"In one of those trials,16 the authors discuss in detail the possible reasons that might explain the negative results of a clinical trial and they analyze their own results in this context. Among the most important reasons they give is that researchers might inadvertently “inflate” the baseline severity of patients included in the study as a consequence of the inclusion criteria, with subsequent overestimation of the therapeutic response.35 In the same study, a “post-hoc” analysis showed that this exaggeration of baseline severity likely occurred in the recruitment centers with the fastest enrollment or in those with fewer screen failures. "
[Show abstract][Hide abstract] ABSTRACT: VORTIOXETINE IS A NEW MULTIMODAL ACTION ANTIDEPRESSANT WITH TWO TYPES OF ACTION: serotonin transporter (SERT) blockade and a strong affinity for several serotoninergic receptors. It is an antagonist of the 5-HT3 and 5-HT7 receptors, a partial agonist of 5-HT1B, and an agonist of 5-HT1A. Its combined action on SERT and four subtypes of serotoninergic receptors increases the extracellular concentration of serotonin, dopamine, and noradrenaline. Twelve clinical trials have been carried out, nine of which had positive results versus placebo. When active comparators were included in the study design, no significant differences were found except in one study in which the efficacy of vortioxetine was superior to the comparator (agomelatine) in depression resistant to selective serotonin reuptake inhibitors (SSRI)/serotonin-norepinephrine reuptake inhibitors (SNRI) treatment. Tolerability studies indicate that the drug does not cause any important problems on blood tests, vital signs, or on electrocardiography. The lack of weight gain and induction of metabolic syndrome and the lack of significant changes in the QTc are especially important. The incidence rate of sexual dysfunction is low and similar to placebo in various trials. Similarly, cognitive function remains intact with vortioxetine.
"Therefore, we hypothesize that the smaller ES in patients with a baseline HAM-D 18 was probably due to the proximity to the HAM-D inclusion cutoff of the study rather than due to a specific HAM-D severity score that eliminates mild patients. The problem of baseline score inflation in antidepressant clinical trials has been identified in several reports (Kobak et al., 2007; Rutherford and Roose 2013; Mundt et al., 2007a). "
[Show abstract][Hide abstract] ABSTRACT: An increasing rate of antidepressant trials fail due to large placebo responses. This analysis aimed to identify variables influencing signal detection in clinical trials of major depressive disorder. Patient-level data of randomized patients with a duloxetine dose ≥60 mg/day were obtained from Lilly. Total scores of the Hamilton Depression Rating scale (HAM-D) were used as efficacy endpoints. In total, 4661 patients from 14 studies were included in the analysis. The overall effect size (ES), based on the HAM-D total score at endpoint, between duloxetine and placebo was -0.272. Although no statistically significant interactions were found, the following results for factors influencing ES were seen: a very low ES (-0.157) in patients in the lowest baseline HAM-D category and in patients recruited in the last category of the recruitment period (-0.122). A higher ES in patients recruited in centers with a site-size at but not more than 2.5 times the average site-size for the study (-0.345). Study characteristics that resulted in low signal detection in our database were: <80% study completers, a HAM-D placebo response >5 points, a high variability of placebo response (SD > 7 points HAM-D), >6 post baseline visits per study, and use of an active control drug. Simpler trial designs, more homogeneous and mid-sized study sites, a primary analysis based on a higher cutoff blinded to investigators to avoid the influence of score inflation in mild patients and, if possible, studies without an active control group could lead to a better signal detection of antidepressive efficacy.
Journal of Psychiatric Research 01/2014; 51(1). DOI:10.1016/j.jpsychires.2014.01.001 · 3.96 Impact Factor
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