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.     

Determination of the dose of agomelatine,a melatoninergic agonist and selective 5-HT(2C) antagonist,in the treatment of major depressive disorder: a placebo-controlled dose range study

Agomelatine (S 20098) has a unique and new pharmacological profile. It is a melatoninergic agonist and selective antagonist of 5-HT2C receptors, and has been shown to be active in several animal models of depression. The aim of this study was to determine the active dose of agomelatine in the treatment of major depressive disorder (DSM-IV criteria). The methodology used was a conventional double-blind design comparing three different doses of agomelatine (1, 5 and 25 mg once a day) with placebo over an 8-week treatment period. Paroxetine was used as the study validator. Seven hundred and eleven patients with a baseline mean score of 27.4 on the 17-item Hamilton Rating Scale for Depression (HAM-D) were included. On the pivotal analysis, the mean final HAM-D total score (Full Analysis Set LOCF) demonstrated agomelatine 25 mg to be statistically more effective than placebo. This was confirmed by other analyses and criteria (responders, remission, subpopulation of severely depressed patients, Montgomery-Asberg Depression Rating Scale, Clinical Global Impression-Severity of Illness). Agomelatine 25 mg alleviated the anxiety associated with depression, as measured on Hamilton Anxiety Scale. Paroxetine was found to be effective on pivotal analysis and most of the secondary criteria used to validate the study methodology and population. Agomelatine, whatever the dose, showed good acceptability with a side-effects profile close to that of placebo. In conclusion, this study demonstrates that agomelatine is efficient in the treatment of major depressive disorder and that 25 mg is the target dose.     

A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder

Converging lines of evidence suggest that the glutamatergic system may play an increasingly important role in the development of novel therapeutics for major depressive disorder (MDD), particularly agents associated with rapid antidepressant effects. Diverse glutamatergic modulators targeting N-methyl-D-aspartate receptors have shown efficacy in MDD, but their associated psychotomimetic effects presently preclude their use in larger samples. This small, randomized, double-blind, placebo-controlled, crossover pilot study evaluated the potential antidepressant efficacy and tolerability of an oral formulation of the selective N-methyl-D-aspartate NR2B antagonist MK-0657 in patients with treatment-resistant MDD (TRD). The TRD subjects underwent a 1-week drug-free period and were subsequently randomized to receive either MK-0657 monotherapy (4-8 mg/d) or placebo for 12 days. Because of recruitment challenges and the discontinuation of the compound's development by the manufacturer, only 5 of the planned 21 patients completed both periods of the crossover administration of MK-0657 and placebo. Significant antidepressant effects were observed as early as day 5 in patients receiving MK-0657 compared with those receiving placebo, as assessed by the Hamilton Depression Rating Scale and Beck Depression Inventory; however, no improvement was noted when symptoms were assessed with the Montgomery-Asberg Depression Rating Scale, the primary efficacy measure. No serious or dissociative adverse effects were observed in patients receiving this oral formulation of MK-0657. Despite the small sample size, this pilot study suggests that an oral formulation of the NR2B antagonist MK-0657 may have antidepressant properties in TRD patients. Further studies with larger sample sizes are necessary to confirm these preliminary findings.     

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.     

A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in the treatment of major depressive disorder

The antidepressant efficacy and safety of desvenlafaxine succinate (desvenlafaxine) were evaluated in a phase III, double-blind, placebo-controlled study. Outpatients with a primary diagnosis of major depressive disorder were treated with fixed once-daily doses of desvenlafaxine 200 or 400 mg for 8 weeks. The primary efficacy measure was change from baseline on the 17-item Hamilton Rating Scale for Depression. At the final on-therapy evaluation, adjusted mean change from baseline in 17-item Hamilton Rating Scale for Depression total score was greater for desvenlafaxine 200 and 400 mg/day vs. placebo. Both desvenlafaxine doses showed greater efficacy than placebo on the secondary efficacy measures, including the Clinical Global Impressions-Improvement scale scores, Montgomery-Asberg Depression Rating Scale scores, CGI-Severity, and 17-item Hamilton Rating Scale for Depression response rate. Desvenlafaxine 200 mg/day was also significantly better than placebo on remission, Visual Analog Scale-Pain Intensity overall scores, and some Visual Analog Scale-Pain Intensity subscale scores. Desvenlafaxine 400 mg/day was significantly better than placebo on selected Visual Analog Scale-Pain Intensity subscale scores. Most adverse events were mild or moderate in severity, and safety assessments revealed few clinically significant changes in vital signs, laboratory tests, and electrocardiogram results. These data provide support for the efficacy and safety of desvenlafaxine in the treatment of major depressive disorder.     

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: 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.     

Eight-week, placebo-controlled, double-blind comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR

The efficacy, safety and tolerability of bupropion XR and venlafaxine XR was assessed and compared with placebo in adult outpatients with major depressive disorder (MDD). Adults meeting DSM-IV criteria for MDD with a minimum Hamilton Depression Rating Scale (HAMD) 17-Item total score of > or =18 were randomized to eight weeks of double-blind treatment with either bupropion XR (150 mg/day), venlafaxine XR (75 mg/day) or placebo. At the end of the fourth week of treatment, a dosage increase to bupropion XR 300 mg/day or venlafaxine XR 150 mg/day was allowed if, in the opinion of the investigator, response was inadequate. The primary efficacy endpoint was mean change from baseline at week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score last observation carried forward (LOCF). Mean changes from baseline at week 8 (LOCF) in MADRS total score were statistically significant for bupropion XR and venlafaxine XR patients compared to the placebo group: -16.0 for bupropion XR (P = 0.006 vs placebo), -17.1 for venlafaxine XR (P < 0.001 vs placebo) and -13.5 for placebo. Secondary outcomes (including CGI-S, HAM-A, MEI, Q-LES-Q-SF, responder and remitter analyses) also improved significantly for both active treatment groups compared with placebo. The most frequently reported adverse events were dry mouth and insomnia for bupropion XR, and nausea, hyperhidrosis, fatigue, and insomnia for venlafaxine XR. In this double-blind, placebo-controlled trial, bupropion XR at doses up to 300 mg/day and venlafaxine XR at doses up to 150 mg/day demonstrated comparable antidepressant efficacy.     

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.     

Efficacy, safety, and tolerability of fixed-dose desvenlafaxine 50 and 100 mg/day for major depressive disorder in a placebo-controlled trial

The objective of this study was to assess the efficacy, safety, and tolerability of desvenlafaxine (administered as desvenlafaxine succinate) 50 and 100 mg/day for major depressive disorder (MDD). A multicenter, randomized, double-blind, placebo-controlled trial was conducted in Europe and South Africa. Outpatients with MDD received fixed-dose desvenlafaxine (50 or 100 mg/day) or placebo for 8 weeks. The primary efficacy variable was the 17-item Hamilton Rating Scale for Depression total score; secondary measures included Clinical Global Impressions-Improvement scores. The intent-to-treat population included 483 patients: desvenlafaxine 50 mg (n=164), desvenlafaxine 100 mg (n=158), and placebo (n=161). At the last-observation-carried-forward analysis (final evaluation) using analysis of covariance, adjusted mean changes from baseline on the Hamilton Rating Scale for Depression were significantly greater for both desvenlafaxine 50 mg (-13.2; P=0.002) and 100 mg (-13.7; P<0.001) versus placebo (-10.7). Significant differences on the Clinical Global Impressions-Improvement scores were observed for desvenlafaxine 50 mg (P=0.002) and 100 mg (P<0.001) versus placebo. Both doses of desvenlafaxine were generally well tolerated. The most common treatment-emergent adverse events were nausea, dizziness, insomnia, constipation, fatigue, anxiety, and decreased appetite. Fixed doses of desvenlafaxine 50 and 100 mg/day are safe, generally well tolerated, and effective at a clinically relevant level for the treatment of MDD.     

Efficacy and tolerance profile of agomelatine and practical use in depressed patients

Agomelatine is a new agent with a unique pharmacological profile, as the first melatonergic antidepressant. Its antidepressant efficacy has been demonstrated in the treatment of major depressive disorder (MDD) at a dose of 25 mg/day. Expectations from antidepressant therapies now go beyond efficacy alone, to include advantages in tolerability and safety. Due to its pharmacological profile, agomelatine does not induce the side-effects typical of other therapies, such as selective serotonin reuptake inhibitors (i.e. gastrointestinal disorders, weight gain, serotonergic syndrome and insomnia). Moreover, a placebo-controlled trial in MDD comparing the effects of agomelatine and venlafaxine on sexual dysfunction (another significant side-effect with current antidepressant medications) indicated the very favourable profile of agomelatine; in the same study, there was similar antidepressant efficacy in the same two groups. A double-blind, placebo-controlled trial investigating the effect of abrupt cessation of treatment demonstrated the absence of discontinuation symptoms with agomelatine, which was in contrast with the results observed with paroxetine. The ability of an antidepressant to relieve sleep complaints with no sedative effects is a key advantage because sleep complaints are a major presenting feature of depression. Again due to its unique pharmacological profile, agomelatine has been shown to positively influence disturbed circadian rhythms in depressed patients by significantly improving all phases of disturbed sleep and the overall quality of sleep, with a favourable impact on daytime alertness. In conclusion, experience with agomelatine across a range of clinical studies suggests that this compound offers a novel approach to the treatment of depression combining efficacy, even in severe depression, with an extremely favourable side-effect profile and sleep regulation. These properties give agomelatine a definite clinical advantage in the treatment of depression.     

Vilazodone: in major depressive disorder

Vilazodone, a novel antidepressant agent that combines selective serotonin reuptake inhibitor (SSRI) activity and serotonin 5-HT(1A) receptor partial agonist activity in a single molecule, is indicated for the treatment of major depressive disorder (MDD) in the US. It is administered orally, once daily, with food. At the recommended dosage of 40?mg/day, vilazodone was effective in the short-term treatment of MDD in adults, as evidenced by significant improvements versus placebo on multiple measures of depression, including the Montgomery-?sberg Depression Rating Scale (MADRS) and the 17-item Hamilton Rating Scale for Depression (HAM-D-17), in two pivotal, 8-week, randomized, double-blind, phase III studies. Significant differences between vilazodone and placebo on the MADRS and HAM-D-17 were seen after 1 week of treatment (first efficacy timepoint) in one of the two studies. Long-term treatment with vilazodone 40?mg/day was associated with an improvement from baseline in depressive symptoms in a 52-week, noncompar-ative, phase III study. Vilazodone was generally well tolerated in the short- and long-term treatment of MDD, with diarrhoea and nausea being the most frequently occurring treatment-emergent adverse events. Vilazodone had a minimal impact on sexual functioning in the three phase III studies.     

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.     

Escitalopram : a review of its use in the management of major depressive and anxiety disorders

Escitalopram is the therapeutically active S-enantiomer of RS-citalopram, a commonly prescribed SSRI. The R-enantiomer is essentially pharmacologically inactive. Escitalopram 10 or 20 mg/day produced significantly greater improvements in standard measurements of antidepressant effect (Montgomery-Asberg Depression Rating Scale [MADRS], Clinical Global Impressions Improvement and Severity scales [CGI-I and CGI-S] and Hamilton Rating Scale for Depression [HAM-D]) in patients with major depressive disorder (MDD) than placebo in several 8-week, placebo-controlled, randomised, double-blind, multicentre studies. Symptom improvement was rapid, with some parameters improving within 1-2 weeks of starting escitalopram treatment. In addition, escitalopram showed earlier and clearer separation from placebo than RS-citalopram, at one-quarter to half the dosage, in 8-week, placebo-controlled trials; had significantly better efficacy than RS-citalopram in a subgroup of patients with moderate MDD in a 24-week trial; and produced sustained response and remission significantly faster than venlafaxine extended release in patients with MDD. Escitalopram reduced relapse rate compared with placebo and increased the percentage of patients in remission in long-term trials (up to 52 weeks). Consistently significant improvements for all efficacy parameters were also observed in patients with generalised anxiety disorder, social anxiety disorder and panic disorder treated with escitalopram for 8-12 weeks in individual, randomised, placebo-controlled, double-blind investigations. The good tolerability profile of escitalopram is predictable and similar to that of RS-citalopram. Such adverse events as nausea, ejaculatory problems, diarrhoea and insomnia are expected but, with the exception of ejaculatory problems and nausea, which is mild and transient, these were generally no more frequent than with placebo in fully published clinical trials. No adverse events not previously seen in acute trials were reported with long-term use.CONCLUSIONS: Escitalopram, the S-enantiomer of RS-citalopram, is a highly selective inhibitor for the serotonin transporter, ameliorates depressive symptoms in patients with MDD at half the RS-citalopram dosage, has a rapid onset of symptom improvement and has a predictable tolerability profile of generally mild adverse events. Like RS-citalopram, escitalopram is expected to have a low propensity for drug interactions, a potential benefit in the management of patients with comorbidities. In combination, these properties place escitalopram, like other SSRIs, as first-line therapy in patients with MDD. Escitalopram is indicated for use in patients with panic disorder in Europe and, should further evidence confirm early findings that escitalopram reduces anxiety, the drug may well find an additional role in the management of anxiety disorders.     

Quetiapine extended release: adjunctive treatment in major depressive disorder

Quetiapine extended release (XR) is a once-daily oral formulation of the atypical antipsychotic quetiapine that is available for use as adjunctive therapy in major depressive disorder (MDD). Systemic quetiapine exposure after orally administered quetiapine XR is similar to that of quetiapine immediate release at the same dosage, although quetiapine XR is absorbed more slowly and plasma concentrations are more stable over time. In two 6-week, randomized, double-blind, placebo-controlled, multinational trials in patients with MDD with an inadequate response to antidepressants, quetiapine XR 300?mg/day adjunctive to antidepressant reduced depressive symptoms significantly more than antidepressant plus placebo, according to changes in Montgomery-?sberg Depression Rating Scale (MADRS) total scores. In one trial, adjunctive quetiapine XR 150?mg/day also led to significantly greater reductions in MADRS total scores than antidepressant plus placebo. MDD response rates were significantly higher with adjunctive quetiapine XR 300?mg/day (but not 150?mg/day) than with antidepressant plus placebo. The numbers needed to treat to achieve an additional response over antidepressant plus placebo were 11-18 and 8-9 in the quetiapine XR 150 and 300?mg/day dosage groups, respectively. Treatment-emergent adverse events were mostly of mild to moderate severity; 1% of adjunctive quetiapine XR and 1.3% of antidepressant plus placebo recipients reported serious adverse events.     

Efficacy of extended release quetiapine fumarate monotherapy in patients with major depressive disorder: a pooled analysis of two 6-week, double-blind, placebo-controlled studies

Prospectively planned pooled analysis evaluating the efficacy of quetiapine extended release (XR) monotherapy in major depressive disorder (MDD). Data were pooled from two 6-week, randomized, double-blind, placebo-controlled studies of quetiapine XR in outpatients with MDD. The primary endpoint was Montgomery-?sberg Depression Rating Scale (MADRS) total score change from randomization at week 6. Other evaluations were MADRS response/remission, Hamilton Rating Scale for Anxiety, and subgroup analyses. A total of 968 patients were randomized to quetiapine XR, 150 mg/day (n=315), 300 mg/day (n=323), or placebo (n=330). The mean MADRS total score reductions from randomization were significant at week 6 with quetiapine XR, 150 mg/day (-14.7; P<0.001) and 300 mg/day (-14.7; P<0.001) versus placebo (-11.1), with significant reductions versus placebo from week 1 onward. Response rates (week 6): 52.7% (P<0.001) quetiapine XR 150 mg/day and 49.5% (P<0.001) quetiapine XR 300 mg/day versus placebo (33.0%). MADRS remission (score≤8; week 6): 23.5% (P=0.208) quetiapine XR 150 mg/day and 28.8% (P<0.01) quetiapine XR 300 mg/day versus placebo (19.4%). Quetiapine XR (both doses) significantly improved eight of 10 MADRS items versus placebo at week 6. The therapeutic effect of quetiapine XR was neither limited to nor driven by factors such as sex, age, or severity of depression. In patients with MDD, quetiapine XR (150 and 300 mg/day) monotherapy reduced depressive symptoms, with significant improvements compared with placebo from week 1 onward.     

Efficacy and safety of 30 mg/d and 45 mg/d nemifitide compared to placebo in major depressive disorder

Nemifitide is a novel pentapeptide antidepressant, which appears to be effective in the treatment of major depressive disorder (MDD). In the present study 81 patients with MDD, DSM-IV criteria were randomized following a 1-wk screening period to receive 30 mg/d nemifitide, 45 mg/d nemifitide or placebo in a 6-wk double-blind, multicentre, outpatient efficacy study. Nemifitide or placebo was delivered by subcutaneous injection for 2 wk daily for 5 days (Monday to Friday) in the first 2 wk and patients were followed up for a further 4 wk. The primary efficacy measure was the change from baseline on the Montgomery-Asberg Depression Rating Scale. Secondary measures included the 17-item Hamilton Psychiatric Rating Scale for Depression (HAMD), the CGI severity and improvement scale and the Carroll Self-Rating Scale for Depression. This proof-of-principle study demonstrated a statistically significant superiority of the 45-mg/d dose vs. placebo at the time-point of peak effect (1 wk after the end of treatment). There appeared to be a greater effect with the 45 mg/d nemifitide dose than with 30 mg/d. An additional exploratory analysis by stratification of all patients by severity above and below or equal to the median baseline HAMD score of 22 showed a higher percentage of responders for both doses of nemifitide with statistical separation from placebo for patients with baseline HAMD score of >22 (above the median). There was no significant difference among treatment groups for patients with baseline HAMD score of 相似文献   

Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial

Background: Duloxetine is a balanced and potent dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) that has previously been shown to be effective in the acute treatment of major depressive disorder (MDD). This placebo-controlled study assesses the safety and efficacy of duloxetine (80 or 120 mg/day) and paroxetine (20 mg QD) during an initial 8-week acute phase and subsequent 6-month continuation phase treatment of MDD. Method: In this randomized, double-blind, placebo-controlled trial, adult outpatients (age ≥18 years) meeting DSM-IV criteria for MDD received placebo (n=93), duloxetine 80 mg/day (40 mg BID; n=95), duloxetine 120 mg/day (60 mg BID; n=93), or paroxetine (20 mg QD; n=86) for 8 weeks. Patients who had a ≥30% reduction from baseline in HAMD₁₇ total score during the acute phase were allowed to continue on the same (blinded) treatment for a 6-month continuation phase. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD₁₇) total score, HAMD₁₇ subscales, the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAMA), Visual Analog Scales (VAS) for pain, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, the 28-item Somatic Symptom Inventory (SSI), and the Sheehan Disability Scale (SDS). Safety and tolerability were assessed using treatment-emergent adverse events, discontinuations due to adverse events, vital signs, ECGs, laboratory tests, and the Arizona Sexual Experiences Scale (ASEX). Results: During the acute phase, patients receiving duloxetine 80 mg/day, duloxetine 120 mg/day, or paroxetine 20 mg QD had significantly greater reductions in HAMD₁₇ total score compared with placebo. Both duloxetine (80 and 120 mg/day) and paroxetine treatment groups had significantly greater improvement, compared with placebo, in MADRS, HAMA, CGI-S, and PGI-I scales. Estimated probabilities of remission at week 8 for patients receiving duloxetine 80 mg/day (51%), duloxetine 120 mg/day (58%), and paroxetine (47%) were significantly greater compared with those receiving placebo (30%). The rate of discontinuation due to adverse events among duloxetine-treated patients (80 and 120 mg/day) did not differ significantly from the rate in the placebo group. Treatment-emergent adverse events reported significantly more frequently by duloxetine-treated patients than by patients receiving placebo were constipation (80 and 120 mg/day), increased sweating (120 mg/day), and somnolence (120 mg/day). The incidence of acute treatment-emergent sexual dysfunction in duloxetine- and paroxetine-treated patients was 46.5% and 62.8%, respectively. During the 6-month continuation phase, duloxetine (80 and 120 mg/day) and paroxetine treatment groups demonstrated significant improvement in HAMD₁₇ total score. Treatment-emergent adverse events occurring most frequently in each active treatment group during the continuation phase were viral infection (duloxetine 80 mg/day), diarrhea (duloxetine 120 mg/day), and headache (paroxetine 20 mg QD). Conclusion: These data support previous findings that duloxetine is safe, efficacious, and well tolerated in the acute treatment of MDD. Furthermore, these data provide the first demonstration under double-blind, placebo-controlled conditions that the efficacy and tolerability of duloxetine are maintained during chronic treatment.