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ObjectiveTo examine the safety and efficacy of sertraline augmentation therapy in the treatment of behavioral manifestations of Alzheimer's disease (AD) in outpatients treated with donepezil. Methods and materialsPatients with probable or possible AD, and a Neuropsychiatric Inventory (NPI) total score >5 (with a severity score ≥2 in at least one domain), were treated with donepezil (5–10 mg) for 8 weeks, then randomly assigned to 12 weeks of double-blind augmentation therapy with either sertraline (50–200 mg) or placebo. Primary efficacy measures were the 12-item Neuropsychiatric Inventory (NPI) and the Clinical Global Impression Improvement (CGI-I) and Severity (CGI-S) scales. Results24 patients were treated with donepezil+sertraline and 120 patients with donepezil+placebo. There were no statistically significant differences at endpoint on any of the three primary efficacy measures. However, a linear mixed model analysis found modest but statistically significantly greater improvements in the CGI-I score on donepezil+sertraline. Moreover, in a sub-group of patients with moderate-to-severe behavioral and psychological symptoms of dementia, 60% of patients on sertraline vs 40% on placebo (p = 0.006) achieved a response (defined as ≥;50% reduction in a four-item NPI-behavioral subscale). One adverse event (diarrhea) was significantly (p < 0.05) more common in the donepezil+sertraline group compared to the donepezil+placebo group. ConclusionSertraline augmentation was well-tolerated in this sample of AD outpatients. In addition, post hoc analyses demonstrated a modest but statistically significant advantage of sertraline over placebo augmentation in mixed model analyses and a clinically and statistically significant advantage in a subgroup of patients with moderate-to-severe behavioral and psychological symptoms of dementia. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]