Efficient estimation of the attributable fraction when there are monotonicity constraints and interactions.

The PAF for an exposure is the fraction of disease cases in a population that can be attributed to that exposure. One method of estimating the PAF involves estimating the probability of having the disease given the exposure and confounding variables. In many settings, the exposure will interact with the confounders and the confounders will interact with each other. Also, in many settings, the probability of having the disease is thought, based on subject matter knowledge, to be a monotone increasing function of the exposure and possibly of some of the confounders. We develop an efficient approach for estimating logistic regression models with interactions and monotonicity constraints, and apply this approach to estimating the population attributable fraction (PAF). Our approach produces substantially more accurate estimates of the PAF in some settings than the usual approach which uses logistic regression without monotonicity constraints.

Bayesian multivariate growth curve latent class models for mixed outcomes.

In many clinical studies, the disease of interest is multifaceted, and multiple outcomes are needed to adequately capture information about the characteristics of the disease or its severity. In the analysis of such diseases, it is often difficult to determine what constitutes improvement because of the multivariate nature of the outcome. Furthermore, when the disease of interest has an unknown etiology and/or is primarily a symptom-defined syndrome, there is potential for the disease population to have distinct subgroups. Identification of population subgroups is of interest as it may assist clinicians in providing appropriate treatment or in developing accurate prognoses. We propose multivariate growth curve latent class models that group subjects on the basis of multiple symptoms measured repeatedly over time. These groups or latent classes are defined by distinctive longitudinal profiles of a latent variable, which is used to summarize the multivariate outcomes at each point. The mean growth curve for the latent variable in each class defines the features of the class. We develop this model for any combination of continuous, binary, ordinal, or count outcomes within a Bayesian hierarchical framework. We use simulation studies to validate the estimation procedures. We apply our model to data from a randomized clinical trial evaluating the efficacy of Bacillus Calmette-Guerin in treating symptoms of interstitial cystitis where we are able to identify a class of subjects for whom treatment is effective.

Effectiveness of long-term acute care hospitalization in elderly patients with chronic critical illness.

BACKGROUND: For patients recovering from severe acute illness, admission to a long-term acute care hospital (LTAC) is an increasingly common alternative to continued management in an intensive care unit (ICU). OBJECTIVE: To examine the effectiveness of LTAC transfer in patients with chronic critical illness. RESEARCH DESIGN: Retrospective cohort study in United States hospitals from 2002 to 2006. SUBJECTS: Medicare beneficiaries with chronic critical illness, defined as mechanical ventilation and at least 14 days of intensive care. MEASURES: Survival, costs, and hospital readmissions. We used multivariate analyses and instrumental variables to account for differences in patient characteristics, the timing of LTAC transfer, and selection bias. RESULTS: A total of 234,799 patients met our definition of chronic critical illness. Of these, 48,416 (20.6%) were transferred to an LTAC. In the instrumental variable analysis, patients transferred to an LTAC experienced similar survival compared with patients who remained in an ICU [adjusted hazard ratio=0.99; 95% confidence interval (CI), 0.96 to 1.01; P=0.27). Total hospital-related costs in the 180 days after admission were lower among patients transferred to LTACs (adjusted cost difference=-$13,422; 95% CI, -26,662 to -223, P=0.046). This difference was attributable to a reduction in skilled nursing facility admissions (adjusted admission rate difference=-0.591; 95% CI, -0.728 to -0.454; P<0.001). Total Medicare payments were higher (adjusted cost difference=$15,592; 95% CI, 6343 to 24,842; P=0.001). CONCLUSIONS: Patients with chronic critical illness transferred to LTACs experience similar survival compared with patients who remain in ICUs, incur fewer health care costs driven by a reduction in postacute care utilization, however, invoke higher overall Medicare payments.

Simulation study of instrumental variable approaches with an application to a study of the antidiabetic effect of bezafibrate.

PURPOSE: We studied the application of the generalized structural mean model (GSMM) of instrumental variable (IV) methods in estimating treatment odds ratios (ORs) for binary outcomes in pharmacoepidemiologic studies and evaluated the bias of GSMM compared to other IV methods. METHODS: Because of the bias of standard IV methods, including two-stage predictor substitution (2SPS) and two-stage residual inclusion (2SRI) with binary outcomes, we implemented another IV approach based on the GSMM of Vansteelandt and Goetghebeur. We performed simulations under the principal stratification setting and evaluated whether GSMM provides approximately unbiased estimates of the causal OR and compared its bias and mean squared error to that of 2SPS and 2SRI. We then applied different IV methods to a study comparing bezafibrate versus other fibrates on the risk of diabetes. RESULTS: Our simulations showed that unlike the standard logistic, 2SPS, and 2SRI procedures, our implementation of GSMM provides an approximately unbiased estimate of the causal OR even under unmeasured confounding. However, for the effect of bezafibrate versus other fibrates on the risk of diabetes, the GSMM and two-stage approaches yielded similarly attenuated and statistically non-significant OR estimates. The attenuation of the OR by the two-stage and GSMM IV approaches suggests unmeasured confounding, although violations of the IV assumptions or differences in the parameters estimated could be playing a role. CONCLUSION: The GSMM IV approach provides approximately unbiased adjustment for unmeasured confounding on binary outcomes when a valid IV is available.

A difference-in-differences analysis of health, safety, and greening vacant urban space.

Greening of vacant urban land may affect health and safety. The authors conducted a decade-long difference-in-differences analysis of the impact of a vacant lot greening program in Philadelphia, Pennsylvania, on health and safety outcomes. "Before" and "after" outcome differences among treated vacant lots were compared with matched groups of control vacant lots that were eligible but did not receive treatment. Control lots from 2 eligibility pools were randomly selected and matched to treated lots at a 3:1 ratio by city section. Random-effects regression models were fitted, along with alternative models and robustness checks. Across 4 sections of Philadelphia, 4,436 vacant lots totaling over 7.8 million square feet (about 725,000 m(2)) were greened from 1999 to 2008. Regression-adjusted estimates showed that vacant lot greening was associated with consistent reductions in gun assaults across all 4 sections of the city (P < 0.001) and consistent reductions in vandalism in 1 section of the city (P < 0.001). Regression-adjusted estimates also showed that vacant lot greening was associated with residents' reporting less stress and more exercise in select sections of the city (P < 0.01). Once greened, vacant lots may reduce certain crimes and promote some aspects of health. Limitations of the current study are discussed. Community-based trials are warranted to further test these findings.

A latent class model for testing for linkage and classifying families when the sample may contain segregating and non-segregating families.

In a quantitative trait locus (QTL) study, it is usually not feasible to select families with offspring that simultaneously display variability in more than one phenotype. When multiple phenotypes are of interest, the sample will, with high probability, contain 'non-segregating' families, i.e. families with both parents homozygous at the QTL. These families potentially reduce the power of regression-based methods to detect linkage. Moreover, follow-up studies in individual families will be inefficient, and potentially even misleading, if non-segregating families are selected for the study. Our work extends Haseman-Elston regression using a latent class model to account for the mixture of segregating and non-segregating families. We provide theoretical motivation for the method using an additive genetic model with two distinct functions of the phenotypic outcome, squared difference (SqD) and mean-corrected product (MCP). A permutation procedure is developed to test for linkage; simulation shows that the test is valid for both phenotypic functions. For rare alleles, the method provides increased power compared to a 'marginal' approach that ignores the two types of families; for more common alleles, the marginal approach has better power. These results appear to reflect the ability of the algorithm to accurately assign families to the two classes and the relative weights of segregating and non-segregating families to the test of linkage. An application of Bayes rule is used to estimate the family-specific probability of segregating. High predictive value positive values for segregating families, particularly for MCP, suggest that the method has considerable value for identifying segregating families. The method is illustrated for gene expression phenotypes measured on 27 candidate genes previously demonstrated to show linkage in a sample of 14 families.

Acute alcohol consumption, alcohol outlets, and gun suicide.

A case-control study of 149 intentionally self-inflicted gun injury cases (including completed gun suicides) and 302 population-based controls was conducted from 2003 to 2006 in a major US city. Two focal independent variables, acute alcohol consumption and alcohol outlet availability, were measured. Conditional logistic regression was adjusted for confounding variables. Gun suicide risk to individuals in areas of high alcohol outlet availability was less than the gun suicide risk they incurred from acute alcohol consumption, especially to excess. This corroborates prior work but also uncovers new information about the relationships between acute alcohol consumption, alcohol outlets, and gun suicide. Study limitations and implications are discussed.

Emotional and behavioral functioning of offspring of African American mothers with depression.

Extensive research demonstrates the negative impact of maternal depression on their offspring. Unfortunately, few studies have been explored in African American families. This study examined emotional and behavioral functioning among children of African American mothers with depression. African American mothers (n = 63), with a past year diagnosis of a depressive disorder, and one of their children (ages 7-14) completed behavioral rating scales in a cross-sectional design. Results showed that 6.5 and 15% scored within the clinical range for depression and anxiety symptoms, respectively. Approximately a third of the offspring reported suicidal ideation. Based on mothers' report, 25.4 and 20.6% of the offspring exhibited internalizing and externalizing symptoms in the clinical range, respectively. Offspring whose mothers were in treatment exhibited higher levels of self-reported anxiety symptoms. Offspring of African American mothers with depression were exhibiting socioemotional problems in ways that are similar to offspring of European American mothers with depression.

Determinants of the optimal first-line therapy for follicular lymphoma: a decision analysis.

Combination immunochemotherapy is the most common approach for initial therapy of patients with advanced-stage follicular lymphoma, but no consensus exists as to the optimal selection or sequence of available regimens. We undertook this decision analysis to systematically evaluate the parameters affecting the choice of early therapy in patients with this disease. We designed a Markov model incorporating the three most commonly utilized regimens (RCVP, RCHOP, and RFlu) in combinations of first- and second-line therapies, with the endpoint of number of quality-adjusted life years (QALYs) until disease progression. Data sources included Phase II and Phase III trials and literature estimates of long-term toxicities and health state utilities. Meta-analytic methods were used to derive the values and ranges of regimen-related parameters. Based on our model, the strategy associated with the greatest number of expected quality-adjusted life years was treatment with RCHOP in first-line therapy followed by treatment with RFlu in second-line therapy (9.00 QALYs). Strategies containing RCVP either in first- or second-line therapy resulted in the lowest number of QALYs (range 6.24-7.71). Sensitivity analysis used to determine the relative contribution of each model parameter identified PFS after first-line therapy and not short-term QOL as the most important factor in prolonging overall quality-adjusted life years. Our results suggest that regimens associated with a longer PFS provide a greater number of total QALYs, despite their short-term toxicities. For patients without contraindications to any of these regimens, use of a more active regimen may maximize overall quality of life.

Adaptive designs for randomized trials in public health.

In this article, we present a discussion of two general ways in which the traditional randomized trial can be modified or adapted in response to the data being collected. We use the term adaptive design to refer to a trial in which characteristics of the study itself, such as the proportion assigned to active intervention versus control, change during the trial in response to data being collected. The term adaptive sequence of trials refers to a decision-making process that fundamentally informs the conceptualization and conduct of each new trial with the results of previous trials. Our discussion below investigates the utility of these two types of adaptations for public health evaluations. Examples are provided to illustrate how adaptation can be used in practice. From these case studies, we discuss whether such evaluations can or should be analyzed as if they were formal randomized trials, and we discuss practical as well as ethical issues arising in the conduct of these new-generation trials.

Investigating the link between gun possession and gun assault.

OBJECTIVES: We investigated the possible relationship between being shot in an assault and possession of a gun at the time. METHODS: We enrolled 677 case participants that had been shot in an assault and 684 population-based control participants within Philadelphia, PA, from 2003 to 2006. We adjusted odds ratios for confounding variables. RESULTS: After adjustment, individuals in possession of a gun were 4.46 (P < .05) times more likely to be shot in an assault than those not in possession. Among gun assaults where the victim had at least some chance to resist, this adjusted odds ratio increased to 5.45 (P < .05). CONCLUSIONS: On average, guns did not protect those who possessed them from being shot in an assault. Although successful defensive gun uses occur each year, the probability of success may be low for civilian gun users in urban areas. Such users should reconsider their possession of guns or, at least, understand that regular possession necessitates careful safety countermeasures.

Nested Markov compliance class model in the presence of time-varying noncompliance.

SUMMARY: We consider a Markov structure for partially unobserved time-varying compliance classes in the Imbens-Rubin (1997, The Annals of Statistics 25, 305-327) compliance model framework. The context is a longitudinal randomized intervention study where subjects are randomized once at baseline, outcomes and patient adherence are measured at multiple follow-ups, and patient adherence to their randomized treatment could vary over time. We propose a nested latent compliance class model where we use time-invariant subject-specific compliance principal strata to summarize longitudinal trends of subject-specific time-varying compliance patterns. The principal strata are formed using Markov models that relate current compliance behavior to compliance history. Treatment effects are estimated as intent-to-treat effects within the compliance principal strata.

Use of latent variable modeling to delineate psychiatric and cognitive profiles in Parkinson disease.

OBJECTIVES: A range of psychiatric symptoms and cognitive deficits occur in Parkinson disease (PD), and symptom overlap and comorbidity complicate the classification of nonmotor symptoms. The objective of this study was to use analytic-based approaches to classify psychiatric and cognitive symptoms in PD. DESIGN: Cross-sectional evaluation of a convenience sample of patients in specialty care. SETTING: Two outpatient movement disorders centers at the University of Pennsylvania and Philadelphia Veterans Affairs Medical Center. PARTICIPANTS: One hundred seventy-seven patients with mild-moderate idiopathic PD and without significant global cognitive impairment. MEASUREMENTS: Subjects were assessed with an extensive psychiatric, neuropsychological, and neurological battery. Latent class analysis (LCA) was used to statistically delineate group-level symptom profiles across measures of psychiatric and cognitive functioning. Predictors of class membership were also examined. RESULTS: Results from the LCA indicated that a four-class solution best fit the data. The 32.3% of the sample had good psychiatric and normal cognitive functioning, 17.5% had significant psychiatric comorbidity but normal cognition, 26.0% had few psychiatric symptoms but had poorer cognitive functioning across a range of cognitive domains, and 24.3% had both significant psychiatric comorbidity and poorer cognitive functioning. Age, disease severity, and medication use predicted class membership. CONCLUSIONS: LCA delineates four classes of patients in mild-moderate PD, three of which experience significant nonmotor impairments and comprise over two thirds of patients. Neuropsychiatric symptoms and cognitive deficits follow distinct patterns in PD, and further study is needed to determine whether these classes are generalizable, stable, predict function, quality of life, and long-term outcomes and are amenable to treatment at a class level.

Corticosteroids and mortality in children with bacterial meningitis.

CONTEXT: In adults, adjuvant corticosteroids significantly reduce mortality associated with bacterial meningitis; however, in children, studies reveal conflicting results. OBJECTIVE: To determine the association between adjuvant corticosteroids and clinical outcomes in children with bacterial meningitis. DESIGN, SETTING, AND PATIENTS: A retrospective cohort study conducted between January 1, 2001, and December 31, 2006, of 2780 children discharged with bacterial meningitis as their primary diagnosis from 27 tertiary care children's hospitals located in 18 US states and the District of Columbia that provide data to the Pediatric Health Information System's administrative database. MAIN OUTCOME MEASURES: Propensity scores, constructed using patient demographics and markers of illness severity at presentation, were used to determine each child's likelihood of receiving adjuvant corticosteroids. Primary outcomes of interest, time to death and time to hospital discharge, were analyzed by using propensity-adjusted Cox proportional hazards regression models stratified by age categories. RESULTS: The median age was 9 months (interquartile range, 0-6 years); 57% of the patients were males. Streptococcus pneumoniae was the most commonly identified cause of meningitis. Adjuvant corticosteroids were administered to 248 children (8.9%). The overall mortality rate was 4.2% (95% confidence interval [CI], 3.5%-5.0%), and cumulative incidences were 2.2% and 3.1% at 7 days and 28 days, respectively, after admission. Adjuvant corticosteroids did not reduce mortality, regardless of age (children <1 year: hazard ratio [HR], 1.09; 95% CI, 0.53-2.24; 1-5 years: HR, 1.28; 95% CI, 0.59-2.78; and >5 years: HR, 0.92; 95% CI, 0.38-2.25). Adjuvant corticosteroids were also not associated with time to hospital discharge. In subgroup analyses, the results did not change in either children identified with pneumococcal or meningococcal meningitis or children with a cerebrospinal fluid culture performed at the admitting hospital. CONCLUSION: In this multicenter observational study of children with bacterial meningitis, adjuvant corticosteroid therapy was not associated with time to death or time to hospital discharge.

Effect of depression treatment on depressive symptoms in older adulthood: the moderating role of pain.

OBJECTIVES: To investigate whether pain severity and interference with normal work activities moderate the effects of depression treatment on changes in depressive symptoms over time in older adults in primary care. DESIGN: Patient-randomized, clinical trial. SETTING: Multisite: three clinics located in Veterans Affairs Medical Centers. PARTICIPANTS: Adults aged 60 and older (n=524) who screened positive for depression and participated in the Primary Care Research in Substance Abuse and Mental Health for the Elderly Study. INTERVENTION: Integrated care versus enhanced specialty referral care. MEASUREMENTS: Pain severity, the degree to which pain interferes with work inside and outside of the home, and depressive symptoms were examined at baseline and 3, 6, and 12 months. RESULTS: Intention-to-treat analyses revealed that both treatment groups showed reduced depressive symptoms over time, although self-reported pain moderated reductions in depressive symptoms. At higher levels of pain severity and interference with work activities, improvements in depressive symptoms were blunted. Furthermore, pain interference appeared to have a greater effect on depressive symptoms than did pain severity; in individuals with major depression, pain interference fully accounted for the moderating effects of pain severity on changes in depressive symptoms over time. CONCLUSION: Pain and its interference with functioning interfere with recovery from depression. Findings highlight the importance of addressing multiple domains of functioning (e.g., physical and social disability) and the degree to which pain and other forms of physical comorbidity may hinder or minimize treatment-related improvements in depressive symptoms.

Differential transitions between cocaine use and abstinence for men and women.

The longitudinal course of cocaine dependence is characterized by alternating periods of abstinence and relapse. Although gender has emerged as an important predictor of relapse, previous studies have examined mean differences in use by gender. Focusing strictly on differences in averages between men and women does not address potential gender differences in transitions between use and abstinence. Transition rates for men and women were compared using data from the National Institute on Drug Abuse Collaborative Cocaine Treatment Study. Abstinence and nonabstinence for each of the 6 months of active treatment was determined by using a composite measure of use that incorporated information from weekly and monthly self-reports and urine toxicology screenings. Random effects were introduced to describe intersubject heterogeneity in transition rates. In this sample of 454 patients, rates of transition between abstinence and use were significantly different between men and women, with men showing twice the rate of transition between states despite similar average levels of use. These data may have important implications for both treatment planning and the types of outcomes considered in clinical practice and research.

Outcomes of minor and subsyndromal depression among elderly patients in primary care settings.

BACKGROUND: Although depressive conditions in later life are a major public health problem, the outcomes of minor and subsyndromal depression are largely unknown. OBJECTIVE: To compare outcomes among patients with minor and subsyndromal depression, major depression, and no depression, and to examine putative outcome predictors. DESIGN: Cohort study. SETTING: Patients from primary care practices in greater New York City, and Philadelphia and Pittsburgh, Pennsylvania. PATIENTS: 622 patients who were at least 60 years of age and presented for treatment in primary care practices that provided usual care in a randomized, controlled trial of suicide prevention. Of the 441 (70.9%) patients who completed 1 year of follow-up, 122 had major depression, 205 had minor or subsyndromal depression, and 114 did not have depression at baseline. MEASUREMENTS: One year after a baseline evaluation, data were collected by using the following tools: Hamilton Depression Rating Scale, the depressive disorders section of the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, fourth edition), Charlson Comorbidity Index, Multilevel Assessment Instrument for measuring instrumental activities of daily living, Physical Component Summary of the Medical Outcomes Study Short Form-36, and Duke Social Support Index. RESULTS: Patients with minor or subsyndromal depression had intermediate depressive and functional outcomes. Mean adjusted 1-year Hamilton depression score was 10.9 (95% CI, 9.6 to 12.2) for those with initial major depression, 7.0 (CI, 5.9 to 8.1) for those with minor or subsyndromal depression, and 2.9 (CI, 1.6 to 4.2) for those without depression (P < 0.001 for each paired comparison). Compared with patients who were not depressed, those who had minor or subsyndromal depression had a 5.5-fold risk (CI, 3.1-fold to 10.0-fold) for major depression at 1 year after controlling for demographic characteristics (P < 0.001). Cerebrovascular risk factors were not associated with a diagnosis of depression at 1 year after controlling for overall medical burden. Initial medical burden, self-rated health, and subjective social support were significant independent predictors of depression outcome. LIMITATIONS: Participants received care at practices that had personnel who had been given enhanced education about depression treatment; 29.1% of participants withdrew from the study before completing 1 year of follow-up. CONCLUSIONS: The intermediate outcomes of minor and subsyndromal depression demonstrate the clinical significance of these conditions and suggest that they are part of a spectrum of depressive illness. Greater medical burden, poor subjective health status, and poorer subjective social support confer a higher risk for poor outcome.

Effectiveness of a two-part educational intervention to improve hypertension control: a cluster-randomized trial.

STUDY OBJECTIVE: To measure the effectiveness of a multifaceted educational intervention to improve ambulatory hypertension control. DESIGN: Cluster-randomized trial. SETTING: Academic health system using an ambulatory electronic medical record. SUBJECTS: A total of 10,696 patients with a diagnosis of hypertension cared for by 93 primary care providers. INTERVENTION: Academic detailing, provision of provider-specific data about hypertension control, provision of educational materials to the provider, and provision of educational and motivational materials to patients. MEASUREMENTS AND MAIN RESULTS: The primary outcome was blood pressure control, defined as a blood pressure measurement below 140/90 mm Hg, and was ascertained from electronic medical records over 6 months of follow-up. We determined the adjusted odds ratio for the association between the intervention and the achievement of controlled blood pressure. When we accounted for clustering by provider, this adjusted odds ratio was 1.13 (95% confidence interval 0.87-1.47). Adjusted odds ratios were 1.03 (95% confidence interval 0.78-1.36) in patients whose blood pressure was controlled at baseline and 1.25 (95% confidence interval 0.94-1.65) in those whose blood pressure was not. These odds ratios were not significantly different (p=0.11). CONCLUSIONS: These results were consistent with no effect or, at best, a relatively modest effect of the intervention among patients with hypertension. Had we not included a concurrent control group, the data would have provided an unduly optimistic view of the effectiveness of the program. The effectiveness of future interventions may be improved by focusing on patients whose blood pressure is uncontrolled at baseline.

Association of depression with viral load, CD8 T lymphocytes, and natural killer cells in women with HIV infection.

OBJECTIVE: Clinical and epidemiology studies have implicated depression as a risk factor in the morbidity and mortality of many human diseases. This study sought to determine if depression was associated with alterations in cellular immunity variables-specifically, natural killer (NK) cells and CD8 T lymphocytes-in women with HIV infection. METHOD: Ninety-three women (63 HIV-seropositive, 30 HIV-seronegative) were studied as part of an ongoing longitudinal study conducted at two sites. Subjects underwent extensive clinical, psychiatric, and immunological evaluations. CBC counts and flow cytometry panels were conducted and NK cell activity assayed for all subjects; viral load was determined for HIV-seropositive subjects. RESULTS: The overall rate of major depression in the HIV-seropositive and HIV-seronegative women was 15.87% (N=10 of 63) and 10.00% (N=3 of 30), respectively. HIV-seropositive women had higher depressive symptom scores than did the comparison subjects (Hamilton depression scale: mean=8.62 [SD=7.26] versus mean=5.67 [SD=7.33], respectively). Both groups had similar anxiety scores. Depressive and anxiety symptoms were significantly associated with higher activated CD8 T lymphocyte counts and higher viral load levels. Major depression was associated with significantly lower natural killer cell activity, and depressive and anxiety symptom scores showed a similar correlation. CONCLUSIONS: Our findings provide the first evidence that depression may alter the function of killer lymphocytes in HIV-infected women and suggest that depression may decrease natural killer cell activity and lead to an increase in activated CD8 T lymphocytes and viral load. The rate of current major depression in these HIV-seropositive women (none of whom had current substance abuse) is approximately twice that reported for HIV-seropositive men. The rate is also consistent with studies of women with other medical illnesses and with a recent epidemiology study that associated depression with mortality in HIV-infected women with chronic depressive symptoms. Depression may have a negative impact on innate immunity. Examination of killer lymphocytes may prove useful in assessing the potential relationship between depression, immunity, and HIV disease progression in women.

Probing the safety of medications in the frail elderly: evidence from a randomized clinical trial of sertraline and venlafaxine in depressed nursing home residents.

BACKGROUND: In nursing home residents and other frail elderly patients, old age and potential drug-drug and drug-disease interactions may affect the relative safety and efficacy of medications. The purpose of this study was to examine the efficacy and tolerability of venlafaxine and sertraline for the treatment of depression among nursing home residents. METHOD: The study was a 10-week randomized, double-blind, controlled trial of venlafaxine (doses up to 150 mg/day) versus sertraline (doses up to 100 mg/day) among 52 elderly nursing home residents with a DSM-IV depressive disorder and, at most, moderate dementia. The primary measure of outcome was the Hamilton Rating Scale for Depression (HAM-D). Adverse events were monitored and recorded systematically during the trial. RESULTS: Twelve subjects were discontinued due to serious adverse events (SAE), 5 were discontinued due to other significant side effects, and 2 withdrew consent. Tolerability estimated by the time to termination was lower for venlafaxine than sertraline for serious adverse events (log rank statistic = 5.28, p =.022), for serious adverse events or side effects (log rank statistic = 8.08, p =.005), or for serious adverse events, side effects, or withdrawal of consent (log rank statistic = 10.04, p =.002). Mean (SD) HAM-D scores at baseline were 20.2 (3.4) for sertraline and 20.3 (3.7) for venlafaxine; intent-to-treat endpoint HAM-D scores were 12.2 (5.1) and 15.7 (6.2) (F = 3.45; p =.069). There were no differences in categorical responses for the intent-to-treat sample or completers. CONCLUSION: In this frail elderly population, venlafaxine was less well tolerated and, possibly, less safe than sertraline without evidence for an increase in efficacy. This unexpected finding demonstrates the need for systematic research on the safety of drugs in the frail elderly.