Changes in Neuropsychiatric Inventory Associated with Semagacestat Treatment of Alzheimer’s Disease

Article type: Research Article

Authors: Rosenberg, Paul B.^{a; *} | Lanctôt, Krista L.^{b; c} | Herrmann, Nathan^{d; e} | Mintzer, Jacobo E.^{f; g; h; i} | Porsteinsson, Anton P.^j | Sun, Xiaoying^k | Raman, Rema^l

Affiliations: [a] Department of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA | [b] Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada | [c] Departments of Psychiatry and Pharmacology/Toxicology, University of Toronto, Toronto, ON, Canada | [d] Division of Geriatric Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada | [e] Department of Psychiatry, Division of Geriatric Psychiatry, University of Toronto, Toronto, ON, Canada | [f] Roper St. Francis Clinical Biotechnology Research Institute, Charleston, SC, USA | [g] Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA | [h] Medical University of South Carolina, Charleston, SC, USA | [i] School of Internal Medicine, University of South Carolina, Columbia, SC, USA | [j] Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA | [k] Biostatistics Research Center, University of California, San Diego, La Jolla, CA, USA | [l] Alzheimer’s Therapeutic Research Institute (ATRI), Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA

Correspondence: [*] Correspondence to: Paul B. Rosenberg, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, 5300 Alpha Commons Drive, 4th Floor, Baltimore, MD 21224, USA. Tel.: +1 410 550 9883; Fax: +1 410 550 1407; E-mail: [email protected].

Abstract: Background: In a recent report, 76 weeks’ treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer’s 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 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. 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.

Keywords: Alzheimer’s disease, amyloid, clinical trial, depression, neuropsychiatry

DOI: 10.3233/JAD-151113

Journal: Journal of Alzheimer's Disease, vol. 54, no. 1, pp. 373-381, 2016