Erik J. Giltay

n–3 Fatty Acids and Cardiovascular Events after Myocardial Infarction

BACKGROUND Results from prospective cohort studies and randomized, controlled trials have provided evidence of a protective effect of n-3 fatty acids against cardiovascular diseases. We examined the effect of the marine n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and of the plant-derived alpha-linolenic acid (ALA) on the rate of cardiovascular events among patients who have had a myocardial infarction. METHODS In a multicenter, double-blind, placebo-controlled trial, we randomly assigned 4837 patients, 60 through 80 years of age (78% men), who had had a myocardial infarction and were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy to receive for 40 months one of four trial margarines: a margarine supplemented with a combination of EPA and DHA (with a targeted additional daily intake of 400 mg of EPA-DHA), a margarine supplemented with ALA (with a targeted additional daily intake of 2 g of ALA), a margarine supplemented with EPA-DHA and ALA, or a placebo margarine. The primary end point was the rate of major cardiovascular events, which comprised fatal and nonfatal cardiovascular events and cardiac interventions. Data were analyzed according to the intention-to-treat principle, with the use of Cox proportional-hazards models. RESULTS The patients consumed, on average, 18.8 g of margarine per day, which resulted in additional intakes of 226 mg of EPA combined with 150 mg of DHA, 1.9 g of ALA, or both, in the active-treatment groups. During the follow-up period, a major cardiovascular event occurred in 671 patients (13.9%). Neither EPA-DHA nor ALA reduced this primary end point (hazard ratio with EPA-DHA, 1.01; 95% confidence interval [CI], 0.87 to 1.17; P=0.93; hazard ratio with ALA, 0.91; 95% CI, 0.78 to 1.05; P=0.20). In the prespecified subgroup of women, ALA, as compared with placebo and EPA-DHA alone, was associated with a reduction in the rate of major cardiovascular events that approached significance (hazard ratio, 0.73; 95% CI, 0.51 to 1.03; P=0.07). The rate of adverse events did not differ significantly among the study groups. CONCLUSIONS Low-dose supplementation with EPA-DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction and who were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy. (Funded by the Netherlands Heart Foundation and others; ClinicalTrials.gov number, NCT00127452.).

Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials

Objective The antihypertensive effect of fish oil was estimated from randomized trials using metaregression analysis. Modification of the blood pressure (BP) effect by age, gender, blood pressure, and body mass index was examined. Methods A total of 90 randomized trials of fish oil and BP were identified through MEDLINE (1966–March 2001). Trials with co-interventions, patient populations, non-placebo controls, or duration of < 2 weeks were excluded. A total of 36 trials (50 strata) were included, 22 of which had a double-blind design. Original reports were retrieved for data collection on sample size, study design, duration, fish oil dose, BP changes and baseline characteristics of trial populations. Pooled BP estimates were obtained by metaregression analysis, weighted for trial sample sizes. Stratified analyses according to population characteristics were performed. Results Intake of fish oil was high in most trials (median dose: 3.7 g/day). Fish oil reduced systolic BP by 2.1 mmHg [95% confidence interval (CI): 1.0, 3.2;P < 0.01] and diastolic BP by 1.6 mmHg (95% CI: 1.0. 2.2;P < 0.01). Restricting the analysis to double-blind trials yielded BP reductions of 1.7 mmHg (95% CI: 0.3, 3.1) and 1.5 mmHg (95% CI: 0.6, 2.3), respectively. BP effects tended to be larger in populations that were older (> 45 years) and in hypertensive populations (BP ⩾ 140/90 mmHg). Conclusions High intake of fish oil may lower BP, especially in older and hypertensive subjects. The antihypertensive effect of lower doses of fish oil (< 0.5 g/day) however, remains to be established.

Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.

Objective  Men with the metabolic syndrome (MetS) have low plasma testosterone (T) levels. The aim of this study was to establish whether the normalization of plasma T improves the features of the MetS.

A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones

OBJECTIVE Adverse effects of long-term cross-sex hormone administration to transsexuals are not well documented. We assessed mortality rates in transsexual subjects receiving long-term cross-sex hormones. DESIGN A cohort study with a median follow-up of 18.5 years at a university gender clinic. Methods Mortality data and the standardized mortality rate were compared with the general population in 966 male-to-female (MtF) and 365 female-to-male (FtM) transsexuals, who started cross-sex hormones before July 1, 1997. Follow-up was at least 1 year. MtF transsexuals received treatment with different high-dose estrogen regimens and cyproterone acetate 100 mg/day. FtM transsexuals received parenteral/oral testosterone esters or testosterone gel. After surgical sex reassignment, hormonal treatment was continued with lower doses. RESULTS In the MtF group, total mortality was 51% higher than in the general population, mainly from increased mortality rates due to suicide, acquired immunodeficiency syndrome, cardiovascular disease, drug abuse, and unknown cause. No increase was observed in total cancer mortality, but lung and hematological cancer mortality rates were elevated. Current, but not past ethinyl estradiol use was associated with an independent threefold increased risk of cardiovascular death. In FtM transsexuals, total mortality and cause-specific mortality were not significantly different from those of the general population. CONCLUSIONS The increased mortality in hormone-treated MtF transsexuals was mainly due to non-hormone-related causes, but ethinyl estradiol may increase the risk of cardiovascular death. In the FtM transsexuals, use of testosterone in doses used for hypogonadal men seemed safe.

Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects

objective Sex differences are found in most components of the insulin resistance syndrome and the associated cardiovascular risk profile. These differences are attributed to sex‐specific sex steroid profiles, but the effects of sex steroids on the individual components of the insulin resistance syndrome remain incompletely understood.

Childhood life events and childhood trauma in adult patients with depressive, anxiety and comorbid disorders vs. controls

Hovens JGFM, Wiersma JE, Giltay EJ, van Oppen P, Spinhoven P, Penninx BWJH, Zitman FG. Childhood life events and childhood trauma in adult patients with depressive, anxiety and comorbid disorders vs. controls.

Critical slowing down as early warning for the onset and termination of depression

Significance As complex systems such as the climate or ecosystems approach a tipping point, their dynamics tend to become dominated by a phenomenon known as critical slowing down. Using time series of autorecorded mood, we show that indicators of slowing down are also predictive of future transitions in depression. Specifically, in persons who are more likely to have a future transition, mood dynamics are slower and different aspects of mood are more correlated. This supports the view that the mood system may have tipping points where reinforcing feedbacks among a web of symptoms can propagate a person into a disorder. Our findings suggest the possibility of early warning systems for psychiatric disorders, using smartphone-based mood monitoring. About 17% of humanity goes through an episode of major depression at some point in their lifetime. Despite the enormous societal costs of this incapacitating disorder, it is largely unknown how the likelihood of falling into a depressive episode can be assessed. Here, we show for a large group of healthy individuals and patients that the probability of an upcoming shift between a depressed and a normal state is related to elevated temporal autocorrelation, variance, and correlation between emotions in fluctuations of autorecorded emotions. These are indicators of the general phenomenon of critical slowing down, which is expected to occur when a system approaches a tipping point. Our results support the hypothesis that mood may have alternative stable states separated by tipping points, and suggest an approach for assessing the likelihood of transitions into and out of depression.

Increased sympathetic and decreased parasympathetic activity rather than changes in hypothalamic-pituitary-adrenal axis activity is associated with metabolic abnormalities.

CONTEXT Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome, but the underlying biological mechanisms are not yet well understood. OBJECTIVE We examined the relationship between two main str systems, the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, with the metabolic syndrome and its components. DESIGN The design was baseline data (yr 2004-2007) of a prospective cohort: the Netherlands Study of Depression and Anxiety (NESDA). SETTING The study comprised general community, primary care, and specialized mental health care. PARTICIPANTS This study included 1883 participants aged 18-65 yr. MAIN OUTCOME MEASURES Autonomic nervous system measures included heart rate, respiratory sinus arrhythmia (RSA; high RSA reflecting high parasympathetic activity), and preejection period (PEP; high PEP reflecting low sympathetic activity). HPA axis measures included the cortisol awakening response, evening cortisol, and a 0.5 mg dexamethasone suppression test as measured in saliva. Metabolic syndrome was based on the updated Adult Treatment Panel III criteria and included high waist circumference, serum triglycerides, blood pressure, serum glucose, and low high-density lipoprotein cholesterol. RESULTS RSA and PEP were both independently negatively associated with the presence of the metabolic syndrome, the number of metabolic dysregulations as well as all individual components except high-density lipoprotein cholesterol (all P < 0.02). Heart rate was positively related to the metabolic syndrome, the number of metabolic dysregulations, and all individual components (all P < 0.001). HPA axis measures were not related to metabolic syndrome or its components. CONCLUSION Our findings suggest that increased sympathetic and decreased parasympathetic nervous system activity is associated with metabolic syndrome, whereas HPA axis activity is not.

Routine outcome monitoring in the Netherlands: practical experiences with a web-based strategy for the assessment of treatment outcome in clinical practice.

Routine outcome monitoring (ROM) is a method devised to systematically collect data on the effectiveness of treatments in everyday clinical practice. ROM involves documenting the outcome of treatments through repeated assessments. Assistants are employed who perform a baseline assessment comprising a standardized diagnostic interview, administration of rating scales and completion of several self-report measures by the patient. At fixed time intervals, assessments are repeated. Dedicated Web-based software has been developed to assist in this task. ROM informs therapists and patients on the severity of the complaints at intake, and the waxing and waning of symptoms over the course of treatment. Researchers can use ROM for effectiveness research, and managers can use it for benchmarking. The use of ROM for research is illustrated by presenting data on the diagnostic status of patients participating in ROM and data on treatment outcome of a subgroup of patients (with panic disorder) in our database. The results show that implementation of ROM is feasible, and after some initial reservations, most therapists now consider ROM to be a necessary and important adjunct to the clinical treatment. In addition, ROM furthers research as the data can be used to study the phenomenology of psychiatric disorders and the outcome of treatments delivered in everyday practice.

Impact of childhood life events and trauma on the course of depressive and anxiety disorders

Hovens JGFM, Giltay EJ, Wiersma JE, Spinhoven P, Penninx BWJH, Zitman FG. Impact of childhood life events and trauma on the course of depressive and anxiety disorders.