BACKGROUND & AIMS: :Fluoxetine (FLX) the active pharmaceutical ingredient (API) in Prozac(®) is a widely prescribed psychoactive drug which ubiquitous occurrence in the aquatic environment is associated to a poor removal rate in waste-water treatment plant (WWTP) systems. This API acts as a selective serotonin reuptake inhibitor (SSRI) frequently reported to cause disrupting effects in non-target species. The objective of this study includes a multibiomarker response evaluation on mussel Mytilus galloprovincialis during two weeks exposure to 75 ng L(-1) FLX assessing antioxidant enzymes activities--superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST); lipid peroxidation (LPO), acetylcholinesterase (AChE) neurotoxic response and endocrine disruption through alkali-labile phosphates (ALP) indirect measurement of vitellogenin-like proteins. Results show transient tissue-specific enzymatic responses and damage affecting mostly mussel gills. However, the clear ALP levels inhibition throughout time in both sex-differentiated gonads gives evidence to FLX reinforced action as an endocrine disruptor rather than an oxidative or neurotoxic inducer.

背景与目标： : 氟西汀 (FLX) 百忧解中的活性药物成分 (API) (®) 是一种广泛使用的精神活性药物，在水生环境中普遍存在，这与废水处理厂 (WWTP) 系统的去除率差有关。该API充当选择性5-羟色胺再摄取抑制剂 (SSRI)，经常报道会在非目标物种中引起破坏作用。这项研究的目的包括在暴露于75 ng L(-1) FLX的两周内对贻贝Mytilus galloprovincialis进行多生物标志物反应评估，评估抗氧化酶活性-超氧化物歧化酶 (SOD)，过氧化氢酶 (CAT) 和谷胱甘肽-S-转移酶 (GST); 脂质过氧化 (LPO)，乙酰胆碱酯酶 (AChE) 通过碱性不稳定磷酸盐 (ALP) 间接测量卵黄蛋白原样蛋白的神经毒性反应和内分泌破坏。结果显示，短暂的组织特异性酶反应和损伤主要影响贻贝g。然而，在两种性别分化的性腺中，整个过程中明显的ALP水平抑制提供了FLX作为内分泌干扰物而不是氧化或神经毒性诱导剂增强作用的证据。

BACKGROUND & AIMS: :Previous studies suggest epigenetic alterations may contribute to the association between maternal prenatal depression and adverse offspring outcomes. Developmental researchers have recently begun to examine these associations in relation to epigenetic age acceleration/deceleration, a biomarker of developmental risk that reflects the deviation between epigenetic age and chronological age. In the perinatal period, preliminary studies indicate that maternal prenatal depression may lead to epigenetic age deceleration in newborns, which may predict adverse developmental outcomes. The present study examined the relationship between maternal prenatal exposures (i.e., depression, stress, and SSRI use) and offspring epigenetic age deceleration in 303 mother-offspring dyads. Women were recruited in the first trimester of pregnancy and followed longitudinally until delivery. Maternal depression, perceived stress, and SSRI use were assessed at each prenatal visit. Newborn epigenetic age was determined via cord blood samples. Results indicated maternal prenatal stress was not associated with newborn epigenetic age deceleration (ΔR2 = 0.002; p = 0.37). Maternal prenatal depression was associated with decelerated epigenetic age (ΔR2 = 0.01, p = 0.04), but this relationship did not hold when accounting for maternal use of SSRIs (ΔR2 = 0.002, p = 0.43). Conversely, maternal SSRI use significantly predicted newborn epigenetic age deceleration over and above the influence of maternal depression (ΔR2 = 0.03, p = 0.001). These findings suggest maternal prenatal SSRI use may significantly contribute to the previously documented association between maternal prenatal depression and epigenetic age deceleration. Further studies are needed to examine how these epigenetic differences at birth may contribute to adverse outcomes in later development.

背景与目标： : 先前的研究表明，表观遗传改变可能有助于孕产妇产前抑郁与不良后代结局之间的关联。发育研究人员最近开始研究与表观遗传年龄加速/减速有关的这些关联，表观遗传年龄加速/减速是发育风险的生物标志物，反映了表观遗传年龄和时间年龄之间的偏差。在围产期，初步研究表明，产妇产前抑郁可能导致新生儿表观遗传年龄减速，这可能预测不良的发育结果。本研究检查了303母体-后代二元组的母体产前暴露 (即抑郁，压力和SSRI使用) 与后代表观遗传年龄减速之间的关系。在妊娠的前三个月招募妇女，并纵向跟踪直至分娩。每次产前访视时都会评估产妇的抑郁，感知压力和SSRI的使用。通过脐带血样本确定新生儿表观遗传年龄。结果表明，孕妇产前压力与新生儿表观遗传年龄减速无关 (ΔR2 = 0.002; p = 0.37)。产妇产前抑郁与表观遗传年龄减速相关 (ΔR2 = 0.01，p = 0.04)，但当考虑到产妇使用SSRIs时，这种关系不成立 (ΔR2 = 0.002，p = 0.43)。相反，母体SSRI使用显著预测的新生儿表观遗传年龄减速超过或超过母体抑郁症的影响 (ΔR2 = 0.03，p = 0.001)。这些发现表明，母亲产前使用SSRI可能会显着促进先前记录的母亲产前抑郁与表观遗传年龄减速之间的关联。需要进一步的研究来检查出生时的这些表观遗传差异如何导致后期发育的不良结果。

BACKGROUND & AIMS: :Failure in treating major depression with SSRI is common in clinical psychiatry. To date, there is no specific guideline how to deal with such a failure. This review is aimed at trying to answer the important question of the next step. Since there are no such guidelines, this decision should be made according to the clinical response for the first SSRI, the tolerability to the drug and the clinical practice of the physician.

背景与目标： : SSRI治疗重度抑郁症失败在临床精神病学中很常见。迄今为止，还没有具体的指导方针如何处理这样的失败。这篇评论旨在试图回答下一步的重要问题。由于没有此类指南，因此应根据首次SSRI的临床反应，对药物的耐受性和医师的临床实践做出此决定。

BACKGROUND & AIMS: :The lack of public trust in the pharmaceutical sector (i.e. industry, authorities and doctors) could compromise the future of drug development and the regulatory system. Public trust integrates two important components, namely the vulnerability of the truster and the competence of the trustee. Because trust appears to have eroded as a result of drug safety controversies, this paper analyzes the role of public trust during the selective serotonin reuptake inhibitor (SSRI) and suicidality controversy focusing on the aforementioned trust components. Because the competence component of trust is argued to be paramount in determining and maintaining public trust, the SSRI case shows that this component is a part of public trust where these institutions can build on, and might therefore be better used to substantiate and reinforce, public trust. Efforts to build trust should rely on the ethical, professional (competence) and societal commitment of institutions and individuals to protect the vulnerability of the public during controversies. Because shared values can create trust or increase its levels within a specific environment, industry, authorities and physicians ought to develop novel and cooperative strategies to highlight their shared values and motivations. Rules, regulations and settlements are indispensable tools but undue regulation is costly and can backfire on the rather sensitive trust relationships in the pharmaceutical sector.

背景与目标： : 公众对制药部门 (即行业，当局和医生) 缺乏信任可能会损害药物开发和监管体系的未来。公共信任整合了两个重要组成部分，即委托人的脆弱性和受托人的能力。由于药物安全性争议似乎使信任受到侵蚀，因此本文分析了公众信任在选择性5-羟色胺再摄取抑制剂 (SSRI) 和自杀性争议中的作用，重点是上述信任成分。由于认为信任的能力部分在确定和维持公众信任方面至关重要，因此SSRI案例表明，该部分是公共信任的一部分，这些机构可以在此基础上建立，因此可能更好地用于证实和加强公众信任。建立信任的努力应依靠机构和个人的道德，专业 (能力) 和社会承诺，以在争议中保护公众的脆弱性。由于共享价值观可以在特定环境中建立信任或提高信任水平，因此行业，当局和医生应制定新颖的合作策略，以突出其共享价值观和动机。规则，法规和和解是必不可少的工具，但不当的监管成本很高，并且可能对制药行业中相当敏感的信任关系产生适得其反的影响。

BACKGROUND & AIMS: :Sexual dysfunction is a major side effect of selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). We conducted a genome-wide association study to identify the genetic factors contributing to the risk of SSRI/SNRI-induced sexual dysfunction by testing 186 320 single nucleotide polymorphism (SNP) markers in a cohort of 201 Japanese major depression patients including 36 with sexual dysfunction induced by SSRI (paroxetine or fluvoxamine) or SNRI (milnacipran). The Cochran-Armitage trend test showed that 11 SNPs, tightly clustered in a distinct region on chromosome 14q21.3, were associated with SSRI/SNRI-induced sexual dysfunction at a genome-wide significance level after false discovery rate (FDR) correction, and the strongest SNP association was with rs1160351 (P=3.04 × 10(-7), risk ratio=2.92, 95% confidence interval (CI)=1.79-4.76). These SNPs mapped to the intronic region of the MDGA2 gene. A Manhattan plot showed that the strong association peak remained in MDGA2 after adjustment for sex and age in a multivariable logistic regression analysis although P values increased slightly and became non-significant. Replication studies with larger sample sizes are required to validate this exploratory study, but our findings may provide insights into the genetic basis of sexual dysfunction induced by SSRI/SNRI.

背景与目标： : 性功能障碍是选择性5-羟色胺再摄取抑制剂 (SSRIs) 和5-羟色胺-去甲肾上腺素再摄取抑制剂 (SNRIs) 的主要副作用。我们进行了一项全基因组关联研究，通过在201名日本重度抑郁症患者队列中测试186 320单核苷酸多态性 (SNP) 标记，确定了导致SSRI/SNRI诱发性功能障碍风险的遗传因素，包括36名由SSRI (帕罗西汀或氟伏沙明) 或SNRI诱发的性功能障碍 (米那西普兰)。Cochran-Armitage趋势测试表明，在错误发现率 (FDR) 校正后，在全基因组显着水平上，紧密聚集在染色体14q21.3的一个不同区域中的11个snp与SSRI/SNRI诱导的性功能障碍相关，SNP关联最强的是rs1160351 (P = 3.04 × 10(-7)，风险比 = 2.92，95% 置信区间 (CI)= 1.79-4.76)。这些snp定位到MDGA2基因的内含子区域。曼哈顿图显示，在多变量逻辑回归分析中对性别和年龄进行调整后，MDGA2的强关联峰值仍然存在，尽管p值略有增加并且变得不显着。需要较大样本量的复制研究来验证这项探索性研究，但我们的发现可能为SSRI/SNRI诱发的性功能障碍的遗传基础提供见解。

BACKGROUND & AIMS: :Sexual dysfunction is common with selective serotonin reuptake inhibitor use for major depressive disorder. Studies have shown associations between genetic variation in the adenosine triphosphate (ATP)-binding cassette, subfamily B, member 1 gene (ABCB1), which encodes the drug efflux transporter P-glycoprotein (PGP), and selective serotonin reuptake inhibitor response. This study measured functionally implicated ABCB1 variants (rs2235015, rs1128503, rs2032582, and rs1045642) and sexual dysfunction using the Changes in Sexual Functioning Questionnaire. This study included outpatients (18-40 years of age) treated for major depressive disorder with a selective serotonin reuptake inhibitor for 6 weeks. Changes in Sexual Functioning Questionnaire outcomes were stratified by ABCB1 genotype and PGP substrate status. The authors recruited 82 individuals (22 men and 57 women). Women receiving a PGP substrate with a rs1128503 TT genotype had a significantly lower Changes in Sexual Functioning Questionnaire total score (37.2 ± 5.4), indicating greater sexual dysfunction, than did those with the CT (42.9 ± 6.3) or CC genotypes (46.6 ± 5.6), F(2) = 6.00, p = .005, p = .02, with multiple testing correction. The results indicate a relationship between genotypes at rs1128503, total sexual dysfunction, and PGP substrates use for women and may explain some of the sexual dysfunction variability seen with selective serotonin reuptake inhibitor treatment. Results need to be confirmed with a larger sample size that includes men.

背景与目标： : 性功能障碍与选择性5-羟色胺再摄取抑制剂治疗重度抑郁症很常见。研究表明，三磷酸腺苷 (ATP) 结合盒，亚家族B，成员1基因 (ABCB1) (编码药物外排转运蛋白P-糖蛋白 (PGP)) 的遗传变异与选择性5-羟色胺再摄取抑制剂反应之间存在关联。这项研究使用性功能问卷的变化来测量与功能有关的ABCB1变体 (rs2235015，rs1128503，rs2032582和rs1045642) 和性功能障碍。这项研究包括门诊患者 (18-40岁) 接受选择性5-羟色胺再摄取抑制剂治疗6周的重度抑郁症。通过ABCB1基因型和PGP底物状态对性功能问卷结果的变化进行分层。作者招募了82人 (22名男性和57名女性)。与具有CT (42.9 ± 6.3) 或CC基因型 (46.6 ± 5.6) 的女性相比，接受rs1128503 TT基因型的PGP底物的女性在性功能问卷总分 (37.2 ± 5.4) 明显降低，表明性功能障碍更大，F(2) = 6.00，p = .005，p = .02，具有多次测试校正。结果表明rs1128503处的基因型，总性功能障碍和女性使用PGP底物之间存在关系，这可能解释了选择性5-羟色胺再摄取抑制剂治疗所发现的某些性功能障碍变异性。结果需要用包括男性在内的更大样本量来确认。

BACKGROUND & AIMS: :Serotonin reuptake inhibitors (SSRIs) have immediate effects on synaptic levels of serotonin but their therapeutic effects are often delayed. This delay has been suggested to reflect time required for new learning and therefore that SSRIs might be having effects on the learning process. We examined the effects of elevating serotonin levels, through short-term SSRI administration (escitalopram), on learning about perceptions of instrumental control. A randomised double blind procedure was used to allocate healthy people, categorised as mildly depressed (high BDI⩾10: n=76) or not depressed (low BDI⩽5: n=78) to either a drug (escitalopram, 10mg/7days) or placebo control group. Following treatment, participants were trained with a simple task that involved learning the effectiveness of an instrumental action (key press) and the background context at eliciting an outcome (auditory cue) where there was no programmed contingency. The effects of the drug were (i) to moderate response rates and (ii) to enhance sensitivity to the background or context rate of occurrence of the outcome. These findings suggest that serotonin modulates learning about the long-term rate of outcomes, which supports perception of instrumental control, and that this may provide a clue to the mechanism for supporting the development of the therapeutic effects of the drug.

背景与目标： : 5-羟色胺再摄取抑制剂 (SSRIs) 对5-羟色胺的突触水平具有立竿见影的作用，但其治疗作用通常会延迟。有人建议这种延迟反映新学习所需的时间，因此ssri可能会对学习过程产生影响。我们研究了通过短期SSRI给药 (艾司西酞普兰) 升高5-羟色胺水平对学习仪器控制感知的影响。使用随机双盲程序将健康人分配给药物 (依他普仑，10mg/7天) 或安慰剂对照组，分为轻度抑郁 (高bid: 10: n = 76) 或不抑郁 (低bid: 5: n = 78)。治疗后，对参与者进行了一项简单的任务培训，该任务涉及学习工具动作的有效性 (按键) 以及在没有编程偶然性的情况下引发结果 (听觉提示) 的背景环境。药物的作用是 (i) 中等反应率和 (ii) 增强对结果发生的背景或背景率的敏感性。这些发现表明，5-羟色胺调节对长期结局率的了解，这支持了对仪器控制的感知，并且这可能为支持药物治疗效果发展的机制提供了线索。

BACKGROUND & AIMS: PURPOSE:We wanted to determine to what extent adverse drug effects associated with a selective serotonin reuptake inhibitor (SSRI) were known but not assessed before application for registration of paroxetine. METHODS:With a special permit from the Norwegian Ministry of Health, we obtained reports from 82 clinical trials presented by the paroxetine license holder in 1989. There were 17 double blind, placebo controlled clinical trials with parallel design with 903 patients on paroxetine and 592 on placebo. Altogether 32 adverse effects showed a risk difference (RD) between paroxetine and control groups of more than 0.5%. We did a meta-analysis for each of these adverse effects. We then compared the outcome with the frequencies stated in the Summary of Product Characteristics (SPC) at the time of registration and those reported in the current SPC. RESULTS:At the time of registration 19 of the adverse effects were statistically significant. Only eight of these adverse effects were listed as being common in the first SPC from 1989. Five out of the nineteen adverse effects are not mentioned in the current SPC. Among them are headache with RD 5.4%, decreased libido RD 2.6%, nervousness RD 2.0% and paresthesia RD 1.7%. CONCLUSIONS:Frequently occurring adverse reactions that are included in today's SPC for paroxetine were evident and documented already in the early studies accompanying the application for marketing authorization in 1989. Some other adverse effects observed then are still not mentioned in the SPC of today. Meta-analyses of adverse effects should be mandatory at the stage of first registration of a drug.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Tetrahydrobiopterin (BH4) plays an important role in the biosynthesis of serotonin, melatonin and catecholamines, all of which are implicated in the pathophysiology of mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Production of BH4 is regulated by GTP cyclohydrolase transcription and activity. Thus, we considered the GTP cyclohydrolase gene (GCH1) to be a good candidate gene in the pathophysiology of MDs and of the serotonin selective reuptake inhibitors (SSRIs) response in MDD, and conducted a case-control study utilizing three SNPs (rs8007267, rs3783641 and rs841) and moderate sample sizes (405 MDD patients, including 262 patients treated by SSRIs, 1022 BP patients and 1805 controls). METHOD:A multiple logistic regression analysis was carried out to compare the frequencies of each SNP genotype for the target phenotype across patients and controls in several genetic models, while adjusting for possible confounding factors. A clinical response was defined as a decrease of more than 50% from the baseline score on the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D) within 8 weeks, and clinical remission as a SIGH-D score of less than 7 at 8 weeks. RESULT:No associations between three SNPs in GCH1 and MDD or BP were observed; however, GCH1 was associated with SSRI therapeutic response in MDD in all the marker's haplotype analysis (Global P value=0.0379). CONCLUSIONS:Results suggest that GCH1 may predict response to SSRI in MDD in the Japanese population. Nevertheless, a replication study using larger samples may be required for conclusive results, since our sample size was small.

背景与目标：

BACKGROUND & AIMS: :Prenatal hypoxia induced by transient intrauterine ischemia is a serious clinical problem, and at present, effective treatments are lacking. Currently, it is unknown how prenatal hypoxia affects behaviors in adulthood. Therefore, we developed a mouse model that mimics prenatal hypoxia in humans using uterine artery occlusion in late gestation. We examined whether prenatal hypoxia induces behavioral changes in adult male and female offspring by conducting a series of behavioral tests. In adulthood, longer immobility was observed in the forced swim test in males, whereas females showed decreased inhibition in the prepulse inhibition test. We then investigated the effects of two different selective serotonin reuptake inhibitors (SSRIs), fluoxetine (FLX) and escitalopram (ESC), on these behavioral changes. These drugs affect the neurodevelopmental process and have long-term neurological consequences. FLX treatment from postnatal day 3 (P3) to P21 ameliorated the behavioral changes in both male and female mice. In comparison, ESC treatment ameliorated the behavioral changes only in female mice. Neurochemical analysis revealed that dopamine was increased in the female hippocampus, but not in males. Thus, neonatal SSRI treatment decreases dopamine levels in the hippocampus in females selectively. Our findings suggest that prenatal hypoxia is a risk factor for behavioral abnormalities in adulthood, and that neonatal SSRI treatment might have clinical potential for alleviating these long-term behavioral deficits.

背景与目标： 短暂性宫内缺血引起的产前缺氧是一个严重的临床问题，目前缺乏有效的治疗方法。目前，尚不清楚产前缺氧如何影响成年后的行为。因此，我们开发了一种小鼠模型，该模型在妊娠后期使用子宫动脉闭塞来模拟人类的产前缺氧。我们通过进行一系列行为测试，检查了产前缺氧是否会引起成年雄性和雌性后代的行为变化。成年后，男性在强迫游泳测试中观察到较长的不动，而女性在脉冲前抑制测试中表现出抑制作用降低。然后，我们研究了两种不同的选择性5-羟色胺再摄取抑制剂 (SSRIs) 氟西汀 (FLX) 和艾司西酞普兰 (ESC) 对这些行为变化的影响。这些药物会影响神经发育过程，并具有长期的神经后果。从出生后第3天 (P3) 到P21的FLX治疗改善了雄性和雌性小鼠的行为变化。相比之下，ESC治疗仅改善了雌性小鼠的行为变化。神经化学分析显示，多巴胺在雌性海马中增加，但在雄性中却没有。因此，新生儿SSRI治疗选择性地降低了女性海马中的多巴胺水平。我们的发现表明，产前缺氧是成年期行为异常的危险因素，新生儿SSRI治疗可能具有缓解这些长期行为缺陷的临床潜力。

BACKGROUND & AIMS: BACKGROUND:Approximately 50% of patients with major depressive disorder (MDD) do not respond after adequate first-line treatment with a selective serotonin reuptake inhibitor (SSRI). Special interest is paid to whether specialist level inpatient psychiatric care results differ from community studies. AIM:To compare switching alternatives after treatment failure with an SSRI; switching to venlafaxine (Dexcel Pharma Israel) versus switching to another SSRI in depressed inpatients. METHOD:A retrospective register study of inpatients was undertaken in a psychiatric tertiary care university center serving an urban catchment area in Israel with a population of more than 900,000. RESULTS:A total of 401 MDD inpatients were assigned to antidepressant treatment. Of these, 232 records (47 venlafaxine, 185 SSRI) were included in the analysis. Patients assigned to venlafaxine treatment were older (mean age 64.3 ± 15 years versus 53.6 ± 17; p<0.01) and had more comorbid physical disorders (80% versus 57%; p<0.001). In the primary analysis, there was no statistical difference between groups in reduction in CGI-S total scores. The secondary end point of achieving a CGI-S score of 2 or less (1 = normal, not at all ill or 2 = borderline mentally ill) was statistically significantly better for the venlafaxine treated inpatients (P=0.02). AEs were reported less than 10% of patients in both groups. CONCLUSION:Patients who remain severely depressed following treatment with an SSRI may gain benefit from the dual-action drug venlafaxine, rather than switching to another SSRI. These findings need to be further supported by prospective studies.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:To evaluate the prevalence of new onset or worsening of anxiety symptoms, as well as their clinical implications, during the first 2 weeks of Selective Serotonin Reuptake Inhibitor (SSRI) pharmacotherapy for depression. METHOD:Adult outpatients with nonpsychotic major depressive disorder were enrolled in an 8-week acute phase SSRI treatment trial at 15 clinical sites across the United States. Worsening anxiety was defined as a greater than 2-point increase on the Beck Anxiety Inventory (BAI) between baseline and Week 2. New onset of anxiety symptoms was ascribed when the BAI baseline rating was 0 and the Week 2 value was greater or equal to 2 points on the BAI. RESULTS:Overall, after 2 weeks of treatment, 48.8% (98 of 201 participants) reported improvement in anxiety symptoms, 36.3% (73 of 201) reported minimal symptom change, and 14.9% (30 of 201) reported worsening of anxiety symptoms. No association was found between change in anxiety symptoms within the first 2 weeks and change in depressive symptoms or remission at the end of 8 weeks of treatment. For participants with clinically meaningful anxiety symptoms at baseline, however, worsening of anxiety during the first 2 weeks of treatment was associated with worsening depressive symptoms by 8 weeks (P = .054). CONCLUSIONS:The trajectory of anxiety symptom change early in SSRI treatment is an important indicator of eventual outcome for outpatients with major depression and baseline anxiety symptoms.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:To compare healthcare utilization and costs for major depressive disorder (MDD) patients treated with escitalopram and who were switched to another SSRI for non-medical reasons versus those who did not switch. RESEARCH DESIGN AND METHODS:Patients were identified in the Ingenix Impact Database (2003-2006). The analysis group included patients who remained on escitalopram for ≥ 90 days and switched to another SSRI within 45 days of end of supply days for non-medical reasons; the control group included matched individuals who did not switch within 45 days. Switching for medical reasons was defined as switching within 7 days after having a hospitalization, an emergency room (ER) visit, or a psychotherapy visit. Outcomes (all-cause and MDD-related) were analyzed over 3 months and included use of hospital, ER, outpatient visits and professional services, and healthcare costs. Outcomes were compared between the two groups using descriptive statistics and regression analyses controlling for differences in baseline characteristics. Costs were inflation adjusted to 2006 US dollars. RESULTS:The study included 2,805 matched pairs. Compared to controls, switchers had higher rates of all-cause and MDD-related hospitalizations (relative risk [RR] = 1.4 and 2.0, respectively) and all-cause and MDD-related ER visits (RR = 1.2 and 1.6, respectively, all p ≤ 0.05). Results from multivariate analyses show that switchers had higher medical costs (+$138), drug costs (+$149) and total healthcare costs (+$322) compared to patients in the control group (all p < 0.0001). LIMITATIONS:This study's limitations include its short observational period and definition of switching for non-medical reasons. CONCLUSION:Patients who were switched to another SSRI for non-medical reasons after being stabilized on escitalopram used more resources and had higher healthcare costs within 3 months of switching than patients who did not switch.

背景与目标：

BACKGROUND & AIMS: PURPOSE:In clinical molecular imaging the interaction between antidepressant medication and SPECT ligands is a significant potential confound. This study measured nAChR availability, as determined by SPECT imaging, on and off selective serotonin reuptake inhibitors in first episode depressed patients. METHODS:Five patients in their first episode of major depressive disorder (MDD) on a single SSRI underwent [(123)I]5-I-A85380- SPECT neuroimaging prior to stopping their medication and again 6 weeks following medication cessation. Autoradiography of post mortem brain tissue with [(125)I]5-I-A85380 in the presence or absence of four commonly prescribed antidepressants was also assessed. RESULTS:SSRI antidepressants did not affect the relative binding availability of alpha4beta2 nicotinic acetylcholine receptors for the [(123)I]5-I-A85380 ligand in vivo. Radioligand binding in vitro was unaffected by a single, high pharmacological concentration of antidepressants. CONCLUSION:SPECT imaging studies using [(123)I]5-I-A85380 to measure alpha4beta2 nAChR availability in depressed patients are unlikely to be confounded to a major degree by concurrent antidepressant medication.

背景与目标：

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVE:The anti-oestrogen tamoxifen requires metabolic activation to endoxifen by cytochrome P450 (CYP) enzymes, predominantly CYP2D6. Potent CYP2D6-inhibiting antidepressants can seriously disrupt tamoxifen metabolism, probably influencing the efficacy of tamoxifen. For this reason, paroxetine and fluoxetine are recommended not to be used with tamoxifen in breast cancer patients. We investigated the effects of switching potent CYP2D6-inhibiting antidepressants to weak CYP2D6-inhibiting antidepressants on the plasma pharmacokinetics of tamoxifen. METHODS:Ten breast cancer patients who were treated with tamoxifen in combination with a potent CYP2D6-inhibiting antidepressant (paroxetine or fluoxetine) for at least 4 weeks were enrolled. Under close supervision by a psychiatrist, patients were switched to treatment with escitalopram or venlafaxine (weak CYP2D6-inhibiting antidepressants). Before and after the switch, pharmacokinetic blood sampling was performed over 24 h. Pharmacokinetic parameters were estimated using noncompartmental analysis. Adverse effects were recorded during the study. RESULTS:Endoxifen exposure was ~3-fold higher during escitalopram co-administration than during paroxetine or fluoxetine co-administration (median 387 nM·h [range 159-637 nM·h] versus 99.2 nM·h [range 70.0-210 nM·h]; P = 0.012; Wilcoxon signed-rank test). The ratio of endoxifen to N-desmethyltamoxifen and the ratio of 4-hydroxytamoxifen to tamoxifen increased by 3.3- and ~1.5-fold, reflecting increased CYP2D6 activity. Antidepressant switching did not result in psychiatric problems or antidepressant-related adverse effects. CONCLUSION:In this study, switching to the weak CYP2D6 inhibitor escitalopram was safe and feasible and resulted in clinically relevant rises in endoxifen concentrations. We therefore advise switching paroxetine and fluoxetine to escitalopram in patients using tamoxifen. However, switching should always be weighed in individual patients.

背景与目标：