Respiratory muscle dysfunction and training in chronic heart failure

A characteristic feature of chronic heart failure (CHF) is reduced exercise tolerance. Several factors contributing to this have been identified, including alterations in central haemodynamics, skeletal muscle oxygen utilisation and respiratory muscle dysfunction. This review focuses on abnormalities identified in respiratory muscle structure and function in CHF and recent evidence for the benefit of selective inspiratory muscle training in CHF. Included in this review are findings from original investigations, with a specific focus on recent published data.

Mothers' AdvocateS In the Community (MOSAIC)- non-professional mentor support to reduce intimate partner violence and depression in mothers: a cluster randomised trial in primary care

Background : Effective interventions to increase safety and wellbeing of mothers experiencing intimate partner violence (IPV) are scarce. As much attention is focussed on professional intervention, this study aimed to determine the effectiveness of non-professional mentor support in reducing IPV and depression among pregnant and recent mothers experiencing, or at risk of IPV.

Methods : MOSAIC was a cluster randomised trial in 106 primary care (maternal and child health nurse and general practitioner) clinics in Melbourne, Australia. 63/106 clinics referred 215 eligible culturally and linguistically diverse women between January 2006 and December 2007. 167 in the intervention (I) arm, and 91 in the comparison (C) arm. 174 (80.9%) were recruited. 133 (76.4%) women (90 I and 43 C) completed follow-up at 12 months.

Intervention: 12 months of weekly home visiting from trained and supervised local mothers, (English & Vietnamese speaking) offering non-professional befriending, advocacy, parenting support and referrals.

Main outcome measures: Primary outcomes; IPV (Composite Abuse Scale CAS) and depression (Edinburgh Postnatal Depression Scale EPDS); secondary measures included wellbeing (SF-36), parenting stress (PSI-SF) and social support (MOS-SF) at baseline and follow-up.

Analysis: Intention-to-treat using multivariable logistic regression and propensity scoring.

Results : There was evidence of a true difference in mean abuse scores at follow-up in the intervention compared with the comparison arm (15.9 vs 21.8, AdjDiff -8.67, CI -16.2 to -1.15). There was weak evidence for other outcomes, but a trend was evident favouring the intervention: proportions of women with CAS scores ≥7, 51/88 (58.4%) vs 27/42 (64.3%) AdjOR 0.47, CI 0.21 to 1.05); depression (EPDS score ≥13) (19/85, 22% (I) vs 14/43, 33% (C); AdjOR 0.42, CI 0.17 to 1.06); physical wellbeing mean scores (PCS-SF36: AdjDiff 2.79; CI -0.40 to 5.99); mental wellbeing mean scores (MCS-SF36: AdjDiff 2.26; CI -1.48 to 6.00). There was no observed effect on parenting stress. 82% of women mentored would recommend mentors to friends in similar situations.

Conclusion : Non-professional mentor mother support appears promising for improving safety and enhancing physical and mental wellbeing among mothers experiencing intimate partner violence referred from primary care.

Intervention for depression among palliative care patients and their families : a study protocol for evaluation of a training program for professional care staff

Background: Clinical depression is highly prevalent yet under-detected and under-treated in palliative care settings and is associated with a number of adverse medical and psychological outcomes for patients and their family members. This article presents a study protocol to evaluate a training intervention for non-physician palliative care staff to improve the recognition of depression and provide support for depressed patients and their family members. Details of the hypotheses and expected outcomes, study design, training program development and evaluation measures are described.
Methods and Design: A randomised controlled trial will be implemented across two palliative care services to evaluate the “Training program for professional carers to recognise and manage depression in palliative care settings”. Pre-, post- and three-month follow-up data will be collected to assess: the impact of the training on the knowledge, attitudes, self-efficacy and perceived barriers of palliative care staff when working with depression; referral rates for depression; and changes to staff practices. Quantitative and qualitative methods, in the form of self-report questionnaires and interviews with staff and family members, will be used to evaluate the effectiveness of the intervention.
Discussion: This study will determine the effectiveness of an intervention that aims to respond to the urgent need for innovative programs to target depression in the palliative care setting. The expected outcome of this study is the validation of an evidence-based training program to improve staff recognition and appropriate referrals for depression, as well as improve psychosocial support for depressed patients and their family members.

Co-morbid depression is associated with poor work outcomes in persons with cardiovascular disease (CVD) : a large, nationally representative survey in the Australian population

Background: Co-morbid major depressive disorder (MDD) and cardiovascular disease (CVD) is associated with poor clinical and psychological outcomes. However, the full extent of the burden of, and interaction between, this co-morbidity on important vocational outcomes remains less clear, particularly at the population level. We examine the association of co-morbid MDD with work outcomes in persons with and without CVD.

Methods. This study utilised cross-sectional, population-based data from the 2007 Australian National Survey of Mental Health and Wellbeing (n = 8841) to compare work outcomes of individuals with diagnostically-defined MDD and CVD, MDD but not CVD, CVD but not MDD, with a reference group of "healthy" Australians. Workforce participation was defined as being in full- or part-time employment. Work functioning was measured using a WHO Disability Assessment Schedule item. Absenteeism was assessed using the 'days out of role' item.

Results: Of the four groups, those with co-morbid MDD and CVD were least likely to report workforce participation (adj OR:0.4, 95% CI: 0.3-0.6). Those with MDD only (adj OR:0.8, 95% CI:0.7-0.9) and CVD only (adj OR:0.8, 95% CI: 0.6-0.9) also reported significantly reduced odds of participation. Employed individuals with co-morbid MDD and CVD were 8 times as likely to experience impairments in work functioning (adj OR:8.1, 95% CI: 3.8- 17.3) compared with the reference group. MDD was associated with a four-fold increase in impaired functioning. Further, individuals with co-morbid MDD and CVD reported greatest likelihood of workplace absenteeism (adj. OR:3.0, 95% CI: 1.4-6.6). Simultaneous exposure to MDD and CVD conferred an even greater likelihood of poorer work functioning.

Conclusions: Co-morbid MDD and CVD is associated with significantly poorer work outcomes. Specifically, the effects of these conditions on work functioning are synergistic. The development of specialised treatment programs for those with co-morbid MDD and CVD is required.

New drug targets in depression : inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors

This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy.

Depression's multiple comorbidities explained by (neuro)inflammatory and oxidative & nitrosative stress pathways

There is now evidence that depression, as characterized by melancholic symptoms, anxiety, and fatigue and somatic (F&S) symptoms, is the clinical expression of peripheral cell-mediated activation, inflammation and induction of oxidative and nitrosative stress (IO&NS) pathways and of central microglial activation, decreased neurogenesis and increased apoptosis. This review gives an explanation for the multiple “co-morbidities” between depression and a large variety of a) brain disorders related to neurodegeneration, e.g. Alzheimer’s, Parkinson’s and Huntington’s disease, multiple sclerosis and stroke; b) medical disorders, such as cardiovascular disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, leaky gut, diabetes type 1 and 2, obesity and the metabolic syndrome, and HIV infection; and c) conditions, such as hemodialysis, interferon-α-based immunotherapy, the postnatal period and psychosocial stressors. The common denominator of all those disorders/conditions is the presence of microglial activation and/or activation of peripheral IO&NS pathways. There is evidence that shared peripheral and / or central IO&NS pathways underpin the pathophysiology of depression and the previously mentioned disorders and that activation of these IO&NS pathways contributes to shared risk. The IO&NS pathways function as a smoke sensor that detect threats in the peripheral and central parts of the body and signal these threats as melancholic, anxiety, and fatigue and somatic (F&S) symptoms. The presence of concomitant depression is strongly associated with a lower quality of life and increased morbidity and mortality in medical disorders. This may be explained since depression contributes to increased (neuro)inflammatory burden and may therefore drive the inflammatory and degenerative progression. It is concluded that the activation of peripheral and / or central IO&NS pathways may explain the co-occurrence of depression with the above disorders. This shows that depression belongs to the spectrum of inflammatory and degenerative disorders.

A randomised, feasibility trial of a tele-health intervention for acute coronary syndrome patients with depression (‘MoodCare’): study protocol

Background Coronary heart disease (CHD) and depression are leading causes of disease burden globally and the two often co-exist. Depression is common after Myocardial Infarction (MI) and it has been estimated that 15-35% of patients experience depressive symptoms. Co-morbid depression can impair health related quality of life (HRQOL), decrease medication adherence and appropriate utilisation of health services, lead to increased morbidity and suicide risk, and is associated with poorer CHD risk factor profiles and reduced survival. We aim to determine the feasibility of conducting a randomised, multi-centre trial designed to compare a tele-health program (MoodCare) for depression and CHD secondary prevention, with Usual Care (UC).

Methods Over 1600 patients admitted after index admission for Acute Coronary Syndrome (ACS) are being screened for depression at six metropolitan hospitals in the Australian states of Victoria and Queensland. Consenting participants are then contacted at two weeks post-discharge for baseline assessment. One hundred eligible participants are to be randomised to an intervention or a usual medical care control group (50 per group). The intervention consists of up to 10 × 30-40 minute structured telephone sessions, delivered by registered psychologists, commencing within two weeks of baseline screening. The intervention focuses on depression management, lifestyle factors (physical activity, healthy eating, smoking cessation, alcohol intake), medication adherence and managing co-morbidities. Data collection occurs at baseline (Time 1), 6 months (post-intervention) (Time 2), 12 months (Time 3) and 24 months follow-up for longer term effects (Time 4). We are comparing depression (Cardiac Depression Scale [CDS]) and HRQOL (Short Form-12 [SF-12]) scores between treatment and UC groups, assessing the feasibility of the program through patient acceptability and exploring long term maintenance effects. A cost-effectiveness analysis of the costs and outcomes for patients in the intervention and control groups is being conducted from the perspective of health care costs to the government.

Discussion This manuscript presents the protocol for a randomised, multi-centre trial to evaluate the feasibility of a tele-based depression management and CHD secondary prevention program for ACS patients. The results of this trial will provide valuable new information about potential psychological and wellbeing benefits, cost-effectiveness and acceptability of an innovative tele-based depression management and secondary prevention program for CHD patients experiencing depression.

Depression as a predictor of work resumption following myocardial infarction (MI): a review of recent research evidence

Background Depression often coexists with myocardial infarction (MI) and has been found to impede recovery through reduced functioning in key areas of life such as work. In an era of improved survival rates and extended working lives, we review whether depression remains a predictor of poorer work outcomes following MI by systematically reviewing literature from the past 15 years.

Methods Articles were identified using medical, health, occupational and social science databases, including PubMed, OVID, Medline, Proquest, CINAHL plus, CCOHS, SCOPUS, Web of Knowledge, and the following pre-determined criteria were applied: (i) collection of depression measures (as distinct from 'psychological distress') and work status at baseline, (ii) examination and statistical analysis of predictors of work outcomes, (iii) inclusion of cohorts with patients exhibiting symptoms consistent with Acute Coronary Syndrome (ACS), (iv) follow-up of work-specific and depression specific outcomes at minimum 6 months, (v) published in English over the past 15 years. Results from included articles were then evaluated for quality and analysed by comparing effect size.

Results Of the 12 articles meeting criteria, depression significantly predicted reduced likelihood of return to work (RTW) in the majority of studies (n = 7). Further, there was a trend suggesting that increased depression severity was associated with poorer RTW outcomes 6 to 12 months after a cardiac event. Other common significant predictors of RTW were age and patient perceptions of their illness and work performance.

Conclusion Depression is a predictor of work resumption post-MI. As work is a major component of Quality of Life (QOL), this finding has clinical, social, public health and economic implications in the modern era. Targeted depression interventions could facilitate RTW post-MI.

ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression

The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood–brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Single-nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals (N=113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonin-transporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively (P=0.0001). This equates to a 2.0- (95% confidence interval=1.5–3.4; P<0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio=6.69; 95% confidence interval=1.72–25.9, P=0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.

Barriers to the detection and management of depression by palliative care professional carers among their patients : perspectives from professional carers and patients' family members

Introduction: Clinical depression is highly prevalent yet underdetected and poorly managed within palliative care settings.

Objectives: This qualitative study explored the identification, monitoring, and management of symptoms of depression in patients receiving palliative care from 2 juxtaposed perspectives that are of care providers and care recipients' family members. Examining the barriers that restrict professional carers detecting and managing depression in their patients was a central focus of the study.

Methods: Focus groups were held with 18 professional carers, including 8 holding managerial positions, across 2 palliative care services, 1 regional and 1 metropolitan, which provided both inpatient and community-based care. Individual interviews were conducted with 10 family members of patients who had received or were receiving palliative care through these services.

Results: Thematic analysis of these data identified that both professional carers and family members perceived that depression is a wide-spread concern for patients receiving palliative care; however, numerous barriers were identified that affect professional carers’ ability to identify depression. These included knowledge and training deficits, low self-efficacy, prioritization of physical concerns and time constraints, patient/family characteristics, and system/process issues. These themes (and related subthemes) are discussed in this article.

Conclusions: Specialized training in depression is recommended for professional carers in order to improve their depression-related knowledge, detection skills, and self-efficacy. The ultimate goal of such training is to increase the rate of recognition of depression that in turn will lead to appropriate treatment for depressed patients.

The effects of apoptosis vulnerability markers on the myocardium in depression after myocardial infarction

Background : There is an increased incidence of major depressive disorder (MDD) in individuals after myocardial infarction (MI), but the pathophysiological processes mediating this association are unclear. Our previous study demonstrated an increase in pro-apoptotic pathways in the myocardium and hippocampus in MDD, which was reversed by venlafaxine. This study aimed to attempt to confirm the effects of apoptosis vulnerability markers on the myocardium in a model of depression after myocardial infarction.

Methods : Rats were divided into four groups: sham (N = 8), depression (N = 8, chronic mild unpredictable stress and separation were used in the depression group), MI (N = 13) and post-MI depression (N = 7). The rats in all four groups underwent the same open field and sucrose preference behavioral tests. Evan Blue staining was used to determine the area at risk of myocardial infarction in the left ventricle, and 2,3,5-triphenyl tetrazolium chloride (1.5% TTC) dye was used to detect the size of the myocardial infarction. The expression of bax and bcl-2 protein in the myocardium was investigated by immunohistochemistry, and the mRNA expression of bax, bcl-2 and caspase-3 in the myocardium was investigated by real time RT-PCR. Apoptosis was estimated in the myocardium by measuring the Bax:Bcl-2 ratio.

Results : In the depression and post-MI depression rats, there were significantly decreased movements and total sucrose consumption, modeling behavioral deficits and an anhedonic-like state. In terms of myocardial infarction size, no difference was seen between the MI and post-MI depression groups. There was an up-regulated Bax:Bcl-2 ratio in the depression, MI and post-MI depression groups. Furthermore, in the latter group, there was a greater up-regulated Bax:Bcl-2 ratio. However, caspase-3 did not differ among the four groups.

Conclusions : These results of this animal model suggest that active pro-apoptotic pathways may be involved in the nexus between myocardial infarction and depression. This mechanism may be germane to understanding this relationship in humans.

Leukocyte numbers and function in subjects eating n-3 enriched foods: selective depression of natural killer cell levels

Introduction : While consumption of omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) has been recommended for those at risk of inflammatory disease such as rheumatoid arthritis, the mechanism of their anti-inflammatory effect remains to be clearly defined, particularly in relation to the dose and type of n-3 LCPUFA. The objective of this study was to determine whether varying the levels of n-3 LCPUFA in erythrocyte membrane lipids, following dietary supplementation, is associated with altered numbers and function of circulating leukocytes conducive to protection against inflammation. Methods : In a double-blind and placebo-controlled study, 44 healthy subjects aged 23 to 63 years consumed either standard or n-3 LCPUFA-enriched versions of typical processed foods, the latter allowing a target daily consumption of 1 gram n-3 LCPUFA. After six months, peripheral blood leukocyte and subpopulation proportions and numbers were assessed by flow cytometry. Leukocytes were also examined for lymphoproliferation and cytokine production, neutrophil chemotaxis, chemokinesis, bactericidal, adherence and iodination activity. Erythrocytes were analyzed for fatty-acid content. Results : Erythrocyte n-3 LCPUFA levels were higher and absolute leukocyte and lymphocyte numbers were lower in subjects consuming n-3 enriched foods than in controls. There were no changes in the number of neutrophils, monocytes, T cells (CD3+), T-cell subsets (CD4+, CD8+) and B cells (CD19+). However, natural killer (NK) (CD3-CD16+CD56+) cell numbers were lower in n-3 supplemented subjects than in controls and were inversely related to the amount of eicosapentaenoic acid or docosahexaenoic acid in erythrocytes. No significant correlations were found with respect to lymphocyte lymphoproliferation and production of IFN-γ and IL-2, but lymphotoxin production was higher with greater n-3 LCPUFA membrane content. Similarly, neutrophil chemotaxis, chemokinesis, bactericidal activity and adherence did not vary with changes in erythrocyte n-3 LCPUFA levels, but the iodination reaction was reduced with higher n-3 LCPUFA content. Conclusion : The data show that regular long-term consumption of n-3 enriched foods leads to lower numbers of NK cells and neutrophil iodination activity but higher lymphotoxin production by lymphocytes. These changes are consistent with decreased inflammatory reaction and tissue damage seen in patients with inflammatory disorders receiving n-3 LCPUFA supplementation.

A randomised, controlled trial of a dietary intervention for adults with major depression (the "SMILES" trial): study protocol

Despite increased investment in its recognition and treatment, depression remains a substantial health and economic burden worldwide. Current treatment strategies generally focus on biological and psychological pathways, largely neglecting the role of lifestyle. There is emerging evidence to suggest that diet and nutrition play an important role in the risk, and the genesis, of depression. However, there are limited data regarding the therapeutic impact of dietary changes on existing mental illness. Using a randomised controlled trial design, we aim to investigate the efficacy and cost-efficacy of a dietary program for the treatment of Major Depressive Episodes.