Abstract
Background: In a recent report, 76 weeks treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimers disease (AD). Objective: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS). Methods: 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 Alzheimers Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measureswas 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. Results: 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. Conclusion: 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.
Original language | English (US) |
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Pages (from-to) | 373-381 |
Number of pages | 9 |
Journal | Journal of Alzheimer's Disease |
Volume | 54 |
Issue number | 1 |
DOIs | |
State | Published - Aug 23 2016 |
Keywords
- Alzheimer's disease
- Amyloid
- Clinical trial
- Depression
- Neuropsychiatry
ASJC Scopus subject areas
- General Neuroscience
- Clinical Psychology
- Geriatrics and Gerontology
- Psychiatry and Mental health