Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT): Study Protocol for a Randomized Controlled Trial

ABSTRACT: BACKGROUND: Limited controlled data exist to guide treatment choices for clinicians caring for patients with major depressive disorder (MDD). Although many putative predictors of treatment response have been reported, most were identified through retrospective analyses of existing datasets and very few have been replicated in a manner that can impact clinical practice. One major confound in previous studies examining predictors of treatment response is the patient's treatment history, which may affect both the predictor of interest and treatment outcomes. Moreover, prior treatment history provides an important source of selection bias, thereby limiting generalizability. Consequently, we initiated a randomized clinical trial designed to identify factors that moderate response to three treatments for MDD among patients never treated previously for the condition. METHODS: Treatment-naive adults aged 18-65 years with moderate-to-severe, non-psychotic MDD are randomized equally to one of three 12-week treatment arms: 1) cognitive behavior therapy (CBT, 16 sessions), 2) duloxetine (30-60 mg/d), or 3) escitalopram (10-20 mg/d). Prior to randomization, patients undergo multiple assessments, including resting state functional magnetic resonance imaging (fMRI), immune markers, DNA and gene expression products, and dexamethasone-corticotropin releasing hormone (Dex/CRH) testing. Prior to or shortly after randomization, patients also complete a comprehensive personality assessment. Repeat assessment of the biological measures (fMRI, immune markers, and gene expression products) occur at an early time-point in treatment, and upon completion of 12-week treatment, when a a second Dex/CRH test is also conducted, Patients remitting by the end of this acute treatment phase are then eligible to enter a 21-month follow-up phase, with quarterly visits to monitor for recurrence. Non-remitters are offered augmentation treatment for a second 12-week course of treatment, during which they receive a combination of CBT and antidepressant medication. Predictors of the primary outcome, remission, will be identified for overall and treatment-specific effects, and a statistical model incorporating multiple predictors will be developed to predict outcomes. DISCUSSION: The PReDICT study's evaluation of biological, psychological, and clinical factors that may differentially impact treatment outcomes represents a sizeable step toward developing personalized treatments for MDD. Identified predictors should help guide the selection of initial treatments, and identify those patients most vulnerable to recurrence, who thus warrant maintenance or combination treatments to achieve and maintain wellness.     

Long-term assessment of efficacy of permeable pond covers for odour reduction

Three anaerobic ponds used to store and treat piggery wastes were fully covered with permeable materials manufactured from polypropylene geofabric, polyethylene shade cloth and supported straw. The covers were assessed in terms of efficacy in reducing odour emission rates over a 40-month period. Odour samples were collected from the surface of the covers, the surface of the exposed liquor and from the surface of an uncovered (control) pond at one of the piggeries. Relative to the emission rate of the exposed liquor at each pond, the polypropylene, shade cloth and straw covers reduced average emission rates by 76%, 69% and 66%, respectively. At the piggery with an uncovered control pond, the polypropylene covers reduced average odour emission rates by 50% and 41%, respectively. A plausible hypothesis, consistent with likely mechanisms for the odour reduction and the olfactometric method used to quantifying the efficacy of the covers, is offered.     

Evaluation of Copper Supplementation to Control <Emphasis Type="Italic">Haemonchus contortus</Emphasis>Infections of Sheep in Sweden

A pen study was conducted to assess the effect of providing daily copper mineral supplement, or copper wire particle (COWP) capsules, on established or incoming mixed nematode infections in young sheep. For lambs with established (6 week old) infections, COWP resulted in 97% and 56% reduction of the adult and early L4 stages of H. contortus, respectively, compared with controls (p < 0.001). Additionally there was a 74% reduction in Teladorsagia circumcincta infections in the COWP lambs compared with controls (p < 0.01). However, no effect was observed when COWP were given at the commencement of a larval dosing period of 6 weeks. There was no significant effect of copper mineral supplement (given at the recommended rate to prevent Cu deficiency) on either established, or developing parasite infections. In addition, a field trial was conducted on a commercial farm to assess the effects of COWP in the management of recurrent H. contortus infections, but lack of parasites during the grazing season prevented an adequate assessment from being made. These results indicate that there is little, if any, benefit from a parasite control standpoint in recommending copper therapy, specifically to control parasites in Swedish sheep flocks.     

Development of a scintillation proximity assay binding method for the human 5-hydroxytryptamine 6 receptor using intact cells

We describe the first validated scintillation proximity assay (SPA) binding method for quantitation of ³H-labeled d-lysergic acid diethylamide (LSD) binding to recombinant human 5-hydroxytryptamine 6 (5-HT₆) receptors expressed in Chinese hamster ovary (CHO)-Dukx and HeLa cells. The assay was developed using intact cells as a receptor source because membrane fractions derived from these cells failed to discern specific binding from a high level of nonspecific binding. The pharmacological binding profile of seven 5-HT₆ agonists and antagonists using intact CHO-Dukx/5-HT₆ cells in the SPA format was similar to data obtained from a filtration binding assay using HeLa/5-HT₆ membranes. K_i values and rank order of potencies obtained in the SPA format were consistent with published filtration data as follows: SB-271046 (K_i = 1.9 nM) > methiothepin (K_i = 6.2 nM) > mianserin (K_i = 74.3 nM) > 5-methoxytryptamine (5-MeOT, K_i = 111 nM) > 5-HT (K_i = 150 nM) > ritanserin (K_i = 207 nM) > 5-carboxamidotryptamine (5-CT, K_i = 704 nM). Additional evaluation with four antipsychotics demonstrated strong agreement with previous literature reports. A high specific binding signal and low assay variability, as determined by Z′ = 0.81 ± 0.017, make the SPA format amenable to automation and higher throughput; hence, this assay can be a viable alternative to the more labor-intensive filtration and centrifugation methods.     

An enigmatic, solifuge-like fossil arachnid from the Lower Carboniferous of Kamienna Göra (Intra-Sudetic Basin), Poland

A new arachnid (Chelicerata: Arachnida) from the Lower Carboniferous (Upper Viséan) Szczawno Formation of Kamienna Göra, Poland, is described asSchneidarachne saganii n. gen. et n. sp. Early Carboniferous arachnids are generally rare and this new fossil cannot be easily assigned to any of the known arachnid Orders. It shares a number of features with some members of the arachnid order Solifugae (camel spiders, sun spiders): namely large, forward-projecting, chelate chelicerae with dentate fixed and free fingers, a distinct median sulcus on the carapace and an interrupted ridge of tubercles on the dorsal opisthosoma set into a loosely-defïned median field. However, it lacks unequivocal autapomorphies of Solifugae. This fossil may be one of a growing number of stem-group Palaeozoic arachnids which lack the füll set of diagnostic characters seen in crown-group members of the various orders. Thus,Schneidarachne saganii could represent a basai member of the lineage leading up to modem solifuges.     

Basal forebrain cholinergic system in the dementias: Vulnerability,resilience, and resistance

The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex. They are involved in the cognitive processes of learning, memory, and attention. These neurons are differentially vulnerable in various neuropathologic entities that cause dementia. This review summarizes the relevance to BFCN of neuropathologic markers associated with dementias, including the plaques and tangles of Alzheimer's disease (AD), the Lewy bodies of diffuse Lewy body disease, the tauopathy of frontotemporal lobar degeneration (FTLD-TAU) and the TDP-43 proteinopathy of FTLD-TDP. Each of these proteinopathies has a different relationship to BFCN and their corticofugal axons. Available evidence points to early and substantial degeneration of the BFCN in AD and diffuse Lewy body disease. In AD, the major neurodegenerative correlate is accumulation of phosphotau in neurofibrillary tangles. However, these neurons are less vulnerable to the tauopathy of FTLD. An intriguing finding is that the intracellular tau of AD causes destruction of the BFCN, whereas that of FTLD does not. This observation has profound implications for exploring the impact of different species of tauopathy on neuronal survival. The proteinopathy of FTLD-TDP shows virtually no abnormal inclusions within the BFCN. Thus, the BFCN are highly vulnerable to the neurodegenerative effects of tauopathy in AD, resilient to the neurodegenerative effect of tauopathy in FTLD and apparently resistant to the emergence of proteinopathy in FTLD-TDP and perhaps also in Pick's disease. Investigations are beginning to shed light on the potential mechanisms of this differential vulnerability and their implications for therapeutic intervention.