抑郁伴焦虑躯体症状.doc

Poor response to antidepressant medication of patients with depression accompanied by somatic symptomatology in the STAR*D StudyStudies suggest that the gender difference in the prevalence of depression results because women exhibit higher prevalence than men of a depressive phenotype associated with somatic symptoms. Because this phenotype has been found to be based in psychosocial forces, it may not respond well to antidepressant medication. In this study, data from the STAR*D Study were analyzed to compare remission rates in response to an SSRI and to several other antidepressants of patients exhibiting depression accompanied by somatic symptomatology versus other patients. Scores on the Clinician Rated Quick Inventory of Depressive Symptomatology were used to measure clinical remission in response to medication. Patients exhibiting depression accompanied by somatic symptomatology exhibited less remission to the SSRI Citalopram (31% versus 43%) and to the various medications administered in level 3 (14% versus 25%) than did other patients in STAR*D. The low rates of remission in response to medication of patients exhibiting somatic symptomatology were not due to the greater proportion of women, nor to the greater proportion of patients exhibiting anxiety disorders, among patients exhibiting somatic symptomatology. Remission rates were found to be related to exhibiting somatic symptomatology not to exhibiting nonsomatic symptoms.1、药理学主要特点文拉法辛及其活性代谢产物0-去甲基文拉法辛（ODV）是一种二环类苯乙胺族化合物，能选择性阻断5-羟色胺（5-HT）转运体和去甲肾上腺素（NE）转运体的再摄取作用，对5-HT的亲和力比NE要高出将近8倍。文拉法辛在75 mg/d-100 mg/d的低剂量时，仅对5-HT再摄取有阻断作用，当剂量150 mg/d时，才同时对NE和5-HT具有双重单胺再摄取抑制作用。在啮齿类动物抑郁样模型研究中，文拉法辛发挥出快速的受体脱敏作用，而不像其它抗抑郁药，需要重复给药才能刺激NE的低敏感性。文拉法辛对5-HT1A受体的作用机制研究发现，阻断前脑5-HT1A受体产生抗抑郁作用，阻断缝际核胞体-树突自受体可增强下行单胺疼痛控制系统产生镇痛作用。对多巴胺（DA）的再摄取抑制作用极弱，对毒覃碱样胆碱受体和组胺H1受体以及肾上腺素能受体的亲和力均较低或无。对背侧缝际核的5-HT神经元和兰斑的NE神经元突触终端及胞体-树突的自受体和异质性受体具有一定的抑制作用，从而增加了突触后5-HT和NE的释放和加快突触前膜自身受体的“脱敏”过程，也从机制上部分解释了SNRIs在抗抑郁和抗焦虑疗效、起效时间方面优于选择性5-HT再摄取抑制剂（selective serotonin reuptake inhibitor SSRI）的可能原因。文拉法辛（venlafaxine）缓释胶囊是5-羟色胺和去甲肾上腺素再摄取抑制剂（serotonin and noradrenaline reuptake inhibitor，SNRI）类抗抑郁药物。动物实验发现该药具有抗抑郁作用，同时对毒蕈碱样或组胺样受体不具有明显亲和力。因此，文拉法辛在抗抑郁作用的同时，并没有明显的三环类抗抑郁药（tricyclic antidepressant，TCA）所致不良反应特点，表现了较为独特的药理性质。自1994年起，该药被美国食品和药品管理局陆续批准用于抑郁障碍、伴焦虑症状的抑郁障碍、广泛性焦虑障碍和社交焦虑障碍的治疗。2001年来，中国国家食品药品监督管理总局也相继批准了抑郁症、广泛性焦虑障碍的适应证，直至2012年7月，该药是中国上市具有广泛性焦虑障碍适应证的唯一新型抗抑郁药。文拉法辛成为加拿大、中国等国家的抑郁症和广泛性焦虑障碍防治指南推荐的一线治疗药物。为进一步规范文拉法辛的临床应用，结合广大专家应用此药的经验及国内外相关循证医学证据，撰写本文为临床医生提供科学、全面的用药和治疗方案。文拉法辛，有普通制剂、缓释制剂及在国内尚未上市的去甲文拉法辛。鉴于多数资料来源于缓释剂，文中除特别注明者，均指文拉法辛缓释剂。1、药理学主要特点文拉法辛及其活性代谢产物0-去甲基文拉法辛（ODV）是一种二环类苯乙胺族化合物，能选择性阻断5-羟色胺（5-HT）转运体和去甲肾上腺素（NE）转运体的再摄取作用，对5-HT的亲和力比NE要高出将近8倍。文拉法辛在75 mg/d-100 mg/d的低剂量时，仅对5-HT再摄取有阻断作用，当剂量150 mg/d时，才同时对NE和5-HT具有双重单胺再摄取抑制作用。在啮齿类动物抑郁样模型研究中，文拉法辛发挥出快速的受体脱敏作用，而不像其它抗抑郁药，需要重复给药才能刺激NE的低敏感性。文拉法辛对5-HT1A受体的作用机制研究发现，阻断前脑5-HT1A受体产生抗抑郁作用，阻断缝际核胞体-树突自受体可增强下行单胺疼痛控制系统产生镇痛作用。对多巴胺（DA）的再摄取抑制作用极弱，对毒覃碱样胆碱受体和组胺H1受体以及肾上腺素能受体的亲和力均较低或无。对背侧缝际核的5-HT神经元和兰斑的NE神经元突触终端及胞体-树突的自受体和异质性受体具有一定的抑制作用，从而增加了突触后5-HT和NE的释放和加快突触前膜自身受体的“脱敏”过程，也从机制上部分解释了SNRIs在抗抑郁和抗焦虑疗效、起效时间方面优于选择性5-HT再摄取抑制剂（selective serotonin reuptake inhibitor SSRI）的可能原因。文拉法辛口服后在胃肠道吸收良好，与食物同时服用会降低其吸收速度，但不影响吸收程度。在肝脏进行首过代谢后，形成唯一的活性代谢物为ODV。服用普通剂型后2h内达到文拉法辛的血药峰浓度，3h达到ODV的峰浓度。文拉法辛缓释剂型的吸收比普通剂型缓慢，达到血药峰浓度约5.5h，ODV则需9h才能达峰，由此形成了低峰高谷的血药浓度而避免了普通剂型的高峰低谷缺陷。两种剂型在吸收程度和生物利用度方面都具有可比性。治疗后3-4d后即可达到稳态血药浓度。剂量范围在75 mg/d-450mg/d时，文拉法辛及其活性代谢产物呈线性药代特征。文拉法辛及其代谢产物主要经肾脏排泄。文拉法辛半衰期为4 h，ODV清除比文拉法辛要慢，半衰期为10 h。缓释剂型每天1次给药的生物利用度为90%以上，与每天2次给药的普通剂型几乎相等。缓释剂型无论早晨或晚上均可给药，与食物同时服用时，生物利用度并不受影响。文拉法辛在肝脏通过细胞色素P450酶系统进行多种代谢，以2D6酶为主，由于文拉法辛及其活性代谢产物ODV在药理学上具有等效性，至少在治疗浓度时，抑制2D6酶后造成的直接后果并无临床意义。尽管文拉法辛是细胞色素P450 2D6酶的底物，但它是所有新型抗抑郁药中对该酶抑制作用最弱的药物之一，通常在与2D6酶抑制剂合用时，不需要调整文拉法辛剂量。Efficacy and tolerability of venlafaxine versus specific serotonin reuptake inhibitors in treatment of major depressive disorder: a meta-analysis of published studies.Specific serotonin reuptake inhibitors (SSRIs) are considered as first-line treatment in major depressive disorder (MDD). There is evidence that venlafaxine may be more effective than several antidepressants in the treatment of MDD. This meta-analysis includes all published, randomized, double-blind, head-to-head trials, which compared venlafaxine and an SSRI in the treatment of MDD in adults. Twenty-six trials comparing venlafaxine with an SSRI were included (total participants: 5858). Meta-analysis using a random effect model showed that venlafaxine was superior to SSRIs in achieving remission odds ratio (OR)=1.13, 95% confidence interval (CI)=1.0-1.28, P=0.05 and response (OR=1.17, 95% CI=1.03-1.34, P=0.02). Subgroup analysis found that venlafaxine had a significantly better response rate than fluoxetine (OR=1.28, 95% CI=1.05-1.55, P=0.01). There were no significant differences in response or remission between venlafaxine and other individual SSRIs. There was no significant difference in all cause discontinuation between venlafaxine and SSRIs (OR=1.10, 95% CI=0.97-1.25, P=0.15). Venlafaxine had significantly higher discontinuation due to adverse events compared with SSRIs (OR=1.41, 95% CI=1.10-1.79, P=0.006). The superior efficacy of venlafaxine over SSRIs is of clinical importance. However, higher rates of discontinuation due to adverse events for venlafaxine compared with SSRIs are a disadvantage. Findings of this meta-analysis that included only published studies were similar to those from meta-analysis that included unpublished data.Rationale and design of the randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with Major Depressive Disorder - the EMC trialAndr Tadi,1Stanislav Gorbulev,2Norbert Dahmen,1,3Christoph Hiemke,1Dieter F Braus,4Joachim Rschke,5,6Dietrich van Calker,7Daniel Wachtlin,2Kai Kronfeld,2Thorsten Gorbauch,2Monika Seibert-Grafe,2andKlaus Lieb1, the EMC Study GroupAuthor informationArticle notesCopyright and License informationThis article has beencited byother articles in PMC.Go to:AbstractBackgroundIn Major Depressive Disorder (MDD), the traditional belief of a delayed onset of antidepressants effects has lead to the concept of current guidelines that treatment durations should be between 3-8 weeks before medication change in case of insufficient outcome. Post hoc analyses of clinical trials, however, have shown that improvement usually occurs within the first 10-14 days of treatment and that such early improvement (Hamilton Depression Rating Scale HAMD decrease 20%) has a substantial predictive value for final treatment outcome. Even more important, non-improvement (HAMD decrease 20%) after 14 days of treatment was found to be highly predictive for a poor final treatment outcome.Methods/DesignThe EMC trial is a phase IV, multi-centre, multi-step, randomized, observer-blinded, actively controlled parallel-group clinical trial to investigate for the first time prospectively, whether non-improvers after 14 days of antidepressant treatment with an early medication change (EMC) are more likely to attain remission (HAMD-17 7) on treatment day 56 compared to patients treated according to current guideline recommendation (treatment as usual; TAU). In level 1 of the EMC trial, non-improvers after 14 days of antidepressant treatment will be randomised to an EMC strategy or TAU. The EMC strategy for this study schedules a first medication change on day 15; in case of non-improvement between days 15-28, a second medication change will be performed. TAU schedules the first medication change after 28 days in case of non-response (HAMD-17 decrease 50% of patients who eventually respond to fluoxetine treatment started to improve during the first 2 weeks of treatment and that early non-response to fluoxetine treatment predicted poor 8-weeks outcomes 19, and references Inside. Katz and colleagues reported on a randomised controlled trial (RCT) in which patients were treated with the selelctive serotonin reuptake inhibitor paroxetine, the tricyclic antidepressant desipramine or placebo 20. In this study, early treatment-specific behavioural changes occurred that were not observed in the placebo-group, and these changes were highly predictive of ultimate clinical response to antidepressant therapy. In multiple studies between 1993 and 2007, Stassen and colleagues analysed individual time courses of response in depressed patients treated with various antidepressants 24, and references inside. A model-finding study with repeated HAMD17 assessments during a 1-week placebo run-in showed that the observed fluctuations did not exceed 15% of baseline score. In consequence, onset of improvement (which models onset of action) has been defined as a 20% baseline score reduction in accordance with clinical practice in which a 4-point HAMD17 reduction (= 20% for a HAMD17 score of 20) is regarded as clinically relevant. Each of their analyses revealed that patients with improvement during the first 2 weeks (= early improvement) of antidepressant treatment showed substantial response at study endpoint. A recent meta-analysis of 2,848 patients with MDD confirmed previous analyses showing that early improvers were far more likely to become responders than patients without early improvement (pooled OR = 9.25, 95%-CI = 7.79-10.98) 24. In separate analyses, Szegedi and colleagues examined early improvement in a randomised controlled trial comparing mirtazapine and paroxetine in MDD patients 25. Improvement (HAMD17 score reduction 20%) occurred in a majority of patients within 2 weeks of treatment, and this improvement was a highly sensitive predictor of later stable response (HAMD17 score reduction 50% at week 4 and onward) and stable remission (HAMD17 score 7 at week 4 and onward) for both drugs. Less than 10% of patients who had not improved af