Antidepressant short-term and long-term brain effects during self-referential processing in major depression.

Acute depression is associated with impaired self-referential processing. Antidepressant effects on the neural bases of self-referential processing in depression are unknown. This study aimed to assess short- and long-term effects of agomelatine on these neural bases in depressed patients and the association between pre-treatment brain activation and remission of depression 6 months later. We conducted a randomized double-blind, placebo-controlled, functional magnetic resonance imaging (fMRI) study during an emotional self-referential task, including three scanning sessions (baseline, after 1 week, and after 7 weeks). Twenty-five depressed outpatients were included, all treated with agomelatine or placebo for 1 week. Then, all patients received agomelatine for 24 weeks. Fourteen matched healthy volunteers (HV) who received placebo for 1 week were also included. After 7 days, only depressed patients receiving agomelatine significantly deactivated the ventrolateral prefrontal cortex during self-referential processing, as observed in HV at baseline. After 7 weeks, depressed patients significantly increased the activation of the ventral anterior cingulate cortex. Finally dorsomedial prefrontal cortex and precuneus activations at baseline significantly separated remitters from non-remitters at 24 weeks. In depressed patients, agomelatine had short- and long-term effects on brain structures involved in anhedonia and emotional regulation during self-referential processing. Activation of the dorsomedial prefrontal cortex and precuneus could be informative in the development of biomarker-based treatment of major depression.

Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: randomised double-blind placebo-controlled trial.

BACKGROUND: Adjunctive antidepressant therapy is commonly used to treat acute bipolar depression but few studies have examined this strategy. AIMS: To examine the efficacy of agomelatine v. placebo as adjuncts to lithium or valproate in bipolar depression. METHOD: Patients who were currently depressed despite taking lithium or valproate for at least 6 weeks were randomised to treatment with agomelatine (n = 172) or placebo (n = 172) for 8 weeks of acute therapy and 44 weeks of continuation therapy (trial registration: ISRCTN28588282). RESULTS: No significant differences in improvement of depressive symptoms were observed between the two groups either at 8 weeks or 52 weeks on the primary efficacy measure of change in Montgomery-Åsberg Depression Rating Scale scores from baseline to end-point. Adverse events including switches into mania/hypomania were low and similar in both groups. CONCLUSIONS: Agomelatine adjunctive therapy was not superior to placebo adjunctive therapy for acute bipolar depression.

Comparison of agomelatine and escitalopram on nighttime sleep and daytime condition and efficacy in major depressive disorder patients.

Agomelatine, an MT1/MT2 receptor agonist and 5-HT2C receptor antagonist antidepressant, is known to have beneficial effects on subjective sleep in major depressive disorder patients. This international multicenter, randomized, double-blind study compared the effects of agomelatine (25-50 mg/day) and escitalopram (10-20 mg/day) on sleep polysomnographic parameters in major depressive disorder patients treated up to 24 weeks. A total of 138 outpatients were randomly allocated to agomelatine (n=71) or escitalopram (n=67). Treatment with agomelatine was associated with a reduction in sleep latency from week 2 onward. The difference between treatments was significant on all evaluations. Rapid eye movement latency was increased with escitalopram compared with agomelatine, with significant between-group differences at every visit. Agomelatine preserved the number of sleep cycles, whereas it was decreased with escitalopram with significant between-group differences at every visit. Assessments on visual analogue scales indicated that treatment with agomelatine improved morning condition, and reduced daytime sleepiness compared with escitalopram.17-item Hamilton depression rating scale total score was reduced in both groups, agomelatine was statistically noninferior to escitalopram at 6 weeks. Both treatments were well tolerated. This study showed that the clinical effects of agomelatine on sleep and wake parameters are different from that of escitalopram.

Rater Training for a Multi-Site, International Clinical Trial: What Mood Symptoms may be most Difficult to Rate?

AIMS: Given resource constraints in conducting clinical trials, it is critical that rater training focuses on scale items wherein standardization is most challenging. This analysis examined mood disorder symptom ratings submitted in an online rater training program conducted preparatory to the initiation of a multi-site, international mood disorder treatment trial. Ratings were entered online and analyzed for consistency and variability, and compared to established standards (Gold Consensus Ratings/ GCRs). METHODS: Raters participated in web-based rater training on the Hamilton Depression Rating Scale (HAM-D), Montgomery Asberg Rating Scale (MADRS), and Young Mania Rating Scale (YMRS). Training included integration of didactic materials and videos of two bipolar depressed patients interviewed by two U.S. clinicians. Raters viewed the videos and rated the mood scales. Inter-rater agreement was assessed using Kappa statistics. Ratings between the raters and the GCRs for individual scale items were assessed using McNemar test for paired binomial proportions. RESULTS: 194 raters from 16 countries, 80 sites and speaking 20 different languages participated. Interrater agreement on videos ratings ranged from substantial to moderate (HAM-D, Kappa video A = 0.72, video B = 0.65, p < 0.001), (MADRS, Kappa = 0.65 and 0.47, p < 0.001), (YMRS, Kappa = 0.75, and 0.64, p < 0.001). There was no significant difference on agreement based upon on English proficiency, clinical experience, or by country. Scale items that differed from the GCR on the HAM-D were depressed mood, delayed insomnia, retardation, and anxiety (psychic). Items that differed on the MADRS were apparent sadness, inner tension, concentration difficulties, lassitude and inability to feel. Items that differed on the YMRS were irritability and disruptive behavior. CONCLUSIONS: Identification of specific rating scale items in which rater variability is greatest may facilitate training approaches that target these areas for more efficient training in international clinical trials.

Major depressive disorder, sleep EEG and agomelatine: an open-label study.

This open study evaluates the effect of agomelatine, a melatonergic receptor agonist and 5-HT2C antagonist antidepressant, on sleep architecture in patients suffering from major depressive disorder. Fifteen outpatients with a baseline HAMD score > or = 20 were treated with 25 mg/d agomelatine for 42 d. Polysomographic studies were performed at baseline, day 7, day 14, and day 42. Sleep efficiency, time awake after sleep onset and the total amount of slow-wave sleep (SWS) increased at week 6. The increase of SWS was predominant during the first sleep cycle. The amount of SWS decreased throughout the first four sleep cycles from day 7 and delta ratio increased from day 14 onwards. No change in rapid eye movement (REM) latency, amount of REM or REM density was observed and agomelatine was well tolerated. In conclusion agomelatine improved sleep continuity and quality. It normalized the distribution of SWS sleep and delta power throughout the night.