Search

Angewandte Chemie / International edition 62(22), e202300531 (2023). doi:10.1002/anie.202300531, Published by Wiley-VCH, Weinheim

Either a random-parameters logit (RPL) or latent class (LC) model can be used to model or explain preference heterogeneity in discrete-choice experiment (DCE) data. The former assumes continuous distribution of preferences across the sample, while the latter assumes a discrete distribution. This study compared RPL and LC models to explore preference heterogeneity when analyzing patient preferences for psoriasis treatments. Using DCE data collected from respondents with moderate-to-severe plaque psoriasis, we calculated and compared preference weights derived from RPL and LC models. We then compared how RPL and LC explain preference heterogeneity by exploring differences across subgroups defined by observed characteristics (i.e., country, age, gender, marital status, and psoriasis severity). While RPL and LC models resulted in the same mean preference weights, different preference-heterogeneity patterns emerged from the two approaches. In both models, country of residence and self-reported disease severity could be linked to systematic differences in preferences. The RPL also identified gender and marital status, but not age, as sources of heterogeneity; the LC membership probability model indicated that age was a significant factor, but not gender or marital status. Using data from a psoriasis patient survey to compare two widely used methods for exploring heterogeneity identified differences in results between stated-preferences: subgroup analysis in the RPL model and inclusion of subgroup characteristics in the class membership probability function of the LC model. Researchers should model data using the most adaptable approach to address the initial study question.

In health technology assessment (HTA), beside network meta-analysis (NMA), indirect comparisons (IC) have become an important tool used to provide evidence between two treatments when no head-to-head data are available. Researchers may use the adjusted indirect comparison based on the Bucher method (AIC) or the matching-adjusted indirect comparison (MAIC). While the Bucher method may provide biased results when included trials differ in baseline characteristics that influence the treatment outcome (treatment effect modifier), this issue may be addressed by applying the MAIC method if individual patient data (IPD) for at least one part of the AIC is available. Here, IPD is reweighted to match baseline characteristics and/or treatment effect modifiers of published data. However, the MAIC method does not provide a solution for situations when several common comparators are available. In these situations, assuming that the indirect comparison via the different common comparators is homogeneous, we propose merging these results by using meta-analysis methodology to provide a single, potentially more precise, treatment effect estimate. This paper introduces the method to combine several MAIC networks using classic meta-analysis techniques, it discusses the advantages and limitations of this approach, as well as demonstrates a practical application to combine several (M)AIC networks using data from Phase III psoriasis randomized control trials (RCT).

Summary Background Interleukin‐17 antagonists have received a first‐line label for moderate‐to‐severe plaque psoriasis. Objectives We conducted the first head‐to‐head trial between the two most commonly used first‐line therapies in Germany, fumaric acid esters (FAEs) and methotrexate, and the interleukin‐17A antagonist, ixekizumab. Methods Systemic‐naive patients were randomized in this parallel‐group, active‐comparator, open‐label, rater‐blinded trial (each group n = 54). The primary outcome was the proportion of patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at 24 weeks. Key secondary outcomes included 24‐week PASI 90 and 100, static Physician's Global Assessment (sPGA) score of 0 or 1, and Dermatology Life Quality Index (DLQI) score of 0 or 1. Safety events at week 24 were analysed using Fisher's exact test. Missing data were imputed using nonresponder imputation. The trial was registered at ClinicalTrials.gov (NCT02634801) and EudraCT (2015‐002649‐69). Results At week 24, more ixekizumab‐treated patients achieved PASI 75 [91% vs. 22% FAEs (P < 0·001) and 70% methotrexate (P = 0·014)], PASI 90 [80% vs. 9% FAEs (P < 0·001) and 39% methotrexate (P < 0·001)] and PASI 100 [41% vs. 4% FAEs (P < 0·001) and 13% methotrexate (P = 0·0041)], as well as sPGA (0,1) and DLQI (0,1). Conclusions Ixekizumab was superior in inducing PASI 75/90/100, sPGA (0,1) and DLQI (0,1) responses at week 24 compared with methotrexate and FAEs. Safety profiles for all treatments were consistent with prior studies., What's already known about this topic? Fumaric acid esters (FAEs) and methotrexate are two frequently used conventional systemic therapies for chronic plaque psoriasis.A recent meta‐analysis of methotrexate showed a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) rate of 45·2% from primary end points at either 12 or 16 weeks.Until recently, FAEs were licensed for psoriasis only in Germany, but were used in many other European countries as off‐label treatment of psoriasis. In 2017, the European Medicines Agency approved dimethyl fumarate, presumed to be the main active ingredient of FAEs, for the treatment of adult patients with moderate‐to‐severe chronic plaque psoriasis. What does this study add? This study is the first randomized, head‐to‐head trial comparing a biologic treatment with these therapies in a systemic‐treatment‐naive patient population.This study shows the low tolerability of FAEs leading to a significant discontinuation rate, the better tolerability and moderate efficacy of methotrexate, and the good tolerability, fast onset of action and high efficacy of ixekizumab in an unbiased comparison.Our findings reinforce the favourable risk–benefit profile of ixekizumab shown previously and provide further evidence of its efficacy at 24 weeks. https://doi.org/10.1111/bjd.18905 available online

17 USC 105 interim-entered record; under temporary embargo. Fifth Generation (5G) wireless technology is ushering in a new age of interconnectivity, and as it does definitions of privacy may well change with it. In this paper we will focus on the changing nature of location privacy, while aspiring to increase community cognizance of vulnerabilities within the 5G network that threaten end-user privacy. To this end, we will ad- dress the statistical efficacy of a multilateration attack utilizing timing advance commands within the 5G cloud radio access network, by showcasing that such an attack meets the Cramér-Rao Lower Bound (CRLB) across each subcarrier spacing. We will also demonstrate how position estimates within 5G can be further refined using methods previously shown to be effective in Long-Term Evolution (LTE) Networks. Lastly, we will demonstrate the attack in a simulated environment modeled after the conference grounds, using current real-world deployments of 5G on Kauai. U.S. Government affiliation is unstated in article text.

Summary Standard network meta-analysis (NMA) and indirect comparisons combine aggregate data from multiple studies on treatments of interest, assuming that any effect modifiers are balanced across populations. Population adjustment methods relax this assumption using individual patient data from one or more studies. However, current matching-adjusted indirect comparison and simulated treatment comparison methods are limited to pairwise indirect comparisons and cannot predict into a specified target population. Existing meta-regression approaches incur aggregation bias. We propose a new method extending the standard NMA framework. An individual level regression model is defined, and aggregate data are fitted by integrating over the covariate distribution to form the likelihood. Motivated by the complexity of the closed form integration, we propose a general numerical approach using quasi-Monte-Carlo integration. Covariate correlation structures are accounted for by using copulas. Crucially for decision making, comparisons may be provided in any target population with a given covariate distribution. We illustrate the method with a network of plaque psoriasis treatments. Estimated population-average treatment effects are similar across study populations, as differences in the distributions of effect modifiers are small. A better fit is achieved than a random effects NMA, uncertainty is substantially reduced by explaining within- and between-study variation, and estimates are more interpretable.

Proceedings of the 53rd Hawaii International Conference on System Sciences | 2020 The article of record as published may be found at https://doi.org/10.24251/HICSS.2020.773 The fifth generation (5G) technological leap has arrived, bringing with it promises of incredible data rates and never before seen precision in location accuracy. However this self-same precision carries with it the significant question: how will it be protected? These questions form the underlying motivation for this article where we examine 5G architecture which employs a radio access part commonly termed a cloud or centralized radio access network (C-RAN). The C-RAN centralizes higher-level physical layer processes while keeping lowlevel processes distributed throughout the physical network. We show how this architecture both increases location-based privacy through improved physical-layer security, but creates new privacy concerns via the extension of the radio access network through fronthauls connecting data transfer among low and high-level processing. Concurrently, the proposed 5G variable subcarrier spacing further exacerbates the former point. Through simulation we quantify the decrease in location privacy given the aforementioned considerations. It is shown that location privacy is inversely proportional to subcarrier spacing for user equipment (UE) connected to multiple 5G access points. Specifically, for a (UE) using the widest allowable subcarrier spacing location privacy drops to approximately three meters.

BACKGROUND: Head-to-head randomised studies comparing ixekizumab and secukinumab in the treatment of psoriasis are not available.OBJECTIVE: Assess efficacy and quality of life with ixekizumab vs. secukinumab treatment using matching-adjusted indirect comparisons.METHODS: Psoriasis Area and Severity Index (PASI) improvement of at least 75%, 90% and 100% and Dermatology Life Quality Index (DLQI) 0/1 response rates for approved doses of ixekizumab (160 mg at Week 0, then 80 mg every two weeks for the first 12 weeks) and secukinumab (300 mg at Weeks 0, 1, 2, 3 and 4, then 300 mg every 4 weeks) treatment were compared using data from active (etanercept and ustekinumab) and placebo-controlled studies. Comparisons were made using the Bucher (BU) and two modified versions of the Signorovitch method (SG total and SG separate). Subsequently, results based on active treatment common comparators were combined using generic inverse-variance meta-analysis.RESULTS: In meta-analysis of studies with active comparators, PASI 90 response rates were 12.7% (95% CI: 5.5%-19.8%; p=0.0005), 10.0% (2.1%-18.0%; p=0.01) and 11.2% (3.2%-19.1%; p=0.006) higher and PASI 100 response rates 11.7% (5.9%-17.5%; pCONCLUSION: Ixekizumab had higher PASI 90 and PASI 100 responses at Week 12 compared to secukinumab using adjusted indirect comparisons. This article is protected by copyright. All rights reserved.

Background Biologics are effective for the treatment of psoriasis. However, treatment outcomes may differ among biologic-naive patients and those switched from previous biological therapies. Objectives The study's objective was to investigate efficacy and safety of ixekizumab, a high-affinity anti-interleukin-17A antibody, in patients with psoriasis with and without previous exposure to biologics. Methods Data were integrated from the 12-week induction phase of two etanercept-controlled Phase III trials. Patients received 80 mg ixekizumab every 2 weeks (IXE Q2W; N = 736) or every 4 weeks (IXE Q4W; N = 733) following a 160-mg starting dose, or placebo (N = 361). Etanercept (50 mg twice weekly; N = 740) was administered as active control. Psoriasis Area and Severity Index (PASI) 75, PASI 90 and PASI 100 response rates at week 12 were evaluated in patients with or without previous exposure to biologics. Treatment effects were analysed with the Cochran–Mantel–Haenszel test stratified by study; missing values were imputed as non-response. Results Overall, 497 (19.3%) patients had prior exposure to biologics and 2073 (80.7%) were naive to biologic therapy. PASI 75 was achieved by 91.5% of biologic-experienced patients and 87.7% of biologic-naive patients for IXE Q2W, 76.2% and 82.2% for IXE Q4W, respectively, and 34.6% and 50.7%, respectively, for etanercept. Higher response rates favouring each ixekizumab dose over etanercept within subgroups were also seen regarding PASI 90 and PASI 100. Conclusions Contrary to etanercept, the efficacy of ixekizumab was similarly high in patients with and without previous exposure to biologics when administered 80 mg every 2 weeks.

Introduction Le psoriasis est une maladie inflammatoire chronique et le delai d’amelioration clinique est tres important pour les patients. L’ixekizumab (IXE), anticorps monoclonal ciblant l’IL-17A, est approuve pour le traitement du psoriasis modere a severe et a demontre une efficacite superieure a celle de l’ustekinumab (UST) et du placebo (PBO) dans plusieurs essais cliniques. Du fait du manque d’essais de comparaison directe de l’IXE versus d’autres traitements d’interet, nous avons realise une comparaison indirecte versus des inhibiteurs selectifs de l’IL-23. La comparaison de l’IXE et du guselkumab (GUS) a deja ete documentee, mettant en evidence la superiorite de l’IXE par rapport au GUS a 12 semaines. Nous presentons ici une comparaison indirecte de l’IXE versus risankizumab (RIS). Materiel et methodes Une comparaison indirecte d’IXE (80 mg toutes les 2 semaines, apres une premiere dose de 160 mg a j1) versus RIS (150 mg a j1 et a S4) a ete conduite via deux comparateurs communs : UST (essais IXORA-S et UltlMMa-1) ou PBO (essais UNCOVER-1, 2, 3 et UltlMMa-1). Les differences de reponse (DR) sur le score PASI aux semaines 4, 8 et 12 ont ete evaluees avec les methodes de Bucher (BU) et de Signorovitch (SG). Pour cette derniere, les resultats ont ete ajustes sur plusieurs caracteristiques initiales, notamment âge, sexe, origine ethnique, IMC, surface corporelle et score PASI. Resultats Des estimations plus precises pour les DR ont ete trouvees en utilisant le PBO comme comparateur commun. D’apres la methode BU, les pourcentages de PASI 75 a S12 (DR = 5,5 %, IC95 % : [0,2 % ; 10,8 %], p = 0,042) et PASI 90 a S4, 8 et 12 etaient significativement plus eleves pour IXE par rapport au RIS (DR = 17,5 %, IC95 % : [4,4 % ; 20,6 %, p Conclusion Les comparaisons indirectes utilisant PBO comme comparateur indiquent que l’IXE offre des benefices cliniques par rapport au RIS en terme de reponses PASI 75 et 90 et de rapidite d’amelioration clinique a la semaine 12. Une taille d’echantillons plus elevee serait necessaire pour confirmer la tendance similaire observee dans les analyses utilisant UST.

In drug development, we ask ourselves which population, endpoint and treatment comparison should be investigated. In this context, we also debate what matters most to the different stakeholders that are involved in clinical drug development, for example, patients, physicians, regulators and payers. With the publication of draft ICH E9 addendum on estimands in 2017, we now have a common framework and language to discuss such questions in an informed and transparent way. This has led to the estimand discussion being a key element in study development, including design, analysis and interpretation of a treatment effect. At an invited session at the 2018 PSI annual conference, PSI hosted a role-play debate where the aim of the session was to mimic a regulatory and payer scientific advice discussion for a COPD drug. Including role-play views from an industry sponsor, a patient, a regulator and a payer. This paper presents the invented COPD case-study design and considerations relating to appropriate estimands are discussed by each of the stakeholders from their differing viewpoints with the additional inclusion of a technical (academic) perspective. The rationale for each perspective on approaches for handling intercurrent events is presented, with a key emphasis on the application of while-on-treatment and treatment policy estimands in this context. It is increasingly recognised that the treatment effect estimated by the treatment policy approach may not always be of primary clinical interest and may not appropriately communicate to patients the efficacy they can expect if they take the treatment as directed.

This study demonstrates that Nannochloropsis sp. can be effectively pre-concentrated by separation from its growth medium (0.28–0.36 g/L) using electro-coagulation–flocculation (ECF) in a continuous flow reactor with both nickel and aluminum electrodes spaced 6.35 mm apart. Flow rates studied range between 0.4 and 3.9 L/min. Treatment uses energy inputs between 0.08 and 6.43 kWh/m3 and voltages between 4 and 20 V. This paper describes a novel method that subjects flowing fluid to direct current for a very short time (between 0.8 and 7.5 s), upon which algae rapidly separate, approximately 30 min after ECF treatment. Fluid flow rate decreases ECF Efficiency as compared to batch tests. Maximum ECF Efficiency recorded in this study was 92% at 0.4 L/min and 7 V with nickel electrodes. Higher voltage inputs and lower flow rates result in higher ECF Efficiencies. However, the ratio of ECF Efficiency to energy input is the highest for the lowest voltage inputs and highest flow rates. Treatments of 3.9 L/min flow rate and 6 V resulted in the highest ratio of ECF Efficiency to energy input (151 and 406%/(kWh/m3) for nickel and aluminum electrodes respectively). The ECF processing leaves a large number of viable algal cells that are separated from their growth medium, 40–60% under conditions studied. Metals analysis shows the microalgae, after ECF treatment with nickel and aluminum electrodes at 8 V and flow rate of 0.8 L/min, sorbs a significant amount of metal, 348.6 ± 66.7 mgNi/gdry biomass and 125.2 ± 15.2 mgAl/gdry biomass.

Background The nocebo effect, when a harmless substance creates harmful effects in a person who takes it, is a clinically salient yet seldom studied phenomenon that may be associated with poorer treatment outcomes, perceived adverse events, and treatment discontinuation. The covert presence of nocebo responders in clinical trials may contribute to outcome variance in both placebo and active treatment arms for important primary and secondary endpoints. Nocebo effects are thought to be driven by expectancy and conditioning. Method This study analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate variables associated with the emergence of adverse outcomes in placebo-treated participants (N = 2,457). Specifically, we examined treatment-emergent adverse events (TEAEs) and discontinuation in placebo-treated individuals. Trials were commenced between 1993 and 2010 as studies of duloxetine versus active comparator and/or placebo. Results TEAEs were reported by 1,569 placebo-treated participants (63.9%), with 115 (4.7%) discontinuing from the studies due to TEAEs and 274 (11.2%) showing worsening of Hamilton Depression Rating Scale total score during placebo treatment. There was specifically no evidence to support the expectancy hypothesis, that reported TEAEs were influenced by adverse effects described in the clinical trials participant information and consent forms, or the conditioning hypothesis, that reported TEAEs would be influenced by adverse effect profiles of previous antidepressant medications used by these study participants. There was some evidence to suggest that people who had previously used complementary medications were more likely to report TEAEs. Variables specific to individual studies were the strongest predictors of TEAEs. Discussion In this study, TEAEs were very common among placebo-treated clinical trial participants. Unexpectedly, there was no evidence to associate TEAEs with adverse clinical outcomes, nor were the conditioning or expectancy hypotheses supported by these data. Conclusions The nocebo effect is a common, covert, and poorly understood driver of clinical outcomes that requires further investigation.

Introduction The conduct of structured benefit-risk assessment (BRA) of pharmaceutical products is a key area of interest for regulatory agencies and the pharmaceutical industry. However, the acceptance of a standardized approach and implementation are slow. Statisticians play major roles in these organizations, and have a great opportunity to be involved and drive the shaping of future BRA. Method We performed a literature search of recent reviews and initiatives assessing BRA methodologies, and grouped them to assist those new to BRA in learning, understanding, and choosing methodologies. We summarized the key points and discussed the impact of this emerging field on various stakeholders, particularly statisticians in the pharmaceutical industry. Results We provide introductory, essential, special interest, and further information and initiatives materials that direct readers to the most relevant materials, which were published between 2000 and 2013. Based on recommendations in these materials we supply a toolkit of advocated BRA methodologies. Discussion Despite initiatives promoting these methodologies, there are still barriers, one of which being the lack of a consensus on the most appropriate methodologies among stakeholders. However, this opens up opportunities, for statisticians in the pharmaceutical industry especially, to champion appropriate BRA methodology use throughout the pharmaceutical product lifecycle. Conclusions This article may serve as a starting point for discussions and to reach a mutual consensus for methodology selection in a particular situation. Regulators and pharmaceutical industry should continue to collaborate to develop and take forward BRA methodologies, and by clear communication develop a mutual understanding of the key issues. Copyright © 2015 John Wiley & Sons, Ltd.

This study aimed to compare the effectiveness of duloxetine (DLX) and the anticonvulsants pregabalin (PGB) and gabapentin (GBP) for the treatment of diabetic peripheral neuropathic pain (DPNP) in routine clinical care.Data from a 6-month, noninterventional study involving 2575 patients in whom treatment of DPNP was initiated with or changed to DLX, PGB, or GBP (n=1523) were analyzed post hoc; patients treated with other medications or combinations were excluded from this analysis. Propensity scoring was used to compare patient groups, assessing Brief Pain Inventory (BPI), Clinical and Patient Global Impression (CGI/PGI), the Hospital Anxiety and Depression Scale (HADS), the Sheehan Disability Scale (SDS), and the Short Form Health Survey (SF 12).Mean median daily dosage over 6 months was 53.9 mg for DLX (N=931), 173.5 mg for PGB (N=248), and 727.8 mg for GBP (N=351). BPI average pain severity (last observation carried forward, mean [SD]) decreased by 2.3 [2.30] points for DLX patients, and by 1.9 [2.22] in PGB, and 1.1 [2.15] in GBP patients. This difference remained statistically significant (DLX vs. PGB: P=0.029; DLX vs. GBP: P0.001) after adjustment by propensity scores. Similar findings were also seen for the BPI interference score, CGI and PGI, the HADS anxiety score, the HADS depression score.When compared with DLX, the low doses of PGB and GBP used in this noninterventional study might have contributed to the lower effectiveness found for both anticonvulsants in the treatment of patients with DPNP.

Evidence of the cost-efficacy of ixekizumab for the treatment of moderate-to-severe plaque psoriasis (PsO) in the US is limited.To estimate the number needed to treat (NNT) and monthly cost of achieving one additional Psoriasis Area and Severity Index (PASI) 75, 90, and 100 responder for ixekizumab and other Food and Drug Administration (FDA)-approved biologics in PsO.A network meta-analysis estimated the probability of achieving PASI 75, 90, or 100 response during induction for each biologic. NNTs were calculated using response difference of each respective biologic vs placebo at the end of induction. Monthly costs per additional PASI responder were based on FDA-approved doses, wholesale acquisition costs, and induction NNTs.Induction NNTs for ixekizumab 80 mg once every 2 weeks (Q2W) relative to placebo were consistently lower across all levels of clearance compared with the other biologics. Monthly cost per additional responder was lowest for ustekinumab 45 mg at PASI 75 and for secukinumab 300 mg and ixekizumab 80 mg Q2W at PASI 90. Ixekizumab 80 mg Q2W had the lowest cost for PASI 100.In this analysis, ixekizumab is the most cost-efficient biologic in the US when targeting complete resolution, as measured by PASI 100 in PsO.

The aim of this study was to explore the course of attention-deficit/hyperactivity disorder (ADHD) core symptoms, ADHD-related difficulties, and emotional expression during ADHD pharmacotherapy and associations between them. This prospective, observational study examines pediatric patients with ADHD who newly initiated stimulant, atomoxetine or a combination of both treatments. Data were collected at baseline; weeks 1, 2, and 4; and months 3, 6, 9, and 12. Physicians rated ADHD core symptoms using the ADHD Rating Scale (ADHD-RS); patients, parents, and physicians rated ADHD-related difficulties using the Global Impression of Perceived Difficulties (GIPD) Scale; and patients and parents rated emotional expression using the Expression of Emotion Scale for Children (EESC). Results were analyzed using mixed model repeated measures. Associations are presented by Spearman's correlations. Overall, 504 patients, mean age 9.6 years, 72.6% males, were analyzed. Fifty percent of patients started atomoxetine, 49.0% stimulant and 1% a combination of both. ADHD-RS, GIPD, and EESC scores decreased significantly in both monotherapy groups. Correlations between ADHD-RS and parent- or physician-rated GIPD scores were at-best moderate and increased over time but remained low to moderate for patient-rated GIPD [patient, r=0.43 (95% CI 0.34, 0.51); parent, r=0.58 (0.50, 0.64); physician, r=0.55 (0.48, 0.62)]. Correlations between ADHD-RS and patient- or parent-rated EESC scores were low at baseline (r

Objective Pain control is the main objective when treating patients with painful diabetic peripheral neuropathic pain (DPNP). However, DPNP is associated with further substantial patient burden that often is not appropriately addressed. Our study identified patients' needs and asked patients what they expected from DPNP treatment. Methods Baseline data were collected in a German prospective, non-interventional study in patients with DPNP starting or switching pain medication at the discretion of the investigator. DPNP severity was evaluated using Brief Pain Inventory (BPI) and Clinician/Patient Global Impression-Severity (CGI-S/PGI-S). Primary objective of this study was to evaluate for which interference item of the BPI DPNP patients expected most to improve due to DPNP therapy. Results We enrolled 2,576 patients with DPNP from 307 outpatient centers (mean [standard deviation {SD}] age: 65.8 years [11.5], 51.2% female). Mean (SD) CGI-S and PGI-S at baseline were 4.4 (0.91) and 4.5 (1.05), respectively. BPI average pain score was 5.1 (2.04). The BPI interference score was 4.8 (2.18); items most impaired at baseline were walking ability 5.5 (2.60) and general activity 5.4 (2.37). The most frequently chosen BPI interference items expected to improve as a result of the pain treatment were: General activity (29.3%; 95% confidence interval [CI] 27.5–31.0%) and walking ability (24.4%; 95% CI 22.8–26.1%), followed by sleep (14.7%), enjoyment of life (13.6%), mood (8.3%), normal work (7.7%), and relations with other people (1.9%). Conclusions The majority of patients identified “general activity” and “walking ability” as most relevant BPI interference items for which they expect improvement from DPNP treatment.

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: 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.

This study demonstrates that Nannochloropsis sp. can be effectively separated from its growth medium (0.2–0.3 g/L) using electro-coagulation–flocculation in a 100 mL batch reactor with nickel electrodes and a treatment time of only 4 s. Minimum energy density input for effective separation is 0.03 kWh/m 3 . Both energy input and treatment time are much smaller than reported elsewhere. The process results in rapid separation of microalgae (over 90% in 120 min) with minimal damage to algal cells (>90% still alive after processing). At around 4 V input, algae can be effectively separated even in very low concentrations. Pulsing is equally effective in separating microalgae as continuous direct current of same magnitude and total exposure time. Algae can separate from their growth medium even if the suspension itself is not treated, but is mixed with treated saltwater with same conductivity. The described method has significant advantages including applicability to continuous processing and water reuse.

Objectives: Patients with major depressive disorder (MDD) and a comorbid anxiety disorder or significant anxiety symptoms have decreased functioning, increased risk of suicidality, and worse post-treatment outcomes. This pooled analysis of 8 duloxetine MDD trials was designed to determine whether early improvement in anxiety symptoms predicts MDD remission. Methods: Eight trials were pooled. Patients with a baseline 17-item Hamilton Rating Scale for Depression (HA-MD17) anxiety/somatization factor score ≥7 were considered to have anxious depression. Early response on the HAMD17 total score was defined as a 20% reduction at weeks 2 or 4, a 30% reduction at weeks 2 or 4, or a 50% reduction at weeks 2 or 4 in the HAMD17 anxiety subscale. Each category was analyzed separately for all patients. MDD remission is a score of ≤7 on the HAMD17 total score at study endpoint. Results: The early responder group in each analysis showed greater numerical improvement at endpoint on the HAMD17 total score than the nonresponder group. Duloxetine showed statistically significantly greater improvement than placebo in most nonresponder and responder subgroups. There were no statistically significant interaction effects for the difference between duloxetine and placebo for any of the anxious categories. Conclusion: Although patients who responded in the various response categories had greater numerical improvement and greater remission rates than nonresponding patients, the response and nonresponse groups did not differ statistically regarding the treatment effect of duloxetine. Therefore, early improvement in anxiety symptoms was not a predictor of greater endpoint remission of depressive symptoms for duloxetine treatment.

Assessment of severity is essential for the management of chronic diseases. Continuous variables like scores obtained from the Hamilton Rating Scale for Depression or the Psoriasis Area and Severity Index (PASI) are standard measures used in clinical trials of depression and psoriasis. In clinical trials of psoriasis, for example, the reduction of PASI from baseline in response to therapy, in particular the proportion of patients achieving at least 75%, 90%, or 100% improvement of disease (PASI 75, PASI 90, or PASI 100), is typically used to evaluate treatment efficacy. However, evaluation of the proportions of patients reaching absolute PASI values (eg, ≤1, ≤2, ≤3, or ≤5) has recently gained greater clinical interest and is increasingly being reported. When relative versus absolute scores are standard, as is the case with the PASI in psoriasis, it is difficult to compare absolute changes using existing published data. Thus, we developed a method to estimate absolute PASI levels from aggregated relative levels. This conversion method is based on a latent 2-dimensional normal distribution for the absolute score at baseline and at a specific endpoint with a truncation to allow for baseline inclusion criterion. The model was fitted to aggregated results from simulations and from 3 phase III studies that had known absolute PASI proportions. The predictions represented the actual results quite precisely. This model might be applied to other conditions, such as depression, to estimate proportions of patients achieving an absolute low level of disease activity, given absolute values at baseline and proportions of patients achieving relative improvements at a subsequent time point.

Objectives To contrast the analgesic effect of duloxetine with antidepressants reported in other published randomized clinical trials (RCTs) and review articles in patients with chronic low back pain (CLBP). Methods In this narrative review, the results of 13 RCTs and 5 systematic reviews examining the analgesic effect of various antidepressants in CLBP were contrasted with those of 3 placebo-controlled duloxetine RCTs. Treatment effects based on the Brief Pain Inventory (BPI) average score in the duloxetine RCTs were assessed in all completers (by study and overall) and in last-observation-carried-forward (LOCF) analyses (extracted from study reports). 30%- and 50%-reduction response rates were compared between duloxetine and placebo. Results Eleven different antidepressants were examined in 13 individual RCTs. Sample sizes, treatment durations, and analysis methods varied across studies. Reviews each included 5 to 9 of the RCTs and came to different conclusions regarding the analgesic effect of antidepressants: 2 found no evidence while 3 reported some evidence. The completer analysis showed greater improvements in BPI average scores with duloxetine vs. placebo (significant in 2 studies). Overall, the least square mean (standard error) difference between treatments was − 0.7 (0.15) (P

In this study we analyze the impact of organization leaders on their fellows’ behavior in academia by utilizing the unique structure of the Max Planck Society. The latter is a leading research organization in Europe with autonomous institutes which center around appointed directors. Using panel data of commercialization activities and royalties received in the period 1980–2007, we observe that both director engagement in disclosure activity and royalty shares received at the institute level lead to a significant increase in invention disclosure by non-directors in the following year. Yet, both effects are only significant when regarding short-term time lags of one year. Utilizing information based on a survey performed with Max Planck scientists in 2007 we find that scientists’ perceived academic relevance of commercialization neither relates to previous director involvement in disclosure activity nor to previous overall disclosure efforts within the institute. We conclude that directors have a short-term...

Comparing multiple treatment options using meta-analytical methods requires complex statistical methods called mixed treatment comparisons (MTCs). Such methods offer the possibility to summarize data from many clinical trials comparing the different available options. However, those methods are based on a number of assumptions and inherent difficulties that are discussed and illustrated with examples from the psychiatric literature to help readers to understand the strengths and weaknesses of these methods. This review will help enable readers to critically appraise the methodology and results of publications that use MTCs. Copyright © 2013 John Wiley & Sons, Ltd.

Using a new dataset with detailed geographic information about licensing activities of the German Max Planck Society, we analyze how the probability and magnitude of commercial success are affected by geographic distance between licensors and licensees. Our evidence suggests that proximity does not generally lead to superior commercialization outcomes. A significantly negative association between distance and commercialization success is identified only for foreign licensees within the subsample of inventions licensed to more than one firm. Positive associations between distance and performance indicators are not robust to controlling for invention quality or selection into licensing.

Concomitant painful physical symptoms in depressive patients frequently impair functioning and failure to treat these symptoms may adversely impact treatment outcomes of depression. Early vs. conventional switch of antidepressants were compared in patients with major depressive disorder (MDD) and moderate to severe pain.Pre-specified subgroup analysis of a 16-week, randomized, double-blind clinical study on MDD patients with30 mm overall pain visual analog scale (VAS). Patients not achieving 30% reduction Hamilton Depression Rating Scale (HAM-D) after 4 weeks escitalopram (10 mg/day) were randomized to duloxetine 60-120 mg/day (early switch) or continued on escitalopram (conventional switch) with non-responders at week 8 switching to duloxetine. Endpoints were time to confirmed response and remission, VAS pain severity, and Sheehan disability scale (SDS). Switch strategies were compared using Kaplan-Meier, logistic regression, and repeated measures analyses.No differences between early and conventional switching were found in time to confirmed response after randomization (3.9 vs. 4.1 weeks, p=0.511) or remission (6.0 vs. 8.0 weeks, p=0.238). Significantly lower VAS mean pain levels at for overall pain, headache, back pain, shoulder pain, interference with daily activities, and time being awake in pain were found for patients in the early switching group. Time to achieving normal functioning (SDS total score6) was shorter in the early switching group (p=0.042). Safety results were comparable between switch strategies.In MDD patients with moderate to severe painful physical symptoms not improving after 4 weeks of treatment with escitalopram, an earlier switch to duloxetine may lead to better pain and functional outcomes.

The primary objective of this study was to evaluate the efficacy of atomoxetine (ATX) on attention-deficit/hyperactivity disorder (ADHD)-related symptoms assessed as standard variables of a computer-based continuous performance test (cb-CPT) combined with a motion-tracking (MT) device. This was a 2-arm, 8-week, randomized, double-blind, placebo-controlled study in patients with ADHD (6-12 years). Therapy with ATX started with 0.5 mg/kg per day for 1 week, followed by 7 weeks on the target dosage of 1.2 mg/kg per day. Primary outcomes were cb-CPT/MT standard scores after 8 weeks using mixed models for repeated measurements. In addition, investigator-rated ADHD Rating Scale (ADHD-RS), Weekly Ratings of Evening and Morning Behavior (WREMB), and Clinical Global Impression - Severity-ADHD (CGI-S-ADHD) scores were assessed. Of 128 patients randomized, 125 were evaluated (ATX/placebo: 63/62). Baseline characteristics were comparable in both groups (overall, 80.2% boys; mean [SD] age, 9.0 [1.79] years; comorbid Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis, 40.0% oppositional defiant disorder/conduct disorder; prior stimulant treatment, 24.8%; ADHD-RS total score, 36.99 [11.56]). At week 8, all cb-CPT/MT q-scores were significantly reduced versus placebo (all P < 0.001) with effect sizes (ESs) of reaction time (RT) variation (ES = 0.71), mean RT (ES = 0.41), number of microevents (ES = 1.00), commission error rate (ES = 0.50), distance of movement (ES = 0.90), area of movement (ES = 1.08), omission error rate (ES = 0.70), time active (ES = 0.69), motion simplicity (ES = 0.38), and normalized variance of RT (ES = 0.50). Secondary end points also improved significantly in favor of ATX: ADHD-RS (total score ES = 1.30, P < 0.001; hyperactivity/impulsivity subscore ES = 1.37, P < 0.001; inattention subscore ES = 1.07, P < 0.001), WREMB (total score ES = 1.00, P < 0.001; morning subscore ES = 0.59, P = 0.002; evening subscore ES = 1.02, P < 0.001), CGI-S-ADHD (ES = 1.11, P < 0.001). The results of this study show that ATX for 8 weeks significantly reduced ADHD-related symptoms as measured by the cb-CPT/MT.

Objective: To compare the reduction of ADHD symptoms under atomoxetine in patients with and without comorbid oppositional defiant disorder (ODD) or conduct disorder (CD) using a computer-based continuous performance test (cb-CPT) combined with an infrared motion tracking (MT) device. Method: Secondary analysis of a placebo-controlled study in ADHD patients (6-12 years old) treated with atomoxetine (target dose: 1.2 mg/kg per day). Cb-CPT/MT scores were analyzed using ANCOVA (last observation carried forward [LOCF]). Results: The data ( N = 125) suggested a more pronounced atomoxetine effect in the group with comorbid ODD/CD as measured by all cb-CPT/MT parameters except for “normalized variation of reaction time” (nVRT). Conclusion: The results showed that atomoxetine reduced ADHD severity as measured by cb-CPT and MT parameters regardless of whether comorbid ODD/CD was present. The treatment effect of atomoxetine on hyperactivity appears to be more pronounced in the subgroup of patients with comorbid ODD/CD than in the subgroup without this comorbidity.

This study questions whether a lower starting dose of duloxetine (DLX) could be beneficial for patients with depression, in terms of tolerability and safety in routine clinical care.Post-hoc analyses of a multicenter, prospective, non-interventional, 6-month study in adult outpatients with a depressive episode was undertaken.Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), discontinuations due to TEAEs and hospitalizations due to depression, were all documented at 2 weeks, 4 weeks, 3 months and 6 months after treatment initiation/switch to DLX.Of 4517 patients enrolled, 4313 were included for TEAE evaluation. TEAEs occurred in 17.2% of patients, and SAEs occurred in 0.79% of patients, including one case of suicidal ideation. 1404 patients discontinued within 6 months (TEAEs: n = 119). Starting treatment with 30 mg/day DLX (72.7%) was favored in females, or after inadequate efficacy of previous antidepressant treatment; 60 mg/day DLX was favored in more severe depression and patients receiving concomitant pain medication.Initiating treatment with 60 mg/day DLX was not associated with poorer tolerability in this study. Physicians may be guided by their clinical experience to carefully consider the individual benefit/risk ratio and TEAE susceptibility when deciding to start treatment with a higher or a lower dose of DLX.

Background: The assessment of emotional expression in patients with ADHD can differ between parent/caregiver and child. Therefore, a new patient-rated version of the Expression and Emotion Scale for Children (EESC) was created and psychometrically analysed. Methods: This is a 6-month follow-up data analysis of a multicenter, prospective, 12-month observational study in children and adolescents with ADHD. Agreement between the two EESC versions (patient- and parent-rated), internal consistency, sensitivity for changes, floor and ceiling effects as well as test-retest variability were evaluated. The relationship between both EESC scores and the physician-rated ADHD-rating scale (ADHD-RS), Clinical Global Impression of Severity (CGI-S), and General Impression of Percieved Difficulties (GIPD) were also calculated. Results: 504 patients (mean age 9.6 years) were included and treated with non-stimulant medication (n=252) or stimulant medication (n=247); 5 patients received both medications. The EESC scores decreased similarly for patients and parents and in parallel over time by about 15 points, with the patient EESC scores being always about 3-4 points less than the parent-rated score. Both satisfaction scores increased in parallel by 2-3 points. The agreement and the correlation between the two EESC versions were in a modest range of approximately 0.5 to 0.6 and stable over time. The item-total correlations and analysis of Cronbach's Alpha showed mostly good support of the different items for the total scores, except items 19 and 24 (r 0.48). Correlations between the EESC score and other ADHD scales (ADHD-RS, CGI-S) were small to moderate for both ratings. The correlation between the GIPD and the EESC within raters was constant over time (r� 0.5). Conclusion: This analysis showed that both EESC versions have sound psychometrical properties and can be used in routine settings.

Objective: The efficacy of atomoxetine as treatment of symptoms of attention-deficit/hyperactivity disorder (ADHD) in patients with autism spectrum disorder (ASD) has not been established. Method: In this study, 97 patients aged 6 to 17 years with ADHD and ASD were randomly assigned to double-blind treatment with 1.2 mg/kg/day atomoxetine or placebo for 8 weeks. The primary endpoint was the ADHD Rating Scale (ADHD-RS) score; secondary endpoints were the Clinical Global Impression of ADHD-Improvement (CGI-I) and the Conners Teacher Rating Scale-Revised: Short Form (CTRS-R:S) score. Results: Baseline mean ADHD-RS scores for atomoxetine versus placebo were 40.7 and 38.6; after 8 weeks, mixed-effect model repeated-measure means were 31.6 (95% confidence interval 29.2-33.9) and 38.3 (36.0-40.6), respectively, with a difference in least square means of -6.7 (-10.0 to -3.4; p .1). There were no serious adverse events. Conclusions: A tomoxetine moderately improved ADHD symptoms in patients with ASD and was generally well tolerated. Adverse events in this study were similar to those in other studies with ADHD patients without ASD. J. Am. Acad. Child Adolesc. Psychiatry, 2012; 51(7):733-741. Clinical trial registration information A Randomized Double-Blind Study of A tomoxetine Versus Placebo for ADHD Symptoms in Children with ASD; www.clinicaltrials.gov; NCT00380692.

The effect of atomoxetine (ATX) on executive function has been assessed by means of questionnaires only. The aim of this study was therefore to evaluate the efficacy of ATX using standard variables of a computer-based continuous performance test (cb-CPT) combined with an infra-red motion-tracking device at different times of the day. One hundred twenty-eight girls and boys aged 6 to 12 years with a diagnosis of ADHD according to DSM-IV-TR criteria were randomized in the study. The primary efficacy measures were the q-scores of the cb-CPT combined with an infra-red motion-tracking device. The test comprises 13 neuropsychological variables that can be taken to reflect hyperactivity, inattention, or impulsivity. One hundred five patients completed the study (ATX group: n=54; placebo group: n=51). ATX (target dose 1.2 mg/kg/day) over 8 weeks was significantly superior to placebo in reducing hyperactivity, inattention, and impulsivity as measured by q-scores of 10 primary variables of the cb-CPT. Both groups of patients showed a circadian pattern of neuropsychological outcomes across the day as reflected by the cb-CPT combined with an infra-red motion-tracking device. In summary, this study demonstrated a positive effect of ATX on some aspects of executive function, inhibitory control, and hyperactivity compared with placebo.

The objective of this pooled analysis was to correlate parameters related to quality of life with attention-deficit/hyperactivity disorder (ADHD) core symptoms analyzing data of 5 atomoxetine clinical trials in children and adolescents with ADHD. Data from 5 clinical trials (4 from Europe and 1 from Canada) with similar inclusion/exclusion criteria and similar duration (8-12 weeks' follow-up) were included. All studies used the Child Health and Illness Profile, Child Edition (CHIP-CE), parent rating form at baseline and end point. Correlation coefficients and effect sizes to ADHD-Rating Scale (ADHD-RS) scores were calculated. A total of 794 patients aged 6 to 15 years (mean, 9.7 years), with mean (SD) baseline Clinical Global Impression of Severity of 4.8 (0.89) and ADHD-RS of 41.8 (8.04), were included. Baseline total CHIP-CE mean t score (standard, 50 [10]) was 28.9 (11.76), and the strongest impairments were seen in risk avoidance (30.2 [14.62]) and achievement (30.5 [10.4]) domains. At baseline, CHIP-CE versus ADHD-RS correlation was low (total, -0.345) except for the risk avoidance domain (total, -0.517). For changes from baseline to end point, a low correlation between the scales was found (total, -0.364; placebo-controlled studies only, n = 372). Quality of life impairment in ADHD was found in CHIP-CE total score and several domains. Correlations between CHIP-CE and ADHD-RS at baseline, end point, and for change from baseline to end point were low to moderate. These findings suggest that measuring quality of life adds clinically relevant insight beyond core symptom evaluation in children and adolescents with ADHD.

Atomoxetine may improve ADHD-related difficulties and hence the quality of life (QoL) in children and adolescents. Perception of these difficulties may differ with the rater perspective (patient, parent, physician) or patients’ sex. The objective of this study was to investigate QoL as reflected by perceived ADHD-related difficulties perceived from these three perspectives and compare boys and girls. Patients aged 6–17 with ADHD were treated with atomoxetine (target dose 0.5–1.2 mg/kg/day) in two studies. In both studies, ADHD-related difficulties were assessed after 8 and 24 weeks using the Global Impression of Perceived Difficulties (GIPD) instrument, which can be taken to reflect the patient’s QoL from the three perspectives. Data from the two studies were combined and analyzed together in order to compare boys and girls. Four hundred and twenty-one patients were treated with atomoxetine, 338 boys and 83 girls. Three hundred and fifty-five patients completed the 8-week study period. QoL, as reflected by perceived ADHD-related difficulties (measured with GIPD), improved over time. Mean GIPD total scores showed a similar course over time for all rater groups, although the patients rated the degree of difficulties significantly lower than parents and physicians. The sexes did not differ significantly in mean GIPD total scores. The GIPD scores over time suggest that patients’ QoL, as reflected by perceived ADHD-related difficulties, improved with time on atomoxetine. However, improvement did not differ significantly between boys and girls. Trial Registration: ClinicalTrials.gov Identifiers NCT00191516 and NCT00191737.

This review provides an overview as to how the social and emotional impairments involved in Attention-Deficit/Hyperactivity Disorder affect the quality of life of patients and their families. A model of three categories into which the emotional difficulties fall, and how they impair quality of life, is also presented.

To report on (1) psychometric properties of the Rosenberg Self-Esteem Scale (SES) studied in adolescents with ADHD, (2) correlations of SES with ADHD scale scores, and (3) change in patient-reported self-esteem with atomoxetine treatment. ADHD patients (12-17 years), treated in an open-label study for 24 weeks. Secondary analyses on ADHD symptoms (assessed with ADHD-RS, CGI, GIPD scales) and self-esteem (SES) were performed. One hundred and fifty-nine patients were treated. A dichotomous structure of the SES could be confirmed. Reliability and internal consistency were moderate to excellent. Highest coefficients were found for the correlation between SES and GIPD scores. Self-esteem significantly increased over time, accompanied by an improvement of ADHD symptoms and related perceived difficulties. The Rosenberg SES was shown to be internally consistent, reliable, and sensitive to treatment-related changes of self-esteem. According to these findings, self-esteem may be an important individual patient outcome beyond the core symptoms of ADHD.

International audience; This 10-week study assessed the efficacy of atomoxetine in combination with psychoeducation compared to placebo and psychoeducation in the improvement of Quality of Life in Swedish stimulant-naive children and adolescents with attention deficit/hyperactivity disorder. A total of 99 patients were treated with atomoxetine (49 patients) or placebo (50 patients) for 10 weeks and assessed regarding broader areas of functioning using the Quality of Life measures Child Health and Illness Profile-Child Edition (CHIP-CE), Family Strain Index [FSI; equivalent to the Family Burden of Illness Module used in the study], Appraisal of Stress in Child-Rearing (ASCR), Five to fifteen (FTF), “I think I am” (“Jag tycker jag är”), and Children's Depression Rating Scale-Revised (CDRS-R) before and after the active treatment phase. Simultaneously, the patients' parents participated in a 4-session psychoeducation program. A statistically significant difference in favor of atomoxetine was seen in the improvement from baseline to study endpoint for the CHIP-CE domains “Achievement” and “Risk avoidance”, for the FSI total score, for the ASCR section (I) domain “Child as a burden”, for all FTF domains except for “Language and Speech”, and for the CDRS-R total score. No difference between treatment groups was observed in the patient-assessed evaluation of self-esteem using the “I think I am” scale. Atomoxetine combined with psychoeducation had a positive effect on various everyday coping abilities of the patients as well as their families during 10 weeks of treatment, whereas the patients' self-image and the parents' image of the climate in the family were not significantly improved.

Objective To study the longitudinal patterns of subjective wellbeing in schizophrenia using cluster analysis and their relation to recovery criteria, further to examine predictors for cluster affiliation, and to evaluate the sensitivity and specificity of baseline subjective wellbeing cut-offs for cluster affiliation. Methods Data was collected in an observational 36-month follow-up study of 2842 patients with schizophrenia in Germany. Subjective wellbeing was assessed using the SWN-K scale. Cluster analyses were applied based on Ward's procedure. Predictors were analyzed using logistic regression models. Optimal SWN-K total score cut-off points for cluster affiliation were analyzed using Cohen's kappa. Results 4 distinct clusters were identified: a stable low (33%), a stable moderate (31%), a stable high (16%), and a cluster with distinct initial improvement and then stable high subjective wellbeing (20%). Highly concordant patterns were also observed for symptoms, social functioning, and quality of life. Sensitivity and specificity of SWN-K total score cut-offs at baseline were 82.8% and 63.8% for ≤ 60 points for the stable low cluster and 84.7% and 95.4% for ≥ 80 points for the stable high cluster. Affiliation to the stable low cluster was related to a 0.6% chance of being in recovery at 3-year endpoint. Conclusions Long-term patterns of subjective wellbeing are stable and highly concordant with course of symptoms, functioning level, and quality of life. Baseline subjective wellbeing cut-off points were found to be sufficient predictors of outcome, which, particularly in case of impaired subjective wellbeing and low baseline functioning level, make early treatment adaptations mandatory.

The second generation antipsychotics clozapine and olanzapine are known to cause weight gain. However, only clozapine is associated with drug-induced fever. Cytokines have been linked to the induction of both weight gain and drug-induced fever. We investigated these potential side effects of clozapine and olanzapine and studied their differential effects on cytokine secretion. Thirty patients suffering from schizophrenia, schizophreniform disorder or schizoaffective disorder were treated with either clozapine (mean modal dose: 266.7+/-77.9mg) or olanzapine (21.2+/-2.5mg) in a randomized, double-blind, 6-week study. Body mass index (BMI), tympanic temperature, and plasma levels of leptin and cytokines (tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 and 2 (sTNFR-1/2), soluble interleukin-2 receptors (sIL-2R), interleukin-6) were determined weekly. BMI, leptin and cytokines significantly increased over time, except interleukin-6 and sTNFR-1 in the olanzapine group. All cytokines numerically increased compared to baseline already during the first week of treatment in both groups. Leptin, TNF-alpha, sTNFR-1, sTNFR-2 and sIL-2R levels correlated with the BMI. Five patients who received clozapine (33%) developed drug-induced fever (>/=38 degrees C). In these, interleukin-6 peak levels were significantly (p

INTRODUCTION: Agitation is a common phenomenon in schizophrenia or acute mania. Because of the inability of patients to give informed consent in such situations, data from consenting studies are limited. METHODS: This observational prospective 5-day study evaluated the effectiveness of olanzapine in a sample of highly agitated patients with aggression. Primary endpoint was mean change of the PANSS-Excited Component (PANSS-EC) score. RESULTS: Mean PANSS-EC score at baseline was 25.5 points, 60.2% were severely agitated and 41.6% severely aggressive. A significant decrease in PANSS-EC total score (−13.3 points) was observed with rapid dose escalation and an average daily dose of 21.2 mg/day of olanzapine. 40 patients (24.1%) required treatment with another antipsychotic and 21 patients (12.7%) were not treated with olanzapine at day 5. At endpoint, 64.2% of patients were in remission of agitation. PANSS-EC reduction was not significantly different in patients with or without concurrent benzodiazepine use. DISCUSSION: Severe agitation with aggression may be well controlled with olanzapine in many cases, possibly by higher initial and overall doses of olanzapine. Controlled studies are needed to confirm these findings.