The neurobiology of depression in later-life: clinical, neuropsychological, neuroimaging and pathophysiological features

As the population ages, the economic and societal impacts of neurodegenerative and neuropsychiatric disorders are expected to rise sharply. Like dementia, late-life depressive disorders are common and are linked to increased disability, high healthcare utilisation, cognitive decline and premature mortality. Considerable heterogeneity in the clinical presentation of major depression across the life cycle may reflect unique pathophysiological pathways to illness; differentiating those with earlier onset who have grown older (early-onset depression), from those with illness onset after the age of 50 or 60 years (late-onset depression). The last two decades have witnessed significant advances in our understanding of the neurobiology of early- and late-onset depression, and has shown that disturbances of fronto-subcortical functioning are implicated. New biomedical models extend well beyond perturbations of traditional monoamine systems to include altered neurotrophins, endocrinologic and immunologic system dysfunction, inflammatory processes and gene expression alterations. This more recent research has highlighted that a range of illness-specific, neurodegenerative and vascular factors appear to contribute to the various phenotypic presentations. This review highlights the major features of late-life depression, with specific reference to its associated aetiological, clinical, cognitive, neuroimaging, neuropathological, inflammatory and genetic correlates. Data examining the efficacy of pharmacological, non-pharmacological and novel treatments for depression are discussed. Ultimately, future research must aim to evaluate whether basic biomedical knowledge can be successfully translated into enhanced health outcomes via the implementation of early intervention paradigms.     

Tetranectin positive expression in tumour tissue leads to longer survival in Danish women with ovarian cancer. Results from the ‘Malova’ ovarian cancer study

The primary objective of this study was to analyse Tetranectin (TN) expression in tumour tissues and TN serum concentration in 758 women with epithelial ovarian tumours. The second was to evaluate, whether TN tissue expression levels correlate with clinico‐pathological parameters and prognosis of the disease. Using tissue arrays we analysed the expression levels in tissues from 166 women with borderline ovarian tumours (BOTs) and 592 women with ovarian cancer (OC). A panel of three antibodies was used for immunohistochemistry: a polyclonal and two monoclonal antibodies. Serum TN was measured using the polyclonal antibody A‐371. Univariate survival analyses stratified for chemotherapy showed that positive tissue TN as demonstrated by the polyclonal antibody indicated a significantly longer overall survival (OS) (p = 0.0001) as well as cancer specific survival (CSS) (p < 0.0001). High serum TN was likewise found to imply longer OS (p < 0.0001) and CSS (p < 0.0001), whereas tissue staining with the two monoclonal antibodies failed to demonstrate any significant correlation with either survival type. Univariate Kaplan–Meier survival analysis performed on all OC cases showed a significantly longer OS (p = 0.0009) and CSS (p = 0.0006) for women with TN positive tumour tissue and in women with high serum TN levels (p < 0.0001 for both). However, in the multivariate Cox regression analysis, only serum TN was found to be an independent prognostic factor for OS (p = 0.01) and not for CSS (p = 0.08). In conclusion, our results predict that a positive TN expression of both tumour tissue and serum points to a more favourable outcome for OC patients.     

Early and late onset depression in old age: different aetiologies, same phenomenology

BACKGROUND: Phenomenological differences between older patients with early onset (EO; onset of first major depressive episode before 60 years) and late onset (LO) depression have been inconsistent but, if real, may reflect differences in aetiology. We aimed to compare aetiological factors, phenomenology and cognitive function in older patients with depression by age of onset. METHODS: Subjects were all patients > or =60 years old (n=73) from 407 consecutive attenders to a Mood Disorders Unit, diagnosed with DSM-III-R Major Depressive Episode, at or close to the nadir of their episode. Putative risk factors were assessed by structured interview. Psychological morbidity and depressive symptoms were assessed by the 21-item Hamilton Rating Scale for Depression, CORE rating of psychomotor disturbance, Newcastle Endogeneity Scale, Zung Depression Scale and General Health Questionnaire. Cognition was assessed by tests of memory, attention, executive function and motor speed. RESULTS: Personality abnormalities, a family history of psychiatric illness and dysfunctional past maternal relationships were significantly more common in EO depression. The two age of onset groups were essentially similar in terms of depressive sub-type and severity, phenomenology, history of previous episode, and in neuropsychological performance. LIMITATIONS: Use of self-report data, moderate sample size, sample not age-matched, tertiary referral patients. CONCLUSIONS: EO and LO depression are similar phenotypically, but differ aetiologically. The pursuit of mechanisms which predispose depressive episodes may be heuristically more valuable than further investigation of individual depressive features in distinguishing early from late onset depression.     

A systematic review of the impact of adherence on the effectiveness of e-therapies

Background

As the popularity of e-therapies grows, so too has the body of literature supporting their effectiveness. However, these interventions are often plagued by high attrition rates and varying levels of user adherence. Understanding the role of adherence may be crucial to understanding how program usage influences the effectiveness of e-therapy interventions.

Objective

The aim of this study was to systematically review the e-therapy literature to (1) describe the methods used to assess adherence and (2) evaluate the association of adherence with outcome of these interventions.

Methods

A systematic review of e-therapy interventions was conducted across disease states and behavioral targets. Data were collected on adherence measures, outcomes, and analyses exploring the relationship between adherence measures and outcomes.

Results

Of 69 studies that reported an adherence measure, only 33 (48%) examined the relationship between adherence and outcomes. The number of logins was the most commonly reported measure of adherence, followed by the number of modules completed. The heterogeneity of adherence and outcome measures limited analysis. However, logins appeared to be the measure of adherence most consistently related to outcomes in physical health interventions, while module completion was found to be most related to outcomes in psychological health interventions.

Conclusions

There is large variation in the reporting of adherence and the association of adherence with outcomes. A lack of agreement about how best to measure adherence is likely to contribute to the variation in findings. Physical and psychological outcomes seem influenced by different types of adherence. A composite measure encompassing time online, activity completion, and active engagements with the intervention may be the best measure of adherence. Further research is required to establish a consensus for measuring adherence and to understand the role of adherence in influencing outcomes.     

Alcohol use and mismatch negativity in young patients with psychotic disorder

Mismatch negativity (MMN) is a neurophysiological indicator of the brain's ability to extract relevant information from an irrelevant background. MMN has been described as a reliable biomarker of schizophrenia and more recently it has found to be impaired in the early stages of psychosis. In addition, drugs (including alcohol) that block glutamate's N-methyl-D-aspartate receptor have been shown to reduce MMN. This study aims to determine whether risky alcohol consumption in young patients with psychotic disorder further impacts or changes their MMN response. Patients with high-alcohol use were found to show reduced temporal MMN amplitudes compared with patients with low-alcohol use and controls. In contrast, early psychosis patients with low-alcohol use showed reduced fronto-central MMN amplitudes compared with controls; whereas patients with high-alcohol use showed an intermediate response at these sites. Correlational analysis revealed distinct patterns of association between MMN and alcohol use in patients with early psychosis compared with controls. This study shows that early psychosis outpatients who engaged in risky drinking have decreased temporal MMN amplitudes, compared with their peers. This may reflect an additive effect of N-methyl-D-aspartate receptor hypofunction and high-alcohol consumption.     

Clinical staging of psychiatric disorders: a heuristic framework for choosing earlier, safer and more effective interventions

Diagnosis in psychiatry increasingly struggles to fulfil its key purposes, namely, to guide treatment and to predict outcome. The clinical staging model, widely used in clinical medicine yet virtually ignored in psychiatry, is proposed as a more refined form of diagnosis which could restore the utility of diagnosis, promote early intervention and also make more sense of the confusing array of biological research findings in psychiatry by organizing data into a coherent clinicopathological framework. A selective review of key papers in clinical medicine and psychiatry which describe clinical and clinicopathological staging, and a range of related issues. Clinical staging has immediate potential to improve the logic and timing of interventions in psychiatry just as it does in many complex and potentially serious medical disorders. Interventions could be evaluated in terms of their ability to prevent or delay progression from earlier to later stages of disorder, and they could be selected on clear-cut risk/benefit criteria. Biological variables and a range of candidate risk factors could be studied within and across stages, and their role, specificity and centrality in risk, onset and progression of disorder could be greatly clarified. A clinicopathological framework could be progressively constructed. Clinical staging with a restructure across and within diagnostic boundaries with the explicit operationalization of criteria for extent and progression of disorder should be actively explored in psychiatry as a heuristic strategy for the development and evaluation of earlier, safer, and more effective clinical interventions, and for clarifying the biological basis of psychiatric disorders.     

Chromosome 7 long arm deletion in myeloid disorders: a narrow breakpoint region in 7q22 defined by molecular mapping

The involvement of the erythropoietin (EPO), plasminogen activator inhibitor type I (PAI1), and multi-drug resistance (MDR2) genes located in chromosomal region 7q21-22 was studied in patients with myeloid disorders and with or without a chromosome 7 abnormality. Separated blood mononuclear cells and granulocytes from 21 patients were used in restriction fragment length polymorphism (RFLP) studies with gene- specific DNA probes. A marked weakness of one of the allelic bands was observed in granulocyte-derived DNA from heterozygous patients with monosomy 7. In four patients with a partial deletion of chromosome 7 long arm (7q-), marked weakness of an allelic band was observed in granulocyte-derived DNA with PAI1 probe (four heterozygous patients) and MDR2 probe (one heterozygous patient), implying deletion of these genes. In contrast, the EPO gene was not deleted in these patients, as demonstrated by the presence of two allelic bands of equal strength in granulocyte-derived DNA (two patients) or by gene dosage estimation (two patients). Two allelic bands of equal strength were also observed in three heterozygous patients with an arbitrary probe (pKV13) located in 7cen-q21.3. Unexpected hemizygosity or hybridization bands were not observed in any patient. We conclude that PAI1 and MDR2 are located distally of EPO in 7q22, and that none of these genes is commonly rearranged in myeloid disorders. The chromosome 7 long arm deletion breakpoint is located in a relatively narrow segment between the PAI1 and EPO genes in different patients. The deletion may involve a specific site in DNA, since the genetic distance between the PAI1 and EPO genes is only 3 cM.