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Introduction: To assess the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) in outpatients with major depressive disorder.
Methods: A meta-analysis of individual patient data was performed on the complete set of registration trials (nine randomized, double-blind, placebo-controlled 8-week studies) of desvenlafaxine. Patients received fixed (50, 100, 200, or 400 mg/day; n = 1,342) or flexible doses (100–400 mg/day; n = 463) of desvenlafaxine or placebo (n = 1,108). The primary efficacy variable was the 17-item Hamilton Rating Scale for Depression (HAM-D17); the primary intent to treat analyses used the last-observation-carried-forward method.
Results: Significantly greater improvement with desvenlafaxine versus placebo on the HAM-D17 total score was observed for the full data set (difference in adjusted means: −1.9; P<.001), each fixed-dose group (all P<.001), and the flexible-dose group (P=.024). Overall rates of HAM-D17 response (≥50% decrease from baseline score: 53% vs 41%) and remission (HAM-D17 ≤7: 32% vs 23%) were significantly greater for desvenlafaxine versus placebo (all P<.001). Discontinuation rates due to adverse events increased with dose (4% to 18%; placebo: 3%).
Conclusion: Desvenlafaxine demonstrated short-term efficacy for treating major depressive disorder across the range of doses studied. No evidence of greater efficacy was observed with doses >50 mg/day; a strong dose-response effect on tolerability was observed.
Dietary methyl donors and their genetic determinants are associated with Crohn's disease risk. We investigated whether a methyl-deficient diet (MDD) may affect development and functions of the small intestine in rat pups from dams subjected to the MDD during gestation and lactation. At 1 month before pregnancy, adult females were fed with either a standard food or a diet without vitamin B12, folate and choline. A global wall hypotrophy was observed in the distal small bowel (MDD animals 0·30 mm v. controls 0·58 mm; P< 0·001) with increased crypt apoptosis (3·37 v. 0·4 %; P< 0·001), loss of enterocyte differentiation in the villus and a reduction in intestinal alkaline phosphatase production. Cleaved caspase-3 immunostaining (MDD animals 3·37 % v. controls 0·4 %, P< 0·001) and the Apostain labelling index showed increased crypt apoptosis (3·5 v. 1·4 %; P= 0·018). Decreased proliferation was observed in crypts of the proximal small bowel with a reduced number of minichromosome maintenance 6 (MDD animals 52·83 % v. controls 83·17 %; P= 0·048) and proliferating cell nuclear antigen-positive cells (46·25 v. 59 %; P= 0·05). This lack of enterocyte differentiation in the distal small bowel was associated with an impaired expression of β-catenin and a decreased β-catenin–E-cadherin interaction. The MDD affected the intestinal barrier in the proximal small bowel by decreasing Paneth cell number after immunostaining for lysosyme (MDD animals 8·66 % v. controls 21·66 %) and by reducing goblet cell number and mucus production after immunostaining for mucin-2 (crypts 8·66 v. 15·33 %; villus 7 v. 17 %). The MDD has dual effects on the small intestine by producing dramatic effects on enterocyte differentiation and barrier function in rats.
This chapter describes the planning process for a clinical trial. Successful clinical trials rely on scientific, clinical, and operational excellence, and discuss the example of large, global studies. Most study management models in the pharmaceutical industry rely on a study or project manager (PM). Efficient communication across the entire study team is a requisite for successful execution of clinical trials. Investigator-initiated studies often try to obtain investigational medicinal product (IMP) directly from the manufacturer at no-cost. Most project teams or PMs use a countdown approach where the main goal is identified as the final task. The FDA has established classifications for approximately 1700 different generic types of devices and grouped them into 16 medical specialties referred to as panels. The Maintenance and Support Services Organization reviews and maintains MedDRA on a regular basis. Drafting the Statistical Analysis Plan (SAP) typically begins shortly after the protocol synopsis is finalized.
This chapter discusses the basic ethical principles and practices for human experimentation. It touches on the related subject of regulatory and legal issues in neurological research. Disorders of the central nervous system (CNS) present a number of challenges for specifying core principles and practices of research ethics. In CNS research, the tensions between regulation and ethics are greatest around the use of placebo controls. Phase 1 trials of new CNS interventions, as with all interventions, generally present a high degree of risk and uncertainty. Many trials involving neurological disorders show evidence of placebo responses. Many CNS drug trials involve brain imaging, in one report, brain abnormalities, like malignancies or vascular malformations, were detected in as many as 18% of healthy volunteers. Issues of justice arise with particular frequency whenever CNS trials involve placebos. Researchers should also attend to various non-verbal or affective elements of communication that shape public expectations.