Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease.

OBJECTIVES: Depression and antidepressant use, especially selective serotonin reuptake inhibitors (SSRIs), are common in Parkinson disease (PD). The objective of this clinical trial was to assess the efficacy of atomoxetine, a selective norepinephrine reuptake inhibitor (SNRI), for the treatment of clinically significant depressive symptoms and common comorbid neuropsychiatric symptoms in PD. METHODS: A total of 55 subjects with PD and an Inventory of Depressive Symptomatology-Clinician (IDS-C) score > or = 22 were randomized to 8 weeks of atomoxetine or placebo treatment (target dosage = 80 mg/day). Depression response (> 50% decrease in IDS-C score or Clinical Global Impression-Improvement [CGI-I] score of 1 or 2) was assessed using intention-to-treat modeling procedures. Secondary outcomes included global cognition, daytime sleepiness, anxiety, apathy, and motor function. RESULTS: There were no between-groups differences in a priori-defined response rates. Using a more liberal response criterion of > 40% decrease in IDS score from baseline, there was a trend (p = 0.08) favoring atomoxetine. Patients receiving atomoxetine experienced significantly greater improvement in global cognition (p = 0.003) and daytime sleepiness (p = 0.001), and atomoxetine was well-tolerated. CONCLUSIONS: Atomoxetine treatment was not efficacious for the treatment of clinically significant depressive symptoms in PD, but was associated with improvement in global cognitive performance and daytime sleepiness. Larger studies of SNRIs in PD for disorders of mood, cognition, and wakefulness are appropriate. CLASSIFICATION OF EVIDENCE: This interventional study provides Class II evidence that atomoxetine (target dosage = 80 mg/day) is not efficacious in improving clinically significant depression in PD.

Cognitive and psychomotor effects of paroxetine and sertraline on healthy elderly volunteers.

The authors evaluated the cognitive and psychomotor effects of serotonin reuptake inhibitors in healthy elderly volunteers. Paroxetine, sertraline, and placebo were compared for 3 weeks of testing in a double-blind study with behavioral testing at baseline and at the end of each week. MANOVA models demonstrated no between-group differences; however, mixed-model random regression analyses revealed that Day 14 plasma paroxetine levels correlated negatively with delayed verbal recall and paired-associate learning scores. In contrast, plasma sertraline levels correlated positively with Day 7 immediate verbal recall, Day 14 tapping, and Day 21 delayed verbal recall scores, and negatively with divided-attention task scores on Day 21. Plasma paroxetine levels were associated with mild behavioral impairment at Day 14, with no other significant adverse effects. Plasma sertraline levels were associated with mild and transient behavioral changes, as well as early termination in several subjects.

DHEA-S levels and depressive symptoms in a cohort of African American and Caucasian women in the late reproductive years.

BACKGROUND: The objective of this study was to elucidate the associations of dehydroepiandrosterone sulfate (DHEA-S) levels and depressive symptoms in African American and Caucasian women in the late reproductive years, a transitional age zone preceding the perimenopause, in which ovarian aging and associated endocrine changes begin. We had hypothesized that lower levels of DHEA-S would be associated with depressive symptoms and that, because DHEA-S levels decline with increasing age, older women would have an increased prevalence of depressive symptoms. METHODS: This cross-sectional study used a population-based urban sample recruited through random digit telephone dialing. The sample was 338 women between the ages of 35 and 47 years with regular menses. Half the sample was African American and half was Caucasian. RESULTS: Higher DHEA-S levels were associated with depressive symptoms in women in the younger half of this cohort. Lower DHEA-S levels were associated with depressive symptoms in the women in the older half of this cohort. The direction of the relationship of DHEA-S and depressive symptoms changes with age, being a positive relationship in younger women and an inverse relationship in the older women in this cohort. This change in the direction of the relationship appears to occur at a younger age in African American women. CONCLUSIONS: Our hypothesis of a relationship between low DHEA-S levels and elevated depressive symptoms was supported only in the older women in this cohort. Unexpectedly, younger women in this cohort demonstrated a positive association between DHEA-S levels and depressive symptoms. Changes in DHEA-S levels, depressive symptoms, and the relationship of other hormones in the hypothalamic-pituitary-adrenal axis need to be better understood in premenopausal women approaching perimenopause.

Adjustments for center in multicenter studies: an overview.

Increasingly, investigators rely on multicenter or multigroup studies to demonstrate effectiveness and generalizability. Authors too often overlook the analytic challenges in these study designs: the correlation of outcomes and exposures among patients within centers, confounding of associations by center, and effect modification of treatment or exposure across center. Correlation or clustering, resulting from the similarity of outcomes among patients within a center, requires an adjustment to confidence intervals and P values, especially in observational studies and in randomized multicenter studies in which treatment is allocated by center rather than by individual patient. Multicenter designs also warrant testing and adjustment for the potential bias of confounding by center, and for the presence of effect modification or interaction by center. This paper uses examples from the recent biomedical literature to highlight the issues and analytic options.

Prevalence of sleep-disordered breathing in women: effects of gender.

The prevalence of sleep-disordered breathing has not been well studied in women, especially in terms of the effects of age, body mass index (BMI), and menopause. We evaluated this question using a two-phase random sample from the general population. In Phase I, 12,219 women and 4,364 men ranging in age from 20 to 100 yr were interviewed; and in Phase II, 1,000 women and 741 men of the Phase I subjects were selected for one night of sleep laboratory evaluation. The results of our study indicated that, for clinically defined sleep apnea (apnea/hypopnea index > or = 10 and daytime symptoms), men had a prevalence of 3.9% and women 1.2%, resulting in an overall ratio of sleep apnea for men to women of 3.3:1 (p = 0.0006). The prevalence of sleep apnea was quite low in premenopausal women (0.6%) as well as postmenopausal women with hormone replacement therapy (HRT) (0.5%). Further, in these women the presence of sleep apnea appeared to be associated exclusively with obesity (BMI > or = 32.3 kg/m2). Postmenopausal women without HRT had a prevalence of sleep apnea that was significantly higher than the prevalence in premenopausal women with HRT (2.7 versus 0.6%, p = 0.02) and was more similar to the prevalence in men (3.9%), although it remained significantly less when controlling for age and BMI (p = 0.001). These data combined indicate that menopause is a significant risk factor for sleep apnea in women and that hormone replacement appears to be associated with reduced risk.

A mixed effects model for the analysis of ordinal longitudinal pain data subject to informative drop-out.

We extend the model of Pulkstenis et al. that models binary longitudinal data, subject to informative drop-out through remedication, to the ordinal response case. We present a selection model shared-parameter approach that specifies mixed models for both ordinal response and discrete survival time to remedication. In this fashion, the random parameter present in both models completely characterizes the relationship between response and time to remedication inducing their conditional independence. With a log-log link function for both response and study 'survival', as well as specification of a log-gamma distribution for the random effect, we obtain a closed-form expression for the marginal log-likelihood of response and time to remedication that does not require approximation or numerical integration techniques. A data analysis is performed and simulation results presented which support the consistency of parameter and standard error estimates.

Clinical laboratory measures in relation to depression, disability, and cognitive impairment in elderly patients.

To characterize the dimensions of physiological abnormalities that commonly occur in older individuals in a residential care setting and to evaluate their association with clinical measures, the authors conducted an exploratory factor analysis on clinical laboratory measures from a sample of 231 elderly residents (mean age: 86) living in a nursing home and congregate apartment facility. An eight-factor solution accounted for 70.2% of the variance in these measures; factors identified were interpreted as indices of renal function, protein/calorie/nutritional status, serum electrolytes/osmolarity, liver function, acute-phase processes, plasma lipids, acid/base status, and renal-tubular function. The nutritional factor was significantly associated with measures of disability and the presence of depression. The acute-phase processes factor was significantly associated with cognitive impairment.

Physical activity, functional limitations, and disability in older adults.

OBJECTIVES: To explore initially how low levels of physical activity influence lower body functional limitations in participants of the Longitudinal Study of Aging. Changes in functional limitations are used subsequently to predict transitions in the activities of daily living/instrumental activities of daily living (ADL/IADL) disability, thus investigating a potential pathway for how physical activity may delay the onset of ADL/IADL disability and, thus, prolong independent living. DESIGN: Analysis of a complex sample survey of US civilian, noninstitutionalized population aged 70 years and older in 1984, with repeated interviews in 1986, 1988, and 1990. SETTING AND PARTICIPANTS: Analyses concentrated on 5151 men and women targeted for interview at all four LSOA interviews. MEASUREMENTS: Characteristics used in analyses: gender, age, level of physical activity, comorbid conditions including the presence of hypertension, diabetes, arthritis, and atherosclerotic heart disease, levels of functional limitations, and ADL/IADL disability. RESULTS: Transitional models provide evidence that older adults who have varying levels of disability and who report at least a minimal level of physical activity experience a slower progression in functional limitations (OR = .45, P < .001 for severe vs less severe limitations). This low level of physical activity, through its influence on changes in functional limitations, is shown to slow the progression of ADL/IADL disability. CONCLUSIONS: Results from analyses provide supporting evidence that functional limitations can mediate the effect that physical activity has on ADL/IADL disability. These results contribute further to the increasing data that seem to suggest that physical activity can reduce the progression of disability in older adults.

Association of hypertension and sleep-disordered breathing.

BACKGROUND: To our knowledge, the association between sleep-disordered breathing (SDB) and hypertension has not been evaluated in subjects from the general population with a wide age range while adjusting for the possible confounding factors of age, body mass index, sex, menopause and use of hormone replacement therapy, race, alcohol use, and smoking. METHODS: In the first phase of this study, we interviewed 4364 men and 12,219 women, aged 20 to 100 years. In the second phase of this study, 741 men and 1000 women, previously interviewed, were selected based on the presence of risk factors for SDB (snoring, daytime sleepiness, obesity, hypertension, and, for women, menopause). Each subject selected for the second phase of the study provided a comprehensive history, underwent a physical examination, and was evaluated for 1 night in the sleep laboratory. In terms of severity of SDB, 4 groups were identified: moderate or severe (obstructive apnea/hypopnea index > or =15.0), mild (snoring and an obstructive apnea/hypopnea index of 0.1-14.9), snoring, and no SDB, the control group. RESULTS: Sleep-disordered breathing was independently associated with hypertension when potential confounders were controlled for in the logistic regression analysis. The strength of this association decreased with age and was proportional to the severity of SDB. In the best-fitted model, neither sex nor menopause changed the relationship between hypertension and SDB. CONCLUSIONS: In the results of this study, SDB, even snoring, was independently associated with hypertension in both men and women. This relationship was strongest in young subjects, especially those of normal weight, a finding that is consistent with previous findings that SDB is more severe in young individuals.

Effects of alcohol consumption on the treatment of depression among elderly patients.

The authors examined the effects of alcohol use on the short-term and 3-4-month treatment outcomes of patients with late-life depression. Patients (N=2,666) were assessed for symptoms of depression, alcohol use, and disability during an initial inpatient hospitalization and then 3-4 months postdischarge. Contrary to our hypothesis that alcohol consumption imparted a significant additive detriment to treatment outcome in patients already suffering from major depression, the results suggest that treatment was effective even in those with concomitant use of alcohol. Moreover, there appeared to be an added benefit when even modest alcohol consumption was decreased among elderly patients suffering from depression.

Heuristic comparison of sertraline with nortriptyline for the treatment of depression in frail elderly patients.

Studies have demonstrated that the selective serotonin reuptake inhibitor antidepressants have similar efficacy to other agents, such as tricyclic antidepressants. However, data are limited for direct comparisons with other antidepressants. The authors conducted a contemporaneous comparison of nursing home residents treated with open-label sertraline in doses up to 100 mg/day with nursing home residents treated in a double-blind randomized study of low vs. regular doses of nortriptyline. There were 97 patients enrolled in the study (28 treated with sertraline), with an average treatment duration of 55 days. There were no differences in the tolerability of sertraline vs. nortriptyline. However, in this group of frail older adults, sertraline was not as effective as nortriptyline for the treatment of depression.

Drug treatment of depression in frail elderly nursing home residents.

The authors conducted a randomized, double-blind, 10-week clinical trial of two doses of nortriptyline in eight nursing homes. Sixty-nine patients, average age 79.5 years, were randomized to receive regular doses (60 mg-80 mg/day) vs. low doses (10 mg-13 mg/day) of nortriptyline. Among the more cognitively intact patients, there was a significant quadratic relationship defining a "therapeutic window" for nortriptyline plasma levels and clinical improvement. There were also significant differences in plasma level-response relationships between depressed patients who were cognitively impaired and those who were more cognitively intact. Depression remains a syndrome that responds to specific treatment, even in frail nursing home patients, and those depressions that occur in patients with significant dementia may represent a treatment-relevant condition with a different plasma level-response relationship than in depression alone.

Mixed effects logistic regression models for longitudinal ordinal functional response data with multiple-cause drop-out from the longitudinal study of aging.

In the context of analyzing ordinal functional limitation responses from the Longitudinal Study of Aging, we investigate the association between current functional limitation and previous year's limitation and its modification by physical activity and multiple causes of drop-out. We accommodate the longitudinal nature of the multiple causes of informative drop-out (death and unknown loss-to-follow-up) with a mixed effects logistic model. Under the proposed model with a random intercept and slope, the ordinal functional outcome and multiple discrete time survival profiles share a common random effect structure. This shared parameter selection model assumes that the multiple causes of drop-out are conditionally independent of the functional limitation outcome given the underlying random effect representing an individual's trajectory of general health status across time. Although it is not possible to fully assess the adequacy of this assumption, we assess the robustness of the approach by varying the assumptions underlying the proposed model, such as the random effects distribution and the drop-out component. It appears that between-subject differences in initial functional limitation are strongly associated with future functional limitation and that this association is stronger for those who do not have physical activity regardless of the random effects and informative drop-out specifications. In contrast, the association between current functional limitation and previous trajectory of functional status within an individual is weaker and more sensitive to changes in the random effects and drop-out assumptions.

Outcomes of a cardiovascular nutrition counseling program in African-Americans with elevated blood pressure or cholesterol level.

OBJECTIVE: To evaluate a cardiovascular nutrition education package designed for African-American adults with a wide range of literacy skills. DESIGN: Comparison of a self-help group and a full-instruction group; each group received nutrition counseling and clinical monitoring every 4 months. SUBJECTS: Three hundred thirty African-American adults, aged 40 to 70 years, with elevated cholesterol level or high blood pressure were randomly assigned to the self-help or full-instruction group; 255 completed the 12-month follow-up. INTERVENTIONS: Counseling to reduce intake of dietary fat, cholesterol, and sodium was based on Cardiovascular Dietary Education System (CARDES) materials, which included food-picture cards, a nutrition guide (self-help and full-instruction group), a video and audiotape series, and 4 classes (full-instruction group only). MAIN OUTCOME MEASURES: Changes in lipid levels and blood pressure after 12 months. STATISTICAL ANALYSES PERFORMED: Primary analyses consisted of repeated-measures analysis of variance to examine effects of time and randomization group on outcomes. RESULTS: Total cholesterol and low-density lipoprotein cholesterol level decreased by 7% to 8% in the self-help and full-instruction groups of men and women (P < .01). The ratio of total cholesterol to high-density lipoprotein cholesterol (HDL-C) decreased in both groups of women and in the men in the full-instruction group (P < .01). In full-instruction and self-help participants with elevated blood pressure at baseline, systolic blood pressure decreased by 7 to 11 mm Hg and diastolic blood pressure decreased by 4 to 7 mm Hg (P < .01). Outcomes did not differ by literacy scores but were positively related to the reported initial frequency of using CARDES materials. APPLICATIONS/CONCLUSIONS: These results suggest that periodic nutrition counseling based on CARDES materials used for home study can enhance management of lipid levels and blood pressure in African-American outpatients.

Health, valuation of life, and the wish to live.

This research investigated the relationship of an affective-cognitive schema, valuation of life (VOL), to older people's responses to a set of health utility (years of desired life) questions. Six hundred healthy and chronically ill elders aged 70 and older were interviewed to measure quality of life (QOL), mental health, and VOL. Valuation of life was significantly correlated with longer Years of Desired Life under 8 of 10 health conditions when background, health, QOL, and mental health states were controlled. We concluded that VOL is an internal representation of the many positive and negative features of the person and her everyday life that is necessary to comprehend how people may cling to life or welcome its end.

A comparison of mixed effects logistic regression models for binary response data with two nested levels of clustering.

We compare mixed effects logistic regression models for binary response data with two nested levels of clustering. The comparison of these models occurs in the context of developmental toxicity data sets, for which multiple types of outcomes (first level) are measured on each rat pup (second level) nested within a litter (third level). Because the nested nature of such data is occasionally accommodated by ignoring one level of clustering, we consider three models: (i) a three-level model adjusting for clustering due to both pup and litter (M1); (ii) a two-level model adjusting for just pup (M2); and (iii) another two-level model adjusting for just litter (M3). The three types of effects of interest are: (i) differences among malformation types (first-level effects); (ii) differences among groups of pups (for example, sex of pup, second-level effects); and (iii) differences among groups of litters (for example, dose, third-level effects). Simulations and data analyses suggest that the M3 model leads to more bias than the M1 or M2 models for all three types of effects. In terms of coverage of confidence intervals for fixed effects log odds ratio parameters, the M1 model achieves nominal coverage, whereas the M2 model reduces coverage for the third-level effects and the M3 model obtains poor coverage for both first- and second-level effects. These reductions in coverage for certain model-parameter combinations worsen as baseline risk increases. The data analyses support these simulation-based conclusions to some extent.

Empirical Bayes estimation of random effects parameters in mixed effects logistic regression models.

We extend an approach for estimating random effects parameters under a random intercept and slope logistic regression model to include standard errors, thereby including confidence intervals. The procedure entails numerical integration to yield posterior empirical Bayes (EB) estimates of random effects parameters and their corresponding posterior standard errors. We incorporate an adjustment of the standard error due to Kass and Steffey (KS; 1989, Journal of the American Statistical Association 84, 717-726) to account for the variability in estimating the variance component of the random effects distribution. In assessing health care providers with respect to adult pneumonia mortality, comparisons are made with the penalized quasi-likelihood (PQL) approximation approach of Breslow and Clayton (1993, Journal of the American Statistical Association 88, 9-25) and a Bayesian approach. To make comparisons with an EB method previously reported in the literature, we apply these approaches to crossover trials data previously analyzed with the estimating equations EB approach of Waclawiw and Liang (1994, Statistics in Medicine 13, 541-551). We also perform simulations to compare the proposed KS and PQL approaches. These two approaches lead to EB estimates of random effects parameters with similar asymptotic bias. However, for many clusters with small cluster size, the proposed KS approach does better than the PQL procedures in terms of coverage of nominal 95% confidence intervals for random effects estimates. For large cluster sizes and a few clusters, the PQL approach performs better than the KS adjustment. These simulation results agree somewhat with those of the data analyses.

Mixed effects models with bivariate and univariate association parameters for longitudinal bivariate binary response data.

When two binary responses are measured for each study subject across time, it may be of interest to model how the bivariate associations and marginal univariate risks involving the two responses change across time. To achieve such a goal, marginal models with bivariate log odds ratio and univariate logit components are extended to include random effects for all components. Specifically, separate normal random effects are specified on the log odds ratio scale for bivariate responses and on the logit scale for univariate responses. Assuming conditional independence given the random effects facilitates the modeling of bivariate associations across time with missing at random incomplete data. We fit the model to a dataset for which such structures are feasible: a longitudinal randomized trial of a cardiovascular educational program where the responses of interest are change in hypertension and hypercholestemia status. The proposed model is compared to a naive bivariate model that assumes independence between time points and univariate mixed effects logit models.

An empirical comparison of several clustered data approaches under confounding due to cluster effects in the analysis of complications of coronary angioplasty.

In the analysis of binary response data from many types of large studies, the data are likely to have arisen from multiple centers, resulting in a within-center correlation for the response. Such correlation, or clustering, occurs when outcomes within centers tend to be more similar to each other than to outcomes in other centers. In studies where there is also variability among centers with respect to the exposure of interest, analysis of the exposure-outcome association may be confounded, even after accounting for within-center correlations. We apply several analytic methods to compare the risk of major complications associated with two strategies, staged and combined procedures, for performing percutaneous transluminal coronary angioplasty (PTCA), a mechanical means of relieving blockage of blood vessels due to atherosclerosis. Combined procedures are used in some centers as a cost-cutting strategy. We performed a number of population-averaged and cluster-specific (conditional) analyses, which (a) make no adjustments for center effects of any kind; (b) make adjustments for the effect of center on only the response; or (c) make adjustments for both the effect of center on the response and the relationship between center and exposure. The method used for this third approach decomposes the procedure type variable into within-center and among-center components, resulting in two odds ratio estimates. The naive analysis, ignoring clusters, gave a highly significant effect of procedure type (OR = 1.6). Population average models gave marginally to very nonsignificant estimates of the OR for treatment type ranging from 1.6 to 1.2 with adjustment only for the effect of centers on response. These results depended on the assumed correlation structure. Conditional (cluster-specific) models and other methods that decomposed the treatment type variable into among- and within-center components all found no within-center effect of procedure type (OR = 1.02, consistently) and a considerable among-center effect. This among-center variability in outcomes was related to the proportion of patients who receive combined procedures and was found even when conditioned on procedure type (within-center) and other patient- and center-level covariates. This example illustrates the importance of addressing the potential for center effects to confound an outcome-exposure association when average exposure varies across clusters. While conditional approaches provide estimates of the within-cluster effect, they do not provide information about among-center effects. We recommend using the decomposition approach, as it provides both types of estimates.

Measuring carotid artery stenosis using CT angiography: the dilemma of artifactual lumen eccentricity.

OBJECTIVE: This study assesses artifactual luminal distortion, or eccentricity, that affects measurement of stenosis on CT angiography performed with a variety of helical protocols. MATERIALS AND METHODS: A 32-vessel carotid artery phantom was built with five known grades of stenoses (25%, 50%, 75%, 88%, and 94%) and three lengths of stenosis (1, 3, and 5 mm). This phantom was scanned with conventional and 1.0-, 1.5-, and 2.0-pitch helical CT with slice thicknesses of 2, 4, and 8 mm, and three vessel orientations: parallel, 45 degrees oblique, and perpendicular to the z-axis. Oblique multiplanar reconstruction was performed with the latter two vessel orientations to produce images similar to the parallel to z-axis orientation. The cross-sectional images were then used to measure the maximum and minimum (longest and shortest) luminal diameters in and out of each stenosis at a computer workstation by a single investigator who was unaware of the scanning technique. Percentage of stenosis was assessed by three methods: cross-sectional area in and out of the stenosis, maximum diameter out of stenosis and minimum in stenosis (North American Symptomatic Carotid Endarterectomy Trial method), and minimum diameter in and out of the stenosis. Comparisons were made with the gold standard using the equation (measured percentage of stenosis-actual percentage of stenosis) based on known luminal diameters of the phantom. Luminal eccentricity was assessed for each of the vessels and scanning parameters as a ratio of minimum to maximum diameters. RESULTS: All three methods of measuring stenoses were strongly affected by luminal eccentricity. The North American Symptomatic Carotid Endarterectomy Trial method overestimated percentage of stenosis an average of 1.64%. The most accurate results were obtained when using the minimum diameter in and out of the stenoses (-0.45% from the gold standard). Eccentricity was significantly greater in stenoses than in normal lumen (p < .0001) and when the vessels were oriented perpendicular to the z-axis (p = .0003). A progressive increase in eccentricity was seen in the 4- and 8-mm slice thicknesses and the 3- and 5-mm-long stenoses (p < .001; p < .001). CONCLUSION: Artifactual luminal eccentricity has significant implications for measuring percentage of stenosis revealed by CT angiography. Eccentricity increases in longer stenoses, thicker slices, and vessels oriented perpendicular to the z-axis. With CT angiography, measurement of minimum diameters in and out of a stenosis provides the most accurate assessment of percentage of stenosis.