The Effects of Four Doses of Vitamin D Supplements on Falls in Older Adults : A Response-Adaptive, Randomized Clinical Trial.

BACKGROUND: Vitamin D supplementation may prevent falls in older persons, but evidence is inconsistent, possibly because of dosage differences. OBJECTIVE: To compare the effects of 4 doses of vitamin D3 supplements on falls. DESIGN: 2-stage Bayesian, response-adaptive, randomized trial. (ClinicalTrials.gov: NCT02166333). SETTING: 2 community-based research units. PARTICIPANTS: 688 participants, aged 70 years and older, with elevated fall risk and a serum 25-hydroxyvitamin D [25-(OH)D] level of 25 to 72.5 nmol/L. INTERVENTION: 200 (control), 1000, 2000, or 4000 IU of vitamin D3 per day. During the dose-finding stage, participants were randomly assigned to 1 of the 4 vitamin D3 doses, and the best noncontrol dose for preventing falls was determined. After dose finding, participants previously assigned to receive noncontrol doses received the best dose, and new enrollees were randomly assigned to receive 200 IU/d or the best dose. MEASUREMENTS: Time to first fall or death over 2 years (primary outcome). RESULTS: During the dose-finding stage, the primary outcome rates were higher for the 2000- and 4000-IU/d doses than for the 1000-IU/d dose, which was selected as the best dose (posterior probability of being best, 0.90). In the confirmatory stage, event rates were not significantly different between participants with experience receiving the best dose (events and observation time limited to the period they were receiving 1000 IU/d; n = 308) and those randomly assigned to receive 200 IU/d (n = 339) (hazard ratio [HR], 0.94 [95% CI, 0.76 to 1.15]; P = 0.54). Analysis of falls with adverse outcomes suggested greater risk in the experience-with-best-dose group versus the 200-IU/d group (serious fall: HR, 1.87 [CI, 1.03 to 3.41]; fall with hospitalization: HR, 2.48 [CI, 1.13 to 5.46]). LIMITATIONS: The control group received 200 IU of vitamin D3 per day, not a placebo. Dose finding ended before the prespecified thresholds for dose suspension and dose selection were reached. CONCLUSION: In older persons with elevated fall risk and low serum 25-(OH)D levels, vitamin D3 supplementation at doses of 1000 IU/d or higher did not prevent falls compared with 200 IU/d. Several analyses raised safety concerns about vitamin D3 doses of 1000 IU/d or higher. PRIMARY FUNDING SOURCE: National Institute on Aging.

Registration of phase 3 crossover trials on ClinicalTrials.gov.

BACKGROUND: In a randomized crossover trial, each participant is randomized to a sequence of treatments and treatment effect is estimated based on within-individual difference because each participant serves as his/her own control. This feature makes the design and reporting of randomized crossover trials different from that of parallel trials. Our objective was to characterize phase 3 crossover trials with results reported on ClinicalTrials.gov and identify issues and best practices for reporting. METHODS: We searched ClinicalTrials.gov for phase 3 randomized crossover trials that provided results, registered at least one primary outcome, and included at least one link to a results publication in the record by August 6, 2019. Two reviewers independently assessed the eligibility and extracted information from each record into an electronic form developed and maintained in the Systematic Review Data Repository. RESULTS: Of the 124 crossover trials analyzed, two thirds were a simple "Intervention A then B" or "Intervention B then A" (AB|BA) design. Most trials (78%, 97/124) provided enough information to understand the participant flow throughout the trial. Baseline characteristics were most often reported for all participants as a single group (52%, 65/124). Primary outcomes and adverse events were most commonly reported "per intervention" (85%, 105/124, and 80%, 99/124, respectively). CONCLUSIONS: The registration and reporting of randomized crossover trials must account for the paired nature of the design. Our observations and recommendations informed the development of guidelines for good reporting practices in the registration and reporting of randomized crossover trials.

Escitalopram for agitation in Alzheimer's disease (S-CitAD): Methods and design of an investigator-initiated, randomized, controlled, multicenter clinical trial.

INTRODUCTION: Alzheimer's disease (AD) is a disabling, common cause of dementia, and agitation is one of the most common and distressing symptoms for patients with AD. Escitalopram for agitation in Alzheimer's disease (S-CitAD) tests a novel, clinically derived therapeutic approach to treat agitation in patients with AD. METHODS: S-CitAD is a NIH-funded, investigator-initiated, randomized, multicenter clinical trial. Participants receive a structured psychosocial intervention (PSI) as standard of care. Participants without sufficient response to PSI are randomized to receive 15 mg escitalopram/day or a matching placebo in addition to PSI. Primary outcome is the Modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (mADCS-CGIC). DISCUSSION: S-CitAD will provide information about a practical, immediately available approach to treating agitation in patients with AD. S-CitAD may become a model of how to evaluate and predict treatment response in patients with AD and agitation as a neuropsychiatric symptom (ClinicalTrials.gov Identifier: NCT03108846).

Sex Differences in the Neuropsychiatric Symptoms of Patients With Alzheimer's Disease.

The aim of this study was to describe sex differences in neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease (AD). Baseline scores on the Cohen-Mansfield Agitation Inventory, Neurobehavioral Rating Scale-Agitation subscale, and the Neuropsychiatric Inventory from patients with AD enrolled in a multicenter trial of citalopram for the treatment of agitation were analyzed. We found not only that patients with AD having agitation were likely to exhibit many other NPSs but also that the women in this study were more likely to exhibit a broader range of NPS than were the men. These results suggest greater heterogeneity in the clinical presentation of women compared to men, and thus in the potential targets for treatment in these patients. Further characterization of sex differences in NPS can inform future efforts aimed at establishing subtypes of patients for whom various treatment approaches will be most appropriate.

Effects of deep brain stimulation on rest tremor progression in early stage Parkinson disease.

OBJECTIVE: To evaluate whether the progression of individual motor features was influenced by early deep brain stimulation (DBS), a post hoc analysis of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) score (after a 7-day washout) was conducted from the 2-year DBS in early Parkinson disease (PD) pilot trial dataset. METHODS: The prospective pilot trial enrolled patients with PD aged 50-75 years, treated with PD medications for 6 months-4 years, and no history of dyskinesia or other motor fluctuations, who were randomized to receive optimal drug therapy (ODT) or DBS plus ODT (DBS + ODT). At baseline and 6, 12, 18, and 24 months, all patients stopped all PD therapy for 1 week (medication and stimulation, if applicable). UPDRS-III "off" item scores were compared between the ODT and DBS + ODT groups (n = 28); items with significant between-group differences were analyzed further. RESULTS: UPDRS-III "off" rest tremor score change from baseline to 24 months was worse in patients receiving ODT vs DBS + ODT (p = 0.002). Rest tremor slopes from baseline to 24 months favored DBS + ODT both "off" and "on" therapy (p < 0.001, p = 0.003, respectively). More ODT patients developed new rest tremor in previously unaffected limbs than those receiving DBS + ODT (p = 0.001). CONCLUSIONS: These results suggest the possibility that DBS in early PD may slow rest tremor progression. Future investigation in a larger cohort is needed, and these findings will be tested in the Food and Drug Administration-approved, phase III, pivotal, multicenter clinical trial evaluating DBS in early PD. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with early PD, DBS may slow the progression of rest tremor.

The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): study protocol for a randomized controlled trial.

BACKGROUND: Alzheimer's disease (AD) is characterized not only by cognitive and functional decline, but also often by the presence of neuropsychiatric symptoms. Apathy, which can be defined as a lack of motivation, is one of the most prevalent neuropsychiatric symptoms in AD and typically leads to a worse quality of life and greater burden for caregivers. Treatment options for apathy in AD are limited, but studies have examined the use of the amphetamine, methylphenidate. The Apathy in Dementia Methylphenidate Trial (ADMET) found that treatment of apathy in AD with methylphenidate was associated with significant improvement in apathy in two of three outcome measures, some evidence of improvement in global cognition, and minimal adverse events. However, the trial only enrolled 60 participants who were followed for only 6 weeks. A larger, longer-lasting trial is required to confirm these promising findings. METHODS: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) is a phase III, placebo-controlled, masked, 6-month, multi-center, randomized clinical trial targeted to enroll 200 participants with AD and apathy. Participants are randomly assigned 1:1 to 20 mg methylphenidate per day prepared as four over-encapsulated tablets or to matching placebo. The primary outcomes include (1) the mean difference in the Neuropsychiatric Inventory Apathy subscale scores measured as change from baseline to 6 months, and (2) the odds of having a given rating or better on the modified AD Cooperative Study Clinical Global Impression of Change ratings at month 6 compared with the baseline rating. Other outcomes include change in cognition, safety, and cost-effectiveness measured at monthly follow-up visits up to 6 months. DISCUSSION: Given the prevalence of apathy in AD and its impact on both patients and caregivers, an intervention to alleviate apathy would be of great benefit to society. ADMET 2 follows on the promising results from the original ADMET to evaluate the efficacy of methylphenidate as a treatment for apathy in AD. With a larger sample size and longer follow up, ADMET 2 is poised to confirm or refute the original ADMET findings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02346201 . Registered on 26 January 2015.

Characterizing Highly Benefited Patients in Randomized Clinical Trials.

Physicians and patients may choose a certain treatment only if it is predicted to have a large effect for the profile of that patient. We consider randomized controlled trials in which the clinical goal is to identify as many patients as possible that can highly benefit from the treatment. This is challenging with large numbers of covariate profiles, first, because the theoretical, exact method is not feasible, and, second, because usual model-based methods typically give incorrect results. Better, more recent methods use a two-stage approach, where a first stage estimates a working model to produce a scalar predictor of the treatment effect for each covariate profile; and a second stage estimates empirically a high-benefit group based on the first-stage predictor. The problem with these methods is that each of the two stages is usually agnostic about the role of the other one in addressing the clinical goal. We propose a method that characterizes highly benefited patients by linking model estimation directly to the particular clinical goal. It is shown that the new method has the following two key properties in comparison with existing approaches: first, the meaning of the solution with regard to the clinical goal is the same, and second, the value of the solution is the best that can be achieved when using the working model as a predictor, even if that model is incorrect. In the Citalopram for Agitation in Alzheimer's Disease (CitAD) randomized controlled trial, the new method identifies substantially larger groups of highly benefited patients, many of whom are missed by the standard method.

Effect of Continuous Positive Airway Pressure on Airway Reactivity in Asthma. A Randomized, Sham-controlled Clinical Trial.

RATIONALE: Studies have demonstrated that application of stress suppresses airway smooth muscle contractility. In animal models of asthma, continuous positive airway pressure (CPAP) reduced airway reactivity. Short-term studies of CPAP in patients with asthma showed reductions in airway reactivity. OBJECTIVES: To evaluate whether nocturnal CPAP decreased the provocative concentration of methacholine to reduce FEV1 by 20% (PC20). METHODS: One hundred ninety-four individuals with asthma were randomized (1:1:1) to use CPAP with warmed, filtered, humidified air at night at pressures either less than 1 cm H2O (sham) or at 5 cm H2O or 10 cm H2O. The primary outcome was change in PC20 after 12 weeks. MEASUREMENTS AND MAIN RESULTS: Adherence to CPAP was low in all groups. Regardless, all groups had a significant improvement in PC20, with 12 weeks/baseline PC20 ratios of 2.12, 1.73, and 1.78 for the sham, 5 cm H2O, and 10 cm H2O groups, respectively, and no significant differences between the active and sham groups. Changes in FEV1 and exhaled nitric oxide were minimal in all groups. The sham group had larger improvements in most patient-reported outcomes measuring asthma symptoms and quality of life, as well as sinus symptoms, than the 5 cm H2O group. The 10 cm H2O group showed similar but less consistent improvements in scores, which were not different from improvements in the sham group. CONCLUSIONS: Adherence to nocturnal CPAP was low. There was no evidence to support positive pressure as being effective for reducing airway reactivity in people with well-controlled asthma. Regardless, airway reactivity was improved in all groups, which may represent an effect of participating in a study and/or an effect of warm, humid, filtered air on airway reactivity. Clinical trial registered with www.clinicaltrials.gov (NCT01629823).

R- and S-citalopram concentrations have differential effects on neuropsychiatric scores in elders with dementia and agitation.

AIMS: The aim was to determine the relationship between (R) and (S)-citalopram enantiomer exposure (AUC(0,24 h)) and therapeutic response in agitated individuals greater than 60 years old with Alzheimer's dementia (AD). METHODS: Citalopram enantiomer exposures (AUC(0,24 h)) derived from an established population pharmacokinetic analysis were utilized to explore the relationship between (R)- and (S)-citalopram area under the curve (AUC(0,24 )) and Mini-Mental State Examination (MMSE), Neurobehavioural Rating Scale-Agitation Subscale (NBRS-A), modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) and Neuropsychiatric Inventory Agitation subscale (NPIA) scores. Time dependent changes in these scores (disease progression) were accounted for prior to exploring the exposure effect relationship for each enantiomer. These relationships were evaluated using a non-linear-mixed effects modelling approach as implemented in nonmem v7.3. RESULTS: (S)-AUC(0,24 h) and (R)-AUC(0,24 h) each contributed to improvement in NBRS-A scores (k3(R) -0.502; k4(S) -0.712) as did time in treatment. However, increasing (R)-AUC(0,24 h) decreased the probability of patient response (maximum Δ -0.182%/AUC(0,24 h)) based on the CGIC while (S)-AUC(0,24 h) improved the probability of response (maximum Δ 0.112%/AUC(0,24 h)). (R)-AUC(0,24 h) was also associated with worsening in MMSE scores (-0.5 points). CONCLUSIONS: Our results suggest that citalopram enantiomers contributed differentially to treatment outcomes. (R)-citalopram accounted for a greater proportion of the adverse consequences associated with racemic citalopram treatment in patients with AD including a decreased probability of treatment response as measured by the CGIC and a reduction in MMSE scores. The S-enantiomer was associated with increased probability of response based on the CGIC.

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.

Principal components analysis of agitation outcomes in Alzheimer's disease.

BACKGROUND: We developed a composite measure of agitation as a secondary outcome of change over time in the Citalopram for Agitation in Alzheimer's disease study (CitAD). CitAD demonstrated a positive effect of citalopram on agitation on the Neurobehavioral Rating Scale agitation subscale (NBRS-A). CitAD included additional agitation measures such as the Cohen-Mansfield Agitation Inventory and the Neuropsychiatric Inventory. METHODS: We performed principal components analyses on change in individual item of these scales for the same, original CitAD subjects. RESULTS: The first principal component accounted for 12.6% of the observed variance and was composed of items that appear to reflect agitation. The effect size for citalopram calculated using this component was 0.53 (95% CI 0.22-0.83) versus 0.32 for the NBRS-A (95% CI 0.01-0.62). CONCLUSIONS: Results suggest that a composite measure of change in agitation might be more sensitive than change in a single primary agitation measure.

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.

Citalopram for the Treatment of Agitation in Alzheimer Dementia: Genetic Influences.

OBJECTIVE: To assess potential genetic influences on citalopram treatment efficacy for agitation in individuals with Alzheimer dementia (AD). Six functional genetic variants were studied in the following genes: serotonin receptor 2A (HTR2A-T102C), serotonin receptor 2C (HTR2C-Cys23Ser), serotonin transporter (5HTT-LPR), brain-derived neurotropic factor (BDNF-Val66Met), apolipoprotein E (ε2, ε3, ε4 variants), and cytochrome P450 (CYP2C19). Treatment response by genotype was measured by (1) the agitation domain of the Neurobehavioral Rating Scale, (2) the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change scale (mADCS-CGIC), (3) the agitation domain of the Neuropsychiatric Inventory (NPI), and (4) the Cohen-Mansfield Agitation Inventory. METHOD: We utilized data from the Citalopram for Agitation in Alzheimer's Disease (CitAD) database. CitAD was a 9-week randomized, double-blind, placebo-controlled multicenter clinical trial showing significant improvement in agitation and caregiver distress in patients treated with citalopram. Proportional odds logistic regression and mixed effects models were used to examine the above-mentioned outcome measures. RESULTS: Significant interactions were noted on the NPI agitation domain for HTR2A (likelihood ratio [LR] = 6.19, df = 2, P = .04) and the mADCS-CGIC for HTR2C (LR = 4.33, df = 2, P = .02) over 9 weeks. DISCUSSION: Treatment outcomes in CitAD showed modest, although statistically significant, influence of genetic variation at HTR2A and HTR2C loci. Future studies should continue to examine the interaction of known genetic variants with antidepressant treatment in patients with AD having agitation.

Outcome of Treatment of Uveitic Macular Edema: The Multicenter Uveitis Steroid Treatment Trial 2-Year Results.

PURPOSE: To evaluate the 2-year outcomes of uveitic macular edema. DESIGN: Longitudinal follow-up of a randomized cohort. PARTICIPANTS: At baseline, 148 eyes of 117 patients enrolled in the Multicenter Uveitis Steroid Treatment (MUST) Trial had macular edema, and 134 eyes of 108 patients completed 2-year follow-up. METHODS: Patients enrolled in the study were randomized to either systemic immunosuppression or intravitreal fluocinolone acetonide implant therapy. Macular edema was defined as thickening of the retina (center point thickness≥240 µm) on time-domain optical coherence tomography (OCT) of macula. MAIN OUTCOME MEASURES: Improvement in macular edema (≥20% reduction in central point thickness on OCT), resolution of macular edema (normalization of thickness on OCT), and best-corrected visual acuity (BCVA). RESULTS: Between randomization and 2-years' follow-up, 62% and 25% of eyes in the systemic and implant groups, respectively, received at least 1 supplemental regional corticosteroid injection. By 2-years' follow-up, macular edema improved in 71% of eyes and resolved in 60%. There were no differences between treatment groups in the proportion of eyes with macular edema improving (systemic therapy vs. implant, 65% vs. 77%; P=0.20) and resolving (52% vs. 68%; P=0.28), but eyes randomized to implant had more improvement in macular thickness (median decrease of 180 vs. 109 µm in the systemic therapy group; P=0.04). Eyes with baseline fluorescein angiographic leakage were more likely to improve than those without (76% vs. 58%; P=0.03). Overall, there was a mean 5-letter (1 line) improvement in BCVA at 2 years. Mean changes in BCVA from baseline at 2 years by macular edema response status were: resolution, +10 letters; improvement without resolution, +10 letters (P=0.92); little to no change, 6 letters (P=0.19); and worsening, -16 letters (worsening acuity; P=0.0003). CONCLUSIONS: About two thirds of eyes with uveitic macular edema were observed to experience improvement in the edema and visual acuity with implant or systemic treatment. Fluocinolone acetonide implant therapy was associated with a greater quantitative improvement in thickness. Fluorescein angiography leakage was associated with a greater likelihood of improvement in macular edema.

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.

Deep brain stimulation may reduce the relative risk of clinically important worsening in early stage Parkinson's disease.

BACKGROUND: The Vanderbilt pilot trial of deep brain stimulation (DBS) in early Parkinson's disease (PD) enrolled patients on medications six months to four years without motor fluctuations or dyskinesias. We conducted a patient-centered analysis based on clinically important worsening of motor symptoms and complications of medical therapy for all subjects and a subset of subjects with a more focused medication duration. Continuous outcomes were also analyzed for this focused cohort. METHODS: A post hoc analysis was conducted on all subjects from the pilot and a subset of subjects taking PD medications 1-4 years at enrollment. Clinically important worsening is defined as both a ≥ 3 point increase in UPDRS Part III and a ≥ 1 point increase in Part IV. RESULTS: DBS plus optimal drug therapy (DBS + ODT) subjects experienced a 50-80% reduction in the relative risk of worsening after two years. The DBS + ODT group was improved compared to optimal drug therapy (ODT) at each time point on Total UPDRS and Part III (p = 0.04, p = 0.02, respectively, at 24 months). Total UPDRS, Part IV, and PDQ-39 scores significantly worsened in the ODT group after two years (p < 0.003), with no significant change in the DBS + ODT group. CONCLUSIONS: DBS + ODT in early PD may reduce the risk of clinically important worsening. These findings further confirm the need to determine if DBS + ODT is superior to medical therapy for managing symptoms, reducing the complications of medications, and improving quality of life. The FDA has approved the conduct of a large-scale, pivotal clinical trial of DBS in early stage PD.

Time to Response to Citalopram Treatment for Agitation in Alzheimer Disease.

OBJECTIVE: Agitation is a common and significant problem in Alzheimer disease (AD). In the recent Citalopram for Agitation in Alzheimer's Disease (CitAD) study, citalopram was efficacious for the treatment of AD agitation. Here we examined the time course and predictors of response to treatment. METHODS: Response in CitAD was defined as a modified Alzheimer Disease Cooperative Study Clinical Global Impression of Change (CGIC) score of 1 or 2 or a Neurobehavioral Rating Scale agitation subscale (NBRS-A) score reduction ≥ 50% from baseline. "Stable early response" was defined as meeting the aforementioned criteria at both weeks 3 and 9, "late response" was response at week 9 but not at week 3, and "unstable response" was response at week 3 but not at week 9. RESULTS: In the primary analyses, citalopram was superior to placebo on both the CGIC and the NBRS-A response measures. Little between-group differences were found in response rates in the first 3 weeks of the study (21% versus 19% on the CGIC). Citalopram patients were more likely than placebo patients to be a late responder (18% versus 8% on CGIC, Fisher's exact p = 0.09; 31% versus 15% on NBRS-A, Fisher's exact p = 0.02). Approximately half of citalopram responders (45%-56%) at end of study achieved response later in the study compared with 30%-44% of placebo responders. CONCLUSION: Treatment with citalopram for agitation in AD needs to be at least 9 weeks in duration to allow sufficient time for full response. Study duration is an important factor to consider in the design of clinical trials for agitation in AD.

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.

PURPOSE: To compare the benefits of fluocinolone acetonide implant therapy versus systemic corticosteroid therapy supplemented (when indicated) with immunosuppression for intermediate uveitis, posterior uveitis, and panuveitis. DESIGN: Additional follow-up of a randomized comparative effectiveness trial cohort. PARTICIPANTS: Two hundred fifty-five patients with intermediate uveitis, posterior uveitis, or panuveitis randomized to implant or systemic therapy. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), visual field mean deviation (MD), activity of uveitis, and presence of macular edema (per reading center grading) ascertained prospectively. METHODS: Trial participants were followed-up for 54 months from original randomization. RESULTS: The visual function trajectory in uveitic eyes demonstrated a similar (P = 0.73) degree of modest (not statistically significant) improvement from baseline to 54 months in both groups (mean improvement in BCVA at 54 months, 2.4 and 3.1 letters in the implant and systemic groups, respectively). Many had excellent initial visual acuity, limiting the potential for improvement. The mean automated perimetry MD score remained similar to baseline throughout 48 months of follow-up in both groups. Overall control of inflammation was superior in the implant group at every time point assessed (P < 0.016), although most eyes in the systemic therapy arm also showed substantial improvement, achieving complete control or low levels of inflammation. Although macular edema improved significantly more often with implant treatment within the first 6 months, the systemic group gradually improved over time such that the proportions with macular edema converged in the 2 groups by 36 months and overlapped thereafter (P = 0.41 at 48 months). CONCLUSIONS: Visual outcomes of fluocinolone acetonide implant and systemic treatment for intermediate uveitis, posterior uveitis, and panuveitis were similarly favorable through 54 months. The implant maintained a clear advantage in controlling inflammation through 54 months. Nevertheless, with systemic therapy, most patients also experienced greatly improved inflammatory status. Macular edema improved equally with longer follow-up. Based on cost effectiveness and side-effect considerations, systemic therapy may be indicated as the initial treatment for many bilateral uveitis cases. However, implant therapy is a reasonable alternative, especially for unilateral cases and when systemic therapy is not feasible or is not successful.

Incidence and long-term outcomes of the human immunodeficiency virus neuroretinal disorder in patients with AIDS.

PURPOSE: Patients with AIDS have an abnormality of retina/optic nerve function, manifested as decreased contrast sensitivity (in the absence of ocular opportunistic infections or media opacity), abnormalities on automated perimetry, and loss of retinal nerve fiber layer, even among those with good visual acuity, termed the "human immunodeficiency virus (HIV) neuroretinal disorder." The objectives of this study were to determine the prevalence, incidence, risk factors, and outcomes of HIV neuroretinal disorder. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 1822 patients with AIDS without ocular infections or media opacities. METHODS: Patients with HIV neuroretinal disorder were identified by a contrast sensitivity <1.50 log units in either eye in the absence of ocular opportunistic infections or media opacity. MAIN OUTCOME MEASURES: Incidence of HIV neuroretinal disorder, mortality, visual impairment (visual acuity ≤20/50), and blindness (≤20/200) on logarithmic visual acuity charts. RESULTS: Sixteen percent of participants had HIV neuroretinal disorder at enrollment. The estimated cumulative incidence by 20 years after AIDS diagnosis was 51% (95% confidence interval [CI], 46-55). Human immunodeficiency virus neuroretinal disorder was more common in women and African Americans. Risk factors for HIV neuroretinal disorder included hepatitis C infection, low CD4+ T cells, and detectable HIV RNA in the blood. Patients with HIV neuroretinal disorder had a 70% excess mortality versus those without it, even after adjusting for CD4+ T cells and HIV load (hazard ratio [HR], 1.7; 95% CI, 1.3-2.1; P < 0.0001). Patients with HIV neuroretinal disorder had increased risks of bilateral visual impairment (HR, 6.5; 95% CI, 2.6-10.6; P < 0.0001) and blindness (HR, 5.9; 95% CI, 2.8-13.7; P = 0.01) versus those without HIV neuroretinal disorder. CONCLUSIONS: Human immunodeficiency virus neuroretinal disorder is a common finding among patients with AIDS, and it is associated with an increased mortality and an increased risk of visual impairment. Successful antiretroviral therapy decreases but does not eliminate the risk of HIV neuroretinal disorder.