The effects of serotonin3 receptor blockade on the psychobiological response to intravenous clomipramine in healthy human subjects.

BACKGROUND: The purpose of this study was to determine the role that serotonin (5-HT)3 receptors play in the prolactin and nausea responses to clomipramine challenge. METHODS: Twenty healthy subjects were randomly assigned to pretreatment with either the selective 5-HT3 receptor antagonist ondansetron, or placebo, prior to intravenous infusion with clomipramine. RESULTS: Ondansetron pretreatment had no effect on the prolactin response to clomipramine challenge. There was a trend toward decreased nausea with ondansetron pre-treatment. CONCLUSIONS: These findings are consistent with other data suggesting that 5-HT3 receptors do not play a major role in the prolactin response to 5-HT challenge in human subjects, but may mediate nausea associated with enhanced 5-HT neurotransmission.

Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2's neurotrophic effects?

BACKGROUND: Recent preclinical studies have shown that lithium (Li) robustly increases the levels of the major neuroprotective protein, bcl-2, in rat brain and in cells of human neuronal origin. These effects are accompanied by striking neuroprotective effects in vitro and in the rodent central nervous system in vivo. We have undertaken the present study to determine if lithium exerts neurotrophic/ neuroprotective effects in the human brain in vivo. METHODS: Using quantitative proton magnetic resonance spectroscopy, N-acetyl-aspartate (NAA) levels (a putative marker of neuronal viability and function) were investigated longitudinally in 21 adult subjects (12 medication-free bipolar affective disorder patients and 9 healthy volunteers). Regional brain NAA levels were measured at baseline and following 4 weeks of lithium (administered in a blinded manner). RESULTS: A significant increase in total brain NAA concentration was documented (p < .0217). NAA concentration increased in all brain regions investigated, including the frontal, temporal, parietal, and occipital lobes. CONCLUSIONS: This study demonstrates for the first time that Li administration at therapeutic doses increases brain NAA concentration. These findings provide intriguing indirect support for the contention that chronic lithium increases neuronal viability/function in the human brain, and suggests that some of Li's long-term beneficial effects may be mediated by neurotrophic/neuroprotective events.

Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness.

OBJECTIVE: The most widely accepted hypothesis regarding the mechanism underlying lithium's therapeutic efficacy in manic-depressive illness (bipolar affective disorder) is the inositol depletion hypothesis, which posits that lithium produces a lowering of myo-inositol in critical areas of the brain and the effect is therapeutic. Lithium's effects on in vivo brain myo-inositol levels were investigated longitudinally in 12 adult depressed patients with manic-depressive illness. METHOD: Medication washout (minimum 2 weeks) and lithium administration were conducted in a blinded manner. Regional brain myo-inositol levels were measured by means of quantitative proton magnetic resonance spectroscopy at three time points: at baseline and after acute (5-7 days) and chronic (3-4 weeks) lithium administration. RESULTS: Significant decreases (approximately 30%) in myoinositol levels were observed in the right frontal lobe after short-term administration, and these decreases persisted with chronic treatment. The severity of depression measured by the Hamilton Depression Rating Scale also decreased significantly over the study. CONCLUSIONS: This study demonstrates that lithium administration does reduce myo-inositol levels in the right frontal lobe of patients with manic-depressive illness. However, the acute myo-inositol reduction occurs at a time when the patient's clinical state is clearly unchanged. Thus, the short-term reduction of myo-inositol per se is not associated with therapeutic response and does not support the inositol depletion hypothesis as originally posited. The hypothesis that a short-term lowering of myo inositol results in a cascade of secondary signaling and gene expression changes in the CNS that are ultimately associated with lithium's therapeutic efficacy is under investigation.

Modulation of CNS signal transduction pathways and gene expression by mood-stabilizing agents: therapeutic implications.

In an attempt to find the key to reducing the excessive morbidity and mortality seen with mood disorders, our laboratory has been extensively investigating lithium's mechanisms of action in an integrated series of clinical and preclinical studies. We have found that the chronic administration of the 2 structurally highly dissimilar agents, lithium and valproate, brings about a strikingly similar reduction in protein kinase C (PKC) alpha and epsilon isozymes in rat frontal cortex and hippocampus. In view of PKC's critical role in regulating neuronal excitability and neurotransmitter release, we have postulated that PKC inhibition may have antimanic efficacy. In a small study, we have found that tamoxifen (which, in addition to its estrogen receptor blockade, is also a PKC inhibitor) has marked antimanic efficacy. These exciting preliminary results suggest that PKC inhibitors may represent a novel class of improved therapeutic agents for bipolar disorder, and this is under further investigation. The beneficial effects of mood stabilizers require a lag period for onset of action and are generally not immediately reversed upon drug discontinuation; such patterns of effects suggest alterations at the genomic level. We have therefore undertaken a series of studies to investigate the effects of these agents on the AP-1 family of transcription factors and have found that both drugs increase AP-1 DNA binding activity in areas of rodent brain ex vivo and in human neuronal cells in culture. Both treatments also increase the expression of a reporter gene driven by an AP-1-containing promoter, and mutations in the AP-1 sites of the reporter gene promoter markedly attenuate these effects. Both treatments also increase the expression of several endogenous proteins, whose genes are known to be regulated by AP-1. Although the precise mechanisms have not been fully elucidated, preliminary results suggest that these effects may be mediated, in part, by mitogen-activating protein kinases and glycogen synthase kinase 3beta. We have also utilized mRNA reverse transcription-polymerase chain reaction (RT-PCR) differential display to identify concordant changes in gene expression induced by the chronic administration of both lithium and valproate. We have identified concordant changes in a number of cDNA bands by both lithium and valproate. Cloning and characterizing of these genes is currently underway. The identification of the functions of these genes offers the potential not only for improved therapeutics for reducing the morbidity and mortality associated with mood disorders, but may also provide important clues about the underlying pathophysiology.

Surveillance of vaccine-related adverse events in the first year of life: a Manitoba cohort study.

This study used data from the population database through which the province of Manitoba, Canada, administers its universal health insurance plan. Enrollment, hospitalization, and immunization files from children born in the 1987-1989 period were linked using the unique identification number assigned to each population member. Analysis of these linked data successfully identified serious potential adverse events in the first year of life and the timing of events around immunization. Not only is population-based active surveillance for immunization-related events feasible, but the techniques described, applied to years of data accumulated through surveillance, offer powerful research tools. Baseline population incidences of adverse events were calculated, temporal relationships between events and immunization assessed, and incidences for events showing true temporal associations determined. Eventual goals are the quantification of vaccine-related risk and the gathering of evidence concerning casual associations. The approach could be used readily by several other Canadian provinces and by health maintenance organizations in the United States.

Neurobiology of social phobia.

Social phobia is an anxiety disorder that is characterized by excessive fear and/or avoidance of situations in which an individual believes that he or she may be the subject of evaluation or scrutiny while interacting with other people or performing a specific task. This article reviews the available literature on the neurobiology underlying social phobia, including autonomic nervous system effects, neuroimaging findings, pharmacologic challenge studies, and neuroendocrine responsivity and function. Overall, such studies have found few consistently demonstrable differences in neurobiology between patients with social phobia and healthy controls, but further investigations are needed.

Using process data to explain outcomes. An illustration from the Child and Adolescent Trial for Cardiovascular Health (CATCH).

The purpose of this article is to illustrate the use of process evaluation for understanding study outcomes. Data from the Child and Adolescent Trial for Cardiovascular Health (CATCH), a large school-based field trial, are used. Teacher characteristics, measures of classroom curriculum implementation, and competing influences are linked to changes in dietary knowledge, intentions, and self-efficacy of students in the intervention schools. Multiple regression analyses indicate that teacher characteristics did not predict program implementation. Teacher characteristics and program fidelity, or the number of modifications made to the classroom curriculum during implementation, had direct and independent effects on student outcomes.

The feasibility of clinical endpoint trials in HIV infection in the highly active antiretroviral treatment (HAART) era.

BACKGROUND: Planning clinical-endpoint trials in patients with HIV remain difficult as long-term follow-up of many patients is required. Cohort studies of patients with HIV can provide key estimates of the likely disease progression, required sample size and follow-up. OBJECTIVES: To verify the assumptions used in designing ESPRIT, a large randomized clinical trial assessing the clinical benefit of interleukin-2 treatment in patients with HIV infection, to use EuroSIDA to mimic the inclusion criterion of ESPRIT in order to compare the observed event rate in ESPRIT with the projected rate in EuroSIDA, and to project the required length of ESPRIT. METHODS: Patients in EuroSIDA who satisfied the ESPRIT recruitment criteria were selected. Patients were followed from baseline to new AIDS or death. RESULTS: The incidence of clinical progression in the selected EuroSIDA patients (N = 4482) was 1.5 per 100 PYFU (95% CI 1.3-1.7), and did not increase with increasing time from baseline, contrary to what was assumed in the design of the ESPRIT trial. In ESPRIT (N = 4150), for which the comparative data remain blinded, the incidence was 1.1 per 100 PYFU (95% CI 0.9-1.3), with no increase over time. The average follow-up required to complete ESPRIT and accrue the 320 events required by protocol would be seven years, 10 months using the projected rates from the EuroSIDA study, and seven years, 11 months if the observed event rate in ESPRIT continued unchanged. LIMITATIONS: Differences between patients recruited to observational studies or clinical trials cannot always be adjusted for. CONCLUSIONS: Event rates in EuroSIDA were similar in the first two years to those used in the design of ESPRIT, but did not increase over time, leading to an increase in the expected duration of ESPRIT. Clinical endpoint trials in HIV infection remain feasible, and large cohort studies are critical to the planning and ongoing assessment of design assumptions in such trials. The underlying assumptions of the clinical trial should be re-examined to ensure the original trial assumptions remain valid.

Drug interaction between rifampin and nortriptyline: a case report.

This case illustrates a pharmacokinetic interaction between the tricyclic antidepressant, nortriptyline, and the antituberculosis drug, rifampin. Higher than expected doses of nortriptyline were required to obtain a therapeutic drug level while the patient was receiving rifampin. Following the discontinuation of rifampin, the patient became drowsy and the serum nortriptyline levels rose precipitously into the toxic range. The authors suggest that patients receiving rifampin and nortriptyline, (or other psychotropic drugs) be monitored closely and that similar drug interactions be anticipated.

Multiple imputation for simple estimation of the hazard function based on interval censored data.

A data augmentation algorithm is presented for estimating the hazard function and pointwise variability intervals based on interval censored data. The algorithm extends that proposed by Tanner and Wong for grouped right censored data to interval censored data. It applies multiple imputation and local likelihood methods to obtain smooth non-parametric estimates for the hazard function. This approach considerably simplifies the problem of estimation for interval censored data as it transforms it into the more tractable problem of estimation for right censored data. The method is illustrated for two real data sets: times to breast cosmesis deterioration and times to HIV-1 infection for individuals with haemophilia. Simulations are presented to assess the effects of various parameters on the estimates and their variances.

Using administrative health data to monitor potential adverse health effects in environmental studies.

Following episodes of environmental contamination, health professionals are limited in their ability to detect adverse health effects in surrounding communities due to lack of relevant baseline health data, resources, and appropriate control populations. The objective of this study was to ascertain the feasibility of using administrative health data for these purposes. The Manitoba Health Services Commission's (MHSC) database is comprehensive since universal health care is free in Canada. As part of an evaluation of two proposed hazardous waste treatment sites, the feasibility of using MHSC's data was tested by (a) defining the two study and control sites through use of MHSC's population registry and (b) determining baseline morbidity rates through analysis of MHSC's physician visit payment files; diagnoses were coded using ICD-9-CM. The results indicated that there were some differences between the groups studied in the age- and sex-standardized morbidity rates of diagnoses potentially influenced by exposures to chemicals. Use of administrative data provided by a national health service is an inexpensive and efficient way to create and follow potentially exposed cohorts residing in defined communities. Despite limitations related to small populations in exposed communities and lack of standardized diagnostic criteria by physicians, this method should be explored further in environmental studies.

Monitoring childhood immunizations: a Canadian approach.

In Manitoba, Canada, a centralized, computerized childhood immunization monitoring system serves a population with insured medical coverage; each individual has a unique identification number. All physicians bill a single payer, and specific billing codes are used to identify immunizations given by physicians and by public health nurses. Together with dates of service, this information is used to construct immunizations-to-date and age-at-immunization profiles for individuals and groups. Reminders seeking missing information are built into the system and executed at strategic ages. The quality of input data has been assessed as high. The approach could be used readily by health maintenance organizations in the United States.

Lithium-induced increase in human brain grey matter.

Rodent studies have shown that lithium exerts neurotrophic or neuroprotective effects. We used three-dimensional magnetic resonance imaging and brain segmentation to study pharmacologically-induced increases in grey matter volume with chronic lithium use in patients with bipolar mood disorder. Grey-matter volume increased after 4 weeks of treatment. The increases in grey matter probably occurred because of neurotrophic effects.

Regulation of signal transduction pathways and gene expression by mood stabilizers and antidepressants.

OBJECTIVE: To determine whether the currently available evidence supports the hypothesis that antidepressants and mood stabilizers may bring about some of their long-term therapeutic effects by regulating signal transduction pathways and gene expression in the central nervous system. METHODS: To address this question, we reviewed the evidence showing that chronic administration of antidepressants and mood stabilizers involves alterations in signaling pathways and gene expression in the central nervous system. RESULTS: A large body of data has shown that lithium and valproate exert effects on the protein kinase C signaling pathway and the activator protein 1 family of transcription factors; in contrast, antidepressants affect the cyclic adenosine monophosphate pathway and may bring about their therapeutic effects by modulating cyclic adenosine monophosphate-regulated gene expression in the central nervous system. CONCLUSIONS: Given the key roles of these signaling cascades in the amplification and integration of signals in the central nervous system, the findings have clear implications not only for research into the etiology and pathophysiology of the severe mood disorders but also for the development of novel and innovative treatment strategies.

Changes in mortality after myocardial revascularization in the elderly. The national Medicare experience.

OBJECTIVE: To examine secular changes in the use and outcome of percutaneous transluminal coronary angioplasty and cardiac bypass graft surgery in the elderly. DESIGN: A retrospective cohort study based on a longitudinal database created from the administrative files of Medicare. SETTING: U.S. hospitals that perform myocardial revascularization procedures covered by Medicare. PATIENTS: 225,915 consecutive patients who had angioplasty and 357,885 consecutive patients who had bypass surgery from 1987 to 1990. MEASUREMENTS: The rates of angioplasty and bypass surgery use; unadjusted 30-day and 1-year mortality rates after revascularization; and adjusted odds ratios for mortality by year of procedure for 1987 to 1990. RESULTS: From 1987 to 1990, the rates of angioplasty and bypass surgery done in the elderly increased by 55% and 18%, respectively. During this period, 30-day unadjusted mortality rates after angioplasty and bypass surgery decreased by 25% (95% CI, 22% to 28%) and 12% (CI, 10% to 14%), and 1-year mortality rates decreased by 10% (CI, 8% to 11%) and 8% (CI, 7% to 10%), respectively. After adjustment for changes in patient characteristics, 30-day mortality rates after these procedures decreased by 37% (CI, 32% to 41%) and 18% (CI, 14% to 21%), and 1-year mortality rates decreased by 22% (CI, 18% to 25%) and 19% (CI, 16% to 21%), respectively. CONCLUSIONS: The use of cardiac revascularization procedures in the elderly has steadily increased. Patients who had revascularization are progressively older, have more coded comorbid conditions, and present with more acute diseases. Although elderly patients have apparently higher risk profiles, mortality rates after angioplasty and bypass surgery in the elderly have decreased, suggesting a national improvement in the outcomes of these interventions. Health policy decisions concerning revascularization procedures in the elderly must consider these trends in improved outcome.

Outcomes of coronary artery bypass graft surgery in 24,461 patients aged 80 years or older.

BACKGROUND: Coronary artery bypass graft surgery is increasingly common in patients of age > or = 80 years. Single-institution reviews have cited a wide range of mortality results after bypass surgery in this age group, in part because of limited sample sizes. Using claims data, we examined recent national trends in the use and outcomes of bypass surgery in the very elderly. METHODS AND RESULTS: From an examination of Medicare data from 1987 through 1990, we identified 24,461 patients of age > or = 80 years who underwent bypass surgery. We compared surgical outcomes in these patients with those in Medicare patients of age 65 to 70 years. We found that the national use of bypass surgery in patients of age > or = 80 years increased 67% between 1987 and 1990. Compared with patients of age 65 to 70 years, the very elderly had significantly longer postoperative hospital stays (mean, 14.3 versus 10.4 days), higher charges (mean, $48,200 versus $38,000), and greater costs (mean, $27,200 versus $21,700). In-hospital (11.5% versus 4.4%), 1-year (19.3% versus 7.9%), and 3-year mortality rates (28.8% versus 13.1%) after bypass surgery were also significantly higher in patients of age > or = 80 years compared with younger patients. Although their initial surgical risk was high, octogenarians who underwent bypass surgery had a long-term survival rate similar to that of the general US octogenarian population. CONCLUSIONS: The use of bypass surgery in patients of age > or = 80 years in increasing. These very elderly patients face high surgical risks and accumulate significant hospital expenses. Further research is indicated to determine whether the long-term benefits from bypass surgery in the very elderly outweigh the increased procedural risks.

The effect of adult participation in a school-based family intervention to improve Children's diet and physical activity: the Child and Adolescent Trial for Cardiovascular Health.

UNLABELLED: BACKGROUND. There are strong theoretical reasons for including a family component with a school-based intervention aimed at eating, activity, and smoking behaviors, but the empirical findings to date are limited and show mixed results. The overall CATCH family intervention added only knowledge and attitudinal effects, but no additional behavioral outcomes. This study provides a dose analysis of the family component of the CATCH study by assessing the effect of the level of adult participation. METHOD: This secondary analysis included students who attended a CATCH family intervention school during all 3 years of the study. The extent of the adult-child interaction, the key aspect of the CATCH family intervention, was measured by the number of activity packets that an adult household member completed with the child. Multiple regression analysis was used to assess the association of adult participation with the child's knowledge, attitudes, and behaviors related to diet and physical activity. RESULTS: Statistically significant results suggested that dose effects were found for knowledge and attitudes related to diet and physical activity. These effects were more pronounced for minority and male students. CONCLUSIONS: These results suggest that dose response of a family intervention has been shown in the acquisition of positive knowledge and attitudes toward health habit changes. The methodology of dose response can be applied to other health promotion projects.

Goodness-of-fit for GEE: an example with mental health service utilization.

Suppose we use generalized estimating equations to estimate a marginal regression model for repeated binary observations. There are no established summary statistics available for assessing the adequacy of the fitted model. In this paper we propose a goodness-of-fit test statistic which has an approximate chi-squared distribution when we have specified the model correctly. The proposed statistic can be viewed as an extension of the Hosmer and Lemeshow goodness-of-fit statistic for ordinary logistic regression to marginal regression models for repeated binary responses. We illustrate the methods using data from a study of mental health service utilization by children. The repeated responses are a set of binary measures of service use. We fit a marginal logistic regression model to the data using generalized estimating equations, and we apply the proposed goodness-of-fit statistic to assess the adequacy of the fitted model.