Susan G. Silva

Progression to AIDS: the effects of stress, depressive symptoms, and social support.

OBJECTIVE We examined the effects of stress, depressive symptoms, and social support on the progression of HIV infection. METHODS Eighty-two HIV-infected gay men without symptoms or AIDS at baseline were followed up every 6 months for up to 5.5 years. Men were recruited from rural and urban areas in North Carolina as part of the Coping in Health and Illness Project. Disease progression was defined using criteria for AIDS (CD4+ lymphocyte count of <200/microl and/or an AIDS-indicator condition). RESULTS We used Cox regression models with time-dependent covariates, adjusting for age, education, race, baseline CD4+ count, tobacco use, and number of antiretroviral medications. Faster progression to AIDS was associated with more cumulative stressful life events (p = .002), more cumulative depressive symptoms (p = .008), and less cumulative social support (p = .0002). When all three variables were analyzed together, stress and social support remained significant in the model. At 5.5 years, the probability of getting AIDS was about two to three times as high among those above the median on stress or below the median on social support compared with those below the median on stress or above the median on support, respectively. CONCLUSIONS These data are among the first to demonstrate that more stress and less social support may accelerate the course of HIV disease progression. Additional study will be necessary to elucidate the mechanisms that underlie these relationships and to determine whether interventions that address stress and social support can alter the course of HIV infection.

Safety and Efficacy of Sertraline for Depression in Patients With Heart Failure: Results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) Trial

OBJECTIVES The objective was to test the hypothesis that heart failure (HF) patients treated with sertraline will have lower depression scores and fewer cardiovascular events compared with placebo. BACKGROUND Depression is common among HF patients. It is associated with increased hospitalization and mortality. METHODS The SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial was a randomized, double-blind, placebo-controlled trial of sertraline 50 to 200 mg/day versus matching placebo for 12 weeks. All participants also received nurse-facilitated support. Eligible patients were age 45 years or older with HF (left ventricular ejection fraction < or =45%, New York Heart Association functional class II to IV) and clinical depression (Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for current major depressive disorder). Those with significant cognitive impairment, psychosis, recent alcohol or drug dependence, bipolar or severe personality disorder, active suicidal ideation, and current antipsychotic or antidepressant medications were excluded. Primary end points were change in depression severity (Hamilton Depression Rating Scale total score) and composite cardiovascular status at 12 weeks. RESULTS A total of 469 patients were randomized (n = 234 sertraline, n = 235 placebo). The mean +/- SE change from baseline to 12 weeks in the Hamilton Depression Rating Scale total score was -7.1 +/- 0.5 (sertraline) and -6.8 +/- 0.5 (placebo) (p < 0.001 from baseline, p = 0.89 between groups, mean change between groups -0.4; 95% confidence interval: -1.7 to 0.92). The proportions whose composite cardiovascular score worsened, improved, or was unchanged were 29.9%, 40.6%, and 29.5%, respectively, in the sertraline group and 31.1%, 43.8%, and 25.1%, respectively, in the placebo group (p = 0.78). CONCLUSIONS Sertraline was safe in patients with significant HF. However, treatment with sertraline compared with placebo did not provide greater reduction in depression or improved cardiovascular status among patients with HF and depression. (Antidepressant Medication Treatment for Depression in Individuals With Chronic Heart Failure [SADHART-CHF]; NCT00078286).

Treatment for Adolescents with Depression Study (TADS): Rationale, design, and methods

OBJECTIVES A rapidly growing empirical literature on the treatment of major depressive disorder (MDD) in youth supports the efficacy of short-term treatment with depression-specific cognitive-behavioral therapy or medication management with a selective serotonin reuptake inhibitor. These studies also identify a substantial probability of partial response and of relapse, which might be addressed by more intensive, longer-term treatments. METHOD Funded by the National Institute of Mental Health, the Treatment for Adolescents With Depression Study (TADS) is a multicenter, randomized, masked effectiveness trial designed to evaluate the short-term (12-week) and long-term (36-week) effectiveness of four treatments for adolescents with MDD: fluoxetine, cognitive-behavioral therapy, their combination, and, acutely, pill placebo. A volunteer sample of 432 subjects aged 12-17 years (inclusive) with a primary DSM-IV diagnosis of MDD who are broadly representative of patients seen in clinical practice will enter the study. The primary dependent measures rated blindly by an independent evaluator are the Childrens Depression Rating Scale and, for responder analysis, a dichotomized Clinical Global Impressions-Improvement score. Consistent with an intent-to-treat analysis, all patients, regardless of treatment status, return for all scheduled assessments. RESULTS This report describes the design of the trial, the rationale for the design choices made, and the methods used to carry out the trial. CONCLUSION When completed, TADS will improve our understanding of how best to initiate treatment for adolescents with MDD.

Recovery and Recurrence Following Treatment for Adolescent Major Depression

CONTEXT Major depressive disorder in adolescents is common and impairing. Efficacious treatments have been developed, but little is known about longer-term outcomes, including recurrence. OBJECTIVES To determine whether adolescents who responded to short-term treatments or who received the most efficacious short-term treatment would have lower recurrence rates, and to identify predictors of recovery and recurrence. DESIGN Naturalistic follow-up study. SETTING Twelve academic sites in the United States. PARTICIPANTS One hundred ninety-six adolescents (86 males and 110 females) randomized to 1 of 4 short-term interventions (fluoxetine hydrochloride treatment, cognitive behavioral therapy, their combination, or placebo) in the Treatment for Adolescents With Depression Study were followed up for 5 years after study entry (44.6% of the original Treatment for Adolescents With Depression Study sample). MAIN OUTCOME MEASURES Recovery was defined as absence of clinically significant major depressive disorder symptoms on the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version interview for at least 8 weeks, and recurrence was defined as a new episode of major depressive disorder following recovery. RESULTS Almost all participants (96.4%) recovered from their index episode of major depressive disorder during the follow-up period. Recovery by 2 years was significantly more likely for short-term treatment responders (96.2%) than for partial responders or nonresponders (79.1%) (P < .001) but was not associated with having received the most efficacious short-term treatment (the combination of fluoxetine and cognitive behavioral therapy). Of the 189 participants who recovered, 88 (46.6%) had a recurrence. Recurrence was not predicted by full short-term treatment response or by original treatment. However, full or partial responders were less likely to have a recurrence (42.9%) than were nonresponders (67.6%) (P = .03). Sex predicted recurrence (57.0% among females vs 32.9% among males; P = .02). CONCLUSIONS Almost all depressed adolescents recovered. However, recurrence occurs in almost half of recovered adolescents, with higher probability in females in this age range. Further research should identify and address the vulnerabilities to recurrence that are more common among young women.

Remission and recovery in the Treatment for Adolescents with Depression Study (TADS): acute and long-term outcomes.

OBJECTIVE We examine remission rate probabilities, recovery rates, and residual symptoms across 36 weeks in the Treatment for Adolescents with Depression Study (TADS). METHOD The TADS, a multisite clinical trial, randomized 439 adolescents with major depressive disorder to 12 weeks of treatment with fluoxetine, cognitive-behavioral therapy, their combination, or pill placebo. The pill placebo group, treated openly after week 12, was not included in the subsequent analyses. Treatment differences in remission rates and probabilities of remission over time are compared. Recovery rates in remitters at weeks 12 (acute phase remitters) and 18 (continuation phase remitters) are summarized. We also examined whether residual symptoms at the end of 12 weeks of acute treatment predicted later remission. RESULTS At week 36, the estimated remission rates for intention-to-treat cases were as follows: combination, 60%; fluoxetine, 55%; cognitive-behavioral therapy, 64%; and overall, 60%. Paired comparisons reveal that, at week 24, all active treatments converge on remission outcomes. The recovery rate at week 36 was 65% for acute phase remitters and 71% for continuation phase remitters, with no significant between-treatment differences in recovery rates. Residual symptoms at the end of acute treatment predicted failure to achieve remission at weeks 18 and 36. CONCLUSIONS Most depressed adolescents in all three treatment modalities achieved remission at the end of 9 months of treatment.

The Treatment for Adolescents With Depression Study (TADS): outcomes over 1 year of naturalistic follow-up.

OBJECTIVE The Treatment for Adolescents With Depression Study (TADS) evaluates the effectiveness of fluoxetine, cognitive-behavioral therapy (CBT), and their combination in adolescents with major depressive disorder. The authors report effectiveness outcomes across a 1-year naturalistic follow-up period. METHOD The randomized, controlled trial was conducted in 13 academic and community sites in the United States. Stages I, II, and III consisted of 12, 6, and 18 weeks of acute, consolidation, and continuation treatment, respectively. Following discontinuation of TADS treatments at the end of stage III, stage IV consisted of 1 year of naturalistic follow-up. The participants were 327 subjects between the ages of 12 and 17 with a primary DSM-IV diagnosis of major depressive disorder. No TADS treatment was provided during the follow-up period; treatment was available in the community. The primary dependent measures, rated by an independent evaluator blind to treatment status, were the total score on the Childrens Depression Rating Scale-Revised and the rate of response, defined as a rating of much or very much improved on the Clinical Global Impressions improvement measure. RESULTS Sixty-six percent of the eligible subjects participated in at least one stage IV assessment. The benefits seen at the end of active treatment (week 36) persisted during follow-up on all measures of depression and suicidality. CONCLUSIONS In contrast to earlier reports on short-term treatments, in which worsening after treatment is the rule, the longer treatment in the TADS was associated with persistent benefits over 1 year of naturalistic follow-up.

Working memory and schizophrenia: evidence for slowed encoding

Previous studies have found impairments in working memory in individuals with schizophrenia, but have not identified the underlying information processing deficit. Because schizophrenia is associated with slowed cognitive processing, deficits on working memory tests may be due to decreased speed of encoding rather than an inability to maintain information over time. This hypothesis was examined using a Delayed Match to Sample (DMTS) Test. Task difficulty under 0-delay conditions was equated by individually establishing the stimulus presentation time needed to reach approximately 80% accuracy. Schizophrenia participants required longer presentation durations, but there were no group differences under delay conditions when performance was equated in the 0-delay condition. These results suggest that poor working memory performance in schizophrenia results from slowed encoding processes.

Safety and efficacy of sertraline for depression in patients with CHF (SADHART-CHF): a randomized, double-blind, placebo-controlled trial of sertraline for major depression with congestive heart failure.

BACKGROUND Sertraline, a selective serotonin-reuptake inhibitor, has demonstrated substantial mood improvement in patients with post myocardial infarction or with unstable angina. The impact of sertraline on the prognosis and depression of patients with chronic heart failure (HF) and comorbid major depressive disorder (MDD) is unknown. METHOD This is a prospective, randomized, double-blind, placebo-controlled study designed to assess the safety and efficacy of sertraline in the treatment of MDD in patients with HF. The study is designed also to examine the effects of treating depression on cardiac events and morbidity/mortality in patients with HF. Approximately 500 men and women who are >or=45 years of age with current MDD and chronic systolic HF, characterized by left ventricular ejection fraction <or=45% and New York Heart Association class >or=II, comprise the study population. Eligible participants are randomized to either sertraline or placebo for a 12-week acute treatment phase. All patients, regardless of acute treatment phase completion, are followed routinely until the last subject completes 6-month follow-up. Quality of life and certain physiologic parameters, as well as pro-inflammatory and HF biomarkers, that may reflect the impact of sertraline in this particular population are measured at baseline and at the end of the acute treatment phase. CONCLUSION Because of the high prevalence of depression and its significant adverse impact on prognosis of patients with ischemic heart disease (IHD) and HF, the Safety and Efficacy of Sertraline for Depression in Patients with Chronic Heart Failure (SADHART-CHF) trial aims to assess the effects of sertraline on response of depression as well as on the cardiac prognosis of patients with HF.

CSF, plasma viral load and HIV associated dementia

Plasma viral burden has proven valuable in predicting the future course of systemic HIV related disease and the response to treatment. It is not known whether plasma or cerebrospinal fluid (CSF) viral burden can be used to predict onset of or response to treatment of nervous system disease. We propose a model of viral load mediated neurotoxicity underlying peripheral and central HIV associated neurological disease. The objective of this preliminary study was to assess the relationship of HIV associated neurological disease to quantitative viral load in plasma and CSF. 47 subjects (HIV- = 10, HIV+ = 37) participated in the study. Plasma and CSF samples were collected within a 3 h window. RT-PCR (Roche Amplicor Monitor) was utilized to assess HIV-1 RNA viral load in both plasma and cell free (centrifuged) CSF. Subjects underwent concurrent comprehensive neurological and neuropsychological evaluations. In general, systemic viral load, as measured in plasma, was greater than that found in cell free CSF. Cell free CSF HIV RNA viral load was significantly correlated with neurological dysfunction, whereas plasma viral load was not. The sole subject with an elevated CSF viral load (> 5 Log 10), had HIV associated dementia (HAD) on clinical examination.

Cost-Effectiveness of Treatments for Adolescent Depression: Results From TADS

OBJECTIVE While the evidence base for treatments for adolescent depression is building, little is known about the relative efficiency of such treatments. Treatment costs are a relevant concern given the competing demands on family and health care budgets. The authors evaluated the cost-effectiveness of three active treatments among adolescents with major depressive disorder. METHOD Volunteers (N=439) ages 12 to 18 with a primary diagnosis of major depressive disorder participated in a randomized, controlled trial conducted at 13 U.S. academic and community clinics from 2000 to 2004. Subjects included those participants who did not drop out and had evaluable outcome and cost data at 12 weeks (N=369). Subjects were randomly assigned to 12 weeks of either fluoxetine alone (10-40 mg/day), CBT alone, CBT combined with fluoxetine (10-40 mg/day), or placebo (equivalent to 10-40 mg/day). Both placebo and fluoxetine were administered double-blind; CBT alone and CBT in combination with fluoxetine were administered unblinded. Societal cost per unit of improvement on the Childrens Depression Rating Scale-Revised and cost per quality-adjusted life year (QALY) were compared. RESULTS Results ranged from an incremental cost over placebo of