BACKGROUND & AIMS: Tricyclic antidepressants have been shown to be useful for the treatment of pain of varying etiology. Monoaminergic systems seem to be implicated in this phenomenon. In this study, the influence of the selective beta 1- (CGP 20712A) and beta 2- (ICI 118551) adrenergic blockers on the antinociceptive effect of desipramine and nortriptyline was studied in mice using physical and chemical nociceptive tests that implicate different levels of sensory-motor integration in the central nervous system (CNS). An activity test was performed to detect "false positive" or "false negative" results. Results obtained show that both CGP 20712A and ICI 118551 are able to antagonize the antinociceptive effect of these antidepressants in physical tests (hot-plate and tail-flick). However, in chemical tests (acetic acid and formalin), the analgesic effect of the antidepressants used was only antagonized by CGP 20712A. These results suggest that the analgesic effect of desipramine and nortriptyline is mediated by beta-adrenoceptors. The beta-adrenoceptor involved depends on the type of nociceptive stimulusbeta 1 and beta 2 are both implicated when the stimulus is physical, but only beta 1 is involved when the stimulus is chemical.

背景与目标： 三环抗抑郁药已被证明可用于治疗不同病因的疼痛。单胺能系统似乎与这种现象有关。在这项研究中，使用物理和化学伤害性测试在小鼠中研究了选择性 β1- (CGP 20712A) 和 β2- (ICI 118551) 肾上腺素能阻滞剂对地昔帕明和去甲替林的抗伤害感受作用的影响，该测试涉及中枢神经系统 (CNS) 中不同水平的感觉-运动整合。进行活性测试以检测 “假阳性” 或 “假阴性” 结果。获得的结果表明，CGP 20712A和ICI 118551都能够在物理测试 (热板和甩尾) 中拮抗这些抗抑郁药的抗伤害感受作用。然而，在化学测试 (乙酸和福尔马林) 中，所使用的抗抑郁药的镇痛作用仅被CGP 20712A拮抗。这些结果表明，地昔帕明和去甲替林的镇痛作用是由 β-肾上腺素受体介导的。涉及的 β-肾上腺素能受体取决于伤害性刺激的类型，当刺激是物理刺激时，β1和 β2都涉及，但当刺激是化学刺激时，只有 β1涉及。

BACKGROUND & AIMS: BACKGROUND:Antidepressant prescribing continues to rise. Contributing factors are increased long-term prescribing and possibly the use of higher selective serotonin re-uptake inhibitor (SSRI) doses. AIM:To review general practice patients prescribed the same antidepressant long-term (≥2 years) and evaluate prescribing and management pre and post-review. DESIGN AND SETTING:Prospective observational cohort study using routine data from 78 urban general practices, Scotland. METHOD:All patients prescribed antidepressants (excluding amitriptyline) for ≥2 years were identified from records November 2009 to March 2010. GPs selected patients for face-to-face review of clinical condition and medication, December 2009 to September 2010. Pre- and post-review data were collected; average antidepressant doses and changes in prescribed daily doses were calculated. Onward referral to support services was recorded. RESULTS:8.6% (33 312/388 656) of all registered patients were prescribed an antidepressant, 47.1% (15 689) were defined as long-term users and 2849 (18.2%) were reviewed. 811 (28.5%) patients reviewed had a change in antidepressant therapy: 7.0% stopped, 12.8% reduced dose, 5.3% increased dose, and 3.4% changed antidepressant, resulting in 9.5% (95% CI = 9.1% to 9.8% P<0.001) reduction in prescribed daily dose and 8.1% reduction in prescribing costs. 6.3% were referred onwards, half to NHS Mental Health Services. Pre-review SSRI doses were 10-30% higher than previously reported. CONCLUSION:Almost half of all people prescribed antidepressants were long-term users. Appropriate reductions in prescribing can be achieved by reviewing patients. Higher SSRI doses may be contributing to current antidepressant growth.

背景与目标：

BACKGROUND & AIMS: :Treatment of chronic hepatitis C with interferon alpha (IFN-alpha) is relatively contraindicated in patients with psychiatric disorders because of possible severe psychiatric side effects. We report on a case of a female patient with a chronic schizoaffective psychosis, who was treated for 3 months with 3 x 3 mio IE IFN-alpha s.c./week because of a chronic hepatitis C (genotype 1b). Psychosis was stable with flupentixol monotherapy. After 2 months, she developed a severe depressive syndrome which lead to suicidal ideation. Until this time, she was without any antidepressive medication. Depressive symptoms disappeared after interferon therapy was stopped. Under prophylactic treatment with low-dose trimipramine (50 mg) or nefazodone (200 mg/day) therapy with IFN-alpha 3 x 3 mio IE/week was re-established after several months and again 2 years later adding ribavirin 1200 mg/day, a virustaticum. In contrast to the symptoms during monotherapy with IFN-alpha, during the time of both combination treatments, no psychiatric side effects occurred. While for ribavirin antidepressant effects are not known, we suppose that antidepressants may prevent changes in serotonergic or noradrenergic neurotransmission caused by IFN-alpha.

背景与目标： : 由于可能存在严重的精神副作用，因此在患有精神疾病的患者中，使用干扰素 α (IFN-α) 治疗慢性丙型肝炎相对禁忌。我们报告了一例患有慢性分裂情感性精神病的女性患者，由于慢性丙型肝炎 (基因型1b)，每周接受3x3 mio IE IFN-alpha s.C.治疗3个月。氟普尼索单药治疗精神病稳定。2个月后，她出现了严重的抑郁综合征，导致自杀意念。在此之前，她没有任何抗抑郁药。干扰素治疗停止后抑郁症状消失。在低剂量曲米帕明 (50 mg) 或奈法唑酮 (200 mg/天) 的预防性治疗下，在几个月后重新建立IFN-α3x3 mio IE/周的治疗，并在2年后再次添加利巴韦林1200 mg/天，一种病毒抑菌素。与IFN-α 单药治疗期间的症状相反，在两种联合治疗期间，没有发生精神副作用。虽然利巴韦林的抗抑郁作用尚不清楚，但我们认为抗抑郁药可以预防由IFN-α 引起的5-羟色胺能或去甲肾上腺素能神经传递的变化。

BACKGROUND & AIMS: OBJECTIVES:Childhood abuse is a powerful prognostic indicator in adults with major depressive disorder (MDD) and is associated with numerous biological risk factors for depression. The purpose of this investigation was to explore if antidepressant medication affinity for the serotonin transporter moderates the association between childhood abuse and treatment response. METHODS:Our sample included 52 outpatients with MDD who had received up to 26 weeks of pharmacotherapy, stratifying antidepressant medications with a high versus a low affinity for the serotonin transporter. Patients completed the Hamilton Rating Scale for Depression, Beck Depression Inventory II, Home Environment Questionnaire, and Ontario Health Supplement: Child Abuse and Trauma Scale to assess depression and childhood abuse. RESULTS:Medication class moderated the link between 3 indices of childhood abuse and treatment response such that higher levels of childhood abuse were associated with higher levels of depression severity after treatment only in those patients receiving antidepressant medications with a weak affinity for the serotonin transporter. CONCLUSIONS:This pilot study suggested that prolonged exposure to stress during childhood may result in biological vulnerabilities for depression, which may in turn be differentially targeted by pharmacological agents which target serotonin to a greater or lesser degree.

背景与目标：

BACKGROUND & AIMS: PURPOSE:This study aimed to estimate the association between prenatal exposure to antidepressants and risk of epilepsy in childhood, taking maternal depression into account. METHODS:We conducted a population-based cohort study including all Danish singletons born alive between 1997 and 2008 (n = 734 237). Information on antidepressant medication and diagnosis of depression and epilepsy was obtained from Danish National Registers. The exposed group comprised children of mothers who used antidepressants from 30 days before pregnancy until the date of birth. The reference group comprised children of mothers who used no antidepressants from 6 months before pregnancy to birth. We estimated the hazard ratios (HR) of epilepsy and 95% confidence intervals (CI) using Cox proportional hazard models. RESULTS:We identified 12 438 (1.7%) children exposed to antidepressants during pregnancy (including 30 days before pregnancy) and 5829 (0.8%) children diagnosed with epilepsy in the follow-up time (mean: 6.7 years). Children exposed to antidepressants during pregnancy had a 27% higher risk of epilepsy (aHR: 1.27; 95%CI: 1.05-1.54) than children in the reference group. The estimate of this association was 1.71 (95%CI: 1.10-2.66) if their mothers also had a registry-based hospital diagnosis of depression in the 6 months before pregnancy or during pregnancy and 1.14 (95%CI: 0.91-1.43) if their mothers had no registry-based hospital diagnosis of depression. Children of mothers who used antidepressants from 2 to 6 months before pregnancy (but not during pregnancy) had an increased risk of epilepsy (aHR: 1.36; 95%CI: 1.07-1.73). CONCLUSIONS:Antidepressant use during pregnancy was associated with a higher risk of epilepsy among children whose mothers had also a registry-based hospital diagnosis of depression during pregnancy. Copyright © 2016 John Wiley & Sons, Ltd.

背景与目标：

BACKGROUND & AIMS: :Antidepressant prescribing has increased year on year since the introduction of the selective serotonin reuptake inhibitors (SSRIs) in the 1980s. More than 10% of adults in England are now taking antidepressants for depression/anxiety, with a median length of treatment of more than 2 years, but antidepressants can cause side effects and withdrawal symptoms which increase with longer use. Surveys of antidepressant users suggest 30-50% have no evidence-based indication to continue, but coming off antidepressants is often difficult due to fears of relapse, withdrawal symptoms and a lack of psychological treatments to replace maintenance treatment and prevent relapse. GPs should not prescribe antidepressants routinely for mild depressive/anxiety symptoms. Patients starting antidepressants should be advised that they are to be taken for a limited period only, and that there is a risk of withdrawal problems on stopping them. Prescribers should actively review long-term antidepressant use and suggest coming off them slowly to patients who are well. The relationship between SSRI dose and serotonin transporter receptor occupancy suggests that hyperbolic tapering regimes may be helpful for patients with troubling withdrawal symptoms who cannot stop treatment within 4-8 weeks, and tapering strips can allow carefully titrated slower dose reduction over some months. Internet and telephone support to patients wanting to reduce their antidepressants is being trialled in the REDUCE programme. More research is needed to establish the incidence of withdrawal symptoms in representative samples of patients coming off antidepressants, and large randomised controlled trials are needed to test different tapering strategies.

背景与目标： : 自从在20世纪80年代中引入选择性5-羟色胺再摄取抑制剂 (SSRIs) 以来，抗抑郁药的处方量逐年增加。英国有超过10% 的成年人现在正在服用抗抑郁药治疗抑郁症/焦虑，中位治疗时间超过2年，但抗抑郁药会引起副作用和戒断症状，随着使用时间的延长而增加。对抗抑郁药使用者的调查表明，30-50% 没有基于证据的指示可以继续下去，但是由于担心复发，戒断症状和缺乏心理治疗来代替维持治疗和预防复发，抗抑郁药通常很困难。全科医生不应为轻度抑郁/焦虑症状常规开抗抑郁药。应建议开始服用抗抑郁药的患者仅在有限的时间内服用，并且停止服用抗抑郁药有戒断问题的风险。处方者应积极审查长期使用抗抑郁药的情况，并建议对健康的患者缓慢使用抗抑郁药。SSRI剂量与5-羟色胺转运蛋白受体占用之间的关系表明，双曲线渐缩方案可能有助于在4-8周内无法停止治疗的令人不安的戒断症状的患者，并且渐缩条可以在几个月内仔细滴定缓慢的剂量减少。在reduce计划中，正在尝试为希望减少抗抑郁药的患者提供互联网和电话支持。需要更多的研究来确定抗抑郁药患者代表性样本中戒断症状的发生率，并且需要大量的随机对照试验来测试不同的缩减策略。

BACKGROUND & AIMS: The European Network of the Teratology Information Services (ENTIS) has collected and evaluated data on 689 pregnancies in which exposure to tricyclic and nontricyclic antidepressants occurred. Data were collected prospectively from the time of in utero exposure and all the cases were followed up to the first few weeks of postnatal life using standardized procedures. In most cases, no longer term follow-up data were available. Approximately two-thirds of the mothers were on multidrug therapy, and of those, half took a benzodiazepine. About 95% of the patients were exposed during the first trimester. The most striking feature of the pregnancy outcomes is that 97% of live-born babies were morphologically normal. The incidence of spontaneous abortion and late fetal/neonatal deaths were within the normal range. Fourteen live-born babies and one fetus had either major or minor malformations, and six had minor anomalies. However, there was no increase in either a particular type of malformation or a specific pattern of defects. Another 31 infants without malformations had neonatal problems; these were usually associated with chronic multidrug therapy, especially near term. Elective termination of pregnancy occurred more frequently in the multidrug groups (86 out of 488) than in the monotherapy groups (20 out of 201), but data concerning the condition of the fetus are not available in the majority of the cases. Overall, no causal relationship could be established between in utero exposure to antidepressants and adverse pregnancy outcome.

背景与目标： 欧洲畸胎学信息服务网络 (ENTIS) 收集并评估了689怀孕发生三环和非三环抗抑郁药的数据。从子宫内暴露时开始前瞻性收集数据，并使用标准化程序对所有病例进行随访，直到出生后的前几周。在大多数情况下，不再提供长期随访数据。大约3分之2的母亲正在接受多药治疗，其中一半服用了苯二氮卓。大约95% 的患者在孕早期暴露。妊娠结局最显著的特征是97% 的活产婴儿在形态上是正常的。自然流产和晚期胎儿/新生儿死亡的发生率均在正常范围内。十四个活产婴儿和一个胎儿有严重或轻微畸形，六个有轻微异常。但是，特定类型的畸形或特定类型的缺陷都没有增加。另外31名没有畸形的婴儿有新生儿问题; 这些通常与慢性多药治疗有关，尤其是近期。多药组 (86个，488个) 的选择性终止妊娠发生率高于单药组 (20个，201个)，但大多数情况下无法获得有关胎儿状况的数据。总体而言，子宫内暴露于抗抑郁药与不良妊娠结局之间没有因果关系。

BACKGROUND & AIMS: :A capillary electrophoretic (CE) method for screening of six tricyclic antidepressants: amitriptyline, nortriptyline, imipramine, desipramine, doxepin and nordoxepin, in human serum, has been developed. The drugs were separated in a bare fused silica capillary (50 microm i.d.) using the background electrolyte: 50 mM CAPSO (pH 9.54) in methanol/water with KCI addition. For increasing the method sensitivity, the sample concentration in the capillary (sample stacking) using pressure and electrokinetic injection has been applied. The standard addition method was used for calibration of the developed analytical procedure. The precision of the identification parameter (the relative migration time) and the quantitative parameter (the relative peak area) was within the range of 0.05-1.65 and 0.73-6.7 (RSD %), respectively. The detection limits were found to be 30 ng/mL for desipramine, 62.5 ng/mL for nortriptyline, and 50 ng/mL for remaining analytes.

背景与目标： : 已开发出一种毛细管电泳 (CE) 方法，用于筛选人血清中的六种三环抗抑郁药: 阿米替林，去甲替林，丙咪嗪，地昔帕明，多塞平和去甲氧磷。使用背景电解质: 50 mmcapso (pH 9.54) 在甲醇/水中添加KCI，在裸露的熔融石英毛细管 (50微米内径) 中分离药物。为了提高方法的灵敏度，已经应用了使用压力和电动注射的毛细管中的样品浓度 (样品堆叠)。标准添加方法用于校准所开发的分析程序。识别参数 (相对迁移时间) 和定量参数 (相对峰面积) 的精度分别在0.05-1.65和0.73-6.7 (RSD %) 的范围内。发现地昔帕明的检出限为30 ng/mL，去甲替林的检出限为62.5 ng/mL，其余分析物的检出限为50 ng/mL。

BACKGROUND & AIMS: BACKGROUND:Delayed onset of efficacy of antidepressants and a high proportion of depressed patients being poor or non-responders to antidepressants are well known clinical challenges. Therefore, it seems to be necessary to identify predictors for response and - even more important - for remission. It has been suggested that reduction of depressive symptoms at an early stage of antidepressant treatment may predict treatment outcome. Our objective was to test, if this hypothesis derived from randomized controlled studies (RCTs) in outpatients, would be confirmed in a large naturalistic study in a cohort of inpatients with major depression. Patients were treated with various antidepressants and co-medication according to the protocol based on evidence-based clinical guidelines. METHODS:This was a large naturalistic prospective study. All patients (N=795) were hospitalized and met DSM-IV criteria for major depression according to a structured clinical interview (SCID). Assessments were conducted biweekly. Several definitions of early improvement (20%, 25% and 30% reduction in HAMD-21 baseline total scores) at two different visits were tested. Sensitivity, specificity and predictive values were calculated for the different definitions of early improvement. ROC-analyses as well as logistic regression models have been performed. Response was defined as 50% improvement of the total baseline HAMD-21 score and remission as a score of

BACKGROUND & AIMS: DESCRIPTION:The American College of Physicians developed this guideline to present the available evidence on the pharmacologic management of the acute, continuation, and maintenance phases of major depressive disorder; dysthymia; subsyndromal depression; and accompanying symptoms, such as anxiety, insomnia, or neurovegetative symptoms, by using second-generation antidepressants. METHODS:Published literature on this topic was identified by using MEDLINE, EMBASE, PsychLit, the Cochrane Central Register of Controlled Trials, and International Pharmaceutical Abstracts from 1980 to April 2007. Searches were limited to English-language studies in adults older than 19 years of age. Keywords for search included terms for depressive disorders and 12 specific second-generation antidepressants-bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine-and their specific trade names. This guideline grades the evidence and recommendations by using the American College of Physicians clinical practice guidelines grading system. RECOMMENDATION 1: The American College of Physicians recommends that when clinicians choose pharmacologic therapy to treat patients with acute major depression, they select second-generation antidepressants on the basis of adverse effect profiles, cost, and patient preferences (Grade: strong recommendation; moderate-quality evidence). RECOMMENDATION 2: The American College of Physicians recommends that clinicians assess patient status, therapeutic response, and adverse effects of antidepressant therapy on a regular basis beginning within 1 to 2 weeks of initiation of therapy (Grade: strong recommendation; moderate-quality evidence). RECOMMENDATION 3: The American College of Physicians recommends that clinicians modify treatment if the patient does not have an adequate response to pharmacotherapy within 6 to 8 weeks of the initiation of therapy for major depressive disorder (Grade: strong recommendation; moderate-quality evidence). RECOMMENDATION 4: The American College of Physicians recommends that clinicians continue treatment for 4 to 9 months after a satisfactory response in patients with a first episode of major depressive disorder. For patients who have had 2 or more episodes of depression, an even longer duration of therapy may be beneficial (Grade: strong recommendation; moderate-quality evidence).

背景与目标：

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: OBJECTIVES:To determine whether antidepressants are a risk factor for ischaemic heart disease and to compare the risk for different subgroups of antidepressants and individual antidepressants. DESIGN:Case-control study. SETTING:Nine general practices recruited from the Trent Focus Collaborative Research Network. PARTICIPANTS:933 men and women with ischaemic heart disease matched by age, sex, and practice to 5516 controls. MAIN OUTCOME MEASURE:Adjusted odds ratio for ischaemic heart disease calculated by logistic regression. RESULTS:Odds ratios for ischaemic heart disease were significantly raised for patients who had ever received a prescription for tricyclic antidepressants even after diabetes, hypertension, smoking, body mass index, and use of selective serotonin reuptake inhibitors had been adjusted for (1.56; 95% confidence interval 1.18 to 2.05). Patients who had ever taken dosulepin (dothiepin) had a significantly raised odds ratio for ischaemic heart disease after adjustment for confounding factors and use of other antidepressants (1.67, 1.17 to 2.36). There was no significant increase in the odds ratios for amitriptyline, lofepramine, and selective serotonin reuptake inhibitors in multivariate analysis. Increasing maximum doses of dosulepin were associated with increasing odds ratios for ischaemic heart disease. Similarly, there was a significant positive trend associated with increasing numbers of prescriptions of dosulepin (adjusted odds ratio 1.52 for 1 prescription, 1.39 for 2-3, and 1.96 for >/=4, P<0.002). CONCLUSION:There is good evidence for an association between dosulepin and subsequent ischaemic heart disease and for a dose-response relation.

背景与目标：

BACKGROUND & AIMS: :Methicillin-resistant Staphylococcus aureus (MRSA) is the leading cause of recurrent infections in humans including endocarditis, pneumonia, and toxic shock syndrome. Novel therapeutics to treat MRSA and other resistant bacteria are urgently needed. Adjuvant therapy, which uses a non-toxic compound to repotentiate the toxic effects of an existing antibiotic, is an attractive response to the growing resistance crisis. Herein, we describe the evaluation of structurally related, FDA-approved tricyclic amine antidepressants that selectively repotentiate MRSA to β-lactam antibiotics. Our results identify important structural features of the tricyclic amine class for β-lactam adjuvant activity. Furthermore, we describe the mechanism of action for our lead compound, amoxapine, and illustrate that it represses the mRNA levels of key β-lactam resistance genes in response to β-lactam treatment. This work is novel in that it highlights an important class of small molecules with the ability to simultaneously inhibit production of both β-lactamase and penicillin binding protein 2a.

背景与目标： : 耐甲氧西林金黄色葡萄球菌 (MRSA) 是人类反复感染的主要原因，包括心内膜炎，肺炎和中毒休克综合征。迫切需要治疗MRSA和其他耐药细菌的新型疗法。辅助疗法使用无毒化合物来增强现有抗生素的毒性作用，是对日益增长的耐药性危机的一种有吸引力的反应。在本文中，我们描述了结构相关的，FDA批准的三环胺抗抑郁药的评估，可选择性地将MRSA转化为 β-内酰胺类抗生素。我们的结果确定了三环胺类对 β-内酰胺佐剂活性的重要结构特征。此外，我们描述了我们的铅化合物阿莫沙平的作用机理，并说明了它在响应 β-内酰胺治疗时抑制关键的 β-内酰胺抗性基因的mRNA水平。这项工作是新颖的，因为它突出了一类重要的小分子，具有同时抑制 β-内酰胺酶和青霉素结合蛋白2a产生的能力。

BACKGROUND & AIMS: :The elderly frequently receive antidepressant medications that can affect cardiac conduction and rhythm, heart rate, and blood pressure. Because coexistent cardiovascular disease is common in the elderly, these medications must be used with caution, remembering that different antidepressants produce different cardiovascular effects. Fortunately, a variety of antidepressant medications are available, facilitating the selection of a safe agent for elderly patients who are at risk for cardiovascular side effects.

背景与目标： : 老年人经常接受抗抑郁药物治疗，这些药物会影响心脏传导和节律，心率和血压。由于并存的心血管疾病在老年人中很常见，因此必须谨慎使用这些药物，并记住不同的抗抑郁药会产生不同的心血管作用。幸运的是，多种抗抑郁药物可供选择，有助于为有心血管副作用风险的老年患者选择安全的药物。

BACKGROUND & AIMS: BACKGROUND:Tricyclic antidepressants have been demonstrated in the laboratory to have anticancer properties. A recent study by our group also suggested a protective effect against development of colorectal cancer and glioma. This study aims to determine whether the anticancer action of tricyclics translates to improved survival in these cancers post-diagnosis. METHODS:A study using the General Practice Research Database examined whether tricyclic antidepressant exposure in the months following diagnosis of glioma or colorectal cancer would affect longer term all-cause mortality. Cox proportional hazards modelling adjusted for age, gender, smoking, body mass index, comorbidity, and diagnosed depression. RESULTS:A cohort of 1,364 glioma and 16,519 colorectal cancer patients were identified. There was a non-significant reduction in the hazard for glioma patients treated with tricyclics (HR = 0.83, CI = 0.53-1.30). This was mainly found in patients who were not previously exposed to tricyclics (HR = 0.56, CI = 0.26-1.18). In contrast, a significant increase in hazard was found for colorectal cancer (HR = 1.37, CI = 1.21-1.54). This was mostly in patients prescribed low-dose tricyclics (HR = 1.57, CI = 1.33-1.86). CONCLUSIONS:We have shown no significant mortality reduction in colorectal cancer or glioma patients treated with tricyclics. An apparent detrimental effect observed in colorectal cancer may be related to prescription of low-dose tricyclics in the management of pain related to disseminated cancer. We cannot rule out small effects or an effect that occurs exclusively at higher doses. Blinded clinical studies may therefore be the only method of determining efficacy in glioma patients.

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