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.

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.

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.

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.

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.

Once-daily atomoxetine for adult attention-deficit/hyperactivity disorder: a 6-month, double-blind trial.

This randomized, double-blind, placebo-controlled, 6-month trial examined the efficacy and safety of once-daily morning-dosed atomoxetine in adult patients with attention-deficit/hyperactivity disorder (ADHD) and the efficacy of atomoxetine in ameliorating symptoms through the evening hours. Patients received once-daily atomoxetine (n = 250) or placebo (n = 251) in the morning for approximately 6 months. The efficacy measures included the Adult ADHD Investigator Symptom Rating Scale (AISRS), Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version, Clinical Global Impressions-ADHD-Severity of Illness, and Adult ADHD Quality of Life Scale. Overall, 94 patients randomized to atomoxetine and 112 patients randomized to placebo completed the study. On the AISRS total score, Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version evening index total score, Clinical Global Impressions-ADHD-Severity of Illness score, and Adult ADHD Quality of Life Scale total score, atomoxetine was statistically superior to placebo at the 10-week and 6-month time points. From the visitwise analysis, the mean (SD) AISRS total scores for atomoxetine decreased from 38.2 (7.5) at baseline to 21.4 (12.3) at the 6-month end point compared with 38.6 (7.0) to 25.8 (13.2) for placebo (P = 0.035). Nausea, dry mouth, fatigue, decreased appetite, urinary hesitation, and erectile dysfunction were the treatment-emergent adverse events reported significantly more often with atomoxetine. Discontinuations due to adverse events were 17.2% and 5.6% for atomoxetine and placebo, respectively (P < 0.001). Once-daily morning-dosed atomoxetine is efficacious for treating ADHD in adults when measured 10 weeks and 6 months after initiating treatment. Atomoxetine demonstrated significant efficacy that continued into the evening. Adverse events were similar to previous trials.

Atomoxetine treatment in adults with attention-deficit/hyperactivity disorder and comorbid social anxiety disorder.

BACKGROUND: To evaluate the effect of atomoxetine (ATX) on attention-deficit/hyperactivity disorder (ADHD) and comorbid social anxiety disorder in adults. METHODS: Randomized, double-blind, placebo-controlled, conducted in adults with ADHD and social anxiety disorder. Patients received 40-100 mg ATX (n=224) or placebo (n=218) for 14 weeks following a 2-week placebo lead-in period. Efficacy measures included the Conners' Adult ADHD Rating Scale: Investigator-Rated: Screening Version (CAARS:Inv:SV), Liebowitz Social Anxiety Scale (LSAS), Clinical Global Impression-Overall-Severity (CGI-O-S), State-Trait Anxiety Inventory (STAI), Social Adjustment Scale-Self Report (SAS), and Adult ADHD Quality of Life Scale-29 (AAQoL). Safety and tolerability were also assessed. RESULTS: ATX mean change (-8.7+/-10.0) from baseline (29.6+/-10.4) on CAARS:Inv:SV Total ADHD Symptoms score was significantly greater than placebo mean change (-5.6+/-10.2) from baseline (31.2+/-9.4; P<.001). ATX mean change (-22.9+/-25.3) from baseline (85.3+/-23.6) on LSAS Total score was significant compared to placebo mean change (-14.4+/-20.3) from baseline (82.1+/-21.3; P<.001). The visit-wise analysis revealed greater improvement on the CAARS:Inv:SV Total ADHD Symptoms score and LSAS Total score for ATX at every time point throughout the study (P values

A randomized, controlled trial to assess the efficacy and safety of a transdermal delivery system of nicotine/mecamylamine in cigarette smokers.

AIMS: To determine the efficacy and safety of nicotine transdermal therapy co-administered with the nicotine antagonist, mecamylamine, compared to a nicotine transdermal patch alone (21 mg nicotine + 6 mg mecamylamine, 21 mg nicotine + 3 mg mecamylamine, and 21 mg nicotine + 0 mg mecamylamine). DESIGN: Multi-center (n = 4), double-blind, randomized, parallel group, repeat-dose study. SETTING: Clinical laboratory. PARTICIPANTS: A total of 540 subjects were enrolled into the study-135 from each of four sites; 180 patients in each of three treatment arms. INTERVENTION: Treatment was administered for the first 6 weeks of the 8-week study. Patients were instructed to continue smoking for the first 2 weeks of treatment. MEASUREMENTS: The primary efficacy parameter was 4-week continuous abstinence after the quit date, confirmed with an expired carbon monoxide of < 10 parts per million. FINDINGS: Analysis of the 4-week continuous abstinence for the intent-to-treat population showed overall rates of 29% (nicotine + 6 mg mecamylamine), 29% (nicotine + 3 mg mecamylamine) and 23% (nicotine only) using the slip definition which allows smoking in the first 2 weeks after the quit date. Statistical analyses revealed no significant treatment differences. Analyses using the strict definition (no smoking after the quit date) yielded similar non-significant group differences (29%, 27%, 26%). CONCLUSION: If adding mecamylamine to nicotine replacement therapy (NRT) improves the chances of success at stopping smoking, the results of this study suggest that the effect is very small.

The Life Participation Scale for Attention-Deficit/Hyperactivity Disorder--Child Version: psychometric properties of an adaptive change instrument.

INTRODUCTION: The Life Participation Scale for Attention-Deficit/Hyperactivity Disorder (ADHD)-Child Version (LPS-C) was developed to capture treatment-related improvements in adaptive functioning, including quality of life, social development, and emotion regulation, that may be missed by scales that assess only the 18 ADHD symptoms in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). The 24-item LPS-C is intended to augment traditional ADHD measures. This analysis assessed the scale's psychometric properties. METHODS: The LPS-C was completed by the investigators while questioning the parents of 979 children in three placebo-controlled clinical trials that measured the effects of atomoxetine for treating ADHD. In addition to a factor analysis, assessments of responsiveness; internal consistency; item-to-total correlations; and convergent, divergent, and discriminant validity were completed. RESULTS: The LPS-C showed evidence of internal consistency and convergent, divergent, and discriminant validity. The factor analysis suggested two subscales (labeled the Self-Control and Agreeable subscales). The LPS-C demonstrated responsiveness in two of the three trials. The effect sizes suggest responsiveness between that for psychosocial measures and core symptom measures. CONCLUSIONS: The LPS-C appears to be a valid research and clinical instrument for assessing change in ADHD-related adaptive functioning that may not be captured by traditional measures of core ADHD symptoms.

Effects of atomoxetine and methylphenidate on sleep in children with ADHD.

STUDY OBJECTIVES: This study compared the effects of atomoxetine and methylphenidate on the sleep of children with attention-deficit/hyperactivity disorder (ADHD). This study also compared the efficacy of these medications for treating ADHD in these children. DESIGN: Randomized, double-blind, crossover trial. SETTING: Two sleep disorders centers in the United States; 1 in a private-practice setting and 1 in a hospital setting. PATIENTS: 85 children diagnosed with ADHD. INTERVENTIONS: Twice-daily atomoxetine and thrice-daily methylphenidate, each for approximately 7 weeks. MEASUREMENTS AND RESULTS: Relative to baseline, the actigraphy data indicated that methylphenidate increased sleep-onset latency significantly more than did atomoxetine (39.2 vs 12.1 minutes, p < .001). These results were consistent with the polysomnography data. Child diaries indicated that it was easier to get up in the morning, it took less time to fall asleep, and the children slept better with atomoxetine, compared with methylphenidate. Parents reported that it was less difficult getting their children up and getting them ready in the morning and that the children were less irritable, had less difficulty getting ready for bed, and had less difficulty falling asleep with atomoxetine, compared with methylphenidate. There were no significant differences between medications using the main measures of efficacy for ADHD treatment. Atomoxetine was superior on some secondary ADHD treatment-efficacy measures, based on parent reports. The only significant differences in treatment-emergent adverse events were greater incidence of decreased appetite and greater incidence of insomnia with methylphenidate. CONCLUSIONS: Patients receiving twice-daily atomoxetine had shorter sleep-onset latencies, relative to thrice-daily methylphenidate, based on objective actigraphy and polysomnography data. Although both medications decreased nighttime awakenings, the decrease was greater for methylphenidate.

Placebo-controlled study of the effects of atomoxetine on bladder control in children with nocturnal enuresis.

INTRODUCTION: Nocturnal enuresis is a condition in which children at least 5 years of age are incontinent of urine at night. Atomoxetine, a potent inhibitor of the presynaptic norepinephrine transporter, is used to treat attention-deficit/hyperactivity disorder (ADHD). This study tested the hypothesis that atomoxetine will provide significant therapeutic benefit for nocturnal enuresis in patients with the diagnosis of nocturnal enuresis. METHODS: Atomoxetine's efficacy for improving nocturnal enuresis was studied in 87 pediatric subjects using an outpatient, multicenter, randomized, double-blind, parallel, placebo-controlled study. Efficacy was determined by measuring the mean number of dry nights per week using an intent-to-treat analysis of the primary outcome measure, the Dry Night Log-Parent Report (DNL-PR), a daily parent diary. RESULTS: Baseline and end point DNL-PR data were available from 42 atomoxetine-treated and 41 placebo-treated subjects. Atomoxetine increased the average number of dry nights per week by 1.47 compared with .60 for placebo (F = 7.06; df = (1, 75); p = 0.01). Fifteen atomoxetine-treated subjects (35.7%) had an increase of at least 2 dry nights per week compared with only 6 (14.6%) placebo-treated subjects (Fisher's exact test; p = 0.042). There were no significant differences in adverse events between the groups. CONCLUSIONS: Compared with placebo, atomoxetine treatment was associated with a significant increase in dry nights in children with nocturnal enuresis.

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.

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.

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.

Effects of buprenorphine sublingual tablet maintenance on opioid drug-seeking behavior by humans.

RATIONALE: Buprenorphine can decrease opioid self-administration by humans and animals, but its ability to decrease drug-seeking behavior and craving (i.e. motivational measures) among outpatient volunteers using clinically relevant dosing schedules has not been extensively studied. OBJECTIVES: We investigated whether daily versus alternating-day administration of high versus low buprenorphine doses influenced choice of, and operant responding for, hydromorphone versus money. METHODS: Fourteen heroin-dependent outpatients were maintained under four buprenorphine sublingual tablet (double blind) dose conditions using a within-subject, randomized crossover design. All participants received, for 2 weeks each, buprenorphine doses of 2 mg daily, 4 mg/placebo on alternating days, 16 mg daily, and 32 mg/placebo on alternating days. In each laboratory test session, participants chose between money ($2/choice) and drug (1/8 of total hydromorphone, 4 or 24 mg IM in different sessions) alternatives using an eight-trial non-independent progressive ratio schedule (FR 100, 200,.12,800). The drug dose and money amount earned was delivered after the end of the 2.5-h work period. RESULTS: Hydromorphone 24 mg was more reinforcing than 4 mg. Higher versus lower average buprenorphine doses (regardless of daily versus alternate-day schedule) significantly decreased hydromorphone 24 mg choice and increased money choice. Baseline heroin craving questionnaire scores predicted drug choice, and craving scores were significantly decreased by high-dose buprenorphine. CONCLUSIONS: High-dose buprenorphine attenuated opioid drug-seeking behavior, heroin craving self-reports and increased sensitivity to alternative reinforcement. These beneficial effects were retained when high-dose buprenorphine was administered on alternate days.

Pharmacologic Determinants of Tobacco Dependence.

Nicotine is one of the most widely abused psychoactive drugs and far more people trying it progress to regular use than those trying heroin, cocaine, or alcohol. Since the early 20th century, it has been understood that tobacco use is driven largely by nicotine's pharmacological actions. Nicotine produces reinforcing effects, tolerance and physical dependence, and pharmacological effects that smokers enjoy, such as modulation of mood, appetite, and task performance. Pharmacokinetic properties of tobacco-based nicotine products optimize abuse potential. Cigarette smoke inhalation delivers high nicotine concentrations to the brain and other organs within 10 s of inhalation. Nicotine's acute effects dissipate in a few minutes, encouraging the smoker to smoke frequently throughout the day to maintain its pleasurable effects and prevent withdrawal symptoms. Nicotine and other constituents of smoke also provide sensory stimuli which, through repeated pairings, become conditioned reinforcers and further strengthen tobacco self-administration, creating an extremely persistant behavior. Nicotine replacement medications provide relief of cigarette withdrawal symptoms and are effective aids in smoking cessation; however, sustaining long-term abstinence can still be very difficult.

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.