Effects of Citalopram on Neuropsychiatric Symptoms in Alzheimer's Dementia: Evidence From the CitAD Study.

OBJECTIVE: Citalopram has been shown to improve agitation in patients with Alzheimer's disease. The authors evaluated whether other neuropsychiatric symptoms improve with citalopram treatment compared with placebo. METHOD: In this planned secondary analysis of the Citalopram for Agitation in Alzheimer's Disease study, the authors evaluated the effect of citalopram on the 12 neuropsychiatric symptom domains assessed by the Neuropsychiatric Inventory (NPI). They compared caregiver-reported NPI scores at week 9 in patients receiving citalopram (30 mg/day) or placebo with regard to both the presence or absence of individual neuropsychiatric symptoms and individual domain scores (reflecting severity) in participants who had symptoms at week 9. RESULTS: At week 9, participants treated with citalopram were significantly less likely to be reported as showing delusions (odds ratio=0.40), anxiety (odds ratio=0.43), and irritability/lability (odds ratio=0.38). A comparison of median scores of participants with symptoms present at week 9 showed significant differences favoring citalopram for hallucinations and favoring placebo for sleep/nighttime behavior disorders. CONCLUSIONS: While dosage constraints must be considered because of citalopram's adverse effect profile, this agent's overall therapeutic effects in patients with Alzheimer's disease and agitation, in addition to efficacy for agitation/aggression, included reductions in the frequency of irritability, anxiety, and delusions; among patients who had these symptoms at week 9, they included a reduction in the severity of hallucinations but an increase in the severity of sleep/nighttime behavior disorders.

Heterogeneity of Treatment Response to Citalopram for Patients With Alzheimer's Disease With Aggression or Agitation: The CitAD Randomized Clinical Trial.

OBJECTIVE: Pharmacological treatments for agitation and aggression in patients with Alzheimer's disease have shown limited efficacy. The authors assessed the heterogeneity of response to citalopram in the Citalopram for Agitation in Alzheimer Disease (CitAD) study to identify individuals who may be helped or harmed. METHOD: In this double-blind parallel-group multicenter trial of 186 patients with Alzheimer's disease and clinically significant agitation, participants were randomly assigned to receive citalopram or placebo for 9 weeks, with the dosage titrated to 30 mg/day over the first 3 weeks. Five planned potential predictors of treatment outcome were assessed, along with six additional predictors. The authors then used a two-stage multivariate method to select the most likely predictors; grouped participants into 10 subgroups by their index scores; and estimated the citalopram treatment effect for each. RESULTS: Five covariates were likely predictors, and treatment effect was heterogeneous across the subgroups. Patients for whom citalopram was more effective were more likely to be outpatients, have the least cognitive impairment, have moderate agitation, and be within the middle age range (76-82 years). Patients for whom placebo was more effective were more likely to be in long-term care, have more severe cognitive impairment, have more severe agitation, and be treated with lorazepam. CONCLUSIONS: Considering several covariates together allowed the identification of responders. Those with moderate agitation and with lower levels of cognitive impairment were more likely to benefit from citalopram, and those with more severe agitation and greater cognitive impairment were at greater risk for adverse responses. Considering the dosages used and the association of citalopram with cardiac QT prolongation, use of this agent to treat agitation may be limited to a subgroup of people with dementia.

Sedation mediates part of Citalopram's effect on agitation in Alzheimer's disease.

BACKGROUND: We found a benefit of citalopram for agitation in the Citalopram for Agitation in Alzheimer's Disease study (CitAD), and wondered if this was mediated by a sedative effect. CitAD was a randomized, placebo-controlled, double-blind, parallel group trial conducted at 8 academic centers in the United States and Canada from August 2009 to January 2013. One hundred sixty-two participants with probable Alzheimer's disease (AD) and clinically significant agitation were analyzed in this study. Participants received a psychosocial intervention and were randomized to receive either citalopram or placebo (approximately half assigned to each group). Participants were rated on the Neurobehavioral Rating Scale Agitation subscale and measures of sedation (i.e., fatigue and somnolence). METHODS: Using the MacArthur Foundation procedures for documenting a mediator effect, we performed a secondary analysis examining whether sedation mediates the effect of treatment on agitation outcome. RESULTS: We found a statistically significant mediating effect of sedation on agitation outcomes, but the magnitude of the effect was small, only explaining 11% of the variance in agitation, with a significant, but modest effect size of 0.16 (95% CI: 0.08 to 0.22). CONCLUSIONS: The benefit of citalopram was partly due to sedation but largely due to other mechanisms of action.

Change in agitation in Alzheimer's disease in the placebo arm of a nine-week controlled trial.

BACKGROUND: Placebo responses raise significant challenges for the design of clinical trials. We report changes in agitation outcomes in the placebo arm of a recent trial of citalopram for agitation in Alzheimer's disease (CitAD). METHODS: In the CitAD study, all participants and caregivers received a psychosocial intervention and 92 were assigned to placebo for nine weeks. Outcomes included Neurobehavioral Rating Scale agitation subscale (NBRS-A), modified AD Cooperative Study-Clinical Global Impression of Change (CGIC), Cohen-Mansfield Agitation Inventory (CMAI), the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (NPI A/A) and Total (NPI-Total) and ADLs. Continuous outcomes were analyzed with mixed-effects modeling and dichotomous outcomes with logistic regression. RESULTS: Agitation outcomes improved over nine weeks: NBRS-A mean (SD) decreased from 7.8 (3.0) at baseline to 5.4 (3.2), CMAI from 28.7 (6.7) to 26.7 (7.4), NPI A/A from 8.0 (2.4) to 4.9 (3.8), and NPI-Total from 37.3 (17.7) to 28.4 (22.1). The proportion of CGI-C agitation responders ranged from 21 to 29% and was significantly different from zero. MMSE improved from 14.4 (6.9) to 15.7 (7.2) and ADLs similarly improved. Most of the improvement was observed by three weeks and was sustained through nine weeks. The major predictor of improvement in each agitation measure was a higher baseline score in that measure. CONCLUSIONS: We observed significant placebo response which may be due to regression to the mean, response to a psychosocial intervention, natural course of symptoms, or nonspecific benefits of participation in a trial.

Delineating a Retesting Zone Using Receiver Operating Characteristic Analysis on Serial QuantiFERON Tuberculosis Test Results in US Healthcare Workers.

Objective. To find a statistically significant separation point for the QuantiFERON Gold In-Tube (QFT) interferon gamma release assay that could define an optimal "retesting zone" for use in serially tested low-risk populations who have test "reversions" from initially positive to subsequently negative results. Method. Using receiver operating characteristic analysis (ROC) to analyze retrospective data collected from 3 major hospitals, we searched for predictors of reversion until statistically significant separation points were revealed. A confirmatory regression analysis was performed on an additional sample. Results. In 575 initially positive US healthcare workers (HCWs), 300 (52.2%) had reversions, while 275 (47.8%) had two sequential positive tests. The most statistically significant (Kappa = 0.48, chi-square = 131.0, P < 0.001) separation point identified by the ROC for predicting reversion was the tuberculosis antigen minus-nil (TBag-nil) value at 1.11 International Units per milliliter (IU/mL). The second separation point was found at TBag-nil at 0.72 IU/mL (Kappa = 0.16, chi-square = 8.2, P < 0.01). The model was validated by the regression analysis of 287 HCWs. Conclusion. Reversion likelihood increases as the TBag-nil approaches the manufacturer's cut-point of 0.35 IU/mL. The most statistically significant separation point between those who test repeatedly positive and those who revert is 1.11 IU/mL. Clinicians should retest low-risk individuals with initial QFT results < 1.11 IU/mL.