Investigating effects of trazodone use on longitudinal cognitive change,

 
   Lead Investigator:    Jeffrey Phillips
   Institution      :    Dept. of Neurology, University of Pennsylvania
   E-Mail           :    jefphi@mail.med.upenn.edu
   Proposal ID      :    897



   Proposal Description:
   Recent research in rodents (Halliday et al., 2017) suggests that trazodone,       which is commonly prescribed for treatment of anxiety and depression, may have    multiple therapeutic effects in neurodegenerative disease. Specifically,          Halliday and colleagues reported alleviation of memory symptoms, prolonged        survival, and slowing of neurodegeneration in mice treated with trazodone or      dibenzoylmethane. The proposed mechanism of these therapeutic effects involves    trazodone???s disruption of the unfolded protein response (UPR). The UPR is a     protective response in which accumulation of unfolded or misfolded proteins in    the endoplasmic reticulum (ER) triggers a cessation of protein synthesis an       overactive UPR characterizes a number of neurodegenerative diseases, including    Alzheimer???s disease (AD) and frontotemporal dementia (FTD). Trazodone           treatment may restore memory in mice by restarting protein transcription and      returning cells to a state approximating healthy function.                        Prior research has already reported a beneficial effect of trazodone therapy on   behavioral symptoms of frontotemporal dementia (Lebert et al., 2004) which is     attributed to its antidepressant effects on serotonergic signaling (Hu et al.,    2010). In contrast, the research of Halliday et al. (2017) suggests that          potential benefits of trazodone may generalize to any neurodegenerative           disease, including AD, that involves accumulation of misfolded proteins in the    ER and consequent activation of the UPR.                                          According a review of past or ongoing projects listed on the NACC website as      well as an independent literature search, a targeted assessment of                trazodone???s effects on longitudinal cognition, diagnostic change, and           mortality in human dementia patients would represent a novel research project.    In a 2013 study, Obermann et al.