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P4‐208: DEPRESCRIBING ANTIPSYCHOTICS IN DEMENTIA: A FEASIBLE WAY TO TREAD? TIPS FROM THE PHARE STUDY
Author(s) -
Gareri Pietro,
Palleria Caterina,
De Fazio Pasquale,
De Sarro Giovambattista
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.07.029
Subject(s) - deprescribing , dementia , antipsychotic , medicine , adverse effect , psychiatry , polypharmacy , emergency medicine , schizophrenia (object oriented programming) , intensive care medicine , disease
profile. An ANAVEX 2-73 concentration-response relation was observed using exploratory endpoints MMSE (Mini-Mental State Examination) and ADCS-ADL (Alzheimer’s Disease Co-operative Study – Activities of Daily Living). Methods: The full exome (DNA) and transcriptome (RNA) of attainable AD patients were sequenced using Illumina HiSeq 2500 with an average sequencing depth of 70x, resulting in the analysis of 33,311 genes and 860 pathways, using non-linear rule based Formal Concept Analysis as implemented in KEM. Results: Systematic analysis identifies several genetic variants impacting the response including SIGMAR1(rs1800866), ANAVEX 2-73 putative target, and COMT(rs113895332/rs61143203), a gene involved in memory function. Excluding these variants from the study population, still leaving about 80% of the population, results in improved MMSE and ADCS-ADL scores (p<0.05, Cohen’s d effect size >0.5 and Specificity1⁄4100%). In addition, we observe that high RNA expression levels for SIGMAR1 are associated with improved outcome as measured by MMSE and ADCS-ADL. Including patients with milder disease stage (baseline MMSE 20) and the exclusion of AD patients carrying SIGMAR1 mutation results in a score improvement of 1.7 MMSE and 3.9 ADCS-ADL, respectively at week 57. The additional exclusion of the COMT mutation results in a score improvement of 2.0 MMSE and 4.9 ADCS-ADL, respectively for the same period. Both effects would be clinically meaningful. Conclusions: This is the first full genomic analysis of ANAVEX 2-73 in AD patients resulting in the identification of actionable genetic variants. Consistent results were found using both DNA and RNA and multiple endpoints and time points. The data provides support to further precision medicine clinical development of ANAVEX 2-73 utilizing genetic biomarkers leading to a pre-specified population, who demonstrated a confirmed response with ANAVEX 2-73. Further larger clinical studies in several indications are planned or underway. Detailed results will be presented at the conference.