Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial.

Importance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] ß = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] ß = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] ß = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] ß = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] ß = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] ß = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] ß = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration: ClinicalTrials.gov Identifier: NCT04623242.

Trial of Solanezumab in Preclinical Alzheimer's Disease.

BACKGROUND: Trials of monoclonal antibodies that target various forms of amyloid at different stages of Alzheimer's disease have had mixed results. METHODS: We tested solanezumab, which targets monomeric amyloid, in a phase 3 trial involving persons with preclinical Alzheimer's disease. Persons 65 to 85 years of age with a global Clinical Dementia Rating score of 0 (range, 0 to 3, with 0 indicating no cognitive impairment and 3 severe dementia), a score on the Mini-Mental State Examination of 25 or more (range, 0 to 30, with lower scores indicating poorer cognition), and elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) were enrolled. Participants were randomly assigned in a 1:1 ratio to receive solanezumab at a dose of up to 1600 mg intravenously every 4 weeks or placebo. The primary end point was the change in the Preclinical Alzheimer Cognitive Composite (PACC) score (calculated as the sum of four z scores, with higher scores indicating better cognitive performance) over a period of 240 weeks. RESULTS: A total of 1169 persons underwent randomization: 578 were assigned to the solanezumab group and 591 to the placebo group. The mean age of the participants was 72 years, approximately 60% were women, and 75% had a family history of dementia. At 240 weeks, the mean change in PACC score was -1.43 in the solanezumab group and -1.13 in the placebo group (difference, -0.30; 95% confidence interval, -0.82 to 0.22; P = 0.26). Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group. Amyloid-related imaging abnormalities (ARIA) with edema occurred in less than 1% of the participants in each group. ARIA with microhemorrhage or hemosiderosis occurred in 29.2% of the participants in the solanezumab group and 32.8% of those in the placebo group. CONCLUSIONS: Solanezumab, which targets monomeric amyloid in persons with elevated brain amyloid levels, did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer's disease. (Funded by the National Institute on Aging and others; A4 ClinicalTrials.gov number, NCT02008357.).

Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease.

OBJECTIVE: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). METHODS: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, ß-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. RESULTS: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. INTERPRETATION: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744.

Phase II (NAVIGATE-AD study) Results of LY3202626 Effects on Patients with Mild Alzheimer's Disease Dementia.

BACKGROUND: LY3202626 is a small molecule inhibitor of ß-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-ß (Aß)1-40 and Aß1-42 concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer's disease (AD). OBJECTIVE: To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild AD dementia. METHODS: Patients received daily 3 mg or 12 mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline. RESULTS: A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo. CONCLUSION: LY3202626 tested at doses generating 70-90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo.

Evaluation of dystonia in children and adolescents treated with atomoxetine within the Truven MarketScan database: a retrospective cohort study.

OBJECTIVE: Atomoxetine is a non-stimulant drug indicated for the treatment of attention-deficit/hyperactivity disorder in children aged ≥6 years, adolescents, and adults. In this retrospective cohort study, the incidence and risk of dystonia in children and adolescents treated with atomoxetine was compared to a propensity score-matched cohort of stimulant users. METHODS: Data between 1 January 2006 and 31 December 2014 from patients aged 6-17 years in the Truven Health Analytics MarketScan database were used to generate two cohorts of patients: (1) atomoxetine users and (2) stimulant (methylphenidates or amphetamines) users. A Cox proportional hazards regression model was used to compare incidence of dystonia across propensity score-matched cohorts. RESULTS: Of the 70,657 atomoxetine users, 70,655 users were propensity score-matched to a stimulant user. In the atomoxetine- and stimulant-treated cohorts, the crude incidence rates of dystonia were 54.9 (95% CI: 27.1-82.7) and 77.9 (95% CI: 49.1-106.8) per 100,000 person-years, respectively. The hazard ratio for occurrence of dystonia with atomoxetine use relative to stimulant use was 0.68 (95% CI: 0.36 - 1.28; P = 0.23). CONCLUSION: In this large retrospective cohort study, there was no significant difference in incidence or risk of dystonia among patients treated with atomoxetine compared to stimulants.

The Use of a High-Tech Knee Pad for Reduction of the Postoperative Effusion after Total Knee Arthroplasty.

Purpose After total knee arthroplasty (TKA), pain and swelling, especially in older and less cooperative patients, can limit the retrieval of a good range of motion and muscle tone and consequently the achievement of an optimal function outcome. A high-tech knee pad made of metal fibers emitting infrared energy was used in a group of patients undergoing TKA to assess its efficacy in the postoperative period with respect to a group with a placebo. Methods Twelve patients used knee pads after surgery for 3 weeks and were evaluated using visual analog scale (VAS), Knee Society Rating Score, Cincinnati Knee Rating Score, and painkillers at specific timings. Results At 3 weeks, all scores improved in a significant manner in the treated group compared with the placebo group. At 2 months after surgery, VAS was better in the study group than the control group, whereas other parameters were similar. However, the use of rescue drugs was less in the study group than in the placebo group. Conclusion A high-tech knee pad may contribute to a faster recovery within the first week after a knee replacement, limiting the use of painkillers and allowing a quick functional recovery by the control of pain and postoperative effusion. Level of Evidence Level II, randomized prospective study with small sample size.

A review of the efficacy of atomoxetine in the treatment of attention-deficit hyperactivity disorder in children and adult patients with common comorbidities.

Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder that is often diagnosed during childhood, but has also increasingly been recognized to occur in adults. Importantly, up to 52% of children (including adolescents) and 87% of adults with ADHD also have a comorbid psychiatric disorder. The presence of a comorbid disorder has the potential to impact diagnosis and could affect treatment outcomes. Atomoxetine is a nonstimulant treatment for ADHD. Despite numerous published studies regarding efficacy of atomoxetine in the treatment of ADHD in patients with comorbid disorders, there is limited information about the impact of individual common comorbid disorders on the efficacy of atomoxetine for ADHD, especially with regard to adults. Moreover, a cumulative review and assessment of these studies has not been conducted. For this reason, we performed a literature review to find, identify, and cumulatively review clinical studies that examined the efficacy of atomoxetine in the treatment of patients with ADHD and comorbid psychiatric disorders. We found a total of 50 clinical studies (37 in children; 13 in adults) that examined the efficacy of atomoxetine in patients with ADHD and a comorbid disorder. The comorbidities that were studied in children or in adults included anxiety, depression, and substance use disorder. Overall, the presence of comorbidity did not adversely impact the efficacy of atomoxetine in treatment of ADHD symptoms in both patient populations. In the studies identified and assessed in this review, atomoxetine did not appear to exacerbate any of the comorbid conditions and could, therefore, be an important therapy choice for the treatment of ADHD in the presence of comorbid disorders.

A systematic review of the quality of studies on dementia prevalence in Italy.

BACKGROUND: Dementia, including Alzheimer's disease (AD), is one of the most burdensome medical conditions. In order to better understand the epidemiology of dementia in Italy, we conducted a systematic search of studies published between 1980 and April 2014 investigating the prevalence of dementia and AD in Italy and then evaluated the quality of the selected studies. METHODS: A systematic search was performed using PubMed/Medline and Embase to identify Italian population-based studies on the prevalence of dementia among people aged ≥60 years. The quality of the studies was scored according to Alzheimer's Disease International (ADI) criteria. RESULTS: Sixteen articles on the prevalence of dementia and AD in Italy were eligible and 75 % of them were published before the year 2000. Only one study was a national survey, whereas most of the studies were locally based (Northern Italy and Tuscany). Overall, the 16 studies were attributed a mean ADI quality score of 7.6 (median 7.75). CONCLUSIONS: Available studies on the prevalence of dementia and AD in Italy are generally old, of weak quality, and do not include all regions of Italy. The important limitations of the few eligible studies included in our analysis, mostly related to their heterogeneous design, make our systematic review difficult to interpret from an epidemiologic point of view. Full implementation of a Dementia National Plan is highly needed to better understand the epidemiology of the disease and monitor dementia patients.

A systematic review of the quality of studies on dementia prevalence in Italy.

BACKGROUND: Dementia, including Alzheimer's disease (AD), is one of the most burdensome medical conditions. In order to better understand the epidemiology of dementia in Italy, we conducted a systematic search of studies published between 1980 and April 2014 investigating the prevalence of dementia and AD in Italy and then evaluated the quality of the selected studies. METHODS: A systematic search was performed using PubMed/Medline and Embase to identify Italian population-based studies on the prevalence of dementia among people aged ≥60 years. The quality of the studies was scored according to Alzheimer's Disease International (ADI) criteria. RESULTS: Sixteen articles on the prevalence of dementia and AD in Italy were eligible and 75 % of them were published before the year 2000. Only one study was a national survey, whereas most of the studies were locally based (Northern Italy and Tuscany). Overall, the 16 studies were attributed a mean ADI quality score of 7.6 (median 7.75). CONCLUSIONS: Available studies on the prevalence of dementia and AD in Italy are generally old, of weak quality, and do not include all regions of Italy. The important limitations of the few eligible studies included in our analysis, mostly related to their heterogeneous design, make our systematic review difficult to interpret from an epidemiologic point of view. Full implementation of a Dementia National Plan is highly needed to better understand the epidemiology of the disease and monitor dementia patients.

Assessment of functional outcomes by Sheehan Disability Scale in patients with major depressive disorder treated with duloxetine versus selective serotonin reuptake inhibitors.

OBJECTIVE: We compared functional impairment outcomes assessed with Sheehan Disability Scale (SDS) after treatment with duloxetine versus selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder. METHODS: Data were pooled from four randomized studies comparing treatment with duloxetine and SSRIs (three double blind and one open label). Analysis of covariance, with last-observation-carried-forward approach for missing data, explored treatment differences between duloxetine and SSRIs on SDS changes during 8 to 12 weeks of acute treatment for the intent-to-treat population. Logistic regression analysis examined the predictive capacity of baseline patient characteristics for remission in functional impairment (SDS total score ≤ 6 and SDS item scores ≤ 2) at endpoint. RESULTS: Included were 2193 patients (duloxetine n = 1029; SSRIs n = 835; placebo n = 329). Treatment with duloxetine and SSRIs resulted in significantly (p < 0.01) greater improvements in the SDS total score versus treatment with placebo. Higher SDS (p < 0.0001) or 17-item Hamilton Depression Rating Scale baseline scores (p < 0.01) predicted lower probability of functional improvement after treatment with duloxetine or SSRIs. Female gender (p ≤ 0.05) predicted higher probability of functional improvement after treatment with duloxetine or SSRIs. CONCLUSIONS: Treatment with SSRIs and duloxetine improved functional impairment in patients with major depressive disorder. Higher SDS or 17-item Hamilton Depression Rating Scale baseline scores predicted less probability of SDS improvement; female gender predicted better improvement in functional impairment at endpoint.

Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants.

An increasing rate of antidepressant trials fail due to large placebo responses. This analysis aimed to identify variables influencing signal detection in clinical trials of major depressive disorder. Patient-level data of randomized patients with a duloxetine dose ≥ 60 mg/day were obtained from Lilly. Total scores of the Hamilton Depression Rating scale (HAM-D) were used as efficacy endpoints. In total, 4661 patients from 14 studies were included in the analysis. The overall effect size (ES), based on the HAM-D total score at endpoint, between duloxetine and placebo was -0.272. Although no statistically significant interactions were found, the following results for factors influencing ES were seen: a very low ES (-0.157) in patients in the lowest baseline HAM-D category and in patients recruited in the last category of the recruitment period (-0.122). A higher ES in patients recruited in centers with a site-size at but not more than 2.5 times the average site-size for the study (-0.345). Study characteristics that resulted in low signal detection in our database were: <80% study completers, a HAM-D placebo response >5 points, a high variability of placebo response (SD > 7 points HAM-D), >6 post baseline visits per study, and use of an active control drug. Simpler trial designs, more homogeneous and mid-sized study sites, a primary analysis based on a higher cutoff blinded to investigators to avoid the influence of score inflation in mild patients and, if possible, studies without an active control group could lead to a better signal detection of antidepressive efficacy.

Stability of unfrozen whole blood DNA for remote genotypic analysis of HIV-1 coreceptor tropism.

BACKGROUND: Maraviroc is an HIV-1 coreceptor antagonist that has shown good efficacy and tolerability in treatment-naive and treatment-experienced patients harboring CCR5-tropic virus. The use of Maraviroc in treatment simplification in patients with suppressed plasma HIV-1 RNA requires analysis of HIV-1 DNA. Coreceptor tropism testing is often performed remotely at reference laboratories. In this study paired whole blood stored at + 4 °C and at-20°C were compared as a source for genotypic coreceptor tropism testing. METHODS: Two hundred paired whole blood samples from different patients were analysed. Each sample was stored in two different conditions: one aliquot was stored at-20 °C until spin column DNA extraction (WB20) and one aliquot was stored at +4°C for two weeks and then placed at room temperature (22-24 °C) for two days before DNA extraction (WB4). Subsequently, a fragment encompassing the HIV-1 gp120 V3 domain was amplified by a singlicate nested PCR followed by triplicate nested PCR in the negative samples. A randomly selected panel of 20 paired WB4 and WB20 duplicate amplification products were sequenced and coreceptor tropism was inferred by geno2pheno [coreceptor]. RESULTS: WB20 yielded a higher amount of DNA than WB4 (median [IQR] values 332.5 ng/µl [117.5-401] and 107 ng/µl [56.6-318], respectively; P < 0.001). However, the DNA purity was higher for WB4 than for WB20 (median distance from the optimal OD260/280 ratio, 0.14 [0.07-0.79] and 0.96 [0.36-1.10], respectively; P < 0.0001). The number of samples successfully amplified was 152 (76.0%) for WB20 and 155 (77.5%) for WB4 with the first PCR and 179 (89.5%) for WB20 and 181 (90.5%) for WB4 (P = ns) following subsequent triplicate analysis. The inferred coreceptor tropism was concordant in 18 out of 20 paired WB4 and WB20 samples. Two samples yielded discordant results, consistent with the discordance rate within duplicates from the same sample source (2/20 with WB4 and 1/20 with WB20) due to the inherent gp120 V3 variability. CONCLUSIONS: Storing whole blood at +4°C for up to two weeks and shipping at room temperature is a convenient method for obtaining HIV-1 gp120 V3 sequence information via testing at a remote laboratory in patients with suppressed viremia.

Treatment response for acute depression is not associated with number of previous episodes: lack of evidence for a clinical staging model for major depressive disorder.

Mental illness has been observed to follow a neuroprogressive course, commencing with prodrome, then onset, recurrence and finally chronic illness. In bipolar disorder and schizophrenia responsiveness to treatment mirrors these stages of illness progression, with greater response to treatment in the earlier stages of illness and greater treatment resistance in chronic late stage illness. Using data from 5627 participants in 15 controlled trials of duloxetine, comparator arm (paroxetine, venlafaxine, escitalopram) or placebo for the treatment of an acute depressive episode, the relationship between treatment response and number of previous depressive episodes was determined. Data was dichotomised for comparisons between participants who had >3 previous episodes (n=1697) or ≤3 previous episodes (n=3930), and additionally for no previous episodes (n=1381) or at least one previous episode (n=4246). Analyses were conducted by study arm for each clinical trial, and results were then pooled. There was no significant difference between treatment response and number of previous depressive episodes. This unexpected finding suggests that treatments to reduce symptoms of depression during acute illness do not lose efficacy for patients with a longer history of illness.

A non-comparative assessment of tolerability and efficacy of duloxetine in the treatment of depressed patients with Parkinson's disease.

OBJECTIVE: Depression is a comorbidity affecting quality of life (QoL) in patients with Parkinson's disease (PD) and requires appropriate treatment. This study evaluated the tolerability, safety, and efficacy of duloxetine 60 mg once daily for 12 weeks in PD patients with major depressive disorder (MDD). RESEARCH AND DESIGN METHODS: Non-comparative, open-label, multi-center study. MAIN OUTCOME MEASURES: Tolerability was evaluated by discontinuation rate (acceptable if ≤ 19%) due to treatment-emergent adverse events (TEAEs) and motor symptoms (UPDRS). Safety measures were TEAEs, the UKU side effect rating scale, vital signs, weight, laboratory tests, and ECG. Efficacy measures included HAMD-17, BDI, CGI-S, PGI-I, and pain VAS. QoL was measured by PDQ-39. RESULTS: Of the 151 patients enrolled, 8.6% (95% upper CI: 13.3%) discontinued the study due to TEAEs. Worsening in PD-related tremor and rigidity was not observed, activities of daily living significantly improved and UKU subscales progressively decreased. Clinically significant abnormalities in laboratory findings were limited to four cases of hypercholesterolemia and one increase of total bilirubin, CPK, and fasting glucose. Blood pressure, weight, and ECG did not change from baseline. HAMD-17 and PDQ-39 total score and individual domains, BDI, CGI-S, and PGI-I total scores significantly improved. CONCLUSIONS: Duloxetine seems well tolerated and likely effective in the treatment of depression associated with PD, with no detrimental effects in PD signs and symptoms.

Evaluation of the effect of duloxetine treatment on functioning as measured by the Sheehan disability scale: pooled analysis of data from six randomized, double-blind, placebo-controlled clinical studies.

The purpose of this work is to describe the effect of duloxetine on functioning as measured by the Sheehan disability scale (SDS) compared with placebo in patients with major depressive disorder (MDD). Pooled data from six randomized, parallel, double-blind, placebo-controlled duloxetine studies in adult MDD patients were analyzed at the short-term (7-13 weeks) and the long-term (>24 weeks) endpoint. The primary variable was the SDS total score. Secondary variables included functional remission (SDS total ≤ 6) rates, Hamilton rating scale for depression total score, and pain visual analog scale. Analysis of covariance and logistic regression methods were used to assess differences in treatment and identify prognostic baseline factors. In total, 2496 patients (1424 duloxetine; 1072 placebo) were included. The between-treatment difference of -2.52 between duloxetine and placebo in the SDS total score at the short-term endpoint was statistically significant in favor of duloxetine vs. placebo (95% confidence interval: -3.17, -1.87; P < 0.001). The endpoint functional remission rates were 39.5% with duloxetine and 28.7% with placebo. Time since first depression episode, antidepressant pretreatment (yes/no), baseline visual analog scale pain (≤30 / >30 mm), and sex were significant prognostic factors. The effect of duloxetine was maintained at the long-term endpoint. Duloxetine is effective in improving MDD patients' functioning. Further antidepressant studies focusing on functioning would be helpful.

Stress-induced changes of hippocampal NMDA receptors: modulation by duloxetine treatment.

It is now well established that the glutamatergic system contributes to the pathophysiology of depression. Exposure to stress, a major precipitating factor for depression, enhances glutamate release that can contribute to structural abnormalities observed in the brain of depressed subjects. On the other hand, it has been demonstrated that NMDA antagonists, like ketamine, exert an antidepressant effect at preclinical and clinical levels. On these bases, the purpose of our study was to investigate whether chronic mild stress is associated with specific alterations of the NMDA receptor complex, in adult rats, and to establish whether concomitant antidepressant treatment could normalize such deficits. We found that chronic stress increases the expression of the obligatory GluN1 subunit, as well as of the accessory subunits GluN2A and GluN2B at transcriptional and translational levels, particularly in the ventral hippocampus. Concomitant treatment with the antidepressant duloxetine was able to normalize the increase of glutamatergic receptor subunit expression, and correct the changes in receptor phosphorylation produced by stress exposure. Our data suggest that prolonged stress, a condition that has etiologic relevance for depression, may enhance glutamate activity through post-synaptic mechanisms, by regulating NMDA receptors, and that antidepressants may in part normalize such changes. Our results provide support to the notion that antidepressants may exert their activity in the long-term also via modulation of the glutamatergic synapse.

Use of duloxetine in patients with an anxiety disorder, or with comorbid anxiety and major depressive disorder: a review of the literature.

IMPORTANCE OF THE FIELD: Except for generalized anxiety disorder, few reports have been published on the efficacy, safety and tolerability of duloxetine in patients with anxiety disorders individually or in comorbidity with major depressive disorder (MDD). AREAS COVERED IN THIS REVIEW: The literature search in Medline (dating back to 1966) and Embase (dating back to 1988) databases was conducted using the OVID interface on 9 April 2009, restricted to any article or abstract in English, per title, reporting any information on the use of duloxetine in patients with any anxiety disorder with or without concomitant MDD. A systematic review approach was taken. WHAT THE READER WILL GAIN: The reader will gain knowledge of the current data available on the use of duloxetine to treat patients with anxiety disorders individually or in comorbidity with MDD. TAKE HOME MESSAGE: Duloxetine could be considered an effective treatment option in the treatment of anxiety disorders individually or in comorbidity with each other, or with MDD; however, apart from the well-demonstrated efficacy, tolerability and safety of duloxetine in the treatment of MDD with or without anxiety and GAD, data on this subject are preliminary and very limited, and more research is warranted.

Duloxetine in acute major depression: review of comparisons to placebo and standard antidepressants using dissimilar methods.

BACKGROUND: Randomized controlled trials (RCTs) of duloxetine (DLX), an inhibitor of both norepinephrine and serotonin transporters (SNRI), have tested its efficacy in acute major depressive disorder (MDD) versus placebo (PBO) or standard serotonin-reuptake inhibitors (SRIs) and require review, comparing analytical methods. METHOD: Computerized searching to identify reports of RCTs of DLX in adult, acute MDD patients permitted meta-analytic pooling to estimate overall response and remission rates, to compare mixed-model, repeated measures (MMRM) versus last-observations-carried-forward (LOCF) analytical methods, and to assess relations of DLX dose to efficacy and adverse outcomes. RESULTS: We identified 17 RCTs involving 22 comparisons (DLX versus PBO [n = 17) and DLX versus an SRI [n = 16]), based on MMRM and LOCF methods that allowed estimates of response (>or=50% improvement of depression scores) or remission (final depression score

Acute stress responsiveness of the neurotrophin BDNF in the rat hippocampus is modulated by chronic treatment with the antidepressant duloxetine.

Compelling evidence suggests that mood disorders are characterized by reduced neuronal plasticity that might be normalized by pharmacological intervention. Our study aimed to establish whether chronic antidepressant treatment could alter the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) under a stressful condition. Therefore, adult male Sprague-Dawley rats were treated for 21 days with vehicle or with the SNRI duloxetine and, 24 h after the last injection, exposed to an acute swim stress (5 min) before being killed 15 min later. We found that chronic duloxetine treatment was able to modulate the rapid transcriptional changes of BDNF isoforms produced by an acute swim stress. Indeed whereas the mRNA levels of BDNF exon IV were upregulated by stress in vehicle as well as in duloxetine-treated rats, a significant increase of exon VI and exon IX was only found in rats that were pretreated with the antidepressant. These differential effects are in part because of selective changes in signaling pathways involved in the control of BDNF transcription. Moreover, the acute stressful episode significantly increased the levels of mature BDNF protein in the synaptosomal compartment in rats that were pretreated with the antidepressant, but not in control animals. Our results suggest that chronic antidepressant treatment might affect the responsiveness of BDNF under stressful conditions, suggesting that pharmacological intervention could 'prime' neuroprotective pathways and render them more responsive to preserve cell function and viability.