Clinical efficacy of agomelatine in depression: the evidence

Despite the advances of recent decades, there is still an urgent need for antidepressants with improved efficacy, safety and tolerability. Agomelatine is a new antidepressant with an innovative pharmacological profile. It is the first melatonergic antidepressant, and is a potent agonist of melatonin receptors (MT1 and MT2) with 5-HT2C antagonist properties. The efficacy of 25 mg/day agomelatine in treating major depressive disorder (MDD) has been demonstrated in a number of placebo-controlled studies. Evidence of improvement in depressive symptoms was observed in a dose-ranging study in which 25 mg/day agomelatine was significantly better than placebo, whatever the rating scale used (Hamilton Rating Scale for Depression, Clinical Global Impression, and Montgomery-Asberg Depression Rating Scale). These results have been confirmed in two similarly designed placebo-controlled studies. Agomelatine also produces a significant improvement in anxiety compared to placebo, according to Hamilton Rating Scale for Anxiety scores. The efficacy of agomelatine has been studied in subpopulations with more severe depression, demonstrating its efficacy in these difficult-to-treat patients. In view of the available data on agomelatine, this antidepressant can be regarded as an innovative treatment for MDD patients, offering a new approach in the management of depressed patients.     

Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine

The efficacy of agomelatine in severe depression has been examined in three positive placebo-controlled studies and in a pooled analysis of the data from the three studies in patients treated with 25-50 mg agomelatine (n=357) and placebo (n=360). Agomelatine was significantly more effective than placebo in a subgroup of patients with severe depression with a severity of 25 or more on the Hamilton Depression Rating Scale 17-item scale in each individual study (P<0.05) and in the pooled analysis (P<0.001). Analysis of the pooled data demonstrated that there was an increase in the magnitude of the agomelatine-placebo difference with increasing severity on the baseline Hamilton Depression Rating Scale. When the population was divided into subgroups using increasing cut-off Hamilton Depression Rating Scale values a significant difference between agomelatine and placebo was observed in each subgroup despite the decreasing numbers of patients with higher severity with a difference of 2.06 rising to 4.45 points on the Hamilton Depression Rating Scale. In conclusion, agomelatine is effective in treating severe depression.     

Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder

Current antidepressants used in major depressive disorder (MDD) are still not efficacious enough for many patients due to high levels of treatment resistance and bothersome side-effects. Using a novel blinding method (interactive voice response system), this flexible-dosing study examined the effects of therapeutic doses of agomelatine, a new approach to depressive therapy offering potent melatonergic MT1/MT2 receptor agonism with 5-HT2C receptor antagonist properties, in patients with moderate-to-severe MDD. This 6-wk, double-blind, parallel-group study randomized 238 patients to 25 mg/d agomelatine (with dose adjustment at 2 wk to 50 mg/d in patients with insufficient improvement) or placebo. Depression severity was assessed using the Hamilton Depression Rating Scale (HAMD) and the Clinical Global Impression (CGI) scale. Agomelatine was significantly more efficacious than placebo, with an agomelatine-placebo difference of 3.44 (p<0.001) using the HAMD final total score. Compared with placebo, agomelatine also had a significant positive impact on CGI - Improvement (treatment difference=0.45) and CGI - Severity (treatment difference=0.50) (both p=0.006), response rate (54.3% vs. 35.5% with placebo, p<0.05) and time to first response (p=0.008). Similar results were seen in patients with the most severe MDD. Depressed mood and sleep items of the HAMD were also significantly improved with agomelatine, which was well tolerated with a safety profile similar to placebo at both doses. This study confirms that agomelatine is effective in treating major depression, including the most severely depressed patients, with a good safety and tolerability profile, therefore providing physicians with an effective pharmacological approach to antidepressant therapy.     

Relative short‐term efficacy and acceptability of agomelatine versus vortioxetine in adult patients suffering from major depressive disorder

Agomelatine and vortioxetine are antidepressants with different mechanisms of action compared to other pharmaceutical treatment options. The objective of this present analysis is to determine the relative efficacy and acceptability of agomelatine (25–50 mg) compared to vortioxetine (10–15–20 mg) in adult patients with major depressive disorder. We performed an adjusted indirect comparison using placebo as a common control. The main outcomes were efficacy (response to treatment by Montgomery‐Åsberg depression rating scale/Hamilton Rating Scale for Depression) and acceptability (withdrawal rate for any reason or due to adverse events). 10 agomelatine and 11 vortioxetine studies were included in the analysis. For efficacy, no difference was shown between agomelatine and vortioxetine (E[95% CI] = ?0.03 [?0.12;0.05]). For acceptability, no significant difference was found between both antidepressants. These findings substantiate current understanding that most antidepressants are of similar average efficacy and tolerability. Such equivalent therapeutic benefit of both compounds, measured by a quantitative clinical research approach, has to be discussed with the knowledge of a qualitative estimation in routine practice.     

Agomelatine in the treatment of seasonal affective disorder

RATIONALE: The novel antidepressant agomelatine acts as a melatonergic (MT(1) and MT(2)) receptor agonist and as a serotonin-2C receptor antagonist. Previous studies showed that agomelatine is able to restore disrupted circadian rhythms, which were implicated in the pathophysiology of seasonal affective disorder (SAD). OBJECTIVES: The aim of this study was to investigate the efficacy and tolerability of agomelatine in the treatment of SAD. MATERIALS AND METHODS: Thirty-seven acutely depressed SAD patients were included in an open study with agomelatine (25 mg/day in the evening) over 14 weeks. Efficacy assessments included the Structured Interview Guide for the Hamilton Depression Rating Scale (SAD version; SIGH-SAD), the Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I), the Circscreen, a self-rating scale for the assessment of sleep and circadian rhythm disorders, and the Hypomania Scale. RESULTS: Agomelatine led to a progressive and statistically significant decrease of SIGH-SAD, CGI-S, and CGI-I scores from week 2 onward (p < 0.001). Furthermore, scores on the Circscreen improved significantly during the study (p < 0.001). Treatment with agomelatine over 14 weeks yielded a response rate of 75.7% (SIGH-SAD <50% of baseline value) and a remission rate (SIGH-SAD <8) of 70.3% in the intention to treat sample. Scores on the Hypomania Scale were consistently low during the study. Agomelatine showed good overall tolerability: throughout the study only one adverse event (mild fatigue) was related to the study drug. CONCLUSIONS: The results of this study suggest that seasonal depression may be effectively and safely treated with agomelatine.     

Agomelatine versus venlafaxine XR in the treatment of anhedonia in major depressive disorder: a pilot study

The primary aim of the present study was to compare the effects of agomelatine (AGO) and venlafaxine XR (VLX) on anhedonia in patients with major depressive disorder. Secondary end points were to test its antidepressant and anxiolytic efficacy.Sixty patients were enrolled and randomly assigned to two different treatments: AGO (25-50 mg/d; n = 30 subjects) or VLX (75-150 mg/d, n = 30 subjects). Psychopathological assessment was performed at baseline and after 8 weeks of treatment with the Snaith Hamilton Rating Scale (SHAPS), the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Clinical Global Impression for anhedonia, depression, anxiety, and global improvement, respectively.Both groups showed a significant reduction in time for the SHAPS, the Hamilton Depression Rating Scale, and the Hamilton Anxiety Rating Scale. A significant between-group difference was observed for SHAPS scores: patients treated with AGO showed a more relevant reduction compared with that in VLX-treated patients. Moreover, only patients treated with AGO showed a statistically significant improvement in Clinical Global Impression scores.In this study, AGO showed significantly greater efficacy on anhedonia and similar antidepressant efficacy to the serotonin-norepinephrine reuptake inhibitor VLX in patients with major depressive disorder during an 8-week treatment period. Anhedonia has been considered a potential trait marker related to vulnerability for depression. Therefore, the efficacy of AGO on this dimension holds particular importance in the treatment of patients with anhedonic features.     

Fluoxetine: relationships among dose, response, adverse events, and plasma concentrations in the treatment of depression

Data from two large, fixed-dose trials support the efficacy of a fixed 20 mg/day dose of fluoxetine in the treatment of depression. Data pooled from these two studies suggest a dose relationship for adverse events during fluoxetine therapy. At a fixed 20 mg/day dose, only nausea and insomnia were reported by a significantly greater percentage of patients (p less than .05) than those treated with placebo. However, at 60 mg/day, nausea, anxiety, dizziness, and insomnia were reported by a significantly greater percentage of patients (p less than .05) than those treated with placebo. The potential relationship of response rate [Hamilton Rating Scale for Depression (HAM-D) total decrease greater than or equal to 50%] to plasma concentrations of fluoxetine, norfluoxetine, and fluoxetine plus norfluoxetine was evaluated in one study which excluded early responders (less than or equal to 3 weeks of therapy). No significant relationship was found. Furthermore, adverse events were not related to plasma concentrations.     

Limited efficacy of ketoconazole in treatment-refractory major depression.

The authors examined the efficacy of ketoconazole in 16 adults with treatment-refractory major depressive disorder. Subjects participated in a 6-week, double-blind, placebo-controlled trial. Assessments of mood were made using the Hamilton Rating Scale for Depression (HAM-D), the Beck Depression Inventory (BDI), and the Clinical Global Impression Scale (CGI). Results showed that none of eight patients randomly assigned to receive placebo and two of eight patients randomly assigned to receive ketoconazole met criteria for response. As a group, patients assigned to receive ketoconazole showed no significant reductions in HAM-D, BDI, or CGI scores during the 6-week trial compared with those receiving placebo. These findings suggest a limited efficacy for ketoconazole in patients with treatment-refractory major 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.     

Reboxetine,a new noradrenaline selective antidepressant,is at least as effective as fluoxetine in the treatment of depression

The clinical profile of reboxetine, a selective noradrenaline reuptake inhibitor, was compared with that of the selective serotonin reuptake inhibitor fluoxetine and placebo in a double-blind, multicenter, parallel-group clinical trial of patients with major depression. Among the 381 patients treated with reboxetine 8 to 10 mg/day, fluoxetine 20 to 40 mg/day, or placebo for up to 8 weeks, a statistically significant greater reduction in the mean Hamilton Rating Scale for Depression (21-item HAM-D) total score (the primary efficacy variable) was seen for both active treatment groups compared with placebo (p < 0.024). A significantly greater proportion of patients treated with either reboxetine or fluoxetine also achieved a response (>or=50% reduction in HAM-D) or remission (HAM-D 相似文献   

Assessing the relationship between functional impairment/recovery and depression severity: a pooled analysis

The objective of this study was to explore the relationship between assessments of functional impairment, emotional well-being, and depression symptoms. Data were pooled from 3530 outpatients with major depressive disorder enrolled in 10 desvenlafaxine clinical trials. The primary outcome measures included (a) the 17-item Hamilton Rating Scale for Depression (HAM-D17) as a measure of depressive symptom severity and (b) the Sheehan Disability Scale (SDS) and five-item World Health Organization Well-Being Index (WHO-5) as measures of functional impairment and well-being. A linear regression model was used to identify the SDS and WHO-5 values that equate to the predetermined clinically relevant three-point difference between active treatment and placebo on the HAM-D17. A receiver operating characteristic analysis was conducted to determine the SDS score that equates to a remission of depression symptoms (i.e. HAM-D17≤7). An approximate three-point difference between active treatment and placebo on the SDS (2.8) and WHO-5 (2.5) was determined to be clinically relevant in relation to improvements in depressive symptoms. An SDS of less than or equal to 7 was equivalent to a remission of depression symptoms, providing a definition of functional remission. A better understanding of the relationship between depressive symptoms and functional impairment and well-being may provide clinicians with a more comprehensive means of assessing treatment effects in major depressive disorder.     

Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study)

This study evaluated the efficacy and tolerability of quetiapine monotherapy for depressive episodes in patients with bipolar I or II disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) who were randomized to 8 weeks of double-blind treatment with quetiapine (300 or 600 mg/d; once daily, evening dosing) or placebo. Patients were assessed weekly using the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAM-D). The primary end point was change in MADRS total score from baseline to Week 8 (analysis of covariance/last-observation-carried-forward analysis). Of 509 patients randomized, 59% completed the study. Improvements from baseline in mean MADRS total scores were significantly greater with quetiapine 300 and 600 mg/d than with placebo from first evaluation (Week 1) through Week 8 (both P 相似文献   

Agomelatine: AGO 178, AGO178, S 20098

Novartis and Servier are developing agomelatine for the treatment of depression. Agomelatine is a specific melatonin (MT1 and MT2) receptor agonist that also has antagonistic activities at serotonin-(2C) (5-HT(2C)) receptors. Novartis believes agomelatine is comparable to current standard therapies for depression with improved tolerability, including a low propensity to cause sexual dysfunction and weight gain. Clinical development is being conducted in the US for the treatment of depression; approval for this indication was declined in the EU, apparently due to insufficient data. Servier has also conducted a trial of the agent in patients with generalized anxiety disorder in France, South Africa and Finland, and a phase II trial in sleep disorders in France. In March 2006, Servier and Novartis signed a licensing agreement for agomelatine. Novartis obtained the exclusive rights for the development and marketing of agomelatine in the US and several other countries. Servier retained the rights to the product in the rest of the world. The clinical development plan for agomelatine includes phase III trials being conducted under the parAGOn clinical trial programme. One US-based trial that began in March 2007 (NCT00463242) is recruiting 490 patients with depression who will receive placebo or agomelatine 25 or 50 mg for 8 weeks and will then receive open-label agomelatine for 52 weeks. Novartis is also conducting an 8-week phase III trial (NCT00411099) comparing the safety and efficacy of agomelatine 25 and 50 mg in patients with major depressive disorder. A follow-up, 52-week open-label extension study (CAGO178A2301E) will also be conducted. Another phase III study underway is NCT00411242, which has the same design and is also followed by a 52-week open-label extension study (CAGO178A2302E). These studies are all expected to be completed by January 2009. In July 2006, the Committee for Medicinal Products for Human Use recommended the refusal of marketing authorisation for agomelatine for the treatment of depression. Servier had applied for a re-examination of the finding but withdrew the request in November 2006. Servier's MAA was not supported due to insufficient data and no recent development has been reported in this indication in the EU. Agomelatine prevented relapse in patients with depression compared with placebo and was well tolerated in an international phase III trial.     

Agomelatine: a preliminary review of a new antidepressant

Agomelatine is a new antidepressant that is a potent agonist of melatonin receptors and an antagonist of the serotonin 5-HT(2C) receptor subtype. It is in late-phase trials for the treatment of major depressive disorder (MDD).Symptoms of depression significantly improved with agomelatine compared with placebo in large placebo-controlled trials, and agomelatine appears to be as efficacious in treating MDD as other antidepressants but with fewer adverse effects. Agomelatine appears to improve sleep quality and ease of falling asleep, as measured subjectively in depressed patients. Polysomnographic studies have shown that agomelatine decreases sleep latency, decreases wake after sleep onset (WASO), and improves sleep stability as measured by changes in the cyclic alternating pattern.Agomelatine is generally well tolerated in patients with MDD; in clinical trials, adverse events were generally mild to moderate in nature, with an overall frequency close to that of placebo. Discontinuation of agomelatine because of adverse effects occurred at a similar rate to placebo.     

Buspirone in depressed outpatients: a controlled study

One hundred fifty-five outpatients suffering from major depression with significant anxiety entered a double-blind study comparing 8 weeks of treatment with buspirone or placebo. Twenty-nine percent of buspirone and 40 percent of placebo patients discontinued treatment before 8 weeks. Major efficacy measures were the Hamilton Rating Scale for Depression (HAM-D) total score, the HAM-D retardation and anxiety factors, the HAM-D Rickels and Bech core depression clusters, the Clinical Global Impressions (CGI), and the Hopkins Symptom Checklist (HSCL). Results were consistent across all outcome measures, including the two core depression clusters, with treatment response to buspirone significantly better than to placebo at treatment endpoint. Seventy percent of buspirone and 35 percent of placebo patients (p less than .01) were rated moderately or markedly improved after 8 weeks of therapy. Buspirone was found to be safe and well-tolerated by patients with major depression and concomitant anxiety at doses of up to 90 mg/day.     

A randomized,placebo-controlled,double-blind trial of sertraline for postpartum depression

Rationale

Postpartum depression (PMD) occurs in roughly 10 % of postpartum women and negatively impacts the mother and her offspring, but there are few placebo-controlled studies of antidepressant treatment in this population.

Objective

The objective was this study is to compare the selective serotonin reuptake inhibitor (SSRI) sertraline to placebo for treating PMD.

Methods

This was a single-center, 6-week, randomized double-blind placebo-controlled trial of sertraline with a 1-week placebo lead-in. The participants (n?=?38) were women with depression onset within 3 months of delivery; a subset (n?=?27) met strict DSM-IV criteria for PMD (onset within 4 weeks of delivery). The participants were prescribed sertraline 50 mg or placebo daily to a maximum of 200 mg/day. Primary outcome variables were the Hamilton Depression Rating Scale (HAM-D) and Clinical Global Impressions (CGI) scores, which were used to determine the rates of response and remission.

Results

Sertraline produced a significantly greater response rate (59 %) than placebo (26 %) and a more than twofold increased remission rate (53 % vs. 21 %). Mixed models did not reveal significant group by time effects, although in the subset of women who met the DSM-IV criteria, there was a statistically significant group by time effect for the HAM-D, Hamilton Anxiety Rating Scale (HAM-A), and CGI.

Conclusions

Women with PMD are more likely to have a remission of their depression with sertraline treatment, a finding that is more pronounced in women who have onset of depression within 4 weeks of childbirth. These data support the continued use of 4 weeks for the DSM-5 postpartum onset specifier for major depressive disorder.     

Alprazolam: an antidepressant? Alprazolam, desipramine, and an alprazolam-desipramine combination in the treatment of adult depressed outpatients

The antidepressant efficacy of alprazolam (ALP) was tested in a double-blind controlled comparison with desipramine (DMI) and an ALP-DMI combination in outpatients diagnosed with major depressive disorder by Research Diagnostic Criteria (90% met criteria for endogenous subtype). Following a placebo period of at least 1 week, subjects who continued to meet severity criteria defined by Hamilton Depression Rating Scale (HDRS) scores were administered oral doses of the active medication (N = 79), in a dose ratio of 1 mg ALP:50 mg DMI:1 mg ALP + 50 mg DMI. Treatment continued for 6 weeks, and all subjects who completed at least 2 weeks (N = 69) were included in endpoint analyses. Following the placebo baseline, symptoms were rated again at day 5 and at the end of weeks 1, 2, 4, and 6. Final doses averaged 4.6 +/- 1.3 mg for the ALP group, 230 +/- 61 mg for the DMI group, and 4.6 +/- 1.2 mg ALP + 229.5 +/- 1.2 mg DMI for the combination group. The final outcome was a comparable degree of improvement at the endpoint among the three treatment groups on measures of depression (HDRS and Beck Depression Inventory), anxiety (Hamilton Anxiety Rating Scale), and global improvement (Global Assessment Scale, and Physician and Patient Global Impressions). A similar outcome was found for the subgroup of patients who completed all 6 weeks (N = 56). Endpoint analyses also showed that ALP-treated subjects responded sooner and continued to show improvement throughout the course of the study on measures of depression, anxiety, and global status. These results suggest that ALP alone is as effective as a standard tricyclic for the acute treatment of patients with major depressive disorder and that significant improvement may occur within the first week of medication. Side effect profiles were compared among treatment groups and are discussed, as are other clinical studies that have investigated ALP's potential antidepressant efficacy.     

A double-blind comparison of sexual functioning, antidepressant efficacy, and tolerability between agomelatine and venlafaxine XR

Impaired sexual function is associated with major depressive disorder in the untreated state and is often more prevalent during antidepressant therapy, which frequently results in poor treatment compliance. In this double-blind, multicenter study, the effects of agomelatine (an MT1 and MT2 agonist and 5HT-2C antagonist) and venlafaxine XR on sexual function were compared using the Sex Effects Scale in depressed patients. A total of 276 male and female patients received either agomelatine (50 mg) or venlafaxine XR (titrated to a target dose of 150 mg/d) for 12 weeks. Those who were sexually active at baseline (n = 193) and those who, in addition, achieved remission (n = 111) were defined a priori for analyses of change in sexual function. Treatment-emergent sexual dysfunction was significantly less prevalent among patients who received agomelatine, and venlafaxine XR was associated with significantly greater deterioration on the Sex Effects Scale domains of desire and orgasm. Both treatments resulted in equivalently high rates of remission (agomelatine, 73%; venlafaxine XR, 66.9%), although fewer patients in the agomelatine group discontinued treatment because of adverse events (agomelatine, 2.2%, vs venlafaxine XR, 8.6%). Agomelatine seems to be an efficacious antidepressant with a superior sexual side effect profile compared with venlafaxine XR, although superiority to placebo was not evaluated in this trial.     

A comparative, randomized, double-blind study of trazodone prolonged-release and sertraline in the treatment of major depressive disorder

OBJECTIVES: To evaluate the efficacy and safety of trazodone prolonged-release compared with sertraline in the treatment of patients with major depression. RESEARCH DESIGN AND METHODS: A total of 122 patients aged 19-64 years were enrolled in this multicenter, double-blind, double-dummy, randomized, comparator-controlled study. Patients received 7 days of single-blind placebo treatment followed by 6 weeks of double-blind treatment with trazodone prolonged-release 150-450 mg/day (n = 62) or sertraline 50-100 mg/day (n = 60). OUTCOME MEASURES: Efficacy was evaluated by mean changes from baseline in the Hamilton Depression Rating scale (HAM-D), Montgomery Asberg Depression Rating Scale, Hamilton Anxiety Rating scale, and the Clinical Global Impression-Global Improvement/Severity scores; and by the rates of patients responding to treatment and considered to be in remission. Time to onset of efficacy and safety were assessed. RESULTS: Trazodone and sertraline were equally effective in reducing depressive symptoms and promoting remission, and had similar onset times. In the Intent-to-Treat population, there were no significant differences in favor of trazodone at study endpoint in all efficacy measures, while a statistically significant difference was detected in the Per-Protocol population on HAM-D and in the percentage of responders. Analysis of HAM-D factors (anxiety/somatization, cognitive disturbance, retardation, and sleep disturbance) indicated that sleep disturbances were significantly less evident for patients taking trazodone at study endpoint. Adverse drug reactions, mostly of mild intensity, were reported in 42% of trazodone-treated patients (mainly of the nervous system) and 43% of sertraline-treated patients (mainly gastrointestinal). One event was considered to be serious: a patient treated with trazodone 450 mg/day showed moderate anxiety/tremor/insomnia and was hospitalized. Treatment was discontinued; the patient made a full recovery. CONCLUSIONS: This study showed that after 6 weeks, trazodone and sertraline were not different in reducing symptoms of depression and in producing disease remission. Tolerability profiles reflected the differing pharmacological properties of these antidepressants. Trazodone may be a therapeutic option in the treatment of patients with major depression showing prevalent sleep disturbances.