Transgenic mice lacking class I major histocompatibility complex-restricted T cells have delayed viral clearance and increased mortality after influenza virus challenge.

To investigate the role of CD8+ T lymphocytes in recovery from influenza pneumonia, we used transgenic mice either homozygous (-/-) or heterozygous (+/-) for beta 2-microglobulin (beta 2-M) gene disruption. These mice lack major histocompatibility complex-restricted class I (CD8+) T cells. We found that after challenge with a nonlethal influenza virus, the beta 2-M (-/-) mice had significantly delayed pulmonary viral clearance. Furthermore, after challenge with a more virulent influenza virus, the beta 2-M (-/-) mice had a significantly higher mortality rate than did control mice. Thus, CD8+ T cells are important in recovery from virulent influenza infections, but other host defense mechanisms can clear the respiratory tract of more benign infections.

The effects of adherence to antidepressant treatment guidelines on relapse and recurrence of depression.

BACKGROUND: Depression is associated with high rates of relapse and recurrence during a patient's lifetime. Current guidelines regarding treatment recommend 4 to 9 months of continuation antidepressant therapy following remission of acute symptoms to allow more complete resolution of the episode. In this article, we test whether adherence to these recommendations reduces the likelihood of relapse or recurrence in a Medicaid population. METHODS: We used a Medicaid database covering 1989 through 1994. The sample consists of the 4052 adult patients who filled an antidepressant prescription at the time of an initial diagnosis of depression. These patients were followed up for up to 2 years. Timing and counts of antidepressant prescription claims are used to construct a proxy measure for adherence to guidelines. Relapse or recurrence is defined by evidence of a new episode requiring antidepressant treatment, hospital admission for depression, electroconvulsive therapy, emergency department visit for mental health, or attempted suicide. We used survival analysis to predict relapse or recurrence for each patient and to examine the effect of following treatment guidelines on relapse and recurrence. RESULTS: Approximately one fourth of the patients had a relapse or recurrence during their follow-up period. Factors that affect relapse and recurrence include comorbidities, race, and guideline adherence. Those who continued therapy with their initial antidepressant were least likely to experience relapse or recurrence; those who discontinued their antidepressant early were most likely to experience relapse or recurrence. CONCLUSION: Adherence to depression treatment guidelines with an antidepressant that is likely to have continuous use by patients reduces the probability of relapse or recurrence.

Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence.

BACKGROUND: Depression and anxiety are common in medical patients and are associated with diminished health status and increased health care utilization. This article presents a quantitative review and synthesis of studies correlating medical patients' treatment noncompliance with their anxiety and depression. METHODS: Research on patient adherence catalogued on MEDLINE and PsychLit from January 1, 1968, through March 31, 1998, was examined, and studies were included in this review if they measured patient compliance and depression or anxiety (with n>10); involved a medical regimen recommended by a nonpsychiatrist physician to a patient not being treated for anxiety, depression, or a psychiatric illness; and measured the relationship between patient compliance and patient anxiety and/or depression (or provided data to calculate it). RESULTS: Twelve articles about depression and 13 about anxiety met the inclusion criteria. The associations between anxiety and noncompliance were variable, and their averages were small and nonsignificant. The relationship between depression and noncompliance, however, was substantial and significant, with an odds ratio of 3.03 (95% confidence interval, 1.96-4.89). CONCLUSIONS: Compared with nondepressed patients, the odds are 3 times greater that depressed patients will be noncompliant with medical treatment recommendations. Recommendations for future research include attention to causal inferences and exploration of mechanisms to explain the effects. Evidence of strong covariation of depression and medical noncompliance suggests the importance of recognizing depression as a risk factor for poor outcomes among patients who might not be adhering to medical advice.

Clonal analysis of peripheral T cell precursors in lpr mice.

MRL/Mp-lpr/lpr mice develop massive lymphadenopathy characterized by expansion of an unusual population of T cells with the Thy 1+, CD3+, CD4-, CD8- (double negative) phenotype. The role these cells play in accelerating the autoimmune syndrome seen in these mice is unknown. In order to better understand the origin of the expanded population of T cells, we have derived a panel hybridomas from double negative lpr lymph node cells. Surprisingly, eleven of twelve hybridomas selected for the absence of surface CD4 and CD8 do not express CD3. Six of eleven confirmed to have inherited the MRL T cell receptor locus have rearrangement at that locus, suggesting commitment to a T cell lineage. Only hybridoma 2.4, which expresses CD3, responds to ConA, anti-CD3 monoclonal antibody, and induces antibody production. The presence of CD3-, CD4-, CD8- T cells in the periphery of lpr mice confirms aberrant T cell development in these mice and suggests an intrinsic cell defect which is expressed early in lymphopoiesis.

Racial variation in antidepressant treatment in a Medicaid population.

BACKGROUND: Many studies have found racial and socioeconomic variation in medical care for a variety of conditions. Undertreatment of depression for individuals of all races is a concern, but especially may affect vulnerable populations such as Medicaid recipients and minorities. With this study, we examine racial differences in the antidepressant usage in a Medicaid population. METHOD: Treatment of 13,065 depressed patients (ICD-9-CM criteria) was examined in a state Medicaid database covering the years 1989 through 1994. Treatment differences were assessed in terms of whether an antidepressant was received at the time of the initial depression diagnosis and the type of antidepressant prescribed (tricyclic antidepressants [TCAs] vs. selective serotonin reuptake inhibitors [SSRIs]), using logistic regression techniques. RESULTS: African Americans were less likely than whites to receive an antidepressant at the time of their initial depression diagnosis (27.2% vs. 44.0%, p < .001). Of those receiving an antidepressant, whites were more likely than African Americans to receive SSRIs versus TCAs. These findings remained even after adjusting for other covariates. CONCLUSION: Despite the easy availability of effective treatments, we found that only a small portion of depressed Medicaid recipients receive adequate usage of antidepressants. Within this Medicaid population, limited access to treatment was especially pronounced among African Americans. Racial differences existed in terms of whether an antidepressant was received and the type of medication used.

Economic consequences of selective serotonin reuptake inhibitor use with drugs also metabolized by the cytochrome P-450 system.

Administration of selective serotonin reuptake inhibitors (SSRIs) may increase plasma concentrations of concomitant medications that are also metabolized by the cytochrome P-450 system (CYP-450), in particular by the 2D6 and 3A4 isoenzymes. This may lead to side effects or other clinical events that might be expected to incur higher health-care expenditures. The purpose of this study was to assess whether there was a difference in expenditures during the first 90 days of SSRI therapy with paroxetine or sertraline versus fluoxetine in patients who were also receiving a stable dosage of a nonpsychiatric drug also metabolized by the CYP-450 2D6 or 3A4 isoenzyme systems. A sample of 2445 patients who initiated therapy with an SSRI while receiving a stable dosage of a nonpsychiatric drug was obtained from a private insurance claims database. Multivariate regression techniques were used to estimate total health-care expenditures in the first 90 days after receiving a prescription for an SSRI. After adjusting for nonrandom SSRI prescription patterns and controlling for observable and unobservable characteristics that might correlate with SSRI selection, total health-care expenditures were 95% higher for patients initiating SSRI therapy with sertraline or paroxetine compared with fluoxetine. Results suggest that there are cost differences between SSRIs during concomitant therapy with drugs also metabolized by the CYP-450 system. To determine whether there are additional differences in expenditures across SSRIs, future research should focus on (1) simultaneous initiation of SSRI therapy and a nonpsychiatric drug also metabolized by the CYP-450 enzyme system, and (2) addition of nonpsychiatric drug therapy to stable SSRI therapy. Relationships between additional expenditures, drug interactions, and clinical outcomes should also be assessed directly using medical records and patient interview data that are not available in claims-based files.

What does treatment of depression really cost?

This DataWatch presents estimates of the health care charges for adults who are diagnosed and treated for depression in primary care. More than nine out of ten of these adults sought care for at least one nondepressive illness during the year following treatment initiation. One average, these conditions accounted for more than 70 percent of the total charges. Attempts to manage the costs of caring for depressed persons must consider the impact of nondepressive illness.

Determinants of antidepressant treatment compliance: implications for policy.

Depression is among the most prevalent, devastating, and undertreated disorders in our society. Treatment with antidepressant medications is effective in controlling symptoms, but treatment beyond the point of symptom resolution is necessary to restore functional status and prevent recurrent episodes. An important step in improving compliance is to identify the determinants of antidepressant treatment compliance. A broader motivation for our study is to examine compliance by patients with a chronic but treatable disease. With claims data between 1990 and 1993, this study uses logistic regression analysis to examine the determinants of compliance among 2,012 antidepressant recipients. The results show that initiating treatment with a tricyclic antidepressant reduces the probability of antidepressant treatment compliance. Initiating treatment with a selective serotonin reuptake inhibitor and undergoing family, group, or individual psychotherapy treatments increase the probability of compliance. Case management does not meaningfully affect compliance. Implications for policy and clinical practice are discussed.

Tricyclic antidepressant and selective serotonin reuptake inhibitors antidepressant selection and health care costs in the naturalistic setting: a multivariate analysis.

BACKGROUND: Providers and payers have an interest in the total health care costs following the initiation of antidepressant treatment in the real world of clinical practice. Analyses of these costs can help evaluate the economic consequences of patient management decisions associated with initial antidepressant selection. OBJECTIVE: The purpose of this study was to assess the 1-year total direct health care costs for patients initiating therapy with one of the available tricyclic antidepressants (TCAs) or one of the three most often prescribed selective serotonin reuptake inhibitors (SSRIs) - paroxetine, sertraline, or fluoxetine. METHOD: A two-stage multivariate econometric model and data from fee-for-service private insurance claims between 1990 and 1994 were used to estimate the total direct health care costs following initial antidepressant drug selection for 2693 patients with a 'new' episode of antidepressant treatment. After controlling for both observed and unobserved characteristics, the 1-year total direct health care costs were found to be (1) statistically significantly lower for patients initiating therapy on fluoxetine than for patients initiating therapy on a TCA; (2) statistically significantly lower for patients who initiated therapy on fluoxetine than for patients initiating therapy on sertraline. CONCLUSIONS: Broadly considered, the findings in this study suggest that total direct health care costs differ across initial antidepressant selection after controlling for both observed and unobserved characteristics.

Bootstrap analyses of cost effectiveness in antidepressant pharmacotherapy.

In this study, we describe 'bootstrap' methodology for placing statistical confidence limits around an incremental cost effectiveness ratio (ICER). This approach was applied to a retrospective study of annual charges for patients undergoing pharmacotherapy for depression. We used MarketScanSM (service mark) data from 1990 to 1992, which includes medical and pharmacy claims for a privately insured group of employed individuals and their families in the US. Our primary effectiveness measure was the proportion of patients who remained stable on their initial antidepressant medication for at least 6 consecutive months. Our primary cost measure was the total annual charge incurred by patients taking the selective serotonin reuptake inhibitor fluoxetine, a tricyclic antidepressant or a heterocyclic antidepressant. On average, fluoxetine pharmacotherapy tended to decrease annual charges by $US16.48 per patient for each percentage increase in depressed patients remaining stable on initial pharmacotherapy for 6 months, resulting in a negative ICER point-estimate. However, the upper ICER confidence limit is positive, which means that fluoxetine treatment may possibly increase annual per patient charges. With 95% confidence, any such increase was no more than $US130 per patient for each percentage increase in patients remaining stable on initial pharmacotherapy for at least 6 months. One advantage of using a bootstrap approach to ICER analysis is that it does not require restrictive distributional assumptions about cost and outcome measures. Bootstrapping also yields a dramatic graphical display of the variability in cost and effectiveness outcomes that result when a study is literally 'redone' hundreds of times. This graphic also displays the ICER confidence interval as a 'wedge-shaped' region on the cost-effectiveness plane. In fact, bootstrapping is easier to explain and appreciate than the elaborate calculations and approximations otherwise involved in ICER estimation. Our discussion addresses key technical questions, such as the role of logarithmic transformation in symmetrising highly skewed cost distributions. We hope that our discussion contributes to a dialogue, leading ultimately to a consensus on analysis of ICERs.

Determinants of antidepressant treatment outcome.

OBJECTIVE: To understand the determinants of the outcome of an episode of major depression, including factors that affect receipt of guideline-consistent care and their subsequent effect on treatment outcomes, particularly relapse or recurrence. Results of previous studies are generalized to a population typical of depressed individuals in the United States, i.e., a cohort of antidepressant users with employer-provided health benefits. STUDY DESIGN: A quasi-experimental design was used to assess the determinants of the outcome of an episode of major depression. Healthcare utilization-based measures of treatment characteristics and outcomes were used. PATIENTS AND METHODS: The final analytical file for this study contained data on 2917 patients who had an antidepressant prescription associated with an indicator of a depressive disorder. We identified relapse or recurrence of depression by (1) a new episode of antidepressant therapy, (2) suicide attempt, (3) psychiatric hospitalization, (4) mental health-related emergency department visits, or (5) electroconvulsive therapy. Antidepressant use patterns were used to construct a measure for adherence to treatment guidelines. Multivariate Cox proportional hazard and logit regression models were used to predict relapse/recurrence and adherence with treatment guidelines, respectively, for each patient. RESULTS: Factors that affect relapse/recurrence include comorbidities, demographics, and adherence to treatment guidelines. Factors that affect adherence to treatment guidelines include choice of initial antidepressant drug, comorbidities, psychotherapy, and frequency of physician visits. CONCLUSIONS: Adherence to treatment guidelines was associated with a significant reduction in the likelihood of relapse or recurrence of depression. Choice of initial antidepressant drug affects adherence to treatment guidelines.

Effect of antidepressant therapy on health care utilization and costs in primary care.

OBJECTIVE: Four groups of patients receiving different antidepressant drugs in a primary care setting were compared in terms of duration of antidepressant therapy and health and mental health care utilization and costs. METHODS: A retrospective analysis of the medical and pharmacy claims of an employed population and their families was conducted. A total of 1,242 patients with a diagnosis of depression were included in the analyses. The four antidepressant cohorts were fluoxetine (N = 799), trazodone (N = 89), the tricyclics amitriptyline and imipramine (N = 104), and the secondary amine tricyclics desipramine and nortriptyline (N = 250). The primary outcome measures were total health care charges, total charges for mental health services, and the pattern of antidepressant use. Secondary measures included charges for outpatient care and pharmacy and the number of outpatient visits. Data analysis involved use of two-stage multivariate regression modeling known as sample selection models. RESULTS: Patients taking fluoxetine achieved higher rates of continuous use for at least six months compared with those taking the other drugs. After selection bias due to observed and unobserved characteristics and other confounding variables was adjusted for, no significant differences were found between drug cohorts in total medical charges. CONCLUSIONS: Improvements in the process of care at no apparent increase in total charges appear possible through appropriate medication therapy.

Access to treatment for depression in a Medicaid population.

Mentally ill Medicaid recipients represent a population that may be vulnerable to limited access to adequate treatment for their mental illness. In this study, depressed Medicaid recipients were compared with those with private insurance. Also examined were racial differences among the Medicaid recipients in the treatment of depression. It was found that in comparison with Medicaid patients, the privately insured patients who are treated with antidepressants are more likely to receive the newer selective serotonin reuptake inhibitors (SSRIs) rather than the older tricyclic antidepressants (TCAs). In the Medicaid group, African Americans are more likely to receive TCAs than are white patients. Privately insured patients are more likely to receive psychotherapy than are Medicaid patients. There is a higher rate of continuous therapy on initial antidepressants in the privately insured group. Results suggest that depressed Medicaid recipients' access to quality mental health care is restricted. Also, among depressed Medicaid patients, there are racial differences with regard to depression treatment.

Indomethacin for closure of patent ductus arteriosus in prematures.

A controlled, double blind trial of indomethacin versus placebo was conducted in prematures of birth weight less than 1750 g, with a murmur of patent ductus arteriosus (PDA). The dose of indomethacin was 0.2 mg/kg for 2 doses, orally, 24 hours apart. Forty-seven patients entered the trial. Twenty-four received indomethacin and 12 of these met the criteria for response; 23 received the placebo and two met the criteria for response (p less than 0.01). Subsequent surgical ligation for symptomatic PDA was required in 13 of 23 in the placebo group and 4 of 24 in the indomethacin group (p less than 0.01). When administered early, indomethacin is moderately effective in closing PDA in premature infants.

Use of claims data for research on treatment and outcomes of depression care.

BACKGROUND: Data sources such as medical insurance claims are increasingly used in outcomes research. In this report, we present opportunities and limitations associated with the use of such data for outcomes research in the area of depression. OBJECTIVES: The purpose of this report is to illustrate the use of administrative claims data in conducting research in the area of depression. Information in this report is intended to be helpful to both experienced health services researchers and to those who may be new to the field of either outcomes research or mental health research. FORMAT: This report covers measurement of outcomes, possible data sources, episode construction, and statistical methodologies that are appropriate when conducting depression research using claims data. Through examples and references, issues to be considered in each of these areas are examined and recommendations are made. Strengths and limitations of claims data will also be pointed out. CONCLUSIONS: The use of claims data to conduct outcomes research in depression should be carried out responsibly. Limitations with using claims data to identify patients with depression must be acknowledged and appropriate methodologies should be used. Still, these data sources provide a rich opportunity to conduct outcomes research in depression, and much can be learned using administrative claims data.

Relationship of anti-beta 2-microglobulin antibodies to T11 and T-cell activation in systemic lupus erythematosus.

Monoclonal anti-beta 2-microglobulin (beta 2m) inhibited in a specific, dose-dependent fashion both in vitro tetanus toxoid-induced human-T-cell proliferation and sheep erythrocyte (E)-rosette formation, a function of the 50 kDa T11 molecule. In these respects, anti-beta 2m exhibited effects similar to those of sera from patients with SLE. Although 10 of 16 SLE sera contained antibody to beta 2m in monoclonal rosette inhibition assays, the presence of antibody of this specificity contributed only partially to the capacity of SLE serum to inhibit E-rosette formation or the T-cell response to tetanus toxoid. Removal of anti-beta 2m from SLE serum by solid phase absorption with beta 2m-Sepharose 4B reduced inhibition of the tetanus toxoid response and E-rosette formation in certain cases, but to a lesser extent than that observed following absorption with T-cell blasts, which completely eliminated inhibitory activity. Neither SLE antilymphocyte antibodies (including anti-beta 2m) nor heterologous anti-beta 2m were directed to the E receptor binding site (T11(1) epitope), as indicated by failure to inhibit OKT11 monoclonal antibody rosette formation or to reduce the relative intensity of OKT11 immunofluorescent staining. These data suggest an interesting functional relationship between beta 2m, the E receptor, and T-cell activation. While anti-beta 2m antibodies in SLE exert some inhibitory effect on antigen-induced T-cell proliferation, other distinct autoantibody systems to T-cell activation antigens appear to play the predominant role in this regard.

Hospitalization and total medical costs for privately insured persons with schizophrenia.

This study used data from the 1991-1993 MarketScan files, a large database of private sector inpatient, outpatient, and prescription drug medical claims, to identify a sample of 665 patients with schizophrenia. Descriptive and multivariate analyses were conducted on the subsamples with hospitalizations (N = 185) and without hospitalizations (N = 480) in the 1-year period following the initial diagnosis for schizophrenia observed in the 1991-1993 time period. After controlling for patient demographic characteristics, medical co-morbidities, and other factors, the cost of hospitalization itself was found to be $15,805.

Effect of antidepressant choice on the incidence and economic intensity of hospitalization among depressed individuals.

This study identified differences in hospital utilization for mental health problems among depressed patients initially treated with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs). A retrospective sample of 2,557 patients was obtained from a private insurance claims database. Quasi-experimental, two-stage multivariate regression modeling was used to estimate the likelihood of hospitalization and subsequent inpatient expenditures. Only 2% of the sample were hospitalized, and the average expenditures per admitted patient was about $8,000. Patients initially prescribed sertraline had the same likelihood of hospitalization for a mental health problem as patients prescribed TCAs. Patients initially prescribed fluoxetine were half as likely to be hospitalized as patients initially prescribed TCAs. Once hospitalized, no differential effects of a specific antidepressant on inpatient expenditures were found.