Rationale and design of the randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with Major Depressive Disorder - the EMC trial

<p>Abstract</p> <p>Background</p> <p>In Major Depressive Disorder (MDD), the traditional belief of a delayed onset of antidepressants' effects has lead to the concept of current guidelines that treatment durations should be between 3-8 weeks before medication change in case of insufficient outcome. Post hoc analyses of clinical trials, however, have shown that improvement usually occurs within the first 10-14 days of treatment and that such early improvement (Hamilton Depression Rating Scale [HAMD] decrease ≥20%) has a substantial predictive value for final treatment outcome. Even more important, non-improvement (HAMD decrease <20%) after 14 days of treatment was found to be highly predictive for a poor final treatment outcome.</p> <p>Methods/Design</p> <p>The EMC trial is a phase IV, multi-centre, multi-step, randomized, observer-blinded, actively controlled parallel-group clinical trial to investigate for the first time prospectively, whether non-improvers after 14 days of antidepressant treatment with an early medication change (EMC) are more likely to attain remission (HAMD-17 ≤7) on treatment day 56 compared to patients treated according to current guideline recommendation (treatment as usual; TAU). In level 1 of the EMC trial, non-improvers after 14 days of antidepressant treatment will be randomised to an EMC strategy or TAU. The EMC strategy for this study schedules a first medication change on day 15; in case of non-improvement between days 15-28, a second medication change will be performed. TAU schedules the first medication change after 28 days in case of non-response (HAMD-17 decrease <50%). Both interventions will last 42 days. In levels 2 and 3, EMC strategies will be compared with TAU strategies in improvers on day 14, who experience a stagnation of improvement during the course of treatment. The trial is supported by the German Federal Ministry of Education and Research (BMBF) and will be conducted in cooperation with the BMBF funded Interdisciplinary Centre Clinical Trials (IZKS) at the University Medical Centre Mainz and at six clinical trial sites in Germany.</p> <p>Discussion</p> <p>If the EMC strategies lead to significantly more remitters, changes of clinical practice, guidelines for the treatment of MDD as well as research settings can be expected.</p> <p>Trial Registration</p> <p><b>Clincaltrials.gov Identifier</b>: NCT00974155; <b>EudraCT</b>: 2008-008280-96.</p

Functional selectivity of adenosine receptor ligands

Adenosine receptors are plasma membrane proteins that transduce an extracellular signal into the interior of the cell. Basically every mammalian cell expresses at least one of the four adenosine receptor subtypes. Recent insight in signal transduction cascades teaches us that the current classification of receptor ligands into agonists, antagonists, and inverse agonists relies very much on the experimental setup that was used. Upon activation of the receptors by the ubiquitous endogenous ligand adenosine they engage classical G protein-mediated pathways, resulting in production of second messengers and activation of kinases. Besides this well-described G protein-mediated signaling pathway, adenosine receptors activate scaffold proteins such as β-arrestins. Using innovative and sensitive experimental tools, it has been possible to detect ligands that preferentially stimulate the β-arrestin pathway over the G protein-mediated signal transduction route, or vice versa. This phenomenon is referred to as functional selectivity or biased signaling and implies that an antagonist for one pathway may be a full agonist for the other signaling route. Functional selectivity makes it necessary to redefine the functional properties of currently used adenosine receptor ligands and opens possibilities for new and more selective ligands. This review focuses on the current knowledge of functionally selective adenosine receptor ligands and on G protein-independent signaling of adenosine receptors through scaffold proteins