Major depressive disorder, anhedonia and agomelatine: An open-label study
Neuroscience and Imaging Department, University of Chieti, Chieti, Italy.Journal of biological regulators and homeostatic agents (Impact Factor: 2.04). 01/2011; 25(1):109-14.
Despite a wide range of available antidepressants, the effect of the treatment is often suboptimal and there is a need for more effective and better tolerated drugs. Unlike other antidepressants, agomelatine represents a new approach to depression with an innovative mechanism of action. It is an agonist of melatoninergic receptors MT1 and MT2 and a selective antagonist of 5-HT2c receptors. In this open-label 8-week study we aimed to investigate the efficacy of agomelatine on depressive symptoms in patients with major depression. Secondary endpoints were the effect of agomelatine on anhedonia. Thirty major depressive patients received a flexible dose (25-50 mg; per os, daily) of agomelatine. Depressive (Hamilton Depression Scale) and anxious (Hamilton Anxiety Scale) symptoms, anhedonia (Snaith Hamilton Rating Scale), and sleep quality (Leeds Sleep Evaluation Questionnaire) were assessed. Twenty-four patients (80%) completed 8 weeks of treatment. Significant improvements were seen at all visits on the HAM-D (p<.05), HAM-A(p<.01), SHAPS (p<.05), LSEQ (p<.05). Nine subjects (30%) were responders and 5 (17%) remitters at week 1; 18 (60%) were remitters by the end of the trial. There was no serious adverse event. No aminotrasferase elevations were noted. In line with previous studies, in which agomelatine was associated with early clinical improvement, this study also provides evidence of an early response and the findings of improvements in depression scores. Moreover, this is the first study where agomelatine was effective in the treatment of anhedonia. Additional trials are needed to delineate the place of agomelatine in the contemporary pharmacotherapy for depressive disorders.
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- "Light et al. (2011) recently found that depressed patients exhibiting lesser VLPFC activity during the inhibition of positive affect showed a greater reduction of anhedonia after 8 weeks of antidepressant treatment. Interestingly, there is some evidence that agomelatine may exert early specific effects on anhedonia in major depression (Di Giannantonio et al., 2011; Martinotti et al., 2012). Although we did not include an anhedonia rating scale in the present study, we may hypothesize that the early effects of agomelatine on anhedonia are mediated by changes on VLPFC activity. "
ABSTRACT: 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.
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- "The higher response and remission rates in the current study could be explained by its open design with involvement of patients who were suitable for treatment with agomelatine in the opinion of the treating psychiatrists. Early response to treatment with agomelatine has been reported in previous studies.40,43 Generally, the time taken for antidepressants to start showing a clinical effect is at least 2 weeks.44 "
ABSTRACT: Agomelatine is a novel antidepressant agonist to MT1 and MT2 subtypes of melatoninergic receptors (MT1 and MT2) and antagonist to 5-HT2C subtype of serotonergic (5-HT2C) receptors, which has shown antidepressant efficacy in short-term and long-term trials as well as in clinical practice. The purpose of this study was to assess the antidepressant efficacy, safety, and the influence of agomelatine on the functioning of patient in common clinical practice. In this open-label, 8-week, multicenter, Phase IV trial, 111 patients with mainly moderate to severe major depressive disorder (39% treatment-naïve) were treated with agomelatine 25-50 mg/day for up to 8 weeks. The primary endpoint was the mean change in total Montgomery and Åsberg Depression Rating Scale (MADRS). Secondary endpoints included assessment of clinical response (defined as a reduction in total MADRS score of ≥50%), and change in Clinical Global Impression scales, Global Assessment of Functioning scale, Sheehan Disability Scale, and CircScreen sleep questionnaire scores. Safety and tolerability were also monitored. Of the 111 patients enrolled, 94 completed the study. The total MADRS score significantly decreased by the first week of treatment and continued to decline significantly until study completion, with an estimated mean change of 3.9 ± 3.9 and 17.2 ± 8.0 at the first and eighth week of the study (last observation carried forward analyses). All other secondary endpoints significantly improved from early treatment evaluation to study completion. A clinical response was observed in 14.1% of patients after the first week, rising to 74.5% of patients at study completion. There were 31 spontaneously reported adverse events in 17 patients, and most were mild to moderate in severity. This study showed good short-term efficacy for agomelatine in outpatients with major depressive episodes. Treatment with agomelatine achieved early and consistent responses for symptoms of depression and other dimensions of clinical and functional status. Agomelatine achieved significant improvements in daily functioning of patients, and had good tolerability. Clinically, no hepatic events were observed.
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- "Melatonin receptors agonists were proposed as potential novel antidepressants. Efficacy of agomelatine, an agonist of MT1 and MT2 melatonin receptors, in clinical trials was found to be similar to that of SSRIs –. In this respect it is interesting that in animal studies chronic administration of fluoxetine induced several-fold increase in brain arylalkylamine N-acetyltransferase (AANAT) mRNA . "
ABSTRACT: Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35) or placebo (n = 40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD17). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, χ(2)(1) = 0.75, p = 0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL.