A Phase II Study Repurposing Atomoxetine for Neuroprotection in Mild Cognitive Impairment

The locus coeruleus (LC) is the initial site of Alzheimers disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. LC dysfunction contributes to Alzheimers pathobiology in experimental models, which can be rescued by increasing norepinephrine (NE) transmission. To test NE augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved NE transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimers disease. The design was a single-center, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment (MCI) and biomarker evidence of Alzheimers disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of NE and metabolites. Prespecified primary outcomes were CSF levels of IL1α and Thymus-Expressed Chemokine. Secondary/exploratory outcomes included clinical measures, CSF analyses of Aβ42, Tau, and pTau181, mass spectrometry proteomics, and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and FDG-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF NE levels. IL-1α and Thymus-Expressed Chemokine were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in Aβ42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism, and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK, and OPG proteins. Treatment was also associated with significantly increased BDNF and reduced triglycerides in plasma. Resting state fMRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. FDG-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus, and fusiform gyrus, with carry-over effects six months after treatment. In summary, atomoxetine treatment was safe, well tolerated, and achieved target engagement in prodromal Alzheimers disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism, and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimers disease progression.

Treatment of Children and Adolescents with Epilepsy with Atomoxetine

Objective The objective of this study was to assess the effectiveness and safety of atomoxetine in Korean children and adolescents with epilepsy.Methods We retrospectively reviewed the electronic medical records of 105 children and adolescents with epilepsy treated with atomoxetine. Effectiveness was measured with the Clinical Global Impressions-Severity (CGI-S) and/or Clinical Global Impressions-Improvement (CGI-I) scales at baseline, and after 4 and 12 weeks. We defined response to atomoxetine as a CGI-I score less than three at week 12. Safety was evaluated at each visit, based on clinical assessment by a child and adolescent psychiatrist and reports from participants or their caregivers.Results In total participants (n=105), 33 (31.4%) showed a response to treatment: a significant decrease in CGI-S scale score was observed over 12 weeks of atomoxetine treatment. The most common adverse event (AE) was decreased appetite (n=16, 15.2%), and life-threatening AEs were not observed. Seizure aggravation due to atomoxetine was observed in 7.6% (n=8) of total participants, and one of them discontinued atomoxetine.Conclusion Our results provide preliminary evidence of the effectiveness and safety of atomoxetine in children and adolescents with epilepsy.

Effect of Demographic Factors on Quality of Life in Children with ADHD under Atomoxetine Treatment: 1-Year Follow-up

Attention-deficit hyperactivity disorder (ADHD) is the most common psychiatric disorder in children and adolescents. Symptoms of ADHD and its treatment can impact an individual's quality of life (QoL). The present study aimed to evaluate the effect of atomoxetine treatment, demographic characteristics, and seasonal variation on QoL in children with a recent diagnosis of ADHD and their parents. The present study included a cohort of 200 children diagnosed with ADHD. In addition to the recruited children, one of their parents was included in the study. ADHD symptoms were assessed using Conners' Parent Rating Scale. QoL of the participants was assessed with the PedsQL, while parents' QoL was evaluated using the World Health Organization Quality of Life questionnaire (WHOQOL-Bref). There was significant improvement in pediatric and parental QoL after treatment with atomoxetine. Significant factors related to better QoL in the participants included spring season, above average Conner's score, male sex, and rural residence. However, after using multivariate regression analysis, only patients' sex and Conner's score were significant predictors of pediatric QoL at the end of treatment with atomoxetine. Medical treatment significantly improved QoL in children with ADHD and their parents. Level of improvement was affected by patients' sex and ADHD severity.