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Evaluates the use of risperidone and olanzapine or a high potential conventional antipsychotic in the treatment of dementia with associated behavior disturbances in the elderly with Alzheimer's disease. Difference in the results regarding global functioning and degree of psychotic symptoms; Measurement of the efficacy of the drugs; History of depression.

Introduction: Baricitinib, a Janus kinase (JAK) 1/2 inhibitor, is an approved treatment for rheumatoid arthritis (RA), atopic dermatitis (AD), and alopecia areata (AA). Further characterisation of adverse events of special interest (AESI) for JAK inhibitors in at-risk populations will improve benefit-risk assessment for individual patients and diseases., Methods: Data were pooled from clinical trials and long-term extensions in moderate-to-severe active RA, moderate-to-severe AD, and severe AA. Incidence rates (IR) per 100 patient-years of major adverse cardiovascular event (MACE), malignancy, venous thromboembolism (VTE), serious infection, and mortality were calculated for patients with low risk (younger than 65 years with no specified risk factors), and patients at risk (≥ 1 of: aged 65 years or older, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension, current smoking, HDL cholesterol < 40 mg/dL, BMI ≥ 30 kg/m 2 , poor mobility on EQ-5D, or history of malignancy)., Results: Datasets included baricitinib exposure up to 9.3 years with 14,744 person-years of exposure (PYE) (RA), 3.9 years with 4628 PYE (AD), and 3.1 years with 1868 PYE (AA). In patients with low risk (RA: 31%, AD: 48%, AA: 49%), IRs for MACE (0.05, 0.04, 0), malignancies (0.20, 0.13, 0), VTE (0.09, 0.04, 0), serious infection (1.73, 1.18, 0.6), and mortality (0.04, 0, 0) in the RA, AD, and AA datasets, respectively, were low. In patients at risk (RA: 69%, AD: 52%, AA: 51%), IRs were for MACE (0.70, 0.25, 0.10), malignancies (1.23, 0.45, 0.31), VTE (0.66, 0.12, 0.10), serious infection (2.95, 2.30, 1.05), and mortality (0.78, 0.16, 0) for RA, AD, and AA datasets, respectively., Conclusion: Populations with low risk have low incidence of the examined JAK inhibitor-related AESI. In the dermatologic indications, incidence is also low for patients at risk. Considering individual disease burden, risk factors, and response to treatment is relevant to make informed decisions for individual patients treated with baricitinib., (© 2023. The Author(s).)

Introduction: The aim of this work is to evaluate baricitinib safety with respect to venous thromboembolism (VTE), major adverse cardiovascular events (MACE), and serious infection relative to tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA)., Methods: Patients with RA from 14 real-world data sources (three disease registries, eight commercial and three government health insurance claims databases) in the United States (n = 9), Europe (n = 3), and Japan (n = 2) were analyzed using a new user active comparator design. Propensity score matching (1:1) controlled for potential confounding. Meta-analysis of incidence rate ratios (IRR) and incidence rate differences (IRD) for each outcome, from each data source was executed using modified Poisson regression and Cochran-Mantel-Haenszel analysis., Results: Of 9013 eligible baricitinib-treated patients, 7606 were propensity score-matched with TNFi-treated patients, contributing 5879 and 6512 person-years of baricitinib and TNFi exposure, respectively. Across data sources, 97 patients (56 baricitinib) experienced VTE during follow-up, 93 experienced MACE (54 baricitinib), and 321 experienced serious infection (176 baricitinib). Overall IRRs comparing baricitinib with TNFi treatment were 1.51 (95% CI 1.10, 2.08) for VTE, 1.54 (95% CI 0.93, 2.54) for MACE, and 1.36 (95% CI 0.86, 2.13) for serious infection. IRDs for VTE, MACE, and serious infection, respectively, were 0.26 (95% CI -0.04, 0.57), 0.22 (95% CI -0.07, 0.52), and 0.57 (95% CI -0.07, 1.21) per 100 person-years greater for baricitinib than TNFi., Conclusions: Overall results suggest increased risk of VTE with baricitinib versus TNFi, with consistent point estimates from the two largest data sources. A numerically greater risk was observed for MACE and serious infection when comparing baricitinib versus TNFi, with different point estimates from the two largest data sources. Findings from this study and their impact on clinical practice should be considered in context of limitations and other evidence regarding the safety and efficacy of baricitinib and other Janus kinase inhibitors., Trial Registration: EU PAS Register ( http://encepp.eu ), identifier #32271., (© 2022. The Author(s).)

Baricitinib is an oral, selective inhibitor of Janus kinase (JAK)1/JAK2 that transiently and reversibly inhibits many proinflammatory cytokines. This mechanism is a key mediator in a number of chronic inflammatory diseases; accordingly, baricitinib has been studied and approved for the treatment of several rheumatological and dermatological disorders, as well as COVID-19. This narrative review summarises and discusses the safety profile of baricitinib across these diseases, with special focus on adverse events of special interest (AESI) for JAK inhibitors, using integrated safety data sets of clinical trial data, and puts findings into context with the underlying risk in the respective disease populations, using supporting literature. We show that rates of infection with baricitinib generally reflected the inherent risk of the disease populations being treated, with serious infections and herpes zoster being more frequent in rheumatic diseases than in dermatological disorders, and herpes simplex being reported particularly in atopic dermatitis. Similarly, rates of major adverse cardiovascular events (MACE), venous thromboembolism (VTE) and malignancies were generally within or below the ranges reported for the respective disease populations, thereby reflecting the underlying risk; these events were therefore more frequent in patients with rheumatic diseases than in those with dermatological disorders, the latter of whom generally had low absolute risk. AESI were usually more common in patients with risk factors specific for each event. When a population similar to that of ORAL Surveillance was considered, the incidence rate of MACE with baricitinib was numerically lower than that reported with tofacitinib and similar to that of tumour necrosis factor inhibitors. No safety concerns were observed in hospitalised patients with COVID-19 who received baricitinib for up to 14 days. Identifying the patterns and likelihoods of AEs that occur during treatment in large groups of patients with different diseases can help the physician and patient better contextualise the benefit-to-risk ratio for the individual patient., (© 2022. © Eli Lilly and Company.)

Objective: To report long-term safety from the completed extension trial of baricitinib, an oral selective Janus kinase inhibitor, in patients with active rheumatoid arthritis (RA)., Methods: Treatment-emergent adverse events are summarised from an integrated database (9 phase III/II/Ib and 1 long-term extension) of patients who received any baricitinib dose (All-bari-RA). Standardised incidence ratio (SIR) for malignancy (excluding non-melanoma skin cancer (NMSC)) and standardised mortality ratio (SMR) were estimated. Additional analysis was done in a subset of patients who had ever taken 2 mg or 4 mg baricitinib., Results: 3770 patients received baricitinib (14 744 patient-years of exposure (PYE)). All-bari-RA incidence rates (IRs) per 100 patient-years at risk were 2.6, 3.0 and 0.5 for serious infections, herpes zoster and major adverse cardiovascular events (MACE), respectively. In patients aged ≥50 with ≥1 cardiovascular risk factor, the IR for MACE was 0.77 (95% CI 0.56 to 1.04). The IR for malignancy (excluding NMSC) during the first 48 weeks was 0.6 and remained stable thereafter (IR 1.0). The SIR for malignancies excluding NMSC was 1.07 (95% CI 0.90 to 1.26) and the SMR was 0.74 (95% CI 0.59 to 0.92). All-bari-RA IRs for deep vein thrombosis (DVT)/pulmonary embolism (PE), DVT and PE were 0.5 (95% CI 0.38 to 0.61), 0.4 (95% CI 0.26 to 0.45) and 0.3 (95% CI 0.18 to 0.35), respectively. No clear dose differences were noted for exposure-adjusted IRs (per 100 PYE) for deaths, serious infections, DVT/PE and MACE., Conclusions: In this integrated analysis including long-term data of baricitinib from 3770 patients (median 4.6 years, up to 9.3 years) with active RA, baricitinib maintained a similar safety profile to earlier analyses. No new safety signals were identified., Trial Registration Number: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT02265705, NCT01721044, NCT01721057, NCT01711359 and NCT01885078., Competing Interests: Competing interests: PCT has received consultant fees from AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, BMS, Pfizer, Roche, Celltrion, Sanofi, Nordic Pharma, Fresenius and UCB; and grant/research support from Celgene, Galapagos, Janssen and Lilly. TT has received grant/research support from Daiichi Sankyo, Takeda, Nippon Kayaku, JCR Pharma, Astellas, Chugai, AbbVie GK, Asahi Kasei Pharma, Mitsubishi Tanabe, UCB Japan and Eisai; consulting fees from Astellas, AbbVie GK, Gilead, Daiichi Sankyo, Taisho Pharma, Nippon Kayaku, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Novartis, Mitsubishi Tanabe and Chugai; and speakers’ bureau fees from Mitsubishi Tanabe, Pfizer, Astellas, Daiichi Sankyo, Eisai, Sanofi, Novartis, Eli Lilly, Gilead, AbbVie GK, Bristol-Myers Squibb and Chugai. G-RRB has received honoraria for lectures and consulting from AbbVie, Gilead, Lilly and Pfizer. PD has received fees for speakers' bureau from BMS, Sanofi, Eli Lilly and Celltrion. JSS has received grant/research support from AbbVie, Eli Lilly and Company, Janssen, MSD, Novartis, Pfizer and Roche; and consultancy fees from AbbVie, Amgen, AstraZeneca, Astro, BMS, Celgene, Celltrion, Chugai, Eli Lilly and Company, Gilead, ILTOO, Janssen, MedImmune, MSD, Novartis, Pfizer, Roche, Samsung, Sanofi and UCB. WD, MI, JRT and NB are employees and stockholders of Eli Lilly and Company. KLW has received grant/research support from Pfizer and BMS; and consulting fees from Pfizer, UCB, AbbVie, Eli Lilly and Company, Amgen, BMS, Galapagos and Gilead., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Interstitial lung disease (ILD) occurs in up to 30% of patients with rheumatoid arthritis (RA), resulting in increased morbidity and death in the absence of proven therapies. The aim of this study is to estimate the number of incident ILD cases reported through development studies with baricitinib in patients with RA., Methods: Estimates were based on 3770 patients with RA from eight randomized clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension study on baricitinib for which ILD was not an exclusion criterion with 12,358 patient-years of exposure (PYE)., Results: Twenty-one non-infectious cases of ILD were reported with an exposure-adjusted incidence rate (EAIR) of 0.17 per 100 PYE. Of the 21 cases, six were reported as serious and 15 as non-serious resulting in an incidence rate of 0.05 per 100 PYE and 0.12 per 100 PYE, respectively. There were also 11 cases caused by an infectious agent: seven serious (IR: 0.06 per 100 PYE) and four non-serious cases (IR: 0.03 per 100 PYE)., Conclusions: The findings of this analysis in patients with RA treated with baricitinib are consistent with a low risk to develop non-infectious ILD during baricitinib treatment, similar to that observed with other Janus kinase inhibitors., (© 2021. The Author(s).)

Introduction: Atopic dermatitis (AD) is associated with risk factors for venous thromboembolism (VTE). However, the risk of VTE among this population is unknown. The aim of this study was to assess the risk of VTE among adults with AD and compare the risk vs. matched non-AD controls., Methods: This retrospective study used claims data from the IBM Watson MarketScan ® Commercial Claims and Encounters, Medicare Supplemental, and Medicaid databases to identify adults aged 18 years or older with AD. Incidence rates (IR) per 100 person-years (PY) of VTE were reported for three cohorts: overall AD, moderate-to-severe AD, and non-AD controls matched by age, sex, and calendar time to the overall cohort. Cox proportional hazards regression was used to estimate hazard ratios (HR) for VTE risk., Results: Overall, 198,685 patients with AD were identified. Crude VTE IRs were 0.24 for AD overall, 0.31 for moderate-to-severe AD, and 0.25 for non-AD controls. VTE risk was similar in patients with AD vs. non-AD controls (partially adjusted HR 1.00, 95% confidence interval [CI] 0.92, 1.09). VTE risk was greater in patients with moderate-to-severe AD vs. non-AD controls in partially adjusted models (HR 1.24, 95% CI 1.13, 1.36), but not after adjustment for healthcare use and VTE risk factors (HR 0.95, 95% CI 0.85, 1.07)., Conclusions: AD was not an independent risk factor for VTE, and the risk of VTE among patients with AD was low. These findings provide valuable context for understanding VTE risk among patients with AD, which is particularly relevant as advanced therapies for the treatment of moderate to severe AD, such as janus kinase inhibitors, become available.

Objective: We aimed to study the epidemiology of the prodromal and mild stages of Alzheimer's disease (AD) patients who are eligible for clinical trials with disease-modifying therapies., Settings: We analysed two large complementary databases to study the incidence and characteristics of this population on a nationwide scope in France from 2014 to 2018. The National Alzheimer Database contains data from 357 memory centres and 90 private neurologists. Data from 2014 to 2018 have been analysed., Participants: Patients, 50-85 years old, diagnosed with AD who had an Mini-Mental State Exam (MMSE) score of ≥20 were included. We excluded patients with mixed and non-AD neurocognitive disorders., Primary Outcome Measure: Descriptive statistics of the population of interest was the primary measure., Results: In the National Alzheimer Database, 550 198 patients were assessed. Among them, 72 174 (13.1%) were diagnosed with AD and had an MMSE ≥20. Using corrections for specificity of clinical diagnosis of AD, we estimated that about 50 000 (9.1%) had a prodromal or mild AD. In the combined electronic clinical records database of 11 French expert memory centres, a diagnosis of prodromal or mild AD, certified by the use of cerebrospinal fluid AD biomarkers, could be established in 195 (1.3%) out of 14 596 patients., Conclusions: AD was not frequently diagnosed at a prodromal or mild dementia stage in France in 2014 to 2018. Diagnosis rarely relied on a pathophysiological marker even in expert memory centres. National databases will be valuable to monitor early stage AD diagnosis efficacy in memory centres when a disease-modifying treatment becomes available., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is little longitudinal data on resource use and costs associated with Alzheimer's disease (AD) in France., Objectives: To evaluate resource use and societal costs associated with AD in a French cohort of patients and their caregivers and the effect of patient cognitive decline on costs over an 18-month period., Methods: Community-dwelling patients with mild, moderate, or moderately severe/severe AD dementia (n = 419) were followed-up for 18 months. Total societal costs were estimated by applying 2010 unit costs to resource use, including outpatient visits, hospital days, institutionalization, and caregiver hours. Cognitive function was assessed by Mini-Mental State Examination scores., Results: Mean cumulative total costs over the 18-month period were €24,140 for patients with mild AD dementia, €34,287 for those with moderate AD dementia, and €44,171 for those with moderately severe/severe AD dementia (P < 0.001; ANOVA comparison between severity groups). The biggest contributor to total societal costs was caregiver informal care (>50% of total costs at all stages of AD dementia). Cognitive decline (≥3-point decrease in Mini-Mental State Examination score or institutionalization) was associated with a 12.5% increase in total costs (P = 0.02). Significant differences were observed across severity groups for caregiver time (P < 0.001); mean monthly caregiver time increased at each time point over the 18 months in each severity group., Conclusions: Increasing severity of AD dementia in France is associated with increased use of resources as well as increased total societal and patient costs; informal care was the greatest cost contributor. Clinically meaningful cognitive decline is associated with significantly increased costs., (Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Aims: To evaluate the impact of amyloid PET imaging on diagnosis and patient management in a multicenter, randomized, controlled study., Methods: Physicians identified patients seeking a diagnosis for mild cognitive impairment or dementia, possibly due to Alzheimer disease (AD), and recorded a working diagnosis and a management plan. The patients underwent florbetapir PET scanning and were randomized to either immediate or delayed (1-year) feedback regarding amyloid status. At the 3-month visit, the physician updated the diagnosis and recorded a summary of the actual patient management since the post-scan visit. The study examined the impact of immediate versus delayed feedback on patient diagnosis/management at 3 and 12 months., Results: A total of 618 subjects were randomized (1:1) to immediate or delayed feedback arms, and 602 subjects completed the 3-month primary endpoint visit. A higher proportion of patients in the immediate feedback arm showed a change in diagnosis compared to the controls (32.6 vs. 6.4%; p = 0.0001). Similarly, a higher proportion of patients receiving immediate feedback had a change in management plan (68 vs. 55.5%; p < 0.002), mainly driven by changes in AD medication. Specifically, acetylcholinesterase inhibitors were prescribed to 67% of the amyloid-positive and 27% of the amyloid-negative subjects in the information group compared with 56 and 43%, respectively, in the control group (p < 0.0001). These between-group differences persisted until the 12-month visit., Conclusion: Knowledge of the amyloid status affects the diagnosis and alters patient management., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

Objective: To assess the burden of illness and health care resource utilization of adult nonpsychotic psychiatric outpatients with attention-deficit/hyperactivity disorder (ADHD) in Europe., Methods: This was a multicountry, cross-sectional, observational study where unselected routine patients from clinical psychiatric outpatient settings were screened and assessed for ADHD. Patients were evaluated using the Clinical Global Impressions of Severity (CGI-S) scale, the Sheehan Disability Scale (SDS), and the EuroQol-5 Dimensions questionnaire. Data on comorbidities, functional impairment, and health care resource utilization were captured., Results: The study enrolled 2284 patients, of whom 1986 completed the study. The prevalence of ADHD was 17.4%, of whom 46.0% had a previous ADHD diagnosis. Patients with ADHD had a high clinical burden with psychiatric comorbidities, especially depression (43.0%) and anxiety disorders (36.4%). Substance abuse (9.2% vs. 3.4%) and alcohol abuse (10.3% vs. 5.2%) were more common in the ADHD cohort vs. the non-ADHD cohort. Only 11.5% of the patients with ADHD had no other psychiatric disorder. Various measures indicated a significantly poorer level of functioning for patients with ADHD than without ADHD, as indicated by higher scores for CGI-S (3.8 vs. 3.3) and SDS (18.9 vs. 11.6) and higher percentages of debt (35.5% vs. 24.3%) and criminality (13.8% vs. 6.1%). Lastly, the health care resource utilization was considerable and similar between adult psychiatric outpatients diagnosed and not diagnosed with ADHD., Conclusions: Although care was taken when choosing the sites for this study, to make it representative of the general outpatient adult psychiatric population, caution should be advised in generalizing the findings of our study to the general ADHD or psychiatric outpatient population. This was an observational study, thus no inference on causality can be drawn. Having ADHD imposes a considerable health and social burden on patient and health care resource utilization comparable to other chronic psychiatric disorders.

Background: Atomoxetine is a well-established pharmacotherapy for adult ADHD. Long-term studies show incremental reductions in symptoms over time. However, clinical experience suggests that patients differ in their response patterns., Methods: From 13 Eli Lilly-sponsored studies, we pooled and analyzed data for adults with ADHD who completed atomoxetine treatment at long-term (24 weeks; n=1443) and/or short-term (12 weeks; n=2830) time-points, and had CAARS-Inv:SV total and CGI-S data up to or after these time-points and at Week 0 (i.e. at baseline, when patients first received atomoxetine). The goal was to identify and describe distinct trajectories of response to atomoxetine using hierarchical clustering methods and linear mixed modelling., Results: Based on the homogeneity of changes in CAARS-Inv:SV total scores, 5 response clusters were identified for patients who completed long-term (24 weeks) treatment with atomoxetine, and 4 clusters were identified for patients who completed short-term (12 weeks) treatment. Four of the 5 long-term clusters (comprising 95% of completer patients) showed positive trajectories: 2 faster responding clusters (L1 and L2), and 2 more gradually responding clusters (L3 and L4). Responses (i.e.≥30% reduction in CAARS-Inv:SV total score, and CGI-S score≤3) were observed at 8 and 24 weeks in 80% and 95% of completers in Cluster L1, versus 5% and 48% in Cluster L4., Conclusions: While many adults with ADHD responded relatively rapidly to atomoxetine, others responded more gradually without a clear plateau at 24 weeks. Longer-term treatment may be associated with greater numbers of responders., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: Attention-deficit/hyperactivity disorder (ADHD) often persists into adulthood. This study was designed to estimate the prevalence of ADHD in adult psychiatric outpatients in several European countries., Method: ADHD diagnosis was made using the Diagnostic Interview for ADHD in Adults, version 2.0 (DIVA), according to criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) and 5th Edition (DSM-5)., Results: Of 5662 patients present/approached, 2284 (40.3 %) consented, of whom 1986 patients (87.0 %) completed the study. Based on the DIVA, and applying DSM-IV-TR or DSM-5 criteria, 15.8 % (95 % confidence interval [CI] 14.2 %-17.4 %) or 17.4 % (95 % CI 15.7 %-19.0 %) of patients were diagnosed with ADHD, respectively. The prevalence of ADHD was 15.3 % when counting as non-ADHD those patients who screened positive but did not complete the DIVA (DSM-5)., Conclusions: Estimates from this study indicate that a relevant part of the psychiatric outpatient care population suffers from ADHD.

Purpose: To investigate the effects of atomoxetine on emotional control in adults with ADHD., Methods: We performed an integrated analysis using individual patient data pooled from three Eli Lilly-sponsored studies. An integrated analysis can be viewed as a meta-analysis of individual patient-level data, rather than study-level summary data., Results: Two populations were identified: a large sample of patients with pre-treatment baseline data (the "overall population"; n=2846); and a subset of these patients with placebo-controlled efficacy data from baseline to 10 or 12 weeks after initiating treatment (the "placebo-controlled population"; n=829). At baseline, in the overall population, ∼50% of ADHD patients had BRIEF-AS (Behavior Rating Inventory of Executive Function-Adult Version Self-Report) Emotional control subscores between 21 and 30, compared with ∼10% of normative subjects in the BRIEF-A manual. At endpoint, in the placebo-controlled population, atomoxetine led to a small (effect size 0.19) but significant (P=0.013) treatment effect for emotional control. The effect size was 0.32 in patients with BRIEF-AS Emotional control scores>20 at baseline. Improvements in emotional control correlated with improvements in the core ADHD symptoms and quality-of-life., Discussion: As deficient emotional control is associated with impaired social, educational and occupational functioning over and above that explained by core ADHD symptoms alone, improvements in emotional control may be clinically relevant., Conclusion: At baseline, adults with ADHD were more likely to have impaired emotional control than normative subjects. In the adult ADHD patients, atomoxetine treatment was associated with improvements in emotional control, as well as in core ADHD symptoms and quality-of-life., (Copyright © 2015. Published by Elsevier Masson SAS.)

The safety profile of atomoxetine in the treatment of attention deficit hyperactivity disorder has been studied in many clinical trials. We performed an integrated safety analysis of 15 clinical trials in adults with attention deficit hyperactivity disorder. The analysis pooled patient data into three groups: acute placebo-controlled trials; long-term placebo-controlled trials; all trials. In total, 4829 adults (18-77 years, median: 36 years) were exposed to atomoxetine. Statistically significantly more atomoxetine-treated than placebo-treated patients experienced treatment-emergent adverse events (81.3% vs. 68.3% acute; 90.6% vs. 76.8% long term) and discontinued due to adverse events (8.9% vs. 4.0% acute; 17.9% vs. 6.3% long term). No statistically significant differences were observed in the proportion of patients experiencing serious adverse events. No previously unknown adverse events were identified. The most common adverse events included nausea, dry mouth, decreased appetite, insomnia and erectile dysfunction. Mean increases in heart rate (+5.2 beats per min) and blood pressure (systolic +2 mmHg, diastolic +1.9 mmHg) were modest. The proportion of patients experiencing clinically significant increases in blood pressure and heart rate at any time was statistically significantly higher with atomoxetine (systolic blood pressure 13-17%, diastolic blood pressure 37-40%, heart rate 42-43%) compared to placebo (systolic blood pressure 8-13%, diastolic blood pressure 29-34%, heart rate 21-26%). There was no increased risk of suicidal ideation or behaviour. Our findings confirm atomoxetine's known safety profile. From a safety perspective, atomoxetine is a useful treatment option for adults with attention deficit hyperactivity disorder., (© The Author(s) 2014.)

Background: To identify distinct groups of patients with fibromyalgia (FM) with respect to multiple outcome measures., Methods: Data from 631 duloxetine-treated women in 4 randomized, placebo-controlled trials were included in a cluster analysis based on outcomes after up to 12 weeks of treatment. Corresponding classification rules were constructed using a classification tree method. Probabilities for transitioning from baseline to Week 12 category were estimated for placebo and duloxetine patients (Ntotal = 1188) using logistic regression., Results: Five clusters were identified, from "worst" (high pain levels and severe mental/physical impairment) to "best" (low pain levels and nearly normal mental/physical function). For patients with moderate overall severity, mental and physical symptoms were less correlated, resulting in 2 distinct clusters based on these 2 symptom domains. Three key variables with threshold values were identified for classification of patients: Brief Pain Inventory (BPI) pain interference overall scores of <3.29 and <7.14, respectively, a Fibromyalgia Impact Questionnaire (FIQ) interference with work score of <2, and an FIQ depression score of ≥5. Patient characteristics and frequencies per baseline category were similar between treatments; >80% of patients were in the 3 worst categories. Duloxetine patients were significantly more likely to improve after 12 weeks than placebo patients. A sustained effect was seen with continued duloxetine treatment., Conclusions: FM patients are heterogeneous and can be classified into distinct subgroups by simple descriptive rules derived from only 3 variables, which may guide individual patient management. Duloxetine showed higher improvement rates than placebo and had a sustained effect beyond 12 weeks.

Background: Randomised, placebo-controlled trials of treatments for depression typically collect outcomes data but traditionally only analyse data to demonstrate efficacy and safety. Additional post-hoc statistical techniques may reveal important insights about treatment variables useful when considering inter-individual differences amongst depressed patients. This paper aims to examine the Gradient Boosted Model (GBM), a statistical technique that uses regression tree analyses and can be applied to clinical trial data to identify and measure variables that may influence treatment outcomes., Methods: GBM was applied to pooled data from 12 randomised clinical trials of 4987 participants experiencing an acute depressive episode who were treated with duloxetine, an SSRI or placebo to predict treatment remission. Additional analyses were conducted on the same dataset using the logistic regression model for comparison between these two methods., Results: With GBM, there were noticeable differences between treatments when identifying which and to what extent variables were associated with remission. A single logistic regression only revealed a decreasing or increasing relationship between predictors and remission while GBM was able to reveal a complex relationship between predictors and remission., Limitations: These analyses were conducted post-hoc utilising clinical trials databases. The criteria for constructing the analyses data were based on the characteristics of the clinical trials., Conclusions: GBM can be used to identify and quantify patient variables that predict remission with specific treatments and has greater flexibility than the logistic regression model. GBM may provide new insights into inter-individual differences in treatment response that may be useful for selecting individualised treatments., Trial Registration: IMPACT clinical trial number 3327; IMPACT clinical trial number 4091; IMPACT clinical trial number 4689; IMPACT clinical trial number 4298; NCT00071695; NCT00062673; NCT00036335; NCT00067912; NCT00073411; NCT00489775; NCT00536471; NCT00666757 (note that trials with IMPACT numbers predate mandatory clinical trial registration requirements)., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Persistence of attention deficit hyperactivity disorder (ADHD) into adulthood can be disabling or lead to substantial impairment. Several clinical trials of atomoxetine (ATX) in adults with ADHD have been reported following the National Institute for Health and Clinical Excellence (NICE) guidelines issued in 2008. We performed an integrated analysis of all Eli Lilly-sponsored, randomized, double-blind, placebo-controlled studies of ATX in adults with ADHD completed as of May 2012. Individual patient data were pooled from six short-term (10-16 week) studies (1961 patients) and three longer-term (six-month) studies (1413 patients). In the short-term analysis, ATX patients achieved a significantly greater mean reduction in ADHD symptoms than placebo patients (-12.2 vs -8.1; Conners' Adult ADHD Rating Scale-Investigator-Rated: Screening Version (CAARS-Inv: SV); p<0.001). In the longer-term analysis, respective improvements after six months were -13.2 vs -9.7 (p<0.001). Response rates at study endpoints for ATX vs placebo, based on CAARS-Inv: SV improvement ≥ 30% and Clinical Global Impressions of ADHD-Severity (CGI-ADHD-S) ≤ 3 were 34.8% vs 22.3% in the short-term and 43.4% vs 28.0% after six months, and CAARS-Inv: SV improvements ≥ 40% were 41.3% vs 25.3% in the short-term and 44.0% vs 31.4% after six months (all p<0.001). Overall, ATX had a clinically significant effect in adults with ADHD, with reductions in core symptoms and clinically meaningful responder rates., (© The Author(s) 2014.)

Background: Attention-deficit/hyperactivity disorder (ADHD) in adults can resemble, and often co-occurs with, bipolar disorder (BD) and borderline personality disorder (BPD). This can lead to mistaken diagnoses and ineffective treatment, resulting in potentially serious adverse consequences. All three conditions can substantially impair well-being and functioning, while BD and BPD are associated with suicidality., Objectives: To update clinicians on the overlap and differences in the symptomatology of ADHD versus BD and BPD in adults; differential diagnosis of ADHD from BD and BPD in adults; and diagnosis and treatment of adults with comorbid ADHD-BD or ADHD-BPD., Methods: We searched four databases, referred to the new Diagnostic and Statistical Manual of Mental Disorders, 5th edition, used other relevant literature, and referred to our own clinical experience., Results: ADHD coexists in ∼20% of adults with BD or BPD. BD is episodic, with periods of normal mood although not necessarily function. In patients with comorbid ADHD-BD, ADHD symptoms are apparent between BD episodes. BPD and ADHD are associated with chronic trait-like symptoms and impairments. Overlapping symptoms of BPD and ADHD include impulsivity and emotional dysregulation. Symptoms of BPD but not ADHD include frantically avoiding real/imagined abandonment, suicidal behavior, self-harm, chronic feelings of emptiness, and stress-related paranoia/severe dissociation. Consensus expert opinion recommends that BD episodes should be treated first in patients with comorbid ADHD, and these patients may need treatment in stages (e.g. mood stabilizer[s], then a stimulant/atomoxetine). Data is scarce and mixed about whether stimulants or atomoxetine exacerbate mania in comorbid ADHD-BD. BPD is primarily treated with psychotherapy. Principles of dialectical behavioral treatment for BPD may successfully treat ADHD in adults, as an adjunct to medication. No fully evidence-based pharmacotherapy exists for core BPD symptoms, although some medications may be effective for individual symptom domains, e.g. impulsivity (shared by ADHD and BPD). In our experience, treatment of ADHD should be considered when treating comorbid personality disorders., Conclusions: It is important to accurately diagnose ADHD, BD, and BPD to ensure correct targeting of treatments and improvements in patient outcomes. However, there is a shortage of data about treatment of adults with ADHD and comorbid BD or BPD.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobiological disorder with childhood onset and persistence into adolescence and adulthood., Methods: Our literature review reports scientific publications and guidelines on the treatment of adult ADHD, with a particular focus on European countries, identified by literature searches in Medline and Embase. The final literature search was performed in July 2012, incorporating literature from 1974 to 2012. The primary research parameters were 'Europe' (including single European countries), 'ADHD', 'attention deficit disorder', 'attention deficit', 'attention disorder', and 'hyperactivity'. Secondary search parameters were 'comorbid', 'epidemiology' or 'prevalence', 'disease management', 'drug therapy', or 'therapy'. The main searches were also limited to adults and English language publications. The papers identified by this literature review were selected for inclusion by consensus of the authors based on clinical relevance., Results: Appropriate resources for the diagnosis and treatment of adult ADHD in Europe are scarce, and many cases go untreated, particularly because of the frequent presence of psychiatric comorbidities. Apart from atomoxetine, and an extended-release form of methylphenidate in Germany, no other medications have been approved for starting treatment in adult ADHD patients in the European Union. However, a variety of stimulant and non-stimulant medications are used off-label, and a number of studies have confirmed that these medications are well tolerated and effective in adult patients with ADHD., Conclusions: Our results emphasize the need for broader access to effective treatments for adult ADHD patients in Europe.

Objective: We examined whether identification of patients with placebo-remitter characteristics and placebo-nonremitter characteristics enhances the ability to identify drug-placebo treatment differences and, perhaps, differences between agents in major depressive disorder (MDD). We hypothesized: 1) that drug-placebo differences in remission rates would be greater for both duloxetine and selective serotonin reuptake inhibitors (SSRIs) among placebo nonremitters than placebo remitters and: 2) that the difference between active treatments would also be greater in placebo nonremitters than placebo remitters., Data and Methods: Data were obtained from seven randomized, parallel, double-blind MDD studies which compared the effects of duloxetine (N = 795), placebo (N = 510), and SSRIs (N = 551). The 17-item Hamilton depression rating scale (HAMD) was used to assess depression severity. The classification of participants as having placebo-remitter or placebo-nonremitter characteristics was based on age, duration of current MDD episode, HAMD anxiety score, and HAMD core score. Odds ratios (ORs) for remission comparing active treatment and placebo were obtained from logistic regression models. Tests of homogeneity were used for between-group comparisons., Results: For placebo nonremitters, both duloxetine (OR = 3.52 [95% CI: 2.21, 5.62; P < 0.0001]) and SSRIs (OR = 2.38 [95% CI: 1.45, 3.89; P = 0.0006]) showed significantly higher remission rates compared to placebo. Drug-placebo differences in remission were significantly greater for placebo nonremitters than for placebo remitters for both duloxetine (P = 0.02) and SSRIs (P = 0.049). For placebo remitters, remission with duloxetine (OR = 1.83 [95% CI: 1.35, 2.47; P = 0.0001]), but not the SSRIs selected for this study (OR = 1.31 [95% CI: 0.93, 1.84; P = 0.12]), was significantly greater than placebo. Contrary to expectation, the advantage of duloxetine over the SSRIs was not greater in placebo nonremitters. However, the fact that our analysis required patient-level data limited the number of agents studied, compromising generalization., Conclusions: Our study suggests that drug-placebo differences in remission rates will be greater in subjects with placebo-nonremitter than with placebo-remitter characteristics.

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.

Background: This analysis of pooled data evaluates treatment outcomes of patients with schizophrenia receiving maintenance treatment with olanzapine long-acting injection (OLAI) by means of a categorical approach addressing the symptomatic and functional status of patients at different times., Methods: Patients were grouped into 5 categories at baseline, 6 months, and 12 months. Shifts between categories were assessed for individual patients and factors associated with improvement were analyzed. 1182 patients from 3 clinical trials were included in the current analysis., Results: At baseline, 434 (36.8%) patients had minimal Positive and Negative Syndrome Scale (PANSS) symptoms but seriously impaired Heinrich Carpenter's Quality of Life Scale (QLS) functioning; 303 (25.6%) had moderate to severe symptoms and seriously impaired function; 208 (17.6%) had mild to moderate symptoms but good functioning, and 162 (13.7%) had minimal symptoms and good functioning. Baseline category was significantly associated with Clinical Global Impression--Severity (CGI-S), extrapyramidal symptoms, working status, age, and number of previous episodes. The majority of all patients starting OLAI treatment maintained or improved (62% at 6 months and 52% at 12 months) their symptom and functioning levels on OLAI maintenance treatment. Less than 8% of the patients showed worsening of symptoms or functioning. An improvement in category was associated with high PANSS positive and low CGI-S scores at baseline., Conclusions: We present evidence that a composite assessment of schizophrenic patients including symptom severity and functioning is helpful in the evaluation of maintenance treatment outcomes. This approach could also be useful for the assessment of treatment options in clinical practice.The trials from which data are reported here were registered on clinicaltrials.gov as NCT00088491, NCT00088465, and NCT00320489.

This report presents efficacy and safety outcomes for patients with borderline personality disorder (BPD) treated with olanzapine for up to 24 weeks. In 2 concurrent studies, patients received open-label olanzapine for 12 weeks after 12 weeks of double-blind olanzapine or placebo. Open-label dosing started at 2.5 or 5 mg/d and could be increased up to 20 mg/d (study 1) or 15 mg/d (study 2). The primary efficacy measure was open-label baseline-to-endpoint change in Zanarini Rating Scale for BPD (ZAN-BPD) total score. Of 472 patients who completed the double-blind acute phase, 444 entered and 320 (72.1%) completed 12 weeks of open-label extension treatment. Mean ZAN-BPD total scores at the start of the acute phase were approximately 17, indicating moderate symptom severity. Mean ZAN-BPD total scores ranged from 7.8 to 10.5 at the start of the open-label treatment and decreased to 5.7 to 6.5, indicating mild symptom severity, by the end of the open-label treatment. Patients taking placebo during the acute phase showed increases in weight, prolactin level, and other laboratory values during open-label olanzapine treatment similar in magnitude to increases seen in olanzapine-treated patients during the acute phase. Patients proceeding from olanzapine during the acute phase to open-label olanzapine showed smaller changes in weight and laboratory values. In conclusion, these results suggest that continued therapy with olanzapine may sustain and build upon improvements seen with acute olanzapine treatment of patients with BPD. However, no medication is currently approved for treatment of BPD, and physicians should carefully weigh potential benefits and risks of antipsychotic treatment in this population.

Objective: To identify predictors of remission with placebo treatment in double-blind randomized controlled trials (RCTs) in major depressive disorder (MDD)., Method: A total of 1017 placebo-treated patients with baseline Hamilton Depression rating scale (HAMD) total ≥15 from eight duloxetine RCTs were included. Remission was defined as endpoint (7-8 weeks) HAMD total ≤7. Data were randomly split into training data (N = 813, 80%) for model selection and test data (N = 204, 20%) for validation. Logistic regression and classification and regression tree (CART) methods were used to identify predictors of remission. Predictive accuracy of models was assessed by Receiver Operator Characteristic (ROC) curves., Results: Baseline predictors for remission with placebo consistently identified with the logistic regression and CART analysis were less severe depressive symptoms (based on HAMD core symptoms), younger age, less anxiety (based on HAMD anxiety/somatization), and shorter current MDD episode duration. Associated cut-off values from the CART method characterized patient groups according to their remission likelihood. However, the predictive accuracy was modest for both methods with areas under the ROC curve of 0.6-0.65 based on test data., Conclusion: The derived models, although of limited value for predicting remission in individual patients, may be useful for adjusting for placebo effects in clinical trials.

Objective: To examine the efficacy and safety of olanzapine at low and moderate doses for the treatment of borderline personality disorder., Method: In this 12-week randomized double-blind placebo-controlled trial, 451 outpatients aged 18-65 years with DSM-IV borderline personality disorder received olanzapine 2.5 mg/d (n = 150), olanzapine 5-10 mg/d (n = 148), or placebo (n = 153). The trial was conducted from February 2004 through January 2006 at 59 community-based and academic study centers in 9 countries (United States, Italy, Poland, Romania, Turkey, Chile, Peru, Argentina, and Venezuela). The primary efficacy measure was mean change from baseline to last-observation-carried-forward endpoint on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) total score. Secondary measures included the Montgomery-Asberg Depression Rating Scale, the Modified Overt Aggression Scale, the Global Assessment of Functioning, the Symptom Checklist-90-Revised, and the Sheehan Disability Scale., Results: An overall mean baseline ZAN-BPD total score of 17.2 (SD = 4.9) indicated moderate symptom severity. Only treatment with olanzapine 5-10 mg/d was associated with significantly greater mean change from baseline to endpoint in ZAN-BPD total score relative to placebo (-8.5 vs -6.8, respectively; P = .010; effect size = 0.29; 95% CI, 0.06-0.52). Response rates (response indicated by ≥ 50% decrease from baseline in ZAN-BPD total score) were significantly higher for olanzapine 5-10 mg/d (73.6%) versus olanzapine 2.5 mg/d (60.1%; P = .018) and versus placebo (57.8%; P = .006). Time to response was also significantly shorter for patients taking olanzapine 5-10 mg/d than for placebo-treated patients (P = .028). Treatment-emergent adverse events reported significantly more frequently among olanzapine-treated patients included somnolence, fatigue, increased appetite, and weight increase (all P values < .05). Mean weight change from baseline to endpoint was significantly greater for olanzapine-treated than for placebo-treated patients (olanzapine 2.5 mg/d: 2.09 kg; olanzapine 5-10 mg/d: 3.17 kg; placebo: 0.02 kg; P < .001). The overall completion rate for the 12-week double-blind treatment period was 65.2% (ie, 64.7% for olanzapine 2.5 mg/d, 69.6% for olanzapine 5-10 mg/d, and 61.4% for placebo)., Conclusions: Olanzapine 5-10 mg/d showed a clinically modest advantage over placebo in the treatment of overall borderline psychopathology. This advantage in effectiveness should be weighed against the risk of adverse events (particularly weight gain), which were consistent with the known safety profile of olanzapine., Trial Registration: clinicaltrials.gov Identifier: NCT00088036., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Purpose: The aim of this study was to investigate whether lower lithium levels (LoLi) or olanzapine doses (LoOL) are risk factors for future mood episodes in patients with bipolar I disorder., Methods: A post-hoc analysis of the olanzapine-lithium-maintenance study [31] was performed using proportional hazards Cox regression models and marginal structural models (MSMs), adjusting for non-random assignments of dose during treatment., Results: The LoLi group (<0.6 mmol/L) had a significantly increased risk of manic/mixed (hazard ratio [HR]=1.96, p=0.042), but not depressive (HR=2.11, p=0.272) episodes, compared to the combined medium (0.6-0.79 mmol/L) and high lithium level (≥0.8 mmol/L) groups. There was no significant difference in risk between the two higher lithium level groups (0.6-0.79 mmol/L; ≥0.8 mmol/L) for new manic/mixed (HR=0.96, p=0.893) or depressive (HR=0.95, p=0.922) episodes. The LoOL group (<10mg/day) showed a significantly increased risk of depressive (HR=2.24, p=0.025) episodes compared to the higher olanzapine (HiOL) dose group (HiOL: 10-20 mg/day), while there was no statistically significant difference in risk for manic/mixed episodes between the two groups (HR=0.94, p=0.895)., Conclusion: Lithium levels≥0.6 mmol/L and olanzapine doses≥10mg/day may be necessary for optimal protection against manic/mixed or depressive episodes, respectively in patients with bipolar I disorder., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

The study's goal was to characterize the typology of patient outcomes based on social and occupational functioning and psychiatric symptoms following antipsychotic drug treatment, and to explore predictors of group membership representing the best/worst outcomes. A hierarchical cluster analysis was used to define groups of patients (n=1449) based on endpoint values for psychiatric symptoms, social functioning, and useful work measured up to 30 weeks of treatment. Stepwise logistic regression was used to construct predictive models of cluster membership for baseline predictors, and with 2/4/8 weeks of treatment. Five distinct clusters of patients were identified at endpoint (Clusters A-E). Patients in Cluster A (25.6%, best outcome) had minimal psychiatric symptoms and mild functional impairment, while patients in Cluster D (14.3%) and E (14.8%) (worst outcome) had moderate-to-severe symptoms and severe functional impairment. Occupational functioning, disorganized thinking, and positive symptoms were sufficient to describe the clusters. Membership in the best/worst clusters was predicted by baseline scores for functioning and symptom severity, and by early changes in symptoms with treatment. Psychiatric symptoms and functioning provided complementary information to describe treatment outcomes. Early symptom response significantly improved the prediction of outcome, suggesting that early monitoring of treatment response may be useful in clinical practice.

Background: Neurocognitive impairment and psychiatric symptoms have been associated with deficits in psychosocial and occupational functioning in patients with schizophrenia. This post-hoc analysis evaluates the relationships among cognition, psychopathology, and psychosocial functioning in patients with schizophrenia at baseline and following sustained treatment with antipsychotic drugs., Methods: Data were obtained from a clinical trial assessing the cognitive effects of selected antipsychotic drugs in patients with schizophrenia. Patients were randomly assigned to 24 weeks of treatment with olanzapine (n = 159), risperidone (n = 158), or haloperidol (n = 97). Psychosocial functioning was assessed with the Heinrichs-Carpenter Quality of Life Scale [QLS], cognition with a standard battery of neurocognitive tests; and psychiatric symptoms with the Positive and Negative Syndrome Scale [PANSS]. A path-analytic approach was used to evaluate the effects of changes in cognitive functioning on subdomains of quality of life, and to determine whether such effects were direct or mediated via changes in psychiatric symptoms., Results: At baseline, processing speed affected functioning mainly indirectly via negative symptoms. Positive symptoms also affected functioning at baseline although independent of cognition. At 24 weeks, changes in processing speed affected changes in functioning both directly and indirectly via PANSS negative subscale scores. Positive symptoms no longer contributed to the path-analytic models. Although a consistent relationship was observed between processing speed and the 3 functional domains, variation existed as to whether the paths were direct and/or indirect. Working memory and verbal memory did not significantly contribute to any of the path-analytic models studied., Conclusion: Processing speed demonstrated direct and indirect effects via negative symptoms on three domains of functioning as measured by the QLS at baseline and following 24 weeks of antipsychotic treatment.

Background: Despite the prevalence and clinical significance of borderline personality disorder, its treatment remains understudied., Aims: To evaluate treatment with variably dosed olanzapine in individuals with borderline personality disorder., Method: In this 12-week randomised, double-blind trial, individuals received olanzapine (2.5-20 mg/day; n=155) or placebo (n=159) (trial registry: NCT00091650). The primary efficacy measure was baseline to end-point change on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) using last-observation-carried-forward methodology., Results: Both olanzapine and placebo groups showed significant improvements but did not differ in magnitude at end-point (-6.56 v. -6.25, P=0.661). Response rates (50% reduction in ZAN-BPD) were 64.7% with olanzapine and 53.5% with placebo (P=0.062); however, time to response was significantly shorter for olanzapine (P=0.022). Weight gain was significantly greater (2.86 v. -0.35 kg, P<0.001), with higher incidence of treatment-emergent abnormal high levels of prolactin for the olanzapine group., Conclusions: Individuals treated with olanzapine and placebo showed significant but not statistically different improvements on overall symptoms of borderline personality disorder. The types of adverse events observed with olanzapine treatment appeared similar to those observed previously in adult populations.

We examined the potential risks and benefits of switching from olanzapine to quetiapine in mentally stable, obese, or overweight patients with schizophrenia or schizoaffective disorder. Patients receiving olanzapine were randomized to continuing olanzapine treatment (N =68; 7.5-20 mg/day) or switching to quetiapine (N =65; 300-800 mg/day). Time to relapse was the primary study objective; secondary objectives included changes in weight, metabolic parameters, and psychiatric symptoms, and discontinuation rates. No significant difference in time to relapse was observed (p =0.293), but significantly more patients remained on treatment in the olanzapine group compared with the quetiapine group (70.6% vs 43.1%; p =0.002). Olanzapine-treated patients had significantly lower rates of study discontinuation for lack of efficacy and psychiatric adverse events (AEs) compared to quetiapine (2.94% vs 15.38%, p =0.015). Significantly more patients in the olanzapine group experienced an increase in BMI ≥1 kg/m(2). Olanzapine-treated patients experienced significantly greater increases in weight from Weeks 2 through 13. Switching patients with stable disease from olanzapine to quetiapine did not significantly shorten time to relapse, but produced more frequent study discontinuations due to lack of efficacy or psychiatric AEs with moderate but variable improvement in weight and no significant between-group differences in mean changes in metabolic laboratory parameters.

Purpose: To evaluate the relationship of dose decrease, symptom worsening, and baseline covariates on subsequent relapse during olanzapine treatment in patients with schizophrenia or schizoaffective disorder., Methods: In two 28-week, randomized, double-blind clinical trials, a Cox proportional hazards model was used to determine potential correlates of relapse (defined as > or =20% worsening on PANSS total and CGI-Severity 3) among patients (N=271) who responded to 8 weeks of olanzapine treatment (10-20mg/day). Variables examined included: demographics, illness characteristics, baseline symptoms, symptom change, dose, adverse events, and functioning., Results: Patients with a lower last dose relative to the preceding visit interval were 4 times more likely to relapse during that visit interval than other patients (p<.001). A similar finding was observed for a decrease in interval modal dose, although this variable was more predictive of relapse in the visit interval immediately following dose decrease (p=.027). In a subgroup analysis by gender, there was a significantly greater incidence of relapse in men with a dose decrease, whereas a dose decrease in women did not correlate with relapse. Relapse was also correlated with the emergence or worsening of a psychiatric adverse event during the same (p<.001) and preceding (p=.007) visit intervals, and with increased rating scale measures of psychopathology. The occurrence of a non-psychiatric adverse event was not associated with relapse., Conclusion: Dose decrease is a significant predictor of relapse in male but not female patients. Psychiatric adverse events also predicted relapse. Patients should be periodically reassessed to determine the need for maintenance treatment with appropriate dose.

To determine predictors of substantial weight gain (SWG) during treatment of bipolar disorder with olanzapine, data were pooled from 4 long-term randomized, multicenter studies in patients with bipolar mania or mixed mania (N = 948 at initiation of olanzapine). SWG was defined as gaining 5 kg or 7% of initial weight in 30 +/- 2 weeks. Logistic regression estimated odds ratios associated with early weight gain and baseline risk factors for predicting SWG. A classification system to identify patients at risk for SWG was constructed by recursive data partitioning. Baseline characteristics significantly associated with SWG included younger age, nonwhite ethnicity, lower body mass index (BMI), nonrapid cycling, and psychotic features. Weight gain of 2 or more kg in the first 3 weeks of therapy predicted SWG by 30 weeks (sensitivity = 57%; specificity = 71%). A classification system with thresholds for early weight gain, baseline BMI, and ethnicity further improved SWG predictability (sensitivity = 79%; specificity = 70%). In conclusion, patients with bipolar disorder who gained 2 to 3 kg during the first 3 weeks of treatment with olanzapine, SWG was predicted after 30 weeks of treatment. Patients with less pronounced early weight gain might still be at risk for later SWG if they have close to normal BMI (< or =27 kg/m) at treatment initiation.