ABSTRACT
OBJECTIVE: The clozapine/N-desmethylclozapine (NDMC) ratio is proposed to be used as a predictor of cognitive performance in clozapine-treated patients, as its principal metabolite, NDMC, has an opposite action with clozapine on the cholinergic system. The aim of this study is to determine whether clozapine has influence on cognitive performance in accordance with changes in the clozapine/NDMC in patients with schizophrenia. METHODS: The data of fifteen patients with schizophrenia, who had initial and follow-up assessments after starting clozapine treatment, were retrospectively collected. The assessments included clinical scale, cognitive battery, and pharmacological data including plasma concentrations of clozapine and NDMC. The data were analyzed with Pearson correlation and stepwise multiple regression analyses. RESULTS: ΔAttention/vigilance, Δsocial cognition, and Δcomposite score had a significant correlation with Δclozapine/NDMC ratio, while ΔWorking memory had correlation with Δclozapine concentration and ΔNDMC concentration, and Δsocial cognition had association with Δclozapine concentration. Multiple regression analysis showed that Δattention/vigilance had negative association with Δclozapine/NDMC ratio, Δworking memory had negative relation with Δclozapine concentration, and that Δsocial cognition had negative association with Δclozapine concentration. CONCLUSION: This finding implicates that lowering the clozapine/NDMC ratio could enhance cognition in patients with schizophrenia treated with clozapine.
ABSTRACT
Alzheimer's disease (AD) is characterized by progressive memory loss accompanied by synaptic and neuronal degeneration. Although research has shown that substantial neurodegeneration occurs even during the early stages of AD, the detailed mechanisms of AD pathogenesis are largely unknown because of difficulties in diagnosis and limitations of the analytical methods. The 5XFAD mouse model harbors five early-onset familial AD (FAD) mutations and displays substantial amyloid plaques and neurodegeneration. Here, we use quantitative mass spectrometry to identify proteome-wide changes in the 5XFAD mouse hippocampus during the early stages of AD pathology. A subset of the results was validated with immunoblotting. We found that the 5XFAD mice display higher expression of ApoE, ApoJ (clusterin), and nicastrin, three important proteins in AD that are known to participate in amyloid-ß processing and clearance, as well as the neurological damage/glial marker protein GFAP and other proteins. A large subset of the proteins that were up- or downregulated in 5XFAD brains have been implicated in neurological disorders and cardiovascular disease, suggesting an association between cardiovascular disease and AD. Common upstream regulator analysis of upregulated proteins suggested that the XBP1, NRF2, and p53 transcriptional pathways were activated, as was IGF-1R signaling. Protein interactome analysis revealed an interconnected network of regulated proteins, with two major sub-networks centered on AßPP processing membrane complexes and mitochondrial proteins. Together with a recent study on the transcriptome of 5XFAD mice, our study allows a comprehensive understanding of the molecular events occurring in 5XFAD mice during the early stages of AD pathology.
