title: Changes in Neuropsychiatric Inventory Associated with Semagacestat Treatment of Alzheimer's Disease.
abstract: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD).
  
  
  
  We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS).
  
  
  
  1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline.
  
  
  
  Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased.
  
  
  
  In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD.
authors: Department of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors: Paul B
authors: PB
authors: Rosenberg
authors: Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada.|Departments of Psychiatry and Pharmacology/Toxicology, University of Toronto, Toronto, ON, Canada.
authors: Krista L
authors: KL
authors: Lanctôt
authors: Division of Geriatric Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.|Department of Psychiatry, Division of Geriatric Psychiatry, University of Toronto, Toronto, ON, Canada.
authors: Nathan
authors: N
authors: Herrmann
authors: Roper St. Francis Clinical Biotechnology Research Institute, Charleston, SC, USA.|Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA.|Medical University of South Carolina, Charleston, SC, USA.|School of Internal Medicine, University of South Carolina, Columbia, SC, USA.
authors: Jacobo E
authors: JE
authors: Mintzer
authors: Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors: Anton P
authors: AP
authors: Porsteinsson
authors: Biostatistics Research Center, University of California, San Diego, La Jolla, CA, USA.
authors: Xiaoying
authors: X
authors: Sun
authors: Alzheimer's Therapeutic Research Institute (ATRI), Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
authors: Rema
authors: R
authors: Raman
mesh_terms: D000368:Aged; D000409:Alanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000523:psychology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D057565:Apathy / Q000187:drug effects; D001066:Appetite / Q000187:drug effects; D001381:Azepines / Q000009:adverse effects* / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects*; D003863:Depression / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D000073216:Mental Status and Dementia Tests; D009043:Motor Activity / Q000187:drug effects; D012720:Severity of Illness Index; D012890:Sleep / Q000187:drug effects
chemical_list: D001381:Azepines; D004791:Enzyme Inhibitors; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine
keywords: Alzheimer’s disease; amyloid; clinical trial; depression; neuropsychiatry