The American Heart Association science advisory on depression and coronary heart disease: an exploration of the issues raised.

The American Heart Association issued a science advisory on depression and coronary heart disease (CHD) in 2008. This paper reviews the purpose and content of the advisory and discusses reactions and new information that have followed the advisory's release. Both the advisory and subsequent data support routine screening for depression in patients with CHD. Such screening can be done efficiently in primary care and cardiology settings and can effectively identify many depressed patients who would otherwise go undetected. Antidepressant drugs such as selective serotonin reuptake inhibitors are safe for use in patients with CHD, can reduce depression, and can improve adherence with medical therapy. Referral to a practice with the knowledge and resources to manage depression promotes successful management of depressed patients with CHD.

Psychiatric characteristics associated with long-term mortality among 361 patients having an acute coronary syndrome and major depression: seven-year follow-up of SADHART participants.

CONTEXT: Major depressive disorder (MDD) after acute coronary syndrome (ACS) is associated with an increased mortality rate. We observed the participants of the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) to establish features of MDD associated with long-term mortality. OBJECTIVES: To determine whether the following variables were associated with long-term mortality: baseline depression severity, previous MDD episodes, onset of MDD before or after the ACS event, 6 months of sertraline hydrochloride therapy, and mood improvement independent of treatment. DESIGN: SADHART was a double-blind, placebo-controlled, randomized trial comparing the safety and antidepressant efficacy of sertraline vs placebo in 369 patients with ACS who met criteria for MDD. The trial was completed in June 2000, and follow-up for vital status was completed in September 2007. SETTING: Academic research. PARTICIPANTS: SADHART participants. MAIN OUTCOME MEASURES: Vital status was determined in 361 participants (97.8%) during a median follow-up of 6.7 years. RESULTS: During the study, 75 participants (20.9%) died. Neither previous episodes of MDD, nor onset before or after the index ACS, nor an initial 6 months of sertraline treatment was associated with long-term mortality. Cox proportional hazards regression models showed that baseline MDD severity (hazard ratio, 2.30; 95% confidence interval, 1.28-4.14; P < .006) and failure of MDD to improve substantially during treatment with either sertraline or placebo (hazard ratio, 2.39; 95% confidence interval, 1.39-2.44; P < .001) were strongly and independently associated with long-term mortality. Marked improvement in depression (Clinical Global Impression-Improvement subscale score of 1) was associated with improved adherence to study medication. CONCLUSIONS: Severity of MDD measured within a few weeks of hospitalization for ACS or failure of MDD to improve during the 6 months following ACS predicted more than a doubling of mortality over 6.7 years of follow-up. Because persistent depression increases mortality and decreases medication adherence, physicians need to aggressively treat depression and be diligent in promoting adherence to guideline cardiovascular drug therapy.

Smokers' response to combination bupropion, nicotine patch, and counseling treatment by race/ethnicity.

BACKGROUND: Evidence on how to tailor nicotine dependence treatment to specific race/ethnic groups is limited. The present study investigated responses to established smoking cessation treatments among African American, Hispanic, and White adults. METHODS: Participants were 559 smokers (126 African American, 73 Hispanic, and 360 White). All received treatment for eight weeks with open-label bupropion, the nicotine patch, and individual counseling. The dependent variable was tobacco abstinence during the last four weeks of treatment. The independent variables were race/ethnicity and other known predictors of abstinence, including sex, age, smoking history (nicotine dependence level, number of cigarettes smoked daily, serum cotinine level and expired carbon monoxide, number of past quit attempts, and age when daily smoking began), confidence in ability to stop smoking, body mass index, psychological status, and psychiatric history (past major depression and alcohol dependence). RESULTS: The total proportion of abstainers in the sample was 53%, with proportional differences by race/ethnicity (Whites 60%, African Americans 38%, Hispanics 41%). Compared to Whites, the odds ratios (OR) for quitting, adjusted for moderators of race/ ethnicity and other predictors of abstinence, were significantly lower among African Americans (OR .44, 95% confidence interval 195% CI] .27-.72) and Hispanics (OR .46, 95% CI .26-.81). CONCLUSION: Disparity in smoking cessation treatment outcome among African American and Hispanic smokers compared to Whites implies that the burden of tobacco-related illness will continue to fall disproportionately among minority racial/ethnic groups. Gaining knowledge on the effectiveness of nicotine dependence treatments and on the factors that facilitate or impede a successful response by minority smokers is a public health priority.

Heart rate variability in acute coronary syndrome patients with major depression: influence of sertraline and mood improvement.

CONTEXT: Major depressive disorder (MDD) associated with acute coronary syndrome (ACS) increases the risk of mortality. Decreased heart rate variability (HRV), also a predictor of mortality, is reduced in patients with MDD after ACS, and has been suggested to be a mediator of MDD mortality after ACS. Although selective serotonin reuptake inhibitors may reduce mortality post-ACS, little is known about their effects on HRV. OBJECTIVE: To examine the influence of both sertraline and improvement in mood on HRV. METHODS: The Sertraline Antidepressant Heart Attack Randomized Trial assessed HRV from 24-hour Holter electrocardiogram recordings at baseline in 290 patients and from a second recording in 258 of these patients 16 weeks after randomization to sertraline or placebo. Frequency domain measures of HRV included high-frequency power, low-frequency power, very low-frequency power, ultra low-frequency power, and total power. Depression severity was measured by the Hamilton Rating Scale for Depression. Clinical response was measured with the Clinical Global Impressions Improvement scale. RESULTS: At baseline, prior episodes of MDD were associated with lower HRV. Sertraline significantly increased ultra low-frequency power, while improvement in mood was associated with higher low-frequency power independent of treatment. However, the expected recovery in HRV following ACS was not observed in patients with MDD. Higher ultra low-frequency during sertraline treatment and higher low-frequency power in patients whose mood improved resulted primarily from these measures decreasing in their comparison groups. CONCLUSIONS: Heart rate variability recovery is impaired in depressed patients after ACS. Previously reported differences in baseline HRV between patients with and without depression after ACS grew larger in the 16 weeks following a coronary event. Both sertraline treatment and symptomatic recovery from depression were associated with increased HRV compared with placebo-treated and nonrecovered post-ACS control groups, respectively, but this results primarily from decreased HRV in the comparison groups.

A randomized trial of bupropion and/or nicotine gum as maintenance treatment for preventing smoking relapse.

AIM: To investigate the efficacy of maintenance treatment with bupropion and/or nicotine gum for reducing smoking relapse. DESIGN, SETTING AND PARTICIPANTS: A 48-week study was conducted at a university-based smoking cessation clinic between February 2001 and October 2005. A total of 588 smokers received bupropion and nicotine patch in 8 weeks of open-label treatment (OLT); 289 abstainers during the last 4 weeks of OLT were randomized in double-blind placebo-controlled fashion to one of four arms for 16 weeks of maintenance treatment (MT) followed by 24 weeks of non-treatment follow-up (NTFU). INTERVENTION: Bupropion (300 mg/day) and 2 mg nicotine gum, used alone or combined, and comparable placebo pill and placebo gum. Behavioral counseling at all visits. OUTCOME: Time to relapse (TTR) from randomization. Relapse is defined as the first 7 consecutive days of smoking. Abstinence verified by carbon monoxide

Depression and cardiovascular comorbidity.

Depression has long had a popular link to cardiovascular disease and death. However, only during the last 15 years has scientific evidence supporting this common wisdom been available. Beginning in the early 1990s, there began to accumulate community-based epidemiological evidence that medically healthy, depressed patients followed for long periods of time were at increased risk of both cardiovascular disease and cardiac death. In the mid-1990s, evidence appeared to indicate that depression following a heart attack increased the risk of death. It is now apparent that depression aggravates the course of multiple cardiovascular conditions. There are two major unanswered questions. One is whether treating depression will reduce the risk of cardiovascular disease and death. Here, preliminary, but not definitive, evidence suggests that the serotonin reuptake inhibitors may be useful. The other unanswered question regards the mechanisms that underlie this link between depression and cardiovascular disease. There is strong evidence linking platelet activation, autonomic activity and inflammatory markers to both depression and heart disease, but why these links exist is far less clear.

Assessment and treatment of depression in patients with cardiovascular disease: National Heart, Lung, and Blood Institute Working Group Report.

OBJECTIVE: The National Heart, Lung, and Blood Institute convened an interdisciplinary working group of experts to develop recommendations for the assessment and treatment of depression in patients with coronary heart disease (CHD). METHOD: Consensus of experts. RESULTS: Our current recommendations are that the Beck Depression Inventory-I be employed for epidemiological studies of depression and CHD, that the Patient Health Questionnaire 2-item version be employed for screening for trial eligibility, that the Depression Interview and Structured Hamilton (DISH) be employed for diagnostic ascertainment for trial inclusion, and that the Hamilton rating scale, which is part of the DISH, be employed for both depression symptom reduction and the remission criterion in any trial. We further recommend that a randomized controlled trial be undertaken to determine whether selective serotonin reuptake inhibitors, psychotherapy, or combined treatment can reduce the risk of CHD events and mortality associated with depression in CHD patients. CONCLUSIONS: This report summarizes the recommendations made by the working group and discusses the rationale for each recommendation, the strengths and weaknesses of alternative approaches to assessment and treatment, and the implications for future research in this area.

Onset of major depression associated with acute coronary syndromes: relationship of onset, major depressive disorder history, and episode severity to sertraline benefit.

CONTEXT: Depression observed following acute coronary syndrome (ACS) is common and associated with an increased risk of death. The Sertraline Antidepressant Heart Attack Trial (SADHART) tested the safety and efficacy of a selective serotonin reuptake inhibitor in this population. No evidence of harm was seen, and sertraline hydrochloride had an overall beneficial effect on mood that occurred primarily in patients with a history of episodes of major depressive disorder (MDD). OBJECTIVES: To determine how frequently the MDD began before ACS and whether onset of the current MDD episode before or after the ACS event influenced response to sertraline. DESIGN, SETTINGS, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled treatment of 369 patients with ACS and MDD was conducted in 40 outpatient clinics in 10 countries between April 1, 1997, and April 30, 2001. MAIN OUTCOME MEASURES: Diagnosis of MDD, number of previous episodes of depression, and episode onset before or after hospitalization were established using the Diagnostic Interview Schedule. Treatment response was measured with the Clinical Global Impression-Improvement scale. RESULTS: Fifty-three percent of MDD episodes began before hospitalization for the index episode of ACS (for 197 of 369 patients), and 94% of the MDD episodes began more than 30 days before the index ACS episode. Episodes of MDD that began prior to ACS responded more frequently to sertraline than to placebo (63% vs 46%, respectively; odds ratio, 2.0; 95% confidence interval, 1.13-3.55) whereas depression with onset beginning after hospitalization showed a high placebo response rate (69% vs 60%, respectively) and low sertraline-placebo response ratio (1.15). Multivariate analysis indicated that time of onset of the current episode, history of MDD, and baseline severity independently predicted the sertraline-placebo response ratio. CONCLUSIONS: Half of the episodes of major depression associated with ACS began long before ACS and therefore were not caused by ACS. Patients whose current episodes of MDD begin before ACS, those with a history of MDD, and those whose episodes are severe should be treated because they will benefit considerably from sertraline. Since these 3 predictors of sertraline response are independent, having more than 1 of them substantially increases the benefit of sertraline while reducing the chance of spontaneous recovery.

Schizophrenia, antipsychotic drugs, and cardiovascular disease.

Since the early 1980s, concern within the psychiatric community about whether antipsychotics are associated with adverse cardiovascular events has grown. In the early 1990s, it became clear that mesoridazine could cause torsades de pointes. More recently, concern has focused on the propensity that some atypical antipsychotics have to prolong corrected QT (QTc) interval and whether this can result in torsades de pointes and sudden death. Unfortunately, it has been difficult to accurately determine what role, if any, that atypical antipsychotics may have in contributing to these events, in part because of the rarity of the events and the lack of a sound, predictable marker. The best currently available markers, QTc interval and binding to the rapid delayed rectifier potassium current, are imprecise and cannot be relied upon to accurately predict torsades de pointes. Current evidence suggests that although atypical antipsychotics may increase the QTc interval, prolongation does not result in torsades de pointes, as observed with many conventional antipsychotics. Among the marketed atypical drugs, there was considerable concern about QTc prolongation with ziprasidone, but currently available data do not support the occurrence of torsades de pointes with any of the available atypical antipsychotic drugs. However, identifying when QTc prolongation carries a risk of torsades de pointes remains a problem in developing new drugs. Psychiatric populations are at high risk for cardiovascular disease, and emerging data indicate that some atypical antipsychotics may be associated with cardiovascular adverse events unrelated to QT prolongation. Thus, it is prudent for the psychiatric community to be aware of psychiatric patients' baseline medical condition and their risk status for cardiovascular disease.

Mood disorders in the medically ill: scientific review and recommendations.

OBJECTIVE: The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research. DATA SOURCES: Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors. STUDY SELECTION/DATA EXTRACTION: Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed. CONCLUSIONS: A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

Relationship between release of platelet/endothelial biomarkers and plasma levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression.

OBJECTIVE: In a platelet/endothelial biomarker substudy of the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART), the authors sought to determine whether plasma levels of sertraline and its primary metabolite N-desmethylsertraline affect the release of platelet/endothelial biomarkers. METHOD: Fifty-five acute coronary syndrome patients with depression were randomly assigned to receive sertraline (N=23) or placebo (N=32). Twenty-six serial plasma samples collected at week 6 (N=12) and week 16 (N=14) were analyzed. Platelet factor 4 (PF4), beta-thromboglobulin (beta-TG), platelet/endothelial cell adhesion molecule 1 (PECAM-1), P-selectin, thromboxane B(2) (TxB(2)), prostacyclin (6-keto-PGF1alpha), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin were measured by enzyme-linked immunosorbent assay. Concentrations of sertraline and N-desmethylsertraline were determined by liquid chromatography with fluorescence detection in autologous samples. RESULTS: Strong, mostly time-dependent negative correlations were found for the plasma levels of sertraline and N-desmethylsertraline with PF4 (week 6: r=-0.69 and -0.33, respectively; week 16: r=-0.63 for both), beta-TG (week 6: r=-0.43 and -0.29; week 16: r=-0.66 and -0.57), PECAM-1 (week 6: r=-0.82 and -0.49; week 16: r=-0.60 for both), P-selectin (week 6: r=-0.82 and -0.49; week 16: r=-0.73 and -0.43), and TxB(2) (week 6: r=-0.66 and -0.59; and week 16: r=-0.64 and -0.41). Regression analysis revealed some borderline correlations for endothelial markers such as 6-keto- PGF1alpha and E-selectin and a positive correlation for VCAM-1. CONCLUSIONS: This is the first documented evidence that plasma release of platelet/endothelial biomarkers is directly related to the levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression. The clinical significance of these findings should be assessed in the setting of a randomized clinical trial.

Pharmacoeconomic analysis of sertraline treatment of depression in patients with unstable angina or a recent myocardial infarction.

BACKGROUND: The prevalence of major depressive disorder in patients with acute coronary syndromes (ACSs) is high and associated with worse cardiovascular outcomes and higher health care costs. Sertraline is the only treatment for major depressive disorder studied in a placebo-controlled trial of patients with ACS and found to be safe and effective. The cost implications of providing antidepressant treatment in this population have not yet been examined. The objective was to evaluate from a payer perspective the potential reduction in costs and psychiatric and cardiovascular events and procedures following sertraline versus placebo treatment of major depressive disorder in patients hospitalized for ACS. METHOD: Data were analyzed from a randomized, double-blind, placebo-controlled 24-week trial (Sertraline Antidepressant Heart Attack Randomized Trial) of sertraline treatment for major depressive disorder in patients hospitalized for ACS. Main outcome measures included frequency and costs (derived from Medicare diagnosis-related group fee schedules) of psychiatric and cardiovascular events occurring during the treatment period. RESULTS: There was a trend toward significantly fewer psychiatric or cardiovascular hospitalizations in the sertraline compared with the placebo group (55/186 vs. 76/183; p = .054). The mean per patient cost associated with psychiatric and medical events over the course of treatment was 2733 US dollars for sertraline and 3326 US dollars for placebo, but the difference was not statistically significant (p = .32). After including the costs of the sertra-line (360 US dollars over 24 weeks), there was no increase in treatment costs for sertraline compared with placebo. CONCLUSION: Sertraline treatment of major depressive disorder following hospitalization for a recent myocardial infarction or unstable angina appears to be a cost-effective strategy.

Influence of depression and effect of treatment with sertraline on quality of life after hospitalization for acute coronary syndrome.

Major depressive disorders complicate recovery from acute coronary syndrome in approximately 1 in 5 patients, and have been found to be associated with significant impairments of quality of life and functioning. The aim of the present analysis was to evaluate the efficacy of sertraline in improving quality of life and functioning in patients diagnosed with major depression who had recently been hospitalized for acute coronary syndrome. Three hundred sixty-nine patients hospitalized in the previous month for acute coronary syndrome (myocardial infarction, 74%; unstable angina, 26%) who also met criteria for major depressive disorder were randomized to 24 weeks of double-blind treatment with sertraline (50 to 200 mg/day) or placebo. Quality-of-life and functional status were assessed using the Quality of Life, Enjoyment, and Satisfaction scale (Q-LES-Q) and the Medical Outcomes Study SF-36. Data from the total sample, and the recurrent depression subgroup, were analyzed. Severe baseline impairment was found in the Q-LES-Q and all subscales of the SF-36. A multivariate regression analysis identified depression as the strongest predictor of baseline quality-of-life impairment (partial r, -0.37, p = 0.001). In the recurrent depression group, treatment with sertraline resulted in significantly greater improvement than placebo in the Q-LES-Q total score and SF-36 mental component summary score, as well as the SF-36 role limitations, emotional, and mental health factors. Depression has a substantial negative impact on quality of life and functioning in patients hospitalized for acute coronary syndrome. Sertraline was associated with clinically meaningful improvement in multiple quality-of-life domains in patients with acute coronary syndrome and recurrent depression.