supplementary material The online version of this article (doi:10.1007/s13300-015-0118-y) contains supplementary material, which is available to authorized users.

International audience; Basic research advances in recent years have furthered our understanding of the natural history of Alzheimer's disease (AD). It is now recognized that pathophysiological changes begin many years prior to clinical manifestations of disease and the spectrum of AD spans from clinically asymptomatic to severely impaired. Defining AD purely by its clinical presentation is thus artificial and efforts have been made to recognize the disease based on both clinical and biomarker findings. Advances with biomarkers have also prompted a shift in how the disease is considered as a clinico-pathophysiological entity, with an increasing appreciation that AD should not only be viewed with discrete and defined clinical stages, but as a multifaceted process moving along a seamless continuum. Acknowledging this concept is critical to understanding the development process for disease-modifying therapies, and for initiating effective diagnostic and disease management options. In this article, we discuss the concept of a disease continuum from pathophysiological, biomarker, and clinical perspectives, and highlight the importance of considering AD as a continuum rather than discrete stages. While the pathophysiology of AD has still not been elucidated completely, there is ample evidence to support researchers and clinicians embracing the view of a disease continuum in their study, diagnosis, and management of the disease.

GLADIATOR was a prospective, randomized, open-label, phase 3 study of lasmiditan 100 mg or 200 mg dosed intermittently for up to 1 year in patients with episodic migraine. Most patients had completed one of two single-attack studies before participation. A total of 2030 patients received ≥1 lasmiditan dose and 19,879 migraine attacks were treated. Safety results were similar to the previously reported interim analysis. The most frequently reported treatment-emergent adverse events (TEAEs) included dizziness (18.5%), somnolence (8.5%), and paresthesia (6.8%), with frequency of adverse events appearing to decrease with subsequently treated attacks. At 2 h post-dose, 26.7% and 32.2% of all attacks treated with lasmiditan 100 mg and 200 mg, respectively, were pain free. This pattern was generally consistent across study quarters and treated attacks. In conclusion, during a 1-year treatment period, intermittent lasmiditan for episodic migraine treatment was associated with generally decreasing TEAEs and consistent efficacy.

SUMMARY Objective: The safety and tolerability of three treatments for diabetic peripheral neuropathic pain (DPNP) were compared. Methods: A 12-week, randomized, open-label study confirming the non-inferiority of duloxetine (N = 138) vs. pregabalin (N = 134) and the combination of duloxetine plus gabapentin (N = 135) as the primary outcome was previously published. Patients had an inadequate pain response to a stable dose of gabapentin (≥ 900 mg/day) for ≥ 5 weeks prior to study enrolment. Data from that study were assessed in this current analysis for a detailed report of safety and tolerability. Results: Completion rates did not differ significantly between the groups. Discontinuation because of adverse events was significantly greater in the duloxetine (19.6%) vs. pregabalin group (10.4%; p = 0.04); no differences emerged between the duloxetine vs. duloxetine plus gabapentin (13.3%) groups (p = 0.19) or pregabalin vs. duloxetine plus gabapentin groups (p = 0.57). Adverse event rates varied: nausea, insomnia, hyperhidrosis and decreased appetite were reported significantly more often in patients treated with duloxetine vs. patients treated with pregabalin (each p ≤ 0.01); insomnia significantly more in patients treated with duloxetine vs. duloxetine plus gabapentin (p = 0.01); peripheral oedema significantly more in patients treated with pregabalin vs. duloxetine and duloxetine plus gabapentin (p ≤ 0.001 each) and nausea, hyperhidrosis, decreased appetite and vomiting significantly more in patients treated with duloxetine plus gabapentin vs. pregabalin (each p ≤ 0.05). At end-point, weight change differed significantly among treatment groups: patients in the pregabalin group on average gained weight (1.0 0.04 kg); while, patients in the duloxetine and duloxetine plus gabapentin groups on average lost weight (2.39 0.04 and 1.06 0.04 kg, respectively) (pregabalin vs. duloxetine, p ≤ 0.001; pregabalin vs. duloxetine plus gabapentin, p ≤ 0.001; duloxetine vs. duloxetine plus gabapentin, p = 0.01). Conclusion: Duloxetine, pregabalin and duloxetine plus gabapentin were generally safe and tolerable for the treatment of DPNP. What’s known

Background Orodispersible tablets (ODTs) are tablet or wafer forms of medication that disintegrate in the mouth, aided only by saliva. ODTs rely on different fast dissolve/disintegration manufacturing technologies. Objectives Disintegration time differences for several olanzapine ODT forms were investigated. Risperdal M-Tab® was included as a non-olanzapine ODT comparator. Research Design and Methods Eleven olanzapine ODT examples and orodispersible risperidone strengths were evaluated in vitro for formulation composition, manufacturing method, disintegration and dissolution characteristics, and formulation differences in comparison with freeze dried Zydis® ODT. Automated dissolution test equipment captured ODT dissolution rates by measuring real-time release of active ingredient. A high-speed video camera was used to capture tablet disintegration times in warm simulated saliva. Main Outcome Measure The main outcome measure was the disintegration and dissolution characteristics of the ODT formulations. Results The ODT manufacturing method was associated with time to disintegrate; the fastest were freeze dried tablets, followed by soft compressed tablets and then hard/dense tablets. Olanzapine Zydis® was the only ODT that completely disintegrated in less than 4 s for all strengths (5, 10, 15, and 20 mg), followed by 5-mg Prolanz FAST® (12 s) and then risperidone ODT 4 mg (40 s). Reasons for slow dissolution of the olanzapine generics may include low product potency, excipient binding, excipient solubility, active ingredient particle size and incomplete disintegration. Conclusions Differences in the formulation and manufacturing process of olanzapine ODTs appear to have a strong influence on the disintegration time of the active compound; differences that may potentially impact their use in clinical practice. Electronic supplementary material The online version of this article (doi:10.1007/s40268-013-0030-8) contains supplementary material, which is available to authorized users.

The objective of this study was to examine the safety and tolerability of duloxetine hydrochloride, a serotonin-norepinephrine reuptake inhibitor, in a large cohort of elderly patients with major depressive disorder. Data were pooled from 8-week and 12-week, double-blind, randomized, placebo-controlled trials of duloxetine 60 mg/day (duloxetine=456; placebo=225). Discontinuation rates because of adverse events, treatment-emergent adverse events, abnormal changes in vital signs and weight, and changes in laboratory analytes were compared between treatments using a Cochran-Mantel-Haenszel test. Changes in laboratory analytes were analyzed using an analysis of variance model. Adverse event-related discontinuation rates were not significantly different between duloxetine and placebo (10.7 vs. 7.1%; P=0.13). Treatment-emergent adverse events for duloxetine of at least 5% and twice the rate of placebo were dry mouth, constipation, nausea, diarrhea, dizziness, and fatigue. Abnormal changes in vital signs and weight were not significantly different at any time between duloxetine and placebo. The mean changes in platelet count, alkaline phosphatase, potassium, random glucose, uric acid, and cholesterol were significantly different between duloxetine and placebo (P

The global impact of Alzheimer’s disease (AD) continues to increase, and focused efforts are needed to address this immense public health challenge. National leaders have set a goal to prevent or effectively treat AD by 2025. In this paper, we discuss the path to 2025, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs). Under the current conditions, only drugs currently in late Phase 1 or later will have a chance of being approved by 2025. If pipeline attrition rates remain high, only a few compounds at best will meet this time frame. There is an opportunity to reduce the time and risk of AD drug development through an improvement in trial design; better trial infrastructure; disease registries of well-characterized participant cohorts to help with more rapid enrollment of appropriate study populations; validated biomarkers to better detect disease, determine risk and monitor disease progression as well as predict disease response; more sensitive clinical assessment tools; and faster regulatory review. To implement change requires efforts to build awareness, educate and foster engagement; increase funding for both basic and clinical research; reduce fragmented environments and systems; increase learning from successes and failures; promote data standardization and increase wider data sharing; understand AD at the basic biology level; and rapidly translate new knowledge into clinical development. Improved mechanistic understanding of disease onset and progression is central to more efficient AD drug development and will lead to improved therapeutic approaches and targets. The opportunity for more than a few new therapies by 2025 is small. Accelerating research and clinical development efforts and bringing DMTs to market sooner would have a significant impact on the future societal burden of AD. As these steps are put in place and plans come to fruition, e.g., approval of a DMT, it can be predicted that momentum will build, the process will be self-sustaining, and the path to 2025, and beyond, becomes clearer.

Background The burden on caregivers of patients with Alzheimer’s disease (AD) is associated with the patient’s functional status and may also be influenced by chronic comorbid medical conditions, such as diabetes. This post-hoc exploratory analysis assessed whether comorbid diabetes in patients with AD affects caregiver burden, and whether caregivers with diabetes experience greater burden than caregivers without diabetes. Caregiver and patient healthcare resource use (HCRU) were also assessed. Methods Baseline data from the GERAS observational study of patients with AD and their caregivers (both n = 1495) in France, Germany and the UK were analyzed. Caregiver burden was assessed using the Zarit Burden Interview (ZBI). Caregiver time on activities of daily living (ADL: basic ADL; instrumental ADL, iADL) and supervision (hours/month), and caregiver and patient HCRU (outpatient visits, emergency room visits, nights hospitalized) were assessed using the Resource Utilization in Dementia instrument for the month before the baseline visit. Regression analyses were adjusted for relevant covariates. Time on supervision and basic ADL was analyzed using zero-inflated negative binomial regression. Results Caregivers of patients with diabetes (n = 188) were younger and more likely to be female (both p

Objective:This retrospective post-hoc analysis of observational studies assesses the frequency of painful physical symptoms (PPS) in patients with major depressive disorder (MDD) of varied severity as may be seen in clinical practice.Methods:Observational studies of MDD that collected a clinician-reported measure of depression severity and included assessment of PPS were screened for this individual patient-level analysis. Six observational studies were included that enrolled outpatients with a diagnosis of MDD (assessed using the 17-item Hamilton depression scale, Hospital Anxiety and Depression Scale–Depression, or Inventory of Depressive Symptomatology). Measures of PPS were based on the original study assessment (modified Somatic Symptom Inventory [SSI] and Visual Analogue Scale [VAS]). Patients were divided into analysis cohorts based on the presence or absence of PPS. To model PPS status, odds ratios were calculated from logistic regression for cross-sectional analysis (main analysis) and ge...

Summary Aims: To estimate the frequency of painful physical symptoms (PPS) in elderly subjects (≥ 65 years) with major depressive disorder (MDD) in real-world clinical conditions and to establish whether PPS are associated with poor depression outcomes, including more severe depression and worse health-related quality of life (HRQoL). Methods: Observational studies of MDD that included assessment of PPS and elderly subjects were screened. Measures of PPS were based on the Somatic Symptom Inventory (SSI) or Visual Analogue Scale (VAS). Data from a variety of depressive symptom severity and HRQoL scales were used. Analysis cohorts were based on age [aged ≥ 65 years (elderly) or

Apathy in the context of treated major depressive disorder (MDD) is a common but understudied symptom. This multicenter, double-blind, randomized study investigated whether switching from a selective serotonin reuptake inhibitor (SSRI) to a serotonin-norepinephrine reuptake inhibitor (SNRI), compared with switching to another SSRI, improved apathy symptoms in patients who had been treated with a SSRI for MDD for ≥ 3 months, were no longer depressed (Montgomery-Asberg Depression Rating Scale [MADRS] total score ≤ 15), and continued to have apathy (Apathy Evaluation Scale--Clinician rated version [AES-C] total score >30). Following 8 weeks of treatment, both the duloxetine (SNRI, 244 patients) and escitalopram (SSRI, 239 patients) groups significantly improved from baseline on the AES-C total score (least squares mean change [standard error]: duloxetine -13.9 [0.54]; escitalopram -13.5 [0.54], both P < 0.001), and on the secondary apathy, depression, and functional outcomes. There were no significant differences between the two groups on any measure, including AES-C total score (least squares mean difference [95% confidence interval]: -0.4 [-1.87 to 1.10], P = 0.612; primary objective). There was a significant within-group improvement in apathy in the subgroup who received escitalopram before and during the study. There were few differences in safety between the two groups. This study did not support the hypothesis that switching from a SSRI to a SNRI has a beneficial effect on apathy symptoms. However, given the study limitations, it is possible that more specific targeting of the noradrenergic pathway would be of benefit.

To evaluate frequencies of treatment-emergent sexual dysfunction (TESD) in patients with major depressive disorder (MDD) treated with duloxetine or selective serotonin reuptake inhibitor (SSRI) monotherapy for up to 6 months in a prospective, observational study.Sexually active MDD patients without sexual dysfunction at entry were enrolled from twelve countries (N = 1,647). TESD was assessed over the study period using the Arizona sexual experience (ASEX) scale. A priori-specified secondary 6-month clinical endpoints were also examined.The frequency of TESD at 6 months with duloxetine was comparable to that with SSRI monotherapy (23.4 and 28.7%, respectively; P = 0.087). Improvements in Clinical Global Impressions of Severity (CGI-S), 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR(16)), Integral Inventory for Depression (IID) total scores, remission and sustained remission rates were statistically significantly greater with duloxetine than SSRI monotherapy at 6 months (P0.001 for each), but TESD attenuated improvements in quality of life measures. Four factors were consistently significantly (P ≤ 0.05) associated with TESD at week 8 and 6 months.Six-month TESD rates were comparable between duloxetine and SSRIs, with greater MDD effectiveness in favour of duloxetine. Improved recognition and management of TESD may improve quality of life for MDD patients in usual clinical practice.

To assess the reliability and validity of the Integral Inventory for Depression (IID) scale using post hoc analyses of data from a multi-country study (ClinicalTrials.gov: NCT00561509) of patients with major depressive disorder (MDD).Patients (N = 1629) completed the IID (comprising two separate dimensions for emotional and physically painful symptoms; maximum score of 65) and a reference scale (16-item Quick Inventory of Depressive Symptomatology Self-Report) at baseline and at follow-up (8 and 24 weeks). Physicians rated MDD symptoms using the Clinical Global Impressions of Severity scale at each visit. Inter-item correlation, internal consistency, external validity, factor structure, and exploratory analysis of an optimal severity cut-off point were assessed.The IID displayed two distinct dimensions (i.e. painful and emotional) with little item redundancy and good internal consistency (Cronbach's α0.83 at each visit). The IID displayed good external validity (Pearson's correlations coefficients0.60 at each visit) and statistically significant agreement (McNemar's test; P0.001 at follow-up) with the reference scale. Results suggest that a cut-off score of ≤24 had adequate precision (80%) to identify patients with and without moderate MDD.Results suggest that the IID may be a reliable and valid tool for assessing emotional and painful symptoms of MDD.

Summary Background: This study was designed to assess clinical and functional outcomes associated with switching to duloxetine treatment in patients with major depressive disorder (MDD) experiencing emotional and painful physical symptoms in their current episode. Methods: In this 8-week, multinational, multicentre, single-arm, open-label clinical trial, 242 MDD patients were switched to duloxetine 60 mg/day after selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) treatment. The primary analysis compared mean change from baseline in Brief Pain Inventory – Modified Short Form (BPI-SF) interference score between initial responders [≥ 50% reduction from baseline on the 17-item Hamilton Depression Rating Scale (HAMD17) Maier subscale] and initial non-responders after 4 weeks. Initial responders continued with duloxetine 60 mg/day. Initial non-responders received duloxetine 120 mg/day for the remaining 4 weeks. Depression, pain, anxiety and functional outcomes were also compared after 8 weeks. Results: BPI-SF interference decreased from baseline in initial responders (n = 108) and initial non-responders (n = 85) after 4 weeks of duloxetine treatment, with greater reductions in initial responders [BPI-SF mean difference in reduction: 1.01 (95% CI 0.42–1.61); p

ObjectiveaaThis paper aims to examine the association between painful physical symptoms (PPS) and major depressive disorder (MDD) in a naturalistic clinical practice setting within a Korean population. MethodsaaPatients with acute MDD that joined a multicountry, observational, three-month study in six Asian countries and regions were classified as PPS+ (mean score ≥2) and PPS(mean score

Objective: We present a post-hoc analysis of the safety and efficacy of duloxetine, a selective serotonin/ norepinephrine reuptake inhibitor, for treatment of diabetic peripheral neuropathic pain (DPNP) in older patients. Methods: Data from three double-blind, placebo-controlled trials in adult patients with DPNP were pooled and stratified by age ( < 65, ≥65 years). Patients were randomized to duloxetine (DLX) 60 mg once-daily, 60 mg twice-daily, or placebo for 12 weeks, followed by a 52-week extension phase (re-randomization to routine care or DLX 120 mg/day). Intent-totreat analyses were used for safety and efficacy assessment. Results: In the acute phase, overall TEAE rates did not differ significantly by age. A greater percentage of older patients discontinued due to TEAEs (P < 0.001), regardless of treatment group. Duloxetine improved weekly mean 24-hour average pain scores versus placebo in both age groups (P < 0.01). In the extension phase, a significant therapy-by-age interaction (P < 0.05) was observed in overall TEAE rate; with routine care, 86.6% of older patients had ≥1 TEAE versus 74.6% of younger patients. Conclusions: Although TEAEs more frequently lead to discontinuation in older patients, duloxetine was well tolerated and efficacious for treatment of DPNP regardless of age. These data suggest duloxetine may be beneficial for treatment of DPNP in patients ≥65.

Because many patients do not respond to pharmacotherapy for generalized anxiety disorder (GAD), it would be beneficial to know if early response is predictive of final outcome so that timely clinical decisions can be made about augmentation or alternative treatments. This topic has not been examined with the now recommended first-line treatments (selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors) for GAD. Combined data from three 9 to 10week acute treatment, multi-center, randomized, placebo-controlled studies of duloxetine for GAD were used to explore early improvement on the Hamilton Anxiety Rating Scale (HAMA) in relation to endpoint HAMA response (or = 50% improvement from baseline), HAMA remission (or = 7), Clinical Global Impression-Improvement (CGI-I) response (or = 2), and functional remission as measured by the Sheehan Disability Scale Global Functional Improvement (or = 5). For duloxetine-treated patients (n=668), the relationships between the proportion of patients who achieved each category of early (week 2 and week 4) HAMA improvement (or = 20%,or = 40%,or = 60%, andor = 80%) and achievement of endpoint HAMA response, HAMA remission, CGI response, and SDS remission status were all statistically significant (all P'sor = 0.003). One hundred percent of the duloxetine-treated patients who showed substantial HAMA improvement (80%) at week 2, and 93% at week 4, were HAMA responders at endpoint. At week 2, 79% of the duloxetine-treated patients who achieved a HAMA improvement of 40-59% were HAMA responders at endpoint. About half of duloxetine-treated patient showing 40-59% early HAMA improvement were remitters on the SDS at endpoint. These data suggest a connection between early improvement and endpoint response and remission status that can be used to guide clinical decision-making.

Background Clinical trials assessing antidepressant therapies typically include separate assessments of efficacy (benefit) and adverse events (risk). Global benefit–risk (GBR) assessment allows the simultaneous evaluation of both efficacy and adverse events. The objective was to compare the serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine and venlafaxine using GBR assessment. Methods Data were combined from two similarly designed, multicenter, randomized, double-blind, parallel group studies in which patients with major depressive disorder were randomized to either duloxetine 60 mg/day or venlafaxine extended release (XR) 150 mg/day (75 mg/day for the first 2 weeks) for a 6-week fixed dosing period followed by an additional 6 weeks of treatment in which the dose could be increased up to 120 mg/day for duloxetine and 225 mg/day for venlafaxine. Patients completing the study (or receiving study drug for 2 weeks or more) were eligible to enter a taper period where the dose of study drug was gradually reduced over 1–2 weeks prior to drug discontinuation. The primary outcome measure (defined a priori) was the GBR comparison of duloxetine 60 mg/day and venlafaxine XR 150 mg/day after 6 weeks of treatment. In the GBR analysis, benefit was defined as remission at endpoint [17-item Hamilton Depression Rating Scale (HAMD17) ⩽ 7]. Risk was defined by four categories: patients having either no adverse events (AEs), AEs with no severity rating greater than moderate, AEs with at least one severity rating of severe, or having discontinued with a reason of self-reported adverse event (regardless of any AE severity). Additional efficacy measures included HAMD17 total score and subscales, HAMA, CGI-S, and PGI-I. Safety and tolerability were assessed via analysis of reasons for discontinuation, treatment-emergent adverse events (TEAEs), discontinuation-emergent adverse events, and changes in vital signs, weight, and laboratory analytes. Results There were no significant differences between duloxetine 60 mg/day and venlafaxine 150 mg/day as measured by GBR assessment at the end of 6 weeks (−1.418 vs. −1.079, P = 0.217) or 12 weeks (−0.349 vs. −0.121, P = 0.440), nor were there significant differences between treatment groups on the majority of efficacy measures. Significantly more venlafaxine-treated patients (74.5%) completed 12 weeks of treatment compared with duloxetine-treated patients (64.8%, P = .006). Nausea was the most common treatment-emergent adverse event (TEAE) for both drugs, and was significantly higher with duloxetine 60 mg/day compared to venlafaxine 150 mg/day during the first 6 weeks of treatment (43.6% vs. 35.0%, P ⩽ 0.05). During the taper period, significantly more venlafaxine-treated patients reported discontinuation-emergent adverse events (DEAEs) than duloxetine-treated patients. From a safety perspective, significantly more venlafaxine-treated patients (n = 4) than duloxetine-treated patients (n = 0, P = .047) experienced sustained elevations of systolic blood pressure during the fixed dosing period. Otherwise, there were few significant differences in safety measures found between treatment groups during 6 and 12 weeks of therapy. Conclusions Duloxetine 60 mg/day and venlafaxine XR 150 mg/day have similar benefit–risk profiles on the basis of a comparison utilizing GBR assessment. The implications of the more subtle differences between these drugs, as well as for interpreting the GBR assessment, are discussed.

Summary Aims: This was a post hoc analysis to determine whether baseline severity of depression influenced the efficacy of duloxetine in treating major depressive disorder (MDD) and to better characterise the symptom response profile for duloxetine in patients with mild, moderate or more severe depression. Methods: Data were pooled from four double-blind, placebo-controlled studies in which outpatients with MDD were randomised to duloxetine (60 mg/day) or placebo for 8–9 weeks. Patients were retrospectively stratified according to baseline 17-item Hamilton Depression Rating scale (HAMD17) total scores: mild = total score ≤ 19 (duloxetine, n = 246; placebo, n = 184); moderate = 20–24 (duloxetine, n = 333; placebo, n = 217); severe = 25+ (duloxetine, n = 127; placebo, n = 87). Results: Duloxetine produced significantly greater baseline-to-end-point improvement vs. placebo (p

Summary Aim and methods: The impact of medical comorbidity on the efficacy and tolerability of duloxetine in elderly patients with major depressive disorder (MDD) was investigated in this study. Data were obtained from a multicentre, randomised, double-blind, placebo-controlled study in 311 patients with MDD aged 65–89. The primary outcome measure was a prespecified composite cognitive score based on four cognitive tests: (i) Verbal Learning and Recall Test; (ii) Symbol Digit Substitution Test; (iii) 2-Digit Cancellation Test and (iv) Letter-Number Sequencing Test. Secondary measures included the Geriatric Depression Scale (GDS), 17-Item Hamilton Depression Scale (HAMD17), Clinical Global Impression-Severity (CGI-S) Scale, Visual Analogue Scale (VAS) for pain and 36-Item Short Form Health Survey (SF-36). Tolerability measures included adverse events reported as the reason for discontinuation and treatment-emergent adverse events (TEAEs). The consistency of the effect of duloxetine vs. placebo comparing patients with and without medical comorbidity (vascular disease, diabetes, arthritis or any of these) was investigated. Results: Overall, duloxetine 60 mg/day demonstrated significantly greater improvement compared with placebo for the composite cognitive score, GDS and HAMD17 total scores, CGI-Severity, HAMD17 response and remission rates, and some of the SF-36 and VAS measures. There were few significant treatment-by-comorbidity subgroup interactions for these efficacy variables, or for adverse events reported as the reason for discontinuation and common TEAEs. Conclusions: The present analyses suggested that the efficacy of duloxetine on cognition and depression in elderly patients, and its tolerability, were not largely affected by the comorbidity status. These results further support the use of duloxetine in elderly patients with MDD.

This study compared the effects of duloxetine, 60 mg/day, versus placebo on cognition, depression, and pain in elderly patients with recurrent major depressive disorder.Patients were randomly assigned (2:1) to duloxetine, 60 mg/day (N=207), or placebo (N=104) for 8 weeks in a double-blind study. The primary outcome measure was a prespecified composite cognitive score composed of four individual tests. Secondary measures included the Geriatric Depression Scale, the Hamilton Depression Rating Scale, the Visual Analogue Scale assessing pain, and standard safety and tolerability assessments.Patients had a median age of 72 years (range=65-90). Duloxetine demonstrated significantly greater improvement in the composite cognitive score versus placebo (least-squares mean change from baseline to endpoint: 1.95 versus 0.76), driven by improved verbal learning and memory. Duloxetine treatment showed significantly greater baseline-to-endpoint reductions in both Hamilton depression scale (-6.49 versus -3.72) and Geriatric Depression Scale (-4.07 versus -1.34) total scores compared with placebo. Hamilton depression scale response (37.3% versus 18.6%) and remission (27.4% versus 14.7%) rates at endpoint were significantly higher for duloxetine than for placebo. Duloxetine significantly improved Visual Analogue Scale scores for back pain and time in pain while awake versus placebo. Significantly fewer patients receiving duloxetine withdrew from the study because of lack of efficacy (2.9% versus 9.6%); the incidences of discontinuation due to adverse events were similar for duloxetine and placebo (9.7% versus 8.7%).Duloxetine improved cognition, depression, and some pain measures and was safe and well tolerated in elderly patients with recurrent major depressive disorder.

The aim of the present paper was to compare the efficacy and safety of duloxetine with paroxetine in the acute treatment of major depressive disorder (MDD). In a randomized, double-blind trial of 8 weeks active treatment, patients with non-psychotic MDD were randomized to duloxetine 60 mg (n = 238) or paroxetine 20 mg (n = 240) once daily. Efficacy was primarily measured on change in the 17-item Hamilton Rating Scale for Depression (HAMD(17)) using a non-inferiority test with a margin of 2.2. Secondary efficacy measures included the HAMD(17) subscales, Hamilton Rating Scale for Anxiety, Clinical Global Impressions-Severity, Patient Global Impressions-Improvement, Somatic Symptoms Inventory and Visual Analog Scales (VAS) for pain. Safety measures included treatment-emergent adverse events (TEAE), vital signs, weight, laboratory analyses and electrocardiograms. Non-inferiority of duloxetine to paroxetine was demonstrated because the upper bound of the confidence interval for mean difference in HAMD(17) change (0.71) was less than the non-inferiority margin. Secondary efficacy end-points did not differ significantly between treatments with the exception of VAS back pain, where the pooled mean was lower in the duloxetine group (17.1) compared with the paroxetine group (20.3, P = 0.048). No significant differences were observed in the number of early discontinuations and overall TEAE. However, significantly greater proportions of patients in the duloxetine group experienced nausea and palpitations. No clinically relevant changes in laboratory values, vital signs, weight or electrocardiograms were observed with either treatment. The present study verifies the utility of duloxetine as an efficacious and safe treatment for both emotional and physical symptoms of MDD in this predominantly Asian patient sample.

OBJECTIVE Generalized anxiety disorder (GAD) is associated with impaired role functioning and diminished well-being. The present work examined the efficacy of duloxetine treatment for improving functional outcomes for patients with GAD in 3 independent clinical studies. METHOD Studies were randomized, double-blind, placebo-controlled multicenter trials conducted in adult outpatients with DSM-IV-defined GAD. One study compared 9-week fixed-dose treatment with duloxetine 60 or 120 mg (N = 168 and N = 170, respectively) with placebo (N = 175). The other 2 studies compared 10-week flexible-dose treatment with duloxetine 60-120 mg (study 2, N = 168; study 3, N = 162) with placebo (study 2, N = 159; study 3, N = 161). The main functional outcome measure for each study was the Sheehan Disability Scale (SDS). Additional measures were the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form and the European Quality of Life 5 Dimensions. The 3 studies were conducted in the time period from June 2004 to November 2005. RESULTS Duloxetine-treated patients improved significantly more than placebo-treated patients on SDS global functioning (study 1, p

Background and objective: In recent years, new classes of medication, such as the serotonin-noradrenaline reuptake inhibitors (SNRIs), have been developed for use in the treatment of major depressive disorder (MDD). For many years, treatment options were largely limited to the use of monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). However, there have been published reports of orthostatic hypotension, arrhythmias and corrected QT (QTc) interval changes in patients treated with TCAs. As new medications become available, it is important to understand how their cardiovascular safety profile compares with that of more established agents to aid clinicians and patients in choosing the best treatment options. This study was designed to evaluate the cardiovascular safety profile of the SNRI duloxetine through evaluation of cardiovascular-related parameters and adverse events (AEs). Methods: The cardiovascular safety of duloxetine was assessed using all placebocontrolled duloxetine clinical trial data as of December 2005. This consisted of data from 42 placebo-controlled clinical trials of 8504 patients who were treated with duloxetine. Additional information from a high-dose clinical pharmacology study and postmarketing safety surveillance are also presented. Of the placebocontrolled trials included in this analysis, clinical indications under investigation included MDD (15 studies), diabetic peripheral neuropathic pain (3 studies), fibromyalgia (2 studies), generalised anxiety disorder (3 studies) and lower urinary tract disorders (19 studies, all related to incontinence). Cardiovascular safety was evaluated based on vital signs, ECGs and the incidence of treatment-emergent AEs potentially related to cardiovascular safety. These safety parameters were analysed across all indications. To identify both serious and non-serious cardiovascular-related AEs, as well as AEs reported as the reason for discontinuation, a comprehensive list of terms derived from the Medical Dictionary for Regulatory Activities (version 8.0) was generated and used to search the duloxetine databases for cardiovascular-related events. Results: Calculation of change from baseline to maximum in ECG parameters showed significant differences between treatment groups for all parameters, with decreases from baseline in RR, QRS and QT intervals for patients receiving duloxetine and increases from baseline for patients treated with placebo. These shifts were related to small heart rate changes, but the mean differences were not considered clinically relevant. Categorical analyses of shifts from normal to abnormal (or abnormal to normal) for heart rate and QT corrected for heart rate using Fridericia’s formula (QTcF) values showed that most patients did not shift from their baseline category. Patients with MDD who were treated for up to 1 year with duloxetine had blood pressure changes early in treatment that then stabilised. Even in patients with elevated blood pressure at baseline in these clinical trials, no increased risk of sustained blood pressure elevation with duloxetine treatment was found. Conclusion: Overall, the findings presented here support our conclusions that use of duloxetine does not appear to be associated with significant cardiovascular risks in patients with conditions for which the drug has been approved or studied.

Summary Background Duloxetine has been approved in the United States, European Union and some Asian countries for the treatment of diabetic peripheral neuropathic pain (DPNP). We assessed the efficacy and safety of duloxetine (60 mg once daily) compared with placebo in Chinese patients suffering from DPNP. Methods This was a phase 3, multicenter, randomised, double-blind, parallel, placebo-controlled, 12-week trial of the treatment of DPNP with duloxetine. Subjects were male and female outpatients ≥ 18 years of age with DPNP, as assessed by the Michigan Neuropathy Screening Instrument, and had a rating of ≥ 4 on the Brief Pain Inventory-Modified Short Form-Severity weekly average pain item. The primary efficacy measure was the reduction in pain severity from baseline to 12 weeks, as measured by the weekly mean of 24-h average pain ratings recorded in the patient's diary. Mean changes from baseline in efficacy measures were analysed by a restricted maximum likelihood-based, mixed-effects model repeated measures approach and by analysis of covariance. Results Of the 405 patients randomised, 203 patients were assigned to duloxetine 60 mg once daily and 202 patients were assigned to placebo. Duloxetine-treated patients showed significantly greater pain relief on 24-h average pain ratings compared with placebo-treated patients each week of the 12-week study period [week 12: least squares (LS) mean change duloxetine: −2.40, placebo: −1.97; LS mean change difference (95% confidence interval) = −0.43 (−0.82, −0.04), p = 0.030]. Compared with placebo, patients treated with duloxetine experienced higher rates of nausea (p = 0.010), somnolence (p

Background: Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder with interrelated molecular, physiological, anatomical, biomarker, and cognitive dimensions. Methods: This article reviews the biological changes (genetic, molecular, and cellular) underlying AD and their correlation with the clinical syndrome. Results: Dementia associated with AD is related to the aberrant production, processing, and clearance of beta-amyloid and tau. Beta-amyloid deposition in brain follows a distinct spatial progression starting in the basal neocortex, spreading throughout the hippocampus, and eventually spreading to the rest of the cortex. The spread of tau pathology through neural networks leads to a distinct and consistent spatial progression of neurofibrillary tangles, beginning in the transentorhinal and hippocampal region and spreading superolaterally to the primary areas of the neocortex. Synaptic dysfunction and cell death is shown by progressive loss of cerebral metabolic rate for glucose and progressive brain atrophy. Decreases in synapse number in the dentate gyrus of the hippocampus correlate with declining cognitive function. Amyloid changes are detectable in cerebrospinal fluid and with amyloid imaging up to 20 years prior to the onset of symptoms. Structural atrophy may be detectable via magnetic resonance imaging up to 10 years before clinical signs appear. Conclusion: This review highlights the progression of biological changes underlying AD and their association with the clinical syndrome. Many changes occur before overt symptoms are evident and biomarkers provide a means to detect AD pathology even in patients without symptoms.

The evidence that the effects of the antidepressant duloxetine on painful physical symptoms in depression and chronic pain disorders are a direct analgesic effect rather than an indirect antidepressant effect is reviewed. Data from placebo-controlled acute studies of duloxetine in major depressive disorder, diabetic peripheral neuropathic pain and fibromyalgia syndrome are included in this review. In placebo-controlled studies of duloxetine in patients with major depressive disorder, non-depressed diabetic peripheral neuropathic pain, and fibromyalgia syndrome, duloxetine has a statistically significantly greater effect on pain than placebo. Path analysis suggests that in these patient populations, approximately 50, 90, and 80%, respectively, of the observed effect on pain is a direct analgesic effect rather than an indirect antidepressant effect. In fibromyalgia syndrome studies, duloxetine had similar and substantial effects on pain regardless of whether patients had comorbid major depressive disorder. Pain is a complex experience, involving both the physiological responses of the nociceptive system and the processing of that information in brain regions associated with emotion. While some effects of duloxetine on painful symptoms can be accounted for by its antidepressant action, the data strongly suggest that duloxetine also exerts a substantial direct analgesic effect over and above its antidepressant effects, in patients with major depressive disorder, diabetic peripheral neuropathic pain, and fibromyalgia syndrome.

Background: Serotonin (5-HT) and norepinephrine (NE) are involved in pain modulation via descending inhibitory pathways in the brain and spinal cord. Objective: To assess the efficacy of duloxetine, a dual reuptake inhibitor of 5-HT and NE, on the reduction of pain severity, as well as secondary outcome measures in patients with diabetic peripheral neuropathic pain (DPNP). Methods: In this double-blind study, patients with DPNP and without comorbid depression were randomly assigned to treatment with duloxetine 60 mg once daily (QD), duloxetine 60 mg twice daily (BID), or placebo for 12 weeks. The primary outcome measure was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. Secondary measures and health outcome measures were also assessed. Results: Duloxetine 60 mg QD and 60 mg BID demonstrated improvement in the management of DPNP and showed rapid onset of action, with separation from placebo beginning at week 1 on the 24-hour average pain severity score. For all secondary measures for pain (except allodynia), mean changes showed an advantage of duloxetine over placebo, with no significant difference between 60 mg QD and 60 mg BID. Clinical Global Impression of Severity and Patient’s Global Impression of Improvement evaluation demonstrated greater improvement on duloxetine- vs placebo-treated patients. Duloxetine showed no notable interference on diabetic controls, and both doses were safely administered. Conclusions: This study confirms previous findings that duloxetine at 60 mg QD and 60 mg BID is effective and safe in the management of diabetic peripheral neuropathic pain.

Duloxetine, an inhibitor of serotonin and norepinephrine reuptake, has been approved for the treatment of major depressive disorder. In this analysis, data from eight, double-blind, placebo-controlled duloxetine trials were pooled, and the response to duloxetine treatment (40-120 mg/day) was compared between patients experiencing their first episode of depression (n=581) or a subsequent episode (n=1321), and between patients experiencing a depressive episode of short (n=596), medium (n=669), or long (n=649) duration based on tertile divisions. Treatment response was determined on the basis of changes from baseline in the 17-item Hamilton Rating Scale for Depression total score, the Clinical Global Impressions of Severity Scale, and painful physical symptoms (Somatic Symptom Inventory and Visual Analog Scales). Overall, changes on all outcome measures and response and remission rates were significantly greater in duloxetine-treated patients than in placebo-treated patients. Furthermore, the effect of duloxetine was similar across all episode characteristic groups (first/subsequent episode, short/medium/long episode duration). Only for the Somatic Symptom Inventory was the effect of duloxetine significantly different between groups (greater in the subsequent episode group than in the first episode group). Duloxetine was effective in the treatment of first and subsequent episodes of major depressive disorder, and regardless of duration of the current depressive episode.

Objective. Duloxetine is a relatively balanced and potent reuptake inhibitor of both serotonin and norepinephrine. Because these neurotransmitters play a role in pain inhibition, duloxetine was considered a possible treatment for diabetic peripheral neuropathic pain (DPNP). This study assessed the 6-month safety and tolerability of duloxetine in patients with DPNP; evaluation of efficacy was a secondary objective. Design. In this 28-week, open-label study, in the clinical setting, 449 patients with DPNP were randomized (3:1) to receive duloxetine 60 mg twice daily (BID) (N = 334) or duloxetine 120 mg once daily (QD) (N = 115). Comprehensive safety evaluations including laboratory analyses and electrocardiograms were performed for all patients. Efficacy measures included the Brief Pain Inventory (BPI) and Clinical Global Impression of Severity (CGI-S) scales. Results. Protocol completion rates were 63.8% and 62.6% for the 60 mg BID and 120 mg QD groups, respectively ( P = 0.823). Discontinuations were primarily due to adverse events, 20.1% for 60 mg BID and 27.0% for 120 mg QD ( P = 0.149). Heart rate increased slightly in both treatment groups ( P ≤ 0.02 in both groups). Systolic blood pressure was unaffected, while diastolic blood pressure decreased slightly in the 120 mg QD group ( P = 0.04). Sustained elevation in blood pressure was reported for 18 (5.5%) patients in the 60 mg BID group and six (5.4%) in the 120 mg QD group. Duloxetine treatment was not associated with significant QTc prolongation. There was significant improvement at endpoint on all subscales of the BPI and CGI-S ( P < 0.001 in both groups). Conclusions. In this study, duloxetine 60 mg BID and 120 mg QD were safely administered and well tolerated in patients with DPNP for up to 28 weeks. There were few differences in safety or tolerability between the two dosages. At both doses, duloxetine provided clinically significant pain relief.

There is ongoing debate regarding the effectiveness of antidepressants in patients with milder major depressive disorder (MDD). This post-hoc analysis evaluated the efficacy and tolerability of duloxetine in the subset of 159 (75 duloxetine and 84 placebo) patients with milder MDD (baseline HAMD17 total score ≥15 and ≤18) who were treated once daily with duloxetine 60 mg or placebo in two identical, 9-week, randomised, double-blind trials. At endpoint, change from baseline on HAMD17 was greater in the duloxetine group (−7.0) than in the placebo group (−4.1) (p = 0.005). Response and remission rates, and improvement on the Clinical Global Impressions-Severity (CGI-S) scale, the Patient Global Impressions-Improvement (PGI-I) scale, and measures of painful symptoms were also significantly better in the duloxetine group (p < 0.05). Tolerability was consistent with that seen in previous studies of duloxetine in patients with more severe depression. In conclusion, duloxetine 60 mg/day is effective and well tolerated in milder MDD.

Objective. Assess efficacy and safety of duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, on the reduction of pain severity, in patients with diabetic peripheral neuropathic pain (DPNP). Methods. This was a multicenter, parallel, double-blind, randomized, placebo-controlled trial that enrolled 348 patients with pain due to peripheral neuropathy caused by type 1 or type 2 diabetes mellitus. Patients (N = 116 per group) were randomly assigned to receive duloxetine 60 mg once daily (QD), duloxetine 60 mg twice daily (BID), or placebo, for 12 weeks. The primary outcome measure was the weekly mean score of 24-hour average pain severity evaluated on an 11-point Likert scale. Secondary outcome measures and safety were evaluated. Results. Compared with placebo-treated patients, both duloxetine-treated groups improved significantly more (P

This analysis assessed the incidence, severity, onset, and duration of nausea among patients with major depressive disorder (MDD) treated with the new antidepressant duloxetine.Data were pooled from 8 double-blind, randomized, placebo- and active comparator-controlled trials employing patients with MDD that were submitted to the US Food and Drug Administration to support duloxetine's new drug application for treatment of MDD.The numbers of patients receiving each regimen were as follows: placebo, n = 777; duloxetine 40 mg/d, n = 177; duloxetine 60 mg/d, n = 251; duloxetine 80 mg/d, n = 363; duloxetine 120 mg/d, n = 348; paroxetine 20 mg/d, n = 359; and fluoxetine 20 mg/d, n = 70. In acute placebo-controlled trials of duloxetine 40 to 120 mg/d, treatment-emergent nausea was reported by more duloxetine-treated patients than those receiving placebo (19.9% [227/1139] vs 6.9% [154/777], respectively; P0.001). Among duloxetine-treated patients, the median time to onset of nausea was 1 day, and the median duration of nausea was 7 days. The incidence of nausea was similar to placebo rates after 1 week. In paroxetine-controlled studies, the incidence of treatment-emergent nausea in patients receiving duloxetine did not differ significantly from paroxetine (14.4% vs 12.0%, respectively). In head-to-head studies, the incidence of treatment-emergent nausea with duloxetine did not differ significantly from that with fluoxetine (17.1% vs 15.7%, respectively). Most duloxetine-treated patients reported nausea to be mild (52.9%) or moderate (41.4%). Treatment discontinuation secondary to nausea occurred in more duloxetine-treated patients than those receiving placebo (1.4% [16/1139] vs 0.1% [1/777], respectively; P = 0.002). Following abrupt discontinuation after acute treatment, 5.9% of duloxetine-treated patients exhibited nausea compared with 0.3% of patients receiving placebo (P0.001). The incidence of treatment-emergent nausea during 6-month continuation of duloxetine treatment (80 mg/d, 2.1%; 120 mg/d, 1.3%) was similar to placebo (1.6%). Following abrupt discontinuation after 8 months of treatment, nausea was reported by 1.6% of patients receiving duloxetine 120 mg/d compared with 0% for those receiving duloxetine 80 mg/d and 0% for placebo.Duloxetine induced mild to moderate nausea in a subset of patients with MDD during treatment initiation. Nausea resolved rapidly with continued treatment. The incidence of duloxetine-induced nausea resembled that produced by paroxetine and fluoxetine.

Background: This study was designed to evaluate the effect of combining bupropion sustained release (SR) with venlafaxine, paroxetine, or fluoxetine in patients who reported unacceptable sexual dysfunction when treated with monotherapy with the latter 3 agents. Method: Following a minimum of 6 weeks of antidepressant treatment with a selective serotonin reuptake inhibitor (SSRI) or venlafaxine (a serotonin-norepinephrine reuptake inhibitor), eligible subjects received a further 8 weeks of monitored combination therapy with bupropion SR at a dose of 150 mg/day with no alterations to index antidepressant dosing. Results: There was a clinically significant benefit in 14 (78%) of 18 partial responders or nonresponders, and 33% (N = 6) achieved a full response (X 2 = 8.06, df = = 2, p =.017). Sexual dysfunction, particularly a decrease in orgasmic delay, was also significantly improved with combination therapy (men: paired t = -2.1, df = 6, p =.08; women: paired t = -3.0, df = 7, p =.02). Plasma monitoring of drugs and their metabolites revealed a statistically significant increase in venlafaxine levels (F = 6.89, df = 4,24; p =.001) accompanied by a decrease in O-desmethyl-venlafaxine (F = 14.26; df = 4,24; p