Lea T. Drye

Effect of Citalopram on Agitation in Alzheimer Disease: The CitAD Randomized Clinical Trial

IMPORTANCE Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory. OBJECTIVE The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability. DESIGN, SETTING, AND PARTICIPANTS The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013. INTERVENTIONS Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability. MAIN OUTCOMES AND MEASURES Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events. RESULTS Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was -0.93 (95% CI, -1.80 to -0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (-1.05 points; 95% CI, -1.97 to -0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group. CONCLUSIONS AND RELEVANCE Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00898807.

Sertraline for the treatment of depression in Alzheimer disease: week-24 outcomes.

BACKGROUND Depression and antidepressant use are common in Alzheimer disease (AD), but the effect of antidepressant treatment for depression on longer term outcomes is unknown. The authors report the Week-24 outcomes of patients who participated in a 12-week efficacy study of sertraline for depression of AD. METHODS One hundred thirty-one participants (sertraline = 67, placebo = 64) with mild-moderate AD and depression participated in the study. Patients who showed improvement on the modified Alzheimers Disease Cooperative Study Clinical Global Impression-Change (mADCS-CGIC) after 12 weeks of randomized treatment with sertraline or placebo continued double-blinded treatment for an additional 12 weeks. Depression response and remission at 24 weeks were based on mADCS-CGIC score and change in Cornell Scale for Depression in Dementia (CSDD) score. Secondary outcome measures included time to remission, nonmood neuropsychiatric symptoms, global cognition, function, and quality of life. RESULTS One hundred seventeen (89.3%) participants completed all study assessments and 74 (56.5%; sertraline = 38, placebo = 36) completed all 24 weeks on randomized treatment. By 24 weeks, there were no between-group differences in depression response (sertraline = 44.8%, placebo = 35.9%; odds ratio [95% CI] = 1.23 [0.64-2.35]), change in CSDD score (median difference = 0.6 [95% CI: -2.26 to 3.46], chi2 [df = 2] = 1.03), remission rates (sertraline = 32.8%, placebo = 21.8%; odds ratio [95% CI] = 1.61 [0.70-3.68]), or secondary outcomes. Common selective serotonin reuptake inhibitor-associated adverse events, specifically diarrhea, dizziness, and dry mouth, and pulmonary serious adverse events were more frequent in sertraline-randomized patients than in placebo subjects. CONCLUSIONS Sertraline treatment is not associated with delayed improvement between 12 and 24 weeks of treatment and may not be indicated for the treatment of depression of AD.

Associations among Visual Acuity and Vision- and Health-Related Quality of Life among Patients in the Multicenter Uveitis Steroid Treatment Trial

PURPOSE To evaluate the associations between visual acuity and self-reported visual function; visual acuity and health-related quality of life (QoL) metrics; a summary measure of self-reported visual function and health-related QoL; and individual domains of self-reported visual function and health-related QoL in patients with uveitis. METHODS Best-corrected visual acuity, vision-related functioning as assessed by the NEI VFQ-25, and health-related QoL as assessed by the SF-36 and EuroQoL EQ-5D questionnaires were obtained at enrollment in a clinical trial of uveitis treatments. Multivariate regression and Spearman correlations were used to evaluate associations between visual acuity, vision-related function, and health-related QoL. RESULTS Among the 255 patients, median visual acuity in the better-seeing eyes was 20/25, the vision-related function score indicated impairment (median, 60), and health-related QoL scores were within the normal population range. Better visual acuity was predictive of higher visual function scores (P ≤ 0.001), a higher SF-36 physical component score, and a higher EQ-5D health utility score (P < 0.001). The vision-specific function score was predictive of all general health-related QoL (P < 0.001). The correlations between visual function score and general quality of life measures were moderate (ρ = 0.29-0.52). CONCLUSIONS The vision-related function score correlated positively with visual acuity and moderately positively with general QoL measures. Cost-utility analyses relying on changes in generic healthy utility measures will be more likely to detect changes when there are clinically meaningful changes in vision-related function, rather than when there are only changes in visual acuity. (ClinicalTrials.gov number, NCT00132691.).

Changes in QTc Interval in the Citalopram for Agitation in Alzheimer's Disease (CitAD) Randomized Trial

Background A Food and Drug Administration (FDA) safety communication in August 2011 warned that citalopram was associated with a dose dependent risk of QT prolongation and recommended dose restriction in patients over the age of 60 but did not provide data for this age group. Methods CitAD was a randomized, double-masked, placebo-controlled, multicenter clinical trial for agitation in Alzheimers disease (AD). Participants were assigned to citalopram (target dose of 30 mg/day) or placebo in a 1∶1 ratio. 186 people, 181 of whom were over the age of 60, having probable AD with clinically significant agitation were recruited from September 2009 to January 2013. After the FDA safety communication about citalopram, ECG was added to the required study procedures before enrollment and repeated at week 3 to monitor change in QTc interval. Forty-eight participants were enrolled after enhanced monitoring began. Results Citalopram treatment was associated with a larger increase in QTc interval than placebo (difference in week 3 QTc adjusting for baseline QTc: 18.1 ms [95% CI: 6.1, 30.1]; p = 0.004). More participants in the citalopram group had an increase ≥30 ms from baseline to week 3 (7 in citalopram versus 1 in placebo; Fishers exact p = 0.046), but only slightly more in the citalopram group met a gender-specific threshold for prolonged QTc (450 ms for males; 470 ms for females) at any point during follow-up (3 in citalopram versus 1 in placebo, Fishers exact p = 0.611). One of the citalopram participants who developed prolonged QTc also displayed ventricular bigeminy. No participants in either group had a cardiovascular-related death. Conclusion Citalopram at 30 mg/day was associated with improvement in agitation in patients with AD but was also associated with QT prolongation. Trial Registration ClinicalTrials.gov NCT00898807

Celecoxib or Naproxen Treatment Does Not Benefit Depressive Symptoms in Persons Age 70 and Older: Findings From a Randomized Controlled Trial

BACKGROUND Several lines of evidence suggest that inflammatory mechanisms may be involved in the severity and progression of depression. One pathway implicated is the production of prostaglandins via the enzyme cyclooxygenase (COX). Although late-life depression in particular has been associated with inflammation, we know of no published studies using COX inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), in the treatment of depressive syndromes in this population. OBJECTIVE To evaluate the effect of the NSAIDs celecoxib and naproxen on depressive symptoms in older adults. METHODS The Alzheimers Disease Anti-inflammatory Prevention Trial was a randomized, placebo-controlled, double-masked clinical trial conducted at six U.S. memory clinics. Cognitively normal volunteers age 70 and older with a family history of Alzheimer-like dementia were randomly assigned to receive celecoxib 200 mg twice daily, naproxen sodium 220 mg twice daily, or placebo. The 30-item version of the Geriatric Depression Scale (GDS) was administered to all participants at enrollment and at yearly follow-up visits. Participants with a GDS score greater than 5 at baseline were classified as depressed. RESULTS Of 2,528 participants enrolled, 2,312 returned for at least one follow-up visit. Approximately one-fifth had significant depressive symptoms at baseline. Mean GDS score, and the percentage with significant depressive symptoms, remained similar over time across all three treatment groups. Furthermore, there was no treatment effect on GDS scores over time in the subgroup of participants with significant depressive symptoms at baseline. In longitudinal analysis using generalized estimating equations (GEE) regression, higher baseline GDS scores, a prior psychiatric history, older age, time in the study, and lower cognition interacting with time, but not treatment assignment, were associated with significantly higher GDS scores over time. CONCLUSION Treatment with celecoxib or naproxen did not improve depressive symptoms over time compared with placebo. While inflammation has been implicated in late-life depression, these results do not support the hypothesis that inhibition of the COX pathway with these NSAIDs at these doses alleviates depressive symptoms in older adults.

Cognitive outcomes after sertaline treatment in patients with depression of Alzheimer disease

OBJECTIVES Although many depressed patients with Alzheimer disease (AD) are treated with antidepressants, the effect of such treatment on cognitive performance in these patients is not known. The authors report cognitive outcomes in patients with depression of AD (dAD) after a 24-week trial of sertraline or placebo. DESIGN Placebo-controlled, randomized, double-blind trial. SETTING Outpatient memory clinics at five academic medical centers in the United States. PARTICIPANTS A total of 131 patients with dAD (60 men) and Mini-Mental State Examination scores of 10-26. INTERVENTION Sertraline (n = 67), target dose of 100 mg daily or matching placebo (n = 64). Caregivers received standardized psychosocial intervention throughout the trial. MEASUREMENTS Mini-Mental State Examination, cognitive subscale of the Alzheimers Disease Assessment Scale, letter fluency, backward digit span, Symbol Digit Modalities Test, and Finger Tapping Test, administered at baseline, and 8, 16, and 24 weeks following baseline. RESULTS A series of linear models indicated no effect of treatment or of depression remission on cognitive test performance at 24 weeks. Regardless of treatment condition, very little change in cognitive test performance was noted in general. CONCLUSIONS Treatment with sertraline in patients with dAD is not associated with greater improvement in cognition at week 24 than treatment with placebo.

Citalopram for agitation in Alzheimer's disease: Design and methods

Agitation is one of the most common neuropsychiatric symptoms of Alzheimers disease (AD), and is associated with serious adverse consequences for patients and caregivers. Evidence‐supported treatment options for agitation are limited. The citalopram for agitation in Alzheimers disease (CitAD) study was designed to evaluate the potential of citalopram to ameliorate these symptoms.

Cost-effectiveness of fluocinolone acetonide implant versus systemic therapy for noninfectious intermediate, posterior, and panuveitis.

OBJECTIVE To evaluate the 3-year incremental cost-effectiveness of fluocinolone acetonide implant versus systemic therapy for the treatment of noninfectious intermediate, posterior, and panuveitis. DESIGN Randomized, controlled, clinical trial. PARTICIPANTS Patients with active or recently active intermediate, posterior, or panuveitis enrolled in the Multicenter Uveitis Steroid Treatment Trial. METHODS Data on cost and health utility during 3 years after randomization were evaluated at 6-month intervals. Analyses were stratified by disease laterality at randomization (31 unilateral vs 224 bilateral) because of the large upfront cost of the implant. MAIN OUTCOME MEASURES The primary outcome was the incremental cost-effectiveness ratio (ICER) over 3 years: the ratio of the difference in cost (in United States dollars) to the difference in quality-adjusted life-years (QALYs). Costs of medications, surgeries, hospitalizations, and regular procedures (e.g., laboratory monitoring for systemic therapy) were included. We computed QALYs as a weighted average of EQ-5D scores over 3 years of follow-up. RESULTS The ICER at 3 years was

Follow-up evaluation of cognitive function in the randomized Alzheimer's disease anti-inflammatory prevention trial and its follow-up study

297,800/QALY for bilateral disease, driven by the high cost of implant therapy (difference implant - systemic [Δ]:

Benefits of Systemic Anti-inflammatory Therapy versus Fluocinolone Acetonide Intraocular Implant for Intermediate Uveitis, Posterior Uveitis, and Panuveitis: Fifty-four-Month Results of the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study.

16,900; P < 0.001) and the modest gains in QALYs (Δ = 0.057; P = 0.22). The probability of the ICER being cost-effective at thresholds of