Baricitinib Safety for Events of Special Interest in Populations at Risk: Analysis from Randomised Trial Data Across Rheumatologic and Dermatologic Indications.

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/m2, 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.

Evaluation of VTE, MACE, and Serious Infections Among Patients with RA Treated with Baricitinib Compared to TNFi: A Multi-Database Study of Patients in Routine Care Using Disease Registries and Claims Databases.

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.

A Review of Safety Outcomes from Clinical Trials of Baricitinib in Rheumatology, Dermatology and COVID-19.

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.

The oral selective inhibitor of Janus kinase (JAK)1/JAK2 baricitinib transiently and reversibly inhibits elements of the inflammatory pathway, which are key mechanisms for several chronic, inflammatory rheumatological and dermatological diseases but, as with all drugs, it can be associated with unwanted effects. This narrative review summarises adverse events of special interest (AESI) for baricitinib, considered as such either because of characteristics of patients with the disease being treated (rheumatological and dermatological disorders and COVID-19) or the mechanism of action of the drug. The risk of these events is considered in light of the inherent risk of each event in populations with the respective diseases. We show that serious infections and herpes zoster during baricitinib therapy were most common in patients with rheumatological disorders, and herpes simplex was reported particularly in patients with atopic dermatitis, likely because of disease-related risk factors. MACE, VTE and malignancies generally occurred in baricitinib-treated patients with a frequency within or below the ranges reported for the respective disease populations. Rates generally reflected the underlying risk of the disease populations, being higher in patients with rheumatological diseases than in those with dermatological disorders, and mostly occurring in patients with underlying risk factors for the AESI. No safety concerns were observed in hospitalised patients with COVID-19 who received baricitinib for up to 14 days. Characterising patterns and likelihoods of unwanted events that occur during treatment in large groups of patients with different diseases can help put the actual risk to an individual patient into perspective.

Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database.

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.

Baricitinib and the Risk of Incident Interstitial Lung Disease: A Descriptive Clinical Case Report from Clinical Trials.

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.

Risk of Venous Thromboembolism Among Patients with Atopic Dermatitis: A Cohort Study in a US Administrative Claims Database.

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.

How many patients are eligible for disease-modifying treatment in Alzheimer's disease? A French national observational study over 5 years.

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.

Resource Use and Cost of Alzheimer's Disease in France: 18-Month Results from the GERAS Observational Study.

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.

Effectiveness of Florbetapir PET Imaging in Changing Patient Management.

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.

Burden of illness and health care resource utilization in adult psychiatric outpatients with attention-deficit/hyperactivity disorder in Europe.

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.

Prevalence of ADHD in nonpsychotic adult psychiatric care (ADPSYC): A multinational cross-sectional study in Europe.

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.

Safety and tolerability of atomoxetine in treatment of attention deficit hyperactivity disorder in adult patients: an integrated analysis of 15 clinical trials.

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.

Typology of patients with fibromyalgia: cluster analysis of duloxetine study patients.

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.

Application of the Gradient Boosted method in randomised clinical trials: Participant variables that contribute to depression treatment efficacy of duloxetine, SSRIs or placebo.

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).

Efficacy of atomoxetine in adults with attention deficit hyperactivity disorder: an integrated analysis of the complete database of multicenter placebo-controlled trials.

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.

Differential diagnosis, comorbidity, and treatment of attention-deficit/hyperactivity disorder in relation to bipolar disorder or borderline personality disorder in adults.

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.

Attention deficit hyperactivity disorder in the European adult population: prevalence, disease awareness, and treatment guidelines.

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.

Baseline patient characteristics associated with placebo remission and their impact on remission with duloxetine and selected SSRI antidepressants.

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.

Schizophrenia symptoms and functioning in patients receiving long-term treatment with olanzapine long-acting injection formulation: a pooled analysis.

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.