Targeting and transforming major depression.

OBJECTIVE: To detail limitations to the construct of 'major depression', argue for repositioning it as a proxy for 'clinical depression' and then operationalize it and its principal constituent depressive subtypes, while preserving the DSM criteria-based format. METHOD: We summarize limitations to major depression being viewed as a diagnostic entity. Data from 391 clinically depressed patients were analysed to identify high-prevalence non-specific depressive symptoms to define 'clinical depression' as well as the features showing specificity to a melancholic depressive subtype. RESULTS: We identified a set of high-prevalence and generalized symptoms for defining clinical depression and with many being current criteria for major depression. We also developed a refined set of melancholic features and with their underlying distributions generating two classes that correlated strongly with clinical diagnoses of a melancholic or non-melancholic depression, thus validating its capacity to so differentiate. We append criteria sets for diagnosing clinical depression and its principal diagnostic subtypes (psychotic, melancholic and non-melancholic). CONCLUSION: This heuristic study reframes and modifies major depression's criteria set to define a domain of clinical depression with additional criteria and then allowing the delineation of three diagnostic subtypes. If this paradigm shift is accepted and further refined, greater precision in diagnosis, treatment and research would be anticipated.

GABA (γ-Aminobutyric Acid) Uptake Via the GABA Permease GabP Represses Virulence Gene Expression in Pseudomonas syringae pv. tomato DC3000.

The nonprotein amino acid γ-aminobutyric acid (GABA) is the most abundant amino acid in the tomato (Solanum lycopersicum) leaf apoplast and is synthesized by Arabidopsis thaliana in response to infection by the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 (hereafter called DC3000). High levels of exogenous GABA have previously been shown to repress the expression of the type III secretion system (T3SS) in DC3000, resulting in reduced elicitation of the hypersensitive response (HR) in the nonhost plant tobacco (Nicotiana tabacum). This study demonstrates that the GABA permease GabP provides the primary mechanism for GABA uptake by DC3000 and that the gabP deletion mutant ΔgabP is insensitive to GABA-mediated repression of T3SS expression. ΔgabP displayed an enhanced ability to elicit the HR in young tobacco leaves and in tobacco plants engineered to produce increased levels of GABA, which supports the hypothesis that GABA uptake via GabP acts to regulate T3SS expression in planta. The observation that P. syringae can be rendered insensitive to GABA through loss of gabP but that gabP is retained by this bacterium suggests that GabP is important for DC3000 in a natural setting, either for nutrition or as a mechanism for regulating gene expression. [Formula: see text] Copyright © 2016 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

The utility of a classificatory decision tree approach to assist clinical differentiation of melancholic and non-melancholic depression.

BACKGROUND: Studies suggest that differentiating melancholic from non-melancholic depressive disorders is advanced by use of illness course as well as symptom variables but, in practice, potentially differentiating variables are generally positioned as having equal value. Judging that differentiating features are more likely to vary in their signal intensity, we sought to determine the number of features required to effect differentiation and their hierarchical order. METHODS: The 24-item clinician-rated Sydney Melancholia Prototype Index (SMPI-CR) was completed for 364 unipolar depressed patients. The sample was divided into two cohorts according to the recruitment period. An RPART classification tree analysis identified the most discriminating SMPI items in the development sample of 197 patients, and examined the sensitivity and specificity of the diagnostic decisions, then sought to replicate findings in a validation sample of 169 patients. RESULTS: Independent analyses of putative SMPI items identified only seven items as required to discriminate those with clinically-diagnosed melancholic or non-melancholic depression when the conditions were examined separately. An RPART analysis considering differentiation of melancholic and non-melancholic depression in the total samples retained five of those items in the classification tree, three of which were non-symptom items, and with 92% sensitivity and 80% specificity in the development sample. This reduced item set showed 93% sensitivity and 82% specificity in the validation sample. LIMITATIONS: Our clinical judgment of melancholic or non-melancholic depression may not correspond with the clinical logic employed by other clinicians. CONCLUSION: Only five SMPI items were required to derive a succinct and efficient decision tree, comprising high sensitivity and specificity in differentiating melancholic and non-melancholic depression. Current study findings provide an empirical model that could enrich clinicians׳ approach to differentiating melancholic and non-melancholic depression.

The 'disconnect' between initial judgments of lamotrigine vs. its real-world effectiveness in managing bipolar disorder. A tale with wider ramifications.

OBJECTIVE: To detail the disconnect between the quantified efficacy of the mood stabilizer lamotrigine in its registration controlled trials and its later judged clinical effectiveness and consider some determinants of disconnects between some efficacy trial findings and 'real-world' clinical effectiveness judgments. METHOD: Published articles considering lamotrigine as a treatment for the bipolar I or II disorders were selected for review. While randomized controlled trials were weighted, we also consider open trials and effectiveness observations from clinician researchers and demonstrate that lamotrigine has been quite variably judged over time. RESULTS: We suggest that the early trials evaluating lamotrigine for acute bipolar disorder depression focused on a suboptimal clinical target, and in so doing, ensured less lamotrigine efficacy compared with trials of bipolar disorder preventative treatment. Moreover, a number of additional methodological limitations compromised analyses. We also detail variable reporting of actual study results. The initial sharp disconnect (between efficacy and effectiveness judgments) has narrowed as lamotrigine has been evaluated and progressively taken up as a maintenance mood stabilizer. CONCLUSION: The lamotrigine disconnect story provides a number of salutary lessons that are salient to evaluating the effectiveness and ecological niche of any psychotropic medication. The lamotrigine story presented here argues strongly for the wisdom of encouraging an iterative process between efficacy studies and clinical observation.

Functional alterations in brain activation and deactivation in mild cognitive impairment in response to a graded working memory challenge.

AIM: To investigate dynamic changes in functional brain activity in mild cognitive impairment (MCI) in response to a graded working memory (WM) challenge with increasing memory load. METHODS: In an event-related functional magnetic resonance imaging (fMRI) study, 35 MCI and 22 cognitively normal subjects performed a visuospatial associative WM task with 3 load levels. Potential performance differences were controlled for by individually calibrating the number of items presented at each load. RESULTS: An interaction between group and WM load was observed during stimulus encoding. At lower loads, greater activity in the right anterior cingulate and right precuneus was observed in MCI subjects. As the load increased to higher levels, reduced activation in these regions and greater deactivation in the posterior cingulate-medial precuneus were observed in MCI compared to control subjects. Stronger expression of load-related patterns of activation and deactivation in MCI subjects was associated with greater clinical severity and a more abnormal pattern of performance variability. CONCLUSION: Patterns of overactivation, underactivation and deactivation during successful encoding in MCI subjects were dependent on WM load. This type of graded cognitive challenge may operate like a 'memory stress test' in MCI and may be a useful biomarker of disease at the pre-dementia stage.