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

Is the nonREM–REM sleep cycle reset by forced awakenings from REM sleep?

In selective REM sleep deprivation (SRSD), the occurrence of stage REM is repeatedly interrupted by short awakenings. Typically, the interventions aggregate in clusters resembling the REM episodes in undisturbed sleep. This salient phenomenon can easily be explained if the nonREM–REM sleep process is continued during the periods of forced wakefulness. However, earlier studies have alternatively suggested that awakenings from sleep might rather discontinue and reset the ultradian process. Theoretically, the two explanations predict a different distribution of REM episode duration. We evaluated 117 SRSD treatment nights recorded from 14 depressive inpatients receiving low dosages of Trimipramine. The alarms were triggered by an automatic mechanism for the detection of REM sleep and had to be canceled by the subjects themselves. The REM episodes were determined as in undisturbed sleep—they had to include the remaining REM activity and were separated by 30 min without REM epochs. The frequency histogram of REM episodes declined exponentially with episode duration for each of the first four sleep cycles. The duration of nonREM intervals revealed bimodal distributions. These results were found consistent with the model assuming a reset of the ultradian cycle upon awakening. Whether REM or nonREM activity is resumed on return to sleep can be modeled by a random decision whereby the probability for REM sleep might depend on the momentary REM pressure.