Paula T. Trzepacz

Neuropsychiatric symptoms in Alzheimer’s disease

Neuropsychiatric symptoms (NPS) are core features of Alzheimers disease and related dementias. Once thought to emerge primarily in people with late‐stage disease, these symptoms are currently known to manifest commonly in very early disease and in prodromal phases, such as mild cognitive impairment. Despite decades of research, reliable treatments for dementia‐associated NPS have not been found, and those that are in widespread use present notable risks for people using these medications. An Alzheimers Association Research Roundtable was convened in the spring of 2010 to review what is known about NPS in Alzheimers disease, to discuss classification and underlying neuropathogenesis and vulnerabilities, and to formulate recommendations for new approaches to tailored therapeutics.

Atomoxetine treatment of adults with ADHD and comorbid alcohol use disorders

OBJECTIVEnAdults with attention-deficit/hyperactivity disorder (ADHD) have higher rates of alcohol and drug use disorders than adults without ADHD. The study aim was to determine if atomoxetine was superior to placebo in improving ADHD and alcohol use in recently abstinent adults with ADHD and comorbid alcohol use disorder.nnnMETHODSnAdults with DSM-IV diagnoses of ADHD and alcohol abuse and/or dependence were abstinent from alcohol at least 4 days (maximum 30 days) before study randomization. Participants received atomoxetine (25-100mg daily) or placebo for 12 weeks. ADHD symptoms were assessed using ADHD Investigator Symptom Rating Scale (AISRS) total score. Time-to-relapse to heavy alcohol use was analyzed using a 2-sided log-rank test based on Kaplan-Meier estimates and cumulative heavy drinking events over time were evaluated post hoc with recurrent-event analysis.nnnRESULTSnSubjects received atomoxetine (n=72) or placebo (n=75) and 80 subjects completed the 12-week double-blind period (n=32 and 48, respectively). ADHD symptoms were significantly improved in the atomoxetine cohort compared to placebo (AISRS total score mean [S.D.], atomoxetine: -13.63 [11.35], P<.001; placebo: -8.31 [11.44], P<.001, difference: P=.007; effect size=0.48). No significant differences between treatment groups occurred in time-to-relapse of heavy drinking (P=.93). However, cumulative heavy drinking days were reduced 26% in atomoxetine-treated subjects versus placebo (event ratio=0.74, P=.023). There were no serious adverse events or specific drug-drug reactions related to current alcohol use.nnnCONCLUSIONSnThis 3-month, double-blind, placebo-controlled study of atomoxetine in adults with ADHD and comorbid alcohol use disorder demonstrates clinically significant ADHD improvement, and inconsistent effects on drinking behavior.

Meta-Analysis of Suicide-Related Behavior Events in Patients Treated With Atomoxetine

OBJECTIVEnThe present work examined suicide-related events in acute, double-blind, and placebo- or active comparator-controlled trials with atomoxetine.nnnMETHODnFourteen trials in pediatric patients were included. Potential events were identified in the adverse events database using a text-string search. Potential suicide-related events were categorized according to U.S. Food and Drug Administration-defined codes using blinded patient summaries. The meta-analyses used the Mantel-Haenszel incidence difference and Mantel-Haenszel risk ratio methods.nnnRESULTSnNo patient in atomoxetine attention-deficit/hyperactivity disorder (ADHD) trials committed suicide. The frequency of suicidal ideation was 0.37% (5/1357) in pediatric patients taking atomoxetine versus 0% (0/851) for the placebo group; Mantel-Haenszel incidence difference of 0.46 (95% confidence interval 0.09-0.83; p =.016) and Mantel-Haenszel risk ratio of 2.92 (95% confidence interval 0.63-13.57; p =.172). Frequencies of suicide-related events in pediatric patients with ADHD did not differ between methylphenidate and atomoxetine treatments (Mantel-Haenszel incidence difference of -0.12 (95% confidence interval -0.62 to 0.38; p =.649). The number needed to harm in pediatric patients for an additional suicide-related event is 227 compared to the number needed to treat of five to achieve remission of ADHD symptoms.nnnCONCLUSIONSnAlthough uncommon, suicidal ideation was significantly more frequent in pediatric ADHD patients treated with atomoxetine compared to those treated with placebo. Retrospective analysis has limitations in ascertaining intent.

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 Alzheimers dementia using data from the Alzheimers Disease Neuroimaging Initiative cohort. Numeric neuroimaging variables generated by the Alzheimers 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 Alzheimers 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.

Safety and Tolerability of Atomoxetine Over 3 to 4 Years in Children and Adolescents With ADHD

OBJECTIVEnTo assess the long-term safety and tolerability of atomoxetine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder treated for > or = 3 years.nnnMETHODnData from 13 double-blind, placebo-controlled trials and 3 open-label extension studies were pooled. Outcome measures were patient-reported treatment-emergent adverse events (AEs); discontinuations due to AEs, serious AEs, and changes in body weight, height, vital signs, electrocardiogram, and hepatic function tests.nnnRESULTSnIn total, 714 patients were treated with atomoxetine for > or = 3 years (mean follow-up 4.8 years [SD 1.1 years]), including a subset of 508 treated for > or = 4 years (mean follow-up 5.3 years [SD 0.8 years]). Most subjects were younger than 12 years at entry (73.8%), male (78.4%), and white (88.9%). The mean final daily dose of atomoxetine was 1.35 mg/kg (SD 0.37 mg/kg). No new or unexpected AEs were observed compared with acute-phase treatment. Less than 6% of patients exhibited aggressive/hostile behaviors, and less than 1.6% reported suicidal ideation/behavior. No clinically significant effects were seen on growth rate, vital signs, or electrocardiographic parameters, and < or = 2% of patients showed potentially clinically significant hepatic changes.nnnCONCLUSIONnAtomoxetine was safe and well tolerated for children and adolescents with > or = 3 and/or > or = 4 years of treatment.

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

RationaleTreatment 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.ObjectivesIn 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.MethodsResults from receptor binding, in vitro electrophysiology, in vivo microdialysis, preclinical behavioral, and human laboratory studies have been reviewed.ResultsAtomoxetine has no appreciable affinity for, or action at, central receptors through which drugs of abuse typically act, i.e., dopamine transporters, GABAA 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.ConclusionNeurochemical, 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 10xa0years.

Retrospective Safety Analysis of Atomoxetine in Adult ADHD Patients with or without Comorbid Alcohol Abuse and Dependence

This post hoc analysis compared the safety of atomoxetine treatment of ADHD in adults with or without comorbid alcohol abuse/dependence. Study completion rates in patients receiving atomoxetine were comparable between heavy drinkers (60.9%) and patients with no alcohol-use disorder (71.0%) but lower in nonheavy drinkers (35.7%); however, there was no significant difference in discontinuation rates due to adverse events or lack of efficacy among these groups. Alcohol-use disorder patients, especially heavy drinkers, generally experienced the greatest frequency of treatment-emergent adverse events in both the atomoxetine and placebo groups. Vital signs and measures of hepatic function were not significantly different among the 3 drinking status groups taking atomoxetine.

Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer's disease

BACKGROUNDnMibampator, an amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor potentiator, was evaluated for treatment of agitation and aggression (A/A) in Alzheimers disease (AD).nnnMETHODSnOutpatients (n = 132) with probable AD and A/A randomized to 12 weeks of double-blind treatment with 3-mg po mibampator or placebo were assessed using the 4-domain A/A subscale of the Neuropsychiatric Inventory (NPI-4-A/A) derived from the Neuropsychiatric Inventory. Secondary measures included the Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia, Frontal Systems Behavior Inventory (FrSBe), and Alzheimers Disease Assessment Scale-Cognitive. Efficacy was analyzed using mixed-effects model repeated measures from baseline to endpoint. Adverse events (AEs), labs, vital signs, and electrocardiograms were monitored.nnnRESULTSnBaseline characteristics were comparable between groups. Both groups improved on the NPI-4-A/A, but without group differences. Among secondaries, mibampator was significantly better (p = 0.007) than placebo only on the FrSBe. AEs were similar between groups. One death occurred in the placebo group.nnnCONCLUSIONnPossible explanations for no significant group differences include caregiver, drug target engagement, and design issues. This trial is registered on ClinicalTrials.gov; ID: NCT00843518.

Clinical use of amyloid-positron emission tomography neuroimaging: Practical and bioethical considerations

Until recently, estimation of β‐amyloid plaque density as a key element for identifying Alzheimers disease (AD) pathology as the cause of cognitive impairment was only possible at autopsy. Now with amyloid‐positron emission tomography (amyloid‐PET) neuroimaging, this AD hallmark can be detected antemortem. Practitioners and patients need to better understand potential diagnostic benefits and limitations of amyloid‐PET and the complex practical, ethical, and social implications surrounding this new technology. To complement the practical considerations, Eli Lilly and Company sponsored a Bioethics Advisory Board to discuss ethical issues that might arise from clinical use of amyloid‐PET neuroimaging with patients being evaluated for causes of cognitive decline. To best address the multifaceted issues associated with amyloid‐PET neuroimaging, we recommend this technology be used only by experienced imaging and treating physicians in appropriately selected patients and only in the context of a comprehensive clinical evaluation with adequate explanations before and after the scan.

Long-term safety and tolerability of atomoxetine in Japanese adults with attention deficit hyperactivity disorder.

The primary aim of this study was to evaluate the long‐term safety/tolerability of atomoxetine in Japanese adults with attention deficit hyperactivity disorder (ADHD).