C. Hendricks Brown

The Effect of Corticosteroids for Acute Optic Neuritis on the Subsequent Development of Multiple Sclerosis

BACKGROUND Optic neuritis is often the first clinical manifestation of multiple sclerosis, but little is known about the effect of corticosteroid treatment for optic neuritis on the subsequent risk of multiple sclerosis. METHODS We conducted a multicenter study in which 389 patients with acute optic neuritis (and without known multiple sclerosis) were randomly assigned to receive intravenous methylprednisolone (250 mg every six hours) for 3 days followed by oral prednisone (1 mg per kilogram of body weight) for 11 days, oral prednisone (1 mg per kilogram) alone for 14 days, or placebo for 14 days. Neurologic status was assessed over a period of two to four years. The patients in the first group were hospitalized for three days; the others were treated as outpatients. RESULTS Definite multiple sclerosis developed within the first two years in 7.5 percent of the intravenous-methyl-prednisolone group (134 patients), 14.7 percent of the oral-prednisone group (129 patients), and 16.7 percent of the placebo group (126 patients). The adjusted rate ratio for the development of definite multiple sclerosis within two years in the intravenous-methylprednisolone group was 0.34 (95 percent confidence interval, 0.16 to 0.74) as compared with the placebo group and 0.38 (95 percent confidence interval, 0.17 to 0.83) as compared with the oral-prednisone group. The beneficial effect of the intravenous-steroid regimen appeared to lessen after the first two years of follow-up. Signal abnormalities on magnetic resonance imaging (MRI) of the brain were a strong indication of risk for the development of definite multiple sclerosis (adjusted rate ratio in patients with three or more lesions, 5.53; 95 percent confidence interval, 2.41 to 12.66). The beneficial effect of treatment was most apparent in patients with abnormal MRI scans at entry. CONCLUSIONS In patients with acute optic neuritis, treatment with a three-day course of high-dose intravenous methylprednisolone (followed by a short course of prednisone) reduces the rate of development of multiple sclerosis over a two-year period.

Effects of a universal classroom behavior management program in first and second grades on young adult behavioral, psychiatric, and social outcomes.

BACKGROUND The Good Behavior Game (GBG), a method of classroom behavior management used by teachers, was tested in first- and second-grade classrooms in 19 Baltimore City Public Schools beginning in the 1985-1986 school year. The intervention was directed at the classroom as a whole to socialize children to the student role and reduce aggressive, disruptive behaviors, confirmed antecedents of later substance abuse and dependence disorders, smoking, and antisocial personality disorder. This article reports on impact to ages 19-21. METHODS In five poor to lower-middle class, mainly African American urban areas, three or four schools were matched and within each set randomly assigned to one of three conditions: (1) GBG, (2) a curriculum-and-instruction program directed at reading achievement, or (3) the standard program. Balanced assignment of children to classrooms was made, and then, within intervention schools, classrooms and teachers were randomly assigned to intervention or control. RESULTS By young adulthood significant impact was found among males, particularly those in first grade who were more aggressive, disruptive, in reduced drug and alcohol abuse/dependence disorders, regular smoking, and antisocial personality disorder. These results underline the value of a first-grade universal prevention intervention. REPLICATION: A replication was implemented with the next cohort of first-grade children with the same teachers during the following school year, but with diminished mentoring and monitoring of teachers. The results showed significant GBG impact for males on drug abuse/dependence disorders with some variation. For other outcomes the effects were generally smaller but in the predicted direction.

The short-term impact of two classroom-based preventive interventions on aggressive and shy behaviors and poor achievement☆

Abstract Two classroom-based preventive interventions were carried out on an epidemiologically defined, varied population of children in a metropolitan area in the United States. This is a report of the short-term impact and specificity of the two interventions from fall through spring of first grade. The first intervention, the Good Behavior Game, was aimed at reducing aggressive behavior and shy behavior. Aggressive behavior has been shown to be an important developmental antecedent in first grade of later delinquency and heavy drug use, particularly when coupled with shy behavior. The second intervention, Mastery Learning, was designed to improve poor reading achievement, which has been shown to be an antecedent for later depressive symptoms, as well as a correlate of aggressive and shy behaviors. Each of the two interventions had a significant and very specific impact only on its own proximal target(s). In addition to main effects, there were theoretically important variations of impacts among subgroups of children. The Good Behavior Game appeared to have a greater impact in reducing aggressive behavior among the more aggressive children. The nature of the impact of Mastery Learning differed by gender, with female high achievers benefiting more from the intervention than female low achievers, and male low achievers benefiting more than male high achievers. Developmental epidemiologically based preventive trials provide a powerful means of addressing questions about etiology and development, particularly around the issue of the malleability of developmental processes. Important questions that future work could test are whether achievement is improved by improving aggressive or shy behaviors and whether aggressive or shy behaviors are improved by improving achievement. Such investigation would inform our understanding of their etiology.

Benefits From Antidepressants: Synthesis of 6-Week Patient-Level Outcomes From Double-blind Placebo-Controlled Randomized Trials of Fluoxetine and Venlafaxine

CONTEXT Some meta-analyses suggest that efficacy of antidepressants for major depression is overstated and limited to severe depression. OBJECTIVE To determine the short-term efficacy of antidepressants for treating major depressive disorder in youth, adult, and geriatric populations. DATA SOURCES Reanalysis of all intent-to-treat person-level longitudinal data during the first 6 weeks of treatment of major depressive disorder from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine hydrochloride and 21 adult trials of venlafaxine hydrochloride. STUDY SELECTION All sponsor-conducted randomized controlled trials of fluoxetine and venlafaxine. DATA EXTRACTION Childrens Depression Rating Scale-Revised scores (youth population), Hamilton Depression Rating Scale scores (adult and geriatric populations), and estimated response and remission rates at 6 weeks were analyzed for 2635 adults, 960 geriatric patients, and 708 youths receiving fluoxetine and for 2421 adults receiving immediate-release venlafaxine and 2461 adults receiving extended-release venlafaxine. DATA SYNTHESIS Patients in all age and drug groups had significantly greater improvement relative to control patients receiving placebo. The differential rate of improvement was largest for adults receiving fluoxetine (34.6% greater than those receiving placebo). Youths had the largest treated vs control difference in response rates (24.1%) and remission rates (30.1%), with adult differences generally in the 15.6% (remission) to 21.4% (response) range. Geriatric patients had the smallest drug-placebo differences, an 18.5% greater rate of improvement, 9.9% for response and 6.5% for remission. Immediate-release venlafaxine produced larger effects than extended-release venlafaxine. Baseline severity could not be shown to affect symptom reduction. CONCLUSIONS To our knowledge, this is the first research synthesis in this area to use complete longitudinal person-level data from a large set of published and unpublished studies. The results do not support previous findings that antidepressants show little benefit except for severe depression. The antidepressants fluoxetine and venlafaxine are efficacious for major depressive disorder in all age groups, although more so in youths and adults compared with geriatric patients. Baseline severity was not significantly related to degree of treatment advantage over placebo.

Developmental epidemiologically based preventive trials: Baseline modeling of early target behaviors and depressive symptoms

Describes a conceptual framework for identifying and targeting developmental antecedents in early childhood that have been shown in previous work to predict delinquency and violent behavior, heavy drug use, depression, and other psychiatric symptoms and possibly disorders in late adolescence and into adulthood. Criteria are described that guided choices of targets for two epidemiologically based, randomized preventive trials carried out in 19 elementary schools in the eastern half of Baltimore, involving more than 2,400 first-grade children over the course of first and second grades. Baseline models derived from the first of two cohorts show the evolving patterns of concurrence among the target antecedents. The central role of concentration problems emerged. From Fall to Spring in first grade, concentration problems led to shy and aggressive behavior and poor achievement in both genders and to depressive symptoms among girls. There was evidence for reciprocal relationships in girls. For example, depressive symptoms led to poor achievement in both girls and boys, whereas poor achievement led to depressive symptoms in girls but not boys, at least over the first-grade year. These results provide important epidemiological data relevant to the developmental paths leading to the problem outcomes and suggest preventive trials.

The Role of Family Factors, Physical Abuse, and Sexual Victimization Experiences in High-Risk Youths' Alcohol and Other Drug Use and Delinquency: A Longitudinal Model

Our understanding of the adverse effects of early child physical and sexual abuse has developed to a point where there is need to elucidate the processes by which various developmental outcomes occur. Limited variability on key measures of family stress and in youths’ drug use, other delinquent behavior and abuse histories in the general population has limited theory development. Using data from an ongoing, longitudinal study of juvenile detainees, we test a developmental damage model of the relationships among the youths’ family background and problem factors, their sexual victimization and physical abuse experiences, and their substance use and delinquent behavior over time. The hypothesized model was supported by the data. Theoretical and policy implications of the results are drawn. In particular, early intervention with high-risk youths and their families is needed to address effectively their problems and troubled behavior before drug use and delinquent careers become firmly established.

Suicidal Thoughts and Behavior With Antidepressant Treatment: Reanalysis of the Randomized Placebo-Controlled Studies of Fluoxetine and Venlafaxine

CONTEXT The US Food and Drug Administration issued a black box warning for antidepressants and suicidal thoughts and behavior in children and young adults. OBJECTIVE To determine the short-term safety of antidepressants by standard assessments of suicidal thoughts and behavior in youth, adult, and geriatric populations and the mediating effect of changes in depressive symptoms. DATA SOURCES All intent-to-treat person-level longitudinal data of major depressive disorder from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine hydrochloride and 21 adult trials of venlafaxine hydrochloride. STUDY SELECTION All sponsor-conducted randomized controlled trials of fluoxetine and venlafaxine. DATA EXTRACTION The suicide items from the Childrens Depression Rating Scale-Revised and the Hamilton Depression Rating Scale as well as adverse event reports of suicide attempts and suicide during active treatment were analyzed in 9185 patients (fluoxetine: 2635 adults, 960 geriatric patients, 708 youths; venlafaxine: 2421 adults with immediate-release venlafaxine and 2461 adults with extended-release venlafaxine) for a total of 53 260 person-week observations. DATA SYNTHESIS Suicidal thoughts and behavior decreased over time for adult and geriatric patients randomized to fluoxetine or venlafaxine compared with placebo, but no differences were found for youths. In adults, reduction in suicide ideation and attempts occurred through a reduction in depressive symptoms. In all age groups, severity of depression improved with medication and was significantly related to suicide ideation or behavior. CONCLUSIONS Fluoxetine and venlafaxine decreased suicidal thoughts and behavior for adult and geriatric patients. This protective effect is mediated by decreases in depressive symptoms with treatment. For youths, no significant effects of treatment on suicidal thoughts and behavior were found, although depression responded to treatment. No evidence of increased suicide risk was observed in youths receiving active medication. To our knowledge, this is the first research synthesis of suicidal thoughts and behavior in depressed patients treated with antidepressants that examined the mediating role of depressive symptoms using complete longitudinal person-level data from a large set of published and unpublished studies.

Principles for Designing Randomized Preventive Trials in Mental Health: An Emerging Developmental Epidemiology Paradigm

An emerging population-based paradigm is now being used to guide the design of preventive trials used to test developmental models. We discuss elements of the designs of several ongoing randomized preventive trials involving reduction of risk for children of divorce, for children who exhibit behavioral or learning problems, and for children whose parents are being treated for depression. To test developmental models using this paradigm, we introduce three classes of design issues: design for prerandomization, design for intervention, and design for postintervention. For each of these areas, we present quantitative results from power calculations. Both scientific and cost implications of these power calculations are discussed in terms of variation among subjects on preintervention measures, unit of intervention, assignment, balancing, number of pretest and posttest measures, and the examination of moderation effects.

Methods for testing theory and evaluating impact in randomized field trials: Intent-to-treat analyses for integrating the perspectives of person, place, and time

Randomized field trials provide unique opportunities to examine the effectiveness of an intervention in real world settings and to test and extend both theory of etiology and theory of intervention. These trials are designed not only to test for overall intervention impact but also to examine how impact varies as a function of individual level characteristics, context, and across time. Examination of such variation in impact requires analytical methods that take into account the trials multiple nested structure and the evolving changes in outcomes over time. The models that we describe here merge multilevel modeling with growth modeling, allowing for variation in impact to be represented through discrete mixtures--growth mixture models--and nonparametric smooth functions--generalized additive mixed models. These methods are part of an emerging class of multilevel growth mixture models, and we illustrate these with models that examine overall impact and variation in impact. In this paper, we define intent-to-treat analyses in group-randomized multilevel field trials and discuss appropriate ways to identify, examine, and test for variation in impact without inflating the Type I error rate. We describe how to make causal inferences more robust to misspecification of covariates in such analyses and how to summarize and present these interactive intervention effects clearly. Practical strategies for reducing model complexity, checking model fit, and handling missing data are discussed using six randomized field trials to show how these methods may be used across trials randomized at different levels.

Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets.

OBJECTIVE In late 2006, a U.S. Food and Drug Administration advisory committee recommended that the 2004 black box warning regarding suicidality in pediatric patients receiving antidepressants be extended to include young adults. This study examined the relationship between antidepressant treatment and suicide attempts in adult patients in the Veterans Administration health care system. METHOD The authors analyzed data on 226,866 veterans who received a diagnosis of depression in 2003 or 2004, had at least 6 months of follow-up, and had no history of depression from 2000 to 2002. Suicide attempt rates overall as well as before and after initiation of antidepressant therapy were compared for patients who received selective serotonin reuptake inhibitors (SSRIs), new-generation non-serotonergic-specific (non-SSRI) antidepressants (bupropion, mirtazapine, nefazodone, and venlafaxine), tricyclic antidepressants, or no antidepressant. Age group analyses were also performed. RESULTS Suicide attempt rates were lower among patients who were treated with antidepressants than among those who were not, with a statistically significant odds ratio for SSRIs and tricyclics. For SSRIs versus no antidepressant, this effect was significant in all adult age groups. Suicide attempt rates were also higher prior to treatment than after the start of treatment, with a significant relative risk for SSRIs and for non-SSRIs. For SSRIs, this effect was seen in all adult age groups and was significant in all but the 18-25 group. CONCLUSIONS These findings suggest that SSRI treatment has a protective effect in all adult age groups. They do not support the hypothesis that SSRI treatment places patients at greater risk of suicide.