A review of the efficacy and tolerability of agomelatine in the treatment of major depression

Agomelatine is a novel agent that is under late-stage development as a potential antidepressant. Compared with available antidepressant agents, the drug may have a distinct mechanism of action, with significant interactions with melatonin receptors, in addition to serotonergic brain systems. Agomelatine has been shown to be active in preclinical models indicative of antidepressant activity and the results of a large-scale clinical trial programme, conducted in major depressive disorder, indicate both antidepressant activity and a favourable tolerability profile. As agomelatine may have a pharmacological profile and mechanism of action distinct from available agents, it may come to represent a valuable additional treatment option in those patients who do not respond fully or who prove unable to tolerate the side effects of existing antidepressants.     

A review of the efficacy and tolerability of agomelatine in the treatment of major depression

Agomelatine is a novel agent that is under late-stage development as a potential antidepressant. Compared with available antidepressant agents, the drug may have a distinct mechanism of action, with significant interactions with melatonin receptors, in addition to serotonergic brain systems. Agomelatine has been shown to be active in preclinical models indicative of antidepressant activity and the results of a large-scale clinical trial programme, conducted in major depressive disorder, indicate both antidepressant activity and a favourable tolerability profile. As agomelatine may have a pharmacological profile and mechanism of action distinct from available agents, it may come to represent a valuable additional treatment option in those patients who do not respond fully or who prove unable to tolerate the side effects of existing antidepressants.     

Efficacy and tolerability of milnacipran in the treatment of major depression in comparison with other antidepressants : a systematic review and meta-analysis

BACKGROUND: Milnacipran, a dual serotonin-noradrenaline reuptake inhibitor, is one of the newer antidepressants that clinicians use for the routine care of patients with major depression. We undertook a systematic review and meta-analysis of randomized controlled trials that compared the efficacy and tolerability of milnacipran with other antidepressants. OBJECTIVE: To assess the efficacy and tolerability of milnacipran in comparison with TCAs, SSRIs and other drugs in the acute phase of treatment for major depression. METHODS: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials registers, journals, conference proceedings, trial databases of the drug-approving agencies and ongoing clinical trial registers for all published and unpublished randomized controlled trials that compared the efficacy and adverse events of milnacipran versus any other antidepressant. The search was conducted in December 2006 and updated in May 2007. No language restrictions were applied. All relevant authors were contacted to supplement any incomplete reporting in the original papers. Randomized controlled trials comparing milnacipran with any other active antidepressants as monotherapy in the acute phase of treatment for major depression were selected. Participants were aged > or =18 years, of both sexes and with a primary diagnosis of unipolar major depression. Studies were excluded when the participants had specific psychiatric and medical co-morbidities.Two independent reviewers assessed the quality of trials for inclusion, and subsequently extracted data. Disagreements were resolved by consensus. Meta-analyses were conducted for efficacy and tolerability outcomes. Sixteen randomized controlled trials (n = 2277) were included in the meta-analyses. RESULTS: No differences were found in achieving clinical improvement, remission or overall tolerability when comparing milnacipran with other antidepressants. However, compared with the TCAs, fewer patients taking milnacipran were early treatment withdrawals due to adverse events (number needed to harm (NNH) = 15; 95% CI 10, 48). Significantly more patients taking TCAs experienced adverse events compared with milnacipran (NNH = 4; 95% CI 3, 7). CONCLUSIONS: The overall effectiveness and tolerability of milnacipran versus other antidepressants does not seem to differ in the acute phase of treatment for major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of premature withdrawal due to adverse events and the rates of patients experiencing adverse events. Milnacipran may benefit some patient populations who experience adverse effects from other antidepressants in the acute phase of treatment for major depression.     

The efficacy of selective serotonin re-uptake inhibitors in depression: a meta-analysis of studies against tricyclic antidepressants

A meta-analysis of the efficacy of five selective serotonin re-uptake inhibitors (SSRIs) against non-selective and noradrenergic re-uptake inhibitors (mainly tricyclic antidepressants, TCAs) is presented. Fifty five double- blind studies were identified after excluding those multiply reported or with methodological problems likely to bias the outcome in favour of SSRIs. Standardised effect sizes and 95% confidence intervals were calculated based on the difference in the reduction in mean Hamilton depression rating scale (HDRS) scores for the two antidepressants. For studies not reporting standard deviations, the pooled variance from complete studies was used and a variance-weighted mean effect size calculated. There were no differences in efficacy between SSRIs and comparator antidepressants for SSRIs taken together or individually. If studies were classified into high and low depression scores based on a median split of initial HDRS scores, there was a slight advantage to TCAs in the high HDRS group. In addition, SSRIs were slightly less effective than TCAs in in-patients and against combined serotonin and noradrenaline re-uptake inhibitors (clomipramine and amitriptyline). These findings were accounted for by a clinically significant lower efficacy of paroxetine in these subgroups. In contrast, SSRIs as a group were marginally more effective than noradrenergic antidepressants, a finding accounted for by two studies with sertraline. Fluvoxamine was the only SSRI to have been tested adequately in in-patients, where it displayed equal efficacy to TCAs. This meta-analysis confirms that SSRIs and TCAs are in general equally effective, but suggests that paroxetine's efficacy in in-patients and against clomipramine and amitriptyline is not proven.     

Cost analysis of paroxetine versus imipramine in major depression

A simulation decision analytical model was used to compare the annual direct medical costs of treating patients with major depression using the selective serotonin reuptake inhibitor (SSRI) paroxetine or the tricyclic antidepressant (TCA) imipramine. Medical treatment patterns were determined from focus groups of general and family practitioners and psychiatrists in Boston, Dallas and Chicago, US. Direct medical costs included the wholesale drug acquisition costs (based on a 6-month course of drug therapy), psychiatrist and/or general practitioner visits, hospital outpatient visits, hospitalisation and electroconvulsive therapy. Acute phase treatment failure rates were derived from an intention-to-treat analysis of a previously published trial of paroxetine, imipramine and placebo in patients with major depression. Maintenance phase relapse rates were obtained from a 12-month trial of paroxetine, supplemented from the medical literature. The relapse rates for the final 6 months of the year were obtained from medical literature and expert opinion. Direct medical costs were estimated from a health insurance claims database. The estimated total direct medical cost per patient was slightly lower using paroxetine ($US2348) than generic imipramine ($US2448) as first-line therapy. This result was sensitive to short term dropout rates but robust to changes in other major parameters, including hospitalisation costs and relapse rates. The financial benefit of paroxetine, despite its 15-fold higher acquisition cost compared with imipramine, is attributable to a higher rate of completion of the initial course of therapy and consequent reduced hospitalisation rates.     

Mirtazapine and paroxetine in major depression: A comparison of monotherapy versus their combination from treatment initiation

This double-blind study compared initial combination therapy against monotherapy using two antidepressant drugs with complementary mechanisms of action on the serotonin (5-HT) and norepinephrine (NE) systems. Sixty one adult patients with a DSM-IV diagnosis of unipolar depression were randomized to receive mirtazapine (30 mg/day), paroxetine (20 mg/day), or the combination of both drugs for 6 weeks. Response at week 4 was defined as a 30% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS), and at week 6 as a 50% reduction in the MADRS. Remission was defined as a reduction in the MADRS score to 10 points or less. After 4 weeks, non-responders in the monotherapy groups had their medication dose increased by 50%. After 6 weeks, non-responders on monotherapy had the second trial drug added to their current regimen. Non-responders on combination therapy had the dosage of both drugs increased by 50%. There was a significantly greater decrease in MADRS scores in the combination group compared to the monotherapy groups at days 28, 35 and 42, with a 10 point difference separating the combination from the monotherapies at day 42. Remission rates at week 6 were 19% on mirtazapine, 26% on paroxetine, and 43% on the combination. Fifteen patients in the mirtazapine arm and 10 in the paroxetine arm who did not respond had the other drug added to their current regimen, and 5 on the combination had an increase in dose of both drugs secondary to non-response. Of these 30 patients, approximately 50% went on to achieve remission in the subsequent 2 weeks. These results indicate that the combined use of two antidepressants was well tolerated and produced a greater improvement than monotherapy.     

A randomized, double-blind controlled comparison of nefazodone and paroxetine in the treatment of depression: safety, tolerability and efficacy in continuation phase treatment

We investigated the safety, tolerability and efficacy of nefazodone and paroxetine in the continuation phase of treatment of depression. The study comprised a double-blind, parallel-group comparison over 4 months, of patients who had previously improved following random allocation to nefazodone or paroxetine during an 8-week acute treatment study. Assessments included Clinical Global Impression Scales, Hamilton Rating Scales for Depression and Anxiety, Montgomery-Asberg Depression Rating Scale and the Patient Global Assessment Scale, in addition to a review of reported adverse events, vital sign measurements, electrocardiograms and clinical laboratory tests. One hundred and eight patients participated in the continuation study (53 received paroxetine, 55 nefazodone) and 73 completed treatment. No clinically relevant differences in antidepressant efficacy were seen. Headache and somnolence were the most common reported adverse events in both treatment groups. Both nefazodone and paroxetine maintain their efficacy in continuation treatment, and both are generally well tolerated.     

A double-blind study comparing the efficacy and tolerability of mirtazapine and doxepin in patients with major depression

One hundred and sixty-three patients with major depression were randomly assigned to treatment with mirtazapine or doxepin for 6 weeks in a double-blind clinical trial. Initially, patients received mirtazapine 20 mg/day or doxepin 75 mg/day, dosages were then titrated up to a maximum of 60 mg/day and 300 mg/day, respectively. Both drugs produced considerable improvement in depressive symptoms with no statistically significant differences between the two patient groups. In the mirtazapine group only two patients prematurely terminated the study due to adverse drug experiences, as compared to six in the doxepin-treated group. Moreover, doxepin-treated patients complained more frequently of dry mouth and movement disorders. In conclusion, mirtazapine is an effective treatment for major depression and appears to offer advantages in tolerability over doxepin.     

帕罗西汀与小剂量奥氮平治疗老年抑郁症的临床疗效

目的 探讨帕罗西汀与小剂量奥氮平治疗老年抑郁症的临床疗效.方法 选取无锡市精神卫生中心2018年9月-2019年9月收治的老年抑郁症患者100例,按照奇偶法分为奥氮平组和帕罗西汀组,每组50例.帕罗西汀组予以帕罗西汀治疗,奥氮平组在帕罗西汀组基础上予以小剂量奥氮平治疗.2组均治疗8周.比较2组治疗前后抑郁自评量表(SD...     

帕罗西汀治疗脑卒中后抑郁症的临床疗效和安全性分析

目的：探讨帕罗西汀治疗脑卒中后抑郁症的临床疗效和安全性。方法选取2010年9月—2012年3月于徐州市电力医院就诊的73例脑卒中后抑郁症患者,随机分为对照组34例和治疗组39例。对照组给予常规神经系统药物及对症支持治疗,治疗组在对照组基础上给予帕罗西汀治疗,比较两组患者的临床疗效及治疗前后的神经功能缺损（NIHSS）评分、抑郁自评量表（SDS）评分、生活质量评定量表（ADL）评分、汉密尔顿抑郁量表（HAMD）评分。结果治疗组总有效率（92.3%）高于对照组（70.6%）,治疗后 SDS、NIHSS、HAMD 评分低于对照组,ADL评分高于对照组,躯体功能、生理功能、社会功能、物质生活得分均高于对照组,差异均有统计学意义（P ＜0.05）。结论帕罗西汀治疗脑卒中后抑郁症具有显著疗效,可明显改善患者焦虑、抑郁情绪,安全性高。     

Serotonergic function in major depression and effect of sertraline and paroxetine treatment

We investigated platelet [14C]serotonin (5-HT) uptake and lysergic acid diethylamide [N-methyl-3H] ([3H]LSD)- and phenyl-6'-paroxetine ([3H]paroxetine) binding in 30 patients with major depression at baseline and after 6 months of treatment with either paroxetine or sertraline. The study was of a double-blind design. Baseline data was compared with an age- and gender-matched group of healthy volunteers. Baseline Vmax was significantly lower in patients than in controls. Bmax for [3H]paroxetine binding were similar in patients and controls, but patients who suffered their first depression had significantly lower Bmax for [3H]paroxetine binding than patients who had suffered multiple depressions. Twenty-three patients (76%) (13 in the paroxetine group and 10 in the sertraline group) responded to treatment as judged by a 50% or more reduction in Montgomery-Asberg Depression Rating Scale (MADRS) scores after 6 months of treatment. There were no significant differences between the paroxetine and sertraline treated groups. Both paroxetine and sertraline caused a significant reduction in Vmax and a significant increase in Km. There was a strong correlation between Km and plasma drug concentration in patients who experienced their first depression but not in patients who had suffered multiple episodes. Bmax for [3H]paroxetine binding increased after paroxetine treatment while the opposite occurred after sertraline treatment. There was a significant interaction between the impact of drug and earlier depressions. All patients included in the study had been drug free for at least 2 months. Earlier antidepressant treatment may have long withstanding effects on the serotonin uptake machinery but it cannot be excluded that the sensitivity of the uptake mechanism may become more resistant to change in patients with recurrent depressive episodes.     

帕罗西汀治疗单纯抑郁症和抑郁合并焦虑症病人的疗效比较

目的:比较帕罗西汀对单纯抑郁症和抑郁合并焦虑症的临床疗效。方法:采用前瞻性、多中心合作研究,所有病人均于每日早餐后服用20mg帕罗西汀。对180例资料完整的病人分别于治疗基期、治疗3个月和6个月时进行随访,并评价生活质量(quality of life,QOL)。结果:两组病人的QOL总评分和各维度评分随治疗时间延长而逐步升高,且抑郁合并焦虑症组的QOL改善情况优于单纯抑郁症组。结论:帕罗西汀能显著改善单纯抑郁症和抑郁合并焦虑症病人的QOL,使用足够疗程改善程度更大。     

丁螺环酮与帕罗西汀联合治疗抑郁症的疗效分析

目的探讨丁螺环酮联合帕罗西汀治疗抑郁症的临床疗效及安全性。方法本院收治的76例患者均符合中国精神障碍分类与诊断标准第3版（CCMD-3）中抑郁症诊断标准,将其随机分为实验组和对照组,两组均给予帕罗西汀治疗,实验组在此基础上给予丁螺环酮治疗。分别于治疗前、治疗后1、2、4、6周采用汉密尔顿抑郁量表（HAMD）对患者进行评价,并采用副反应量表（TESS）评价不良反应。结果实验组有效率达97.3％,显著高于对照组89．5％（P〈0．05）;实验组2、4、6周HAMD评分显著低于对照组（P〈0．05）,两组TESS评分差异无显著性（P〉0．05）。结论丁螺环酮能够增强帕罗西汀治疗抑郁症的临床疗效,且不增加不良反应的发生率,值得临床推广应用。     

Efficacy, tolerability and side-effect profile of fluvoxamine for major depression: meta-analysis

Fluvoxamine, one of the oldest selective serotonin reuptaking inhibitors, is commonly prescribed to patients with major depression. Several studies have reviewed the efficacy and tolerability of fluvoxamine for the treatment of major depression. However, these reviews are outdated, have not been systematic and/or suffered from several methodological weaknesses. We conducted a systematic review to synthesize the best available evidence on the efficacy of fluvoxamine for adult patients suffering from major depression in comparison with other active antidepressive agents. Relevant randomized controlled trials were identified through a comprehensive search. The primary outcome was a relative risk of response, and the secondary outcome was a relative risk of remission. Tolerability and side-effect profile were also examined. Fifty-three trials were included. There were no large differences between fluvoxamine and any other antidepressants in terms of efficacy and tolerability. There is evidence of differing side effect profiles, especially when comparing gastrointestinal side effects between fluvoxamine and tricyclics. Clinicians should focus on practically or clinically relevant differences including those in side-effect profiles.     

Clinical efficacy of paroxetine in resistant depression

The antidepressant effects of a specific reuptake inhibitor of 5-hydroxytryptamine (5-HT), paroxetine, were tested in 24 patients with resistant depression who had failed to respond to conventional antidepressants after at least 4 weeks of treatment. A novel exper imental design was chosen in which all patients had 12 weeks of treatment beginning and ending with placebo therapy with 6 weeks of active drug treatment at some point in between. Ratings of depressive symptoms were made using the Hamilton rating scale (HRS) for depression, and the checklist for unwanted effects and their severity was also recorded before and during treatment at 2 week intervals. The change from placebo to active paroxetine therapy was made using a double-blind procedure. Patients who made a significant placebo response in the first 2 weeks of treatment were excluded from further analysis; 20 patients completed the study and satisfied all criteria for inclusion. Both groups of showed a significant improvement in symptoms after 4 weeks of paroxetine therapy. There were no significant treatment differences between the groups, but improvement in symptoms occurred sig nificantly later in the patients who had a longer period of initial placebo therapy. The experimental design also allowed study of withdrawal effects after stopping active treatment. There was no increase in adverse effects, including a subgroup associated with withdrawal problems, either during treatment with paroxetine or after the drug was stopped. The results suggest that paroxetine is probably an effective antidepressant, is well tolerated and has few adverse effects.     

Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients

Rationale: Previous studies showed that adjunctive paroxetine increases tricyclic antidepressant (TCA) serum levels by inhibiting cytochrome P4502D6. This effect has, however, been examined only in experimental studies using low doses of TCAs in healthy volunteers. Objective: The present study investigated TCA serum level changes and side-effects after the addition of paroxetine in depressed patients treated with doses customarily used for inpatients. Method: 14 patients who had a moderate or severe depressive episode according to ICD-10 and who had not sufficiently responded (≤25% reduction of the Hamilton depression scale) to 3-week monotherapy with amitriptyline (n=9) or imipramine (n=5) with daily doses between 125 and 200 mg/day, received 20 mg/day paroxetine additionally under steady state conditions. Results: After 2 weeks the serum levels of the metabolites nortriptyline (from 88±49 ng/ml to 176±57 ng/ml) and desipramine (from 152±78 ng/ml to 338±104 ng/ml) had risen to a significantly greater extent than those of the parent compounds amitriptyline (123±50 ng/ml to 195±128 ng/ml) and imipramine (from 75±36 ng/ml to 98±51 ng/ml). It is noteworthy that, with the exception of one case of incipient delirium, the combination therapy was well tolerated despite high TCA serum level rises. Conclusion: The higher increase of the metabolites as compared with the parent compounds can be explained by a paroxetine-induced inhibition of the liver enzyme cytochrome P4502D6, which catalyses the second step of the TCA metabolism, i.e. the hydroxylation of the metabolites. Blood levels should be meticulously monitored, if TCAs are combined with paroxetine. Received: 8 March 1999 / Final version: 23 July 1999     

The efficacy and tolerability of bupropion in the treatment of major depressive disorder

Major depressive disorder (MDD) is a highly recurrent condition associated with a substantial burden of disease. Antidepressants alone or in combination with psychotherapy are the mainstay of treatment. Evidence demonstrates that antidepressant agents are significantly more efficacious than placebo in treating MDD, and antidepressants of different types have similar efficacies. However, not all patients respond to initial pharmacological treatment, suggesting the need for antidepressants with different mechanisms of action. Bupropion is a second-generation antidepressant, with a mechanism of action different from most antidepressants, in that it is a dopamine and norepinephrine reuptake inhibitor. Bupropion has demonstrated efficacy in the treatment of MDD, measured by Hamilton depression rating scale total and clinical global impressions severity and improvement scores, the proportion of responders, the proportion of patients in remission of disease, the prevention of relapse and beneficial effect on a range of health-related quality of life measures. With an efficacy that is at least similar to most other common antidepressants, including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors and other second-generation drugs, bupropion has a favourable acceptability and tolerability profile. In particular, it has a minimal effect on sexual function, comparable or lower rates of somnolence than placebo, and is associated with lower rates of weight gain and sedation than some other commonly used antidepressants. Combination therapy of bupropion with other second-generation antidepressants has been shown to improve outcomes in patients failing antidepressant monotherapy. Bupropion is approved for the treatment of MDD in the USA, Canada and many countries in Europe, and current evidence-based guidelines reinforce its place as an efficacious and well-tolerated treatment option in the pharmacological management of MDD.