Health care resource utilization and costs associated with treatment among patients initiating calcitonin gene-related peptide inhibitors vs other preventive migraine treatments in the United States.

BACKGROUND: Limited data are available on health care resource utilization (HCRU) and health care costs of calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) for preventive treatment of migraine. OBJECTIVE: To compare all-cause and migraine-related HCRU and direct health care costs in patients with migraine initiating CGRP mAbs, galcanezumab (GMB), vs standard-of-care (SOC) preventive treatments in the United States. METHODS: This retrospective observational study used insurance claims data collected from IBM MarketScan Research Databases. Adults (aged ≥ 18 years) with 1 or more claims for CGRP mAb (GMB, erenumab, or fremanezumab) or SOC preventive treatment between May 1, 2018, and June 30, 2019, were included. The date of earliest migraine treatment claim during this period was the index date. Annual all-cause and migraine-related HCRU included inpatient visits, emergency department visits, and acute and preventive migraine medication fills. After matching, HCRU and costs at 6- and 12-month follow-up in CGRP mAb, specifically GMB, vs SOC cohorts were analyzed using paired t-test and chi-square test. RESULTS: In the 12-month follow-up study, 4,528 patients using CGRP mAb (GMB, n = 426) and 10,897 patients using SOC were included. After matching, 3,082 pairs were identified in the CGRP mAb and SOC cohorts and 421 pairs in the GMB and SOC cohorts. After matching, all variables were well balanced across cohorts. At 12-month follow-up, the percentage decrease in acute and preventive migraine medication fills was significantly greater in the CGRP mAb (acute: -1.5% vs -0.2%, P < 0.001; preventive: -1.1% vs 3.8, P < 0.001) and GMB cohorts (acute: -1.5% vs -0.2%, P = 0.002; preventive: -1.8 vs 3.0, P < 0.001) compared with the SOC cohort. At follow-up, compared with the SOC cohort, the mean change of annual all-cause total costs was significantly higher in both the CGRP mAb ($6,043 vs $1,323, P < 0.001) and GMB cohorts ($8,398 vs $68, P < 0.001), and the mean change of annual migraine-related total costs was significantly higher in both the CGRP mAb ($3,416 vs $976, P < 0.001) and GMB cohorts ($4,334 vs $1,245, P < 0.001). Significant cost savings in mean acute and preventive migraine prescription costs occurred in both the CGRP mAb (acute: -$358 vs -$80, P < 0.001; preventive: -$298 vs $1,376, P < 0.001) and GMB cohorts (acute: -$280 vs -$36, P = 0.034; preventive: -$374 vs $1,537, P < 0.001) compared with the SOC cohort. CONCLUSIONS: Although treatment with CGRP mAbs and GMB increase total costs, they may lead to significantly greater cost savings in outpatient acute and preventive migraine medication costs vs SOC. Further studies assessing indirect health care costs are important to understand additional cost savings with CGRP mAbs. DISCLOSURES: Drs Varnado, Ye, and Schuh are employees and stockholders of Eli Lilly and Company. Dr Wenzel is a former employee of Eli Lilly and Company. Dr Manjelievskaia is an employee of IBM Watson Health. Ms Perry is a former employee of IBM Watson Health. This study was sponsored by Eli Lilly and Company. IBM Watson Health received funding for this study from Eli Lilly and Company. Independent analyses were conducted by IBM Watson Health. Eli Lilly and Company and IBM Watson Health collaborated on designing the study and interpreting results.

Treatment Patterns for Calcitonin Gene-Related Peptide Monoclonal Antibodies Including Galcanezumab versus Conventional Preventive Treatments for Migraine: A Retrospective US Claims Study.

Background: Most conventional, oral, preventive treatments for migraine are non-specific and ~50% of patients discontinue them within six months. In 2018, the Food and Drug Administration approved three preventive migraine treatments: monoclonal antibodies (mAb) targeting the calcitonin gene-related peptide (CGRP) pathway implicated in migraine; galcanezumab and fremanezumab which target CGRP ligand; and erenumab which targets CGRP receptor. Real-world treatment patterns for CGRP mAb are limited. Purpose: To compare real-world treatment patterns for CGRP mAb, specifically galcanezumab versus standard-of-care (SOC) migraine preventive treatments. Patients and methods: This retrospective, observational study included 12-month baseline and 6- and 12-month follow-up analyses using IBM® MarketScan® databases. Patients identified were aged ≥18 years with ≥1 claim (first claim=index) for CGRP mAb (erenumab, fremanezumab, or galcanezumab) or SOC preventives (eg, antiepileptics, beta-blockers, antidepressants, or onabotulinumtoxinA) as index drugs between May/01/2018 and June/30/2019. Propensity score matching was used to address confounding by observed covariates. Outcomes analyzed included proportion of days covered (PDC), persistence (≤60-day gap), and first non-index drug switch. Descriptive, chi-square (categorical), and t-test (continuous) analyses were conducted. Results: The study included 3082 (CGRP mAb versus SOC) and 421 (galcanezumab versus SOC) matched patient pairs with 12-month follow-up. Mean age across cohorts ranged 43.2-44.4 years (females: 85.7-88.6%). Compared with SOC, the CGRP mAb cohort had higher mean persistence (212.5 vs 131.9 days), adherence (PDC: 55.1% vs 35.2%), and more patients were adherent with PDC ≥80% (32.7% vs 18.7%) (all p <0.001). During 12-month follow-up, fewer patients discontinued CGRP mAb versus SOC (58.8% vs 77.6%, p <0.001). Galcanezumab versus SOC comparisons yielded similar results. In the CGRP mAb cohort, most switchers (28.3%) used galcanezumab as subsequent treatment. Largely similar results were observed for 6-month follow-up cohorts. Conclusion: Patients on CGRP mAb and specifically galcanezumab showed higher adherence and persistence than patients on SOC migraine preventive treatments.

Efficacy of Galcanezumab for Migraine Prevention in Patients With a Medical History of Anxiety and/or Depression: A Post Hoc Analysis of the Phase 3, Randomized, Double-Blind, Placebo-Controlled REGAIN, and Pooled EVOLVE-1 and EVOLVE-2 Studies.

OBJECTIVE: This post hoc analysis evaluated the efficacy of galcanezumab for the prevention of migraine in patients with and without comorbid anxiety and/or depression. BACKGROUND: Patients with migraine have a higher risk of anxiety and/or depression. Given the high prevalence of psychiatric symptoms and their potential negative prognostic impact, determining the efficacy of migraine treatments in patients with these comorbidities is important. METHODS: The results of 2 phase 3 episodic migraine studies of patients with 4-14 migraine headache days (MHD) per month were pooled. A third chronic migraine study, which was evaluated separately, enrolled patients with ≥15 headache days per month, of which ≥8 had migraine-like features. Patients in all 3 studies were randomized 2:1:1 to placebo, galcanezumab 120 mg, or galcanezumab 240 mg. The efficacy of galcanezumab on migraine was measured in subgroups of patients with anxiety and/or depression (current or past) and patients without. A repeated measures model was used to compare treatment groups within each subgroup and to test for consistency of treatment effect across the anxiety/depression subgroups (subgroup-by-treatment interaction) during the double-blind treatment phases. RESULTS: Among 1773 intent-to-treat patients with episodic migraine, both doses of galcanezumab demonstrated statistically significant improvements relative to placebo in overall number of MHD for the subgroups of patients with anxiety and/or depression (mean change difference from placebo [95% CI]: -2.07 [-2.81, -1.33] for galcanezumab 120 mg [P < .001], -1.91 [-2.78, -1.04] for 240 mg [P < .001]) and without anxiety and/or depression (mean change difference from placebo [95% CI]: -1.92 [-2.36, -1.47] for 120 mg [P < .001], -1.77 [-2.20, -1.33] for 240 mg [P < .001]), as was observed for the secondary outcomes of MHD with acute medication use and functional impairment. Among 1113 intent-to-treat patients with chronic migraine, those with anxiety and/or depression had significant reductions in overall MHD frequency with the 240-mg dose (mean change difference from placebo [95% CI]: -1.92 [-3.52, -0.33]; P = .018), whereas significant reductions were observed at both the 120-mg (mean change difference from placebo [95% CI]: -2.29 [-3.26, -1.31]; P < .001) and 240-mg (-1.85 [-2.83, -0.87]; P < .001) doses in patients without anxiety and/or depressions. Significant reductions (P < .01) in MHD with acute medication use were observed at both doses within both anxiety/depression subgroups and for overall functional impairment for patients without anxiety and/or depression, though neither dose significantly reduced overall functional impairment beyond placebo in the subgroup with anxiety and/or depression. In the episodic and chronic migraine studies, the subgroup-by-treatment interaction was not statistically significant for MHD, MHD with acute medication use, or functional impairment (chronic study only), suggesting a lack of evidence of differential effect between subgroups. Furthermore, differences between subgroups in the mean change differences from placebo, as well as overlapping 95% confidence intervals for the subgroups, indicated lack of a clinical or statistical difference between subgroups for these outcome variables. There was a significantly higher percentage of patients with episodic migraine attaining ≥50%, ≥75%, and 100% reductions, and a higher percentage of patients with chronic migraine attaining ≥50% and ≥75% reductions from baseline with galcanezumab compared with placebo, regardless of medical history of anxiety and/or depression. CONCLUSIONS: A medical history of anxiety and/or depression does not seem to interfere with response to galcanezumab among patients with episodic migraine, and both doses of galcanezumab appear efficacious for these individuals regardless of this psychiatric history. Among patients with chronic migraine and comorbid anxiety and/or depression, the 240-mg dose, but not the 120-mg dose, significantly decreased overall MHD, but neither dose resulted in significantly greater functional improvement. Patients with migraine and comorbid anxiety and/or depression often require additional interventions, and this may be more important in chronic migraine.

Quantile regression to characterize solanezumab effects in Alzheimer's disease trials.

INTRODUCTION: In two solanezumab trials for mild-to-moderate Alzheimer's disease (AD) dementia, 27% of patients had biomarker confirmation of amyloid status. Of these, approximately 25% of mild patients and approximately 10% of moderate patients were amyloid negative and, as a group, did not exhibit clinical progression typical of AD. This post-hoc analysis describes a statistical surrogate for amyloid status. METHODS: Quantile regression was used to examine solanezumab treatment effects at fixed percentiles of varying degrees of clinical progression, with lowest percentiles (minimal progression atypical of AD) and higher percentiles acting as surrogates for amyloid negativity or positivity, respectively. RESULTS: In mild patients, solanezumab treatment effect was greater in higher percentiles of progression and less in lowest percentiles (AD-atypical). In moderate patients, solanezumab did not show effects across most percentiles. DISCUSSION: Results are compatible with design of the ongoing solanezumab EXPEDITION 3 trial that limits patients to those with mild AD dementia and evidence of amyloid pathology.

Atomoxetine monotherapy compared with combination therapy for the treatment of ADHD: a retrospective chart review study.

OBJECTIVE: To analyze Clinical Global Impression-Severity (CGI-S) in ADHD patients treated with atomoxetine (ATX) monotherapy versus ATX combination therapy with another ADHD-indicated medication. METHODS: This was a 2-site retrospective observational chart review study of child and adult ADHD patients, not necessarily treatment naïve, but treated ≥50 days post baseline with an endpoint assessment. To adjust for measured confounders, monotherapy (n = 77) versus combination (n = 108) cohort comparisons were performed using propensity score stratification and adjusted ANCOVA. RESULTS: There were no significant baseline cohort differences after propensity stratification. CGI-S scores after a mean 264 days of treatment were not statistically significantly different between cohorts, with no cohort differences observed in any assessed symptom subcategory. The cohorts were similar in discontinuation due to any reason, adverse event, and lack of efficacy. CONCLUSION: ATX combination therapy showed no evidence of additional benefit over ATX monotherapy in the treatment of ADHD in a community-based setting.

Neurobiology of Alzheimer's Disease: Integrated Molecular, Physiological, Anatomical, Biomarker, and Cognitive Dimensions.

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

A phase 2, placebo-controlled study of the opioid receptor antagonist LY2196044 for the treatment of alcohol dependence.

BACKGROUND: Endogenous opioid-mediated reward pathways may play a role in the development and maintenance of alcohol dependence. This study tested whether LY2196044, an opioid receptor antagonist, in combination with medical management would reduce drinking in alcohol-dependent patients. METHODS: This was a multicenter, outpatient, randomized, double-blind, parallel, and placebo-controlled trial with a 16-week treatment period. Patients (N = 375) were alcohol-dependent, treatment-seeking adults. Patients were randomly assigned to once-daily LY2196044 (final doses of 125 or 250 mg/d) or placebo. DNA samples were collected at baseline. At each visit, patients underwent safety assessments, laboratory testing, efficacy measures, and medical management. Blood samples were also obtained for pharmacokinetic testing. The primary measure was the change from baseline in the percent heavy drinking days (HDD). Secondary efficacy measures were percent days abstinent per month and number of drinks per day. RESULTS: The treatment difference in change from baseline in % HDD between LY2196044 and placebo was not statistically significant (-43.02 vs. -38.72%, respectively; p = 0.12). There was a trend toward greater change from baseline in the percent days abstinent per month for the LY2196044 group compared with the placebo group (33.49 vs. 28.12%, respectively; p = 0.051). The decrease from baseline for mean number of drinks per day was statistically significantly greater in the LY2196044 group compared with the placebo group (-5.37 vs. -4.66 drinks per day, respectively; p = 0.013). LY2196044-treated patients who were dopamine receptor type 4-variable number tandem repeat L carriers had greater reductions in % HDD (p = 0.0565), increased percent days abstinent (p = 0.0496), and reduced drinks per day (p = 0.0069) than placebo-treated L carriers. The safety profile for LY2196044 appeared similar to that of other opioid antagonists. CONCLUSIONS: The results from this proof-of-concept clinical trial warrant further evaluation of LY2196044 for the treatment of alcohol dependence.

Comparison of neuroimaging modalities for the prediction of conversion from mild cognitive impairment to Alzheimer's dementia.

In this study we compared Pittsburgh compound-B (PIB) positron emission tomography (PET) amyloid imaging, fluorodeoxyglucose PET for metabolism, and magnetic resonance imaging (MRI) for structure to predict conversion from amnestic mild cognitive impairment (MCI) to Alzheimer's dementia using data from the Alzheimer's Disease Neuroimaging Initiative cohort. Numeric neuroimaging variables generated by the Alzheimer's Disease Neuroimaging Initiative-funded laboratories for each neuroimaging modality along with apolipoprotein-E genotype (n = 29) were analyzed. Performance of these biomarkers for predicting conversion from MCI to Alzheimer's dementia at 2 years was evaluated in 50 late amnestic MCI subjects, 20 of whom converted. Multivariate modeling found that among individual modalities, MRI had the highest predictive accuracy (67%) which increased by 9% to 76% when combined with PIB-PET, producing the highest accuracy among any biomarker combination. Individually, PIB-PET generated the best sensitivity, and fluorodeoxyglucose PET had the lowest. Among individual brain regions, the temporal cortex was found to be most predictive for MRI and PIB-PET.

Real-world use patterns of olanzapine long-acting injection in the United States: comparison to the recommended dosing strategy.

OBJECTIVE: Recommended doses for olanzapine long-acting injection (olanzapine LAI) are 150 mg/2 weeks, 210 mg/2 weeks, 300 mg/2 or 4 weeks, and 405 mg/4 weeks. This analysis evaluated the dosing and interval patterns to compare the actual dosing patterns with the recommended dosing strategy. RESEARCH DESIGN AND METHODS: These data, from March 2010 through September 2011, were collected as part of a Risk Evaluation and Mitigation Strategy mandatory patient registry that captures all post-approval olanzapine injections in the US. This registry includes both active and inactive (60 + days since last injection) patients. RESULTS: All patients with at least one olanzapine injection were included (n = 1694). The mean number of injections received was 6.6 (range of 1-40). The most frequent numbers of injections were one (26.3%) and two (12.9%). For the 11,228 olanzapine injections, the most common doses were 300 mg and 405 mg, accounting for 92.9% of injections. Although the most common time intervals between injections was about 14 days for 150 mg, 210 mg, and 300 mg, and about 28 days for 405 mg, the intervals ranged from less than 10 to more than 60 days for all doses. Among active patients (48.2% of registry), 68.2% had >120 days of treatment with any dose, and the number of days since the last injection was around 2 weeks or less for 61.2% of patients, around 3 weeks for 16.5% of patients, and around 4 weeks for 7.1% of patients. Among inactive patients (51.8% of registry), 48.6% had <30 days of treatment. For the pattern of the first five injections, most patients (70.9%) received four subsequent injections of the same dose as their initial injection. CONCLUSIONS: This registry will continue to change. There is a broad range in time between injections. Most patients continue to receive the same initial dose instead of switching to a maintenance dose. This may suggest that some clinicians are not reassessing the dose after the initial starting dose because the patient was stabilized on olanzapine oral before beginning olanzapine long-acting injection. The study is limited by a database that does not include reasons for dose and dosing interval decisions or reasons for delaying or discontinuing treatment.

Movement disorder profile and treatment outcomes in a one-year study of patients with schizophrenia.

BACKGROUND: This study identified subgroups of patients with schizophrenia who differed on their movement disorder profile and compared their treatment outcomes. METHODS: Data from a randomized, open-label, one-year study of patients with schizophrenia who were treated with antipsychotics in usual clinical care settings were analyzed (n = 640). Five measures of movement disorder were incorporated into a single Movement Disorder Index (MDI). Subgroups that differed in their movement disorder profile over the one-year study period were compared on clinical and functional outcomes. RESULTS: THREE SUBGROUPS WERE IDENTIFIED: a worsening of MDI in 15% of patients, an improvement in 33%, and no change in 53%. Compared with the other two subgroups, the MDI-worsened subgroup had poorer symptom improvement measured by the Positive and Negative Syndrome Scale (PANSS) total score (mean changes of -11.0, -18.4, and -16.8 for the patients who had a worsening of MDI, no change, and an improvement, respectively), poorer symptom improvement on the PANSS positive and anxiety/depression subscale scores, worsening on the 36-Item Short Form Health Survey (SF-36) physical component summary score, and a higher rate of hospitalization (P < 0.05). CONCLUSION: Patients with schizophrenia who experience worsening of their MDI score appear to have poorer clinical and functional outcomes, suggesting that such worsening may be a marker of poorer prognosis.

A review of the abuse potential assessment of atomoxetine: a nonstimulant medication for attention-deficit/hyperactivity disorder.

RATIONALE: Treatment of attention-deficit/hyperactivity disorder (ADHD) has for many years relied on psychostimulants, particularly various formulations of amphetamines and methylphenidate. These are central nervous system stimulants and are scheduled because of their abuse potential. Atomoxetine (atomoxetine hydrochloride; Strattera®) was approved in 2002 for treatment of ADHD, and was the first nonstimulant medication approved for this disorder. It was classified as an unscheduled medication indicating a low potential for abuse. However, the abuse potential of atomoxetine has not been reviewed. OBJECTIVES: In this article, we review the evidence regarding abuse potential of atomoxetine, a selective inhibitor of the presynaptic norepinephrine transporter, which is unscheduled/unrestricted in all countries where it is approved. METHODS: Results from receptor binding, in vitro electrophysiology, in vivo microdialysis, preclinical behavioral, and human laboratory studies have been reviewed. RESULTS: Atomoxetine has no appreciable affinity for, or action at, central receptors through which drugs of abuse typically act, i.e., dopamine transporters, GABA(A) receptors, and opioid µ receptors. In behavioral experiments in rodents, atomoxetine does not increase locomotor activity, and in drug discrimination studies, its profile is similar to that of drugs without abuse potential. Atomoxetine does not serve as a reinforcer in monkey self-administration studies, and human laboratory studies suggest that atomoxetine does not induce subjective effects indicative of abuse. CONCLUSION: Neurochemical, preclinical, and early clinical studies predicted and supported a lack of abuse potential of atomoxetine, which is consistent with the clinical trial and postmarketing spontaneous event data in the past 10 years.

Effects of olanzapine long-acting injection on levels of functioning among acutely ill patients with schizophrenia.

OBJECTIVE: To assess the effects of olanzapine long-acting injection (olanzapine-LAI) on levels of functioning in acutely ill patients with schizophrenia. RESEARCH DESIGN AND METHODS: During this 8-week randomized, double-blind, placebo-controlled trial, 404 inpatients were randomized to four treatment arms (olanzapine-LAI 210 mg/2 weeks = 106; olanzapine-LAI 300 mg/2 weeks = 100; olanzapine-LAI 405 mg/4 weeks = 100; placebo = 98). Also, data from the three active dosing arms were combined and compared to placebo data. CLINICAL TRIAL REGISTRATION: NCT00088478. MAIN OUTCOME MEASURES: The treatment group comparison of mean change from baseline to endpoint in the total score and four subdomains of the Heinrichs-Carpenter Quality of Life Scale (QLS) and in the 2 summary scores and 8 subscale scores of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) were assessed using an ANOVA model. RESULTS: All three olanzapine-LAI treatment groups and the combined olanzapine-LAI group were superior to placebo on the QLS total score (all p-values < 0.01) and the Intrapsychic Foundations subdomain (all p-values < 0.02). Olanzapine-LAI 210 mg/2 weeks (p < 0.001), 300 mg/2 weeks (p = 0.006), and the combined olanzapine-LAI group (p = 0.003) were superior to placebo on the Interpersonal Relations subdomain. The 300 mg/2 weeks group (p = 0.027) and the combined olanzapine-LAI group (p = 0.014) were also superior to placebo on the Instrumental Role subdomain. For the SF-36, the 300 mg/2 weeks and 405 mg/4 weeks olanzapine-LAI groups and the combined olanzapine-LAI group were superior to placebo on the Mental component score (all p-values < 0.05). Each olanzapine-LAI group and the combined group were superior on the Mental Health scale (all p-values < 0.05). Significant negative correlations between PANSS scores and measures of functioning indicate that as symptoms decreased, functioning increased. CONCLUSION: These results suggest that olanzapine-LAI may improve level of functioning in acutely ill patients with schizophrenia within 8 weeks of initiating treatment.

Reasons for continuing or discontinuing olanzapine in the treatment of schizophrenia from the perspectives of patients and clinicians.

BACKGROUND: The aim of this study was to assess the reasons for discontinuing or continuing olanzapine in patients with schizophrenia, from the perspectives of the patients and their clinicians. METHODS: The Reasons for Antipsychotic Discontinuation/Continuation (RAD) is a pair of questionnaires assessing these reasons from the perspectives of patients and their clinicians. Outpatients with schizophrenia (n = 199) who were not acutely ill participated in a 22-week open-label study of olanzapine from November 2006 to September 2008. Reasons for continuing or discontinuing olanzapine (on a five-point scale), along with the single most important reason and the top primary reasons, were identified. Concordance between reasons given by patients and clinicians was assessed. RESULTS: The top primary reasons for continuing olanzapine were patients' perceptions of improvement, improvement of positive symptoms, and improved functioning. The study discontinuation rate was low (30.2%), and only a subset of patients who discontinued reported reasons for medication discontinuation. The top primary reasons for discontinuing olanzapine were insufficient improvement or worsening of positive symptoms, adverse events, and insufficient improvement or worsening of negative symptoms. Ratings given by patients and clinicians were highly concordant. CONCLUSION: The main reason for continuing or discontinuing olanzapine appears to be medication efficacy, especially for positive symptoms. Reasons for medication discontinuation differ somewhat from reasons for continuation, with a high level of concordance between patient and clinician responses.

Decline in hospitalization risk and health care cost after initiation of depot antipsychotics in the treatment of schizophrenia.

PURPOSE: To assess change in hospitalization and cost of care from 6 months pre- to 6 months post-initiation on any depot antipsychotic among schizophrenia patients. PATIENTS AND METHODS: Using a large United States commercial claims and encounters database, patients younger than 65 years diagnosed with schizophrenia were identified. Patients initiated on a depot antipsychotic were studied in a mirror-image design to assess change in hospitalization rates, mean duration hospitalized, and hospitalization cost. McNemar's test and paired t-tests compared the proportions of patients hospitalized and the mean duration. Paired t-test and bootstrapping methods compared costs. RESULTS: In these patients (n = 147), psychiatric hospitalizations declined from 49.7% pre-initiation to 22.4% post-initiation (P < 0.001), and the mean hospitalized duration for psychiatric purposes numerically declined from 7.3 to 4.7 days (P = 0.05). Total health care costs declined from $11,111 to $7884 (P < 0.05) driven by reduction in costs for psychiatric hospitalizations from $5384 to $2538 (P < 0.05). CONCLUSION: Initiation of depot antipsychotic therapy appeared to be associated with a decline in hospitalization rates and costs. Current findings suggest that treatment with depot antipsychotics may be a cost-effective option for a subgroup of patients with schizophrenia who are at high risk of nonadherence with their oral antipsychotic medication regimen.

Does caregiver burden mediate the effects of behavioral disturbances on nursing home admission?

OBJECTIVES: The primary objective of this study was to determine whether caregiving burden mediated the relationship between specific behavior disturbances and time to nursing home admission (NHA) for persons with dementia (i.e., Alzheimer disease or a related disorder). DESIGN: The study used secondary longitudinal data from the Medicare Alzheimer's Disease Demonstration, a Medicare-covered home care benefit and case management program for family caregivers of persons with dementia. Primary caregivers of persons with dementia were assessed via in-person and telephone interviews every 6 months over a 3-year period. SETTING: Dementia caregivers were recruited from eight catchment areas throughout the United States. PARTICIPANTS: The baseline sample included 5,831 dementia caregivers. Just more than 40% (43.9%; N = 2,556) of persons with dementia permanently entered a nursing home during the 3-year study period. MEASUREMENTS: Individual behavior problems were measured with the Memory and Behavior Problem Checklist. Caregiving burden was assessed with a short version of the Zarit Burden Inventory. Key covariates, including sociodemographic background, functional status, and service utilization, were also considered. RESULTS: Event history analyses revealed that time-varying measures of caregiver burden fully mediated the relationship between four behavioral disturbances (episodes of combativeness, property destruction, repetitive questions, and reliving the past) and NHA. CONCLUSIONS: The findings highlight the multifaceted, complex pathway to NHA for persons with dementia and their family caregivers. The results emphasize the need for comprehensive treatment approaches that incorporate the burden of caregivers and the behavioral/psychiatric symptoms of persons with dementia simultaneously.

Effect of atomoxetine on executive function impairments in adults with ADHD.

OBJECTIVE: To assess the effect of atomoxetine on ADHD-related executive functions over a 6-month period using the Brown Attention-Deficit Disorder Scale (BADDS) for Adults, a normed, 40-item, self-report scale in a randomized, double-blind, placebo-controlled clinical trial. METHOD: In a randomized, double-blind clinical trial, adults with ADHD received either atomoxetine 25 to 100 mg/day or placebo for 6 months. Patients completed the BADDS to report their current daily functioning in 5 clusters of ADHD-related impairments of executive functioning: (1) Organizing and Activating to Work; (2) Focusing for Tasks; (3) Regulating Alertness and Effort; (4) Modulating Emotions; and (5) Utilizing Working Memory. RESULTS: Mean scores were significantly more improved in the atomoxetine group compared to the placebo group: total score, -27.0 versus -19.0 (p < .001); all 5 cluster scores, p < .01. CONCLUSIONS: Once-daily atomoxetine can improve executive function impairments in adults with ADHD as assessed by the BADDS.

Reasons for discontinuation and continuation of antipsychotics in the treatment of schizophrenia from patient and clinician perspectives.

OBJECTIVE: To identify reasons for discontinuation and continuation of antipsychotic medications in the treatment of schizophrenia from the patients' and their clinicians' perspectives. RESEARCH DESIGN AND METHODS: Two measures were previously developed to assess the Reasons for Antipsychotic Discontinuation/Continuation (RAD), one from the patient's perspective and another from the clinician's perspective. These measures were administered to acutely ill schizophrenia patients enrolled in a 12-week study of antipsychotic medications (N = 596) and to their clinicians. The RAD was assessed at baseline and at endpoint. Reasons were rated on a 5-point scale from 'primary reason' to 'not a reason.' The single most important reason was also identified. The 'single most important reason' and the 'primary reasons' for discontinuing the drug used prior to enrollment, and for discontinuing or continuing the study drug were identified. Levels of concordance between patients' and clinicians' reasons were assessed. CLINICAL TRIAL REGISTRATION: The data source for this study is a clinical trial registered at www.clinicaltrials.gov (NCT00337662). MAIN OUTCOME MEASURES: Reasons for Antipsychotic Discontinuation/Continuation (RAD). RESULTS: Patients and clinicians identified several reasons for medication discontinuation and continuation (2.3 to 6.3 reasons, on average). The top 'single most important' reason for discontinuing the drug used prior to enrollment and for discontinuing the study drug was 'positive symptoms not sufficiently improved or made worse,' followed by 'medication-related adverse events.' The most frequent 'single most important' reason for medication continuation was 'improved positive symptoms,' followed by 'patient's perception of improvement,' and 'functional improvement.' A high level of concordance was observed between patients' and clinicians' ratings. CONCLUSIONS: Medication efficacy appears to be the core driver of medication discontinuation and continuation, especially with regard to positive symptoms. There was a high level of concordance between patients' and clinicians' perspectives. Limitations include the study requirement that patients be at least moderately ill and experiencing acute psychotic exacerbation, a potential selection bias in the readiness to respond to measures, and small sample sizes for some analyses. Further research is needed to replicate findings in patients who are not acutely ill.

Effects of atomoxetine on self-reported high-risk behaviors and health-related quality of life in adolescents with ADHD.

OBJECTIVE: This study measured the effects of atomoxetine HCl on high-risk behaviors and health-related quality of life in adolescents with attention-deficit/hyperactivity disorder (ADHD), using a subgroup analysis of data from a previous clinical trial. RESEARCH DESIGN AND METHODS: In the base study, which was conducted at 26 sites in the United States, patients ages 13-16 years were randomized in a double-blind manner to atomoxetine treatment by one of two dose titration schedules for 8 weeks. Patients who responded to treatment were rerandomized to atomoxetine at a daily dose of 0.8 or 1.4 mg/kg for 40 weeks. Patients in the highest-risk quartile for each category of behavior or domain were included and the dosing groups combined. MAIN OUTCOME MEASURES: Efficacy measures included the Youth Risk Behavior Surveillance (YRBS) and Child Health and Illness Profile - Adolescent Edition (CHIP-AE). The YRBS has six categories of behavior, and the CHIP-AE has six domains. Data for mean change from baseline were analyzed using a last-observation-carried-forward analysis. RESULTS: A total of 267 patients were randomized, but the high-risk subgroup analyzed in the present study was much smaller (range of n = 5-68 per group). YRBS scores for tobacco use, unhealthful dietary behaviors, inadequate physical activity, and behaviors contributing to unintentional injuries showed statistically significant improvements (p < 0.05) by atomoxetine treatment at Week 8. At the end of the 40-week maintenance period, unhealthful dietary behaviors, inadequate physical activity, and behaviors contributing to unintentional injuries continued to show statistically significant improvements (p < 0.001). When the highest-risk quartile of the CHIP-AE data was analyzed, there were statistically significant improvements on all six domains after atomoxetine treatment at 8 weeks (p < 0.001) and on five of the six domains at 40 weeks (p < or = 0.01). CONCLUSIONS: Atomoxetine improved self-reported high-risk behaviors and overall health-related quality of life in adolescents with ADHD. Potential limitations of this study include small sample sizes and the fact that it involved a subgroup analysis, which is by nature hypothesis-generating. Further, well-controlled, prospective studies in larger and more heterogeneous ADHD populations, including older patients, are warranted to confirm or reject these findings.

Atomoxetine treatment for ADHD: younger adults compared with older adults.

OBJECTIVE: Atomoxetine is a nonstimulant medication for treating child, adolescent, and adult ADHD. This meta-analysis compared the effects in younger and older adults. METHOD: A post hoc analysis was conducted using data from two double-blind, placebo-controlled clinical trials. Data from patients aged 18-25 years were compared with data from patients older than 25 years. RESULTS: In younger adults (mean age = 21.7), atomoxetine produces greater improvement than placebo on the Conners' Adult ADHD Rating Scale's total ADHD symptom score (p = .041, effect size = .797) and the clinical global impressions severity (p = .006, effect size = 1.121). In older adults (mean age = 43.4 years), atomoxetine also produces significant benefit on the CAARS-Inv:SV (p < .001, effect size = .326) and CGI-ADHD-S (p < .001, effect size = .346). The study findings reveal response rates to be 56.4% and 47.8% for the younger and older adults, respectively (p = .188). Tolerability is similar although older adults reported more sexual side effects. CONCLUSION: Younger and older adults show similar improvements at endpoint. The effect size is higher in younger adults, but this is due primarily to greater variability of response in older patients.

Validation of the adult ADHD investigator symptom rating scale (AISRS).

OBJECTIVE: Validation of the Adult ADHD Investigator Symptom Rating Scale (AISRS) that measures aspects of ADHD in adults. METHOD: Psychometric properties of the AISRS total and AISRS subscales are analyzed and compared to the Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) and the Clinical Global Impression-ADHD-Severity Scale using data from a placebo-controlled 6-month clinical trial of once-daily atomoxetine. RESULTS: The AISRS has high internal consistency, good convergent, and discriminant validities; modest divergent validity; and small ceiling and floor effects (