Abstract: Nine trials including a total of 692 individuals were included in the review. Five studies compared SSRIs to placebo and two studies were combined in a meta-analysis for the outcome of change in Cohen-Mansfield Agitation Inventory (CMAI) scores. There was a significant difference between antidepressants and placebo on measures of agitation as reported on the change in CMAI total score (mean difference (MD), -0.89, 95% CI, -1.22 to -0.57) although the results were heavily weighted by one large study. There were no significant differences in change in behavioral symptoms of dementia for SSRIs compared to placebo in the one study that reported on changes in the Neuropsychiatric Inventory and Behavioral Pathology in Dementia scales. One study comparing citalopram to placebo found a significant difference in NPS as measured on the Neurobehavioral Rating Scale (NBRS) after controlling for baseline severity NBRS score although the unadjusted mean difference was not statistically significant (MD - 7.70, 95% CI: -16.57 to 1.17). There was no difference in the rates of trial withdrawals due to adverse events for SSRIs compared to placebo for four studies reporting this outcome (relative risk (RR), 1.07, 95% CI: 0.55 to 2.11) or in the number of trial withdrawals due to any cause in the three studies reporting this outcome (RR, 0.91, 95% CI, 0.65 to 1.26). One study compared the SSRI citalopram to the atypical antipsychotic risperidone and found no difference in NBRS scores, trial withdrawals due to any cause or trial withdrawals due to adverse events although the rates of adverse events as measured on the UKU side effect scale total score were lower for citalopram (MD -2.82, 95% CI: -4.94 to -0.70). Three studies compared SSRIs to typical antipsychotics. In meta-analysis of two studies there was no statistically significant differences in changes in CMAI total scores (MD, 4.66, 95% CI: -3.58 to 12.90). There was also no difference in trial withdrawals due to any cause or due to adverse events for SSRIs compared to typical antipsychotics. One study of trazodone compared to placebo did not find any significant difference in change in CMAI total scores (MD, 5.18, 95% CI, -2.86 to 13.22) or trial withdrawals due to any cause (RR, 1.06, 95% CI, 0.54 to 2.09). Two studies comparing trazodone to haloperidol also failed to detect any difference in change in CMAI total scores (MD, 3.28, 95% CI, -3.28 to 9.85) or trial withdrawals due to any cause (RR, 0.79, 95% CI, 0.43 to 1.46). Currently there are relatively few studies of antidepressants for the treatment of agitation and psychosis in dementia. The SSRIs sertraline and citalopram were associated with a reduction in symptoms of agitation when compared to placebo in two studies. Both SSRIs and trazodone appear to be tolerated reasonably well when compared to placebo, typical antipsychotics and atypical antipsychotics. Future studies involving more subjects are required to determine if SSRIs, trazodone, or other antidepressants are safe and effective treatments for agitation and psychosis in dementia.

Plain-language summary: We reviewed the evidence for the effectiveness and safety of antidepressants for the treatment of agitation and psychosis in older adults with dementia. We classified antidepressants based on their mechanism of action and included studies that compared antidepressants to treatment with either placebo or other medications frequently used to manage these symptoms. A total of nine studies (including 692 individuals) were identified, four comparing selective serotonin reuptake inhibitors (SSRIs) to placebo, three comparing SSRIs to typical antipsychotics, and one study comparing SSRIs to atypical antipsychotics. One study compared the antidepressant trazodone to placebo, and two compared trazodone to haloperidol. Most of the studies included in the review were relatively small and of uncertain risk of bias due to methodological issues. The SSRIs sertraline and citalopram were associated with a modest reduction in symptoms of agitation and psychosis when compared to placebo in two studies. There were few other statistically significant differences in changes in agitation or psychosis or in most measures of medication tolerability for SSRIs or trazodone when compared to placebo or the antipsychotic haloperidol. We conclude that there is some evidence to support the use of certain antidepressants for agitation and psychosis in dementia and further studies are required to determine the effectiveness and safety of SSRIs and trazodone in managing these symptoms.